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Pancreatic cancer is a common cancer in the United States, with a projected 45,220 cases in 2013. It has an extraordinarily high case fatality rate, with 38,460 deaths projected in the same period.1 Standard therapy for advanced disease had been gemcitabine monotherapy.2 The 1-year survival after gemcitabine therapy was reported at 18% for bolus administration and 29% when given by fixed dose rate infusion.3 De novo gemcitabine resistance is likely partially explained by genomic variation in the uptake and metabolism of this agent.4 Thus, alternate treatments have been urgently needed for this disease, and 2 combination regimens—the combination of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan, known as FOLFIRINOX, and the combination of gemcitabine with nab-paclitaxel, have now been demonstrated to improve survival when compared with gemcitabine alone, albeit median survivals remain under 1 year.5,6 Combinations of gemcitabine with 5-fluorouracil, cisplatin, and oxaliplatin had previously not proven superior to gemcitabine alone.7–9

the combination of gemcitabine with nab-paclitaxel, have now been demonstrated to improve survival when compared with gemcitabine alone, albeit median survivals remain under 1 year.5,6 Combinations of gemcitabine with 5-fluorouracil, cisplatin, and oxaliplatin had previously not proven superior to gemcitabine alone.7–9 Among the cytotoxic agents with single-agent activity in pancreatic cancer are docetaxel and irinotecan. Single-agent docetaxel achieves objective antitumor response rates of ≤15%.10,11 Irinotecan has an objective response rate of 9% in pancreatic cancer.12 Preclinical studies show evidence of synergy between taxanes and irinotecan.13–15 The interaction may be schedule dependent, with administration of taxane followed by irinotecan predicted to be optimal. Phase I studies of docetaxel-irinotecan combination demonstrate neutropenia and diarrhea to be the predominant dose-limiting toxicities.16–18 The recommended phase II doses are docetaxel (35 mg/m2) followed by irinotecan (50 mg/m2), when administered weekly for 4 sequential weeks of a 6-week schedule.16 A phase II study of docetaxel/irinotecan combination administered weekly for 4 of 6 weeks in treatment-naive advanced pancreatic cancer reported an objective response rate by WHO criteria of 27%, median survival of 9.4 months, and 1-year survival of 43%.19 The median survival for patients with metastatic disease in that study was 9.0 months. Reni et al20 incorporated mitomycin C with escalating doses of irinotecan and docetaxel on a less continuous schedule and observed no partial responses in 15 patients with up to 2 prior lines of therapy.

and 1-year survival of 43%.19 The median survival for patients with metastatic disease in that study was 9.0 months. Reni et al20 incorporated mitomycin C with escalating doses of irinotecan and docetaxel on a less continuous schedule and observed no partial responses in 15 patients with up to 2 prior lines of therapy. The epidermal growth factor receptor (EGFR) is expressed in pancreatic cancer and higher levels of expression are associated with worse survival.21 A phase III trial with the EGFR inhibitor erlotinib demonstrated an improved hazard ratio for survival with adjusted log-rank P-value of 0.038 for addition of erlotinib.22 Cetuximab has also been studied. Although a phase II trial reported median and 1-year survival of 7.1 months and 32%, a subsequent cooperative group phase III trial demonstrated no significant improvement in progression-free survival (PFS) or overall survival (OS).23,24

ank P-value of 0.038 for addition of erlotinib.22 Cetuximab has also been studied. Although a phase II trial reported median and 1-year survival of 7.1 months and 32%, a subsequent cooperative group phase III trial demonstrated no significant improvement in progression-free survival (PFS) or overall survival (OS).23,24 The current study was conducted to confirm the activity of docetaxel/irinotecan combination, and determine the feasibility of adding cetuximab to this nongemcitabine-containing first-line regimen. Enrollment was confined to patients with metastatic disease, as prior ECOG trials in pancreatic cancer had consistently found different survival in patients with locally advanced and metastatic pancreatic cancer. We added prophylactic low–molecular weight heparin for all patients who were not receiving therapeutic anticoagulation. Pancreatic cancer is strongly associated with venous thromboembolic disease, which predicts for shorter survival.25,26 At the time this study was designed, prophylactic low–molecular weight heparin had not yet been formally evaluated in patients receiving systemic therapy for pancreatic cancer.

apeutic anticoagulation. Pancreatic cancer is strongly associated with venous thromboembolic disease, which predicts for shorter survival.25,26 At the time this study was designed, prophylactic low–molecular weight heparin had not yet been formally evaluated in patients receiving systemic therapy for pancreatic cancer. MATERIALS AND METHODS Patient Selection Patients were eligible who had histologic evidence of pancreatic cancer that was metastatic, and sufficient tumor from needle aspirate or open biopsy to permit immunohistochemical staining for EGFR. Measurable disease, defined as at least 1 primary or metastatic lesion measurable in at least 1 dimension within 4 weeks before randomization, was required. Patients were required to have ECOG performance status of 0 to 1, ability to provide informed consent, no concomitant medical problems that could interfere with the ability to receive therapy, absolute neutrophil count ≥1500 cells/μL, and platelet count >100,000/μL. Estimated creatinine clearance >60 mL/min was required. Patients were eligible who had normal bilirubin, and AST and ALT<2.5× the institutional upper limit of normal (ULN); alkaline phosphatase could be 4× ULN if transaminases were normal. For patients with AST or ALT ≥normal and ≤1.5× ULN, alkaline phosphatase must have been ≤2.5× ULN. Prior systemic chemotherapy was not permitted. Patients could not have neuropathy grade ≥2, a history of congestive heart failure, or uncontrolled arrhythmia. Women who were pregnant or breast feeding were not eligible. The protocol and consent form were approved by the institutional review boards.

have been ≤2.5× ULN. Prior systemic chemotherapy was not permitted. Patients could not have neuropathy grade ≥2, a history of congestive heart failure, or uncontrolled arrhythmia. Women who were pregnant or breast feeding were not eligible. The protocol and consent form were approved by the institutional review boards. Treatment Plan CT scan of the chest and abdomen were obtained within the 3 weeks before initiating treatment. Laboratory studies, CA19-9, ECG, chest x-ray, and HIV screening were completed within 2 weeks of initiating treatment. Patients received enoxaparin sodium (Sanofi-Aventis), 40 mg subcutaneously, from start of treatment through completion of protocol therapy as prophylaxis against visceral and deep venous thrombosis, unless they were already receiving therapeutic anticoagulation. Patients received dexamethasone (8 mg) orally 12 hours before and 12 hours after docetaxel to reduce the risk of docetaxel-induced fluid retention. Dexamethasone (10 mg) was also given orally as premedication along with antiemetics. Oral antiemetic therapy was prescribed and patients were instructed on the intensive use of loperamide in the event of diarrhea.27 Treatment Arm A: Combination Chemotherapy Docetaxel (35 mg/m2) (Sanofi-Aventis) was administered intravenously over 60 minutes. After the completion of the docetaxel infusion, irinotecan (Pfizer) was administered intravenously over 30 minutes at a dose of 50 mg/m2. Chemotherapy was administered once a week (days 1, 8, 15, and 22) for 4 consecutive weeks followed by 2 weeks rest. This constituted a cycle of treatment.

ravenously over 60 minutes. After the completion of the docetaxel infusion, irinotecan (Pfizer) was administered intravenously over 30 minutes at a dose of 50 mg/m2. Chemotherapy was administered once a week (days 1, 8, 15, and 22) for 4 consecutive weeks followed by 2 weeks rest. This constituted a cycle of treatment. Treatment Arm B: Combination Chemotherapy and Cetuximab Patients received cetuximab intravenous infusion once a week for 6 weeks. On day 1 of cycle 1, 400 mg/m2 was administered over 120 minutes. Thereafter, 250 mg/m2 was given weekly over 60 minutes. The infusion rate was not to exceed 5 mL/min. Diphenhydramine (50 mg IV) was administered before the initial dose and subsequently at the physician’s discretion. Docetaxel and irinotecan were administered as detailed for arm A. Treatment was held for ANC<1200/μL, platelet count <75,000/μL, or diarrhea ≥grade 2. Dose modifications were to be made to docetaxel dosing for hypersensitivity, neutropenia, or hepatic toxicity. For patients who retained no fluid but suffered excess dexamethasone toxicity, dexamethasone could be tapered to eliminate the 12-hour prechemotherapy and postchemotherapy doses. Modifications to irinotecan dosing were mandated for neutropenia and diarrhea. If treatment was held in week 4 due to toxicity, therapy was also held week 5 and the subsequent cycle started 1 week early. Toxicities were graded using the Common Toxicity Criteria v. 2.0.

2-hour prechemotherapy and postchemotherapy doses. Modifications to irinotecan dosing were mandated for neutropenia and diarrhea. If treatment was held in week 4 due to toxicity, therapy was also held week 5 and the subsequent cycle started 1 week early. Toxicities were graded using the Common Toxicity Criteria v. 2.0. Response Assessment Response assessment was performed after 2 cycles with CT scanning, multidetector row CT angiography, or MR. RECIST criteria were used to determine response status, and all responses were confirmed after 1 to 2 subsequent cycles.28 Statistical Design The primary goal of this study was to determine the response rate in patients with metastatic pancreatic cancer treated with irinotecan/docetaxel combination (Arm A) or with irinotecan/docetaxel/cetuximab combination (Arm B). Secondary endpoints were PFS, OS, toxicity, the rate of thromboembolic events when prophylactic enoxaparin sodium is administered, and the proportion of patients with metastatic pancreatic cancer whose tumors overexpress EGFR. A comparison between arms was not formally planned due to limited power. The overall accrual goal for E8200 was 92 patients (84 eligible patients); 46 patients each (42 eligible patients per arm) were to be randomized equally to the irinotecan/docetaxel and the irinotecan/docetaxel plus cetuximab arms. We expected a 5% hypersensitivity rate in the cetuximab arm, thus an additional 3 patients were added to the accrual goal of both arms in an attempt to ensure at least 40 eligible treated patients on Arm B.

arm) were to be randomized equally to the irinotecan/docetaxel and the irinotecan/docetaxel plus cetuximab arms. We expected a 5% hypersensitivity rate in the cetuximab arm, thus an additional 3 patients were added to the accrual goal of both arms in an attempt to ensure at least 40 eligible treated patients on Arm B. A true response rate of ≥20% in either arm would provide evidence of activity. For both arms, the null hypothesis was that the true response rate is ≤5%. The trial had a 2-stage design in each arm.29 At the initial stage, 22 patients were to be entered on each arm. If at least 2 responses were seen among the first 20 eligible patients of an arm, 24 additional patients were to be entered on that arm. If at least 4 responses were observed among the 42 eligible patients on either arm, then the specified treatment would be considered promising. A toxicity monitoring plan was in place throughout the period of accrual.

among the first 20 eligible patients of an arm, 24 additional patients were to be entered on that arm. If at least 4 responses were observed among the 42 eligible patients on either arm, then the specified treatment would be considered promising. A toxicity monitoring plan was in place throughout the period of accrual. This analysis reports on the data as of May 21, 2008. Point estimates and exact 90% confidence intervals (CI) are shown for the primary endpoint of objective response (complete plus partial responses) as well as toxicity severity groupings. Kaplan-Meier estimates were used for OS and PFS.30 OS was defined as time from registration to death from any cause. PFS was defined as the shorter of: (a) the time from registration to progression or (b) the time from registration to death without documentation of progression given that the death occurs within 4 months of the last disease assessment, or registration, whichever is more recent. These cases are censored at the date of last disease assessment without progression, or registration. Data from the 87 eligible and treated patients were used to conduct all analyses in this report with the exception of the analyses related to toxicity, which used data from all 91 treated patients irrespective of eligibility (46 Arm A, 45 Arm B).

the date of last disease assessment without progression, or registration. Data from the 87 eligible and treated patients were used to conduct all analyses in this report with the exception of the analyses related to toxicity, which used data from all 91 treated patients irrespective of eligibility (46 Arm A, 45 Arm B). RESULTS Patient Characteristics The trial accrued 94 patients between July 2003 and April 2006. Four patients were ineligible yet treated and 3 eligible patients never started assigned therapy. Patient characteristics are shown in Table 1. The median age was 60 years (range, 58 to 77 y). The majority were male (70%). ECOG performance status was 0 for 39% of patients. Weight loss of >10% in the preceding 6 months was reported for 34%. TABLE 1 Patient Characteristics Treatment Information The median number of cycles was 2 for each arm of the study. The mean number of cycles administered was 2.9 for Arm A and 3.3 for Arm B. The principal reason for treatment discontinuation was disease progression, noted in 54.5% in Arm A and 53.5% in Arm B. An additional 5 patients in Arm A and 6 patients in Arm B discontinued treatment because of clinical progression or symptomatic deterioration.

cycles administered was 2.9 for Arm A and 3.3 for Arm B. The principal reason for treatment discontinuation was disease progression, noted in 54.5% in Arm A and 53.5% in Arm B. An additional 5 patients in Arm A and 6 patients in Arm B discontinued treatment because of clinical progression or symptomatic deterioration. Toxicity On Arm A, 57% of patients had a worst toxicity grade of 3 and 17% of 4. Toxicity data are presented in Table 2. The most common grade ≥3 toxicities on Arm A were nausea and diarrhea, each 30%. One event of grade 5 toxicity, neutropenic fever after a single day of treatment, was reported in Arm A. In Arm B, 56% had a worst toxicity grade of 3 and 20% had a worst grade of 4. In Arm B, the most common grade 3 or 4 toxicity was diarrhea. There were 2 grade 5 toxicities on Arm B, 1 diarrhea with sepsis and 1 neutropenic fever; these events also occurred in the first cycle. The rate of high-grade toxicities was not statistically different between the arms. The proportion of treated patients who experienced ≥grade 3 diarrhea is 30.4% for Arm A (exact 90% CI [19.4%, 43.4%]), and 46.7% for Arm B (exact 90% CI [33.8%, 59.9%]). TABLE 2 Common Grade 3 or 4 Toxicities

Toxicity On Arm A, 57% of patients had a worst toxicity grade of 3 and 17% of 4. Toxicity data are presented in Table 2. The most common grade ≥3 toxicities on Arm A were nausea and diarrhea, each 30%. One event of grade 5 toxicity, neutropenic fever after a single day of treatment, was reported in Arm A. In Arm B, 56% had a worst toxicity grade of 3 and 20% had a worst grade of 4. In Arm B, the most common grade 3 or 4 toxicity was diarrhea. There were 2 grade 5 toxicities on Arm B, 1 diarrhea with sepsis and 1 neutropenic fever; these events also occurred in the first cycle. The rate of high-grade toxicities was not statistically different between the arms. The proportion of treated patients who experienced ≥grade 3 diarrhea is 30.4% for Arm A (exact 90% CI [19.4%, 43.4%]), and 46.7% for Arm B (exact 90% CI [33.8%, 59.9%]). TABLE 2 Common Grade 3 or 4 Toxicities Thrombosis/Embolism The rate of thromboembolic events among the 91 treated patients was 1.10%. There were 77 patients eligible for prophylactic enoxaparin, and of these, 1 reported grade 3 thrombosis/embolism and 1 grade 3 melena, for rates of venous thromboembolism and bleeding of 1.3% each. An exploratory analysis of baseline thrombosis status and outcome was undertaken. Baseline thrombosis was defined by the presence of any of the following at baseline: (a) visceral thrombosis present on CT, (b) splenic vein occlusion present on CT, (c) history of deep vein thrombosis or pulmonary embolism, or (d) indication of thrombosis or embolism on the baseline toxicity form. Complete data were available for 79 of the 87 eligible and treated patients. For the 22 patients with baseline thrombosis, 21 (95%) were known to have died with a median OS of 7.1 months (90% CI [4.5, 9.9]), compared with the 57 patients without baseline thrombosis, of whom 53 were known to have died (93.0%), and for whom the median OS was 6.5 months (90% CI [5.1, 10.7]). Assuming that the 2 treatment arms could be pooled, an exploratory log-rank test of OS between the 2 baseline thrombosis groups had a 2-sided P-value of 0.62.

red with the 57 patients without baseline thrombosis, of whom 53 were known to have died (93.0%), and for whom the median OS was 6.5 months (90% CI [5.1, 10.7]). Assuming that the 2 treatment arms could be pooled, an exploratory log-rank test of OS between the 2 baseline thrombosis groups had a 2-sided P-value of 0.62. Response The RECIST partial response rates were 4.5% (90% CI [1.5%, 18.4%]) in Arm A and 7% (90% CI [2.4%, 19.8%]) in Arm B. One patient among the 44 eligible and treated in Arm A (2.3%) had a confirmed complete response. This patient was alive at last follow-up. A substantial number of patients were not evaluated for response, largely due to clinical deterioration. One patient on each arm began nonprotocol therapy before restaging. CA19-9 The median CA19-9 level at registration was 1075 U/mL. Patients who had elevated baseline CA19-9 versus normal baseline CA19-9, and those with CA19-9 above the median versus all others, exhibited shorter PFS and OS. Seventy-nine of the 87 (91%) patients had at least 1 follow-up CA19-9 evaluation reported. Overall, 55 of those 79 (70%) had a decline of ≥50% at some follow-up CA19-9. PFS The median PFS for the 40 patients with sufficient information in Arm A was 3.9 months (90% CI [2.4, 5.0]). Sufficient information was available for 37 of the 43 eligible and treated patients on Arm B and their median PFS was 4.5 months (90% CI [2.7, 5.6]). The study was not designed to test for differences between the arms.

dian PFS for the 40 patients with sufficient information in Arm A was 3.9 months (90% CI [2.4, 5.0]). Sufficient information was available for 37 of the 43 eligible and treated patients on Arm B and their median PFS was 4.5 months (90% CI [2.7, 5.6]). The study was not designed to test for differences between the arms. OS OS was defined as time from registration to death from any cause. Figure 1 shows the Kaplan-Meier plot for OS for both treatment arms. As of May 21, 2008, 40 of the 44 eligible and treated patients on Arm A were known to have died (90.9%). Median survival for Arm A was 6.5 months (90% CI [5.6, 9.9]). Forty-two of the 43 eligible and treated patients on Arm B are known to have died (97.7%), with a median survival of 5.3 months (90% CI [4.5, 9.4]). FIGURE 1 Overall survival in months.

OS OS was defined as time from registration to death from any cause. Figure 1 shows the Kaplan-Meier plot for OS for both treatment arms. As of May 21, 2008, 40 of the 44 eligible and treated patients on Arm A were known to have died (90.9%). Median survival for Arm A was 6.5 months (90% CI [5.6, 9.9]). Forty-two of the 43 eligible and treated patients on Arm B are known to have died (97.7%), with a median survival of 5.3 months (90% CI [4.5, 9.4]). FIGURE 1 Overall survival in months. DISCUSSION The demonstration that FOLFIRINOX combination chemotherapy improves response and survival over gemcitabine represents an important advance in the treatment of metastatic pancreatic cancer.5 More recently, the combination of gemcitabine and nab-paclitaxel has also proven to lead to better OS than gemcitabine monotherapy for this devastating malignancy.6 The 2 regimens have not been compared head-to-head, nor have biomarkers been identified which might guide patient selection for one or the other of these regimens; nonetheless, it seems likely that differences in DNA repair, drug metabolism, or expression of drug targets might contribute to the activity of the elements of these combination regimens in individual patients. Significant differences in the expression of human equilibrative nucleoside transporter-1, ribonucleoside reductase subunit M1, and excision repair cross-complementing gene-1 expression have been documented in pancreatic cancer, and are related to prognosis.31 In this context, our demonstration that docetaxel/irinotecan combination therapy has modest activity in treatment-naive metastatic pancreatic cancer may provide another option in future trials of pharmacogenomically determined therapy in this disease.

een documented in pancreatic cancer, and are related to prognosis.31 In this context, our demonstration that docetaxel/irinotecan combination therapy has modest activity in treatment-naive metastatic pancreatic cancer may provide another option in future trials of pharmacogenomically determined therapy in this disease. The primary endpoint of this study was response rate, and the response rates observed were low. Nonetheless, the rate of CA19-9 decline, time to progression, and survival results of the present study suggest activity. The median PFS of 3.9 and 4.5 months in Arms A and B, respectively, compare favorably to the historical experience with gemcitabine or gemcitabine/erlotinib.2,22 Diarrhea, neutropenic infection, and treatment-related death were observed in each arm of the study and median survivals were not equivalent to those achieved with FOLFIRINOX; thus, the regimen cannot be recommended in unselected patients outside of a clinical trial.

ience with gemcitabine or gemcitabine/erlotinib.2,22 Diarrhea, neutropenic infection, and treatment-related death were observed in each arm of the study and median survivals were not equivalent to those achieved with FOLFIRINOX; thus, the regimen cannot be recommended in unselected patients outside of a clinical trial. The median OS in the cetuximab arm seemed less favorable than the OS in Arm A. Given the small size of the current study, which was not powered for comparisons between the arms, conclusions regarding the significance of this observation cannot be drawn; possible explanations include differences in use of second-line therapy with gemcitabine or gemcitabine/erlotinib driven by investigator bias or the patients’ toxicity profiles, and chance. The possibility of accelerated disease progression following cetuximab withdrawal cannot be discounted. Such disease acceleration following discontinuation of an EGFR inhibitor has been described in non–small cell lung cancer.32 CONCLUSIONS Docetaxel and irinotecan combination therapy produces a low objective response rate, and is associated with considerable toxicity. The regimen may add to treatment options for comparison in pharmacogenomically driven trial designs. The addition of cetuximab did not seem to add survival benefit to this regimen in this unselected patient population; addition of cetuximab may also have increased toxicity. Supported by Grant CA-23318, awarded by the National Cancer Institute, DHHS; Bristol-Myers Squibb; Sanofi; and Pharmacia.

CONCLUSIONS Docetaxel and irinotecan combination therapy produces a low objective response rate, and is associated with considerable toxicity. The regimen may add to treatment options for comparison in pharmacogenomically driven trial designs. The addition of cetuximab did not seem to add survival benefit to this regimen in this unselected patient population; addition of cetuximab may also have increased toxicity. Supported by Grant CA-23318, awarded by the National Cancer Institute, DHHS; Bristol-Myers Squibb; Sanofi; and Pharmacia. Dr Burtness reports having served as a consultant for Bristol-Myers Squibb, Sanofi-Aventis, Imclone, Lilly and Pharmacia. Dr Berlin reports having served as a consultant for Imclone and Lilly. Dr. Mitchell reports having served as a consultant for Sanofi-Aventis. Dr Benson reports having served as a consultant for Imclone, Lilly, Bristol-Myers Squibb, and Sanofi-Aventis. The remaining authors declare no conflicts of interest.

Colorectal cancer is the third most common cancer and the fourth leading cause of cancer-related death worldwide, with rectal cancer representing about 40% of cases.1 Between 15% and 20% of patients have synchronous liver metastasis (LM) at the time of diagnosis.2,3 It has been reported that 10% to 30% of these patients have a potentially resectable disease, and surgical resection of both the primary tumor and LM may be curative.4 Current treatment options for colon cancer with resectable synchronous LM are simultaneous or staged surgical resection of the primary tumor and LM with perioperative chemotherapy.5 However, management of rectal cancer in this setting is more complicated, because radiotherapy should be considered for local control, especially in locally advanced rectal cancer (LARC). Current treatment options for these patients are preoperative chemoradiotherapy, followed by surgery and adjuvant chemotherapy, with or without induction chemotherapy. One other option is surgery followed by postoperative chemoradiotherapy.6 However, these treatment guidelines are mainly based on retrospective studies and there have been no prospective trials for the treatment of this group of patients.

wed by surgery and adjuvant chemotherapy, with or without induction chemotherapy. One other option is surgery followed by postoperative chemoradiotherapy.6 However, these treatment guidelines are mainly based on retrospective studies and there have been no prospective trials for the treatment of this group of patients. After curative-intent resection of the primary tumor and LM in patients with colorectal cancer with synchronous LM, recurrences have been reported in up to two thirds of patients, resulting in a poor 5-year survival rate of approximately 40%.4,7 Recurrences mostly occur at distant sites, probably due to the presence of micrometastases at the time of surgery. Therefore, further improvements in the survival outcome will require integration of more effective systemic chemotherapy into the multimodality therapy. In an effort to improve the survival outcome of LARC patients, Rodel et al8 demonstrated that the addition of oxaliplatin to standard preoperative fluorouracil-based chemoradiotherapy was feasible and increased the number of patients achieving a pathologic complete response (pCR). In addition, a number of studies showed that induction chemotherapy with capecitabine and oxaliplatin before preoperative chemoradiotherapy improved exposure to systemic treatment with acceptable toxicity and compliance.9–11

s feasible and increased the number of patients achieving a pathologic complete response (pCR). In addition, a number of studies showed that induction chemotherapy with capecitabine and oxaliplatin before preoperative chemoradiotherapy improved exposure to systemic treatment with acceptable toxicity and compliance.9–11 Our present multicenter randomized phase II study was conducted to evaluate the efficacy, tolerability, and feasibility of the addition of oxaliplatin to a preoperative chemoradiotherapy regimen (CapeOx-RT), with or without induction chemotherapy also composed of capecitabine and oxaliplatin (induction CapeOx), in LARC patients with resectable LM.

mized phase II study was conducted to evaluate the efficacy, tolerability, and feasibility of the addition of oxaliplatin to a preoperative chemoradiotherapy regimen (CapeOx-RT), with or without induction chemotherapy also composed of capecitabine and oxaliplatin (induction CapeOx), in LARC patients with resectable LM. MATERIALS AND METHODS Patient Population The eligibility criteria included an age above 20 years and histopathologically confirmed rectal adenocarcinoma, with an inferior tumor border within 12 cm from the anal verge. The tumor had to be confirmed as cT3-4 or cN+ disease on the basis of rectal magnetic resonance imaging (MRI) and judged to be resectable or expected to be resectable after chemoradiotherapy by a multidisciplinary team. All patients underwent liver MRI and positron emission tomography to assess the exact number of LMs and to exclude extrahepatic metastasis. Metastatic liver lesions had to be resectable according to the following criteria: (1) ≤5 in number; (2) no invasion of major vessels; (3) considered resectable with respect to their distribution by a multidisciplinary team; and (4) expected to maintain adequate liver function after the surgery. Additional inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status ≤2, no prior chemotherapy or radiation therapy, and adequate bone marrow, liver, and renal function. We excluded patients with adenocarcinoma arising from inflammatory bowel disease, extrahepatic distant metastasis, synchronous unresected colon cancer, intestinal obstruction or risk of intestinal obstruction, clinically significant cardiovascular disease, or other cancers diagnosed within 5 years. Pregnant or breast-feeding women were also excluded. All patients provided written informed consent and the study protocol was approved by the institutional review boards of the participating institutions. This trial is registered with ClinicalTrials.gov, number NCT 01643070.

or other cancers diagnosed within 5 years. Pregnant or breast-feeding women were also excluded. All patients provided written informed consent and the study protocol was approved by the institutional review boards of the participating institutions. This trial is registered with ClinicalTrials.gov, number NCT 01643070. Randomization and Treatment This was a prospective, multicenter, randomized phase 2 study, and patients were randomly allocated in a 1:1 ratio to either preoperative treatments of induction CapeOx followed by CapeOx-RT (arm A) or CapeOx-RT alone (arm B) using the allocation table of the stratified randomized design derived from the number of LMs and the carcinoembryonic antigen level. Induction CapeOx consisted of oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1 to 14, every 3 weeks for 2 cycles. CapeOx-RT consisted of radiation therapy with 45 Gy delivered in conventional fractionation (daily fractions of 1.8 Gy over a period of approximately 5 wk, excluding weekends) with or without additional 5.4 Gy delivery in daily fractions of 1.8 Gy over 3 days, oxaliplatin 50 mg/m2 weekly for 5 weeks, and capecitabine 825 mg/m2 twice daily on days 1 to 38 (during radiation therapy). Surgery was planned with total mesorectal excision and simultaneous liver metastasectomy with or without addition of radiofrequency ablation within 6 weeks after completion of preoperative treatments. Postoperative chemotherapy (postoperative CapeOx) consisted of oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1 to 14, every 3 weeks for 6 cycles.

ltaneous liver metastasectomy with or without addition of radiofrequency ablation within 6 weeks after completion of preoperative treatments. Postoperative chemotherapy (postoperative CapeOx) consisted of oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1 to 14, every 3 weeks for 6 cycles. Pathologic Examination R0 and R1 were defined as histologically tumor-free or infiltrated resections margins, respectively, whereas R2 was defined as macroscopic residual tumor. Rectal circumferential resection margins were defined as negative when the distance to the tumor was >1 mm. The regression of the primary tumor was quantified according to the 5-point tumor regression grade proposed by Dworak et al12: The pathologic stage (ypT or N) was recorded according to the International Union Against Cancer TNM system. Pathologic complete response (ypCR) was defined as the absence of viable tumor cells in the surgical specimens, of the primary tumor (ypT0). A major pathologic response of the primary tumor was defined as tumor regression grades 3 and 4. Assessment We repeated abdominopelvic computed tomography or MRI after completion of induction CapeOx, CapeOx-RT, and adjuvant CapeOx. The tumor response was assessed according to the guidelines of the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1).

Pathologic Examination R0 and R1 were defined as histologically tumor-free or infiltrated resections margins, respectively, whereas R2 was defined as macroscopic residual tumor. Rectal circumferential resection margins were defined as negative when the distance to the tumor was >1 mm. The regression of the primary tumor was quantified according to the 5-point tumor regression grade proposed by Dworak et al12: The pathologic stage (ypT or N) was recorded according to the International Union Against Cancer TNM system. Pathologic complete response (ypCR) was defined as the absence of viable tumor cells in the surgical specimens, of the primary tumor (ypT0). A major pathologic response of the primary tumor was defined as tumor regression grades 3 and 4. Assessment We repeated abdominopelvic computed tomography or MRI after completion of induction CapeOx, CapeOx-RT, and adjuvant CapeOx. The tumor response was assessed according to the guidelines of the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1). The primary endpoint was the synchronous complete R0 resection rate, defined as the R0 resection rate of both the primary tumor and LMs. Secondary endpoints were the pCR rate of the primary tumor, radiologic response rate after preoperative treatment, progression-free survival (PFS), overall survival (OS), and pattern of treatment failure. PFS was defined as the time from the date of randomization until progression or death from any cause. OS was calculated from the date of randomization until death from any cause or was censored at the last follow-up. Toxicities were evaluated at each cycle of induction or postoperative CapeOx and weekly during CapeOx-RT according to NCI-CTC version 3.0.

e date of randomization until progression or death from any cause. OS was calculated from the date of randomization until death from any cause or was censored at the last follow-up. Toxicities were evaluated at each cycle of induction or postoperative CapeOx and weekly during CapeOx-RT according to NCI-CTC version 3.0. Statistical Analysis Assuming that induction chemotherapy and the addition of oxaliplatin to preoperative chemoradiotherapy would improve both local and systemic disease control, the target of the synchronous complete R0 resection rate was set to 90% and a rate of 60% or below was considered futile. A 2-stage optimal design, as proposed by Simon,13 was used to allow early termination of any ineffective arm early in the study. With a 1-sided, type I error of 5% and power of 0.9, the planned study was to proceed in 2 steps. In the first step, 8 patients were required per arm and, if synchronous complete R0 resection was observed in 6 or more patients in both arms, the study was to proceed to the second step with 9 additional patients per arm (17 patients per arm). If this condition was not met, the study would be stopped for futility. In the second step, if synchronous complete R0 resection was observed in 14 or more patients in both arms, the treatments were considered effective. Assuming a dropout rate of 10%, 19 patients were required in each arm (a total of 38 patients).

m). If this condition was not met, the study would be stopped for futility. In the second step, if synchronous complete R0 resection was observed in 14 or more patients in both arms, the treatments were considered effective. Assuming a dropout rate of 10%, 19 patients were required in each arm (a total of 38 patients). Both PFS and OS were estimated by using the Kaplan-Meier method and were compared between arms by the log-rank test. The categorical variables are presented as number (percentage) and the continuous variables are presented as median (range). The categorical variables were compared with the χ2 test or Fisher exact test, as appropriate, and the continuous variables were compared with the Mann-Whitney U test. RESULTS Patients Between March 2010 and May 2014, 38 patients from 3 centers in Korea were enrolled. The progress of all patients during the trial is shown in Figure 1. They underwent random assignment: 18 patients were assigned to arm A and 20 to arm B. The cutoff date for this report was March 15, 2015. The baseline characteristics of these patients are presented in Table 1, and most of them were well balanced between the 2 arms. The median number of LMs was 2 and cT3N+ was the most common clinical disease stage in both arms. FIGURE 1 CONSORT diagram. *Proceeded to surgery with no chemoradiotherapy due to a risk of bowel perforation. ITT indicates intention-to-treat. TABLE 1 Patient and Tumor Characteristics

RESULTS Patients Between March 2010 and May 2014, 38 patients from 3 centers in Korea were enrolled. The progress of all patients during the trial is shown in Figure 1. They underwent random assignment: 18 patients were assigned to arm A and 20 to arm B. The cutoff date for this report was March 15, 2015. The baseline characteristics of these patients are presented in Table 1, and most of them were well balanced between the 2 arms. The median number of LMs was 2 and cT3N+ was the most common clinical disease stage in both arms. FIGURE 1 CONSORT diagram. *Proceeded to surgery with no chemoradiotherapy due to a risk of bowel perforation. ITT indicates intention-to-treat. TABLE 1 Patient and Tumor Characteristics Treatment Exposure Treatment exposures are summarized in Supplementary Table S1 (Supplemental Digital Content 1, http://links.lww.com/AJCO/A131, which shows the treatment exposure). Induction Chemotherapy The median relative dose intensities for both oxaliplatin and capecitabine were 100% for the patients who received induction chemotherapy (arm A).

Treatment Exposure Treatment exposures are summarized in Supplementary Table S1 (Supplemental Digital Content 1, http://links.lww.com/AJCO/A131, which shows the treatment exposure). Induction Chemotherapy The median relative dose intensities for both oxaliplatin and capecitabine were 100% for the patients who received induction chemotherapy (arm A). Chemoradiotherapy Three patients (16.7%) in arm A did not receive chemoradiotherapy for several reasons (Fig. 1). One patient underwent stent insertion due to intestinal obstruction during induction chemotherapy without evidence of disease progression and proceeded to surgery with no chemoradiotherapy due to risk of bowel perforation. Another 2 patients withdrew consent. Among the patients who received chemoradiotherapy, 14 patients (93.3%) in arm A and 18 patients (90%) in arm B completed the planned radiotherapy. The median relative dose intensity of oxaliplatin was 89.7% in both arms, whereas those of capecitabine were 95.4% versus 98.4% in arms A and B, respectively. Surgery A total of 16 patients (88.9%) in arm A and 19 patients (95%) in arm B underwent surgery. The median times from the completion of the radiation therapy to surgery were 5.9 weeks (range, 4.6 to 7.3 wk) in arm A and 6.0 weeks (range, 3.0 to 8.1 wk) in arm B, respectively. Two patients in arm A and 1 patient in arm B did not receive surgery due to consent withdrawal (Fig. 1).

(95%) in arm B underwent surgery. The median times from the completion of the radiation therapy to surgery were 5.9 weeks (range, 4.6 to 7.3 wk) in arm A and 6.0 weeks (range, 3.0 to 8.1 wk) in arm B, respectively. Two patients in arm A and 1 patient in arm B did not receive surgery due to consent withdrawal (Fig. 1). Postoperative Chemotherapy Of the resected patients, 14 (87.5%) in arm A and 17 (89.5%) in arm B received postoperative chemotherapy, and 2 patients in each arm did not receive adjuvant chemotherapy for several reasons (Fig. 1). One patient died due to sepsis that was unrelated to the treatment, and another patient in arm A withdrew consent. The disease progressed in 2 patients in arm B. The median relative dose intensity of oxaliplatin was 83.8% in arm A and 96.2% in arm B, whereas that of capecitabine was 82.9% and 89.3%, respectively.

. 1). One patient died due to sepsis that was unrelated to the treatment, and another patient in arm A withdrew consent. The disease progressed in 2 patients in arm B. The median relative dose intensity of oxaliplatin was 83.8% in arm A and 96.2% in arm B, whereas that of capecitabine was 82.9% and 89.3%, respectively. Efficacy and Survival In the intention-to-treat population, the synchronous complete R0 resection rates were 77.8% in arm A and 70.0% in arm B (odds ratio 1.500; 95% confidence interval [CI], 0.346-6.501; P=0.72); the R0 resection rates for the primary tumor were 83.3% versus 95.0% (P=0.33), whereas those for the LM were 77.8% versus 70.0% (P=0.72), respectively (Table 2). The radiologic response rates were 61.1% in arm A and 70.0% in arm B (Supplementary Table S2, Supplemental Digital Content 2, http://links.lww.com/AJCO/A132, which shows the radiologic evaluation of the responses to preoperative treatments). In addition, the pCR rates were 11.1% versus 5.0%, and the major pathologic response rates of the primary tumor were 22.2% versus 25.0% (Table 3), respectively. At a median follow-up of 32.7 months (range, 3.0 to 57.9 mo), the median PFSs were 14.2 versus 15.1 months, the 3-year PFSs were 25.1% versus 36.3% (hazards ratio 0.707; 95% CI, 0.304-1.646; P=0.42) (Fig. 2), and the 3-year OSs were 75.0% versus 88.8% (hazards ratio 0.379; 95% CI, 0.063-2.283; P=0.29) (Fig. 3), respectively. TABLE 2 Quality of Surgery TABLE 3 Pathologic Outcomes FIGURE 2 Kaplan-Meier curve for progression-free survival time according to treatment arms in the intention-to-treat population.

Efficacy and Survival In the intention-to-treat population, the synchronous complete R0 resection rates were 77.8% in arm A and 70.0% in arm B (odds ratio 1.500; 95% confidence interval [CI], 0.346-6.501; P=0.72); the R0 resection rates for the primary tumor were 83.3% versus 95.0% (P=0.33), whereas those for the LM were 77.8% versus 70.0% (P=0.72), respectively (Table 2). The radiologic response rates were 61.1% in arm A and 70.0% in arm B (Supplementary Table S2, Supplemental Digital Content 2, http://links.lww.com/AJCO/A132, which shows the radiologic evaluation of the responses to preoperative treatments). In addition, the pCR rates were 11.1% versus 5.0%, and the major pathologic response rates of the primary tumor were 22.2% versus 25.0% (Table 3), respectively. At a median follow-up of 32.7 months (range, 3.0 to 57.9 mo), the median PFSs were 14.2 versus 15.1 months, the 3-year PFSs were 25.1% versus 36.3% (hazards ratio 0.707; 95% CI, 0.304-1.646; P=0.42) (Fig. 2), and the 3-year OSs were 75.0% versus 88.8% (hazards ratio 0.379; 95% CI, 0.063-2.283; P=0.29) (Fig. 3), respectively. TABLE 2 Quality of Surgery TABLE 3 Pathologic Outcomes FIGURE 2 Kaplan-Meier curve for progression-free survival time according to treatment arms in the intention-to-treat population. FIGURE 3 Kaplan-Meier curve for overall survival time according to treatment arms in the intention-to-treat population.

Efficacy and Survival In the intention-to-treat population, the synchronous complete R0 resection rates were 77.8% in arm A and 70.0% in arm B (odds ratio 1.500; 95% confidence interval [CI], 0.346-6.501; P=0.72); the R0 resection rates for the primary tumor were 83.3% versus 95.0% (P=0.33), whereas those for the LM were 77.8% versus 70.0% (P=0.72), respectively (Table 2). The radiologic response rates were 61.1% in arm A and 70.0% in arm B (Supplementary Table S2, Supplemental Digital Content 2, http://links.lww.com/AJCO/A132, which shows the radiologic evaluation of the responses to preoperative treatments). In addition, the pCR rates were 11.1% versus 5.0%, and the major pathologic response rates of the primary tumor were 22.2% versus 25.0% (Table 3), respectively. At a median follow-up of 32.7 months (range, 3.0 to 57.9 mo), the median PFSs were 14.2 versus 15.1 months, the 3-year PFSs were 25.1% versus 36.3% (hazards ratio 0.707; 95% CI, 0.304-1.646; P=0.42) (Fig. 2), and the 3-year OSs were 75.0% versus 88.8% (hazards ratio 0.379; 95% CI, 0.063-2.283; P=0.29) (Fig. 3), respectively. TABLE 2 Quality of Surgery TABLE 3 Pathologic Outcomes FIGURE 2 Kaplan-Meier curve for progression-free survival time according to treatment arms in the intention-to-treat population. FIGURE 3 Kaplan-Meier curve for overall survival time according to treatment arms in the intention-to-treat population. Patterns of Recurrence Recurrence was experienced by 10 patients in arm A (55.6%) and 12 patients in arm B (60.0%) (Supplementary Table S3, Supplemental Digital Content 3, http://links.lww.com/AJCO/A133, which shows the pattern of recurrence). Local recurrence was observed in 2 patients in arm B (10.0%), whereas no patient in arm A experienced local recurrence. Treatment failure was mainly due to distant recurrence in both arms and the most common site of distant recurrence was the lung and liver in arm A (27.8%) and the liver in arm B (40.0%).

recurrence). Local recurrence was observed in 2 patients in arm B (10.0%), whereas no patient in arm A experienced local recurrence. Treatment failure was mainly due to distant recurrence in both arms and the most common site of distant recurrence was the lung and liver in arm A (27.8%) and the liver in arm B (40.0%). Adverse Events Adverse events related to the treatment are summarized in Supplementary Table S4 (Supplemental Digital Content 4, http://links.lww.com/AJCO/A134, which shows the adverse events). During induction CapeOx, only 1 of 18 patients (5.6%) in arm A experienced grade 3/4 toxicity, specifically grade 3 thrombocytopenia. Grade 3/4 toxicities during CapeOx-RT consisted of thrombocytopenia (6.7%) and diarrhea (6.7%) in arm A and diarrhea (10%) in arm B. The most common grade 3/4 hematologic toxicity during adjuvant chemotherapy was neutropenia in both arms, which was observed in 3 patients (21.4%) in arm A and 2 patients (11.8%) in arm B. The most common grade 3/4 nonhematologic toxicity during adjuvant chemotherapy was hand-foot syndrome or sensory neuropathy (7.1%) in arm A and nausea (17.6%) in arm B. There was no treatment-related mortality.

neutropenia in both arms, which was observed in 3 patients (21.4%) in arm A and 2 patients (11.8%) in arm B. The most common grade 3/4 nonhematologic toxicity during adjuvant chemotherapy was hand-foot syndrome or sensory neuropathy (7.1%) in arm A and nausea (17.6%) in arm B. There was no treatment-related mortality. DISCUSSION This is the first prospective randomized study to investigate the role of intensified chemoradiotherapy with or without induction chemotherapy for LARC patients with resectable LMs. In this phase II study, we found that preoperative CapeOx-RT, with or without induction CapeOx, was effective in both local and systemic control before surgery in LARC patients with resectable LMs. Although LMs progressed in 3 patients (1 in arm A, 2 in arm B) during preoperative treatments, all 3 patients were able to proceed to total mesorectal excision with liver metastasectomy. Considerable synchronous complete R0 resection rates as well as good 3-year PFS and OS were observed in both arms.

th resectable LMs. Although LMs progressed in 3 patients (1 in arm A, 2 in arm B) during preoperative treatments, all 3 patients were able to proceed to total mesorectal excision with liver metastasectomy. Considerable synchronous complete R0 resection rates as well as good 3-year PFS and OS were observed in both arms. Both treatment modalities were feasible with a median relative dose intensity of all chemotherapy agents >80% in both arms. More than 90% of patients in both arms received the planned dose of radiotherapy. The general level of toxicity observed during preoperative treatment was low in both arms. Thrombocytopenia (6.7%) was the only grade 3/4 hematologic toxicity in arm A, whereas no grade 3/4 hematologic toxicity was observed in arm B. Diarrhea was the only grade 3/4 nonhematologic toxicity in both groups (6.7% in arm A vs. 10.0% in arm B). The incidence of grade 3/4 adverse events during preoperative chemoradiotherapy in this study was relatively lower than those observed in the representative trials in whites (range, 23% to 40%).8,14–16 There may exist ethnic differences underlying this observation or because the sample size was rather small to represent our population. The most common grade 3/4 toxicity during postoperative chemotherapy was neutropenia (21.4%) in arm A and nausea (17.6%) followed by neutropenia (11.8%) in arm B.

, 23% to 40%).8,14–16 There may exist ethnic differences underlying this observation or because the sample size was rather small to represent our population. The most common grade 3/4 toxicity during postoperative chemotherapy was neutropenia (21.4%) in arm A and nausea (17.6%) followed by neutropenia (11.8%) in arm B. Although direct comparisons are difficult, due to differences in sample size and patient selection, the overall R0 resection rate (77.8% in arm A and 70.0% in arm B) of our study was comparable to that of previous retrospective studies on LARC patients with LM (55% to 80%).17,18 Furthermore, our 3-year PFS (25.1% in arm A vs. 36.3% in arm B) and OS (75.0% vs. 88.8%) were superior to those studies, which were 19% to 24% for 3-year PFS and 51% to 59% for 3-year OS.17,18 The pCR rate of the primary tumor (11.1% in arm A and 5.0% in arm B) was lower than that of LARC patients without distant metastasis (13% to19.5%).8,14–16 The lower pCR rates of the primary tumor in this study might be related with the shorter interval between completion of chemoradiotherapy and surgery than that in the previous studies for nonmetastatic disease, and also with the selection of patients who had more locally advanced and metastatic disease. Nevertheless, the local recurrence rate (0% in arm A and 10% in arm B) and the rate of sphincter-sparing surgery (72.2% in arm A and 80.0% in arm B) were comparable to those of LARC patients without distant metastasis, with a local recurrence rate of 7.1% to 9.6% and a sphincter-sparing surgery rate of 71% to 79%.8,16,19,20

theless, the local recurrence rate (0% in arm A and 10% in arm B) and the rate of sphincter-sparing surgery (72.2% in arm A and 80.0% in arm B) were comparable to those of LARC patients without distant metastasis, with a local recurrence rate of 7.1% to 9.6% and a sphincter-sparing surgery rate of 71% to 79%.8,16,19,20 Although local control was satisfactory, more than half of the patients in both arms experienced recurrence, mainly due to distant recurrence, which is in line with previous study results.20,21 The main cause of treatment failure in rectal cancer is now distant metastasis, and an improvement in OS will require better control of systemic disease while keeping the rate of local recurrence <10%. The additional 2 cycles of induction CapeOx in arm A did not significantly improve the overall R0 resection rate or any other efficacy outcomes compared with arm B. Thus, the addition of induction chemotherapy may not improve efficacy outcomes in LARC patients with resectable LMs. Nevertheless, a recent phase II study showed that addition of systemic chemotherapy between preoperative chemoradiotherapy and surgery increased the proportion of patients achieving a pCR in LARC without metastasis.22 Moreover, a randomized phase III trial (the RAPIDO trial) comparing short-course radiotherapy, followed by prolonged preoperative chemotherapy and surgery with standard chemoradiotherapy and surgery in LARC is ongoing. The role of additional systemic chemotherapy for rectal cancer before surgery is expected to be established according to the results of this phase III trial.

) comparing short-course radiotherapy, followed by prolonged preoperative chemotherapy and surgery with standard chemoradiotherapy and surgery in LARC is ongoing. The role of additional systemic chemotherapy for rectal cancer before surgery is expected to be established according to the results of this phase III trial. It is still controversial whether the addition of oxaliplatin to the standard single fluoropyrimidine-based preoperative chemoradiotherapy regimen is of benefit to LARC patients without metastasis.8,14–16 However, the addition of oxaliplatin to fluoropyrimidine improved the survival outcomes of metastatic colorectal cancer patients and is now a standard chemotherapy in the metastatic setting.23 Accordingly, oxaliplatin was added to the preoperative chemoradiotherapy regimen for systemic control of LMs in our study, which may have contributed to the considerable efficacy outcomes. Moreover, this intensified chemoradiotherapy regimen is well tolerated, with a toxicity profile similar to that of the standard single fluoropyrimidine-based chemoradiotherapy.8,14 Thus, CapeOx-RT can be an additional reasonable approach to LARC patients with resectable metastases who need both local and systemic control.

eover, this intensified chemoradiotherapy regimen is well tolerated, with a toxicity profile similar to that of the standard single fluoropyrimidine-based chemoradiotherapy.8,14 Thus, CapeOx-RT can be an additional reasonable approach to LARC patients with resectable metastases who need both local and systemic control. Recently, the addition of targeted agents such as epidermal growth factor receptor inhibitor or vascular epithelial growth factor receptor inhibitor to the conventional chemotherapy regimen according to the results of companion diagnostics have significantly improved the outcomes of unresectable colorectal cancer patients with metastasis.24–26 The new EPOC trial, which was conducted to find a benefit of the addition of cetuximab, an epithelial growth factor receptor inhibitor, to chemotherapy in the perioperative setting of resectable colorectal cancer patients with metastasis was stopped early because it met the predefined futility criteria.27 However, the results of that study are not universally accepted due to several limitations, as recently mentioned by Nordlinger et al,28 and further confirmatory clinical studies are required to determine the efficacy of the addition of cetuximab to this group of patients.

use it met the predefined futility criteria.27 However, the results of that study are not universally accepted due to several limitations, as recently mentioned by Nordlinger et al,28 and further confirmatory clinical studies are required to determine the efficacy of the addition of cetuximab to this group of patients. Bevacizumab is a potent inhibitor of VEGF activity, and it has thus been suggested that its use in a perioperative setting could potentially impact postoperative wound healing.29 Nevertheless, when bevacizumab was stopped at least 5 weeks before or started at least 28 days after the surgery, there was no increase in wound complications.30,31 Thus, the addition of bevacizumab can be considered in the treatment of LARC with resectable LMs in future studies in an attempt to improve distant disease control. Triple combination strategies, FOLFOXIRI (oxaliplatin, irinotecan, and 5-fluorouracil), with or without bevacizumab was proven to bring maximal tumor shrinkage as well as improved survival outcomes.32,33 The OLIVIA trial, which compared bevacizumab plus FOLFOX with bevacizumab plus FOLFOXIRI for patients with liver-limited metastases, demonstrated that the R0 resection rate was 49% in the bevacizumab plus FOLFOXIRI arm.34 Thus, triplet combination with or without bevacizumab also can be considered as neoadjuvant strategy for this population.

compared bevacizumab plus FOLFOX with bevacizumab plus FOLFOXIRI for patients with liver-limited metastases, demonstrated that the R0 resection rate was 49% in the bevacizumab plus FOLFOXIRI arm.34 Thus, triplet combination with or without bevacizumab also can be considered as neoadjuvant strategy for this population. In conclusion, intensified chemoradiotherapy with or without induction chemotherapy needs more evidence to come into the clinical practice for LARC patients with resectable LMs, although this randomized phase II study demonstrated considerable complete R0 resection rates with manageable adverse events. Further clinical trials with greater numbers of patients are clearly warranted to evaluate the efficacy and safety of this intensified chemoradiotherapy, with or without addition of targeted agents. Supplementary Material SUPPLEMENTARY MATERIAL Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website, www.amjclinicaloncology.com. ACKNOWLEDGMENT The authors also thank Roche Korea Co., Ltd for providing the capecitabine and Sanofi-Aventis, Korea Co., Ltd. for providing the oxaliplatin. Y.S.H. and T.W.K. are designated as joint corresponding authors.

Supplementary Material SUPPLEMENTARY MATERIAL Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website, www.amjclinicaloncology.com. ACKNOWLEDGMENT The authors also thank Roche Korea Co., Ltd for providing the capecitabine and Sanofi-Aventis, Korea Co., Ltd. for providing the oxaliplatin. Y.S.H. and T.W.K. are designated as joint corresponding authors. Supported by a grant of the Korea Health 21 R&D Project Ministry of Health and Welfare and Family Affairs, Republic of Korea (HI06C0868), the Korea Health Technology R&D Project Ministry of Health & Welfare, Republic of Korea (HI14C1731), and the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (2015-0753). The authors declare no conflicts of interest.

Osteosarcoma is a common primary bone cancer which is invasive and arises from mesenchymal cells. It produces osteoid, which is capable of invading local tissue structures and causing metastasis.1 Extraskeletal osteosarcomas (ESOS) are a rare variant of osteosarcoma located in soft tissue and organs which are not extensions of a primary bone osteosarcoma.2 It represents <1% of all de novo sarcomas, and is historically believed to be an aggressive tumor connoting a poor prognosis.3 Researchers have long known that ESOS behaves differently than its primary counterpart of osseous origin. ESOS seems to affect more elderly patients, and it does not respond well to chemotherapy. Local and distant failures are common.4 However, due to the rarity of ESOS, there have been limited advances in trimodality therapies or new biological agent testing. It has been estimated that no more than 350 cases have been recorded,5 with most being limited to single case reports or small case series. The purpose of this project is to present a recent and relatively large series of ESOS and their associated treatment and survival outcome.

erapies or new biological agent testing. It has been estimated that no more than 350 cases have been recorded,5 with most being limited to single case reports or small case series. The purpose of this project is to present a recent and relatively large series of ESOS and their associated treatment and survival outcome. MATERIALS AND METHODS The Rare Cancer Network (RCN) is a consortium of international oncology investigators dedicated to advancing the knowledge of care for patients with rare tumors.6 A project was initiated to study the collective multi-institutional experience of ESOS. Inclusion criteria were confirmed pathologic diagnosis and a minimum of 6-month follow-up after treatment completion. Pathology was reviewed in each case to reconfirm the diagnosis of ESOS. The local medical records were reviewed in full, and anonymized data were sent to 1 author (T.T.S.) for further analysis. Every effort has been made to protect the integrity and confidentiality of the collected data. Patient and tumor characteristics and multimodality treatment information were included. If ESOS originated from an organ site, the exclusion of carcinoma as a diagnosis had to be confirmed. Clinically, the sequence and choices of surgery, chemotherapy, and radiotherapy were determined according to each hospital’s local policy.

nd tumor characteristics and multimodality treatment information were included. If ESOS originated from an organ site, the exclusion of carcinoma as a diagnosis had to be confirmed. Clinically, the sequence and choices of surgery, chemotherapy, and radiotherapy were determined according to each hospital’s local policy. Thirty-seven eligible patients were analyzed. The patients were diagnosed between 1998 and 2010, with an additional long-term survivor who was initially diagnosed in 1972. All patients received definitive combined modality therapies, including surgery, radiotherapy, or chemoradiotherapy, except for 4 patients with initially metastatic disease. The patients with metastases at diagnosis were all included in the overall survival (OS) but not in the disease-free survival (DFS) analyses. DFS, calculated for the 33 patients who initially presented with nonmetastatic ESOS, was calculated from the date of diagnosis to the date of last follow-up or local/metastatic relapse, whichever was earliest. OS was calculated from the date of diagnosis to the date of last follow-up or death from any cause. The work-up of studied patients included a complete history and physical, laboratory examination, computed tomography, and/or magnetic resonance imaging, and tissue biopsy. For patients who experienced relapse, salvage therapy was given and information collected. This study was approved by the Institutional Review Board at all participating institutions.

uded a complete history and physical, laboratory examination, computed tomography, and/or magnetic resonance imaging, and tissue biopsy. For patients who experienced relapse, salvage therapy was given and information collected. This study was approved by the Institutional Review Board at all participating institutions. Data Analysis Descriptive statistics were used to summarize patient, tumor, and treatment characteristics. DFS and OS plots were generated using the Kaplan-Meier method.7 Log-rank and Cox score P values were used. Cox proportional hazards models were used to obtain likelihood ratio P values for univariate and multivariate significance. Multivariate models were selected using stepwise models and were verified using backward elimination. Univariate and multivariate differences were considered significant if the P value was <0.05 using 2-tailed t tests. All statistical analysis was performed using JMP 9.0.1 (SAS Institute Inc., Cary, NC).

significance. Multivariate models were selected using stepwise models and were verified using backward elimination. Univariate and multivariate differences were considered significant if the P value was <0.05 using 2-tailed t tests. All statistical analysis was performed using JMP 9.0.1 (SAS Institute Inc., Cary, NC). RESULTS Characteristics of Patients and Tumors Through RCN, clinical data of 37 eligible patients with ESOS from 4 institutions were reviewed. Table 1 summarizes patient characteristics and demographics along with tumor information at initial diagnosis. The median age of the 37 patients was 55 years (range, 13 to 81 y). Twenty-one (57%) patients were male. The histology included chondroblastic and fibroblastic types. Thirty-three (89%) patients had osteosarcoma in a soft-tissue site, and 4 (11%) had osteosarcoma in non–soft-tissue sites (hard palate, ethmoid sinus, and breast). Previous radiotherapy is a known risk factor for sarcoma as a secondary malignancy, and 5 (14%) patients had prior radiation to the pelvis, thigh, thorax, or retroperitoneum. TABLE 1 Characteristics of 37 Patients With Extraskeletal Osteosarcoma

RESULTS Characteristics of Patients and Tumors Through RCN, clinical data of 37 eligible patients with ESOS from 4 institutions were reviewed. Table 1 summarizes patient characteristics and demographics along with tumor information at initial diagnosis. The median age of the 37 patients was 55 years (range, 13 to 81 y). Twenty-one (57%) patients were male. The histology included chondroblastic and fibroblastic types. Thirty-three (89%) patients had osteosarcoma in a soft-tissue site, and 4 (11%) had osteosarcoma in non–soft-tissue sites (hard palate, ethmoid sinus, and breast). Previous radiotherapy is a known risk factor for sarcoma as a secondary malignancy, and 5 (14%) patients had prior radiation to the pelvis, thigh, thorax, or retroperitoneum. TABLE 1 Characteristics of 37 Patients With Extraskeletal Osteosarcoma The most common site for soft-tissue ESOS was the lower extremity (14 patients [38%]), followed by intrapelvic area and retroperitoneum (13 patients [35%]). Three (8%) patients had ESOS in the thorax, and 2 (5%) had it in the upper extremities. A 4-grade system in pathologic grading was used; of the 37 patients, most (31 [84%]) had high-grade (grade 3/4) ESOS (Table 1). Tumors from 5 (14%) of the 37 patients were evaluated as intermediate grade (grade 2). There were no low-grade tumors, although in 1 (3%) case the grade was unknown. Using the American Joint Committee on Cancer staging system (7th ed), we classified 5 (14%) of the 37 cases as stage II; 28 (76%) as stage III; and 4 (11%) as stage IV.

(14%) of the 37 patients were evaluated as intermediate grade (grade 2). There were no low-grade tumors, although in 1 (3%) case the grade was unknown. Using the American Joint Committee on Cancer staging system (7th ed), we classified 5 (14%) of the 37 cases as stage II; 28 (76%) as stage III; and 4 (11%) as stage IV. The median follow-up was 45 months, with 6 (16%) local and 11 (30%) distant recurrences as first event, respectively. For patients who were still alive at follow-up, the median follow-up was 80 months (quartiles, 62 to 96 mo; with or without disease). Including the 4 stage IV cases (patients who initially presented with metastases), 16 (43%) patients had died at follow-up, including 13 (35%) who died with disease. Treatment Characteristics Table 2 summarizes the treatment of the 37 patients. Most patients (29 [78%]) had tumors >5 cm clinically; 14 (38%) of these patients had tumors >10 cm. Fourteen (42%) of 33 patients received neoadjuvant chemotherapy, with 3 partial responses and 2 complete responses at the time of surgery. Of 33 patients, 28 (85%) underwent curative surgery. None of the metastatic patients received surgery. TABLE 2 Treatment of 37 Patients With Extraskeletal Osteosarcoma

Treatment Characteristics Table 2 summarizes the treatment of the 37 patients. Most patients (29 [78%]) had tumors >5 cm clinically; 14 (38%) of these patients had tumors >10 cm. Fourteen (42%) of 33 patients received neoadjuvant chemotherapy, with 3 partial responses and 2 complete responses at the time of surgery. Of 33 patients, 28 (85%) underwent curative surgery. None of the metastatic patients received surgery. TABLE 2 Treatment of 37 Patients With Extraskeletal Osteosarcoma Only 3 (19%) of 16 evaluable surgically evaluable specimens had tumor necrosis of >90%. Sixteen (48%) patients received external beam radiotherapy, often concurrent with chemotherapy neoadjuvantly; adjuvant chemotherapy was given to 13 (39%) patients. Six patients received neoadjuvant radiation therapy (median 50.0 Gy; range, 41.4 to 50.4 Gy). Ten patients received adjuvant radiation therapy (median, 53.7 Gy; range, 30.0 to 70.0 Gy). No patients received RT alone. The neoadjuvant chemotherapy regimens were: ifosfamide and doxorubicin (n=3); ifosfamide and doxorubicin alternating with cisplatin and doxorubicin (n=1); ifosfamide, mitomycin/methotrexate, doxorubicin, and cisplatin (n=6); and mitomycin C, doxorubicin, and cisplatin (n=1). The adjuvant chemotherapy regimens were: doxorubicin alone (n=2); ifosfamide and etoposide (n=2); ifosfamide, mitomycin/methotrexate, doxorubicin, and cisplatin-based (n=8); and doxorubicin and cisplatin (n=3). Gemcitabine-based chemotherapy was the most common salvage therapy and appeared effective as a second-line regimen. The median prescribed radiation dose was 50.4 Gy (range, 40 to 70 Gy). The significant heterogeneity in chemotherapy regimens limits the ability to assess the efficacy of chemotherapy in these patients.

. Gemcitabine-based chemotherapy was the most common salvage therapy and appeared effective as a second-line regimen. The median prescribed radiation dose was 50.4 Gy (range, 40 to 70 Gy). The significant heterogeneity in chemotherapy regimens limits the ability to assess the efficacy of chemotherapy in these patients. Survival Analysis The median follow-up was 45 months. For our cohort of patients with ESOS, Figures 1A and B show the Kaplan-Meier plots for OS and DFS, respectively. The DFS analyses excluded 4 patients who had metastatic disease at presentation. At the end of the follow-up period, 20 (55%) patients were alive, and 13 (43%) remained disease free. Median OS has not been reached yet; 75% and 60% of the patients were alive at 26 and 54 months, respectively. At 80 and 120 months, 58% and 52% of the patients were alive, respectively. When the 4 patients with metastases at presentation were excluded, the median DFS for 33 patients was estimated to be 90 months. Of these 33 patients, 65% and 57% remained disease free and alive at 20 and 40 months, respectively. In patients with nonmetastatic disease, 27 (82%) of them had known local control (LC) status in follow-up. The 1-year LC rate was 88% (95% confidence interval, 68% to 95%). Both of the actuarial 3- and 5-year LC rates were 80%. On univariate analyses, LC was not associated with any RT (P=0.17), neoadjuvant RT or chemoradiation (P=0.95), adjuvant RT (P=0.15), or surgery (P=0.63).

known local control (LC) status in follow-up. The 1-year LC rate was 88% (95% confidence interval, 68% to 95%). Both of the actuarial 3- and 5-year LC rates were 80%. On univariate analyses, LC was not associated with any RT (P=0.17), neoadjuvant RT or chemoradiation (P=0.95), adjuvant RT (P=0.15), or surgery (P=0.63). FIGURE 1 Kaplan-Meier survival graphs. Overall survival of all patients with extraskeletal osteosarcoma (A). Disease-free survival of patients with extraskeletal osteosarcoma who initially presented with localized (nonmetastatic) disease (B). Table 3 summarizes the univariate and multivariate analyses for OS in all patients. Univariate analysis showed that poor OS was related to primary size >10 cm (P=0.002), no surgery (P<0.001), and older age at diagnosis (P=0.002). In the final multivariate analysis, pathologic size and age at diagnosis were dropped as variables in the best-fitting Cox model. Primary size >10 cm (P=0.005) remained prognostic for OS in the multivariate Cox model. TABLE 3 Summary of Univariate and Multivariate Analyses for Overall Survival Table 4 shows the univariate and multivariate analyses for the 33 patients with initially nonmetastatic disease. For patients without metastases, univariate analysis showed that DFS was related to primary size >10 cm (P=0.003), surgery (P=0.004), local recurrence (P=0.003), and age at diagnosis (P<0.001). In multivariate analysis for DFS, primary size >10 cm (P=0.01) and age (P<0.001) remained significant. Similar to the findings of the OS analysis, the DFS analysis showed older age to be associated with poor DFS.

imary size >10 cm (P=0.003), surgery (P=0.004), local recurrence (P=0.003), and age at diagnosis (P<0.001). In multivariate analysis for DFS, primary size >10 cm (P=0.01) and age (P<0.001) remained significant. Similar to the findings of the OS analysis, the DFS analysis showed older age to be associated with poor DFS. TABLE 4 Summary of Univariate and Multivariate Analyses for Disease-free Survival DISCUSSION Researchers2,8 have long recognized the clinical identity of the osteosarcoma variant that exists in extraosseous locations. However, due to the rarity of this tumor, most publications have been limited to case reports only.8–14 Pediatric patients have also been reported, for example, in the soft thigh tissue of a 6-year-old boy15 and a high-grade ESOS in the breast of a 16-year-old female.16 Several larger studies have been reported,3–5,17,18 to which the results of our study in this series are comparable (Table 5). TABLE 5 Outcome Summary of Previous ESOS Studies The use of surgery is a strongly statistically significant univariate for improved OS and DFS in our analysis. The RCN group believes that multimodality therapy remains important in the treatment of ESOS, which is also a common choice of practice in our current patient series. Although the use of RT and surgery were not statistically significant in our variate analyses for LC, the interpretation of these results are limited due to the limited number of ESOS cases we could find regarding this very unusual variant of osteosarcoma.

also a common choice of practice in our current patient series. Although the use of RT and surgery were not statistically significant in our variate analyses for LC, the interpretation of these results are limited due to the limited number of ESOS cases we could find regarding this very unusual variant of osteosarcoma. In contrast, indeed, the use of radiotherapy and chemotherapy for ESOS had been questioned before, especially in the older studies. In 1995, Lee et al4 from Mayo Clinic reported one of the earliest series of 40 patients with ESOS. The reported 5-year survival was 37%, and the size of the initial lesion did not correlate with longer survival. McCarter et al3 also reported their experience with 15 ESOS patients, most of whom underwent surgical resection. These authors concluded that the use of adjuvant chemotherapy or radiotherapy did not affect survival in ESOS patients, however, this finding could be related to the small series reported in the literature on ESOS. Ahmad et al5 reported the outcomes of 60 consecutive patients with ESOS. Their 5-year LC rate was excellent at 82% for localized cases. They also reported a respectable rate of response to chemotherapy, with 19% of their patients achieving a complete or partial response to neoadjuvant chemotherapy. Their chemotherapy was doxorubicin-based, which was similar to our regimens. In 2007, the Japanese Musculoskeletal Oncology Group17 reported on a 20-patient ESOS series. Their 5-year LC was 75% with surgery, which resulted in a 66% five-year survival. Most (75%) of their patients received doxorubicin and/or cisplatin-based chemotherapy together, and 33% achieved partial response. Although toxicities from these aggressive chemotherapy regimens were not reported, no grade 5 toxicity (death) was found. The use of chemotherapy, especially for high-grade sarcoma and ESOS, remains a subject for further exploration.

bicin and/or cisplatin-based chemotherapy together, and 33% achieved partial response. Although toxicities from these aggressive chemotherapy regimens were not reported, no grade 5 toxicity (death) was found. The use of chemotherapy, especially for high-grade sarcoma and ESOS, remains a subject for further exploration. The limitations of this study included its small number of patients, retrospective design, and heterogeneity of treatments across hospitals and continents. The strength of our study was the pooling of cases from both US and international medical institutions, which added additional insights to the nature and treatment of this rare type of osteosarcoma. Every effort was made for the clarification of these selected patients’ treatment and their data if questions arose. Because of the low incidence of ESOS, no prospective study has been conducted; as a result, retrospective studies remain an important tool for clinical investigation. Our series has added to and updated the current literature in the treatment and outcome of ESOS in the relatively modern period of era investigated.

ose. Because of the low incidence of ESOS, no prospective study has been conducted; as a result, retrospective studies remain an important tool for clinical investigation. Our series has added to and updated the current literature in the treatment and outcome of ESOS in the relatively modern period of era investigated. CONCLUSIONS The survival outcome in this international cohort of patients with ESOS was similar to those reported in patients with osteogenic sarcomas. Stage IV at diagnosis and large primary tumor size were strong prognostic factors for poor OS, whereas older age and larger primary tumor size predicted poorer DFS. A multimodality treatment approach remains standard in patients with localized disease; however, the indications for neoadjuvant therapy are less clear for ESOS. Future research for novel chemotherapeutic agents and safe dose-escalation radiation techniques for both systemic controls and LCs, respectively, may result in breakthrough treatments for ESOS and osseous sarcomas in general. The authors declare no conflicts of interest.

Evaluating patients’ health-related quality of life (QOL) and toxicity following treatment for prostate cancer provides valuable information for patients and physicians. Various predictors for genitourinary (GU), gastrointestinal (GI), and sexual decline following treatment for prostate cancer have been reported. Pretreatment GI and GU symptoms, prostate volume, previous transurethral radical prostatectomy (TURP), androgen deprivation therapy (ADT), radiation dose, and radiation technique have all been shown to predict toxicity following radiation therapy.1,2 Obesity, patient age, and surgical technique have also been shown to influence toxicity following prostatectomy for patients with prostate cancer.3,4 Whether race independently influences health-related QOL and toxicity following treatment for prostate cancer is a subject of ongoing debate. Some studies have shown worse patient-reported health-related QOL among African American (AA) men following surgery and radiation, especially in the domain of urinary function.2,5,6 Conversely, other studies indicate that AA race predicts for better erectile function following external-beam radiation therapy.7,8

ebate. Some studies have shown worse patient-reported health-related QOL among African American (AA) men following surgery and radiation, especially in the domain of urinary function.2,5,6 Conversely, other studies indicate that AA race predicts for better erectile function following external-beam radiation therapy.7,8 Overall, studies comparing treatment outcomes between AA men and white men have focused on QOL following prostatectomy, brachytherapy, or photon radiotherapy.5,6,9–12 To date, no published series has compared health-related QOL or treatment-related toxicity of AA and white patients treated with proton-based radiation therapy. Proton therapy (PT) has been used for several years with encouraging results and an excellent side effect profile among prostate cancer survivors,13–16 but no reports of PT focus on outcomes for AA patients.17 The purpose of our study was to determine whether race influenced treatment response in terms of toxicity and health-related QOL following definitive PT.

al years with encouraging results and an excellent side effect profile among prostate cancer survivors,13–16 but no reports of PT focus on outcomes for AA patients.17 The purpose of our study was to determine whether race influenced treatment response in terms of toxicity and health-related QOL following definitive PT. MATERIALS AND METHODS This study was approved by our institution’s Institutional Review Board (IRB) and included men treated at our institution definitively for prostate cancer between 2006 and 2010. The charts of 1536 men were reviewed. Each patient was treated on an IRB-approved outcome tracking protocol and each may also have been enrolled on 1 of 3 prospective IRB-approved treatment protocols between August 2006 and January 2010. The 3 protocols included PR01 for low-risk prostate cancer, on which patients received 78 cobalt gray equivalent (CGE) to the prostate at 2 CGE per fraction; PR02 for intermediate-risk prostate cancer patients, a radiation dose-escalation trial on which patients received 78 to 82 CGE to the prostate and proximal seminal vesicles depending on normal-tissue constraints; and PR03 on which patients received 78 CGE to the prostate and seminal vesicles with concomitant weekly docetaxel (20 mg/m2) followed by 6 months of androgen deprivation.

n dose-escalation trial on which patients received 78 to 82 CGE to the prostate and proximal seminal vesicles depending on normal-tissue constraints; and PR03 on which patients received 78 CGE to the prostate and seminal vesicles with concomitant weekly docetaxel (20 mg/m2) followed by 6 months of androgen deprivation. All patients had a pathology-confirmed diagnosis based on biopsy of a minimum of 10 prostate zones as well as a bone scan, chest x-rays within 6 months of enrollment, computed tomography (CT) scans, magnetic resonance imaging (MRI) of the pelvis, and a prostate-specific antigen (PSA) test. Every patient received PT with or without ADT. The decision to receive ADT was based on individual physician and patient choice but most patients with National Comprehensive Cancer Network (NCCN) high-risk disease were encouraged to receive ADT. Ninety-two consecutively treated men who self-identified themselves as AA were the subject of the analysis. A comparative cohort was created by matching each AA patient to a white patient treated contemporaneously for prostate cancer at our institution with the same NCCN risk category and with a similar age, using age bins spanning 5 years.

ly treated men who self-identified themselves as AA were the subject of the analysis. A comparative cohort was created by matching each AA patient to a white patient treated contemporaneously for prostate cancer at our institution with the same NCCN risk category and with a similar age, using age bins spanning 5 years. Patient-reported QOL parameters were assessed before PT and at 6- to 12-month intervals using the following standard tools: the Expanded Prostate Cancer Index Composite (EPIC) and the International Prostate Symptom Score (IPSS). Physician-determined treatment toxicities using the Common Terminology Criteria for Adverse Events version 3.0 were recorded weekly throughout treatment and at 6-month intervals after completing treatment. PSA was assessed before treatment, at the end of treatment, and at 3-month intervals after completing treatment. Patient histories were extracted for prior treatment of urinary retentive and obstructive symptoms, prostatitis, and rectal bleeding as well as factors that might affect tolerance of radiation therapy, such as smoking history, anticoagulation, diabetes mellitus (DM), hypertension, blood disease, cardiovascular disease, and chronic obstructive pulmonary disease. Pretreatment TURP, use of α-blockers, and prostate volume were recorded for each patient. These factors were compared between the 2 cohorts of patients because of their impact on health-related QOL, toxicity, and overall survival for patients following PT.

diovascular disease, and chronic obstructive pulmonary disease. Pretreatment TURP, use of α-blockers, and prostate volume were recorded for each patient. These factors were compared between the 2 cohorts of patients because of their impact on health-related QOL, toxicity, and overall survival for patients following PT. Simulation, Planning, and Treatment The University of Florida Proton Therapy Institute simulation, planning, and treatment guidelines for prostate cancer have previously been published.16 In brief, all patients underwent CT simulation with fiducial markers in place. Thirty minutes before simulation, patients drank 15 ounces of water. Patients were simulated while supine and in a vac-locked body mold. Saline was instilled into the rectum or a rectal balloon was used to stabilize the prostate position.

16 In brief, all patients underwent CT simulation with fiducial markers in place. Thirty minutes before simulation, patients drank 15 ounces of water. Patients were simulated while supine and in a vac-locked body mold. Saline was instilled into the rectum or a rectal balloon was used to stabilize the prostate position. Immediately after CT simulation, an MRI scan was obtained and the CT and MRI images were fused. The prostate, seminal vesicles, penile bulb, bladder, rectum, bowel, and femoral heads were contoured. A planning target volume (PTV) was constructed from the prostate and/or seminal vesicles with margins of 4 mm in the anteroposterior and lateral directions, and 6 mm in the superior-inferior direction. Dosimetric specifications required that 95% of the PTV receive 100% of the prescribed dose and 100% of the PTV receive at least 95% of the prescribed dose. Patients were treated with double-scatter PT with right and left lateral (or slightly oblique) field arrangements with customized brass apertures and compensators. Image-guided treatment was performed by using orthogonal kilovolt imaging for fiducial localization. Depending on the protocol, patients were treated either with 2 CGE per fraction to a total dose of 76 to 82 CGE or at 2.5 CGE per fraction to a total dose of 70 to 72.5 CGE.

customized brass apertures and compensators. Image-guided treatment was performed by using orthogonal kilovolt imaging for fiducial localization. Depending on the protocol, patients were treated either with 2 CGE per fraction to a total dose of 76 to 82 CGE or at 2.5 CGE per fraction to a total dose of 70 to 72.5 CGE. Statistical Analysis All statistical analyses were performed with SAS and JMP software (SAS Institute, Cary, NC). For individual EPIC question endpoints, data were first regrouped as binary levels and Fisher exact test was used to test for ethnicity response differences. Summary scores were analyzed as continuous variables. Baseline summary score between ethnicities was assessed with Wilcoxon rank sum test. Univariate tests of each posttreatment timepoint were then assessed between ethnicity groups by constructing a regression model that also included baseline score as a controlling variable. Posttreatment summary scores were then analyzed using repeated-measures analysis of variance (ANOVA). Ethnicity was the main prognostic factor of interest, but the repeated-measures ANOVA was also set up as a multiple regression that controlled for pretreatment hormone and diabetes status as well as baseline score.

le. Posttreatment summary scores were then analyzed using repeated-measures analysis of variance (ANOVA). Ethnicity was the main prognostic factor of interest, but the repeated-measures ANOVA was also set up as a multiple regression that controlled for pretreatment hormone and diabetes status as well as baseline score. RESULTS Patient and Tumor Characteristics Characteristics of the AA patients and matched white patients are listed in Table 1. For both the groups, the median age at presentation was 65 years. The median time of follow-up was 2.1 years for the entire group. Specifically, it was 2.1 years for AA patients and 2.2 years for white patients. As expected, there was no difference between the groups in the percentage of patients presenting with NCCN-designated low-risk, intermediate-risk, or high-risk disease, which were 31%, 44%, and 25%, respectively, for both the groups. Despite matching for risk category, 32% of AAs presented with pretreatment PSAs of >10 compared with 20% for the matched white patients, a difference that approached statistical significance (P=0.0675). TABLE 1 Racial Differences in Demographic, Clinical, and Treatment Characteristics (n=184)

RESULTS Patient and Tumor Characteristics Characteristics of the AA patients and matched white patients are listed in Table 1. For both the groups, the median age at presentation was 65 years. The median time of follow-up was 2.1 years for the entire group. Specifically, it was 2.1 years for AA patients and 2.2 years for white patients. As expected, there was no difference between the groups in the percentage of patients presenting with NCCN-designated low-risk, intermediate-risk, or high-risk disease, which were 31%, 44%, and 25%, respectively, for both the groups. Despite matching for risk category, 32% of AAs presented with pretreatment PSAs of >10 compared with 20% for the matched white patients, a difference that approached statistical significance (P=0.0675). TABLE 1 Racial Differences in Demographic, Clinical, and Treatment Characteristics (n=184) As described in Table 2, AAs and white patients used α-blockers for urinary obstructive symptoms as well as phosphodiesterase inhibitors for erectile dysfunction, and had TURP for benign prostatic hypertrophy (BPH) at similar rates before receiving radiation therapy. White patients received 5-α reductase inhibitors more often for BPH than AA patients (10% vs. 3%; P=0.08), but the difference was not statistically significant. At presentation, rates of heart disease were similar between both the groups, but rates of DM were much higher among AAs. DM was present in 27% of AAs versus 10% for white patients (P<0.01). TABLE 2 Medication Use and Comorbidities (n=184)

As described in Table 2, AAs and white patients used α-blockers for urinary obstructive symptoms as well as phosphodiesterase inhibitors for erectile dysfunction, and had TURP for benign prostatic hypertrophy (BPH) at similar rates before receiving radiation therapy. White patients received 5-α reductase inhibitors more often for BPH than AA patients (10% vs. 3%; P=0.08), but the difference was not statistically significant. At presentation, rates of heart disease were similar between both the groups, but rates of DM were much higher among AAs. DM was present in 27% of AAs versus 10% for white patients (P<0.01). TABLE 2 Medication Use and Comorbidities (n=184) Treatment Characteristics All patients were treated with primary proton radiotherapy. The median dose for both the AA and the white cohort was 78 CGE. More AAs were treated with ADT (27% vs. 21%) compared with white patients, but the difference was not significant (P=0.38). In the intermediate-risk group, ADT was given to 5 of 40 patients (13%) AAs versus 2 of 40 (5%) white patients. For high-risk patients, ADT was given to 17 of 23 (74%) AAs versus 15 of 23 (65%) white patients. Neoadjuvant ADT was given to 15% of AAs versus 11% of white patients. Adjuvant ADT was given to 13% of AAs versus 12% of white patients. Concurrent ADT was given to 5.4% of patients in each group.

f 40 (5%) white patients. For high-risk patients, ADT was given to 17 of 23 (74%) AAs versus 15 of 23 (65%) white patients. Neoadjuvant ADT was given to 15% of AAs versus 11% of white patients. Adjuvant ADT was given to 13% of AAs versus 12% of white patients. Concurrent ADT was given to 5.4% of patients in each group. Race and Posttreatment QOL A total of 94%, 86%, 87%, and 72% of patients answered the EPIC-26 questionnaire at baseline, 6 months, 1 year, and 2 years. There was no difference between the percentages of AA and white patients who responded. Summary scores for urinary irritative and obstructive symptoms, bowel function, sexual function, and urinary incontinence are depicted in Figures 1A to D. The only >5-point decline from baseline in median score at 2 years following treatment was in urinary irritative/obstructive symptom among AAs, which declined from a median of 93.8 to 87.5. No statistically significant difference was observed between the 2 cohorts during the 2 years of follow-up for bowel summary, urinary irritative/obstructive, urinary incontinence, or sexual summary scores. When patients who did not receive ADT were analyzed separately, a difference was seen in the rate of erectile dysfunction, with lower rates among AAs, but the difference was not statistically significant.

ars of follow-up for bowel summary, urinary irritative/obstructive, urinary incontinence, or sexual summary scores. When patients who did not receive ADT were analyzed separately, a difference was seen in the rate of erectile dysfunction, with lower rates among AAs, but the difference was not statistically significant. FIGURE 1 Expanded Prostate Cancer Index Composite (EPIC) summary scores overtime for men treated with intensity-modulated radiotherapy or proton therapy for prostate cancer. Bar and whisker graphs at baseline and 6 months, 1 year, and 2 years after proton therapy or intensity-modulated radiotherapy for (A) urinary irritative/obstructive score; (B) bowel summary score; (C) sexual summary score; and (D) urinary incontinence score (no androgen deprivation therapy). The bottom whisker represents the cut-off for the score of the lowest 5%, the bottom bar represents the cut-off score for the lowest quartile, the dash represents the median score, the top of the bar represents the cut-off for the top quartile, and the top of the whisker represents the cut-off for the score of the top 5%. As Table 3 demonstrates, AA and white patients initially had minor differences in IPSS score after PT but after 2 years, patient IPSS scores did not differ significantly between the 2 cohorts. The percentage of patients requiring medications for urinary obstructive symptoms was similar between the groups. TABLE 3 Median Change in IPSS Score at 6-Month Intervals

As Table 3 demonstrates, AA and white patients initially had minor differences in IPSS score after PT but after 2 years, patient IPSS scores did not differ significantly between the 2 cohorts. The percentage of patients requiring medications for urinary obstructive symptoms was similar between the groups. TABLE 3 Median Change in IPSS Score at 6-Month Intervals Race and Posttreatment Adverse Effects By 2 years, 23% of AA patients had developed a late grade 2+ GI toxicity compared with 29% of whites, and the difference was not statistically significant (P=0.45). The majority of GI toxicities in the AA (89%; 16/18) and white (79%; 19/24) cohorts were rectal bleeding that required medications only. The median time to late grade 2+ toxicities was 11 months for AAs and 12 months among white patients. Importantly, only 2% of AAs required cautery for rectal bleeding compared with 4.3% of white patients. AAs had a higher absolute risk of late grade 3 GU toxicity (4.4% vs. 0%; P=0.12), which included urinary obstruction requiring a temporary catheter, hematuria, and radiation cystitis. Among AAs, the median time to grade 3 GU toxicity was 22 months. No patient receiving chemotherapy experienced a grade 3 GU toxicity. DISCUSSION This study assesses health-related QOL and treatment toxicity of AAs compared with white men treated for prostate cancer with definitive PT. This is the first study to attempt to compare outcomes for AA men and white men following PT.

Race and Posttreatment Adverse Effects By 2 years, 23% of AA patients had developed a late grade 2+ GI toxicity compared with 29% of whites, and the difference was not statistically significant (P=0.45). The majority of GI toxicities in the AA (89%; 16/18) and white (79%; 19/24) cohorts were rectal bleeding that required medications only. The median time to late grade 2+ toxicities was 11 months for AAs and 12 months among white patients. Importantly, only 2% of AAs required cautery for rectal bleeding compared with 4.3% of white patients. AAs had a higher absolute risk of late grade 3 GU toxicity (4.4% vs. 0%; P=0.12), which included urinary obstruction requiring a temporary catheter, hematuria, and radiation cystitis. Among AAs, the median time to grade 3 GU toxicity was 22 months. No patient receiving chemotherapy experienced a grade 3 GU toxicity. DISCUSSION This study assesses health-related QOL and treatment toxicity of AAs compared with white men treated for prostate cancer with definitive PT. This is the first study to attempt to compare outcomes for AA men and white men following PT. The value of PT in the management of prostate cancer has recently been questioned. In particular, results from a recent Surveillance, Epidemiology, and End Results and Medicare-linked report suggest that rectal toxicity is worse for patients treated with PT for prostate cancer compared with patients treated with intensity-modulated radiation therapy (IMRT).17 Our study was not specifically designed to counter this argument; however, we found overall low rates (<5%) of grade 3 GU toxicity and our patients experienced rectal toxicity rates that were similar to commonly reported rates after IMRT and 3D conformal radiation therapy in prospective trials.15,18,19 We also found that race did not affect the likelihood of toxicity and had no effect on QOL following PT. Specifically, our study demonstrates no differences in EPIC QOL 2 years after treatment between the AA and the white cohort. Urinary irritative/obstruction, urinary incontinence, and bowel function were similar between both the groups. Sexual function was not statistically different between the groups, despite higher rates of diabetes and more ADT use among AA patients. Both factors are known to contribute to the development of erectile dysfunction following radiation therapy.2,7,13

continence, and bowel function were similar between both the groups. Sexual function was not statistically different between the groups, despite higher rates of diabetes and more ADT use among AA patients. Both factors are known to contribute to the development of erectile dysfunction following radiation therapy.2,7,13 AAs had a higher incidence of late GU toxicity than white patients (4.4% vs. 0%) but the difference was not statistically significant (P=0.12). AAs had similar prostate volumes, IPSS scores, and use of medications for BPH before treatment. The number of patients on medications for urinary symptoms after treatment was also similar between the 2 groups, as were radiation doses and techniques. The small difference seen in GU toxicity may be related to the higher use of ADT in AAs compared with white patients (27% vs. 21%, P=0.38). Others have found that ADT may be a risk factor for the development of urinary obstructive symptoms following radiation therapy.7Alternatively, the small difference in GU toxicity may point to racial differences in mucosal sensitivity of the urethra or bladder to high-dose radiation. More likely, the difference is a chance outcome, considering none of the white patients developed grade 3 GU toxicities. We know from other studies at our institution that the rate of Common Terminology Criteria for Adverse Events version 3.0 grade 3 GU toxicity among the overall population of white patients is approximately 5% following PT, so the white cohort in this study may not have been entirely representative of the entire white population of patients treated with PT at our institution.20

of Common Terminology Criteria for Adverse Events version 3.0 grade 3 GU toxicity among the overall population of white patients is approximately 5% following PT, so the white cohort in this study may not have been entirely representative of the entire white population of patients treated with PT at our institution.20 Previous analyses have reported mixed results when exploring differences in QOL and/or toxicity between AAs compared with whites following treatment for prostate cancer. Shah and colleagues found that AA men did not have worse physician-reported toxicity or QOL following brachytherapy or external-beam radiotherapy. AA men were actually less likely to develop urinary incontinence following external-beam radiotherapy compared with white men. No differences were noted between groups in the rates of urinary retention, frequency, rectal pain, or bleeding.21 Rice and colleagues analyzed health-related QOL for AAs and whites following prostatectomy and/or external-beam radiotherapy for prostate cancer. The patients were treated at an equal-access military multidisciplinary prostate cancer clinic. Using the EPIC questionnaire to assess health-related QOL, AAs had a greater risk for a decline in urinary function following therapy than whites regardless of treatment choice. The difference persisted on multivariate analysis.6

atients were treated at an equal-access military multidisciplinary prostate cancer clinic. Using the EPIC questionnaire to assess health-related QOL, AAs had a greater risk for a decline in urinary function following therapy than whites regardless of treatment choice. The difference persisted on multivariate analysis.6 A large prospective trial reported by Sanda et al2 in 2008 on a total of over 1200 patients included 114 AA patients treated with external-beam radiation, brachytherapy, or prostatectomy. Health-related QOL was evaluated for patients treated with each modality. Urinary incontinence following prostatectomy was significantly worse among AAs than white patients. Despite similar care settings, AAs were also less likely to achieve satisfaction with the overall outcome in terms of health-related QOL.

tectomy. Health-related QOL was evaluated for patients treated with each modality. Urinary incontinence following prostatectomy was significantly worse among AAs than white patients. Despite similar care settings, AAs were also less likely to achieve satisfaction with the overall outcome in terms of health-related QOL. Unlike several other studies, our study did not show a difference in health-related QOL or toxicity between AA and white patients following definitive treatment for prostate cancer. The potential reasons include the possibility that AAs in our study may not be biologically, economically, or culturally similar to AAs treated at other centers around the United States. Our patient sample could have presented with differences in pretreatment obesity rates, comorbidities, prostate size, or a combination of those differences, which could affect the likelihood of toxicity or changes in QOL following radiation therapy. Conversely, the reason could relate to the radiation technique used for treatment. PT has been shown to deliver more conformal radiation therapy for localized prostate cancer than 3D conformal radiation or IMRT.22 It is possible that because PT delivers less radiation to the rectum and bladder it also minimizes the chance of racial disparities in QOL and toxicity.

iation technique used for treatment. PT has been shown to deliver more conformal radiation therapy for localized prostate cancer than 3D conformal radiation or IMRT.22 It is possible that because PT delivers less radiation to the rectum and bladder it also minimizes the chance of racial disparities in QOL and toxicity. The limitations of our study include, first, that it was a matched-paired analysis instead of a review of all patients treated with PT at our institution. Although all AA patients treated for prostate cancer at our institution were included, only a cohort of matched white patients was included in the analysis. Second, this is a single-institution study and the men who present to our institution may not represent most AAs and whites with respect to socioeconomic factors or disease characteristics. Third, defining QOL in terms of sexual, bowel, and urinary function is subjective. Although no difference was found between AAs and white patients on the EPIC scale, because median EPIC scores are reported and analyzed, subtle but relevant differences between the 2 groups may be obscured. CONCLUSIONS When matched, on the basis of age and NCCN risk category, AAs and whites did not demonstrate a significant difference in health-related QOL or toxicity following PT, although a nonsignificantly higher incidence of late GU toxicity following PT was observed among AA men. B.S.H. received an honorarium from Procure for a lecture on proton therapy techniques for lung cancer. The other authors declare no conflicts of interest.

Perihilar cholangiocarcinoma is a rare malignancy that is uniformly fatal if left untreated. At Mayo Clinic, a clinical regimen with strict patient selection criteria was developed in 1993 for unresectable hilar cholangiocarcinoma.1,2 The regimen combines neoadjuvant chemoradiation therapy, operative staging, and orthotopic liver transplantation (OLT).3 Neoadjuvant therapy includes external-beam radiation therapy (EBRT), intrabiliary duct brachytherapy,4 and postbrachytherapy chemotherapy (initially fluorouracil and later oral capecitabine). Five-year survival is 54% for all patients who begin the treatment program and 73% for those able to complete the regimen with OLT.1 Approximately 50% of patients have no detectable residual cholangiocarcinoma in their explanted livers.1,2 Portal vein encasement is the only pretreatment prognostic factor that predicts for residual disease in explanted livers.5 Not all patients who begin the regimen complete all the intended therapies. Adverse findings at the staging operation, death, and other factors preclude patients from undergoing OLT. This study was performed to report the outcome and characteristics of patients who began treatment with curative intent on the transplant regimen but subsequently became ineligible for OLT. The outcome of this group of patients who underwent neoadjuvant therapies has not been reported previously.

s from undergoing OLT. This study was performed to report the outcome and characteristics of patients who began treatment with curative intent on the transplant regimen but subsequently became ineligible for OLT. The outcome of this group of patients who underwent neoadjuvant therapies has not been reported previously. METHODS AND MATERIALS The Mayo Clinic Institutional Review Board approved this study. A prospective database has been maintained for the cholangiocarcinoma transplant regimen since its inception in January 1993. Medical records from local and outside hospitals were reviewed. Criteria for enrollment in the transplant regimen have previously been described in detail.1 Briefly, patients with extrahepatic cholangiocarcinoma not amenable to conventional surgical resection and no lymph node metastases were considered as candidates for OLT. Both tissue diagnosis and clinical criteria were used for diagnosing hilar cholangiocarcinoma at our institution. The clinical criteria required the presence of a malignant-appearing stricture on percutaneous or endoscopic retrograde cholangiopancreatography, combined with 1 of the 4 following criteria: positive findings on brushing or biopsy; polysomy on fluorescence in situ hybridization testing; cancer antigen (CA) 19-9 level higher than 100 U/mL in the absence of cholangitis; or mass on axial imaging at the level of the stricture.6 Clinicopathologic factors such as age, sex, confirmed pathology prior to treatment, the presence of primary sclerosing cholangitis (PSC) or inflammatory bowel disease, high CA 19-9 levels, and the presence of a visible mass on cross-sectional imaging were examined for potential correlation with survival.

he stricture.6 Clinicopathologic factors such as age, sex, confirmed pathology prior to treatment, the presence of primary sclerosing cholangitis (PSC) or inflammatory bowel disease, high CA 19-9 levels, and the presence of a visible mass on cross-sectional imaging were examined for potential correlation with survival. The preoperative chemoradiation regimen was previously described.7 For EBRT, 45 Gy at 1.5 Gy twice daily using 3-dimensional conformal techniques was typically prescribed, with concurrent fluorouracil, 225 mg/m2 per day administered by continuous venous infusion. The irradiated volume included the primary tumor and regional (periductal and celiac) lymph nodes. Intrabiliary catheter-guided brachytherapy with iridium-192 followed, for which the radiation dose was prescribed to a 1 cm radius. The catheter placement was directed by endoscopic retrograde cholangiopancreatography. Previously, patients received low-dose rate brachytherapy, typically 20 Gy at a 1 cm radius over approximately 24 hours and, more recently, by high-dose rate brachytherapy, given as 16 Gy in 4 fractions at 1 cm over 2 days. After brachytherapy, patients typically received capecitabine, 2000 mg/m2 per day, divided twice daily, for 2 of every 3 weeks, as maintenance chemotherapy until OLT.

0 Gy at a 1 cm radius over approximately 24 hours and, more recently, by high-dose rate brachytherapy, given as 16 Gy in 4 fractions at 1 cm over 2 days. After brachytherapy, patients typically received capecitabine, 2000 mg/m2 per day, divided twice daily, for 2 of every 3 weeks, as maintenance chemotherapy until OLT. Before OLT, a staging operation was performed that included abdominal exploration for lymph nodes or nodules suspicious for tumor and also regular biopsies of perihilar lymph nodes. Before 2002, the laparotomy was performed as the time neared for OLT. Between 2002 and 2009, staging was carried out immediately after brachytherapy per an agreement with the United Network for Organ Sharing Region 7 Regional Review Board. Since 2010, staging has been carried out close to the time of OLT or 1 day before living donor transplantation. After 2006, most staging operations were performed using hand-assisted laparoscopy with a smaller subcostal incision.

per an agreement with the United Network for Organ Sharing Region 7 Regional Review Board. Since 2010, staging has been carried out close to the time of OLT or 1 day before living donor transplantation. After 2006, most staging operations were performed using hand-assisted laparoscopy with a smaller subcostal incision. The time at which patients became ineligible for OLT, that is, the timing of fallout, in relation to the staging operation was investigated. Survival since diagnosis was calculated according to the Kaplan-Meier method.8 Log-rank tests were used to determine whether individual variables were associated with survival. Cox proportional hazards models were used to obtain multivariate hazard ratios and score P-values. The covariates tested in the multivariate model contained all of the clinicopathologic factors mentioned above (including type of fallout) and the completion status of the individual neoadjuvant treatments by modality. All tests were 2-sided with 5% type I error rates. RESULTS Patient and Tumor Characteristics Since January 1993, 215 patients with unresectable cholangiocarcinoma began neoadjuvant therapy with the intent to proceed with operative staging, then OLT. Adverse findings at the staging operation, death, and other factors precluded 63 patients (29%) from OLT, which is the group that forms the basis for this report.

Since January 1993, 215 patients with unresectable cholangiocarcinoma began neoadjuvant therapy with the intent to proceed with operative staging, then OLT. Adverse findings at the staging operation, death, and other factors precluded 63 patients (29%) from OLT, which is the group that forms the basis for this report. By October 2012, 56 (89%) of the 63 patients unable to undergo an OLT had died. Table 1 lists the patient and tumor characteristics. The mean age at diagnosis was 50.7 years. Thirty-eight patients (60%) had a tissue diagnosis, and clinical criteria provided the diagnosis in 25 (40%). The median preoperative CA 19-9 for the 63 patients was 277.0 U/mL, with a wide range of 1.0 to 13,200 U/mL. Forty-two patients (67%) had a measurable mass visualized at the hilar region by magnetic resonance imaging (MRI) or computed tomography (CT); 33% of patients’ cholangiocarcinomas could not be visualized by either CT or MRI. Thirteen patients (21%) had masses that could be visualized only by MRI. Twenty-four patients (39%) had ulcerative colitis (UC), 33 (52%) had PSC, and 22 (35%) had both. TABLE 1 Patient and Tumor Characteristics (N=63)

By October 2012, 56 (89%) of the 63 patients unable to undergo an OLT had died. Table 1 lists the patient and tumor characteristics. The mean age at diagnosis was 50.7 years. Thirty-eight patients (60%) had a tissue diagnosis, and clinical criteria provided the diagnosis in 25 (40%). The median preoperative CA 19-9 for the 63 patients was 277.0 U/mL, with a wide range of 1.0 to 13,200 U/mL. Forty-two patients (67%) had a measurable mass visualized at the hilar region by magnetic resonance imaging (MRI) or computed tomography (CT); 33% of patients’ cholangiocarcinomas could not be visualized by either CT or MRI. Thirteen patients (21%) had masses that could be visualized only by MRI. Twenty-four patients (39%) had ulcerative colitis (UC), 33 (52%) had PSC, and 22 (35%) had both. TABLE 1 Patient and Tumor Characteristics (N=63) Treatment Characteristics Treatment characteristics for all 63 patients are summarized in Table 2. Sixty-one patients (97%) completed neoadjuvant chemoradiation therapy with EBRT (45 Gy twice daily in 30 fractions); 60 (95%) received brachytherapy or an external-beam boost (4 of 60 patients). Two patients died, while receiving EBRT, of biliary sepsis and extensive abdominal carcinomatosis. Fifty-nine patients (94%) received infusion fluorouracil. Twenty-two patients (35%) became transplant-ineligible before surgical staging, 38 (60%) at the staging operation, and 3 (5%) after staging. Before staging, disease progression (15), failure to thrive (2), other medical events (2, sepsis and renal failure), and death (3, myocardial infarction and pulmonary embolism) disqualified patients for OLT. For the 15 patients who had disease progression before surgical staging, the reasons were liver metastases (4), malignant ascites (3), other distant metastases (3), local tumor progression (1), percutaneous transhepatic cholangiography site recurrence (1), celiac lymph node metastasis (1), and others (2). Except for the patients who dropped out before the planned staging operation (prestaging fallout), 41 patients (65%) underwent the planned staging procedure, which included thorough intra-abdominal inspection, liver palpation, assessment of local disease extent, and regular sampling of hepatic arterial and pericholedochal lymph nodes. Findings at staging included positive lymph nodes (19), peritoneal metastases (14), and local tumor extension (11). These patients became ineligible for OLT as a result of adverse findings during the staging operation. Intrahepatic metastases developed in 2 patients after the staging operation, and 1 patient died of a bleeding ulcer.

ging included positive lymph nodes (19), peritoneal metastases (14), and local tumor extension (11). These patients became ineligible for OLT as a result of adverse findings during the staging operation. Intrahepatic metastases developed in 2 patients after the staging operation, and 1 patient died of a bleeding ulcer. TABLE 2 Outcome and Treatment Characteristics Among Patients Who Became Ineligible for Liver Transplant (N=63) Survival Analysis In this group of 63 patients, the median overall survival was 12.3 months (95% confidence interval [CI], 10.7-13.5 mo) from the date of diagnosis (Fig. 1). Survival was 17% at 18 months and 7% at 24 months. Median survival after fallout was 6.8 months (95% CI, 5.1-8.5 mo). Median survival after the staging operation was 6.0 months (95% CI, 3.8-9.5 mo). Two patients lived for 3.7 and 8.7 years, before dying of cancer and liver failure caused by persistent biliary stricture, either because of persistent cancer or scarring, at the site of the original cancer (autopsy not performed), respectively. From the date of diagnosis, the median time to fallout was 5.5 months (95% CI, 4.6-6.4 mo). The majority of patients fell out of the clinical transplant regimen within 1 year (Fig. 2). FIGURE 1 The Kaplan-Meier curve of overall survival since the date of diagnosis of 63 patients who became ineligible for liver transplant. FIGURE 2 The Kaplan-Meier curve of time from diagnosis to fallout of 63 patients who became ineligible for liver transplant.

Survival Analysis In this group of 63 patients, the median overall survival was 12.3 months (95% confidence interval [CI], 10.7-13.5 mo) from the date of diagnosis (Fig. 1). Survival was 17% at 18 months and 7% at 24 months. Median survival after fallout was 6.8 months (95% CI, 5.1-8.5 mo). Median survival after the staging operation was 6.0 months (95% CI, 3.8-9.5 mo). Two patients lived for 3.7 and 8.7 years, before dying of cancer and liver failure caused by persistent biliary stricture, either because of persistent cancer or scarring, at the site of the original cancer (autopsy not performed), respectively. From the date of diagnosis, the median time to fallout was 5.5 months (95% CI, 4.6-6.4 mo). The majority of patients fell out of the clinical transplant regimen within 1 year (Fig. 2). FIGURE 1 The Kaplan-Meier curve of overall survival since the date of diagnosis of 63 patients who became ineligible for liver transplant. FIGURE 2 The Kaplan-Meier curve of time from diagnosis to fallout of 63 patients who became ineligible for liver transplant. Exploratory univariate analyses of factors potentially affecting overall survival are summarized in Table 3. Age, sex, tissue diagnosis, mass visualization on CT or MRI, the presence of inflammatory bowel disease or PSC, completion of chemotherapy, EBRT, or brachytherapy, and types of fallout (prior to or during surgical staging) were analyzed. Only the completion of EBRT was statistically significant for longer median survival on univariate and multivariate analyses. Patients who fell out as a result of findings at surgical staging lived slightly longer than prestaging fallout patients (12.1 vs. 10.8 mo; P=0.14). Additional univariate analysis showed that time from diagnosis to fallout did correlate with overall survival (P=0.04) but not tissue diagnosis, CA 19-9 level, EBRT or brachytherapy dose, age, type of fallout (prestaging or staging), or UC or PSC status (Fig. 3).

prestaging fallout patients (12.1 vs. 10.8 mo; P=0.14). Additional univariate analysis showed that time from diagnosis to fallout did correlate with overall survival (P=0.04) but not tissue diagnosis, CA 19-9 level, EBRT or brachytherapy dose, age, type of fallout (prestaging or staging), or UC or PSC status (Fig. 3). TABLE 3 Univariate Results for Overall Survival Since Diagnosis FIGURE 3 Covariate plot for overall survival versus time from diagnosis to fallout, in months. Univariate analysis showed time from diagnosis to fallout correlated with overall survival (P=0.04) but not tissue diagnosis, cancer antigen 19-9 level, external-beam radiation therapy or brachytherapy dose, age, blood type, ulcerative colitis or primary sclerosing cholangitis status, or type of fallout (prestaging or staging).

e analysis showed time from diagnosis to fallout correlated with overall survival (P=0.04) but not tissue diagnosis, cancer antigen 19-9 level, external-beam radiation therapy or brachytherapy dose, age, blood type, ulcerative colitis or primary sclerosing cholangitis status, or type of fallout (prestaging or staging). DISCUSSION At present, OLT is the only potentially curative treatment available for patients with hilar cholangiocarcinoma, which is deemed unresectable by conventional surgery. In a group of 48 patients with unresectable cholangiocarcinoma treated with a combination of fluorouracil-based chemotherapy, EBRT, and intraluminal brachytherapy, the 2-year survival rate was 18%.9 In another retrospective study,10 52 patients with unresectable, locally advanced cholangiocarcinoma were treated with definitive chemoradiation therapy. The median survival rate was 10 months. The combination of cisplatin and gemcitabine, evaluated in a randomized phase 3 trial, improved survival for patients with locally advanced or metastatic cholangiocarcinoma,11 although the treatment was not curative. In a surgical series of 373 patients without transplant, the 1- and 5-year survival rates were 33% and 4%, respectively.12 Curative resection was achieved in 36.2% of the patients. Early-stage liver resection and use of adjuvant chemotherapy were favorable characteristics for longer overall survival.12

as not curative. In a surgical series of 373 patients without transplant, the 1- and 5-year survival rates were 33% and 4%, respectively.12 Curative resection was achieved in 36.2% of the patients. Early-stage liver resection and use of adjuvant chemotherapy were favorable characteristics for longer overall survival.12 The patients who are eligible for the liver transplant regimen at our institution are carefully selected.1 The patients have either locally advanced cholangiocarcinoma that is deemed unresectable by a hepatobiliary surgeon or cholangiocarcinoma arising in the background of PSC. At diagnosis, absence of intrahepatic or extrahepatic metastases must be confirmed by imaging, and the patient must be medically fit for both neoadjuvant chemoradiation therapy and subsequent OLT. The surgical staging procedure is mandatory before OLT. Careful selection of patients with cholangiocarcinoma for the liver transplant regimen is critical for the potential chance of long-term cure.

nfirmed by imaging, and the patient must be medically fit for both neoadjuvant chemoradiation therapy and subsequent OLT. The surgical staging procedure is mandatory before OLT. Careful selection of patients with cholangiocarcinoma for the liver transplant regimen is critical for the potential chance of long-term cure. Neoadjuvant treatments, including EBRT, brachytherapy, and chemotherapy, are important components of the transplant regimen, as results are poor with transplant alone.13,14 In the University of Cincinnati experience,13 the 5-year survival was only 23% with transplant alone, and 51% of patients had tumor recurrence after transplant. The majority (84%) of the recurrences was within 2 years, and 76% of the deaths occurred within 6 months of transplant. The Spanish group used OLT alone,14 which similarly yielded a limited 5-year survival rate of 30%. Tumor recurred in 53% of the patients with hilar cholangiocarcinoma, which was the main reason for patient death. In 10 patients who underwent OLT and were found to have incidental cholangiocarcinoma in their explants, the median overall survival was 2.5 years.15 None of them received neoadjuvant chemotherapy or radiotherapy.

ecurred in 53% of the patients with hilar cholangiocarcinoma, which was the main reason for patient death. In 10 patients who underwent OLT and were found to have incidental cholangiocarcinoma in their explants, the median overall survival was 2.5 years.15 None of them received neoadjuvant chemotherapy or radiotherapy. In our study, survival was poor among patients who were initially eligible for the transplant regimen and began neoadjuvant therapy but later became ineligible for OLT. Although male patients had significantly better survival in this group (P=0.03, Table 3), median survival was improved by only 0.9 months. The reason for this very modest improvement in outcome is unknown; it is possible that it is a chance observation in the context of an exploratory subset analysis. Most commonly, the patients became ineligible for OLT as a result of adverse findings at surgical staging. This highlights the critical importance of staging laparotomy for detection of patients unlikely to benefit from transplant. It seems likely that patients found to be unsuitable for transplant following staging laparotomy have either more rapidly progressive disease or are in a later phase in the natural history of their disease, compared with patients who go on to transplant. In this group of transplant-ineligible patients, the median overall survival was 12.3 months, with a median survival after fallout of only 6.8 months. Two patients were long-term survivors despite adverse findings at the staging operation (one had positive pericholedochal lymph nodes and omental metastases, and the other had positive hepatic artery lymph nodes). Patients who fell out as a result of adverse findings at operative staging lived a median period of 12.1 months, which was comparable or slightly better than the survival of patients with locally advanced or metastatic cholangiocarcinoma documented in prospective trials.11,16,17 This is an important observation, as the use of neoadjuvant therapy in this group of patients who were destined to fall out from the OLT regimen did not appear to shorten their expected survival. Palliative treatment after fallout was at the discretion of the treating physician. Until recently, there has been no established standard of care in this regard.

he use of neoadjuvant therapy in this group of patients who were destined to fall out from the OLT regimen did not appear to shorten their expected survival. Palliative treatment after fallout was at the discretion of the treating physician. Until recently, there has been no established standard of care in this regard. In 2010, a phase 3 clinical trial showed that a combination of gemcitabine and cisplatin improves survival among selected patients with incurable bile duct cancer.11 This regimen should be strongly considered for patients with incurable bile duct cancer as it is the only regimen supported by level 1 evidence.

he use of neoadjuvant therapy in this group of patients who were destined to fall out from the OLT regimen did not appear to shorten their expected survival. Palliative treatment after fallout was at the discretion of the treating physician. Until recently, there has been no established standard of care in this regard. In 2010, a phase 3 clinical trial showed that a combination of gemcitabine and cisplatin improves survival among selected patients with incurable bile duct cancer.11 This regimen should be strongly considered for patients with incurable bile duct cancer as it is the only regimen supported by level 1 evidence. At the time of enrollment to the clinical OLT regimen, is there any prognosticator that may predict which patients will become ineligible for liver transplant? Since 2003, we have used endoscopic ultrasound with aspiration of regional lymph nodes prior to neoadjuvant therapy, which has reduced the positive staging exploration rate to 15%. In addition, our recent experience showed that pretreatment pathologic confirmation of cholangiocarcinoma is associated with a higher rate of positive findings at the staging operation and transplant ineligibility; however, for patients who could successfully complete transplant, the recurrence rate was not different.6 In our group of transplant-fallout patients with or without tissue diagnosis, no difference was found in overall survival (P=0.90). For all our patients undergoing the transplant regimen, older age, high CA 19-9 level, residual tumor >2 cm in the explant, and tumor grade predicted a higher chance of recurrence.18 Advanced stage of disease was an independent poor prognosticator for both intrahepatic and extrahepatic cholangiocarcinoma.19

l (P=0.90). For all our patients undergoing the transplant regimen, older age, high CA 19-9 level, residual tumor >2 cm in the explant, and tumor grade predicted a higher chance of recurrence.18 Advanced stage of disease was an independent poor prognosticator for both intrahepatic and extrahepatic cholangiocarcinoma.19 Surgical staging remains a critical part of our clinical transplant regimen. Eleven (92%) of 12 patients with local tumor progression were diagnosed at surgical staging, and 38 patients (60%) who fell out from the transplant regimen were due to adverse findings discovered at the staging operation. The finding at operative staging of nodal involvement was the most common reason for exclusion from OLT after surgical staging, occurring in 19 (50%) of 38 patients.

osed at surgical staging, and 38 patients (60%) who fell out from the transplant regimen were due to adverse findings discovered at the staging operation. The finding at operative staging of nodal involvement was the most common reason for exclusion from OLT after surgical staging, occurring in 19 (50%) of 38 patients. CONCLUSIONS In highly selected patients with cholangiocarcinoma initially suitable for liver transplant, the mortality rate was high, as expected for patients who subsequently became ineligible for transplant. The most common reason for patient fallout was adverse findings at the staging operation, which highlights the importance of the surgical staging before liver transplant to optimize the allocation of limited organ resources to those who would most likely benefit from this combined-modality approach, as well as the need to improve the efficacy of neoadjuvant therapy. The survival for patients who fell out prior to OLT was comparable to other patients with locally advanced and metastatic cholangiocarcinoma treated with best nontransplant-based therapies. As neoadjuvant therapy prior to transplant did not appear to hurt patients who were destined to fall out at operative staging, we should consider being more inclusive in choosing patients (ie, less selective) for the Mayo Clinic transplant regimen in the future. Portions of this work were presented in abstract form at the 54th annual meeting of the American Society for Therapeutic Radiology and Oncology, Boston, MA, October 28 to 31, 2012. The authors declare no conflicts of interest.

Non–small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases in the United States and poses a significant clinical challenge, as a majority of patients present with advanced-stage disease at diagnosis.1 Although first-line platinum-based chemotherapy has provided modest improvements in overall survival (OS) and progression-free survival (PFS) relative to other regimens,2 the prognosis for patients with advanced NSCLC remains poor, with 1-year survival rates of 30% to 40%.3,4 Older patients are an important and sizeable subgroup within the NSCLC population; the median age at diagnosis is estimated to be 70 years.1,5,6 Although elderly patients are less likely to be eligible to participate in clinical trials, they may experience similar outcomes as younger patients when enrolled, particularly when treatment is chosen based on characteristics other than age.7 Overexpression of vascular endothelial growth factor (VEGF-A), a key regulator of angiogenesis, occurs frequently in lung carcinomas.8–13 In the phase III Eastern Cooperative Oncology Group (ECOG) 4599 (E4599) study, the addition of bevacizumab, a humanized monoclonal antibody against VEGF-A, to paclitaxel–carboplatin (PC) significantly prolonged OS and PFS compared with PC alone in patients with NSCLC.14

enesis, occurs frequently in lung carcinomas.8–13 In the phase III Eastern Cooperative Oncology Group (ECOG) 4599 (E4599) study, the addition of bevacizumab, a humanized monoclonal antibody against VEGF-A, to paclitaxel–carboplatin (PC) significantly prolonged OS and PFS compared with PC alone in patients with NSCLC.14 Controversy exists, however, as to whether elderly patients with NSCLC benefit from bevacizumab therapy to the same extent as younger patients. A post hoc analysis of study participants in E4599 found that patients 70 years or above who were treated with PC+bevacizumab had improved PFS, but not OS, compared with patients treated with PC alone.15 In addition, a significantly increased incidence of grade 3 to 5 adverse events (AEs) was observed in patients in the PC+bevacizumab arm (87% vs. 61%, P<0.001). A retrospective analysis of the Surveillance, Epidemiology and End Results registry also found no improvement in survival for Medicare patients aged 65 years and above who received PC+bevacizumab versus PC alone for advanced NSCLC.16

vents (AEs) was observed in patients in the PC+bevacizumab arm (87% vs. 61%, P<0.001). A retrospective analysis of the Surveillance, Epidemiology and End Results registry also found no improvement in survival for Medicare patients aged 65 years and above who received PC+bevacizumab versus PC alone for advanced NSCLC.16 In contrast, other recent analyses have supported the benefit of bevacizumab therapy in elderly patients with stage IIIB or IV NSCLC. The phase III AVAiL study17 documented improved PFS for patients aged 65 years or above who received cisplatin–gemcitabine+bevacizumab 7.5 mg/kg versus cisplatin–gemcitabine alone, without an increase in the overall rate of grade ≥3 toxicities.18 The phase IV SAiL and ARIES observational studies documented similar rates of OS, PFS, and overall AEs among older and younger patient subsets treated with bevacizumab+chemotherapy, with the exception of lower survival rates in patients aged 80 years or above versus those below 80 years of age.19,20 To further examine the relationship between age and the efficacy and safety of bevacizumab therapy in patients with advanced NSCLC, we conducted a pooled analysis of patients receiving PC+bevacizumab in the E4599 and PointBreak trials.14,20

In contrast, other recent analyses have supported the benefit of bevacizumab therapy in elderly patients with stage IIIB or IV NSCLC. The phase III AVAiL study17 documented improved PFS for patients aged 65 years or above who received cisplatin–gemcitabine+bevacizumab 7.5 mg/kg versus cisplatin–gemcitabine alone, without an increase in the overall rate of grade ≥3 toxicities.18 The phase IV SAiL and ARIES observational studies documented similar rates of OS, PFS, and overall AEs among older and younger patient subsets treated with bevacizumab+chemotherapy, with the exception of lower survival rates in patients aged 80 years or above versus those below 80 years of age.19,20 To further examine the relationship between age and the efficacy and safety of bevacizumab therapy in patients with advanced NSCLC, we conducted a pooled analysis of patients receiving PC+bevacizumab in the E4599 and PointBreak trials.14,20 METHODS Data Sources, Patients, and Treatment This analysis was conducted using pooled individual patient data from the first-line, randomized, phase III E4599, and PointBreak studies. Information on the study designs and methodologies have been reported previously.14,20 Briefly, the E4599 trial (NCT00021060) randomized 878 patients with recurrent or advanced NSCLC to PC+bevacizumab or PC alone, with enrollment occurring between 2001 and 2004.14 In PointBreak (NCT00762034), 939 patients with stage IIIB or IV NSCLC were randomized to PC+bevacizumab or pemetrexed–carboplatin+bevacizumab from 2008 to 2012.20 The primary endpoint in both studies was OS.

th recurrent or advanced NSCLC to PC+bevacizumab or PC alone, with enrollment occurring between 2001 and 2004.14 In PointBreak (NCT00762034), 939 patients with stage IIIB or IV NSCLC were randomized to PC+bevacizumab or pemetrexed–carboplatin+bevacizumab from 2008 to 2012.20 The primary endpoint in both studies was OS. Both trials employed similar treatment protocols and eligibility criteria; therefore, pooling the data for bevacizumab-treated patients across these 2 trials appeared appropriate. Two notable differences existed: patients with stable brain metastases were eligible for inclusion in PointBreak, whereas patients with brain metastases were excluded from E4599; in addition, induction therapy consisted of 4 cycles of PC+bevacizumab in PointBreak and 6 cycles in E4599. All patients provided signed informed consent to participate in each trial. Statistical Analyses Patient-level data were pooled from the PC+bevacizumab arms of the E4599 and PointBreak studies and compared with patients in the PC arm of the E4599 study. Analyses were based on data cutoff dates for E4599 of December 30, 2005, and for PointBreak of April 3, 2012. Patients were analyzed according to the following age subgroups: below 65 years, 65 to 74 years, 70 to 74 years, below 75 years, and 75 years or above. Age was measured continuously in days. In PointBreak, age subgroup analyses were prespecified, whereas age-based analyses were retrospective in E4599.14,20

ril 3, 2012. Patients were analyzed according to the following age subgroups: below 65 years, 65 to 74 years, 70 to 74 years, below 75 years, and 75 years or above. Age was measured continuously in days. In PointBreak, age subgroup analyses were prespecified, whereas age-based analyses were retrospective in E4599.14,20 The primary outcome of the analysis was OS (defined as the interval from randomization to death from any cause); secondary outcomes included PFS (defined as the interval from randomization to the earlier of progression or death from any cause), postprogression OS (defined as the time from first disease progression to death from any cause), best overall response rate (ORR), and toxicity. For time-to-event analyses, patients who had not experienced death or progression were censored at the most recent date they were known to be event-free. Responses for patients with measurable disease were assessed according to Response Evaluation Criteria in Solid Tumors, version 1.0.21 AEs were categorized using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 2 (E4599) or version 3 (PointBreak).

e they were known to be event-free. Responses for patients with measurable disease were assessed according to Response Evaluation Criteria in Solid Tumors, version 1.0.21 AEs were categorized using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 2 (E4599) or version 3 (PointBreak). OS, PFS, and postprogression OS were calculated using Kaplan-Meier methods. An adjusted Cox proportional hazards model was used to estimate hazard ratios (HRs) and confidence intervals (CIs) for survival outcomes in the pooled PC+bevacizumab population from both trials compared with the PC-alone arm in E4599, adjusting for sex, race, histology, disease stage, and ECOG performance status. The Fisher exact tests were used to compare ORR and the incidence of AEs between groups. Statistical analyses were performed using SAS 9.2 software (SAS Institute Inc., Cary, NC), and a P-value of <0.05 was considered statistically significant. The primary analysis compared clinical outcomes with PC+bevacizumab to PC alone within age subgroups using pooled data from E4599 and PointBreak. Because of differences in event reporting and data availability between the 2 studies, analyses of treatment exposure, protocol deviations, and postprogression OS were conducted only for patients enrolled in E4599, as pooling these data was not possible. AEs were reported separately for each study.

4599 and PointBreak. Because of differences in event reporting and data availability between the 2 studies, analyses of treatment exposure, protocol deviations, and postprogression OS were conducted only for patients enrolled in E4599, as pooling these data was not possible. AEs were reported separately for each study. RESULTS Patient Characteristics A total of 434 and 467 patients were randomized to PC+bevacizumab in the E4599 and PointBreak trials, respectively. In the pooled PC+bevacizumab population, 485 (53.8%) patients were below 65 years, 302 (33.5%) were 65 to 74 years, 130 (14.4%) were 70 to 74 years, 787 (87.3%) were below 75 years, and 114 (12.7%) were 75 years or above. A total of 444 patients in E4599 received PC alone, of whom 250 (53.6%) were below 65 years, 151 (34.0%) were 65 to 74 years, 73 (16.4%) were 70 to 74 years, 401 (90.3%) were below 75 years, and 43 (9.7%) were 75 years or above. Baseline characteristics were generally similar between the age subgroups (data not shown) and between the pooled population and the PC arm in elderly patients, although the PC arm included a higher proportion of males and a lower proportion of adenocarcinoma histology than the PC+bevacizumab arm among patients below 75 years (Table 1 and see Supplemental Digital Content, http://links.lww.com/AJCO/A77). TABLE 1 Baseline Demographic and Disease Characteristics of Patients Treated With Paclitaxel–Carboplatin+Bevacizumab Versus Paclitaxel–Carboplatin Alone, by Age Subgroup

RESULTS Patient Characteristics A total of 434 and 467 patients were randomized to PC+bevacizumab in the E4599 and PointBreak trials, respectively. In the pooled PC+bevacizumab population, 485 (53.8%) patients were below 65 years, 302 (33.5%) were 65 to 74 years, 130 (14.4%) were 70 to 74 years, 787 (87.3%) were below 75 years, and 114 (12.7%) were 75 years or above. A total of 444 patients in E4599 received PC alone, of whom 250 (53.6%) were below 65 years, 151 (34.0%) were 65 to 74 years, 73 (16.4%) were 70 to 74 years, 401 (90.3%) were below 75 years, and 43 (9.7%) were 75 years or above. Baseline characteristics were generally similar between the age subgroups (data not shown) and between the pooled population and the PC arm in elderly patients, although the PC arm included a higher proportion of males and a lower proportion of adenocarcinoma histology than the PC+bevacizumab arm among patients below 75 years (Table 1 and see Supplemental Digital Content, http://links.lww.com/AJCO/A77). TABLE 1 Baseline Demographic and Disease Characteristics of Patients Treated With Paclitaxel–Carboplatin+Bevacizumab Versus Paclitaxel–Carboplatin Alone, by Age Subgroup Efficacy The use of bevacizumab was associated with a significant reduction in the risk of death for patients aged below 65 years (hazards ratio [HR], 0.75; 95% confidence interval [CI], 0.62-0.89), 65 to 74 years (HR, 0.80; 95% CI, 0.64-1.00), 70 to 74 years (HR, 0.68; 95% CI, 0.48-0.96), and below 75 years (HR, 0.78; 95% CI, 0.68-0.89) in the pooled population (Fig. 1A). Among the 157 patients aged 75 years or above, the difference in OS was not statistically significant between treatment arms (HR, 1.05; 95% CI, 0.70-1.57). A similar pattern of OS benefit with PC+bevacizumab compared with PC alone was seen across age subgroups when comparing outcomes exclusively in the E4599 trial (Fig. 1B). The unadjusted Kaplan-Meier estimates for OS in the pooled analysis are shown for patients aged below 75 years and 75 years or above in Figure 2.

7). A similar pattern of OS benefit with PC+bevacizumab compared with PC alone was seen across age subgroups when comparing outcomes exclusively in the E4599 trial (Fig. 1B). The unadjusted Kaplan-Meier estimates for OS in the pooled analysis are shown for patients aged below 75 years and 75 years or above in Figure 2. FIGURE 1 Forest plots of overall survival (OS) (A and B) and progression-free survival (PFS) (C and D) for patients treated with paclitaxel–carboplatin+bevacizumab versus paclitaxel–carboplatin alone, by age subgroup. CI indicates confidence interval; HR, hazard ratio. FIGURE 2 The Kaplan-Meier estimates for overall survival in patients treated with paclitaxel–carboplatin+bevacizumab (pooled population) versus paclitaxel–carboplatin alone: (A) patients aged below 75 years and (B) patients aged 75 years or above. CI indicates confidence interval; HR, hazard ratio; PC, paclitaxel plus carboplatin.

Kaplan-Meier estimates for overall survival in patients treated with paclitaxel–carboplatin+bevacizumab (pooled population) versus paclitaxel–carboplatin alone: (A) patients aged below 75 years and (B) patients aged 75 years or above. CI indicates confidence interval; HR, hazard ratio; PC, paclitaxel plus carboplatin. With respect to PFS, treatment with PC+bevacizumab in the pooled population was associated with a significant reduction in the risk of progression or death compared with PC alone for patients aged below 65 years (HR, 0.71; 95% CI, 0.60-0.85), 65 to 74 years (HR, 0.62; 95% CI, 0.49-0.78), 70 to 74 years (HR, 0.57; 95% CI, 0.40-0.81), and below 75 years (HR, 0.69; 95% CI, 0.60-0.79) (Fig. 1C). The use of bevacizumab conferred no PFS benefit in patients aged 75 years or above (HR, 0.95; 95% CI, 0.62-1.44). A similar pattern of results was observed in the E4599 trial, with significant extensions of PFS in all age subgroups, except for patients aged 75 years or above (Fig. 1D). The median PFS in the pooled population was 6.1 months for PC+bevacizumab and 4.8 months for PC alone in patients aged below 75 years (P<0.001); median values were 5.6 and 4.9 months, respectively, in patients aged 75 years or above (P=0.83).

S in all age subgroups, except for patients aged 75 years or above (Fig. 1D). The median PFS in the pooled population was 6.1 months for PC+bevacizumab and 4.8 months for PC alone in patients aged below 75 years (P<0.001); median values were 5.6 and 4.9 months, respectively, in patients aged 75 years or above (P=0.83). In the pooled population, PC+bevacizumab also resulted in significantly higher ORRs than PC alone in patients aged below 65 years (42% vs. 25%; P<0.001) and below 75 years (39% vs. 26%; P<0.001) but not in patients aged 65 to 74 years (33% vs. 27%; P=0.197), 70 to 74 years (30% vs. 27%; P=0.695), or 75 years or above (33% vs. 30%; P=0.711). Similar findings were noted when analyses were restricted to only the E4599 trial. Treatment Exposure and Postprogression Survival Treatment exposure was similar between patients aged below 75 years and those aged 75 years or above in the E4599 study. The proportion of patients who received ≥6 cycles of PC+bevacizumab was 62% (224/364) and 59% (34/58) for patients below 75 years and 75 years or above of age, respectively. In the PC arm, these values were 44% (175/395) and 45% (19/42), respectively.

below 75 years and those aged 75 years or above in the E4599 study. The proportion of patients who received ≥6 cycles of PC+bevacizumab was 62% (224/364) and 59% (34/58) for patients below 75 years and 75 years or above of age, respectively. In the PC arm, these values were 44% (175/395) and 45% (19/42), respectively. In the E4599 study, the proportion of patients who initiated subsequent therapy after disease progression was higher for patients aged below 75 years compared with those aged 75 years or above (54% vs. 45%). A lower proportion of patients who received PC+bevacizumab received nonprotocol therapy after progression compared with those who received PC (51% [190/371] vs. 58% [229/398] for patients aged below 75 years, respectively; 40% [23/58] vs. 52% [22/42] for patients aged 75 years or above). Among individuals aged below 75 years in E4599, there was no difference in postprogression OS between treatment arms (median: 6.6 mo for PC+bevacizumab vs. 5.8 mo for PC; HR, 0.91; 95% CI, 0.75-1.10). However, there was a nonsignificant trend in favor of the PC arm for postprogression OS among patients aged 75 years or above (median: 5.0 mo for PC+bevacizumab vs. 6.6 mo for PC; HR, 1.30; 95% CI, 0.77-2.30).

OS between treatment arms (median: 6.6 mo for PC+bevacizumab vs. 5.8 mo for PC; HR, 0.91; 95% CI, 0.75-1.10). However, there was a nonsignificant trend in favor of the PC arm for postprogression OS among patients aged 75 years or above (median: 5.0 mo for PC+bevacizumab vs. 6.6 mo for PC; HR, 1.30; 95% CI, 0.77-2.30). Safety In the E4599 study, the overall incidence of grade ≥3 AEs was significantly higher in the PC+bevacizumab arm than in the PC arm (Table 2) and proportionately greater in those aged 75 years or above: 63% for PC+bevacizumab vs. 48% for PC in patients below 75 years (P<0.05) and 81% versus 56%, respectively, in patients aged 75 years or above (P<0.05). Statistically significant increases in the rate of grade ≥3 neutropenia, hypertension, hemorrhage, proteinuria, and thromboembolism were reported with PC+bevacizumab relative to PC in patients below 75 years. Grade 5 AEs were increased in the PC+bevacizumab arm; the relative incidence in patients aged 75 years or above receiving PC+bevacizumab versus PC alone was 8% (5/59) and 2% (1/43), respectively (P=0.192). In the subgroup of patients below 75 years, grade 5 AEs occurred in 17 patients (5%) in the PC+bevacizumab arm compared with only 1 patient (0.2%) in the PC arm. In the PointBreak trial, the incidence of grade ≥3 AEs with PC+bevacizumab was 65% in patients aged below 75 years and 77% in patients aged 75 years or above. The incidence of grade 5 AEs was 2% for both the below 75 and 75 years or above age groups (Table 2). TABLE 2 AEs by Treatment Arm in the E4599 and PointBreak Studies, by Age Subgroup

In the PointBreak trial, the incidence of grade ≥3 AEs with PC+bevacizumab was 65% in patients aged below 75 years and 77% in patients aged 75 years or above. The incidence of grade 5 AEs was 2% for both the below 75 and 75 years or above age groups (Table 2). TABLE 2 AEs by Treatment Arm in the E4599 and PointBreak Studies, by Age Subgroup Patients receiving PC+bevacizumab were more likely to discontinue treatment because of an AE than those receiving PC (17% [65/375] and 12% [49/401] of patients aged below 75 years and randomized to PC+bevacizumab and PC alone, respectively). In contrast, treatment discontinuation rates in the same arms were 29% (17/59) and 19% (8/43), respectively, in patients aged 75 years or above.

treatment because of an AE than those receiving PC (17% [65/375] and 12% [49/401] of patients aged below 75 years and randomized to PC+bevacizumab and PC alone, respectively). In contrast, treatment discontinuation rates in the same arms were 29% (17/59) and 19% (8/43), respectively, in patients aged 75 years or above. DISCUSSION In this exploratory analysis, patient data from the phase III E4599 and PointBreak studies were pooled to further evaluate the benefits and risks of bevacizumab therapy in patients with advanced NSCLC based on age. The age cohorts used were designed to provide subgroups of sufficient size to draw clinically meaningful conclusions regarding outcomes in relevant elderly populations. The analysis confirmed significant improvements in OS and PFS with the addition of bevacizumab to PC for patients aged below 65, 65 to 74, 70 to 74, and below 75 years. There was no significant benefit in survival observed with the use of bevacizumab in patients aged 75 years or above, although the relatively small number of patients in this subgroup (n=157) limited the statistical power of the analyses conducted in this population. Pooling data from patients who received PC+bevacizumab in 2 phase III trials enhanced the statistical power of these analyses and distinguished the results from previously conducted analyses. Specifically, Ramalingam et al15 observed no statistically significant benefit from bevacizumab in patients aged 70 years or above in the E4599 trial, whereas the results described here demonstrate that benefit was extended to patients aged 70 to 74 years. This subgroup represents a significant population of patients with NSCLC in clinical practice: >324,000 individuals between 70 and 74 years of age were diagnosed with NSCLC between 2003 and 2007 in the United States.1

reas the results described here demonstrate that benefit was extended to patients aged 70 to 74 years. This subgroup represents a significant population of patients with NSCLC in clinical practice: >324,000 individuals between 70 and 74 years of age were diagnosed with NSCLC between 2003 and 2007 in the United States.1 Safety analyses in E4599 patients showed that treatment with PC+bevacizumab was associated with a significantly higher incidence of overall grade ≥3 AEs compared with PC alone in patients below 75 years old and in those aged 75 years or above. The incidence of grade 5 events in patients aged 75 years or above was 8% for those receiving bevacizumab with PC compared with 2% for those receiving chemotherapy alone, although the difference did not reach statistical significance. Grade 5 AEs occurred in 2% of patients who were 75 years of age or above in the PointBreak study. These results are in line with previous reports that indicated a higher likelihood of developing grade ≥3 AEs for older patients receiving bevacizumab with chemotherapy.15,22

ference did not reach statistical significance. Grade 5 AEs occurred in 2% of patients who were 75 years of age or above in the PointBreak study. These results are in line with previous reports that indicated a higher likelihood of developing grade ≥3 AEs for older patients receiving bevacizumab with chemotherapy.15,22 It is worth considering these results in the context of other recent reports that describe outcomes in elderly NSCLC patients treated with bevacizumab+chemotherapy in clinical trials.15,18,19 In a previous E4599 post hoc analysis, which found no OS benefit with bevacizumab and more frequent toxicity in elderly patients, the age cutoff was 70 years or above.15 Conversely, other analyses that have supported the risk:benefit of bevacizumab in both younger and older patients used 65 years, the age at which individuals are eligible for Medicare in the United States, as the age cutoff.18,19 Together with the current analysis, these findings suggest that the population-level benefit of bevacizumab+chemotherapy in NSCLC is less consistent with advancing age and that 75 years of age may be a more practical delineation of “elderly” than 65 or 70 years of age, particularly as the average age of patients diagnosed with NSCLC continues to rise.

s, these findings suggest that the population-level benefit of bevacizumab+chemotherapy in NSCLC is less consistent with advancing age and that 75 years of age may be a more practical delineation of “elderly” than 65 or 70 years of age, particularly as the average age of patients diagnosed with NSCLC continues to rise. The reasons for the lack of observed clinical benefit with bevacizumab+chemotherapy in patients above 75 years in this analysis are likely wide-ranging. For instance, age-related decreases in renal function, immune response, and bone marrow regeneration may impact tolerance and response to therapy.23 The presence of comorbidities, such as respiratory or cardiovascular disorders, may also influence clinical outcomes and can exacerbate treatment-related toxicities, ultimately leading to decreased treatment duration in older patients.24–27 Potentially confounding these findings are the longer-than-expected median OS durations observed in the control arm of E4599 (13.0 mo) and the observed nonsignificant decrease in postprogression OS with PC+bevacizumab in the older patient subgroup, which may have contributed to the apparent lack of clinical benefit with bevacizumab in those above 75 years of age.

e longer-than-expected median OS durations observed in the control arm of E4599 (13.0 mo) and the observed nonsignificant decrease in postprogression OS with PC+bevacizumab in the older patient subgroup, which may have contributed to the apparent lack of clinical benefit with bevacizumab in those above 75 years of age. Despite these concerns, it is increasingly clear that elderly patients, when properly selected, can benefit from standard cancer therapies. Although elderly patients are less likely than younger patients to receive chemotherapy for advanced NSCLC,24–26 retrospective and prospective analyses from phase III trials have shown that platinum-doublet chemotherapy is associated with greater survival benefits than single-agent therapy in elderly populations and that modern third-generation platinum-based combinations are superior to older combinations.25–29 Increasing evidence also suggests that performance status and comorbidities, rather than age, are more appropriate factors to determine which patients should undergo intensive therapy.7,22

herapy in elderly populations and that modern third-generation platinum-based combinations are superior to older combinations.25–29 Increasing evidence also suggests that performance status and comorbidities, rather than age, are more appropriate factors to determine which patients should undergo intensive therapy.7,22 Limitations of the current analysis include its exploratory, post hoc nature, the limited size of the patient population aged 75 years or above, and the lack of adjustment for unmeasured potential confounding factors (eg, comorbidities). As is the case with all post hoc exploratory analyses, we cannot definitively conclude a treatment benefit, or lack thereof, based on these subgroup analyses. We also note that PointBreak did not include a nonbevacizumab control group. However, the consistency of the results observed in the pooled analysis and in the E4599 study alone shown in Figure 1 suggests that the use of the control arm of E4599 as a comparator did not bias the results of the pooled analysis. In addition, differences in reporting between the E4599 and PointBreak studies did not allow for the pooling of data on treatment exposure, postprogression survival, or safety. However, eligibility for the 2 studies was virtually identical, and the difference in intended treatment duration during induction (6 cycles in E4599 vs. 4 cycles in PointBreak) was deemed unlikely to have much bearing on final outcomes.

or the pooling of data on treatment exposure, postprogression survival, or safety. However, eligibility for the 2 studies was virtually identical, and the difference in intended treatment duration during induction (6 cycles in E4599 vs. 4 cycles in PointBreak) was deemed unlikely to have much bearing on final outcomes. We also recognize that older patients who participate in clinical trials represent those on the healthier end of the spectrum and may be very different from the general population of older patients with advanced NSCLC. In fact, a greater percentage of patients included in this analysis aged 75 years or above had an ECOG performance status of 1 compared with younger patient subgroups. Performance status and comorbidities should be taken into consideration, along with age, when determining treatment for patients. In conclusion, this pooled analysis suggests that younger segments of the elderly population (ie, those between the ages of 65 and 75 years) with advanced NSCLC appear to derive meaningful clinical benefit from the addition of bevacizumab to standard PC chemotherapy. Similar benefits were not observed in patients with NSCLC above 75 years of age. Improving outcomes for patients above 75 years remains an important research priority. Supplementary Material SUPPLEMENTARY MATERIAL Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website, www.amjclinicaloncology.com.

In conclusion, this pooled analysis suggests that younger segments of the elderly population (ie, those between the ages of 65 and 75 years) with advanced NSCLC appear to derive meaningful clinical benefit from the addition of bevacizumab to standard PC chemotherapy. Similar benefits were not observed in patients with NSCLC above 75 years of age. Improving outcomes for patients above 75 years remains an important research priority. Supplementary Material SUPPLEMENTARY MATERIAL Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website, www.amjclinicaloncology.com. Sponsored and funded by Genentech Inc. Support for third-party writing assistance for this manuscript was provided by Genentech Inc. C.J.L. has served as a consultant for Eli Lilly and Genentech Inc. M.A.S. has received honoraria and research funding from Eli Lilly and Genentech Inc. J.D.P. has no conflicts to disclose. A.B.S., L.L., and S.J.H. are employees of and hold stock in Genentech Inc. A.B.S. has also served as a consultant, provided outside testimony, received grants and payment for lectures, manuscript preparation, and educational presentations for Genentech Inc., outside the scope of the submitted work. J.H.S. has served as a consultant for and has received research funding and honoraria from Genentech Inc. S.S.R. has served as a consultant for Genentech Inc., Eli Lilly, and Celgene.

Hepatocellular carcinoma (HCC), which accounts for >5% of cancers globally, is ranked as the sixth most common cancer and the third leading cause of cancer-related death worldwide.1 Cirrhosis is the main risk factor for HCC development. Most cases are associated to chronic hepatitis B and C infection as well as alcohol consumption.2 In recent years, nonalcoholic fatty liver disease (NAFLD) has appeared as an important cause of chronic liver disease, cirrhosis, and HCC. In the absence of effective surveillance strategies, the stage of presentation is often advanced.3,4 HCC is unique because in addition to cancer stage, the underlying liver function substantially affects prognosis. The Barcelona Clinic Liver Cancer (BCLC) staging system was proposed and has been validated by several groups in the United States and Europe and offers the best stage classification and guidance for HCC treatment allocation.5,6 BCLC staging system was developed mainly in European populations in which hepatitis C virus infection was dominant. Validation was also done by Asiatic group where hepatitis B virus is dominant.7

roups in the United States and Europe and offers the best stage classification and guidance for HCC treatment allocation.5,6 BCLC staging system was developed mainly in European populations in which hepatitis C virus infection was dominant. Validation was also done by Asiatic group where hepatitis B virus is dominant.7 This system currently recommends radical therapies [liver transplantation, surgical resection, or percutaneous ablation, such as radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI)] for very early (BCLC stage 0) or early-stage (BCLC stage A) HCC, transarterial chemoembolization (TACE) for intermediate-stage (BCLC stage B) HCC, sorafenib administration for advanced-stage (BCLC stage C) HCC, and supportive care for end-stage (BCLC stage D) HCC.8 However, although this staging system was developed using an evidence-based approach, its application can be problematic in NAFLD patients because of different clinical profile of these patients.9 There are few reports of BCLC application in NAFLD patients. Evidence has emerged suggesting that the molecular pathogenesis, clinical features, and the prognosis of NAFLD-related HCC may differ from viral-induced HCC.4 Most of HCC cases are described in cirrhotic patients, but HCC is increasing also in the noncirrhotic setting.10 These findings suggest that hepatocarcinogenesis may be deregulated in early stages of this disease. Some comparative studies suggest that NAFLD-related HCC patients are older and present with comorbidities that may limit HCC therapy according to recommended guidelines.9,11

ncreasing also in the noncirrhotic setting.10 These findings suggest that hepatocarcinogenesis may be deregulated in early stages of this disease. Some comparative studies suggest that NAFLD-related HCC patients are older and present with comorbidities that may limit HCC therapy according to recommended guidelines.9,11 The main objective of this retrospective study was to evaluate whether the BCLC staging system and its treatment algorithm are suitable for patients with HCC arising from NAFLD. We also studied clinical characteristics of NAFLD-related HCC, and aspects related to diagnosis, overall survival, and predictors of survival. METHODS Patients Between January 2010 and December 2012, 42 patients with HCC related either to NAFLD or cryptogenic cirrhosis were retrieved retrospectively from 2 centers in Brazil (Instituto do Câncer do Estado de São Paulo and Universidade Federal do Rio Grande do Sul). The Institutional Review Board of the University of São Paulo approved the study. Part of the included patients comes from an observatory of HCC in NAFLD of the Fatty Liver Inhibition of Progression (FLIP) consortium.12

n Brazil (Instituto do Câncer do Estado de São Paulo and Universidade Federal do Rio Grande do Sul). The Institutional Review Board of the University of São Paulo approved the study. Part of the included patients comes from an observatory of HCC in NAFLD of the Fatty Liver Inhibition of Progression (FLIP) consortium.12 Cirrhosis was diagnosed on histologic features and/or radiologic evidence (imaging studies suggesting chronic liver disease and portal hypertension), laboratory abnormalities such as thrombocytopenia, hypoalbuminemia, prolonged prothrombin time, or clinically decompensated disease (ascites, variceal bleeding, or hepatic encephalopathy). Other causes of chronic liver disease as hepatitis B, hepatitis C, autoimmune hepatitis, α1-antitrypsin deficiency, Wilson disease, and hemochromatosis were excluded by appropriate laboratory tests. Unless features of the metabolic syndrome were present, or NAFLD was evident from histology, cases were regarded as cryptogenic. Baseline information, including patient demographics; risk factors for NAFLD; serum biochemistries; liver biopsy when available, severity of cirrhosis (Child-Pugh classification and Model for End-Stage Liver Disease score); Eastern Cooperative Oncology Group performance status; cancer stage according to the BCLC staging system; α-fetoprotein level; and treatment modalities were collected at enrollment.

iochemistries; liver biopsy when available, severity of cirrhosis (Child-Pugh classification and Model for End-Stage Liver Disease score); Eastern Cooperative Oncology Group performance status; cancer stage according to the BCLC staging system; α-fetoprotein level; and treatment modalities were collected at enrollment. HCC was diagnosed according to noninvasive diagnostic criteria of the American Association for the Study of Liver Diseases updated in 2010 whenever cirrhosis was present.8 Liver histology confirmation was performed in all noncirrhotic patients and inconclusive cases by imaging examination. Staging According to the BCLC BCLC stages were determined based on tumor size and number, liver function tests, performance status, and cancer-related symptoms.8 All patients underwent abdominal dynamic computed tomography or magnetic resonance, chest computed tomography, and a bone scan for staging. Portal hypertension was defined by the presence of esophagogastric varices by upper endoscopy, ascites, or splenomegaly and a platelet count <100,000/mm3. Patients were classified as 0 (very early), A (early), B (intermediate), C (advanced), or D (terminal) using BCLC staging system.

raphy, and a bone scan for staging. Portal hypertension was defined by the presence of esophagogastric varices by upper endoscopy, ascites, or splenomegaly and a platelet count <100,000/mm3. Patients were classified as 0 (very early), A (early), B (intermediate), C (advanced), or D (terminal) using BCLC staging system. Study Outcome A local multidisciplinary team in each center composed of hepatobiliary surgeons, hepatologists, pathologists, oncologists, and interventional radiologists assessed all patients and decided on the best therapeutic option for each particular case, as performed routinely for each patient with HCC. For each patient the administered treatment strategy was compared with the 1 theoretically recommended by the BCLC stage. The main outcome of the study was to determine whether therapeutic options in agreement with the BCLC classification were applicable or not. In the latter case, we investigated the causes of treatment deviations from BCLC recommendations and analyzed the rate of deviation for each BCLC stage.

mmended by the BCLC stage. The main outcome of the study was to determine whether therapeutic options in agreement with the BCLC classification were applicable or not. In the latter case, we investigated the causes of treatment deviations from BCLC recommendations and analyzed the rate of deviation for each BCLC stage. Treatment Curative therapies included surgical resection, liver transplantation, and local ablative therapy such as RFA or PEI.8,13,14 Surgical resection was considered in patients with a single tumor, with well-preserved liver function, normal bilirubin, and absence of portal hypertension.15 This was also the first choice for noncirrhotic patients with a single nodule, regardless of tumor size. Liver transplantation was considered in patients fulfilling the Milan criteria and showed increased portal pressure or bilirubin. During the waiting time on the liver transplant list, patients were treated with percutaneous ablation or TACE as a bridge therapy to liver transplantation.8,13–15 If hepatectomy or liver transplantation were not indicated local ablative therapies such as RFA or PEI were performed depending on the size and number of tumor nodules. In multifocal tumors or large HCCs without extrahepatic spread or vascular invasion, TACE was the treatment of choice.8,13–15 Sorafenib was indicated for patients with advanced HCC. When treatment efficacy was considered limited or treatment-related risk was substantial due to extensive tumor burden, Child-Pugh class C status, or other medical comorbidities, supportive care was given.16,17

If hepatectomy or liver transplantation were not indicated local ablative therapies such as RFA or PEI were performed depending on the size and number of tumor nodules. In multifocal tumors or large HCCs without extrahepatic spread or vascular invasion, TACE was the treatment of choice.8,13–15 Sorafenib was indicated for patients with advanced HCC. When treatment efficacy was considered limited or treatment-related risk was substantial due to extensive tumor burden, Child-Pugh class C status, or other medical comorbidities, supportive care was given.16,17 Statistical Analysis Overall survival was measured from the date of diagnosis until death or last follow-up visit. Survival time was estimated using the Kaplan-Meier method and differences in survival between groups were assessed using the log-rank test. RESULTS Patients Characteristics Baseline characteristics of the 42 patients are shown in Table 1. Median age was 66.5 years (range, 25 to 80 y) and male sex predominated (n=26; 62%). TABLE 1 Baseline Characteristics of the Study Population

Statistical Analysis Overall survival was measured from the date of diagnosis until death or last follow-up visit. Survival time was estimated using the Kaplan-Meier method and differences in survival between groups were assessed using the log-rank test. RESULTS Patients Characteristics Baseline characteristics of the 42 patients are shown in Table 1. Median age was 66.5 years (range, 25 to 80 y) and male sex predominated (n=26; 62%). TABLE 1 Baseline Characteristics of the Study Population Four patients (10%) were classified as cryptogenic cirrhosis because no features of the metabolic syndrome were present, and there was no evidence of NAFLD in liver histology. NAFLD-related HCC were seen in 38 patients. In this group, there were 4 patients without evidence of cirrhosis according to liver biopsy and/or clinical evaluation. In NAFLD group, 24 patients had previous liver biopsy with macrovacuolar and microvacuolar fatty change, zonal distribution, foci of necrosis, portal and perivenular fibrosis, and inflammatory and fibrotic infiltrate with zonal distribution. In NAFLD group, 34 patients (81%) had obesity; 31 patients (73%) had type II diabetes, 29 patients (69%) had arterial hypertension, and 11 patients (26%) had dyslipidemia. The numbers of patients in Child-Pugh classes A, B, and C were 20 (48%), 15 (35%), and 3 (7%), respectively. HCC was diagnosed based on noninvasive diagnostic criteria of the American Association for the Study of Liver Diseases in 24 patients (57%). Diagnosis of HCC was confirmed by histology in 18 patients (43%).

Four patients (10%) were classified as cryptogenic cirrhosis because no features of the metabolic syndrome were present, and there was no evidence of NAFLD in liver histology. NAFLD-related HCC were seen in 38 patients. In this group, there were 4 patients without evidence of cirrhosis according to liver biopsy and/or clinical evaluation. In NAFLD group, 24 patients had previous liver biopsy with macrovacuolar and microvacuolar fatty change, zonal distribution, foci of necrosis, portal and perivenular fibrosis, and inflammatory and fibrotic infiltrate with zonal distribution. In NAFLD group, 34 patients (81%) had obesity; 31 patients (73%) had type II diabetes, 29 patients (69%) had arterial hypertension, and 11 patients (26%) had dyslipidemia. The numbers of patients in Child-Pugh classes A, B, and C were 20 (48%), 15 (35%), and 3 (7%), respectively. HCC was diagnosed based on noninvasive diagnostic criteria of the American Association for the Study of Liver Diseases in 24 patients (57%). Diagnosis of HCC was confirmed by histology in 18 patients (43%). Twenty-nine patients (69%) had a single tumor and the median diameter of largest tumor was 38 mm (range, 17 to 150 mm). Five patients (12%) had macrovascular invasion and 3 (7%) extrahepatic spread. The median α-fetoprotein value was 11 ng/mL (range, 1 to 20,000 ng/mL).

The numbers of patients in Child-Pugh classes A, B, and C were 20 (48%), 15 (35%), and 3 (7%), respectively. HCC was diagnosed based on noninvasive diagnostic criteria of the American Association for the Study of Liver Diseases in 24 patients (57%). Diagnosis of HCC was confirmed by histology in 18 patients (43%). Twenty-nine patients (69%) had a single tumor and the median diameter of largest tumor was 38 mm (range, 17 to 150 mm). Five patients (12%) had macrovascular invasion and 3 (7%) extrahepatic spread. The median α-fetoprotein value was 11 ng/mL (range, 1 to 20,000 ng/mL). Classification of BCLC Stage Noncirrhotic patients were incorporated to BCLC staging system because, in the real-life, they are practically treated with BCLC algorithm. One (2%), 21 (50%), 10 (24%), 5 (12%), and 5 patients (12%) were classified initially to the BCLC 0, A, B, C, and D stages, respectively. Among 42 patients, HCC was diagnosed in a screening program in 55% (there was 1 noncirrhotic patient). Patients with HCC diagnosed outside of a surveillance program (n=19) were mostly not candidates to curative therapies (73%) (P=0.002) (Table 2). TABLE 2 BCLC Stage According to Surveillance Program

Classification of BCLC Stage Noncirrhotic patients were incorporated to BCLC staging system because, in the real-life, they are practically treated with BCLC algorithm. One (2%), 21 (50%), 10 (24%), 5 (12%), and 5 patients (12%) were classified initially to the BCLC 0, A, B, C, and D stages, respectively. Among 42 patients, HCC was diagnosed in a screening program in 55% (there was 1 noncirrhotic patient). Patients with HCC diagnosed outside of a surveillance program (n=19) were mostly not candidates to curative therapies (73%) (P=0.002) (Table 2). TABLE 2 BCLC Stage According to Surveillance Program Allocation of Treatment According BCLC Stages Curative treatments, which included resection, local ablative therapy, and liver transplantation, were performed in 23 (55%) patients, whereas palliative treatments such as TACE or sorafenib were given in 11 (26%) patients. Eight (19%) patients received only the best supportive care. Table 3 summarizes the detailed treatment modalities used for patients classified according to the BCLC staging system. TABLE 3 Allocation of Treatment Modalities According BCLC Staging Systems Liver resection was the first choice therapy in all noncirrhotic patients, based on the decision of the multidisciplinary team as the best therapeutic option in each case. The first patient had 1 nodule of 37 mm. The second patient had 1 nodule of 109 mm. The other 2 patients had >2 nodules, but in the same liver segment. All noncirrhotic patients survived >2 years after treatment.

patients, based on the decision of the multidisciplinary team as the best therapeutic option in each case. The first patient had 1 nodule of 37 mm. The second patient had 1 nodule of 109 mm. The other 2 patients had >2 nodules, but in the same liver segment. All noncirrhotic patients survived >2 years after treatment. Most patients (85%) in BCLC stage A were treated according to BCLC recommendations. Liver resection was performed in 4 patients, liver transplant in 7 patients, and local ablation therapy in 7 patients. There were 3 protocol deviations in this group. Two patients were treated with TACE and 1 received best supportive care. Most patients at the BCLC stage B were treated with TACE. In this group of 7 patients, 1 could be included in the liver transplant list after fulfilling Milan criteria. Only 1 patient presented a BCLC protocol deviation (ie, could not be administered TACE) because of significant comorbidity (heart failure) and received only best supportive care. Two patients in this group were treated with resection, because they were noncirrhotic.

iver transplant list after fulfilling Milan criteria. Only 1 patient presented a BCLC protocol deviation (ie, could not be administered TACE) because of significant comorbidity (heart failure) and received only best supportive care. Two patients in this group were treated with resection, because they were noncirrhotic. Most cases of protocol deviation were found in BCLC C patients (3 of the 5 BCLC C patients). Two patients was initially treated with sorafenib (one of them was included in a clinical trial with brivanib plus sorafenib). One patient was treated with liver resection and 1 received TACE. These 2 cases of protocol deviation had preserved liver function (Child-Pugh A) and were classified as BCLC C because of macrovascular invasion at a segmental branch level. This was an attempt to a more curative therapy in these 2 cases. The third patient presented with rapid deterioration of general status and liver decompensation and received best supportive care.

d liver function (Child-Pugh A) and were classified as BCLC C because of macrovascular invasion at a segmental branch level. This was an attempt to a more curative therapy in these 2 cases. The third patient presented with rapid deterioration of general status and liver decompensation and received best supportive care. All patients in BCLC D stage received best supportive care exclusively. There were 3 patients that received only best supportive care and were included in the group of protocol deviation because they were classified as BCLC A, B, and C staging system. The reason for not treating these patients is the association of poor liver function, compromised general status and advanced age. On the other side, the others patients who did not follow BCLC algorithm presented a very compensated liver function and a more aggressive therapy was attempted in each case. Two patients were classified as BCLC B, but without signs of liver cirrhosis and resection was indicated by the multidisciplinary group. The other 2 patients were those classified as BCLC C because of macrovascular invasion, but the multidisciplinary team decision was for resection in one case and TACE in the other case before indicating sorafenib.

s BCLC B, but without signs of liver cirrhosis and resection was indicated by the multidisciplinary group. The other 2 patients were those classified as BCLC C because of macrovascular invasion, but the multidisciplinary team decision was for resection in one case and TACE in the other case before indicating sorafenib. Survival During the follow-up period (median, 11 mo; range, 0 to 85 mo), 12 patients died of tumor progression or cirrhosis-related complications. The 1- and 2-year overall survival rates were 81% and 66%, respectively (Fig. 1). All noncirrhotic patients were alive after 2 years of follow-up. Child-Pugh A cirrhotic patients presented a better overall survival rate (P=0.02) than Child-Pugh B and C patients. BCLC stage 0 and A patients had a better survival compared with BCLC B, C, and D patients, but it was not statistically significant. FIGURE 1 Overall survival of 42 patients. DISCUSSION HCC is the main cause of death in patients with cirrhosis. The BCLC system is the preferred staging system to evaluate patients with HCC as it takes into account the characteristics of the tumor, the degree of liver impairment, and the physical performance.5,7 Moreover, it is the only one that links prognosis assessment with treatment recommendation. NAFLD is a well-recognized etiology of HCC. Although clinical profile and hepatocarcinogenesis of these patients may be different from viral hepatitis infected patients, the BCLC could be applied in most cases of HCC arising in the context of NAFLD.

nly one that links prognosis assessment with treatment recommendation. NAFLD is a well-recognized etiology of HCC. Although clinical profile and hepatocarcinogenesis of these patients may be different from viral hepatitis infected patients, the BCLC could be applied in most cases of HCC arising in the context of NAFLD. In this study, we characterized the outcome of patients with HCC arising on NAFLD or cryptogenic liver disease. Patients enrolled in a regular surveillance program were more often diagnosed at an early stage. Surveillance in patients with established cirrhosis and nonalcoholic steatohepatitis (NASH) is part of international recommendations. Recently, a Japanese group observed that in 28% of NAFLD patients, HCC developed in less advanced stages of fibrosis.18 In the present study, we observed HCC in 4 noncirrhotic patients that were treated with liver resection. However, recommendation of surveillance in this subgroup of patients can not be generalized and must be made with caution because it is estimated that in the United States, NAFLD can affect 30% of the general population.19

present study, we observed HCC in 4 noncirrhotic patients that were treated with liver resection. However, recommendation of surveillance in this subgroup of patients can not be generalized and must be made with caution because it is estimated that in the United States, NAFLD can affect 30% of the general population.19 Recently, 166 new cases were collected over 22 months in the FLIP consortium and the demographic aspects found in our study were similar to this larger database.12 However, in the FLIP study, 59% patients were symptomatic and consequently BCLC stage C or D, whereas in the present study, 47% were BCLC stage 0 and A. Besides, applicability of the BCLC system was not evaluated in FLIP study. Another difference was the larger proportion of noncirrhotic patients in the FLIP study (43%) compared with 10% in our study. Preliminary data show that almost all noncirrhotic cases occurred in steatohepatitis rather than steatosis alone in both studies.12 The majority of studies describing HCC in the context of NAFLD usually focus on risk factors for liver carcinogenesis. Very little information is available on tumor stage and treatment of HCC after diagnosis. Besides, several factors affect the choice of treatment options and as the BCLC staging system is based on clinical and radiologic findings, it is not possible to determine exact stage in some patients.7

for liver carcinogenesis. Very little information is available on tumor stage and treatment of HCC after diagnosis. Besides, several factors affect the choice of treatment options and as the BCLC staging system is based on clinical and radiologic findings, it is not possible to determine exact stage in some patients.7 In our study, there were 4 noncirrhotic patients who were treated with liver resection. Most cases of protocol deviation were found in BCLC C stage (advanced stage) patients that sorafenib was the treatment of choice in these cases.8 One patient was treated with liver resection despite the presence of vascular invasion because it affected a segmental branch. The other patient who was classified as BCLC C was not evaluated initially by multidisciplinar team approach and received TACE in a private setting. This patient showed a very good tumor control response with TACE sessions besides the presence of segmental vascular invasion. These facts are problematic for the BCLC staging system not only in NAFLD patients, but in all types of HCC because its recommended treatment options are dependent on tumor stage. In another Korean study, applicability of the BCLC staging system to patients with HCC demonstrated that donor shortage, financial problems, the relatively limited efficacy of molecular targeting agents, and the presence of an indeterminate nodule were the main causes of deviation from BCLC recommendations.20

or stage. In another Korean study, applicability of the BCLC staging system to patients with HCC demonstrated that donor shortage, financial problems, the relatively limited efficacy of molecular targeting agents, and the presence of an indeterminate nodule were the main causes of deviation from BCLC recommendations.20 In the other side, there are many concerns about HCC treatment in NAFLD patients. Comparative studies demonstrated that these patients are older, have higher body mass index, and are more likely to be diabetic, obese, or hypertensive.9,21 All these factors may difficult treatment schedule according to BCLC guidelines. They may be older to be candidate to liver transplant or have more renal dysfunction to TACE or have too many comorbidities to surgical resection. In our study, only 1 patient from BCLC A did not receive HCC therapy due to his comorbidities. Another patient did not follow BCLC guideline and received TACE because of technical contraindication to others procedures. In general, protocol deviation was not associated to age or presence of comorbidities. Deviations were associated to the presence of a good liver function allowing a more aggressive oncologic treatment.

r patient did not follow BCLC guideline and received TACE because of technical contraindication to others procedures. In general, protocol deviation was not associated to age or presence of comorbidities. Deviations were associated to the presence of a good liver function allowing a more aggressive oncologic treatment. Liver transplant was performed in 8 patients. United Network for Organ Sharing database showed that the frequency of liver transplant in NASH patients is increasing in the last decades and it is projected that NASH would likely overtake hepatitis C virus as an indication of LT by the year 2020. Besides age and risk factors, NASH patients had an excellent outcome (5-y survival of 80% to 85%) after liver transplantation.21 Survival after resection was also comparable with viral hepatitis patients (P=0.391), but patients with NAFLD showed better disease-free survival on univariate (P=0.048) and multivariate (P=0.020) analyses.9

risk factors, NASH patients had an excellent outcome (5-y survival of 80% to 85%) after liver transplantation.21 Survival after resection was also comparable with viral hepatitis patients (P=0.391), but patients with NAFLD showed better disease-free survival on univariate (P=0.048) and multivariate (P=0.020) analyses.9 NAFLD is recognized as a risk factor for the development of HCC. Most cases are believed to develop in a background of cirrhosis. However, an increasing number of NAFLD-related HCC arising from a noncirrhotic liver has been reported.10 In the present study, 4 of 42 (10%) patients who developed HCC in the context of NAFLD or cryptogenic liver disease had a noncirrhotic liver. In all the cases, HCC diagnosis was confirmed by liver histology. All patients in this subgroup were treated with surgical resection even with tumors >50 mm (50%) or >1 nodule (50%). In this context, a more aggressive HCC therapy was possible because of absence of liver dysfunction and portal hypertension. All patients were alive after 2 years of follow-up. However, in the literature, the BCLC guideline is recommended for cirrhotic patients. In noncirrhotic patients, a more aggressive oncology treatment should be performed.8 The main limitation of this study is the small sample size and the short period of follow-up. A better overall survival and progression-free survival of patients who were treated aggressively than those in the same stage that followed the BCLC algorithm could not be performed due to these limitations.

NAFLD is recognized as a risk factor for the development of HCC. Most cases are believed to develop in a background of cirrhosis. However, an increasing number of NAFLD-related HCC arising from a noncirrhotic liver has been reported.10 In the present study, 4 of 42 (10%) patients who developed HCC in the context of NAFLD or cryptogenic liver disease had a noncirrhotic liver. In all the cases, HCC diagnosis was confirmed by liver histology. All patients in this subgroup were treated with surgical resection even with tumors >50 mm (50%) or >1 nodule (50%). In this context, a more aggressive HCC therapy was possible because of absence of liver dysfunction and portal hypertension. All patients were alive after 2 years of follow-up. However, in the literature, the BCLC guideline is recommended for cirrhotic patients. In noncirrhotic patients, a more aggressive oncology treatment should be performed.8 The main limitation of this study is the small sample size and the short period of follow-up. A better overall survival and progression-free survival of patients who were treated aggressively than those in the same stage that followed the BCLC algorithm could not be performed due to these limitations. CONCLUSIONS The BCLC system is applicable in most cases of NAFLD-related HCC cases. Deviation from BCLC-based therapeutic recommendations is found more frequently in BCLC C stage patients. In noncirrhotic patients, a more aggressive oncology treatment should be performed, preferably with liver resection.

The main limitation of this study is the small sample size and the short period of follow-up. A better overall survival and progression-free survival of patients who were treated aggressively than those in the same stage that followed the BCLC algorithm could not be performed due to these limitations. CONCLUSIONS The BCLC system is applicable in most cases of NAFLD-related HCC cases. Deviation from BCLC-based therapeutic recommendations is found more frequently in BCLC C stage patients. In noncirrhotic patients, a more aggressive oncology treatment should be performed, preferably with liver resection. ACKNOWLEDGMENTS The authors thank Alves de Queiroz Family Fund for Research for financial support and Laboratory of Epidemiology and Statistics of Department of Gastroenterology, School of Medicine, University of São Paulo, SP, Brazil. The authors declare no conflicts of interest.

Pancreatic cancer carries a poor prognosis with a 5-year overall survival (OS) of <5%. Up to 70% of patients die with widespread metastatic disease and 30% die with locally destructive pancreatic cancer.1 Resection provides the only chance of cure, offering 5-year OS rates of 18% to 24%, but unfortunately only one fifth of patients present with resectable disease.2,3 Concurrent chemoradiation (CRT) is often employed in patients with localized pancreatic cancer, who are not considered candidates for upfront surgical resection. Randomized clinical trials evaluating the role of chemoradiation have shown conflicting results, with some trials showing a survival benefit with chemoradiation4–7 and others demonstrating no advantage.8,9 These trials have all used conventionally fractionated external-beam radiation therapy. Stereotactic body radiation therapy (SBRT) uses high doses of radiation delivered over a few number of sessions to a limited target volume. The accuracy, precision, and a rapid dose fall off of SBRT minimizes doses to the adjacent normal tissues. High rates of local control have previously been reported using SBRT for the liver and lung tumors.10,11 Recent studies have demonstrated the feasibility of SBRT for the treatment of pancreatic cancer. SBRT allows for dose escalation, and single-institution studies have demonstrated excellent local control rates without excessive toxicity.12–14

l have previously been reported using SBRT for the liver and lung tumors.10,11 Recent studies have demonstrated the feasibility of SBRT for the treatment of pancreatic cancer. SBRT allows for dose escalation, and single-institution studies have demonstrated excellent local control rates without excessive toxicity.12–14 The advantages of SBRT include shorter treatment duration and better integration with chemotherapy. Conventionally fractionated radiation therapy requires approximately 5 to 6 weeks of treatment and often necessitates alternations in chemotherapy. Given the high rates of distant failure in localized pancreatic cancer, fewer interruptions in chemotherapy may improve treatment outcomes. Herein, we report our experience with 5 fractions of SBRT combined with chemotherapy in patients with localized adenocarcinoma of the pancreas.

itates alternations in chemotherapy. Given the high rates of distant failure in localized pancreatic cancer, fewer interruptions in chemotherapy may improve treatment outcomes. Herein, we report our experience with 5 fractions of SBRT combined with chemotherapy in patients with localized adenocarcinoma of the pancreas. MATERIALS AND METHODS This retrospective review includes patients with biopsy-proven, nonmetastatic pancreatic adenocarcinoma, who were unresectable, borderline resectable, medically inoperable, or refused surgery, treated with SBRT and chemotherapy at Medstar Georgetown University Hospital from January 2008 to December 2012. Unresectable and borderline resectable were defined according to the AHPBA/SSO consensus statement.15 Comorbidity scores were calculated using the Charlson Comorbidity Index (CCI).16 The chemotherapy regimen was chosen at the discretion of the treating medical oncologist. Patients were considered to have received concurrent chemotherapy if it was given within the week before SBRT. In patients receiving “concurrent” gemcitabine, SBRT was administered during the off week of chemotherapy, which was typically week 4 of the first cycle, and the second cycle was begun without delay. Similarly, in patients receiving “concurrent” mFOLFOX, 5-FU, or capecitabine, SBRT was generally given during an off week. Patients who did not receive chemotherapy within the week before SBRT were considered to have received sequential chemotherapy.

k 4 of the first cycle, and the second cycle was begun without delay. Similarly, in patients receiving “concurrent” mFOLFOX, 5-FU, or capecitabine, SBRT was generally given during an off week. Patients who did not receive chemotherapy within the week before SBRT were considered to have received sequential chemotherapy. Radiation planning and delivery techniques have been detailed previously.17 All patients underwent an esophagogastroduodenoscopy with endoscopic ultrasound with placement of 3 to 4 gold fiducial markers. Seven days after fiducial placement, a treatment planning computed tomography (CT) with oral and intravenous contrast was obtained during a breath hold. The planning target volume (PTV) included the gross tumor volume (GTV) plus a 3- to 5-mm margin (excluding the bowel). The PTV was modified at the discretion of the treating physician to include the adjacent vasculature. The adjacent vasculature consisted of the superior mesenteric vessels, celiac axis, and/or para-aortic nodes at the level of the pancreatic mass when involved or immediately adjacent to the GTV. Enlarged lymph nodes were not routinely included in the GTV. Before 2011, the prescribed dose was 25 Gy in 5 fractions. This was subsequently increased to 30 Gy in 5 fractions because of our previous report demonstrating poor local control but also a low toxicity profile with 25 Gy in 5 fractions.17 The prescription isodose line encompassed at least 95% of the PTV. The stomach, duodenum, and bowel constraints were as follows: volume of organ receiving the prescribed dose, 90% prescribed dose, 80% prescribed dose, and 50% prescribed dose were <1 mL, 20%, 40%, and 90%, respectively. SBRT was delivered using the CyberKnife system (Accuray, Sunnyvale, CA) with respiratory tracking as previously described.18 Treatment was typically during 5 consecutive days.

an receiving the prescribed dose, 90% prescribed dose, 80% prescribed dose, and 50% prescribed dose were <1 mL, 20%, 40%, and 90%, respectively. SBRT was delivered using the CyberKnife system (Accuray, Sunnyvale, CA) with respiratory tracking as previously described.18 Treatment was typically during 5 consecutive days. Toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Baseline characteristics and adverse events were tabulated. Each symptom was counted once per patient at the highest grade it occurred in the acute and late setting. Biliary strictures were attributed to radiation if the patient did not have biliary obstruction before treatment or local progression at the time of stricture.

ine characteristics and adverse events were tabulated. Each symptom was counted once per patient at the highest grade it occurred in the acute and late setting. Biliary strictures were attributed to radiation if the patient did not have biliary obstruction before treatment or local progression at the time of stricture. Patients had follow-up imaging by CT scan every 3 months when possible. Local control was determined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria.19 Patients who did not have follow-up imaging at our institution were excluded from the RECIST analysis. Overall survival (OS) and progression-free survival (PFS) were calculated from diagnosis and from the start date of radiation to date of death or progression by the Kaplan-Meier method. PFS was determined radiographically and/or by clinical decline defined as decreasing performance status or development of ascites prohibiting therapeutic treatment in the absence of objective progression. Spearman rank correlation was used to determine if age, Eastern Cooperative Oncology Group (ECOG) performance status, CCI, baseline CA 19-9, dose, chemotherapy regimen, number of chemotherapy cycles before radiation, or time to radiation from diagnosis influenced outcomes. Log-rank was used to examine survival differences among subgroups. Fisher exact test was used to determine if local control and toxicity were affected by radiation dose or chemotherapy regimen. This study was approved by the Georgetown University Institutional Review Board.

radiation from diagnosis influenced outcomes. Log-rank was used to examine survival differences among subgroups. Fisher exact test was used to determine if local control and toxicity were affected by radiation dose or chemotherapy regimen. This study was approved by the Georgetown University Institutional Review Board. RESULTS Patient Characteristics From January 1, 2008 and December 31, 2012, 38 patients were treated with SBRT and chemotherapy for unresected, nonmetastatic pancreatic adenocarcinoma. The first 10 patients were treated on a phase I study and the remainder were treated off protocol. Patient characteristics are given in Table 1. Median age was 70 years (range, 45 to 90 y). ECOG performance status ranged from 0 to 3 and the median CCI was 4 (range, 0 to 8). The majority of patients (n=28) were unresectable, 6 patients were borderline resectable, and the rest were medically inoperable or refused surgery, but had resectable disease. Twenty-seven patients had T4 primary tumors and 21 patients had nodal disease. Median baseline CA 19-9 of the cohort was 463 U/mL. TABLE 1 Patient and Treatment Characteristics

RESULTS Patient Characteristics From January 1, 2008 and December 31, 2012, 38 patients were treated with SBRT and chemotherapy for unresected, nonmetastatic pancreatic adenocarcinoma. The first 10 patients were treated on a phase I study and the remainder were treated off protocol. Patient characteristics are given in Table 1. Median age was 70 years (range, 45 to 90 y). ECOG performance status ranged from 0 to 3 and the median CCI was 4 (range, 0 to 8). The majority of patients (n=28) were unresectable, 6 patients were borderline resectable, and the rest were medically inoperable or refused surgery, but had resectable disease. Twenty-seven patients had T4 primary tumors and 21 patients had nodal disease. Median baseline CA 19-9 of the cohort was 463 U/mL. TABLE 1 Patient and Treatment Characteristics Treatment Most patients received concurrent chemotherapy with gemcitabine (21 patients). Other regimens included mFOLFOX, 5-FU, and capecitabine. Four patients included in this study received sequential chemotherapy. Median time from diagnosis to radiation treatment was 1.9 months. Early on patients were treated with 25 Gy (n=13) in 5 consecutive fractions. Later, patients received 30 Gy (n=24). One patient did not complete the prescribed course of SBRT and is not included in the outcomes analysis. This patient was on study and withdrew for unknown reasons. Median PTV volume was 278 mL (range, 129 to 548 mL) and median prescription isodose line was 77% (range, 71% to 86%) (Table 1). Only 2 patients, who were both borderline resectable, in this cohort went onto surgery. One had a R0 and the other had a R1 resection. The remaining 4 borderline resectable patients did not go on to surgery for various reasons. One patient refused surgery after neoadjuvant treatment was completed, 2 patients had distant progression during neoadjuvant treatment, and finally, 1 patient had a decline in performance status due to age and medical comorbidities, which precluded surgical resection.

ients did not go on to surgery for various reasons. One patient refused surgery after neoadjuvant treatment was completed, 2 patients had distant progression during neoadjuvant treatment, and finally, 1 patient had a decline in performance status due to age and medical comorbidities, which precluded surgical resection. Local Control Local RECIST response was evaluable for 33 patients. Only 1 patient had a partial response, but then had local progression at a later time. All other patients had stable local disease as their best response, except 1 who had progressive local disease at first radiographic follow-up. At a median radiographic follow-up time of 7.2 months from radiation, 7 patients failed locally for an overall local control rate of 79%. The 6-month local control was 82%. Local failure occurred as the first site of failure in 3 patients. Three patients simultaneously failed locally and distantly and 1 patient experienced local failure after distant failure. Higher dose, 30 Gy as opposed to 25 Gy, was almost significant for local control (P=0.07) by Fisher exact test.

al control was 82%. Local failure occurred as the first site of failure in 3 patients. Three patients simultaneously failed locally and distantly and 1 patient experienced local failure after distant failure. Higher dose, 30 Gy as opposed to 25 Gy, was almost significant for local control (P=0.07) by Fisher exact test. Survival Median OS was 14.3 months and median PFS was 9.2 months from diagnosis (Fig. 1A). From the start date of radiation, OS and PFS were 12.3 and 6.8 months, respectively (Fig. 1B). There was not a significant difference in survival when comparing borderline resectable patients to unresectable (P=0.08). Patients with a baseline CA 19-9 below the median before SBRT had significantly better PFS (hazard ratio=0.2800, P=0.0002) (Fig. 2). CA 19-9 remained significant when tested in rank correlation (P=0.0005). Higher dose (30 vs. 25 Gy) was almost a significant factor for PFS from radiation with a P value of 0.0637 (Fig. 3). No other factors tested were found to significantly influence survival outcomes. FIGURE 1 Kaplan Meier overall survival and progression-free survival curves. A, Results calculated from diagnosis. B, Results calculated from radiation. FIGURE 2 Progression-free survival from radiation by CA 19-9 level before radiation treatment. Median CA 19-9=463; hazard ratio=0.2800; 95% CI, 0.1149-0.6822; P=0.0002. FIGURE 3 Progression-free survival from radiation by dose (P=0.0637).

FIGURE 1 Kaplan Meier overall survival and progression-free survival curves. A, Results calculated from diagnosis. B, Results calculated from radiation. FIGURE 2 Progression-free survival from radiation by CA 19-9 level before radiation treatment. Median CA 19-9=463; hazard ratio=0.2800; 95% CI, 0.1149-0.6822; P=0.0002. FIGURE 3 Progression-free survival from radiation by dose (P=0.0637). Toxicity In the acute setting, patients generally experienced grade 1 or 2 fatigue, nausea, abdominal pain, and appetite loss. Two patients experienced grade 3 toxicity due to abdominal pain. In the late setting there was grade 5 hemorrhage in a patient who had no radiographic progression on previous scans 2 months prior. This patient had a pancreatic tail lesion and no evidence of duodenal invasion before treatment. Other late events included 3 grade 2 biliary strictures and 1 grade 4 biliary stricture, where the patient presented with ascending cholangitits and was admitted to the ICU. Finally, 1 patient experienced gastric outlet obstruction and required stent placement. All late toxicities occurred in patients who received 30 Gy except one of the grade 2 biliary strictures. This was not significantly different (P=0.39).

the patient presented with ascending cholangitits and was admitted to the ICU. Finally, 1 patient experienced gastric outlet obstruction and required stent placement. All late toxicities occurred in patients who received 30 Gy except one of the grade 2 biliary strictures. This was not significantly different (P=0.39). DISCUSSION Despite the high rates of distant metastases in pancreas cancer, local control is an important factor in the management of the disease. Local progression adversely affects quality of life and may lead to chronic pain, bleeding, and gastric obstruction. Due to the controversy regarding the role of conventionally fractionated radiation therapy for locally advanced pancreatic cancer, SBRT is an appealing alternative that offers significantly reduced treatment duration and better integration with chemotherapy.

may lead to chronic pain, bleeding, and gastric obstruction. Due to the controversy regarding the role of conventionally fractionated radiation therapy for locally advanced pancreatic cancer, SBRT is an appealing alternative that offers significantly reduced treatment duration and better integration with chemotherapy. We have previously reported the early results of a phase I study of 10 patients with locally advanced pancreatic cancer treated with SBRT (25 Gy in 5 fractions) and concurrent gemcitabine (1000 mg/m2) given the week before and after radiation for a total of 6 cycles.17 In this series, patients underwent serial endoscopies every 2 months postradiation to rigorously assess mucosal toxicities and no severe acute toxicity or late toxicities occurred; however, local control was low at 40%. In the current pooled analysis, the OS and PFS rates were not significantly different for patients treated on protocol versus those treated off protocol (P>0.05). In contrast, there was a trend toward improved PFS and local control with 30 Gy as compared with 25 Gy, which was the dose used during our earlier experience. Higher doses did not result in improved OS, which may indicate that metastatic disease progression has a greater impact on survival than local control. There was no significant difference in late toxicities with higher doses, but a detailed dose-volume histogram analysis is necessary to determine the impact of dose on complications rates.

result in improved OS, which may indicate that metastatic disease progression has a greater impact on survival than local control. There was no significant difference in late toxicities with higher doses, but a detailed dose-volume histogram analysis is necessary to determine the impact of dose on complications rates. There was a grade 5 hemorrhage that occurred 3.7 months after radiation in a patient with a large (PTV=369.2 mL) pancreatic tail lesion, who received 30 Gy in 5 fractions. On previous CT imaging 2 months prior there was no evidence of local progression of disease. The exact location of the bleeding was not determined because autopsy was declined. Review of the dose-volume histogram revealed that dose constraints were met. Although tumor progression could not be excluded as the cause the bleeding, this toxicity was considered as possibly related to treatment. Others have reported on the incidence of gastrointestinal (GI) bleeding after radiation with concurrent chemotherapy for pancreatic cancer. In series with conventional or intensity modulated radiation therapy radiation, the rates vary from 7.5% to 20% for grade 3 or higher GI hemorrhage.20–22 In comparison, published rates of GI bleeding after SBRT range from 4% to 5%.14,23–25 To reduce rates of late GI complications we assessed the duodenal mucosal by endoscopy before SBRT and excluded patients with biopsy-proven duodenal invasion. Further study is necessary to characterize risk factors that are predictive for late radiation-related GI toxicity, including a dose-volume histogram analysis.

5 To reduce rates of late GI complications we assessed the duodenal mucosal by endoscopy before SBRT and excluded patients with biopsy-proven duodenal invasion. Further study is necessary to characterize risk factors that are predictive for late radiation-related GI toxicity, including a dose-volume histogram analysis. Other limitations of this study are because of its retrospective nature and small size. As with any retrospective analysis there is selection bias. Furthermore, most patients were not on a protocol resulting in variable record keeping. Also, there is heterogeneity among the chemotherapy timing and regimens. Although a comparison was made and no difference in outcomes was discovered between number of cycles, time to SBRT, or regimen, our numbers are small and underpowered to detect one if it exists.

on a protocol resulting in variable record keeping. Also, there is heterogeneity among the chemotherapy timing and regimens. Although a comparison was made and no difference in outcomes was discovered between number of cycles, time to SBRT, or regimen, our numbers are small and underpowered to detect one if it exists. The clinical outcomes in this study are similar to the previously published reports of SBRT for pancreatic cancer. A summary of selected trials is shown in Table 2. One of the earliest reports by Schellenberg et al12 administered gemcitabine for 1 cycle followed by SBRT, 25 Gy in 1 fraction with a week break before and after radiation. Patients then received adjuvant gemcitabine until progression. A median OS of 11.4 months and median PFS of 9 months were reported. The local control rate was 81% with all failures occurring after 1 year. There were 2 grade 3 or greater late toxicities which included a duodenal perforation requiring surgery and a duodenal stricture that required stent placement. In an updated report, 73 patients were treated with 25 Gy in 1 fraction, and the 6- and 12-month grade 2 or higher rate of gastrointestinal toxicity was 11% and 29%, respectively.13 TABLE 2 Study Comparison of Stereotactic Body Radiation Therapy (SBRT) for Pancreatic Cancer

The clinical outcomes in this study are similar to the previously published reports of SBRT for pancreatic cancer. A summary of selected trials is shown in Table 2. One of the earliest reports by Schellenberg et al12 administered gemcitabine for 1 cycle followed by SBRT, 25 Gy in 1 fraction with a week break before and after radiation. Patients then received adjuvant gemcitabine until progression. A median OS of 11.4 months and median PFS of 9 months were reported. The local control rate was 81% with all failures occurring after 1 year. There were 2 grade 3 or greater late toxicities which included a duodenal perforation requiring surgery and a duodenal stricture that required stent placement. In an updated report, 73 patients were treated with 25 Gy in 1 fraction, and the 6- and 12-month grade 2 or higher rate of gastrointestinal toxicity was 11% and 29%, respectively.13 TABLE 2 Study Comparison of Stereotactic Body Radiation Therapy (SBRT) for Pancreatic Cancer Chuong et al25 have also reported the results of chemotherapy combined with a 5-fraction SBRT course. Using an integrated boost technique, the tumor received 25 to 30 Gy and the involved vasculature received 35 to 50 Gy. There was no standard adjuvant treatment. Median OS for locally advanced patients was 15 months and median PFS was 9.7 months. Thirty-two of 57 patients with borderline resectable disease underwent resection, demonstrating the feasibility of surgery following SBRT. The median overall OS and PFS for borderline resectable patients were 16.4 and 9.8 months, respectively. For patients who did not undergo resection, local control was 81% at 1 year. Late toxicity included 3 grade 3 GI bleeds and 1 patient who required feeding tube placement for anorexia.

lity of surgery following SBRT. The median overall OS and PFS for borderline resectable patients were 16.4 and 9.8 months, respectively. For patients who did not undergo resection, local control was 81% at 1 year. Late toxicity included 3 grade 3 GI bleeds and 1 patient who required feeding tube placement for anorexia. Conventionally fractionated radiation therapy is delivered over 5 to 6 weeks and often requires alternations in chemotherapy. In our study, 34 patients received chemotherapy within 1 week of initiating SBRT, which significantly minimized interruptions in systemic therapy. Mahadevan et al14 similarly describes excellent outcomes with SBRT applied within a week of receiving chemotherapy. Patients were treated with 24 to 36 Gy in 3 fractions given during the off week between the third and fourth cycle of gemcitabine. The median OS was 20 months and the median PFS was 15 months. Local control was 85% at 21 months. Late toxicity included 2 grade 3 GI bleeds and 1 grade 3 gastric outlet obstruction. Polistina et al26 reports somewhat inferior results with a median OS of 10.6 months and median PFS of 7.3 months using a very similar regimen; however, there was a larger break between chemotherapy and SBRT. The SBRT fractionation was slightly different with all patients receiving 30 Gy in 3 fractions. Interestingly, this study found that quality of life and pain improved after treatment in patients who responded to therapy.

nths using a very similar regimen; however, there was a larger break between chemotherapy and SBRT. The SBRT fractionation was slightly different with all patients receiving 30 Gy in 3 fractions. Interestingly, this study found that quality of life and pain improved after treatment in patients who responded to therapy. These studies of SBRT, predominantly involving patients with locally advanced pancreatic cancer, demonstrate outcomes that compare favorably with contemporary conventional chemoradiation trials. A meta-analysis, which included 274 patients treated with SBRT from single-institution series demonstrated a median survival of 12.6 months.27 Recent trials of conventionally fractionated radiation therapy have been designed with induction chemotherapy followed by chemoradiation. The SCALOP trial reported a median OS of 15.2 months for patients receiving concurrent CRT with capecitabine after induction gemcitabine and capecitabine.28 Patients in this trial, who received concurrent gemcitabine, had a slightly lower median OS of 13.4 months. Median PFS was 12.0 months in the capecitabine group and 10.4 months in the gemcitabine group. The 12-month local control rate was 70% for the entire group. The GERCOR pooled analysis of patients receiving induction chemotherapy followed by CRT reports median OS of 15 months and median PFS of 10.8 months.29 Other CRT trials without induction chemotherapy report median OS rates of 10.2 to 15.5 months.30–32

group. The 12-month local control rate was 70% for the entire group. The GERCOR pooled analysis of patients receiving induction chemotherapy followed by CRT reports median OS of 15 months and median PFS of 10.8 months.29 Other CRT trials without induction chemotherapy report median OS rates of 10.2 to 15.5 months.30–32 The role of conventionally fractionated radiation in locally advanced pancreatic cancer has been questioned with the early results of the LAP07 trail.33 In this study, patients with locally advanced pancreatic cancer were initially randomized to gemcitabine or gemcitabine plus erlotinib. Participants with controlled disease were subsequently randomized to further chemotherapy or conventional chemoradiation with capecitabine. Median OS in the chemotherapy alone arm was 16.4 months compared with 15.2 months for the chemoradiotherapy group. No significant differences in PFS were observed: 11.8 months for chemotherapy compared with 12.5 months for chemoradiotherapy. However, only OS and PFS survival outcomes are presented thus far. The quality of life and local control results have not been reported at this time.

with the investigational agent as previously presented for the initial 16 patients.18 Other than 2 patients who had transient abdominal pain associated with agent plus saline administration, possibly related adverse events were mainly grade 1, transient, asymptomatic laboratory abnormalities that were not dose related. The patients are numbered 1 to 18 by the order of treatment. Monitoring of the enzymes lactic dehydrogenase (LDH), alkaline phosphatase (AlkP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ glutamyltransferase (GGT) showed no elevation among patients 2, 3, 7, 8, 12, 15, 16, 17, and 18. Table 1 shows the time and frequency of patients who developed grade 1 liver function test elevations. As shown in Table 1, 4 patients had elevations before treatment and 6 others experienced elevation to grade 1 level after treatment. These minor fluctuations did not appear dose related; all except patient 14 were below dose level 5 and none occurred at the highest dose level. TABLE 1 Summary of Enzyme Abnormalities by Date

5.2 months for the chemoradiotherapy group. No significant differences in PFS were observed: 11.8 months for chemotherapy compared with 12.5 months for chemoradiotherapy. However, only OS and PFS survival outcomes are presented thus far. The quality of life and local control results have not been reported at this time. Although there is controversy regarding a survival benefit for conventionally fractionated radiation therapy, quality of life may be another relevant endpoint for future studies in unresectable pancreatic cancer. We have previously reported improvements in cancer-related gastrointestinal symptoms and no significant decrement in global quality with chemotherapy and SBRT.17 Several other studies have demonstrated improved quality of life after SBRT.26,34 SBRT can also be delivered with minimal acute treatment-related toxicity to elderly patients and those with a poor performance status. Kim et al35 demonstrated that SBRT is even safe in elderly patients older than 80 years and offered symptom relief in 80% of patients presenting with abdominal pain. In our study, the median age was 70 years old; 6 patients had an ECOG performance status of 2 or 3; and several patients had multiple medical comorbidities. Survival was not negatively affected by age, comorbidity, or performance status, indicating that SBRT is well tolerated in patients who may not be candidates for conventional radiation therapy.

as 70 years old; 6 patients had an ECOG performance status of 2 or 3; and several patients had multiple medical comorbidities. Survival was not negatively affected by age, comorbidity, or performance status, indicating that SBRT is well tolerated in patients who may not be candidates for conventional radiation therapy. Local control may become more relevant in LAPC as improvements in chemotherapy emerge. Eleven patients in our study received mFOLFOX with SBRT, which did not result in improved outcomes as compared with gemcitabine with SBRT. However, the small number patients in this study limits the power to detect a difference in outcomes. One new regimen, FOLFIRINOX has an objective response rate of 31.6% and improved survival rates in the metastatic setting.36 With the increased use of FOLFIRINOX in localized disease, patients with extended survival may benefit from durable local control. Future studies of SBRT should integrate FOLFIRINOX into the treatment paradigm. In summary, SBRT combined with chemotherapy for unresectable pancreatic cancer is convenient, feasible, and generally well tolerated. Our findings support the use of 30 Gy as opposed to 25 Gy due to the improvement in local control. The outcomes of SBRT combined with chemotherapy compare favorably to the results of treatment with chemotherapy and conventional radiation therapy. SBRT for pancreatic cancer should be considered for use in randomized trials. S.P.C. is an Accuray clinical consultant. The other authors declare no conflicts of interest.

Low toxicity intraperitoneal (IP) treatment continues to be an unmet need for disease that spreads through the cavity such as ovarian and pancreatic cancer. IP chemotherapy has improved survival of ovarian cancer patients but carries risk of life-threatening toxicity, and has not become the standard at most institutions.1 Radiopharmaceuticals have greater potential than external beam radiation due to dose-limiting tolerance of normal organs. β-emitting radiopharmaceuticals have shown modest impact but have also been used at dose-limiting toxicity levels.2–5 Targeted α-emitter radiopharmaceuticals, as implemented in this report, have the potential advantages of improved efficacy with less toxicity than β-emitters.

o dose-limiting tolerance of normal organs. β-emitting radiopharmaceuticals have shown modest impact but have also been used at dose-limiting toxicity levels.2–5 Targeted α-emitter radiopharmaceuticals, as implemented in this report, have the potential advantages of improved efficacy with less toxicity than β-emitters. For targeted radionuclide therapy, the high ionization density of α-particles is attractive but their development/implementation has been challenging compared with the more widely available β-emitters.6,7 With the large helium particle emitted, α-decay results in significantly higher energy delivery (linear energy transfer) than β-decay, which results in higher cell-killing effectiveness. Human cell culture studies showed the relative biological effectiveness (RBE) greater for α-particles than that for β-radiation or kilovoltage photons8; this has been confirmed in other preclinical as well as early clinical trials but the RBE range has been variable from ∼1 to 20.9 The clinical experience where 213Bi-HuM195 and 90Y-HuM195 therapy could be directly compared in leukemic patients suggested that the RBE of α-emitter therapy will vary with cell type, geometry, and endpoints utilized.10 Another advantage of α-particles over β-radiation is the limited range of only a few cell diameters. This spares normal tissues but does limit optimal use to selected clinical applications. Appropriate clinical settings for use of high potency α-particles with short half-lives are those where the targeting is very specific and rapid or other conditions, such as into a resection cavity or tumor mass, where there is limited exposure to normal tissues.

The patients are numbered 1 to 18 by the order of treatment. Monitoring of the enzymes lactic dehydrogenase (LDH), alkaline phosphatase (AlkP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ glutamyltransferase (GGT) showed no elevation among patients 2, 3, 7, 8, 12, 15, 16, 17, and 18. Table 1 shows the time and frequency of patients who developed grade 1 liver function test elevations. As shown in Table 1, 4 patients had elevations before treatment and 6 others experienced elevation to grade 1 level after treatment. These minor fluctuations did not appear dose related; all except patient 14 were below dose level 5 and none occurred at the highest dose level. TABLE 1 Summary of Enzyme Abnormalities by Date Whereas hematologic toxicity has been dose-limiting in prior IP radionuclide conjugate studies, the mean platelet counts, total white blood cell counts, and neutrophil counts remained normal after a mean equivalent dose to marrow of 0.002 to 0.14 cGy/MBq. Only 2 patients had transient decreased counts to grade 1 (platelets 142,000/μL, WBC 3500/μL without neutropenia). Anemia was not tracked for toxicity as 6 patients were anemic pretreatment with hemoglobin of 9.8 to 11.2 g/dL. The percent change at 6 weeks for these patients was from a loss of 3.8% to a gain of 16.3%. Three of the 6 had improvement to normal hemoglobin levels during that interval.

oes limit optimal use to selected clinical applications. Appropriate clinical settings for use of high potency α-particles with short half-lives are those where the targeting is very specific and rapid or other conditions, such as into a resection cavity or tumor mass, where there is limited exposure to normal tissues. Because of many hurdles, implementation of systemic administration using antibody targeted α conjugates has been limited to a few studies, mainly in patients with leukemia, lymphoma, and metastatic melanoma.7,11–13 Limited experience with nonsystemic administration has included intralesional melanoma sites, intracavity or intralesional for brain tumors, and intraperitoneal infusion.14–18 Whereas reports of others show more extensive pharmacokinetics and dosimetry of another α-emitter conjugate administered to the peritoneal cavity (211At-Mx35 F(Ab’)2), our following report is the first therapeutic IP administration where safety was the primary objective posttherapy.16,18,19 Targeted α-conjugate therapy has thus far been well tolerated but initial dose levels have been modest to minimize risks to patients undergoing investigational treatment. This first-in-human clinical trial of IP 212Pb-TCMC2-(4-isothiocyanobenzyl)-1,4,7,10-teraaza-1,4,7,10-tetra-(2-carbamonyl methyl)-cyclododecane-trastuzumab was initiated after extensive murine and nonhuman primate investigations provided biodistribution, safety, and antitumor efficacy data.20–24 In this phase I study, a single IP infusion of 212Pb-TCMC-trastuzumab was escalated over 6 dose levels with toxicity monitoring to confirm the safety of this agent.

ne-trastuzumab was initiated after extensive murine and nonhuman primate investigations provided biodistribution, safety, and antitumor efficacy data.20–24 In this phase I study, a single IP infusion of 212Pb-TCMC-trastuzumab was escalated over 6 dose levels with toxicity monitoring to confirm the safety of this agent. This trial, like many other investigations, studied serum tumor markers as indicators of therapeutic efficacy that could be easily and quickly monitored. This is particularly relevant given the limitations inherent in image-based quantification of peritoneal metastatic disease. Seven tumor markers were studied for their correlation to clinical outcome 6 weeks posttherapy. These included carcinoembryonic antigen (CEA), which is used for monitoring patients with gastrointestinal cancer and a minority of patients with other malignancies.25 Carbohydrate antigen (CA125) was monitored in the ovarian cancer patients as this has historically been the standard marker for monitoring of disease response to treatment.26–29 Human epididymis protein 4 (HE-4), serum amyloid A (SAA), mesothelin, interleukin-6 (IL-6), and tumor-associated glycoprotein (TAG-72), were also chosen for study based on prior reports of tumor association.30–36

nts as this has historically been the standard marker for monitoring of disease response to treatment.26–29 Human epididymis protein 4 (HE-4), serum amyloid A (SAA), mesothelin, interleukin-6 (IL-6), and tumor-associated glycoprotein (TAG-72), were also chosen for study based on prior reports of tumor association.30–36 METHODS Details of the trial design and agent preparation have been previously reported.17 Briefly, this trial provided a single IP 212Pb-TCMC-trastuzumab infusion <4 h after 4 mg/kg IV trastuzumab in patients with human epidermal growth factor receptor-2 (HER-2) expressing malignancy that had failed standard therapies. Modifications were made after patient 10 to allow patients with HER-2 of 1+ in ≥10% of cells. Modification was also made to discontinue the saturated solution of potassium iodide as imaging showed no thyroid localization and no abnormal laboratory values had been observed in >1 year for the initial 3 patients. The diuretic regimen was also shortened as there was no evidence of renal localization or toxicity and patients had difficulty with side effects such that most were noncompliant with the entire prescribed regimen. Monitoring over the duration of 1 year included clinical findings, laboratory values, cardiac studies, immunologic assays, serum tumor marker levels, and computed tomographic scans. Patients had clinical and/or laboratory posttherapy evaluations 7 times in the first 6 weeks. If there was no toxicity, scheduled monitoring was extended to 6-, and then to 12-week intervals. Cardiac monitoring used electrocardiogram and echocardiograms. Enzyme linked immunosorbent assay testing of 6-week serum samples was performed to determine if there was any evidence of an immune response to TCMC-trastuzumab. A standard anti-drug antibody assay was developed. Briefly, the anti-Her-2 antibody was both the coat and a biotinylated primary detection antibody. Patient serum or polyclonal antibodies raised against TCMC-trastuzumab was the analyte. In the presence of bivalent anti TCMC-trastuzumab antibodies, the biotinylated trastuzumab antibody becomes linked to the trastuzumab coat. HRP-streptavidin is then added to develop a signal. Toxicity was defined using Common Terminology Criteria for Adverse Events (version 4.03 National Cancer Institute). Imaging interpretation and lesion measurements from baseline (<4 w pretreatment) and 6-week interval posttreatment CT scans were performed as an independent review by Imaging Endpoints (Scottsdale, AZ).

. Toxicity was defined using Common Terminology Criteria for Adverse Events (version 4.03 National Cancer Institute). Imaging interpretation and lesion measurements from baseline (<4 w pretreatment) and 6-week interval posttreatment CT scans were performed as an independent review by Imaging Endpoints (Scottsdale, AZ). Lesion measurements were compared by pretreatment and posttreatment volumes as a modification from RECIST criteria described in the original study design that uses tumor diameter products.37 Levels of standard tumor markers CA125 and CEA were obtained at institution laboratories; commercially available kits were used for other markers HE-4 (Fujirebio Diagnostics Inc., in vitro diagnostics), Cancer antigen (CA 72-4) (TAG-72) (DRG International, Research Use Only), SAA (Life Technologies, Ruo), Mesothelin (Aviscera Bioscience Inc., Ruo), IL-6 (Abcam, Ruo). Serum for tumor markers was obtained pretreatment, at 6 weeks, and at additional timepoints for CEA and CA125 in most patients. Statistical analysis used least squares linear regression to fit the data.

nal, Research Use Only), SAA (Life Technologies, Ruo), Mesothelin (Aviscera Bioscience Inc., Ruo), IL-6 (Abcam, Ruo). Serum for tumor markers was obtained pretreatment, at 6 weeks, and at additional timepoints for CEA and CA125 in most patients. Statistical analysis used least squares linear regression to fit the data. RESULTS Toxicity Eighteen patients (age 46 to 83) treated at 6 dose levels (7.4, 9.6, 12.6, 16.3, 21.1, 27.4 MBq/m2) were monitored for at least 1 year or until death. Seventeen patients were treated at the University of Alabama at Birmingham, and 1 colon cancer patient was treated at the University of California at San Diego. Sixteen patients were females with ovarian cancer and 2 males had colon cancer. Treatment was well tolerated. Mild acute adverse effects were associated with the investigational agent as previously presented for the initial 16 patients.18 Other than 2 patients who had transient abdominal pain associated with agent plus saline administration, possibly related adverse events were mainly grade 1, transient, asymptomatic laboratory abnormalities that were not dose related.

WBC 3500/μL without neutropenia). Anemia was not tracked for toxicity as 6 patients were anemic pretreatment with hemoglobin of 9.8 to 11.2 g/dL. The percent change at 6 weeks for these patients was from a loss of 3.8% to a gain of 16.3%. Three of the 6 had improvement to normal hemoglobin levels during that interval. Four patients experienced periods of grade 1 creatinine elevation (without proteinuria) associated with dehydration or urinary tract obstruction as reported.18 Reducing the diuretic regimen after patient 10 did not increase the serum levels of radioactivity or result in renal toxicity. No late renal, liver, hematologic (excluding anemia as noted above), cardiac, or other toxicity has been observed with monitoring >1 year despite additional therapy after the investigational agent. Although all patients had disease progression in <8 months and proceeded with additional treatment, none refused continued monitoring. There were no clinical signs or symptoms of an immune response, and assays to detect an immune response to 212Pb-TCMC-trastuzumab were negative for all 15 of 15 tested (3 patients had no sample).

ll patients had disease progression in <8 months and proceeded with additional treatment, none refused continued monitoring. There were no clinical signs or symptoms of an immune response, and assays to detect an immune response to 212Pb-TCMC-trastuzumab were negative for all 15 of 15 tested (3 patients had no sample). Tumor Marker Changes Compared With Clinical Response Blood levels of 7 tumor markers were studied and compared with clinical outcome at 6 weeks posttherapy. CEA and CA125 continued to be obtained until progression. CEA increased with disease progression in the 2 colon cancer patients but all the ovarian cancer patients had levels that were within the normal range both pretreatment and posttreatment. Other tumor markers which are often associated with ovarian cancer, including CA125, mesothelin, IL-6, SAA, and HE-4, did not correlate with imaging outcome (Fig. 1). Only a TAG-72 had a pattern similar to that of tumor growth changes. TAG-72 levels covered a wide range from nearly 200% increase to 66% decrease 6 weeks posttherapy. Compared with the imaging changes, the TAG-72 pattern had a steeper slope and higher correlation coefficient with administered level of radioactivity than did tumor growth (R2 for TAG-72 is 0.73 vs. 0.21 for CT) as shown in Figure 2. Five patients did not have measurable tumor lesions (TL) and are not included in Figure 2. Their clinical outcome is included in Table 2, which shows a trend of less tumor growth, including regression, with increasing administered radioactivity. All patients had progression of disease inside and/or outside of the peritoneal cavity before 8 months but the majority lived >1 year, allowing monitoring for late toxicity.

inical outcome is included in Table 2, which shows a trend of less tumor growth, including regression, with increasing administered radioactivity. All patients had progression of disease inside and/or outside of the peritoneal cavity before 8 months but the majority lived >1 year, allowing monitoring for late toxicity. FIGURE 1 Each data point represents the increase or decrease in serum marker as percent change at 6 weeks compared with baseline for individual patients. The change in markers is compared with administered radioactivity in MBq/m2. Data points are not shown when values were within normal limits. FIGURE 2 Each data point represents a single patient who had measureable lesions and TAG-72 >6 U/mL at baseline. The data points are expressed as percent change from baseline. The lines represent best fit from regression analysis. TAG-72 indicates tumor-associated glycoprotein 72. TABLE 2 Comparison of Posttreatment Disease Status With Administered 212Pb Dose Level DISCUSSION The single IP 212Pb-TCMC-trastuzumab infusion was well tolerated with agent-related toxicities limited to grade 1 and the majority of them were asymptomatic, transient laboratory abnormalities. Although there was no visualization of radioactivity outside of the peritoneal cavity, blood collection showed a rate of <1% to 22.9% transit in 24 hours.18 The imaging and blood data allowed dosimetry calculations. These found low radiation exposure to normal organs and a mean tumor milieu to marrow ratio of >1000, as most of the radioactivity decay took place in the peritoneal fluid.17

ritoneal cavity, blood collection showed a rate of <1% to 22.9% transit in 24 hours.18 The imaging and blood data allowed dosimetry calculations. These found low radiation exposure to normal organs and a mean tumor milieu to marrow ratio of >1000, as most of the radioactivity decay took place in the peritoneal fluid.17 With >1 year of follow-up in the majority of patients receiving IP 212Pb-TCMC-trastuzumab, no late toxicity has been observed. The paucity of preclinical toxicity data allowed dose escalation for 6 levels, which is the maximum that was planned for this first-in-human study; further increase in dose levels would have soon exceeded preclinical data and required additional nonhuman primate studies.38 On the basis of this initial clinical experience, 212Pb-TCMC-trastuzumab appears safe for further study at the highest dose level tested or even additional dose escalation. As IP α-emitter therapy should be most effective for microscopic disease, the low toxicity should allow it to be further studied in combination with other agents or as an adjuvant after tumor reduction by standard therapies. The transient early toxicities did not appear to be dose related. The grade 1 leukopenia and thrombocytopenia occurred in patients at dose groups 3 and 5. No drops in blood counts to grade 1 were noted in the highest dose group, suggesting factors other than radiation dose alone were associated with the count levels posttherapy. Both of the affected patients had pretreatment levels of only 12% above the lower limits of normal such that a modest drop reached grade 1 level. As the radiation dose to marrow was small at 0.002 to 0.14 cGy/MBq, significant hematologic toxicity would not be expected and was not observed.18 Six of 16 ovarian cancer patients were anemic pretherapy and 3 had improvement to normal levels even during the initial 6 weeks posttherapy. The early posttreatment increase of hemoglobin would not have been expected with higher, marrow-toxic, doses of radiation and suggests incomplete recovery from toxicities of therapy before administration of this investigational agent.

y and 3 had improvement to normal levels even during the initial 6 weeks posttherapy. The early posttreatment increase of hemoglobin would not have been expected with higher, marrow-toxic, doses of radiation and suggests incomplete recovery from toxicities of therapy before administration of this investigational agent. Both methods of index lesion measurement, individual volume versus sum of lesion diameter products, showed a trend of less tumor growth with increasing level of administered radioactivity. The independent review shows more early patients with progression than previously noted when pretreatment and posttreatment comparison used the product of index lesion diameter (Table 2).17,37 However, the later independent review did not necessarily use the same index lesions, which contributed to less than complete concordance of tumor growth results from those previously reported.17 Although the optimal tumor efficacy with α-emitters is proposed to be for microscopic disease, regression was noted among various sized gross lesions.

dent review did not necessarily use the same index lesions, which contributed to less than complete concordance of tumor growth results from those previously reported.17 Although the optimal tumor efficacy with α-emitters is proposed to be for microscopic disease, regression was noted among various sized gross lesions. Many investigators continue to seek serum tumor markers to facilitate diagnosis and monitoring of therapeutic efficacy. Although CA125 has become the standard marker for monitoring antitumor effects in ovarian cancer, checking this alone has not been rigorous enough to become a standard for diagnostic screening.39 Its use in conjunction with other serum markers, plus additional factors, has been more helpful.30,40 Other potential markers under study for ovarian cancer include IL-6, IL-8, kallikrein-10, mesolthelin, HE-4, and p53.41–44 Also, SAA may be useful in serous subtype of ovarian carcinoma.45

d for diagnostic screening.39 Its use in conjunction with other serum markers, plus additional factors, has been more helpful.30,40 Other potential markers under study for ovarian cancer include IL-6, IL-8, kallikrein-10, mesolthelin, HE-4, and p53.41–44 Also, SAA may be useful in serous subtype of ovarian carcinoma.45 In this study, several tumor markers were monitored to determine their potential utility for noninvasive assessment of therapeutic response. Although levels of the standard ovarian cancer tumor marker CA125 did not have a strong relation to outcome, CA125 may have been a better marker had the pretreatment level been obtained closer to the time to treatment. With the measures of this noncancer specific protein usually 2 to 4 weeks before therapy plus intervening manipulation of the peritoneal cavity with catheter insertion and treatment, the posttreatment levels may have been elevated by factors other than tumor burden. One might expect that elevation related to disruption by catheter placement and therapy would have resolved by 6 weeks but further study would be needed to seek relevant information for this determination.

heter insertion and treatment, the posttreatment levels may have been elevated by factors other than tumor burden. One might expect that elevation related to disruption by catheter placement and therapy would have resolved by 6 weeks but further study would be needed to seek relevant information for this determination. HE-4 has also been studied as a tumor marker of ovarian cancer. It has been more helpful for diagnosis than for monitoring therapeutic response. HE-4 has most frequently been used in conjunction with CA125 and other factors to distinguish ovarian cancer from a benign abdominal process.40,46,47 The mucin-like TAG-72 is generally expressed on adenocarcinomas and less frequently in other types of malignancies.48–50 The only normal tissue with notable TAG-72 expression is secretory endometrium, which was not of concern in this study as none of the patients had an intact uterus.49,50 Tumor shedding of TAG-72 is common and may allow potential noninvasive monitoring of tumor status via blood levels,49 with the assumption that it correlates with tumor burden in an individual patient. TAG-72 had the strongest correlation with CT-monitored tumor changes of the 7 markers reported here. None of the other markers tested showed a good correlation with increasing radioactivity or clinical outcome. Although they have all been associated with ovarian cancer, CA125 is the only marker robust enough to routinely be used and it is not cancer specific. TAG-72 had a relatively robust association with increasing administered radioactivity, having a correlation coefficient of 0.73. On the basis of that, plus its decreasing trend with decreasing tumor growth, a dose/response relation with administered radioactivity is suggested. Additional data are needed to confirm this and to further investigate TAG-72 as a serum marker of response to 212Pb-TCMC-trastuzumab. CEA is a serum marker used as a standard in monitoring response to therapy in colon/rectal cancer. We found it was helpful in the 2 colon cancer patients in this study. CEA may be elevated, and thus is a potential marker for monitoring other gastrointestinal malignancies as well other malignancies of nongastrointestinal origin albeit in a smaller fraction of patients. In this study, all the ovarian cancer patients had normal CEA levels pretreatment and none experienced elevated levels at follow-up, even when disease progression was noted from imaging and other markers (TAG-72).

nancies as well other malignancies of nongastrointestinal origin albeit in a smaller fraction of patients. In this study, all the ovarian cancer patients had normal CEA levels pretreatment and none experienced elevated levels at follow-up, even when disease progression was noted from imaging and other markers (TAG-72). CONCLUSIONS IP 212Pb-TCMC-trastuzumab up to 27.4 MBq/m2 appears safe for further study and dose escalation. Serum TAG-72 monitoring is recommended as a potential tumor marker for assessing antitumor effects in patients with ovarian cancer. ACKNOWLEDGMENTS The authors thank many for conduct of this study that required an international team: J. Maxwell Austin, Souheil Saddekni, Jacob Estes, Andres Forero, Melissa Baird, Charles Leath, III, Mack Barnes, Desiree Morgan, the late Michael Azure, Jinda Fan, Denise Charlotte Jeffers, Sui Shen, Darrell Fisher, Brenda Sandmaier, Olivier Rixe, Kurt Zinn, Ronda Carlise, Alma Del Grosso, Rebecca Quinn, Robert Oster, Rusty Caranto, Daniel Yoder, Lolinda Brown, Martin Brechbiel, Shakeela Dad, Debbie Soldano, Paul Fanta, Thelma Webb, and Brandy Jonas. Supported by AREVA Med and NIH CCTS grant 1UL1TR001417. J.J.T., T.A.R., and E.P.B. are AREVA Med employees. R.F.M. joined the Scientific Advisory Board July 2015. The other authors declare no conflicts of interest.

The rate of contralateral prophylactic mastectomy (CPM) has risen sharply in the past decade.1–4 This increase has been associated with a number of factors including patients’ perception that CPM improves survival (vs. unilateral mastectomy).5 However, there has been no survival benefit from CPM demonstrated in the absence of specific risk factors (eg, a BRCA1/2 mutation),6–9 and the procedure is both more costly than unilateral mastectomy10 and is associated with significant increases in a subset of surgical site complications.11 Consequently, expert medical recommendations, such as those from the National Comprehensive Cancer Network, advise that women with unilateral breast cancer should not undergo CPM in the absence of factors that strongly increase breast cancer risk (http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf, https://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf). Indeed, research on predictors of CPM indicates that the decade’s increase is patient driven rather than surgeon driven.12–14 Large-scale studies of demographic factors demonstrate that women are more likely to undergo CPM if they are younger, more affluent, well insured, and white.15,16 Taken together, these factors suggest a profile of CPM patients who have the resources and competencies to successfully advocate for procedures their physicians do not necessarily support. In addition, a recent study found a 3-fold increase in CPM when patients reported a “patient-driven decision” versus a “physician-driven decision.”5

hese factors suggest a profile of CPM patients who have the resources and competencies to successfully advocate for procedures their physicians do not necessarily support. In addition, a recent study found a 3-fold increase in CPM when patients reported a “patient-driven decision” versus a “physician-driven decision.”5 However, women with breast cancer are also wives, mothers, daughters, sisters, and friends, and as such, their decisions about breast cancer treatments are made in the context of these relationships.17 Breast cancer patients often bring spouses, friends, or children with them to medical visits18 and depend on them for multiple forms of support,19 which can include participation in decision-making.17,20 Women with breast cancer also utilize traditional mass media, the Internet, and social media, where they have a high likelihood of encountering information about breast cancer, ranging from science news reports to stories about celebrities with breast cancer.21–24

hich can include participation in decision-making.17,20 Women with breast cancer also utilize traditional mass media, the Internet, and social media, where they have a high likelihood of encountering information about breast cancer, ranging from science news reports to stories about celebrities with breast cancer.21–24 To the extent that social network members and mass media are significant influences on patient demand for CPM, the medical community will need to address these influences if the existing trend is to be halted and reversed. To date, several authors have asserted that social network members affect patients’ CPM choices,24 but there has been little systematic attention to this influence. In perhaps the only study to date that has assessed social network influence on CPM decisions, Soran et al25 reported that 49% of the women in their study were influenced by spouses or partners, 30% by friends and relatives, and 25% by their mothers. Women in their study also reported that 68% of spouses/partners were positive toward CPM, as were 64% of friends and relatives. The current study was designed to provide a more detailed analysis of social network influence on CPM decision-making, examining not only who influenced the decision-making, and to what extent, but also the type of influence exerted. MATERIALS AND METHODS Ethics This study was approved by the Indiana University Institutional Review Board (IRB-04, protocol number 1210009689; and IRB-03, protocol number 1304011094). All research was carried out in compliance with the Helsinki Declaration.

To the extent that social network members and mass media are significant influences on patient demand for CPM, the medical community will need to address these influences if the existing trend is to be halted and reversed. To date, several authors have asserted that social network members affect patients’ CPM choices,24 but there has been little systematic attention to this influence. In perhaps the only study to date that has assessed social network influence on CPM decisions, Soran et al25 reported that 49% of the women in their study were influenced by spouses or partners, 30% by friends and relatives, and 25% by their mothers. Women in their study also reported that 68% of spouses/partners were positive toward CPM, as were 64% of friends and relatives. The current study was designed to provide a more detailed analysis of social network influence on CPM decision-making, examining not only who influenced the decision-making, and to what extent, but also the type of influence exerted. MATERIALS AND METHODS Ethics This study was approved by the Indiana University Institutional Review Board (IRB-04, protocol number 1210009689; and IRB-03, protocol number 1304011094). All research was carried out in compliance with the Helsinki Declaration. Participants Potential participants were identified from the Indiana University, Wishard (now the Sidney and Lois Eskenazi Hospital), IU Health North and IU Health West hospital billing records using the procedure code for bilateral mastectomy during the years 2008 to 2012. The lists were then curated to identify patients who had undergone CPM (n=326). The patient’s name, address, telephone number, and hospital location were obtained from the medical health record system. These patients were mailed an introductory letter and study information sheet, after which they were contacted by telephone and a structured interview conducted with those who agreed (n=117). Only 16 patients contacted were recorded as explicitly refusing the interview; no reasons were provided, and information about these patients was not retained. Nonparticipation of all others resulted from inability to reach patients at the phone numbers in their records. Data were collected in the summer and fall of 2013, so there was some overlap between the period of data collection and media attention given to Angelina Jolie’s prophylactic double mastectomy (http://www.nytimes.com/2013/05/14/opinion/my-medical-choice.html). However, all the surgical decisions were made before 2013.

Data were collected in the summer and fall of 2013, so there was some overlap between the period of data collection and media attention given to Angelina Jolie’s prophylactic double mastectomy (http://www.nytimes.com/2013/05/14/opinion/my-medical-choice.html). However, all the surgical decisions were made before 2013. All participants were women (n=117, 100%); 4 patients self-identified as BRCA positive, and their data were removed from analysis because this suggests that CPM was medically indicated, changing the nature of the surgical decision-making process. Participant demographics (n=113) reflect participant status at the time of the surgery. Participants were aged 22 to 73 (M=50.29, SD=12.50), predominately married (n=86, 77%), employed (n=73, 66%), and had private insurance (n=80, 71%). Participants identified as white (n=99, 88%), black (n=12, 11%), and Hispanic (n=2, 1.8%). Participants varied by household income: <25K (n=7, 6.20%), 26 to 50K (n=20, 17.7%), 51 to 75K (n=25, 22.1%), 76 to 100K (n=17, 15%), and >101K (n=30, 10.6%). Participants reported various degrees of education: high school or less (n=22, 19.5%), some college (n=36, 31.9%), bachelor’s degree (n=32, 28.3%), and graduate education (n=21, 18.6%). Most women reported diagnoses of invasive ductal cancer (n=31, 26.5%), ductal carcinoma in situ (n=24, 20.5%), invasive cancer (n=27, 23.1%), and invasive lobular cancer (n=9, 7.7%). Most were diagnosed in 2008 to 2012. Four participants with diagnosis dates before 2008 reported having had CPM after a local recurrence.

Most women reported diagnoses of invasive ductal cancer (n=31, 26.5%), ductal carcinoma in situ (n=24, 20.5%), invasive cancer (n=27, 23.1%), and invasive lobular cancer (n=9, 7.7%). Most were diagnosed in 2008 to 2012. Four participants with diagnosis dates before 2008 reported having had CPM after a local recurrence. Protocol This analysis was part of a larger investigation of how breast cancer patients select CPM. Participants initially responded to items reporting their individual motivations for undergoing CPM; analyses of these data are reported elsewhere (Baptiste DF, MacGeorge EL, Venetis MK, Mouton A, Friley LB, Pastor R, Hatten K, Lagoo J, Clare SE, and Bowling MW. 2016; submitted for publication). Then, participants were asked to identify everyone with whom they had talked about what kind of surgery to have, including both social network members and health care providers other than surgeons. For each member of the social network, participants provided the relationship to the other (ie, friend, mother, husband), the other’s history with breast cancer (with or without history of breast cancer), the degree of influence ranging from 0 (no influence) to 5 (great deal of influence), and a free-response description of the type of influence exerted. For each health care provider, participants provided the type of relationship (eg, nurse practitioner, counselor), degree of influence, and free-response description of influence. Participants were then asked to describe the discussion they had with the surgeon about the surgical decision, followed by 2 closed-ended questions about whether the surgeon suggested CPM and supported CPM. Finally, participants were asked whether the media had played role in their decisions, and if so, to describe that influence. The interview concluded with questions about race, education, employment, income, and insurance.

, followed by 2 closed-ended questions about whether the surgeon suggested CPM and supported CPM. Finally, participants were asked whether the media had played role in their decisions, and if so, to describe that influence. The interview concluded with questions about race, education, employment, income, and insurance. On the basis of review of the data, 2 of the authors (E.L.M. and M.K.V.) created coding categories for the types of influence exerted by social network members and nonsurgeon health care professionals. Definitions and examples are provided in Table 1. Similarly, coding categories were created for the types of influence exerted by surgeons (Table 2). These authors individually coded the data. Coding reliability between authors was good (Krippendorff α=0.77 for the 8 types of network influence and 0.84 for the 4 types of surgeon influence). Discrepancies were resolved through discussion. TABLE 1 Types of Influence TABLE 2 Surgeon Influence in Discussion of Surgery

On the basis of review of the data, 2 of the authors (E.L.M. and M.K.V.) created coding categories for the types of influence exerted by social network members and nonsurgeon health care professionals. Definitions and examples are provided in Table 1. Similarly, coding categories were created for the types of influence exerted by surgeons (Table 2). These authors individually coded the data. Coding reliability between authors was good (Krippendorff α=0.77 for the 8 types of network influence and 0.84 for the 4 types of surgeon influence). Discrepancies were resolved through discussion. TABLE 1 Types of Influence TABLE 2 Surgeon Influence in Discussion of Surgery RESULTS As shown in Table 3, nearly all participants reported discussing their surgical options with at least 1 person other than a surgeon; only 3 reported not talking with anyone. Many reported talking with male spouses or partners, 1 or more friends or family members who had experienced breast cancer, and 1 or more friends or family members who had not experienced breast cancer. Smaller percentages reported talking with health professionals, such as a medical oncologist, nurse, therapist, or member of the clergy, and with children. Median and modal values indicate that the “typical” participant talked with 2 or 3 people about the surgical decision. TABLE 3 People Talked With and Influenced by

RESULTS As shown in Table 3, nearly all participants reported discussing their surgical options with at least 1 person other than a surgeon; only 3 reported not talking with anyone. Many reported talking with male spouses or partners, 1 or more friends or family members who had experienced breast cancer, and 1 or more friends or family members who had not experienced breast cancer. Smaller percentages reported talking with health professionals, such as a medical oncologist, nurse, therapist, or member of the clergy, and with children. Median and modal values indicate that the “typical” participant talked with 2 or 3 people about the surgical decision. TABLE 3 People Talked With and Influenced by Also as shown in Table 3, most participants also reported at that least one of the individuals they talked with influenced the decision to some degree. Participants most frequently reported as “influencers” their spouses, family, and friends with a history of breast cancer, followed by health professionals, family, and friends without experience of breast cancer, and children. As indicated by the median and modal values, the “typical” participant’s decision was influenced by 2 people.

frequently reported as “influencers” their spouses, family, and friends with a history of breast cancer, followed by health professionals, family, and friends without experience of breast cancer, and children. As indicated by the median and modal values, the “typical” participant’s decision was influenced by 2 people. On average, spouses, children, family, friends, and health professionals exerted a meaningful degree of influence, with a mean of 3.2 (SD=1.25) on a scale where 3 corresponds with “some influence.” The greatest average influence was reported from spouses/partners (M=3.67, SD=1.36) and children (M=3.65, SD=1.32), followed by family and friends without a history of breast cancer (M=3.48, SD=1.45), family and friends with a history of breast cancer (M=3.43, SD=1.37), and nonsurgeon health professionals (M=2.95, SD=1.41). However, paired-samples t tests revealed that these mean differences were not significant; P-values for all tests exceeded 0.05, indicating that the quantity of influence exerted by individuals in these groups is not statistically different.

ncer (M=3.43, SD=1.37), and nonsurgeon health professionals (M=2.95, SD=1.41). However, paired-samples t tests revealed that these mean differences were not significant; P-values for all tests exceeded 0.05, indicating that the quantity of influence exerted by individuals in these groups is not statistically different. As shown in Table 4, there was variation in the type of influence exerted by members of the social network. A 1-way χ2 test indicates that this variation is significant (χ27=106.66, P<0.001). The most common type of influence was experiential, in which a social network member had direct or indirect experience with breast cancer that the participant reported as influence. Although the details reported were diverse, most responses in this category focused on cancer recurrence after lumpectomy or a new contralateral primary after a single mastectomy, family history of cancer, or (less commonly) on satisfaction with CPM. Consequently, the experiential form of influence consists largely of implicit support for CPM (from the patient’s perspective). Moderately (and similarly) frequent forms of influence were (in order of frequency) supporting the patient’s choice, providing information, encouraging CPM (explicitly), being generally supportive, and allowing the patient to talk about the decision. Deciding together and discouraging CPM were infrequent. TABLE 4 Frequency of Influence Types in Different Relationships

As shown in Table 4, there was variation in the type of influence exerted by members of the social network. A 1-way χ2 test indicates that this variation is significant (χ27=106.66, P<0.001). The most common type of influence was experiential, in which a social network member had direct or indirect experience with breast cancer that the participant reported as influence. Although the details reported were diverse, most responses in this category focused on cancer recurrence after lumpectomy or a new contralateral primary after a single mastectomy, family history of cancer, or (less commonly) on satisfaction with CPM. Consequently, the experiential form of influence consists largely of implicit support for CPM (from the patient’s perspective). Moderately (and similarly) frequent forms of influence were (in order of frequency) supporting the patient’s choice, providing information, encouraging CPM (explicitly), being generally supportive, and allowing the patient to talk about the decision. Deciding together and discouraging CPM were infrequent. TABLE 4 Frequency of Influence Types in Different Relationships Different influence strategies were also more and less frequent in different types of relationships. Discouraging CPM and deciding together occurred too infrequently to be included in a 2-way χ2 analysis (they resulted in multiple cells with very low expected frequencies). The number of influence attempts reported from children was also too small to be treated as a separate category, so influence by children was combined with spouse/partner, as these relationships were both in the participant’s nuclear family and their reported quantity of influence was highly similar. The 2-way χ2 assessing the frequency of the 6 most frequent influence types in the 4 relationship types indicated that the observed variation is significant (χ215=233.04, Cramer V=0.557, P<0.001). As shown in Table 4, family and friends who had experienced breast cancer were most frequently reported to exert experiential influence, whereas health professionals typically provided information. Spouses, children, and family or friends who had not experienced breast cancer tended to use the remaining influence types: talking, encouraging CPM, supporting the patient’s choice, and being generally supportive.

ly reported to exert experiential influence, whereas health professionals typically provided information. Spouses, children, and family or friends who had not experienced breast cancer tended to use the remaining influence types: talking, encouraging CPM, supporting the patient’s choice, and being generally supportive. As shown in Table 2, most participants described the surgeon’s behavior during the discussion of surgery as providing options. Relatively few were reported to explicitly encourage or discourage CPM. A 1-way χ2 test indicates that this variation is statistically significant (χ23=117.11, P<0.001). However, somewhat more than half (N=62, 54.9%) of participants reported that their surgeons suggested CPM, whereas somewhat less than half (N=49, 43.4%) said their surgeons did not (2 participants did not answer this question). Only 1 participant reported that the surgeon did not support her choice of CPM; aside from the 2 who did not answer, all other participants believed their surgeons supported their choice. A minority of participants (N=31, 27.4%) reported some degree of media influence on the decision to elect CPM. Sources of reported influence included television (n=12), Internet (n=11), radio (n=2), and books (n=6). Some participants mentioned specific celebrities and authors such as Christina Applegate, Suzanne Summers, Susan Love, and Dianna Duberry (an Indianapolis news anchor). Others mentioned a range of stories focused on breast cancer topics, including mammograms, diagnosis, mortality, mastectomy, and breast reconstruction.

Some participants mentioned specific celebrities and authors such as Christina Applegate, Suzanne Summers, Susan Love, and Dianna Duberry (an Indianapolis news anchor). Others mentioned a range of stories focused on breast cancer topics, including mammograms, diagnosis, mortality, mastectomy, and breast reconstruction. DISCUSSION Prior research on CPM decisions suggests that the increase in this procedure is patient driven rather than physician driven.12–14 The current study provides additional perspective on this phenomenon, contributing evidence that women who chose to pursue CPM elect this surgery, at least in part, with influence and support from members of their social networks, including spouses, children, other family, friends, as well as nonsurgeon health care professionals. Surgeons are regarded as neutral providers of options, and media influence is present, but limited.

e to pursue CPM elect this surgery, at least in part, with influence and support from members of their social networks, including spouses, children, other family, friends, as well as nonsurgeon health care professionals. Surgeons are regarded as neutral providers of options, and media influence is present, but limited. Most women in this study talked to multiple social network members about their CPM decision, and reported some degree of influence from those others. Observed differences in the degree of influence between different relational categories did not achieve statistical significance, though this may be a function of sample size. The current data suggest that surgeons need to anticipate the possibility of meaningful influence on their patients’ decisions from others who inhabit a variety of relational roles, ranging from spouses and children to therapists and clergy. These findings suggest a strategy of actively involving these individuals in the information sharing and educational portion of the clinic visit. In their commentary on overtreatment in breast cancer, Katz and Morrow26 state that the outcomes of the various treatment options being considered in the examination room must be clarified. Both they and Angelos et al13 point out that heuristics (gut reactions) and counterfactual thinking drive patient desire for more extensive treatment. With patients’ consent, spouses, partners, and children should be encouraged to attend the discussion of treatment options. They should be actively engaged in the conversation and given the opportunity to ask questions, and ideally transformed from implicit or explicit supporters of CPM (almost 20% in our sample) to providers of accurate information about the utility of the procedure. During their subsequent interactions with the patient, the information these individuals glean from the clinical encounter may help them counter the patient’s gut reactions and anticipated regret.

licit supporters of CPM (almost 20% in our sample) to providers of accurate information about the utility of the procedure. During their subsequent interactions with the patient, the information these individuals glean from the clinical encounter may help them counter the patient’s gut reactions and anticipated regret. Efforts to educate members of breast cancer patients’ social networks need not be confined to the examination room. The Pew Research Center’s Internet Project determined as of January 2014 that a majority of US adults use social networking sites such as Facebook. Percentages were 49% for age 65+, 65% for ages 50 to 64, 82% for ages 30 to 49, and 89% for ages 18 to 29 (http://www.pewinternet.org/fact-sheets/social-networking-fact-sheet/). This suggests another strategy to combat unindicated CPM. Material should be developed that provide data on the likelihood of a metachronous contralateral breast cancer, survival as a function of the known cancer, complications, cost of CPM, and long-term satisfaction/dissatisfaction of patients who have undergone reconstruction. This material should be written to address low levels of health and scientific literacy and be presented in a visually appealing electronic format. This would provide patients with an opportunity to share evidence-based information with those they will be consulting with regarding CPM; it would be ideal if this information were shared across the patients’ social networks so as to reach and inform much larger audiences than those accessible through clinical interactions.

ould provide patients with an opportunity to share evidence-based information with those they will be consulting with regarding CPM; it would be ideal if this information were shared across the patients’ social networks so as to reach and inform much larger audiences than those accessible through clinical interactions. The most frequent type of reported influence was experiential, or being influenced by another person’s experience. This type of influence was exerted principally by friends and family who had gone through breast cancer, and consisted largely of reports of cancer recurrence or a new primary breast cancer, and family history of breast cancer. Thus, although coded separately from explicit encouragement of CPM, participants clearly regarded this type of influence as implicit support for the CPM choice. Although it is not surprising that patients sought out family and friends who had gone through breast cancer and had contemplated similar treatment decisions, the fact that their experiences supported the choice of CPM should give us pause. Data suggest that regret regarding treatment decisions for localized breast cancer is low and relatively stable over time for most patients.27,28 Most friends and family members diagnosed with breast cancer would have been treated by breast conservation, and a lesser number by unilateral mastectomy.29 Given that regret regarding treatment decisions is low, we would have expected that these individuals would have voiced satisfaction with their treatment decisions. They may have done so but that is not the message our respondents heard. Local recurrence is a relatively infrequent occurrence,30,31 but the report of this event by the friend or family member or perhaps an anecdotal report of local recurrence in someone the friend/family member is acquainted with seems to have been determinative. This underscores the challenge of combating powerful individual narratives with aggregate statistical data.32 Further research is needed to determine how to accomplish this goal in the context of breast cancer treatment decisions.

in someone the friend/family member is acquainted with seems to have been determinative. This underscores the challenge of combating powerful individual narratives with aggregate statistical data.32 Further research is needed to determine how to accomplish this goal in the context of breast cancer treatment decisions. Whereas most of our participants reported social network influence on their decisions, mass media influence was reported by a minority. This influence stemmed principally from television or Internet sources; some participants mentioned specific celebrities. Because the CPM decisions reported in this study took place before the publicity surrounding Angelina Jolie and Sandra Lee’s “double mastectomies,” we may have underestimated the current potential for media influence on CPM decisions. However, the data to date indicates that the “Jolie Effect” has been mainly to increase the number of women seeking genetic counseling/BRCA testing.33,34 In all likelihood, the more powerful influence is now taking place through social media, where patients who post about themselves or others choosing CPM combine the impact of personal endorsement with broad reach into their own social networks and beyond. This too speaks to the value of developing accurate and attractive educational materials that are easy to share electronically.

ace through social media, where patients who post about themselves or others choosing CPM combine the impact of personal endorsement with broad reach into their own social networks and beyond. This too speaks to the value of developing accurate and attractive educational materials that are easy to share electronically. In free-response descriptions of the surgical consultation, participants reported few surgeons as either overtly favoring or opposing CPM, but instead described them as providing options. Analyzing the ethics of surgeon involvement in the CPM decision, Angelos et al13 have framed the challenge facing surgeons as one of respecting patient autonomy versus abdication of responsibility to avoid doing harm. If the recollections of our respondents are accurate, the surgeons presented themselves as having no strong opinion for or against CPM. Although more than half of respondents also reported that their surgeon “suggested” CPM, it has to be assumed that this was in the context of listing the treatment options. It is also unsurprising that participants overwhelmingly reported “support” for the CPM decision, as few surgeons would continue expressing lack of support once they had agreed to perform CPM. Collectively, these findings suggest that surgeons need to be more assertive in conveying their perspective. As Katz and Morrow26 point out, the responsibility for minimizing overtreatment in breast cancer rests largely in the hands of the physician. The National Accreditation Program for Breast Centers 2014 Edition of the Standards Manual states that centers are compliant when they utilize evidence-based breast cancer management guidelines such as those of the NCCN (https:/~/www.facs.org//media/files/quality%20programs/napbc/2014%20napbc%20standards%20manual.ashx). The NCCN guidelines clearly discourage CPM unless the patient is 35 years and below or premenopausal and carrier of a known BRCA1/2 mutation (http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf). Therefore, it is essential that surgeons are perceived to have an opinion, which is to limit CPM to where it is appropriate, and that they can clearly articulate the reasons and evidence for their opinion.

nopausal and carrier of a known BRCA1/2 mutation (http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf). Therefore, it is essential that surgeons are perceived to have an opinion, which is to limit CPM to where it is appropriate, and that they can clearly articulate the reasons and evidence for their opinion. This study exhibits several limitations that should be taken into account when interpreting our findings and conducting future research. Our sample was limited to women whose CPM procedures were conducted in a single geographic region, and who were mostly white. Future research should continue to examine how factors such as race and socioeconomic status affect CPM decisions. In addition, all of our interviewees elected CPM, and we report on a decision that was made as much as 6 years before participation in the study. Over time, choice-supportive bias35 may have resulted in diminished memory of interactions that were less positive toward CPM, skewing participants’ reports in a pro-CPM direction. Addressing this limitation in our work will likely require that researchers study women who are in the process of making their treatment decisions. Comparing women who strongly considered CPM but ultimately chose breast conservation or unilateral mastectomy with those who chose CPM, Hawley et al36 reported that those who chose CPM were significantly more likely to be “very worried about recurrence” (93.8% vs. 80.1%, P=0.001). Nevertheless, 4 out of 5 women who did not choose CPM were still “very worried about recurrence,” but chose another surgical therapy suggesting there were additional considerations affecting their decisions. To guide surgeon’s consultations, future research should also examine why women decide against CPM, who influences them, and especially how women who initially wanted CPM are dissuaded (ethically and compassionately) from pursuing this path.

apy suggesting there were additional considerations affecting their decisions. To guide surgeon’s consultations, future research should also examine why women decide against CPM, who influences them, and especially how women who initially wanted CPM are dissuaded (ethically and compassionately) from pursuing this path. Identifying the individuals who exert the greatest influence and the type of influence they exert provides an additional opportunity for medical professionals, in general, and surgeons, in particular, to dampen and reverse the increase in CPM. These individuals can be partners in this endeavor by reinforcing the information provided to the patient. From a surgeon’s perspective, it would be far preferable to use information, social networks, and social media to reduce CPMs rather than having the same result imposed by payers. Present address: L. Brooke Friley, MA, Department of Communication and Media, Texas A&M—Corpus Christi, 6300 Ocean Dr, Corpus Christi, TX 78412. Present address: Rebekah Pastor, MA, CoreClarity, P.O. Box 863692, Plano, TX 75086. Present address: Kristen Hatten, PhD, School of Communication, Western Michigan University, 1903 W Michigan Ave., Kalamazoo, MI 49008 Present address: Janaka Lagoo, MD, Ariadne Labs, 401 Park Drive, Boston, MA 02215. Present address: Monet W. Bowling, MD, Hendricks Regional Health, 1000 East Main Street, Danville, IN 46122. Publication costs were defrayed by generous donations to the “Take my Hand Luncheon” in Lake Geneva, WI. The authors declare no conflicts of interest.

Complete surgical R0 resection has traditionally been considered the only curative treatment in localized gastric cancer. However, both local and distant relapses are common after surgical R0 resection alone, resulting in suboptimal 5-year overall survival (OS) rates of approximately 20%.1–3 These poor survival outcomes provide a strong rationale for adjuvant or neoadjuvant treatment. The landmark Intergroup 0116 trial was the first to demonstrate that adjuvant postoperative chemoradiotherapy offers a significant survival benefit.4 In this study, the 3-year OS and relapse-free survival rates were improved from 41% and 31%, respectively, in the surgery only group to 50% and 48%, respectively, in the chemoradiotherapy group. However, despite this improved survival, half of these patients will die within 3 years of R0 resection. Notably, the patients receiving chemoradiotherapy had a higher rate of distant metastasis Furthermore, the toxicity rate observed in the Intergroup 0116 trial was substantial. Thus, it is reasonable to optimize the Intergroup 0116 chemoradiotherapy regimen. Docetaxel, administered as monotherapy, is active in both the first-line and second-line treatment of advanced stage gastric cancer.5,6 In addition, in vitro and in vivo studies demonstrated that docetaxel is a potent radiosensitizer in human cancer cell lines, making it an attractive agent when combined with radiation.7 A phase I study identified the phase II recommended dose of docetaxel as 20 mg/m2 weekly for 6 weeks when administered with concurrent chest radiation of 60 Gy.8

vivo studies demonstrated that docetaxel is a potent radiosensitizer in human cancer cell lines, making it an attractive agent when combined with radiation.7 A phase I study identified the phase II recommended dose of docetaxel as 20 mg/m2 weekly for 6 weeks when administered with concurrent chest radiation of 60 Gy.8 Furthermore, it was demonstrated that docetaxel together with standard cisplatin and infused 5-fluorouracil (FU) (DCF regimen) prolonged survival and resulted in a higher response rate (RR) than cisplatin and 5-FU (CF) alone, but the regimen also resulted in significant toxicity.9 In addition, a favorable RR and median OS for DCF over epirubicin, cisplatin, and protracted venous infusion fluorouracil (ECF) was demonstrated in a randomized phase II trial.10 We therefore designed a phase II trial to evaluate the impact of a novel adjuvant chemoradiotherapy regimen on the survival of patients with curatively resected gastric cancer. This regimen consisted of radiotherapy and concurrent weekly docetaxel plus preradiation and postirradiation chemotherapy with modified DCF. Intensity-modulated radiation treatment (IMRT) was used on the basis of data illustrating that IMRT protects the surrounding normal tissues better than both conventional techniques and 3-dimensional conformal radiotherapy.11,12 The primary endpoint of the study was the progression-free survival (PFS) rate, and the second objective was to evaluate toxicity, OS, and patterns of failure.

s of data illustrating that IMRT protects the surrounding normal tissues better than both conventional techniques and 3-dimensional conformal radiotherapy.11,12 The primary endpoint of the study was the progression-free survival (PFS) rate, and the second objective was to evaluate toxicity, OS, and patterns of failure. METHODS Statement of Ethics Approval This study was approved by the ethics committee of each hospital and was performed in accordance with the Declaration of Helsinki. Patients provided written informed consent before study entry.

s of data illustrating that IMRT protects the surrounding normal tissues better than both conventional techniques and 3-dimensional conformal radiotherapy.11,12 The primary endpoint of the study was the progression-free survival (PFS) rate, and the second objective was to evaluate toxicity, OS, and patterns of failure. METHODS Statement of Ethics Approval This study was approved by the ethics committee of each hospital and was performed in accordance with the Declaration of Helsinki. Patients provided written informed consent before study entry. Patients The eligibility criteria included histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction, complete resection of the tumor defined as surgical resection performed with curative intent and resulting in negative resection margins, disease stage IB through IV (M0) according to the 2002 American Joint Commission for Cancer Staging System, age of 20 to 75 years, Zubrod performance status (PS) of 0 to 2, a platelet count≥100×109/L, an absolute granulocyte count≥2×109/L, a hemoglobin level≥10 g/dL, adequate renal and hepatic function (serum creatinine≤1.5×the upper limit of normal, bilirubin and aspartate transaminase ≤1.5×the upper limit of normal), a caloric intake of at least 1500 kcal/d, and initiation of adjuvant treatment within 6 weeks of surgery. The exclusion criteria included a history of prior upper abdominal radiotherapy or chemotherapy, any metastatic disease, active inflammatory bowel disease, and ischemic heart disease. The protocol was reviewed and approved by the institutional review board. When a patient was enrolled, surgery and pathology reports were reviewed to confirm the completeness of the resection and the extent of the lymphadenectomy. The latter was classified as follows. A D1 dissection included perigastric lymph nodes along the right and left cardiac, the lesser and larger curvature, suprapyloric area along the right gastric artery, and infrapyloric area. A D2 dissection entailed a D1 dissection plus lymph nodes along the left gastric artery, common hepatic artery, celiac artery, splenic hilum, and splenic artery. A D0 dissection was less than a D1 dissection.

diac, the lesser and larger curvature, suprapyloric area along the right gastric artery, and infrapyloric area. A D2 dissection entailed a D1 dissection plus lymph nodes along the left gastric artery, common hepatic artery, celiac artery, splenic hilum, and splenic artery. A D0 dissection was less than a D1 dissection. At baseline, the initial evaluation included a detailed clinical history and complete physical examination, assessment of Zubrod PS, weight and height measurements, a complete blood cell count with differential and platelet count, a chemistry panel, and computed tomography (CT) of the chest, abdomen, and pelvis, Nutritional counseling was offered to all patients. Treatment Plan Chemotherapy The treatment scheme is illustrated in Figure 1. The patients received preradiation chemotherapy for 2 cycles and postradiation chemotherapy for 2 cycles. Each 21-day cycle consisted of the DCF regimen based on the V325 study but modified due to the significant toxicity observed. This involved the administration of docetaxel (37.5 mg/m2, 1-h intravenous [IV] infusion on days 1 and 8), cisplatin (25 mg/m2, 2-h IV infusion on days 1 to 3), and 5-FU (750 mg/m2/d by continuous infusion with a central venous access over 5 d). All patients received appropriate hydration, premedication, and dose reduction for individual drugs based on the worst toxicity experienced, as previously described.13 FIGURE 1 Treatment schema. CIV indicates continuous intravenous; FU, fluorouracil.

Treatment Plan Chemotherapy The treatment scheme is illustrated in Figure 1. The patients received preradiation chemotherapy for 2 cycles and postradiation chemotherapy for 2 cycles. Each 21-day cycle consisted of the DCF regimen based on the V325 study but modified due to the significant toxicity observed. This involved the administration of docetaxel (37.5 mg/m2, 1-h intravenous [IV] infusion on days 1 and 8), cisplatin (25 mg/m2, 2-h IV infusion on days 1 to 3), and 5-FU (750 mg/m2/d by continuous infusion with a central venous access over 5 d). All patients received appropriate hydration, premedication, and dose reduction for individual drugs based on the worst toxicity experienced, as previously described.13 FIGURE 1 Treatment schema. CIV indicates continuous intravenous; FU, fluorouracil. Chemoradiotherapy Chemoradiotherapy began on day 43. Radiotherapy was administered through a linear accelerator with 6 to 15 MV photons, and IMRT treatment planning was performed in all cases. Patients were immobilized in a vacuum pad in a supine position with their arms above their head and 5-mm-thick treatment planning. CT images were acquired on a CT simulator (Philips Medical Madison, WI). The clinical tumor volume (CTV) included the tumor bed, anastomoses and stumps, regional draining lymph nodes (perigastric, celiac, portahepatis, gastroduodenal, splenic-suprapancreatic, retropancreaticoduodenal, and para-aortic), and 3 cm beyond the proximal and distal margins of surgical resection, as described in the Intergroup 0116 study. The tumor bed was determined by preoperative CT imaging and surgical clips in some cases. It was necessary to include the medial left hemidiaphragm in the CTV, in the case of a proximal T3 lesion.

-aortic), and 3 cm beyond the proximal and distal margins of surgical resection, as described in the Intergroup 0116 study. The tumor bed was determined by preoperative CT imaging and surgical clips in some cases. It was necessary to include the medial left hemidiaphragm in the CTV, in the case of a proximal T3 lesion. For proximal lesions involving the cardia or gastroesophageal junction, paracardial and paraesophageal lymph nodes were included in the radiation fields, but pancreaticoduodenal radiation was not required. Exclusion of the splenic nodes was permitted in cases of antral lesions. The planning target volume (PTV) consisted of the CTV plus a 0.5-cm margin in all directions to account for daily patient set-up variation. IMRT plans were generated and optimized using commercial planning software (Eclipse; Varian, Palo Alto, CA). Typically, a 6-field nonaxial beam arrangement was used. The PTV received a total dose of 45 Gy in 25 fractions at 1.8 Gy per fraction delivered once daily for 5 weeks. Treatment planning was performed with the isocenter calculated at 100%, with at least 95% of the PTV receiving the prescribed dose. The dose constraints for critical organs were as follows: mean liver dose, <28 Gy; spinal cord dose, ≤45 Gy; at least two thirds of 1 kidney received <20 Gy; and maximum dose to the duodenum, ≤45 Gy.

lanning was performed with the isocenter calculated at 100%, with at least 95% of the PTV receiving the prescribed dose. The dose constraints for critical organs were as follows: mean liver dose, <28 Gy; spinal cord dose, ≤45 Gy; at least two thirds of 1 kidney received <20 Gy; and maximum dose to the duodenum, ≤45 Gy. Concurrent chemotherapy consisted of 5 docetaxel doses of 20 mg/m2 delivered through a 1-hour IV infusion on days 1, 8, 15, 22, and 29 of radiation. Radiation was delivered 2 hours after completion of the docetaxel infusion. Best supportive care including nutritional support, antiemetics, and antacid was provided as clinically indicated. No dose modifications were planned for radiation and docetaxel. In cases of grade 3 or greater nonhematological or grade 4 hematological toxicity, chemoradiotherapy could be delayed by up to 2 weeks until these symptoms resolved to no worse than grade 1 for nonhematological toxicity or no worse than grade 2 for hematological toxicity.

tions were planned for radiation and docetaxel. In cases of grade 3 or greater nonhematological or grade 4 hematological toxicity, chemoradiotherapy could be delayed by up to 2 weeks until these symptoms resolved to no worse than grade 1 for nonhematological toxicity or no worse than grade 2 for hematological toxicity. Patient Follow-up Patients were observed weekly during treatment. Complete blood counts and serum chemistries were assessed weekly. Acute toxicities were graded according to the National Cancer Institute-Common Toxicity Criteria Version 3.0. Follow-up evaluations were conducted at 3-month intervals for the first 2 years, every 6 months for 3 years, and yearly thereafter together with a physical examination, a complete blood count, serum chemistries, and CT scanning. Late radiation toxicities were graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Schema.

for 3 years, and yearly thereafter together with a physical examination, a complete blood count, serum chemistries, and CT scanning. Late radiation toxicities were graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Schema. Statistical Analysis This single-stage phase II trial was designed to have 93% power to detect a 20% improvement in the 20-month PFS rate from 50% to 70% with a 2-sided significance level of exactly 0.05. The present 20-month PFS was based on a median PFS of 19 months for 275 patients in the surgery-alone arm of the Intergroup 0116 study. The accrual goal was 61 patients, assuming 55 patients would be eligible. If at least 34 of 55 evaluable patients were progression-free at 20 months, then the regimen would be considered worthy of further investigation. PFS was measured from the date of study entry to the first event (ie, local-regional relapse or progression, distant recurrence, or death from any cause), and OS was defined as the time from the date of study entry to the date of death or the last follow-up. Data on patients who were event-free were censored on the date they were last reviewed. The Kaplan-Meier method was used to generate the OS and PFS curves. All statistical analyses were performed using IBM SPSS statistics 19.0.

defined as the time from the date of study entry to the date of death or the last follow-up. Data on patients who were event-free were censored on the date they were last reviewed. The Kaplan-Meier method was used to generate the OS and PFS curves. All statistical analyses were performed using IBM SPSS statistics 19.0. RESULTS Patient Characteristics A total of 61 patients were enrolled between April 2004 and January 2007, of whom 55 were evaluable. Of the 6 ineligible patients, 3 patients had a Zubrod PS of 3, 2 were registered more than 6 weeks after the date of surgical resection, and 1 withdrew from the trial before initiating protocol therapy. The baseline characteristics of these assessable patients are listed in Table 1. The median age was 59 years (range, 28 to 75 y). The majority of patients had locally advanced disease (stage T3 or T4, 71%; N1-3, 93%). TABLE 1 Patient Characteristics (N=55)

RESULTS Patient Characteristics A total of 61 patients were enrolled between April 2004 and January 2007, of whom 55 were evaluable. Of the 6 ineligible patients, 3 patients had a Zubrod PS of 3, 2 were registered more than 6 weeks after the date of surgical resection, and 1 withdrew from the trial before initiating protocol therapy. The baseline characteristics of these assessable patients are listed in Table 1. The median age was 59 years (range, 28 to 75 y). The majority of patients had locally advanced disease (stage T3 or T4, 71%; N1-3, 93%). TABLE 1 Patient Characteristics (N=55) Treatment Delivery Of the 55 evaluable patients, 54 (98%) completed both cycles of preradiation chemotherapy; conversely, the other patient received only 1 cycle due to disease progression, and this patient was removed from the study per the protocol, but included in the analysis on an intention-to-treat basis. No dose reduction or treatment delay was required for toxic effects. Of the 54 patients who started concurrent chemoradiotherapy (CCRT), 46 completed all 5 doses of weekly docetaxel and the planned 45-Gy radiotherapy. Meanwhile, 1 patient had a 2-week break due to vomiting, and 4 patients had a 1-week delay due to vomiting, anorexia, or diarrhea. Eight patients did not complete the planned CCRT; of these, 2 patients completed 5 doses of weekly chemotherapy and 43.2 Gy of radiation, 4 patients received 5 doses of chemotherapy and 41.4 Gy of radiation, and 2 patients received 4 doses of chemotherapy and 36 Gy of radiation. Failure to complete the planned CCRT was due to vomiting (4 patients), deteriorating health (2 patients), diarrhea (1 patient), and patient refusal (1 patient). Of the 46 patients who completed the planned CCRT, 42 completed both cycles of postradiation chemotherapy. Conversely, 1 patient withdrew from the study due to peritoneal carcinomatosis, 1 patient did not receive postradiation chemotherapy due to deteriorating health, and 2 patients completed only 1 cycle of chemotherapy. Dose reductions and/or treatment delays were required for 3 patients because of toxic effects. Overall, 76% of the patients completed the prescribed therapy.

eritoneal carcinomatosis, 1 patient did not receive postradiation chemotherapy due to deteriorating health, and 2 patients completed only 1 cycle of chemotherapy. Dose reductions and/or treatment delays were required for 3 patients because of toxic effects. Overall, 76% of the patients completed the prescribed therapy. Toxicity The grade 3 and 4 toxicities observed in this study are listed in Table 2. During the preradiation and postradiation chemotherapy phase, the most common grade 3 and 4 hematological toxicity was neutropenia, which was observed in 13 patients (24%) during preradiation chemotherapy and 10 patients (23%) during postradiation chemotherapy. Maximum grade 3 or 4 nonhematological toxicities occurred mainly during the postradiation chemotherapy phase, consisting of nausea (18%), and vomiting (14%). TABLE 2 Grade III or IV Hematological and Nonhematological Toxicity Associated With Preradiation and Postradiation Chemotherapy and CCRT

Toxicity The grade 3 and 4 toxicities observed in this study are listed in Table 2. During the preradiation and postradiation chemotherapy phase, the most common grade 3 and 4 hematological toxicity was neutropenia, which was observed in 13 patients (24%) during preradiation chemotherapy and 10 patients (23%) during postradiation chemotherapy. Maximum grade 3 or 4 nonhematological toxicities occurred mainly during the postradiation chemotherapy phase, consisting of nausea (18%), and vomiting (14%). TABLE 2 Grade III or IV Hematological and Nonhematological Toxicity Associated With Preradiation and Postradiation Chemotherapy and CCRT Of the 54 patients for whom toxicity could be assessed during the CCRT phase, grade 3 or 4 hematological toxicities consisted of neutropenia in 7 patients (13%) and lymphocytopenia in 18 patients (33%). The most significant nonhematological toxicities were nausea and vomiting. Grade 3 or greater nausea and vomiting occurred in 17 (32%) and 14 patients (26%), respectively. Nausea and vomiting generally began in the third week of CCRT, peaked in the last 2 weeks, and resolved within 2 to 3 weeks of CCRT completion. Other significant nonhematological toxicities included anorexia in 10 patients (19%) and fatigue in 8 patients (15%). Parenteral or enteral support was required for most of these patients, especially those with grade 3 or 4 nausea or vomiting. No cases of grade 2 or greater hepatic or renal toxicity were observed, and there were no treatment-related deaths.

cities included anorexia in 10 patients (19%) and fatigue in 8 patients (15%). Parenteral or enteral support was required for most of these patients, especially those with grade 3 or 4 nausea or vomiting. No cases of grade 2 or greater hepatic or renal toxicity were observed, and there were no treatment-related deaths. Only 1 patient developed late toxicity. This patient developed a duodenal ulcer with severe bleeding 7 months after the completion of radiotherapy that required surgical intervention. There was 1 patient with second tumor, who was diagnosed as lung cancer 58 months after the study entry. Survival and Relapse The median follow-up time for all 55 evaluable patients was 61 months, with 21 patients dying during this period. The 20-month PFS rate was 75% (95% confidence interval [CI], 64%-86%). The 3- and 5-year PFS rates were 67 (95% CI, 54%-80%) and 59% (95% CI, 46%-72%), respectively (Fig. 2), and the 3- and 5-year OS rates were 72 (95% CI, 60%-84%) and 61% (95% CI, 48%-74%), respectively (Fig. 3). Of 21 documented sites of first treatment failure, local-regional relapse occurred in 5 patients, distant relapse including peritoneal carcinomatosis was observed in 13 patients, and 3 patients had both local-regional and distant recurrences.

s were 72 (95% CI, 60%-84%) and 61% (95% CI, 48%-74%), respectively (Fig. 3). Of 21 documented sites of first treatment failure, local-regional relapse occurred in 5 patients, distant relapse including peritoneal carcinomatosis was observed in 13 patients, and 3 patients had both local-regional and distant recurrences. FIGURE 2 The Kaplan-Meier plot of progression-free survival for 55 assessable patients treated in the phase II trial using postoperative adjuvant docetaxel/cisplatin/5-fluorouracil before and after intensity-modulated radiotherapy with concurrent docetaxel weekly. The progression-free survival was 67% (95% confidence interval, 54%-80%) at 3 years and 59% at 5 years (95% confidence interval, 46%-72%). FIGURE 3 The Kaplan-Meier plot of overall survival for 55 assessable patients treated in the phase II trial using postoperative adjuvant docetaxel/cisplatin/5-fluorouracil before and after intensity-modulated radiotherapy with concurrent docetaxel weekly. The overall survival was 72% (95% confidence interval, 60%-84%) at 3 years and 61% (95% confidence interval, 48%-74%) at 5 years.

ble patients treated in the phase II trial using postoperative adjuvant docetaxel/cisplatin/5-fluorouracil before and after intensity-modulated radiotherapy with concurrent docetaxel weekly. The overall survival was 72% (95% confidence interval, 60%-84%) at 3 years and 61% (95% confidence interval, 48%-74%) at 5 years. DISCUSSION Although surgery is the standard of care for localized gastric cancer, the outcome remains poor due to local and distant failure after R0 resection. Many adjuvant therapies including chemotherapy, radiation, or a combination of the 2 modalities have been investigated to enhance surgical results.3,14,15 The Intergroup 0116 study demonstrated that postoperative chemoradiotherapy can significantly improve OS and PFS compared with the effects of surgery alone.4 An analysis of failure patterns suggests that this improvement was mainly attributable to improved local control, indicating that 5-FU/leucovorin, used as systemic treatment in the Intergroup 0116 study, had little effect on distant disease. Another landmark study, Medical Research Council Adjuvant Gastric Infusional Chemotherapy, reported a statistically significant survival benefit for patients with gastric cancer treated with perioperative ECF chemotherapy over surgery alone. Treatment consisted of three courses of ECF before and after surgery.16 This survival benefit was believed to arise primarily from the effect of perioperative chemotherapy on micrometastatic disease. Therefore, we postulated that the combination of more effective local (ie, chemoradiotherapy) and systemic treatments (ie, chemotherapy) may further improve surgical outcomes.

after surgery.16 This survival benefit was believed to arise primarily from the effect of perioperative chemotherapy on micrometastatic disease. Therefore, we postulated that the combination of more effective local (ie, chemoradiotherapy) and systemic treatments (ie, chemotherapy) may further improve surgical outcomes. The DCF chemotherapy regimen is more active in patients with advanced gastric cancer than the standard CF or ECF regimen based on the results of randomized trials.9,10 Theoretically, this regimen may also have an excellent effect on micrometastases, but it has not yet been tested in the adjuvant setting. Hence, we chose the DCF regimen as a systemic treatment to improve the control of distant disease. To enhance local treatment efficacy, we substituted docetaxel for 5-FU as a radiosensitizing agent administered weekly with concurrent radiotherapy, as it has been reported that 5-FU–based chemoradiotherapy was less active and more toxic in the primary management of advanced gastric cancer.17–19 Docetaxel, a relatively newer agent, is a potent radiosensitizer in addition to its significant antitumor activity as monotherapy or in combination with other agents. Docetaxel-based chemoradiotherapy has been used extensively in the treatment of many tumors including lung cancer and head and neck cancer,20 but it has never been evaluated in gastric cancer. We recently reported that 36 patients with inoperable gastric cancer were treated using the same chemoradiotherapy regimen used in the present study, although the radiation dose was 50.4 Gy in 28 fractions as opposed to 45 Gy in 25 fractions, as used in this series. Overall and complete RRs of 83 (95% CI, 75%- 97%) and 36% (95% CI, 19%-53%), respectively, were achieved, and the median survival time and 3-year survival rate were 25.8 months (95% CI, 7.1-44.5 mo) and 42% (95% CI, 23%-59%), respectively.21 These outcomes are encouraging, and thus, it is logical to evaluate this regimen in the adjuvant setting.

83 (95% CI, 75%- 97%) and 36% (95% CI, 19%-53%), respectively, were achieved, and the median survival time and 3-year survival rate were 25.8 months (95% CI, 7.1-44.5 mo) and 42% (95% CI, 23%-59%), respectively.21 These outcomes are encouraging, and thus, it is logical to evaluate this regimen in the adjuvant setting. In this phase II trial, the estimated 20-month PFS rate of 75% achieved the primary end point of a regimen considered for further investigation. The 3- and 5-year estimated PFS rates were 67% and 59%, respectively, and the 3- and 5-year estimated OS rates were 72% and 61%, respectively. Although the main prognostic factors such as T stage and N stage are comparable, our results appear superior to those obtained in the Intergroup 0116 trial.

rther investigation. The 3- and 5-year estimated PFS rates were 67% and 59%, respectively, and the 3- and 5-year estimated OS rates were 72% and 61%, respectively. Although the main prognostic factors such as T stage and N stage are comparable, our results appear superior to those obtained in the Intergroup 0116 trial. Several chemoradiotherapy regimens incorporating other chemotherapeutic agents have recently been examined as adjuvant therapies for resected gastric cancer.15,22,23 Schwartz and colleagues evaluated 2 paclitaxel-containing and cisplatin-containing regimens, 1 with 5-FU (PCF) and the other without FU (PC), in the treatment of patients with resected gastric cancer. Patients received 2 cycles of postoperative chemotherapy followed by 45 Gy of radiation with either concurrent 5-FU and paclitaxel or paclitaxel and cisplatin. The PCF arm was closed early after the enrollment of 28 patients due to the higher rate of grade 3 or 4 gastrointestinal (GI) toxicity. The 2-year DFS rate was 52% (95% CI, 36%-68%) for the 45 patients in the PC arm.22 It is worth noting that patients in Schwartz trial received only 2 cycles of preradiation chemotherapy, potentially resulting in suboptimal control of systemic disease. In another phase II trial, Leong et al23 treated 54 patients with 1 cycle of ECF, followed by radiotherapy (45 Gy) with concurrent infusional 5-FU and then 2 additional cycles of ECF. Radiotherapy was delivered using 3-dimensional conformal techniques. The 3-year OS rate was estimated at 61.6%. The main trials evaluating different adjuvant chemoradiotherapy regimens are shown in Table 3. Although we acknowledge that comparisons between the trials are inappropriate, our 3-year PFS rate of 67% is promising in contrast to the PFS rate of 48% to 62% reported in these trials for resected gastric cancer. Nevertheless, the standard adjuvant chemoradiotherapy regimen for resected gastric cancer remains uncertain, and subsequent prospective randomized controlled trials are required for clarification.

FS rate of 67% is promising in contrast to the PFS rate of 48% to 62% reported in these trials for resected gastric cancer. Nevertheless, the standard adjuvant chemoradiotherapy regimen for resected gastric cancer remains uncertain, and subsequent prospective randomized controlled trials are required for clarification. TABLE 3 Main Trials With Adjuvant Chemoradiotherapy in Completely Resected Gastric Cancer One of our concerns was the toxicity potentially associated with the treatment at the initiation of this study, considering the significant toxicity observed in the Intergroup 0116 trial, which reported grade 3 and 4 toxicities in 41% and 32% of patients, respectively. By contrast, the toxicity appears acceptable in the present study and comparable with that observed in other trials (Table 3). During the periradiation chemotherapy phase, the main toxicity was grade 3 or 4 neutropenia, which was observed in approximately a quarter of the patients. Significant GI toxicity was observed despite including only docetaxel in CCRT. The increased rate of GI toxicity may reflect the higher dose intensity and the relatively larger irradiation field. Despite significant GI toxicity, 76% of the assessable patients completed the protocol therapy. Our favorable toxicity profile may be attributable to the combination of the mDCF regimen chemotherapy (less aggressive), a single-agent radiosensitizer in docetaxel (in place of 5-FU), and sophisticated radiation techniques used.

e significant GI toxicity, 76% of the assessable patients completed the protocol therapy. Our favorable toxicity profile may be attributable to the combination of the mDCF regimen chemotherapy (less aggressive), a single-agent radiosensitizer in docetaxel (in place of 5-FU), and sophisticated radiation techniques used. In an attempt to improve outcomes for patients with gastric cancer, there is a trend to initially treat patient with chemoradiotherapy followed by surgery.24,25 This approach is supposed to have a few advantages: (a) radiotherapy and systemic therapy are more effective due to the existence of intact tumor vasculature and oxygenation; (b) patients generally have better treatment compliance; (c) tumor downstaging after preoperative chemoradiotherapy may facilitate surgical resection and decrease the risk of local relapse; and (d) during preoperative therapy, some patients may develop overt metastases due to their aggressive biological disease and avoid unnecessary surgery. Although preoperative chemoradiotherapy has not been evaluated in a phase III setting, several phase II trials were reported, with a pathologic complete response rate of 20% to 30%.24,25 In addition, patients with a pathologic complete response or <10% residual cancer cells in the resected specimen can achieve long-term survival. Nevertheless, the survival outcomes achieved in this series seems more favorable as compared with the MAGIC trial and other trials using neoadjuvant strategies. The MAGIC trial demonstrated a 5-year survival rate of 36% among patients in the ECF perioperative-chemotherapy group although the tumor stage is similar to that of the present trial.16 Ajani et al24 reported a 2-year survival rate of 54% in 33 patients treated with preoperative chemoradiotherapy consisting of two 28-day cycles of FU, leucovorin, and cisplatin, followed by 45 Gy of radiation plus concurrent FU. Obviously, no definite conclusion can be drawn based on the outcomes achieved in this phase 2 series. A direct comparison of the postoperative chemoradiotherapy with this preoperative approach should be considered as well.

8-day cycles of FU, leucovorin, and cisplatin, followed by 45 Gy of radiation plus concurrent FU. Obviously, no definite conclusion can be drawn based on the outcomes achieved in this phase 2 series. A direct comparison of the postoperative chemoradiotherapy with this preoperative approach should be considered as well. In conclusion, we demonstrated that a periradiation mDCF chemotherapy regimen plus docetaxel-based chemoradiotherapy can be delivered safely with acceptable toxicity in the postoperative adjuvant setting in patients who underwent R0 resection. The survival results appear favorable compared with those observed in the Intergroup 0116 trial. On the basis of our data, we have designed a randomized phase III trial directly comparing the Intergroup 0116 chemoradiotherapy regimen with our regimen in this series (http://www.clinicaltrials.gov/NCT02640898). This research was supported by the Scientific Research Foundation for the Returned Overseas Chinese Scholars (No. N130204) from the China State Education Ministry, by the National Natural Science Foundation of China (Nos. 81202148, 31370838), and by National Key Clinical Discipline-Oncology. The authors declare no conflicts of interest.

To date, lung cancer, especially non–small cell lung cancer (NSCLC) remains the most frequently diagnosed malignancy and the leading cause of cancer-related death worldwide.1,2 Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been the standard care for advanced NSCLC patients with EGFR mutation in the first line. EGFR-TKIs have shown superiority of progression-free survival (PFS) in patients with EGFR mutations, compared with platinum doublet-based chemotherapy.3–5 However, acquired resistance to EGFR-TKIs with disease progression in majority of initial responders remains a major challenge.6 Before the approval of third-generation EGFR-TKI Osimertinib, patients always received chemotherapy in the second line. Even now, the chemotherapy is still the standard treatment after first-generation EGFR-TKI resistance in NSCLC patients without T790M mutation. However, no third-line standard of care exists for patients who have already received first-line EGFR-TKI treatment. Therefore, there is an urgent need and of great clinical importance to establish salvage treatment after the second-line chemotherapy.

ration EGFR-TKI resistance in NSCLC patients without T790M mutation. However, no third-line standard of care exists for patients who have already received first-line EGFR-TKI treatment. Therefore, there is an urgent need and of great clinical importance to establish salvage treatment after the second-line chemotherapy. Some evidence has hinted that there is coexistence of sensitive and resistant clones in tumor tissues. Upon EGFR-TKI administration, a fraction of sensitive cells is eradicated, leaving resistant clones behind to proliferate and lead to clinical resistance. Second-line cytotoxic chemotherapy acts on these resistant cells, sparing TKI-sensitive clones, whose re-growth leads to progression of disease. As these cells retain sensitivity to EGFR-TKI, subsequent re-challenge with the inhibitor would then provide clinical benefit theoretically.7–11 Previous studies have generated preliminary results of re-administering first-generation EGFR-TKI to NSCLC patients. However, some of those studies were retrospective analysis.12 Others were before IPASS study in which the first-generation EGFR-TKI was not the standard treatment yet in the first line for the NSCLC patients with EGFR mutation or patients may have received ≥1 chemotherapy regimens. So, EGFR-TKI re-challenge may be in the fourth or fifth line, which was not in line with the current clinical practice of treatment for NSCLC patients with EGFR mutations.13,14 There were also a few studies which were short of biomarkers analysis during EGFR-TKI re-challenge.15–17 Thus, a prospective study is warranted to provide stronger evidence for EGFR-TKI re-challenge in the current treatment model for NSCLC patients and explore potential biomarkers to correlate with clinical outcome.

14 There were also a few studies which were short of biomarkers analysis during EGFR-TKI re-challenge.15–17 Thus, a prospective study is warranted to provide stronger evidence for EGFR-TKI re-challenge in the current treatment model for NSCLC patients and explore potential biomarkers to correlate with clinical outcome. In the current study, we aimed to evaluate the efficacy and safety of gefitinib as third-line treatment on NSCLC patients who had progressed from first-line gefitinib treatment (PFS≥6 mo) and second-line chemotherapy (≥4 cycles). The study also explored prognostic biomarkers by dynamically monitoring EGFR mutation status in plasma of NSCLC patients during third-line treatment. MATERIALS AND METHODS Study Design and Participants This multicenter, single-arm, phase II clinical trial (NCT01933347) was conducted to investigate the efficacy, safety, and tolerability of oral gefitinib 250 mg/d as a re-challenge treatment in locally advanced or metastatic NSCLC patients with EGFR sensitizing mutations (exon 19del/L858R), who responded to first-line gefitinib and progressed after second-line chemotherapy. Patients were enrolled prospectively between March 2014 and May 2016, at 7 sites in China.

itinib 250 mg/d as a re-challenge treatment in locally advanced or metastatic NSCLC patients with EGFR sensitizing mutations (exon 19del/L858R), who responded to first-line gefitinib and progressed after second-line chemotherapy. Patients were enrolled prospectively between March 2014 and May 2016, at 7 sites in China. Patients were considered for third-line gefitinib retreatment if they had (i) advanced NSCLC and EGFR exon 19 deletion/exon 21 L858R mutation and had positive response with first-line gefitinib (PFS≥6 mo) and second-line chemotherapy (platinum-based doublet chemotherapy, ≥4 cycles of chemotherapy); (ii) patients with ECOG performance status of 0-2; ≥1 measurable irradiated lesion by RECIST 1.1 criteria18; (iii) life expectancy of ≥12 weeks; (iv) elevated liver function parameters (total bilirubin ≤1.5 times upper limit of normal; AST and ALT≤2 and ≤5 times upper limit of normal for patients without and with hepatic metastasis; (v) and creatinine clearance ≥45 mL/min). Patients were excluded if they were (i) treated with bevacizumab or drugs directed at VEGF, VEGFR, or EGFR except gefitinib; (ii) known hypersensitivity to gefitinib; (iii) preexisting interstitial lung disease/pulmonary fibrosis; (iv) any unresolved toxicity of prior chemotherapy; (v) other active malignancies; (vi) pregnant or lactating women and those in the childbearing age.

mab or drugs directed at VEGF, VEGFR, or EGFR except gefitinib; (ii) known hypersensitivity to gefitinib; (iii) preexisting interstitial lung disease/pulmonary fibrosis; (iv) any unresolved toxicity of prior chemotherapy; (v) other active malignancies; (vi) pregnant or lactating women and those in the childbearing age. The study protocol was approved by the institutional review board of each participating site in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice (ICH-GCP E6, 1996), Declaration of Helsinki (1964) and its subsequent revisions. All patients received information on the purpose and conduct of this study, and provided written, informed consent before enrollment. Study Treatment and Follow-up All the patients received oral gefitinib at a dose of 250 mg/d until tumor progression or death or occurrence of intolerable adverse event (AE) or adverse drug reaction.

The study protocol was approved by the institutional review board of each participating site in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice (ICH-GCP E6, 1996), Declaration of Helsinki (1964) and its subsequent revisions. All patients received information on the purpose and conduct of this study, and provided written, informed consent before enrollment. Study Treatment and Follow-up All the patients received oral gefitinib at a dose of 250 mg/d until tumor progression or death or occurrence of intolerable adverse event (AE) or adverse drug reaction. All the assessments were made at screening/baseline period (week 2 to week 0), interview period (week 0 until disease progression), and follow-up period (≤2 y after interview period or until death). At screening, demographic data and medical history was recorded along with the collection of blood samples for genetic testing, laboratory examination, and radiologic examination. In each visit, it is during the interview period which involved collection of samples for genetic testing; laboratory and radiologic examination; assessment of the tumor status, quality of life (QoL), and safety. During the follow-up, survival status of patients was recorded every 3 months by telephone, which continued for 2 years or until the death of patients.

riod which involved collection of samples for genetic testing; laboratory and radiologic examination; assessment of the tumor status, quality of life (QoL), and safety. During the follow-up, survival status of patients was recorded every 3 months by telephone, which continued for 2 years or until the death of patients. Biomarkers Analysis Serial plasma samples were collected at every visit from baseline until disease progression. EGFR mutation status was dynamically analyzed using droplet digital polymerase chain reaction (ddPCR) assays for L858R, 19del, and T790M mutations as described previously.19–21 Study Outcomes The primary endpoint was to assess the disease control rate (DCR) at week 8 according to RECIST criteria version 1.1. Secondary endpoints included assessment of objective response rate (ORR), PFS, overall survival (OS), and safety. Drug safety evaluation was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE version 4.0).22

8 according to RECIST criteria version 1.1. Secondary endpoints included assessment of objective response rate (ORR), PFS, overall survival (OS), and safety. Drug safety evaluation was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE version 4.0).22 DCR was defined as the combined proportion of CR+PR+SD patients and ORR was defined as the combined proportion of patients with CR+PR. OS was defined as the interval between third-line gefitinib treatment initiation and death from any cause. PFS was defined as the interval between third-line gefitinib treatment initiation and the date of documented progressive disease (PD) or death from any cause. An exploratory endpoint was to evaluate the relationship between status of EGFR mutations and clinical outcome. QoL was measured using FACT-L questionnaire,23,24 including the lung cancer subscale. Statistical Analyses Sample Size Calculation The sample size was determined by exact single-stage phase II design. With a target DCR of 75% in previous study,25 the expected actual number was 33 patients with a power of 90% (P0=50%, P1=75%, α[1-side]=0.05, 1-β=0.90). If 22 patients or more attain disease control at week 8, the study would meet expectation. Allowing for a 30% attrition during study period, a total of 43 patients were planned for enrollment.

in previous study,25 the expected actual number was 33 patients with a power of 90% (P0=50%, P1=75%, α[1-side]=0.05, 1-β=0.90). If 22 patients or more attain disease control at week 8, the study would meet expectation. Allowing for a 30% attrition during study period, a total of 43 patients were planned for enrollment. Statistical Methods Full analysis set (FAS) includes all subjects who had received at least 1 trial drug treatment and at least 1 record of efficacy evaluation. DCR and ORR were presented in terms of proportion (%) of patients and unilateral 95% confidence interval (CI). Assessment for DCR and ORR were performed in FAS of the study population. Kaplan-Meier survival analysis was used to calculate cumulative distribution function of PFS and OS. The subject lost to follow-up, were defined as censored patients. The correlations of PFS and OS with sensitive mutation abundance at baseline were analyzed by Spearman. QoL scores from FACT-L questionnaire were analyzed using descriptive statistics at each visit and the difference at each visit being calculated via paired t test or Wilcoxon signed rank test. A P-value of <0.05 was considered statistically significant. All the analyses were performed using SAS version 9.1 (SAS Institute Inc.).

es from FACT-L questionnaire were analyzed using descriptive statistics at each visit and the difference at each visit being calculated via paired t test or Wilcoxon signed rank test. A P-value of <0.05 was considered statistically significant. All the analyses were performed using SAS version 9.1 (SAS Institute Inc.). RESULTS Patients Enrollment and Baseline Characteristics Between March 2014 and May 2016, a total of 46 patients with stage IV NSCLC were enrolled in this study. Three patients were excluded from the FAS, including that 1 patient who did not take gefitinib and died the next day, and 2 patients deviated from the study protocol. All the data were assessed in FAS (N=43). The median age was 57 (46 to 77) years; 30 (69.8%) females, 42 (97.7%) patients had adenocarcinoma with only 1 (2.3%) patient having adenosquamous cell carcinoma. About, 1 (2.3%) patient had CR, 16 (37.2%) patients showed PR, 23 (53.5%) patients had SD, and 3 (7.0%) patient’s response was unknown to first-line gefitinib treatment. Other baseline characteristics of the patients are presented in Table 1 and patient recruitment is represented in Figure 1. TABLE 1 Demographic and Baseline Clinical Characteristics FIGURE 1 Patient disposition. DCR indicates disease control rate; FAS, full analysis set; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

RESULTS Patients Enrollment and Baseline Characteristics Between March 2014 and May 2016, a total of 46 patients with stage IV NSCLC were enrolled in this study. Three patients were excluded from the FAS, including that 1 patient who did not take gefitinib and died the next day, and 2 patients deviated from the study protocol. All the data were assessed in FAS (N=43). The median age was 57 (46 to 77) years; 30 (69.8%) females, 42 (97.7%) patients had adenocarcinoma with only 1 (2.3%) patient having adenosquamous cell carcinoma. About, 1 (2.3%) patient had CR, 16 (37.2%) patients showed PR, 23 (53.5%) patients had SD, and 3 (7.0%) patient’s response was unknown to first-line gefitinib treatment. Other baseline characteristics of the patients are presented in Table 1 and patient recruitment is represented in Figure 1. TABLE 1 Demographic and Baseline Clinical Characteristics FIGURE 1 Patient disposition. DCR indicates disease control rate; FAS, full analysis set; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. Efficacy Outcomes At 8 weeks of follow-up, 30 (69.8%; 95% CI, 49.87-74.91) patients achieved the predefined DCR (primary endpoint) from baseline after gefitinib re-challenge (Table 2). ORR was reported in 2 (4.7%; 95% CI, 0.78-13.06) patients. Median PFS after gefitinib re-challenge was 4.4 months (95% CI, 3.2-4.8), (Fig. 2A). Median OS was 10.3 months (95% CI, 5.8-15.4) (Fig. 2B). TABLE 2 Treatment Response to Gefitinib Re-challenge

Efficacy Outcomes At 8 weeks of follow-up, 30 (69.8%; 95% CI, 49.87-74.91) patients achieved the predefined DCR (primary endpoint) from baseline after gefitinib re-challenge (Table 2). ORR was reported in 2 (4.7%; 95% CI, 0.78-13.06) patients. Median PFS after gefitinib re-challenge was 4.4 months (95% CI, 3.2-4.8), (Fig. 2A). Median OS was 10.3 months (95% CI, 5.8-15.4) (Fig. 2B). TABLE 2 Treatment Response to Gefitinib Re-challenge FIGURE 2 Kaplan-Meier curves. A, At 30-month follow-up the overall PFS was 4.4 months (95% CI, 3.1-4.7) in 43 patients. B, Overall OS was 10.2 months (95% CI, 7.7-20.8) in 43 patients at 30-month follow-up. CI indicates confidence interval; OS, overall survival; PFS, progression-free survival. Biomarker Exploration Dynamic Monitoring of EGFR Mutation Status In the baseline plasma of the third line, 11 (25.6%) were 19de/L858R coexisting with T790M; 14 (32.6%) were 19de/L858R alone, and the remaining 18 (41.9%) had undetectable EGFR mutations (Fig. 3A). During dynamic monitoring of EGFR mutations, 23 (53.5%) patients were T790M positive either at the time of PD or even before PD. T790M-positive patients increased significantly (from 11 to 23, P=0.0081) after EGFR-TKI re-challenge (Fig. 3B).

alone, and the remaining 18 (41.9%) had undetectable EGFR mutations (Fig. 3A). During dynamic monitoring of EGFR mutations, 23 (53.5%) patients were T790M positive either at the time of PD or even before PD. T790M-positive patients increased significantly (from 11 to 23, P=0.0081) after EGFR-TKI re-challenge (Fig. 3B). FIGURE 3 The dynamic change of EGFR gene mutation. A, Percentage of patients with 19de/L858R with T790M (26.1%); T790M positive alone (2.2%); 19de/L858R alone (32.6%), and undetectable EGFR mutations (39.1%) in their baseline plasma. B, Dynamic monitoring of EGFR mutations showing patients were T790M positive (54.3%) either at the time of PD or even before PD. T790M-positive patients increased significantly (from 13 to 25, P=0.011) after EGFR-TKI re-challenge when compared with baseline. EGFR-TKI indicates epidermal growth factor receptor tyrosine kinase inhibitors; PD, progressive disease. Baseline T790M Status and Clinical Outcomes Significantly higher DCR was observed in T790M-negative patients in comparison to T790M-positive patients (78.1% vs. 45.5%, P=0.0418). T790M-negative patients achieved more PR and SD. None of the patients showed CR (Table 3). TABLE 3 Treatment Response to Gefitinib Re-challenge and T790M Compared with T790M-positive patients, T790M-negative patients also had significantly longer median PFS (4.7 vs. 2.0 mo; hazard ratio, 0.25; 95% CI, 0.11-0.57; P=0.0009) and median OS (15.2 vs. 7.7 mo; hazard ratio, 0.28; 95% CI, 0.10-0.77; P=0.0132) (Figs. 4A, B).

TABLE 3 Treatment Response to Gefitinib Re-challenge and T790M Compared with T790M-positive patients, T790M-negative patients also had significantly longer median PFS (4.7 vs. 2.0 mo; hazard ratio, 0.25; 95% CI, 0.11-0.57; P=0.0009) and median OS (15.2 vs. 7.7 mo; hazard ratio, 0.28; 95% CI, 0.10-0.77; P=0.0132) (Figs. 4A, B). FIGURE 4 Kaplan-Meier curves. A, At 30-month follow-up the median PFS was lower in T790M-positive patients compared with T790M-negative patients (2.0 vs. 4.7 mo), HR=0.25 (95% CI, 0.11-0.57), P=0.0009. B, The median OS was lower in T790M-positive patients compared with T790M-negative patients (15.2 vs. 7.7 mo), HR=0.28 (95% CI, 0.10-0.77; P=0.0132) in 43 patients at 30-month follow-up. CI indicates confidence interval; HR, hazard ratio; PFS, progression-free survival. EGFR Mutation Abundance With PFS and OS A negative correlation was observed between PFS (r=−0.4396, P=0.0032), and OS (r=−0.3630, P=0.0167) with abundance of sensitizing mutations at baseline (Figs. 5A, B). Indeed, among 8 patients who had PFS≥9 months, only 3 of them had EGFR mutation detectable in their baseline plasma (Table 4). FIGURE 5 Association between EGFR mutation burden and PFS and OS. A, EGFR mutation burden correlated negatively with PFS (r=−0.45, P=0.0017). B, At baseline the EGFR mutation burden was negatively correlated with OS (r=−0.3891, P=0.0075). EGFR indicates epidermal growth factor receptor; OS, overall survival; PFS, progression-free survival. TABLE 4 Characteristics of Patients Who had PFS ≥9 Months in Gefitinib Re-challenge TABLE 4 (Continued)

FIGURE 5 Association between EGFR mutation burden and PFS and OS. A, EGFR mutation burden correlated negatively with PFS (r=−0.45, P=0.0017). B, At baseline the EGFR mutation burden was negatively correlated with OS (r=−0.3891, P=0.0075). EGFR indicates epidermal growth factor receptor; OS, overall survival; PFS, progression-free survival. TABLE 4 Characteristics of Patients Who had PFS ≥9 Months in Gefitinib Re-challenge TABLE 4 (Continued) Safety Analysis Of the 43 patients who underwent gefitinib re-challenge, 32 (74.42%) reported the occurrence of AEs. At least 1 AE was reported in 32 (74.42%) patients and drug-related AEs occurred in 19 (44.19%) patients. Severe AEs were reported in 7 (16.28%) patients among the study population, with none of the severe AEs related to the drug. Four (9.30%) patients discontinued the treatment due to drug-related AEs. Majority of the AE events reported were of the gastrointestinal system (32.56%), skin and subcutaneous tissue related (30.23%), and respiratory, thoracic, and mediastinal diseases (16.28%). We also observed 1 death among the study population but these were attributed to the symptomatic outcomes of lung cancer. QoL Assessment All the fields of QoL, that is, QoL function status score, QoL score with additional Concern, and total Score of baseline QoL showed a reasonable improvement from that of baseline across all visits but were not significant (P>0.05) (Table 5). TABLE 5 Change in QoL at Different Visits

Safety Analysis Of the 43 patients who underwent gefitinib re-challenge, 32 (74.42%) reported the occurrence of AEs. At least 1 AE was reported in 32 (74.42%) patients and drug-related AEs occurred in 19 (44.19%) patients. Severe AEs were reported in 7 (16.28%) patients among the study population, with none of the severe AEs related to the drug. Four (9.30%) patients discontinued the treatment due to drug-related AEs. Majority of the AE events reported were of the gastrointestinal system (32.56%), skin and subcutaneous tissue related (30.23%), and respiratory, thoracic, and mediastinal diseases (16.28%). We also observed 1 death among the study population but these were attributed to the symptomatic outcomes of lung cancer. QoL Assessment All the fields of QoL, that is, QoL function status score, QoL score with additional Concern, and total Score of baseline QoL showed a reasonable improvement from that of baseline across all visits but were not significant (P>0.05) (Table 5). TABLE 5 Change in QoL at Different Visits DISCUSSION Our study results demonstrated that third-line gefitinib re-challenge was efficient in improving DCR, PFS, and OS in patients, with overall PFS of 4.4 months and OS of 10.3 months. Longer PFS (4.7 vs. 2.0 mo) and OS (15.2 vs. 7.7 mo) was observed in T790M-negative patients compared with T790M positive patients. In addition, as T790M mutation increased after third-line EGFR-TKI, routine testing of this mutation is important for the clinical decision-making process and planning treatment strategies in patients with resistance to EGFR-TKIs.

s. 7.7 mo) was observed in T790M-negative patients compared with T790M positive patients. In addition, as T790M mutation increased after third-line EGFR-TKI, routine testing of this mutation is important for the clinical decision-making process and planning treatment strategies in patients with resistance to EGFR-TKIs. Previously, several studies have reported that re-challenge with TKI is beneficial for initial TKI responders following a drug holiday.12,25–27 Vasile and colleagues studied the effect of erlotinib after failure of gefitinib in patients who had previously responded to gefitinib and were treated with 2 line of chemotherapy. The median duration of response with erlotinib was 8 months and the median time to progression and OS was 5.9 and 14.6 months suggestive of potential use of erlotinib in patients who had previously responded on gefitinib.26 A phase II study evaluated the effect of erlotinib in NSCLC patients who progressed with gefitinib. The DCR and RR was 28.6% and 9.5% in all the patients. Moreover, there was significant greater DCR and RR observed in patients who had stable disease with gefitinib (75% vs. 17.6% and 50.0% vs. 0%, P=.029), showing the correlation of prior gefitinib treatment response with efficacy parameters of erlotinib. In addition, patients who did not harbor EGFR mutations and had stable disease with gefitinib also reported higher DCR (100% vs. 21.4%, P=0.029) and RR (66.7% vs. 0%, P=0.22) compared with the patients who harbored EGFR mutations. However, this study had patients who received 2 to 3 prior chemotherapy regimens unlike our study which has only 1 chemotherapy regimens. The results of this study revealed the potential use of erlotinib for patients with stable disease on prior gefitinib treatment and wild-type EGFR NSCLC,13 the results are in line with the our results suggestive of the potential use of re-challenge for NSCLC patients with wild-type EGFR. In a retrospective study by Tomizawa et al,28 the authors reported a median survival time of 10 months following chemotherapy and gefitinib re-challenge, with a DCR of 65%.

EGFR NSCLC,13 the results are in line with the our results suggestive of the potential use of re-challenge for NSCLC patients with wild-type EGFR. In a retrospective study by Tomizawa et al,28 the authors reported a median survival time of 10 months following chemotherapy and gefitinib re-challenge, with a DCR of 65%. However, our study was a prospective study and showed better efficacy data than previous studies, which could be attributed to the specific selection of the patients due to the prospective design of the study indicating that more survival benefit could be obtained from TKI re-challenge for selected NSCLC patients with activating mutations who responded to first-line gefitinib and progressed after second-line chemotherapy. Other clinical characteristics are also associated with efficacy of re-challenge with EGFR-TKI including chemotherapy regimens between EGFR-TKIs, TKI-free interval, and time to progression after initial EGFR-TKI.25,27,29,30 Adults with progressed NSCLC and EGFR exon 19 deletion/exon 21 L858R substitution who had previously achieved positive response with first-line gefitinib (PFS≥6 mo) and second-line chemotherapy (platinum-based doublet chemotherapy, ≥4 cycles of chemotherapy) were included in our study. The prerequisite for our study was that second-line chemotherapy should be ≥4 cycles. There are 2 main purposes for this, firstly to destroy more cells resistant to EGFR-TKI by chemotherapy and secondly to gain more longer holiday period for EGFR-TKI. Therefore, our study suggested that better response to EGFR-TKI re-challenge might need a longer PFS during initial EGFR-TKI treatment and more cycles of chemotherapy in TKI-free interval.

, firstly to destroy more cells resistant to EGFR-TKI by chemotherapy and secondly to gain more longer holiday period for EGFR-TKI. Therefore, our study suggested that better response to EGFR-TKI re-challenge might need a longer PFS during initial EGFR-TKI treatment and more cycles of chemotherapy in TKI-free interval. Recently, a similar phase II trial that demonstrated first-line EGFR-TKI response (PFS≥12 wk) and ≥4 cycles of chemotherapy reported median PFS of 2.8 months and OS of 10.2 months. However, this study lacked the biomarker analysis.31 Dynamic biomarker monitor is very important in the EGFR-TKI re-challenge. Nakamura and colleagues retrospectively evaluated the association of T790M and HGF quantification using plasma with the efficacy of EGFR re-challenge in a small cohort of 16 patients and reported that elevated HGF (≥1.5 fold) and T790M positivity was associated with poor response, whereas low HGR ratio (<1.5) and absence of T790M mutation was associated with positive response, suggesting the potential use of plasma in dynamic monitoring of these biomarkers in predicting response to TKIs.30 Our study results confirmed the use of plasma in dynamically monitoring the emergence of resistant mutations and the role of T790M mutation as a biomarker in predicting the response to gefitinib re-challenge, and observed that patients with T790M mutation positive had lower DCR, shorter survival data compared with patients who did not harbor the resistant mutation. Our study showed that T790M mutation negativity plays an eminent role in determining the efficacy of gefitinib re-challenge.

response to gefitinib re-challenge, and observed that patients with T790M mutation positive had lower DCR, shorter survival data compared with patients who did not harbor the resistant mutation. Our study showed that T790M mutation negativity plays an eminent role in determining the efficacy of gefitinib re-challenge. In addition, we also observed long-term survival in 8 patients with PFS of >9 months. All of these patients were nonsmokers and received pemetrexed and platinum, except one who received gemcitabine and platinum-based chemotherapy. Interestingly, among them, it was also noticed that only 3 patients were EGFR mutation positive at baseline. The reason why they have so long PFS in third-line EGFR-TKI re-challenge, may need further study to exploration.

ived pemetrexed and platinum, except one who received gemcitabine and platinum-based chemotherapy. Interestingly, among them, it was also noticed that only 3 patients were EGFR mutation positive at baseline. The reason why they have so long PFS in third-line EGFR-TKI re-challenge, may need further study to exploration. It is observed that ∼50% to 60% of patients treated with TKI develop T790M-positive tumors following disease progression.27,29 In our study, at baseline of third line, only 28.3% of patients had T790M mutation. There might be 2 reasons for occurrence of this phenomenon. Firstly, we used the plasma sample to test the EGFR mutation, and it is known that the sensitivity of plasma testing is lower than the tissue sample. Secondly, the chemotherapy in the second line may kill some cancer cells with T790M mutation. We also observed in current study an increase in T790M positivity after third-line EGFR-TKI. This has a very important clinical significance, which implies that NSCLC patients who acquired T790M mutation after third-line first-generation EGFR-TKI re-challenge have an opportunity to receive third-generation EGFR-TKI treatment.

observed in current study an increase in T790M positivity after third-line EGFR-TKI. This has a very important clinical significance, which implies that NSCLC patients who acquired T790M mutation after third-line first-generation EGFR-TKI re-challenge have an opportunity to receive third-generation EGFR-TKI treatment. This study has few limitations, such as being a single-arm study with no control, nonrandomized design and small sample size. In addition, there is inherent selection bias due to the specific inclusion of the patients progressing on gefitinib and undergoing platinum-based chemotherapy (≥4 cycles) that plausibly be the underlying reason for treatment response due to the emergence of sensitive mutations. However, this is the first prospective trial to assess the efficacy of gefitinib re-challenge as third line in NSCLC patients with activating EGFR mutations treated with first-line treatment followed by second-line chemotherapy in Chinese population. Furthermore, dynamically monitoring of EGFR mutations in plasma in each visit during gefitinib re-challenge is also another highlight in this study.

b re-challenge as third line in NSCLC patients with activating EGFR mutations treated with first-line treatment followed by second-line chemotherapy in Chinese population. Furthermore, dynamically monitoring of EGFR mutations in plasma in each visit during gefitinib re-challenge is also another highlight in this study. In conclusion, our findings highlight and strengthen the body of evidence that re-challenge with gefitinib after first-line treatment with EGFR-TKI is effective and could be possibly considered as a salvage treatment for Asian patients with clinical resistance. Especially, NSCLC without T790M mutation after the initial first-generation EGFR-TKI resistance and second-line chemotherapy could benefit more from EGFR-TKI re-challenge. In addition, molecular profiling of EGFR in the later stage of disease is crucial to identify patients in whom maximal benefits could be derived from novel treatment strategies. ACKNOWLEDGMENTS The authors thank Dr Anuradha Nalli (PhD) and Dr Priyanka Bannikoppa (PhD) (Indegene, Bangalore, India) for providing medical writing support and technical assistance in the development of this manuscript. The authors thank the investigators, study nurse (Xin-cui Song), CTONG representatives, and patients and their families who participated in this study. Supported by AstraZeneca China and the Chinese Thoracic Oncology Group (CTONG).

ACKNOWLEDGMENTS The authors thank Dr Anuradha Nalli (PhD) and Dr Priyanka Bannikoppa (PhD) (Indegene, Bangalore, India) for providing medical writing support and technical assistance in the development of this manuscript. The authors thank the investigators, study nurse (Xin-cui Song), CTONG representatives, and patients and their families who participated in this study. Supported by AstraZeneca China and the Chinese Thoracic Oncology Group (CTONG). Y.S.: build the study concepts. Y.S. and Y.-L.W.: designed the study. Y.S., Y.-L.W., L.-J.C, J.H.C, Z.-Y.M, J.-W.C, J.W., and H.-B.L.: performed the data acquisition. Y.S., Y.-L.W., L.-J.C., J.-H.C., Z.-Y.M., J.-W.C., J.W., and H.-B.L.: quality control of the data and algorithms. H.-B.L, J.-Y.D, and M.H.: analysis of data and interpretation. H.-B.L., J.-Y.D., and M.H.: statistical analysis. Y.S. and H.B.L.: prepared the manuscript. Y.S.: edited the manuscript. Y.S., Y.-L.W., L.-J.C., J.-H.C., Z.-Y.M., J.-W.C., and J.W.: reviewed and approved the manuscript. J.-Y.D. and M.H. were full-time employees of AstraZeneca when working on this study. The remaining authors declare no conflicts of interest.

Small cell carcinoma of the esophagus (SCEC) is a rare subtype of esophageal cancer with an incidence of only 0.1% to 2.4% of all cases of esophageal cancer.1–4 It is a highly aggressive tumor, with about half of the patients presenting with metastatic disease.4,5 In localized disease, a multimodality treatment combining chemotherapy with radiotherapy and/or surgery is often used. However, even with multimodality treatment, overall survival is poor with a median survival of 8 to 21 months.4–6 Due to its rare nature, randomized studies are not available and are unlikely to be conducted. Several large retrospective series using nationwide databases show differences in survival depending on treatment modality.4,5 However, as these series lack patient specific data, they cannot draw conclusions on an optimal treatment regime. In this retrospective nationwide study, we analyzed individual patients’ charts to determine treatment factors related to outcome in patients with nonmetastasized SCEC of the esophagus. We specifically investigated patterns of failure and the effect of type and number of chemotherapy cycles and dose of radiotherapy. METHODS Patients Patients were identified through the Netherlands Cancer Registry and by the hospitals’ local data registration systems from the radiation oncology departments.7 Data on treatment and outcome were retrieved from the clinical chart and retrospectively recorded in an electronic database. All but 1 Dutch radiotherapy institute participated in the study.

h the Netherlands Cancer Registry and by the hospitals’ local data registration systems from the radiation oncology departments.7 Data on treatment and outcome were retrieved from the clinical chart and retrospectively recorded in an electronic database. All but 1 Dutch radiotherapy institute participated in the study. We identified patients of any age who were diagnosed with a histologically confirmed SCEC of the esophagus without distant metastases at initial diagnosis. Mixed histology was accepted, but only if part of the histology was true small cell carcinoma. Neuroendocrine tumors without small cell carcinoma were thus excluded from analyses. Patients with involved supraclavicular nodes were included. All patients received treatment with curative intent including radiotherapy between January 2000 and December 2014. All data were retrieved in 2016 to ensure a minimum follow-up of at least 12 months.

hout small cell carcinoma were thus excluded from analyses. Patients with involved supraclavicular nodes were included. All patients received treatment with curative intent including radiotherapy between January 2000 and December 2014. All data were retrieved in 2016 to ensure a minimum follow-up of at least 12 months. The absence of distant metastases at diagnosis was confirmed by CT or PET scan. Data on pretreatment brain scans were not recorded. For esophageal radiotherapy, data regarding dose and fractionation were collected. Prophylactic cranial irradiation (PCI) was registered (yes/no). For chemotherapy, data on type of chemotherapy, number of cycles, and whether administered concurrent or sequentially were collected. For surgical treatment, date of surgery and histology after surgery were collected. For recurrences, date of recurrence, histologic confirmation (yes/no), and location in relation to radiotherapy (locoregional infield, locoregional outfield, distant, or a combination) were scored. Brain metastases were scored both as distant metastases and separately as brain metastases. Death was reported either in the presence of disease, absence of disease, or disease status unknown.

The absence of distant metastases at diagnosis was confirmed by CT or PET scan. Data on pretreatment brain scans were not recorded. For esophageal radiotherapy, data regarding dose and fractionation were collected. Prophylactic cranial irradiation (PCI) was registered (yes/no). For chemotherapy, data on type of chemotherapy, number of cycles, and whether administered concurrent or sequentially were collected. For surgical treatment, date of surgery and histology after surgery were collected. For recurrences, date of recurrence, histologic confirmation (yes/no), and location in relation to radiotherapy (locoregional infield, locoregional outfield, distant, or a combination) were scored. Brain metastases were scored both as distant metastases and separately as brain metastases. Death was reported either in the presence of disease, absence of disease, or disease status unknown. Statistical Analyses All data were analyzed using the statistical package IBM SPSS Statistics for Windows 24.0 (IBM Corporation, Armonk, NY). Continuous and categorical variables were summarized by descriptive statistics. Descriptive data are given as a mean (±SD) or median (range). Overall survival was calculated from the start of first treatment until the date of death or last follow-up, using the Kaplan-Meier method with the log rank test to determine significance. Data were censored at the last follow-up for patients still alive. Recurrence free rate was calculated from the start of treatment until the date of recurrence (locoregional, distant, or both), using the Kaplan-Meier method. Data were censored at date of death in the absence of disease or at date of last follow-up for patients without a recurrence.

follow-up for patients still alive. Recurrence free rate was calculated from the start of treatment until the date of recurrence (locoregional, distant, or both), using the Kaplan-Meier method. Data were censored at date of death in the absence of disease or at date of last follow-up for patients without a recurrence. Univariable and multivariable Cox proportional hazards models were fit to evaluate the impact of factors predictive of survival. All testing was 2-tailed with 0.05 as level of significance. Multivariable analyses were performed for factors with P<0.20 in univariate analyses. RESULTS Patients Between 2000 and 2015, a total of 16,492 patient were present in the Netherlands with an esophageal carcinoma without distant metastases. Of these, 9966 patients had an adenocarcinoma and 5897 patients had a squamous cell carcinoma.7 In total, 83 patients with a small cell carcinoma were identified. Twenty-five patients (20 treated with chemotherapy only and 5 with surgery only) were excluded from the study since additional data were unavailable, rendering 58 patients available for analyses. Baseline characteristics are reported in Table 1. TABLE 1 Characteristics of the Study Population (N=58)

RESULTS Patients Between 2000 and 2015, a total of 16,492 patient were present in the Netherlands with an esophageal carcinoma without distant metastases. Of these, 9966 patients had an adenocarcinoma and 5897 patients had a squamous cell carcinoma.7 In total, 83 patients with a small cell carcinoma were identified. Twenty-five patients (20 treated with chemotherapy only and 5 with surgery only) were excluded from the study since additional data were unavailable, rendering 58 patients available for analyses. Baseline characteristics are reported in Table 1. TABLE 1 Characteristics of the Study Population (N=58) Treatment Type Most patients were treated with concurrent chemoradiation (31 patients, 53%), 22 patients (38%) with sequential chemoradiation and 5 patients (9%) with radiotherapy only. Four patients (7%) had a resection after neoadjuvant therapy, 1 patient received chemoradiation after endoscopic mucosal resection. Median radiotherapy dose was 45 Gy (range, 9 to 66 Gy). One patient died after complications after 9 Gy. The dose range for the remaining group was 36 to 66 Gy. The majority of patients received between 45 and 50 Gy (44 patients, 76%). Only 5 patients received >50 Gy, 3 of whom received no chemotherapy. The dose per fraction ranged between 1.8 and 3 Gy. Most patients received 1.8 or 2 Gy fractions (44 patients, 76%). Five patients received radiotherapy twice daily in 1.5 Gy fractions, with a total dose of 45 Gy. Most patients (53) received chemotherapy, of whom 43 received platinum-based therapy. Chemotherapy details are reported in Supplement 1 (Supplemental Digital Content 1, http://links.lww.com/AJCO/A256).

s (44 patients, 76%). Five patients received radiotherapy twice daily in 1.5 Gy fractions, with a total dose of 45 Gy. Most patients (53) received chemotherapy, of whom 43 received platinum-based therapy. Chemotherapy details are reported in Supplement 1 (Supplemental Digital Content 1, http://links.lww.com/AJCO/A256). Survival Median follow-up for patients alive was 43 months. Median survival for the entire cohort was 16 months [95% confidence interval (CI), 11-21 mo]. Survival at 1, 3, and 5 years was 65%, 30%, and 22%, respectively (Fig. 1). At last follow-up, 13 patients were still alive (22%). Seven patients (12%) died without evidence of disease, 32 patients (55%) died with evidence of disease and for 6 patients (10%) disease status was unknown. FIGURE 1 Overall survival (months). Disease Outcome Thirty-two of 51 patients for whom recurrence data were available, had a locoregional or distant disease recurrence (63%). For 7 patients (12%) recurrence data were unavailable. Isolated locoregional recurrence thus in the absence of systemic disease, occurred in 9 patients (18%), all of which were infield. There were no isolated regional outfield recurrences. Any infield recurrence were identified in 13 patients (25%). Distant metastases, including brain metastases, were identified in 23 patients (45%). Recurrence patterns are shown in Table 2. TABLE 2 Pattern of Recurrences

Disease Outcome Thirty-two of 51 patients for whom recurrence data were available, had a locoregional or distant disease recurrence (63%). For 7 patients (12%) recurrence data were unavailable. Isolated locoregional recurrence thus in the absence of systemic disease, occurred in 9 patients (18%), all of which were infield. There were no isolated regional outfield recurrences. Any infield recurrence were identified in 13 patients (25%). Distant metastases, including brain metastases, were identified in 23 patients (45%). Recurrence patterns are shown in Table 2. TABLE 2 Pattern of Recurrences Median time to any recurrence was 9 months, where 69% recurred within 1 year and 91% within 1.5 years (Fig. 2). Data on development of brain metastases were available for 43 patients. Brain metastases were identified in 5 patients (12%). PCI was applied in 6 patients, of which 1 developed brain metastases. Out of the 52 patients without PCI, 4 developed brain metastases. FIGURE 2 Time to recurrence (months). The infield recurrence rate was 30% (8/27) in the group receiving ≤45 Gy, and 21% (5/24) for those receiving >45 Gy (P=ns). Univariable Analyses Radiotherapy dose and number of received chemotherapy cycles (grouped) were significantly associated with better survival. The T and N stage, histologic subtype, and treatment period were not associated with survival. No difference in survival was seen between concurrent or sequential chemotherapy and radiotherapy. Further details are available in Table 3. TABLE 3 Univariable Analyses for Overall Survival

Univariable Analyses Radiotherapy dose and number of received chemotherapy cycles (grouped) were significantly associated with better survival. The T and N stage, histologic subtype, and treatment period were not associated with survival. No difference in survival was seen between concurrent or sequential chemotherapy and radiotherapy. Further details are available in Table 3. TABLE 3 Univariable Analyses for Overall Survival Multivariable Analyses Results for multivariable analyses are reported in Table 4. Only the number of chemotherapy cycles remained significant for survival. We also analyzed cycles of chemotherapy and radiotherapy dose as a continuous variable. When analyzed as a continuous variable, the hazard ratio for the number of cycles of chemotherapy was 0.78 (95% CI, 0.65-0.93; P=0.006). When radiotherapy dose was analyzed as a continuous variable, the hazard ratio was 1.03 (95% CI, 0.99-1.10; P=0.44). TABLE 4 Multivariable Analyses for Overall Survival

Multivariable Analyses Results for multivariable analyses are reported in Table 4. Only the number of chemotherapy cycles remained significant for survival. We also analyzed cycles of chemotherapy and radiotherapy dose as a continuous variable. When analyzed as a continuous variable, the hazard ratio for the number of cycles of chemotherapy was 0.78 (95% CI, 0.65-0.93; P=0.006). When radiotherapy dose was analyzed as a continuous variable, the hazard ratio was 1.03 (95% CI, 0.99-1.10; P=0.44). TABLE 4 Multivariable Analyses for Overall Survival DISCUSSION In this nationwide retrospective study we analyzed treatment outcome and recurrence patterns in patients with SCEC treated with radiotherapy with or without chemotherapy. Recurrences occur frequently and usually within 1 year after curative treatment. Most failures occurred at distant sites (37%), as found by others.8–10 The total number of infield recurrences, thus including patients with simultaneous outfield or distant failures, was 23%. Isolated infield recurrences are relatively rare, occurring in 13% of patients only, suggesting that more aggressive locoregional treatment will not have a large effect on overall survival.

ers.8–10 The total number of infield recurrences, thus including patients with simultaneous outfield or distant failures, was 23%. Isolated infield recurrences are relatively rare, occurring in 13% of patients only, suggesting that more aggressive locoregional treatment will not have a large effect on overall survival. The benefit from multimodality treatment over single modality in SCEC of the esophagus has been well established over the years.4,5,9,11 Kukar and colleagues analyzed the Surveillance, Epidemiology, and End Results (SEER) database, showing that both radiotherapy and surgery were associated with improved survival on multivariate analysis. However, as chemotherapy use is not registered within the SEER database, no conclusions can be drawn on the role of chemotherapy.4 Wong and colleagues performed a retrospective analyses of 583 patients with SCEC of whom 340 with nonmetastatic disease. In multivariate analysis, chemoradiation was superior in survival compared to chemotherapy alone (hazard ratio, 1.44; P=0.003).5 However, no additional data on type and number of chemotherapy cycles were available. To the best of our knowledge, our study is the first investigating these factors. We found the number of received chemotherapy cycles to be highly predictive for overall survival, where patients receiving more cycles of chemotherapy had a markedly better survival. We did not have information on the planned number of chemotherapy cycles, thus effects of preliminary termination due to toxicity could not be assessed. This could induce a potential bias, where patients in a better general condition might have received more cycles of chemotherapy. We found no significant difference in survival between platinum or non–platinum-based chemotherapy. This is in line with the results from a recent Cochrane review on outcome in small cell lung cancer.12

nduce a potential bias, where patients in a better general condition might have received more cycles of chemotherapy. We found no significant difference in survival between platinum or non–platinum-based chemotherapy. This is in line with the results from a recent Cochrane review on outcome in small cell lung cancer.12 Reports in literature describe a wide variety of prescribed radiation doses, ranging between 40 and 70 Gy, usually in fractions of 1.8 to 2 Gy.8,13 To the best of our knowledge, this is the first study to analyze the effect of radiotherapy dose on survival. In univariable analysis, a lower radiotherapy dose was significantly associated with a better survival. In multivariable analysis however, we found no effect of radiotherapy dose on overall survival, neither when analyzing dose in groups nor when analyzing dose as a continuous variable. These results have to be interpreted with caution though. The vast majority of patients received between 45 and 50 Gy (44 patients) and only 5 patients received >50 Gy. Furthermore, 5 patients received radiotherapy twice a day, perhaps yielding a stronger radiobiological effect. As the majority of patients are clustered around such a narrow dose range any possible existing dose effect relationship is very unlikely to be found. The question whether or not a dose effect relationship exists simply cannot be answered with these data.

twice a day, perhaps yielding a stronger radiobiological effect. As the majority of patients are clustered around such a narrow dose range any possible existing dose effect relationship is very unlikely to be found. The question whether or not a dose effect relationship exists simply cannot be answered with these data. In small cell cancer of the lung, a dose of 60 Gy yielded superior results compared with 45 Gy in conventionally fractionated schedules once daily.14 Reducing the overall treatment time of radiotherapy by twice daily radiation has been shown to be more effective for overall survival and reduced infield recurrence (36% vs. 52%).15 A large randomized trial has recently shown that a twice daily schedule of 45 Gy to be equally effective as a once daily schedule of 66 Gy with comparable toxicity.16 In our cohort only 5 patients received radiotherapy twice daily, and only 1 patient received 66 Gy, so we cannot draw any conclusions on the possible benefit of either dose escalation or reducing overall treatment time, as has been suggested by others.8,17

e as a once daily schedule of 66 Gy with comparable toxicity.16 In our cohort only 5 patients received radiotherapy twice daily, and only 1 patient received 66 Gy, so we cannot draw any conclusions on the possible benefit of either dose escalation or reducing overall treatment time, as has been suggested by others.8,17 Brain metastases occurred in 12% of patients. Only 6 patients received PCI, of which 1 developed brain metastases. This seems to be much lower than reported in small cell lung cancer where a meta-analysis showed an incidence of 58.6%, decreasing to 33.3% for the group treated with PCI.18 However, in other series reporting on SCEC cases, brain metastases are reported in 5% to 14% of patients mostly without PCI, which is in agreement with the presented series.10,13,19 Considering the above, we currently see no role for PCI in SCEC.

incidence of 58.6%, decreasing to 33.3% for the group treated with PCI.18 However, in other series reporting on SCEC cases, brain metastases are reported in 5% to 14% of patients mostly without PCI, which is in agreement with the presented series.10,13,19 Considering the above, we currently see no role for PCI in SCEC. Since data were collected from medical files of nationwide radiotherapy institutions, no data are available on outcomes of surgery alone. Notwithstanding the possible benefit of esophagectomy in early stage disease,3,20–22 there has been considerable debate regarding the added value of surgery, either substituting radiotherapy or in addition to it.9,20,22 Raja and colleagues performed a meta-analysis, showing the benefit of combining either surgery or radiotherapy with chemotherapy in terms of survival. No additional benefit was found for the trimodality treatment.9 As isolated infield recurrences occurred in only 16% of patients after radiochemotherapy only in the present study, combined with a high distant recurrence rate at short term, major surgery such as an esophagectomy is unlikely to have a large clinical effect on the outcome and may not be advised as part of standard care. Strengths and Limitations The main strength of this study is the detailed information available from the original patient’s charts, allowing analyses of the effects of variations in treatment on both survival and failure patterns. Furthermore, it is a nationwide study representing 20 different institutions.

Since data were collected from medical files of nationwide radiotherapy institutions, no data are available on outcomes of surgery alone. Notwithstanding the possible benefit of esophagectomy in early stage disease,3,20–22 there has been considerable debate regarding the added value of surgery, either substituting radiotherapy or in addition to it.9,20,22 Raja and colleagues performed a meta-analysis, showing the benefit of combining either surgery or radiotherapy with chemotherapy in terms of survival. No additional benefit was found for the trimodality treatment.9 As isolated infield recurrences occurred in only 16% of patients after radiochemotherapy only in the present study, combined with a high distant recurrence rate at short term, major surgery such as an esophagectomy is unlikely to have a large clinical effect on the outcome and may not be advised as part of standard care. Strengths and Limitations The main strength of this study is the detailed information available from the original patient’s charts, allowing analyses of the effects of variations in treatment on both survival and failure patterns. Furthermore, it is a nationwide study representing 20 different institutions. The main drawbacks are the small sample size, the retrospective nature and the exclusion of surgery or chemotherapy only patients. To the best of our knowledge, it is however the largest series to date containing detailed individual patient data.

Strengths and Limitations The main strength of this study is the detailed information available from the original patient’s charts, allowing analyses of the effects of variations in treatment on both survival and failure patterns. Furthermore, it is a nationwide study representing 20 different institutions. The main drawbacks are the small sample size, the retrospective nature and the exclusion of surgery or chemotherapy only patients. To the best of our knowledge, it is however the largest series to date containing detailed individual patient data. CONCLUSIONS SCEC is an aggressive disease. Recurrences occur frequently and usually within 1 year after the start of curative treatment. Most recurrences include distant metastases, emphasizing the importance of systemic treatment. Incidence of brain metastases was low, even without PCI. We found a clear relationship between number of received chemotherapy cycles and survival. In this study, the best results were obtained with regimes consisting of at least 4 cycles of chemotherapy and radiotherapy. With a radiotherapy dose of 45 to 50 Gy, infield recurrence rate was low, suggesting that more aggressive locoregional treatment will probably not affect survival. Supplementary Material SUPPLEMENTARY MATERIAL Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.amjclinicaloncology.com.

CONCLUSIONS SCEC is an aggressive disease. Recurrences occur frequently and usually within 1 year after the start of curative treatment. Most recurrences include distant metastases, emphasizing the importance of systemic treatment. Incidence of brain metastases was low, even without PCI. We found a clear relationship between number of received chemotherapy cycles and survival. In this study, the best results were obtained with regimes consisting of at least 4 cycles of chemotherapy and radiotherapy. With a radiotherapy dose of 45 to 50 Gy, infield recurrence rate was low, suggesting that more aggressive locoregional treatment will probably not affect survival. Supplementary Material SUPPLEMENTARY MATERIAL Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.amjclinicaloncology.com. ACKNOWLEDGMENTS The authors thank the registration team of the Netherlands Comprehensive Cancer Organization (IKNL) for the collection of data for the Netherlands Cancer Registry. The authors declare no conflicts of interest.

Cervical cancer has the highest incidence and mortality of female genital tract cancers in China.1 Radical hysterectomy (RH) established by Ernst Wertheim has been the classical approach for the surgical treatment of early-stage cervical cancer.2 However, the quality of life of patients is intensively influenced by RH due to a high rate of postoperative morbidities involving the pelvic autonomic nervous system, including bladder dysfunction, colorectal disorder, and sexual dissatisfaction.3 Takashi Kobayashi introduced the nerve-sparing radical hysterectomy (NSRH) procedure to preserve pelvic autonomic nerves,2 which was then modified and improved by other gynecologists during the last 2 decades.4 Although NSRH was probably associated with less bladder dysfunction, the surgical and oncologic outcomes for these patients could not be fully assessed because of scarcity and heterogeneity of effect estimates, and various limitations in study designs addressing the advantages of NSRH versus traditional radical hysterectomy (TRH).5 More meticulous data and well-designed studies were needed to clarify the superiority of NSRH over TRH. This retrospective study aimed to reveal the safety of NSRH and the survival outcomes in patients with stage IB cervical cancer who received NSRH compared with patients who received TRH in a Chinese tertiary teaching hospital. All the primary procedures of NSRH or TRH for patients included in this cohort were performed by a single physician (M.W.).

to reveal the safety of NSRH and the survival outcomes in patients with stage IB cervical cancer who received NSRH compared with patients who received TRH in a Chinese tertiary teaching hospital. All the primary procedures of NSRH or TRH for patients included in this cohort were performed by a single physician (M.W.). METHODS Ethical Approval The Institutional Review Board had approved this study. Informed consent was obtained from all individual participants included in the study before any treatment. All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Study Design This retrospective cohort study was conducted at the Department of Obstetrics and Gynecology of a tertiary teaching hospital. We identified all patients diagnosed with cervical cancer of stage IB from February 1, 2001, to November 31, 2015, through the medical records system. All patients were followed-up in outpatient clinics, and the follow-up ended on December 31, 2016. The primary objectives were the disease-free survival (DFS) and overall survival (OS) of patients treated with NSRH and TRH. The secondary objectives were the residual urine volume at 14 days, at 4 months, and 12 months after the surgeries. The urinary comorbidities after surgeries were also evaluated in the study.

16. The primary objectives were the disease-free survival (DFS) and overall survival (OS) of patients treated with NSRH and TRH. The secondary objectives were the residual urine volume at 14 days, at 4 months, and 12 months after the surgeries. The urinary comorbidities after surgeries were also evaluated in the study. Study Participants All stage IB patients who accepted the NSRH or TRH by the corresponding author were included. The inclusion criteria consisted of the following (and they are): histopathologically proven primary cervical cancer of squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma; stage IB of International Federation of Gynecology and Obstetrics (FIGO) 20096 diagnosed using imaging evaluations (pelvic magnetic resonance imaging with computed tomography or positron emission tomography for evaluation of other sites) and pelvic examinations by 2 experienced physicians of gynecologic oncology; and normal bladder filling and voiding function based on patients’ complaints before and after surgeries. The definite diagnosis was made by transferring to the urologic clinics. Patients were excluded if they had distant metastasis in preoperative imaging or postoperative pathologic examinations. For patients who accepted surgical interventions, their pathologic outcomes were reviewed again by L.L. and S.Z. and modified according to FIGO 2009 criteria.

by transferring to the urologic clinics. Patients were excluded if they had distant metastasis in preoperative imaging or postoperative pathologic examinations. For patients who accepted surgical interventions, their pathologic outcomes were reviewed again by L.L. and S.Z. and modified according to FIGO 2009 criteria. Surgical Interventions, Adjuvant Therapy, and Follow-Up Surgical treatment consisted of RH, bilateral salpingo-oophorectomy or salpingectomy, and lymphadenectomy of pelvic lymph nodes (LNs) with or without para-aortic LNs. For young patients with the requirement of preserving ovaries, salpingectomy was undertaken along with suspension of the ovaries to the peritoneum above the level of the anterior superior spine. All the primary procedures, including the resection of the parametrium and retroperitoneal LNs, were performed by the corresponding author in accordance with class III or with Meigs’ surgeries of Piver-Rutledge-Smith classification7 before 2011, and in accordance with type C of the Querleu-Morrow classification8 after 2011. Type C1, that is, NSRH, requires the separation of 2 parts of the dorsal parametria: the medial part, which contains the rectouterine and rectovaginal ligaments, and the lateral part, which is a laminar structure and which contains the hypogastric plexus.8,9 Although type C2 surgery represents RH without preservation of the autonomic nerves, the paracervix is resected completely, including the part close to the end of the deep uterine vein. Surgical years were further divided into 3 phases: 2001 to 2005, 2006 to 2010, and 2011 to 2015. The decision of NSRH or TRH was made due to the judgment and learning curve of the surgeon (M.W.). Since 2011, all the RH surgeries belonged to nerve-sparing procedures.

g the part close to the end of the deep uterine vein. Surgical years were further divided into 3 phases: 2001 to 2005, 2006 to 2010, and 2011 to 2015. The decision of NSRH or TRH was made due to the judgment and learning curve of the surgeon (M.W.). Since 2011, all the RH surgeries belonged to nerve-sparing procedures. All histologic specimens underwent thorough pathologic examinations. Neoadjuvant chemotherapy was administered to some patients with stage IB2. Postoperative adjuvant therapies, including systematic chemotherapy, radiotherapy, concurrent chemoradiotherapy, or a combination of these therapies, were provided for patients according to relevant contemporary guidelines. Regimens of chemotherapy consisted of paclitaxel/carboplatin, paclitaxel/cisplatin, or fluorouracil/cisplatin. Complications such as adverse events within 3 months after the surgery were reviewed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.10 These complications included pulmonary, renal, and cerebrovascular morbidity; wound and vault complications (infection, breakdown, and dehiscence); septicemia and thromboembolic complications (deep vein thrombosis, pulmonary embolism); and lymphocyst or abscess formation lymphedema, incisional hernia formation, vaginal evisceration.11

ons included pulmonary, renal, and cerebrovascular morbidity; wound and vault complications (infection, breakdown, and dehiscence); septicemia and thromboembolic complications (deep vein thrombosis, pulmonary embolism); and lymphocyst or abscess formation lymphedema, incisional hernia formation, vaginal evisceration.11 Postoperative catheters were preserved until 14 days after NSRH. Bladder training was performed for all participants over 3 to 4 days by intermittently closing the catheters. On the morning of the 14th day, the urinary catheters were removed for all participants. After sufficient hydration by routine diet and drinking, the first spontaneous voiding was recorded. Clean catheterization was used to obtain precise residual urine volume. At residual urine volume >100 mL, the catheter was kept in place until a second removal of the catheter was appropriate. At 14 days, 4 months, and 1 year from the surgery, the residual urine volumes were measured by clean catheterization. The potential urinary dysfunctions were identified and obtained a definite diagnosis during the follow-up consistent with the recommendations of the International Urogynecological Association/International Continence Society.12

1 year from the surgery, the residual urine volumes were measured by clean catheterization. The potential urinary dysfunctions were identified and obtained a definite diagnosis during the follow-up consistent with the recommendations of the International Urogynecological Association/International Continence Society.12 A close follow-up according to the customed protocol was provided for all patients, who would visit the outpatient clinics every 3 to 4 months for the first year, every 6 months for the second to third year, and every year for the rest of the follow-up period. Patients will accept physical examinations, cytology test, and imaging evaluation. Recurrence was validated by imaging examination and/or biopsy. DFS was defined as the time interval from the date of primary surgery to the date of disease progression and/or recurrence. OS was defined in months as the time interval from the date of the primary surgery to the date of death or censoring at the date of the last contact.

alidated by imaging examination and/or biopsy. DFS was defined as the time interval from the date of primary surgery to the date of disease progression and/or recurrence. OS was defined in months as the time interval from the date of the primary surgery to the date of death or censoring at the date of the last contact. Statistical Analysis Comparisons of continuous variables were conducted with parametric methods if assumptions of normal distribution were confirmed. Non-normally distributed variables and categorical data were compared between 2 groups with the use of nonparametric tests. Survival curves were generated with the use of the Kaplan-Meier method, and proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the effect of epidemiological and clinicopathologic factors on DFS, progression-free survival, and OS. Multivariable analysis of DFS was performed with adjustment for important baseline risk factors. Unless otherwise stated, all analyses were performed with a 2-sided significance level of 0.05 and conducted with the use of the software SPSS 23.0 (SPSS Inc., Chicago, IL; Supplement 1, Supplemental Digital Content 1, http://links.lww.com/AJCO/A282).

S was performed with adjustment for important baseline risk factors. Unless otherwise stated, all analyses were performed with a 2-sided significance level of 0.05 and conducted with the use of the software SPSS 23.0 (SPSS Inc., Chicago, IL; Supplement 1, Supplemental Digital Content 1, http://links.lww.com/AJCO/A282). RESULTS Epidemiological and Preoperative Clinical Characteristics of Patients A total of 406 patients diagnosed with clinical stage IB and treated were identified, with 111 (27.3%) patients in the TRH group and 295 (72.7%) patients in the NSRH group. Table 1 shows the demographic and clinical characteristics of all the patients, with comparisons between the TRH group and NSRH group shown as well. There was no statistically significant difference observed in FIGO stage, histologic subtype, differentiation, neoadjuvant chemotherapy, ovarian preservation, residual tumor, invasion of stroma, lymphovascular space invasion, uterine involvement, vaginal margin involvement, LN positivity, radiotherapy, chemotherapy, or complications within 3 months after surgery, as shown in Table 1. However, patients in the NSRH groups had more conization procedures, more laparoscopic surgeries, and less parametrium involvement. Since 2011, all RH procedures belonged to NSRH. A more detailed description was listed in Supplement 1 (Supplemental Digital Content 1, http://links.lww.com/AJCO/A282). TABLE 1 Epidemiological, Clinicopathologic, and Surgical Characteristics of the Patients

RESULTS Epidemiological and Preoperative Clinical Characteristics of Patients A total of 406 patients diagnosed with clinical stage IB and treated were identified, with 111 (27.3%) patients in the TRH group and 295 (72.7%) patients in the NSRH group. Table 1 shows the demographic and clinical characteristics of all the patients, with comparisons between the TRH group and NSRH group shown as well. There was no statistically significant difference observed in FIGO stage, histologic subtype, differentiation, neoadjuvant chemotherapy, ovarian preservation, residual tumor, invasion of stroma, lymphovascular space invasion, uterine involvement, vaginal margin involvement, LN positivity, radiotherapy, chemotherapy, or complications within 3 months after surgery, as shown in Table 1. However, patients in the NSRH groups had more conization procedures, more laparoscopic surgeries, and less parametrium involvement. Since 2011, all RH procedures belonged to NSRH. A more detailed description was listed in Supplement 1 (Supplemental Digital Content 1, http://links.lww.com/AJCO/A282). TABLE 1 Epidemiological, Clinicopathologic, and Surgical Characteristics of the Patients Surgical Outcomes and Complications The NSRH group and RH group had similar mean operating times and mean number of LNs harvested. However, the TRH group had more mean blood loss during the operation (439.64 vs. 296.31 mL, P<0.05) and longer mean postoperative stay (11 vs. 17 d, P<0.05) than the NSRH group. The cases with severe (grade 3/4) complications comprised 5.41% (6/111) of the TRH group and 7.46% (22/295) of the NSRH group, between which no significant difference was observed (P=0.467). Severe lower limb lymphedema and lymphocysts demanding drainage occurred in 6 and 8 patients, respectively. No large vessel or visceral damage was found during the operation. However, ureteral fistula occurred in 1 case in the TRH group and in 2 cases in the NSRH group. No mortality occurred during the operation or the early postoperative period in either of the groups.

ng drainage occurred in 6 and 8 patients, respectively. No large vessel or visceral damage was found during the operation. However, ureteral fistula occurred in 1 case in the TRH group and in 2 cases in the NSRH group. No mortality occurred during the operation or the early postoperative period in either of the groups. Urinary Outcomes At 14 days, 4 months, and 12 months from the surgery, 398, 366, and 338 patients had their residual urine measured, respectively. At each phase in the NSRH group, there were fewer patients having residual urine volumes <50 mL compared with those in the TRH group (Table 2). The significances still exist in the subgroup analysis of various surgical years, various surgical approaches, and the utilization of neoadjuvant chemotherapy. TABLE 2 Residual Urine Volumes Measured by Clean Catheterization At 1 year from surgery, NSRH patients had fewer urinary dysfunction incidents than TRH patients (4/295 [1.4%] and 11/111 [9.9], P<0.001). In the NSRH groups, detrusor dysfunction, low compliance, and stress urinary incontinence were diagnosed in 1, 1, and 2 cases, respectively. In the NSRH groups, detrusor dysfunction, low compliance, stress urinary incontinence and mixed urinary incontinence were diagnosed in 2, 4, 3 and 2 cases, respectively. There were 3 and 0 patients with the diagnosis of neurogenic adynamia of detrusor muscle in the TRH and NSRH groups, respectively, who needed clean intermittent self-catheterization.

function, low compliance, stress urinary incontinence and mixed urinary incontinence were diagnosed in 2, 4, 3 and 2 cases, respectively. There were 3 and 0 patients with the diagnosis of neurogenic adynamia of detrusor muscle in the TRH and NSRH groups, respectively, who needed clean intermittent self-catheterization. Survival Outcomes A total of 371 cases (91.4%) with definite survival outcomes were included in the survival analysis. The cases with recurrence confirmed by imaging methods or pathologic examinations comprised 28.9% (26/90) of the TRH group and 15.7% (44/281) of the NSRH group, which showed a significant difference (P<0.05). The recurrent sites had no significant differences (Table 1). Table 3 shows the comparisons of survival outcomes between the 2 groups. In the univariate analyses, the OS and DFS for patients in the NSRH group were significantly better than those for patients in the TRH group (Fig. 1). In the multivariate analysis (Fig. 2), both OS and DFS in the NSRH group were similar to those in the TRH group (with NSRH as a reference, HR of OS 1.79, 95% CI: 0.64-5.02, P=0.268; HR of DFS 1.50, 95% CI: 0.72-3.11, P=0.280), after adjusting for the following variables: age, body mass index, gravidity, parity, surgical years, FIGO stage, neoadjuvant chemotherapy, surgical approach, and postoperative adjuvant therapy. TABLE 3 Comparison of OS and DFS in the Multivariate-Adjusted Model Between the NSRH and TRH Groups

Survival Outcomes A total of 371 cases (91.4%) with definite survival outcomes were included in the survival analysis. The cases with recurrence confirmed by imaging methods or pathologic examinations comprised 28.9% (26/90) of the TRH group and 15.7% (44/281) of the NSRH group, which showed a significant difference (P<0.05). The recurrent sites had no significant differences (Table 1). Table 3 shows the comparisons of survival outcomes between the 2 groups. In the univariate analyses, the OS and DFS for patients in the NSRH group were significantly better than those for patients in the TRH group (Fig. 1). In the multivariate analysis (Fig. 2), both OS and DFS in the NSRH group were similar to those in the TRH group (with NSRH as a reference, HR of OS 1.79, 95% CI: 0.64-5.02, P=0.268; HR of DFS 1.50, 95% CI: 0.72-3.11, P=0.280), after adjusting for the following variables: age, body mass index, gravidity, parity, surgical years, FIGO stage, neoadjuvant chemotherapy, surgical approach, and postoperative adjuvant therapy. TABLE 3 Comparison of OS and DFS in the Multivariate-Adjusted Model Between the NSRH and TRH Groups FIGURE 1 Overall survival and disease-free survival curves of the TRH and NSRH patients described by Kaplan-Meier tests. A, Overall survival curve. B, Disease-free survival curve. NSRH indicates nerve-sparing radical hysterectomy; TRH, traditional radical hysterectomy.

TABLE 3 Comparison of OS and DFS in the Multivariate-Adjusted Model Between the NSRH and TRH Groups FIGURE 1 Overall survival and disease-free survival curves of the TRH and NSRH patients described by Kaplan-Meier tests. A, Overall survival curve. B, Disease-free survival curve. NSRH indicates nerve-sparing radical hysterectomy; TRH, traditional radical hysterectomy. FIGURE 2 Overall survival and disease-free survival curves of the TRH and NSRH patients described by multivariate analysis. A, Overall survival curve. B, Disease-free survival curve. NSRH indicates nerve-sparing radical hysterectomy; TRH, traditional radical hysterectomy.

FIGURE 1 Overall survival and disease-free survival curves of the TRH and NSRH patients described by Kaplan-Meier tests. A, Overall survival curve. B, Disease-free survival curve. NSRH indicates nerve-sparing radical hysterectomy; TRH, traditional radical hysterectomy. FIGURE 2 Overall survival and disease-free survival curves of the TRH and NSRH patients described by multivariate analysis. A, Overall survival curve. B, Disease-free survival curve. NSRH indicates nerve-sparing radical hysterectomy; TRH, traditional radical hysterectomy. DISCUSSION Our report supports the superior bladder functions in the NSRH patients, who had similar surgical and survival outcomes as the non-NSRH patients. Despite ample evidence of favorable urinary, sexual, and anorectal outcomes for patients with cervical cancer after NSRH,13–15 it has not yet become a widely applied procedure among gynecologic surgeons, mainly because of the difficulty of recognizing and protecting nerve fibers in the operation.16 Although the Querleu-Morrow classification8,9 provides a reproducible anatomic terminology for NSRH, it was not designed to impose a universal surgical technique. The description of surgical procedures and energy instruments for NSRH and TRH differ considerably among different studies,17,18 suggesting that different surgeons are performing operations without standardized techniques and processes, even though the autonomic nerves form well-defined anatomic boundaries for NSRH. The success determining factors of nerve-sparing, such as FIGO stage or pathologic subtype, were little known.5,19,20 Thus far, NSRH still lacks standardization in surgical techniques and procedures, resulting in the large heterogeneity among different studies, which makes it difficult to compare the results of NSRH and TRH.21 In our study, all the surgeries were performed by a single surgeon, which probably could decrease the bias from surgical techniques. However, the learning curve of surgical experiences would interfere with the interpretation of survival outcomes.

udies, which makes it difficult to compare the results of NSRH and TRH.21 In our study, all the surgeries were performed by a single surgeon, which probably could decrease the bias from surgical techniques. However, the learning curve of surgical experiences would interfere with the interpretation of survival outcomes. The definite pathologic outcomes in our report had given enough evidence of the surgical scope of RH procedures. Few studies had reported the comparison of surgical scope between NSRH and TRH. One of the concerns with regard to NSRH is the possibility that, by taking measures to preserve the nerves, NSRH may restrict the scope of the operation and lead to insufficient treatment, which will eventually have effects on patients’ survival.22 This problem is hard to determine even for skilled surgeons who are familiar with the pelvic anatomy and the procedure of RH. Some authors found NSRH resulted in a shorter length of the resected vagina.23 A strict randomized study with a longer follow-up with regard to survival outcomes would indirectly explain the equivalence of surgical scope. More careful evaluation and pathologic examination of the uterine specimen would also probably provide valuable perspectives for such an issue. In our study, the mean number of LNs was 43.61 and 40.12 in the NSRH group and RH group, respectively, showing no significant difference (P>0.05). In addition, Bogani et al24 even reported more LNs in NSRH than in TRH. However, the numbers of harvested LNs did not offer enough evidence sustaining the extent of RH. A full-description of pathology by independent pathologists, including the length and/or width of the parametrium, uterosacral ligaments, and vagina, would provide more substantial verification of surgical scope in a prospective study.

numbers of harvested LNs did not offer enough evidence sustaining the extent of RH. A full-description of pathology by independent pathologists, including the length and/or width of the parametrium, uterosacral ligaments, and vagina, would provide more substantial verification of surgical scope in a prospective study. Overall, our data suggested NSRH had favorable surgical outcomes. Compared with TRH, NSRH was reported to have no significant differences in blood loss, in the proportion of patients who required a blood transfusion, or in severe complications during the operation.23,25–27 The operating time exhibited differences among many studies, which were considered to be related to differences in the surgeons’ experiences, techniques, and surgical procedures for NSRH. In our study, there was no statistically significant difference observed in the mean operating time or in the complications during the operation, whereas the mean blood loss during operation in the TRH group was significantly greater than that in the NSRH group. In previous studies, the incidence of postoperative complications in NSRH was reported to be lower than that in TRH, perhaps because of the protection of bladder and rectal functions.28 Consistent with previous studies, our results showed that the mean postoperative stay of the TRH group was significantly longer than that of the NSRH group, suggesting that NSRH was generally associated with a shorter postoperative stay, which might be associated with less bladder dysfunction and fewer postoperative complications.28,29

revious studies, our results showed that the mean postoperative stay of the TRH group was significantly longer than that of the NSRH group, suggesting that NSRH was generally associated with a shorter postoperative stay, which might be associated with less bladder dysfunction and fewer postoperative complications.28,29 Our data suggested that NSRH had favorable oncologic outcomes. As NSRH has not been connected with a reduced scope of operation, theoretically, patients who received NSRH will not have worse survival than those who received TRH. Although it is proposed that patients with cervical cancer who received NSRH might have an increased rate of recurrence because of the perineural invasiveness of residual tumor tissues that may have attached to the reserved nerve fibers, this concern had little evidence to support to date. Almost no report had reported that NSRH was associated with worse survival, even for locally advanced stage cervical cancer.30,31 A randomized controlled trial reported that patients who underwent NSRH had no difference in the 10-year rate of DFS compared with that of patients who underwent TRH.32 Systematic review and meta-analysis revealed that the local and overall recurrence rate data did not show significant differences between NSRH and TRH procedures.33,34 The results of our study showed that both OS and DFS in the NSRH group were similar to those in the TRH group, after adjusting for preoperative factors, operative approaches, and adjuvant therapy. These findings support the safety and survival benefits of NSRH. However, according to the study of Basaran et al,5 the evidence addressing the oncologic safety of NSRH over that of conventional RH in cervical cancer is neither adequate nor statistically relevant. The current knowledge on oncologic outcomes may not be insufficient to assess the equality of survival between NSRH and TRH.

ver, according to the study of Basaran et al,5 the evidence addressing the oncologic safety of NSRH over that of conventional RH in cervical cancer is neither adequate nor statistically relevant. The current knowledge on oncologic outcomes may not be insufficient to assess the equality of survival between NSRH and TRH. As a retrospective cohort study, the main limitations of our study were the recall bias and selection bias. A lack of consistent criteria for pathologic examinations is an important confounding factor in our study. The limited number of cases of TRH might have influenced the results and restricted the extrapolation of related conclusions. We did not apply urodynamic analysis with multiparameters for the comparison of urinary outcomes, which would hinder the extrapolation of our findings. Although the LACC trial35 and another epidemiological study36 suggested minimally invasive surgeries could cause significant deteriorative survival outcomes, we could not support meaningful evidence in the field of NSRH. First, this is a cohort study in a single center; second, almost all the NSRH procedures were performed in recent periods and in laparoscopic routs. The learning curves of a single physician would significantly distract the stratification analysis.

utcomes, we could not support meaningful evidence in the field of NSRH. First, this is a cohort study in a single center; second, almost all the NSRH procedures were performed in recent periods and in laparoscopic routs. The learning curves of a single physician would significantly distract the stratification analysis. CONCLUSION In conclusion, the results of this study showed that NSRH might be a promising surgical approach for early-stage cervical cancer patients without sacrificing oncologic safety. The NSRH procedure should be standardized to create uniform assessment criteria. More well-designed and large-scale multicenter clinical trials are needed to evaluate the efficacy and oncologic safety of NSRH before it is recommended as a standard approach for cervical cancer treatment. Supplementary Material SUPPLEMENTARY MATERIAL Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.amjclinicaloncology.com. Supported by the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (CAMS-2017-I2M-1-002). The authors declare no conflicts of interest.

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies worldwide. It is estimated that, by 2030, CRC diagnosis will increase by >50%.1 As metastases are expected in 20% of patients with CRC, the development of new markers for more effective therapeutic options is pivotal.2,3 CRC represents one of many malignancies in which autophagy, a necessary catabolic process, has been identified to play an essential role in tumorigenesis. Autophagy-related genes (ATGs) play a crucial role in facilitating the regulation of autophagy.4 Several proteins such as Beclin-1 (Atg6), MAP1LC3B (Atg8), p62/SQSTM1, and the Ras-related protein Rab-7 have been identified as vital elements of autophagy in cancer.5 Beclin-1 is rarely mutated in the majority of tumors and it is associated with the initiation of autophagy through interaction with PI3k. LC3B-I protein through lipidation is converted into LC3-BII. LC3-BII is associated with the formation of autophagic vesicles and is used as an indicator of autophagy. Another essential protein for autophagy is p62/SQSTM1, which targets packaging and delivery proteins for autophagic digestion. This protein has been identified as a crossroad of apoptosis, autophagy, and cancer. Rab-7 is involved in endocytosis, a process in which some of its steps are similar to those of the maturation of autophagosome.6

otein for autophagy is p62/SQSTM1, which targets packaging and delivery proteins for autophagic digestion. This protein has been identified as a crossroad of apoptosis, autophagy, and cancer. Rab-7 is involved in endocytosis, a process in which some of its steps are similar to those of the maturation of autophagosome.6 A plethora of studies support the idea of the dual role of autophagy in CRC. Autophagy plays a crucial role in energy homeostasis of cells, which is required for several cellular functions, such as angiogenesis,7 migration,8 proliferation, and epithelial-mesenchymal transition phenotype.9 Autophagy is enhanced in the hypoxic region of already established tumors where the energy demands are elevated.10 Furthermore, cancer cells of high-graded tumors seem to be linked to autophagy to maintain their energy balance.11 The impact of autophagy in cancer patients’ response to chemotherapy is already known. Elevated levels of autophagy are associated with inadequate response to chemotherapeutic drugs and dismal survival rates.12,13

ore, cancer cells of high-graded tumors seem to be linked to autophagy to maintain their energy balance.11 The impact of autophagy in cancer patients’ response to chemotherapy is already known. Elevated levels of autophagy are associated with inadequate response to chemotherapeutic drugs and dismal survival rates.12,13 In several cancer types, including CRC, a single-nucleotide polymorphism, in ATGs, such as ATG16L1, is connected with the reduction of autophagy and a significant negative predictive value for patients’ survival with metastatic disease.14 In contrast, several other studies identified the positive impact of monoallelic deletion or total loss of other ATGs.15 UVRAG proteins are linked to BECN1 and function as autophagy regulators.16 The mutation of UVRAG reduces autophagy, resulting in enlarged cancer cell proliferation in CRC cells.17 Moreover, BIF-1 proteins that are associated with BECN1 have been observed to turn into abnormal or absent in a range of cancer types, such as CRC.18

teins are linked to BECN1 and function as autophagy regulators.16 The mutation of UVRAG reduces autophagy, resulting in enlarged cancer cell proliferation in CRC cells.17 Moreover, BIF-1 proteins that are associated with BECN1 have been observed to turn into abnormal or absent in a range of cancer types, such as CRC.18 Furthermore, KRAS, an essential oncogene in CRC development, is strongly associated with autophagy.13 Under stressful conditions such as hypoxic tumor regions, cancer cells of KRAS-dependent tumors use autophagy to support growth and maintain an energy balance.19 Inhibition of upregulated autophagy in KRAS-dependent tumors decreases cell proliferation and promotes tumor suppression.20 The increasing amount of dysfunctional proteins and cellular organelles along with the inhibition of autophagy increase the risk of malignancy. Lastly, several studies with a knockout of different ATGs, Beclin-1 or AMBRA, have justified that low levels of autophagy are essential for cell survival.21,22 All these studies support the controversial role of autophagy in these mechanisms as either a tumor promoter or tumor suppressor. The controversial role of autophagy in cancer as a cytoprotective or tumor suppressor mechanism needs to be further investigated.23,24 The aim of this study was to assess the impact of autophagy-related proteins on the survival rate of patients with CRC and the potential autophagy mechanism in CRC cell lines.

ppressor. The controversial role of autophagy in cancer as a cytoprotective or tumor suppressor mechanism needs to be further investigated.23,24 The aim of this study was to assess the impact of autophagy-related proteins on the survival rate of patients with CRC and the potential autophagy mechanism in CRC cell lines. MATERIAL AND METHODS Patients Characteristics The data of 41 (aged 34 to 81) patients with CRC treated at our Department from January 1 to December 31, 2016 were studied. For these patients, there were available data regarding tumor histology grade, TNM classification, and mutation status of the genes ΚRAS (48.8%), NRAS (9.8%), and BRAF (7.4%), and on whether they were microsatellite instability (MSI) positive (7.4%). Molecular analyses were performed on patient samples before they received any treatment. In addition, there was available information regarding their treatment protocol (chemotherapy and/or radiotherapy). By the time of the data evaluation (December 2017), 4 patients (9.8%) had died because of their disease (Table 1). TABLE 1 The Data of 68 Colorectal Cancer Enrolled Patients’ Samples, n (%)

MATERIAL AND METHODS Patients Characteristics The data of 41 (aged 34 to 81) patients with CRC treated at our Department from January 1 to December 31, 2016 were studied. For these patients, there were available data regarding tumor histology grade, TNM classification, and mutation status of the genes ΚRAS (48.8%), NRAS (9.8%), and BRAF (7.4%), and on whether they were microsatellite instability (MSI) positive (7.4%). Molecular analyses were performed on patient samples before they received any treatment. In addition, there was available information regarding their treatment protocol (chemotherapy and/or radiotherapy). By the time of the data evaluation (December 2017), 4 patients (9.8%) had died because of their disease (Table 1). TABLE 1 The Data of 68 Colorectal Cancer Enrolled Patients’ Samples, n (%) DNA Extraction From Formalin-fixed Paraffin-embedded Tissues and Molecular Analysis Sections of 10-μm thickness were cut from paraffin-embedded tissue blocks. DNA was extracted from the selected tissue areas following a standard DNA extraction kit protocol (NucleoSpin Tissue, Macherey-Nagel, Duren, Germany). The extracted DNA was quantitated on a Picodrop microliter spectrophotometer. Samples were screened in duplicates for mutations of KRAS, NRAS, and BRAF, using a real-time polymerase chain reaction approach followed by high-resolution melting analysis on a Light Cycler 480 (Roche Diagnostics, GmbH, Germany).25 Polymerase chain reaction products positive by high-resolution melting analysis were purified and subjected to Sanger sequencing and/or pyrosequencing. MSI status was evaluated by molecular analysis of sensitive mononucleotide MSI markers (BAT25, BAT26, NR24, and NR21) and confirmed by analysis of MMR protein expression.26

merase chain reaction products positive by high-resolution melting analysis were purified and subjected to Sanger sequencing and/or pyrosequencing. MSI status was evaluated by molecular analysis of sensitive mononucleotide MSI markers (BAT25, BAT26, NR24, and NR21) and confirmed by analysis of MMR protein expression.26 Immunochemistry Immunohistochemistry of p62, LC3B, Beclin-1, and Rab-7 was performed on 5-μm-thick formalin-fixed, paraffin-embedded tissue samples. The sections were microwave heated with 10 mM citrate buffer (pH 6.0) for antigen retrieval (p62, LC3, and Rab-7). For Beclin-1, antigen retrieval was carried out with a hot water bath at pH 9.0. Three percent H2O2 was applied to quench the endogenous peroxidase. Tissue sections were incubated at 4°C overnight with one of the following primary antibodies: SQSTM1/p62 (Cell Signaling #88588; 1:200 dilution), LC3B (Cell Signaling #3868; 1:200 dilution), Beclin-1 (Invitrogen #ΜΑ5-15825; 1:100 dilution), and Rab-7 (Invitrogen #PA5-72549; 1:100 dilution). Sections were subsequently incubated with SignalStain Boost Detection Reagent in a humidified chamber for 30 minutes at room temperature. The sections were developed with diaminobenzidine and counterstained with hematoxylin.

n-1 (Invitrogen #ΜΑ5-15825; 1:100 dilution), and Rab-7 (Invitrogen #PA5-72549; 1:100 dilution). Sections were subsequently incubated with SignalStain Boost Detection Reagent in a humidified chamber for 30 minutes at room temperature. The sections were developed with diaminobenzidine and counterstained with hematoxylin. Immunohistochemistry Evaluation H-score evaluated the immunoreactivity of p62, LC3B, Beclin-1, and Rab-7 according to the intensity and percentage of positively stained cells. Tissues without any staining were rated as 0, with faint staining as 1, with moderate staining as 2, and with intense staining as 3. The H-scores were determined by multiplying the intensity score by the percentage of positively stained cells. Tumors with an immunoreactive score of 0 to 100 were evaluated as negative, and those with 101 to 300 were classified as positive.27–29 Statistical Analysis Statistical analysis was performed with SPSS22 software (SPSS Inc., Chicago, IL). Pearson’s χ2 test was used to evaluate the correlation of p62, LC3B, Beclin-1, and Rab-7 expressions with clinicopathologic parameters of patients with CRC. Univariate survival analysis was performed according to the Kaplan-Meier method, and survival was compared using the log-rank test. Differences were considered very significant if a P-value was <0.05 (2-tailed) and a statistical trend if a P-value was <0.1 (2-tailed).

clinicopathologic parameters of patients with CRC. Univariate survival analysis was performed according to the Kaplan-Meier method, and survival was compared using the log-rank test. Differences were considered very significant if a P-value was <0.05 (2-tailed) and a statistical trend if a P-value was <0.1 (2-tailed). Cell Lines Colo-205 (CCL-222), HT29 (HTB-38), SW-480 (CCL-228) human colon adenocarcinoma, and Caco-2 (ATCCHTB-37) colon intermediate adenoma cell lines were obtained from the American Type Culture Collection (ATCC). All cell lines used in this study were grown in Dulbecco’s Modified Eagle Medium supplemented with 10% fetal bovine serum, l-glutamine, vitamins, penicillin, and streptomycin antibiotics and amino acids (all from Invitrogen). Cells were maintained at 37°C in a humidified incubator containing 5% CO2. All experiments were under the approval of the Ethics Committee of our University.

fied Eagle Medium supplemented with 10% fetal bovine serum, l-glutamine, vitamins, penicillin, and streptomycin antibiotics and amino acids (all from Invitrogen). Cells were maintained at 37°C in a humidified incubator containing 5% CO2. All experiments were under the approval of the Ethics Committee of our University. Western Blot After the incubation time, radioimmunoprecipitation assay buffer is used for the preparation of whole-cell lysates. The protein concentration was determined using the Bradford method (Bio-Rad, 5000006). A total of 25 μg of protein was resolved on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to nitrocellulose membrane (Whatman; Scheicher & Schuell, Dassel, Germany). Membranes were incubated with the primary antibodies overnight at 4°C. After the incubation time, membranes were washed with Tris Buffered Saline with Tween 20 and then incubated with the appropriate secondary antibody, for 1 hour at 24°C.30 Antibodies targeting SQSTM1/p62 (Cell Signaling #8025), LC3B (Cell Signaling #3868), Beclin-1 (Cell Signaling #3777), Rab-7 (Cell Signaling #9367; Cell Signaling, Danvers, MA), and Actin (sc-8035; Biotechnology Inc., Santa Cruz, CA) were used. The signal of the antibodies was identified with the enhanced chemiluminescence and specific detection system (Amersham Biosciences, Uppsala, Sweden) after exposure to Fuji Medical X-Ray Film. The number of protein levels was measured using specific software (ImageQuant software, Amersham Biosciences). The normalization of protein levels was against actin. We performed 3 independent experiments and the SD is presented. The amount of loading protein for western blot is 25 μg of the sample in a total volume of 20 μL. ImageJ is used for the quantification of protein bands.

re (ImageQuant software, Amersham Biosciences). The normalization of protein levels was against actin. We performed 3 independent experiments and the SD is presented. The amount of loading protein for western blot is 25 μg of the sample in a total volume of 20 μL. ImageJ is used for the quantification of protein bands. 2-dimensional Culture For the 2-dimensional culture, cells (5000 cells/well) were grown on coverslips in 24-well plates in medium, at 37°C. The cells were treated with 10 and 20 μΜ of oxaliplatin or irinotecan for 24 hours. For the confocal analysis, the cells were fixed with 4% paraformaldehyde, washed with phosphate-buffered saline, and immediately analyzed in confocal to detect the autophagic vacuoles. Monodancylcadaverine (MDC) is an autofluorescent marker that preferentially accumulates in autophagic vacuoles. MDC accumulation in autophagic vacuoles is because of a combination of ion trapping and specific interactions with vacuole membrane lipids. Cell cytoskeleton was stained with phalloidin (Alexa Fluor 546, A22283, Life Technologies).

DC) is an autofluorescent marker that preferentially accumulates in autophagic vacuoles. MDC accumulation in autophagic vacuoles is because of a combination of ion trapping and specific interactions with vacuole membrane lipids. Cell cytoskeleton was stained with phalloidin (Alexa Fluor 546, A22283, Life Technologies). RESULTS Expression of Autophagy Markers in CRC Tissues The expression of 4 autophagy markers p62, LC3, Beclin-1, and Rab-7 was successfully performed in CRC human tissues. Τhen, a pathologist with no knowledge of the clinical data scored all immunohistochemical staining, according to the staining intensity and the percentage of positively stained tumor cells (Fig. 1). Furthermore, the normal mucosa was stained with the same autophagic markers. It appears that normal mucosa has null or very low expression of the 4 autophagy markers lymphocytes appear to have positive staining (Supplementary 1, Supplemental Digital Content, http://links.lww.com/AJCO/A286). FIGURE 1 Immunohistochemical staining of p62, LC3B, Beclin-1, and Rab-7 in human colorectal carcinomas (×40).

RESULTS Expression of Autophagy Markers in CRC Tissues The expression of 4 autophagy markers p62, LC3, Beclin-1, and Rab-7 was successfully performed in CRC human tissues. Τhen, a pathologist with no knowledge of the clinical data scored all immunohistochemical staining, according to the staining intensity and the percentage of positively stained tumor cells (Fig. 1). Furthermore, the normal mucosa was stained with the same autophagic markers. It appears that normal mucosa has null or very low expression of the 4 autophagy markers lymphocytes appear to have positive staining (Supplementary 1, Supplemental Digital Content, http://links.lww.com/AJCO/A286). FIGURE 1 Immunohistochemical staining of p62, LC3B, Beclin-1, and Rab-7 in human colorectal carcinomas (×40). Association of Autophagy Markers Expression With Clinicopathologic Characteristics, Molecular Status, and Therapeutic Approach None of the autophagy markers were found to correlate with their expression with pathologic factors after analysis through the χ2 test. Also, their expression levels were not correlated with mutations in KRAS, NRAS, and BRAF genes, and with MSI-positive tumors (Table 2). However, patients with CRC treated with chemotherapy and Beclin-1 expression showed a statistically significant correlation (P=0.006). TABLE 2 Comparison of Clinical, Molecular, and Treatment Factors With Autophagy Marker

Association of Autophagy Markers Expression With Clinicopathologic Characteristics, Molecular Status, and Therapeutic Approach None of the autophagy markers were found to correlate with their expression with pathologic factors after analysis through the χ2 test. Also, their expression levels were not correlated with mutations in KRAS, NRAS, and BRAF genes, and with MSI-positive tumors (Table 2). However, patients with CRC treated with chemotherapy and Beclin-1 expression showed a statistically significant correlation (P=0.006). TABLE 2 Comparison of Clinical, Molecular, and Treatment Factors With Autophagy Marker Effects of Autophagy Markers Expression on Overall Survival (OS) and Progression-free Survival (PFS) Patients with low levels of Beclin-1 expression showed a statistically greater therapeutic benefit in terms of OS (log-rank test, P=0.001) and PFS (log-rank test, P=0.069) than patients with high levels of Beclin-1 expression. Patients with low Rab-7 expression seemed to have better PFS compared with those with high expression (log-rank test, P=0.088) (Figs. 2A, B). FIGURE 2 A, Kaplan-Meier estimates of overall survival of patients with CRC with low and high expression of autophagy markers p62, LC3B, Beclin-1, and Rab-7. High expression of Beclin-1 reduces life span. B, Kaplan-Meier estimates of PFS of patients with CRC with low and high expression of autophagy markers p62, LC3B, Beclin-1, and Rab-7. In low expression of Beclin-1 and Rab-7, we observed better PFS. CRC indicates colorectal cancer; PFS, progression-free survival.

Rab-7. High expression of Beclin-1 reduces life span. B, Kaplan-Meier estimates of PFS of patients with CRC with low and high expression of autophagy markers p62, LC3B, Beclin-1, and Rab-7. In low expression of Beclin-1 and Rab-7, we observed better PFS. CRC indicates colorectal cancer; PFS, progression-free survival. Oxaliplatin and Irinotecan Inhibit Autophagy in Microsatellite stable (MSS) CRC Cell Lines Four different MSS colon adenocarcinoma and intermediate adenoma cell lines (Caco-2, Colo-205, HT29, and SW-480) were examined, regarding autophagic properties, after treatment with 10 and 20 μΜ of oxaliplatin and irinotecan for 24 hours. The protein levels of Beclin-1, LC3B, p62, and Rab-7 were measured with western blot analysis. In both CRC cell lines, Caco-2 and Colo-205 cell lines, autophagy was inhibited after treatment with oxaliplatin and irinotecan, as confirmed with the increased protein levels of p62 despite the enhancement of Beclin-1 (Fig. 3A). In another CRC cell line, HT29, a dose-dependent pattern of the reduction of Beclin-1 occurred after treatment with irinotecan and 20 μΜ of oxaliplatin. Furthermore, autophagy inhibition was confirmed by the increasing levels of p62, despite the increasing levels of LC3 at the same treatment points (Fig. 3A). In SW-480 CRC cell lines, treatment with irinotecan and oxaliplatin decreased Beclin-1 and p62 protein levels in all treatment points. Moreover, in the same cell line, both drugs increased the total amount of LC3 (Fig. 3A). Also the marker of endocytosis Rab-7 was further tested.

at the same treatment points (Fig. 3A). In SW-480 CRC cell lines, treatment with irinotecan and oxaliplatin decreased Beclin-1 and p62 protein levels in all treatment points. Moreover, in the same cell line, both drugs increased the total amount of LC3 (Fig. 3A). Also the marker of endocytosis Rab-7 was further tested. FIGURE 3 Oxaliplatin and irinotecan inhibit autophagy in microsatellite stable colorectal cancer cell lines. Western blot analysis after 24-hour exposure of cells in 10 and 20 μM of oxaliplatin or irinotecan. The protein levels of Beclin-1, p62, LC3, and Rab-7 were identified by specific antibody. The quantification of LC3 reflects the whole protein levels as compared with the untreated sample in each cell line (i) and the ratio of LC3II/LC3I in each sample separately (ii). Protein levels were normalized against actin (A). The formation of autophagic vacuoles in Caco-2, Colo-205, HT29, and SW-480 cells because of treatments was determined with 0.1 mM of MDC (light blue) through confocal microscopy, whereas phalloidin staining (red) was used for cytoskeleton detection. The yellow arrows show the autophagic vacuoles. The graph represents the quantification of MDC in each cell line (B). MDC indicates monodansylcadaverine. In Caco-2 and Colo-205, the presence of both drugs (irinotecan and oxaliplatin) led to a decrease in the protein levels of Rab-7. In HT29, is revealed a dose-dependent pattern of the reduction of Rab (Fig. 3A and Table 3).

FIGURE 3 Oxaliplatin and irinotecan inhibit autophagy in microsatellite stable colorectal cancer cell lines. Western blot analysis after 24-hour exposure of cells in 10 and 20 μM of oxaliplatin or irinotecan. The protein levels of Beclin-1, p62, LC3, and Rab-7 were identified by specific antibody. The quantification of LC3 reflects the whole protein levels as compared with the untreated sample in each cell line (i) and the ratio of LC3II/LC3I in each sample separately (ii). Protein levels were normalized against actin (A). The formation of autophagic vacuoles in Caco-2, Colo-205, HT29, and SW-480 cells because of treatments was determined with 0.1 mM of MDC (light blue) through confocal microscopy, whereas phalloidin staining (red) was used for cytoskeleton detection. The yellow arrows show the autophagic vacuoles. The graph represents the quantification of MDC in each cell line (B). MDC indicates monodansylcadaverine. In Caco-2 and Colo-205, the presence of both drugs (irinotecan and oxaliplatin) led to a decrease in the protein levels of Rab-7. In HT29, is revealed a dose-dependent pattern of the reduction of Rab (Fig. 3A and Table 3). TABLE 3 The Effect of Irinotecan and Oxaliplatin on Beclin-1 and Autophagy Activation as it was Identified Through the Protein Levels of p62 and LC3B after 24 Hours

In Caco-2 and Colo-205, the presence of both drugs (irinotecan and oxaliplatin) led to a decrease in the protein levels of Rab-7. In HT29, is revealed a dose-dependent pattern of the reduction of Rab (Fig. 3A and Table 3). TABLE 3 The Effect of Irinotecan and Oxaliplatin on Beclin-1 and Autophagy Activation as it was Identified Through the Protein Levels of p62 and LC3B after 24 Hours As an additional confirmation of autophagy inhibition, MDC staining revealed the presence of autophagic vacuoles in a high percentage of phalloidin-stained cells. In all CRC cell lines, treatment with the chemotherapeutic drugs (irinotecan and oxaliplatin) significantly decreased the presence of autophagic vacuoles, identified through the detection of MDC staining. The quantification of MDC in each cell line is also presented (Fig. 3B). The Levels of Autophagic Markers After Effective Inhibition of Autophagy Two inhibitors of autophagy (20 μΜ hydroxychloroquine [HCQ] and 5 mM of 3-methyladenine [3-MA]) were used for 24 hours in CRC cell lines to identify the protein levels of these autophagic markers after inhibition of autophagy in different stages—3-MA inhibits autophagy by blocking autophagosome formation through inhibition of type III phosphatidylinositol 3-kinases and HCQ prevents lysosomal acidification. Thus, 3-MA and HCQ inhibit the initiation and the autophagy flux in different stages, respectively. In the Caco-2 cell line, HCQ and 3-MA increased Beclin-1.

-MA inhibits autophagy by blocking autophagosome formation through inhibition of type III phosphatidylinositol 3-kinases and HCQ prevents lysosomal acidification. Thus, 3-MA and HCQ inhibit the initiation and the autophagy flux in different stages, respectively. In the Caco-2 cell line, HCQ and 3-MA increased Beclin-1. Moreover, the inhibition of autophagy after treatment with these 2 inhibitors was identified by the increased expression of p62 and the increased total amount of LC3 (Fig. 4). In Colo-205, HCQ and 3-MA inhibit autophagy as it was identified through the reduction of protein levels of Beclin-1 (and enhancing protein levels of p62). In addition, in the same cell line, HCQ increased and 3-MA decreased the total protein of LC3 (Fig. 4). In HT29, HCQ increased and 3-MA reduced the protein levels of Beclin-1. Besides, LC3 and p62 protein levels were increased after treatment with both inhibitors. In SW-480 CRC cell line, Beclin-1 was decreased after treatment with both autophagy inhibitors. The protein levels of p62 and the total amount of LC3 were increased.

9, HCQ increased and 3-MA reduced the protein levels of Beclin-1. Besides, LC3 and p62 protein levels were increased after treatment with both inhibitors. In SW-480 CRC cell line, Beclin-1 was decreased after treatment with both autophagy inhibitors. The protein levels of p62 and the total amount of LC3 were increased. FIGURE 4 The protein levels of autophagy markers after treatment with 5 mM of 3-MA and 20 μM of HCQ in colorectal cancer cell lines. Western blot analysis after 24-hour exposure of cells in 5 mM of 3-MA and 20 μM of HCQ. The protein levels of Beclin-1, p62, LC3, and Rab-7 are presented. The quantification of LC3 reflects the whole protein levels as compared with the untreated sample in each cell line (i) and the ratio of LC3II/LC3I in each sample separately (ii). Protein levels were normalized against actin. HCQ indicates hydroxychloroquine; 3-MA, 3-methyladenine. The increasing ratio of LC3II/I and p62 in all cell lines after treatment with both inhibitors confirmed the inhibition of autophagy (Fig. 4). The autophagy-dependent endocytotic process was tested through the protein levels of Rab-7. In Caco-2 and Colo-205 cell lines, Rab-7 is increased. In HT29, treatment with HCQ and 3-MA decreased the protein levels of Rab-7. In SW-480 CRC cell line, HCQ and 3-MA increase and decrease the protein levels of Rab-7, respectively (Fig. 4).

dependent endocytotic process was tested through the protein levels of Rab-7. In Caco-2 and Colo-205 cell lines, Rab-7 is increased. In HT29, treatment with HCQ and 3-MA decreased the protein levels of Rab-7. In SW-480 CRC cell line, HCQ and 3-MA increase and decrease the protein levels of Rab-7, respectively (Fig. 4). DISCUSSION Autophagy is a mechanism involved in both the survival and growth of cancer cells.11,31 In our experiments, we have shown that in the majority of MSS CRC cell lines, oxaliplatin and irinotecan inhibit autophagy in the later phases of autophagosome formation. Our results are consistent with other studies that report worse OS and PFS after chemotherapy in patients with CRC with a high expression of Beclin-1 compared with patients with low Beclin-1 expression.32,33

MSS CRC cell lines, oxaliplatin and irinotecan inhibit autophagy in the later phases of autophagosome formation. Our results are consistent with other studies that report worse OS and PFS after chemotherapy in patients with CRC with a high expression of Beclin-1 compared with patients with low Beclin-1 expression.32,33 Autophagy is characterized by the formation of the autophagosome, a double-membrane structure that is strongly associated with the LC3B protein. In several solid tumors, including CRC, LC3B staining is usually associated with high levels of autophagy.34 It seems from our experiments that chemotherapeutic drugs, such as oxaliplatin and irinotecan, inhibit autophagy at later stages of autophagosome formation. It has been observed that the process of autophagy is inhibited at later stages, as shown by the accumulation of both p62 and LC3B, although autophagy is triggered in the initial stages as observed by the increased protein levels of Beclin-1. The accumulation of LC3B and p62 in CRC cell lines after treatment with one of these drugs confirms the inhibition of autophagy in our model. p62 plays a crucial role in autophagosome formation and delivery of ubiquitinated cargoes to the autophagosome for autophagic degradation.35,36 The protein itself is degraded and is used as an autophagy marker, as during inhibition of autophagy, p62 accumulates, and in contrast, decreased levels of p62 are observed when autophagy is induced.37,38 The inhibition of autophagy in MSS CRC cell lines after treatment with oxaliplatin and irinotecan is further identified through MDC staining a molecule that preferentially accumulates in autophagic vacuoles because of a combination of ion trapping and specific interactions with membrane lipids.39

phagy is induced.37,38 The inhibition of autophagy in MSS CRC cell lines after treatment with oxaliplatin and irinotecan is further identified through MDC staining a molecule that preferentially accumulates in autophagic vacuoles because of a combination of ion trapping and specific interactions with membrane lipids.39 Another critical protein in the maturation of the autophagophore is Rab-7.40 Rab-7 is responsible for the delivery of cargoes and participates in the fusion step of the autophagophore with endocytic vesicle and lysosomes. Thus, Rab-7 is a multifunctional regulator of both autophagy and endocytosis.41,42 According to this study, oxaliplatin and irinotecan seem to affect the protein levels of Rab-7 after the inhibition of autophagy in later stages in MSS CRC cell lines. The value of Rab-7 as a marker is rising as patients with CRC who show high expression of Rab-7 have better PFS compared with those with low expression.

According to this study, oxaliplatin and irinotecan seem to affect the protein levels of Rab-7 after the inhibition of autophagy in later stages in MSS CRC cell lines. The value of Rab-7 as a marker is rising as patients with CRC who show high expression of Rab-7 have better PFS compared with those with low expression. To study the levels of primary autophagy markers during inhibition of autophagy, we incubated MSS cell lines with 2 inhibitors of autophagy. 3-MA inhibits the initiation of autophagy and HCQ blocks autophagy at a subsequent stage.43,44 Several clinical trials on patients with metastatic colorectal cancer have shown that chloroquine and HCQ are useful only when they are combined with chemotherapeutic agents, inhibitors of histone deacetylases and antiangiogenic agents.45,46 Inhibition of autophagy with molecules such as HCQ and 3-MA is identified by the accumulation of p62 and LC3B in CRC cell lines.47,48 Furthermore, 3-MA inhibits the first steps of autophagy and seems to reduce the protein levels of Beclin-1 in 3 out of 4 used MSS CRC cell lines. Oxaliplatin and irinotecan can inhibit autophagy in MSS CRC cell lines in a similar manner as HCQ and 3-MA. Chemotherapy (oxaliplatin and irinotecan) inhibits the cytoprotective mechanism of autophagy in a later stage, as we demonstrated by measuring the protein expression levels of autophagy markers such as Beclin-1, p62, LC3B, and Rab-7 in samples of patients with CRC.

SS CRC cell lines in a similar manner as HCQ and 3-MA. Chemotherapy (oxaliplatin and irinotecan) inhibits the cytoprotective mechanism of autophagy in a later stage, as we demonstrated by measuring the protein expression levels of autophagy markers such as Beclin-1, p62, LC3B, and Rab-7 in samples of patients with CRC. CONCLUSIONS The present study supports the hypothesis that in patients with CRC who are treated with chemotherapy, induction of Beclin-1 expression and worse OS and PFS are correlated. Also, patients with CRC who show high expression of Rab-7 have better PFS compared with those with low expression. Also, several chemotherapeutic drugs such as oxaliplatin and irinotecan inhibit autophagy in MSS CRC cell lines in a similar way like HCQ and 3-MA. Thus, we can conclude that patients who have CRC, irrespective of their stage and tumor mutational status, should be tested for both microsatellite stability and autophagy markers Beclin-1 and Rab-7 as independent prognostic factors. For MSS patients who have undergone chemotherapy should combine treatment with inhibitors of autophagy, or treatments such as immunotherapy. Further clinical trials are needed to investigate these therapeutic strategies. Supplementary Material SUPPLEMENTARY MATERIAL Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.amjclinicaloncology.com. E.K. and P.S. contributed equally. The authors declare no conflicts of interest.

Prostate cancer (PCa) remains a disease of significant public health importance globally and exhibits regional variation in incidence and mortality patterns.1 It is the leading cancer diagnosis among men in Africa with higher mortality rates relative to western countries partly because of inadequate access to diagnostic and treatment facilities. Radiation treatment by external beam radiotherapy (EBRT) and brachytherapy remains an integral armor in the management of PCa. However, reviews of installed capacity for radiotherapy treatment in Africa continue to paint an ominous picture regarding access to quality care for patients requiring radiation treatment in low to middle-income countries which are projected to bear two thirds of new cancer burden globally by 2020.2,3 In most of these countries poor access leads to low radiotherapy utilization rates.4 A Ghanaian cancer center National Radiotherapy Oncology and Nuclear Medicine Centre, Korle Bu Teaching Hospital (NRONMC) in Accra, Ghana, has been offering 3-dimensional conformal external beam radiotherapy (3DCRT) via a telecobalt therapy unit (Co-60) and iodine (I125) brachytherapy services to PCa patients in the West African sub region for over a decade. The facility sees over 1200 new cancer patients annually with PCa accounting for 10% to 15% of this figure with an upward trend in numbers from a recent review.5 PCa brachytherapy outcomes from a Hospital in Ghana revealed disease control rates comparable to historical controls from high volume centers.6–9

er a decade. The facility sees over 1200 new cancer patients annually with PCa accounting for 10% to 15% of this figure with an upward trend in numbers from a recent review.5 PCa brachytherapy outcomes from a Hospital in Ghana revealed disease control rates comparable to historical controls from high volume centers.6–9 The facility has recently begun offering EBRT with a modern linear accelerator unit. It is necessary to evaluate treatment outcomes in Co-60 era to consolidate gains made and identify potential avenues for improvement and research opportunities in this transition. This study is a cross-continental comparative study of National Comprehensive Cancer Network (NCCN) low and intermediate risk category PCa patients treated at NRONMC and a Moffitt Cancer Center and Research Institute (MMC), aimed at investigating curative radiation therapy outcomes and exploring determinants of these outcomes in low and intermediate risk PCa patients treated at the 2 centers with the goal of identifying avenues for technology exchange and further improvement in patient outcomes. MATERIALS AND METHODS Patient Selection This study received Institutional Review Board (IRB) approval from NRONMC and MCC, utilizing the databases of NRONMC and Radiation Oncology Department of MCC covering the period from 2002 to 2016. Clinical records of 1084 patients treated at NRONMC and 1301 patients at US institution over this period were available for review.

dy received Institutional Review Board (IRB) approval from NRONMC and MCC, utilizing the databases of NRONMC and Radiation Oncology Department of MCC covering the period from 2002 to 2016. Clinical records of 1084 patients treated at NRONMC and 1301 patients at US institution over this period were available for review. To obviate the potential risk of confounding due to observed higher pretreatment prostate-specific antigen (PSA) among Ghanaian men (GM), only nonmetastatic NCCN low and intermediate risk patients were included in final analytical cohort (Gleason score≤7; PSA <20 ng/mL; and clinical stage T2C).10 Intermediate risk patients were further subdivided into favorable intermediate risk and unfavorable intermediate risk.11 In addition, patients who had received prior radical prostatectomy were also excluded. A total of 987 eligible patients from NRONMC (n=173) and US institution (n=814) were included in the final analysis. Freedom from biochemical failure (FFBF) was the study end point. Biochemical failure was defined as nadir PSA+2 (according to the RTOG-ASTRO Phoenix Consensus Conference) and the period estimated from the date of treatment completion.12

To obviate the potential risk of confounding due to observed higher pretreatment prostate-specific antigen (PSA) among Ghanaian men (GM), only nonmetastatic NCCN low and intermediate risk patients were included in final analytical cohort (Gleason score≤7; PSA <20 ng/mL; and clinical stage T2C).10 Intermediate risk patients were further subdivided into favorable intermediate risk and unfavorable intermediate risk.11 In addition, patients who had received prior radical prostatectomy were also excluded. A total of 987 eligible patients from NRONMC (n=173) and US institution (n=814) were included in the final analysis. Freedom from biochemical failure (FFBF) was the study end point. Biochemical failure was defined as nadir PSA+2 (according to the RTOG-ASTRO Phoenix Consensus Conference) and the period estimated from the date of treatment completion.12 RADIATION THERAPY EBRT Treatment details at our study centers have been summarized in Table 1. Radiation treatment planning at NRONMC before 2008 was executed with 2-dimensional 4-field box technique generated by a conventional simulator. The treatment fields were defined by inferior sacroiliac joint; 1 cm superior to the ischial tuberosity; 1 to 2 cm lateral pelvic brim; mid pubic arch; and mid-point of S2/S3 interphase served as the superior, inferior, lateral, anterior and posterior borders, respectively, with customized Cerrobend blocking prescribed to 70 Gy in 35 fractions, 2 Gy/d, 5 days a week over 7 weeks. TABLE 1 Patient Population, Radiation Treatment Planning, and Delivery Summary

RADIATION THERAPY EBRT Treatment details at our study centers have been summarized in Table 1. Radiation treatment planning at NRONMC before 2008 was executed with 2-dimensional 4-field box technique generated by a conventional simulator. The treatment fields were defined by inferior sacroiliac joint; 1 cm superior to the ischial tuberosity; 1 to 2 cm lateral pelvic brim; mid pubic arch; and mid-point of S2/S3 interphase served as the superior, inferior, lateral, anterior and posterior borders, respectively, with customized Cerrobend blocking prescribed to 70 Gy in 35 fractions, 2 Gy/d, 5 days a week over 7 weeks. TABLE 1 Patient Population, Radiation Treatment Planning, and Delivery Summary After 2008, all curative cases were planned with 3DCRT with a Prowess Panther version 4.6 treatment planning system (TPS). Patients were setup with the aid of the 3-point laser system of the conventional simulator in the absence of computerized tomography (CT) simulator. Fiducial marker reference points were marked on patients and recorded to enable marker placement before DICOM data acquisition at diagnostic CT scan centers. These CT scanners must have flat-top couch inserts and compatible DICOM format. The CT scanners were calibrated with a tissue characterization phantom (CIRS, USA) by Physicists from NRONMC to ensure tissue heterogeneity corrections by the TPS. The DICOM data were imported from external devices into the TPS for target volume delineation. The prostate was the clinical target volume (CTV) for low and favorable risk patients while the proximal 1 cm of seminal vesicles was included in the CTV for patients with unfavorable intermediate risk or >15% risk of seminal vesicle involvement on Partin Nomogram. The planning target volume (PTV) was generated by a 1 cm margin on the CTV in all directions except posteriorly which was expanded by 0.6 cm. Dose prescription to center was 74 Gy in 37 fractions over 7.5 weeks at 2 Gy per fraction respecting the Organ at Risk (ORV) constraints of the Quantitative Analysis of Normal Tissue Toxicity in the Clinic for bladder, rectum, and femoral heads (QUANTEC) which were enhanced using multiple treatment fields, wedges, and customized Cerrobend blocks. Treatment plans were subsequently evaluated with dose volume histograms, depicted in Figure 1 and QUANTEC dose constraints.13 Treatment field parameters were transferred onto patient with the aid of a conventional simulator and digitally reconstructed radiographs generated for planned treatment fields. Before treatment delivery, treatment plans were taken through pretreatment quality assurance review. Portal imaging of all treatment fields was performed before treatment and midway, reviewed and approved by the treating physician.

imulator and digitally reconstructed radiographs generated for planned treatment fields. Before treatment delivery, treatment plans were taken through pretreatment quality assurance review. Portal imaging of all treatment fields was performed before treatment and midway, reviewed and approved by the treating physician. FIGURE 1 Three-dimensional conformal radiotherapy plan treated on Co-60 teletherapy unit at National Radiotherapy Oncology and Nuclear Medicine Centre, Korle Bu Teaching Hospital. CTV indicates clinical target volume; DVH, dose volume histograms; PTV, planning target volume. EBRT at MCC was delivered by intensity modulated radiotherapy technique in >95% of cases using multienergy linear accelerators (Linacs) which employed motorized wedges and multileaf collimation to optimize PTV coverage while achieving ORVs objectives. Treatment planning CT DICOM data were acquired in-house and networked to the TPS where the CTV defined as at NRONMC was contoured with ORVs. A 7 mm margin PTV (5 mm posteriorly, inferiorly, and superiorly) generated on the CTV was prescribed 78 to 81 Gy in 39 to 45 fractions in 8 to 9 weeks at 1.8 to 2 Gy per fraction. Treatment plan quality assurance (or patient-specific dosimetry) was undertaken on treatment phantoms before treatment delivery and image guidance was employed for daily patient set-up. A record and verify system automatically recorded all delivered treatments per patient and verified this data against the planned treatment.

ent plan quality assurance (or patient-specific dosimetry) was undertaken on treatment phantoms before treatment delivery and image guidance was employed for daily patient set-up. A record and verify system automatically recorded all delivered treatments per patient and verified this data against the planned treatment. Brachytherapy Template-based low-dose rate brachytherapy with I125 permanent seeds (Bard Medical Division, Covington, GA) planned in real-time intraoperatively and implanted transperineal under ultrasound guidance is the practice at NRONMC. Low and favorable intermediate risk patients received 160 Gy while higher risk patients received partial implant prostate boost of 110 Gy to the 90% isodose line pre-TG 43 formalism in combination with EBRT. Constraints were D30 <150% of prescribed dose for urethra and V100<1.3 cm3 for rectum. Brachytherapy at US institution in the earlier years included Palladium (Pd103) and I125 low-dose rate seed implants (similar to NRONMC), as well as Iridium (Ir192) high-dose rate (HDR) brachytherapy. However, this practice has been supplanted by CT-planned HDR in the last decade. Transperineal HDR catheter placement guided by ultrasound and preoperative staging pelvic magnetic resonance imaging was performed in the operating room. Treatments were delivered in the HDR suite with monotherapy dose of 28 Gy in 2 fractions or boost dose of 23 Gy in 2 fractions spaced by 2 to 4 weeks. Single boost prescriptions of 15 Gy were less commonly utilized.

trasound and preoperative staging pelvic magnetic resonance imaging was performed in the operating room. Treatments were delivered in the HDR suite with monotherapy dose of 28 Gy in 2 fractions or boost dose of 23 Gy in 2 fractions spaced by 2 to 4 weeks. Single boost prescriptions of 15 Gy were less commonly utilized. ANDROGEN DEPRIVATION THERAPY (ADT) ADT for 4 to 6 months with either goserelin acetate (Zoladex) or leuprolide (Lupron) was prescribed with the start of radiotherapy based on patient’s disease risk profile and treatment modality. ADT was also prescribed for patients with large prostate volumes for cytoreduction purposes to render them eligible for brachytherapy. FOLLOW-UP Patients were reviewed at weekly clinic visits during their course of EBRT and within a week of brachytherapy procedure for treatment-related toxicity. Patients were seen with PSA reports at 3 to 6 months intervals upon treatment completion in the first 5 years and yearly thereafter with PSA reports.

ANDROGEN DEPRIVATION THERAPY (ADT) ADT for 4 to 6 months with either goserelin acetate (Zoladex) or leuprolide (Lupron) was prescribed with the start of radiotherapy based on patient’s disease risk profile and treatment modality. ADT was also prescribed for patients with large prostate volumes for cytoreduction purposes to render them eligible for brachytherapy. FOLLOW-UP Patients were reviewed at weekly clinic visits during their course of EBRT and within a week of brachytherapy procedure for treatment-related toxicity. Patients were seen with PSA reports at 3 to 6 months intervals upon treatment completion in the first 5 years and yearly thereafter with PSA reports. Statistical Analysis Patients’ baseline characteristics including demographic, clinical, and treatment information were summarily described. In addition, our study cohorts were stratified by treatment received and NCCN risk groups. The differences between the 2 populations were analyzed using methods of categorical analysis (USA and Ghana). χ2 test for categorical and Mann-Whitney test for numeric variables was used. In the outcome analysis a Cox proportional hazard model along with Kaplan-Meier analysis was used to estimate the risk of biochemical recurrence (FFBF) postradiotherapy between the US and Ghana cohort. Multivariable cox model stratified using NCCCN risk groups was adjusted for differences in radiotherapy and the use of hormonal therapy. Risk estimates using both unadjusted hazard ratio and adjusted hazard ratio (HR) along with 95% confidence interval (CI) were reported. Finally, all the variables used in the multivariate cox model were also assessed for their time-varying effect to ensure that the proportionality assumption holds true. None of the variables used in the model showed a deviation from the proportionality assumption. Two-sided α value <0.05 was considered as statistically significant. All the analysis was completed using SAS 9.4.

el were also assessed for their time-varying effect to ensure that the proportionality assumption holds true. None of the variables used in the model showed a deviation from the proportionality assumption. Two-sided α value <0.05 was considered as statistically significant. All the analysis was completed using SAS 9.4. RESULTS Patient and Disease Characteristics This retrospective cross-continental comparative paper evaluated disease presentation and treatment-related factors among 987 NCCN low and intermediate-risk PCa patients pooled from the largest referral facility in Ghana (GM, n=173) which serves the entire West African subregion and a US institution (US men [USM], n=814), an NCI-designated comprehensive cancer center and covered a 15-year period. The combined median follow-up for GM of 40 months (interquartile range: 22 to 80) and USM of 36 months (interquartile range: 18 to 58) were comparable. GM were diagnosed at a younger median age (64 vs. 68 y, P<0.001); presented more frequently with unfavorable intermediate risk disease (32.4% vs. 19.2%) and higher PSA (10.8 mg/dL vs. 5.1 mg/dL) while most USM presented with low risk disease (54.7% vs. 28.3%) as shown in Table 2. Also, GM experienced longer intervals from diagnosis to initiation of radiation treatment (median: 194 d vs. 111 d, P<0.001) (Table 2). TABLE 2 Baseline Patient Characteristics at Ghana and US Institutions

RESULTS Patient and Disease Characteristics This retrospective cross-continental comparative paper evaluated disease presentation and treatment-related factors among 987 NCCN low and intermediate-risk PCa patients pooled from the largest referral facility in Ghana (GM, n=173) which serves the entire West African subregion and a US institution (US men [USM], n=814), an NCI-designated comprehensive cancer center and covered a 15-year period. The combined median follow-up for GM of 40 months (interquartile range: 22 to 80) and USM of 36 months (interquartile range: 18 to 58) were comparable. GM were diagnosed at a younger median age (64 vs. 68 y, P<0.001); presented more frequently with unfavorable intermediate risk disease (32.4% vs. 19.2%) and higher PSA (10.8 mg/dL vs. 5.1 mg/dL) while most USM presented with low risk disease (54.7% vs. 28.3%) as shown in Table 2. Also, GM experienced longer intervals from diagnosis to initiation of radiation treatment (median: 194 d vs. 111 d, P<0.001) (Table 2). TABLE 2 Baseline Patient Characteristics at Ghana and US Institutions Treatment and Outcomes Compared with USM, GM received 5.6 Gy lower median EBRT dose and were less likely to receive brachytherapy as EBRT boost or monotherapy (49.7% vs. 80.7%, P<0.001) as shown in Tables 2 and 3. Differences in brachytherapy utilization were more marked among unfavorable intermediate-risk patients with only 1.8% GM receiving this treatment compared with 60.3% of USM in this risk category (Table 3). ADT utilization was more than twice as likely among both favorable intermediate risk and unfavorable intermediate risk GM compared with USM (45.6% vs. 16%, and 67.9% vs. 28.2%, respectively) (Table 3).

e-risk patients with only 1.8% GM receiving this treatment compared with 60.3% of USM in this risk category (Table 3). ADT utilization was more than twice as likely among both favorable intermediate risk and unfavorable intermediate risk GM compared with USM (45.6% vs. 16%, and 67.9% vs. 28.2%, respectively) (Table 3). TABLE 3 Comparison of Treatment at Ghana and US Institutions Stratified by NCCN Risk Category The NCCN risk stratified unadjusted rates of biochemical recurrence in Kaplan-Meier analysis showed less durable FFBF among GM compared with USM across all risk categories (Fig. 2). However, in the treatment adjusted and NCCN risk stratified multivariable cox model (Table 4), risk of biochemical recurrence was only significantly higher among low (HR=5.15; 95% CI, 1.27-20.7; P=0.02) and favorable intermediate risk (HR=4.64; 95% CI, 1.20-17.92; P=0.02) GM compared with USM. No difference in biochemical control was observed among unfavorable intermediate risk patients from our study cohorts (HR=1.36; 95% CI; 1.36-4.41; P=0.6). FIGURE 2 Kaplan-Meier graphs estimating freedom from biochemical failure for Ghana and Moffitt Cancer Center and Research Institute. FFBF indicates Freedom from biochemical failure; NCCN, National Comprehensive Cancer Network. TABLE 4 Risk of Biochemical Recurrence Among US and Ghanaian Men by NCCN Risk Category

The NCCN risk stratified unadjusted rates of biochemical recurrence in Kaplan-Meier analysis showed less durable FFBF among GM compared with USM across all risk categories (Fig. 2). However, in the treatment adjusted and NCCN risk stratified multivariable cox model (Table 4), risk of biochemical recurrence was only significantly higher among low (HR=5.15; 95% CI, 1.27-20.7; P=0.02) and favorable intermediate risk (HR=4.64; 95% CI, 1.20-17.92; P=0.02) GM compared with USM. No difference in biochemical control was observed among unfavorable intermediate risk patients from our study cohorts (HR=1.36; 95% CI; 1.36-4.41; P=0.6). FIGURE 2 Kaplan-Meier graphs estimating freedom from biochemical failure for Ghana and Moffitt Cancer Center and Research Institute. FFBF indicates Freedom from biochemical failure; NCCN, National Comprehensive Cancer Network. TABLE 4 Risk of Biochemical Recurrence Among US and Ghanaian Men by NCCN Risk Category DISCUSSION Modern radiation dose delivery via 3DCRT and intensity modulated radiotherapy with image-guided conformal treatment techniques and use of brachytherapy have revolutionized PCa treatment. EBRT dose escalation delivered with highly innovative and sophisticated therapy units with brachytherapy result in better biochemical control in low and intermediate risk groups.14,15 Setbacks to the universal adoption of this technology, however, are the need for stable and constant electricity supply; high cost of initial investment and maintenance; and personnel in under-resourced environments.16,17 The disease control benefit and toxicity profile of these technologies have not been adequately examined when discussing the global deficit of radiotherapy facilities particularly in low to middle-income countries.3,16 This has become more imperative as patients increasingly present with the curable disease. The NRONMC has until recently delivered EBRT utilizing a Co-60 unit without multileaf collimation and onboard portal imaging. All PCa patients with localized disease who opt for nonsurgical treatment were treated with 3DCRT techniques. Limitations of this unit include averagely higher integral doses to normal tissues and a larger penumbra compared with linear accelerators which make it difficult to achieve precise organs-at-risk constraints at higher radiation doses with conformal techniques especially in patients with wider separation. Highly complex field arrangements in the absence of multileaf collimators and on board imaging are not practical at present but anticipated in the near future with the installation of a 6 MV linear accelerator.

constraints at higher radiation doses with conformal techniques especially in patients with wider separation. Highly complex field arrangements in the absence of multileaf collimators and on board imaging are not practical at present but anticipated in the near future with the installation of a 6 MV linear accelerator. Patient and Disease Characteristics This study specifically focused on patients with low risk of harboring metastatic disease to minimize its likelihood of confounding the observed outcome. A recent NRONMC PCa study spanning 15 years indicates that only 10% of PCa referrals to the center were eligible for this study accounting partly for the small number of patients from NRONMC.18 Patients treated at NRONMC presented at a younger age compared with the US cohort and had a proportionately higher burden of unfavorable intermediate risk. This is contrary to reports associating older age with advanced PCa from registries such as the Cancer of the Prostate Strategic Urologic Endeavor (CaPSURE) as Gleason Scores generally increase with age.19,20 Therefore, it is possible that the overall difference in age at diagnosis and the presentation with the less favorable disease at a younger age in the Ghana cohort may be surrogates for differences in disease biology.

the Prostate Strategic Urologic Endeavor (CaPSURE) as Gleason Scores generally increase with age.19,20 Therefore, it is possible that the overall difference in age at diagnosis and the presentation with the less favorable disease at a younger age in the Ghana cohort may be surrogates for differences in disease biology. Radiotherapy Delivery The pattern of radiotherapy treatment was significantly different between the 2 cohorts in this analysis with nearly 2-fold brachytherapy utilization rate among USM as GM. This difference was more evident among unfavorable intermediate risk patients with <5% of GM receiving brachytherapy boost. This makes it difficult to evaluate the benefit of incorporating brachytherapy in the treatment of this population of patients in our study. Furthermore, a higher median EBRT dose was achievable among USM as a result of the use of multienergy linacs in treatment planning and delivery under daily image guidance. Both of these factors may have accounted for better FFBF among USM consistent with the established benefit of radiation dose escalation in disease control.14,15 Use of intraprostatic fiducial markers for prostate localization during EBRT is the practice at US institution. A study from Mayo clinic reported the prostate movement of >1 cm in some instances between treatment fractions.21,22 Fiducial-based prostate localization is comparable to using cone-beam CT for prostate localization and this may be explored as an avenue to dose escalate in Ghana.23–25

is the practice at US institution. A study from Mayo clinic reported the prostate movement of >1 cm in some instances between treatment fractions.21,22 Fiducial-based prostate localization is comparable to using cone-beam CT for prostate localization and this may be explored as an avenue to dose escalate in Ghana.23–25 Androgen Suppression Androgen suppression usage was higher among GM and was generally prescribed to intermediate risk patients who received EBRT alone to make up for the low dose received. Some low risk patients also received ADT either before referral to the NRONMC or, on a few occasions, for prostate volume reduction before brachytherapy. Two studies from the United States have reported improved FFBF outcomes among intermediate risk patients receiving 4 to 6 months ADT concomitant with EBRT but the prescribed radiation doses of 66.6 to 70 Gy in these studies would be considered suboptimal today and may explain to some degree the FFBF benefit seen with androgen suppression.26,27 Reported dose-escalated studies have generally omitted or reduced the duration of androgen suppression even among patients with high-risk disease.14,28,29 As a result, the role of androgen suppression in this setting remains unresolved but this may be clarified by on-going trials.30

seen with androgen suppression.26,27 Reported dose-escalated studies have generally omitted or reduced the duration of androgen suppression even among patients with high-risk disease.14,28,29 As a result, the role of androgen suppression in this setting remains unresolved but this may be clarified by on-going trials.30 Treatment Outcome The estimated FFBF was less favorable among low and favorable intermediate risk but not unfavorable intermediate risk patients treated at NRONMC compared with US institution. The overall biochemical control achieved at the NRONMC, however, compares favorably to a similarly planned and dose-treated cohort which included a sizeable proportion of high risk patients.31 It is plausible that differences in radiation treatment delivery may have contributed to the observed differences in FFBF, however, adjusting for this in the Cox Proportional Hazards model failed to account fully for this difference. This finding suggests potential inherent differences in our study population contributing to this observation.

ferences in radiation treatment delivery may have contributed to the observed differences in FFBF, however, adjusting for this in the Cox Proportional Hazards model failed to account fully for this difference. This finding suggests potential inherent differences in our study population contributing to this observation. Efforts at Improving Treatment Outcomes The NRONMC has installed a new 6 MV linear accelerator capable of arc therapy which will operate on a record and verify platform. Efforts are also underway to introduce image guidance for set-up verification to enable escalated EBRT delivery. In addition, on-going genomic-based clinical studies in collaboration with MMC are anticipated to provide some clarity on the biology of PCa in GM. These interventions are anticipated to significantly enhance treatment outcomes in our population and will be the subject of future reports. Limitations Limitations associated with this study include its retrospective design; differences in the socioeconomic status of our patient populations; variations in patterns of care as well as utilization of imaging in diagnosis, staging and treatment planning and delivery at our study institutions. Our study remains extremely relevant as it provides valuable information on the uniqueness of disease and treatment characteristics of a population largely absent in the PCa literature situated within the context of treatment outcome attainable with current standard-of-care and documents adaptation of low-resource technology to improve care.

mely relevant as it provides valuable information on the uniqueness of disease and treatment characteristics of a population largely absent in the PCa literature situated within the context of treatment outcome attainable with current standard-of-care and documents adaptation of low-resource technology to improve care. CONCLUSIONS We highlight likely differences in risk profile and biochemical control among early-stage prostate patients undergoing radiation treatment from an African population and a predominantly Caucasian American population. Factors inherent in radiotherapy modality, dose and delivery as well as inherent differences in our study populations possibly account for this variation and need to be addressed to improve treatment outcomes. Work was performed at the National Center for Radiotherapy, Oncology and Nuclear Medicine, Korle Bu Teaching Hospital, Accra, Ghana, West Africa and H. Lee Moffitt Cancer Center, Tampa, FL. Supported by grant awards to K.Y. from the Prostate Cancer Foundation and P20-CA233255. F.A.A. was supported by an Audrey Myer Mars International Fellowship in Clinical Oncology, SPAMM 17-218-01, from the American Cancer Society. The authors declare no conflicts of interest.

Although targeted therapy has substantially improved the prognosis of patients with metastatic renal cell carcinoma (mRCC), survival rates seem to plateau, despite the development of targeted agents. The objective response rate (ORR) after targeted monotherapy ranges from 10% to 30%, with complete and durable responses being rarely observed.1–3 The combined use of immunotherapy and targeted therapy has improved survival time and doubled the ORR; however, complete response (CR) remains rare, accounting for about 3% cases.4 Definitive local therapy directed against metastatic sites represents an important component of multidisciplinary treatment. Local therapy is not only an indispensable symptom palliation approach, but also an effective way to eradicate metastatic tumor deposits. Complete metastasectomy combined with targeted therapy could prolong overall survival (OS); however, perioperative targeted therapy is associated with an increasing incidence of wound-related complications.5 In addition, metastasectomy is only feasible in carefully selected patients, and those with unfavorable tumor size, site, local extent, comorbidity, or functional status lose their potential chance to benefit. By contrast, radiotherapy is a less selective form of local therapy.

ncidence of wound-related complications.5 In addition, metastasectomy is only feasible in carefully selected patients, and those with unfavorable tumor size, site, local extent, comorbidity, or functional status lose their potential chance to benefit. By contrast, radiotherapy is a less selective form of local therapy. Radiotherapy was reserved for symptom relief because of the dogma that renal cell carcinoma is radioresistant. Stereotactic body radiotherapy (SBRT) could overcome radioresistance by intensified dose delivery, emphasizing long-term local control (LC) rather than short-term palliation. Previous studies suggested that SBRT could yield a noninferior LC compared with surgical resection (1-year LC, 80% to 90%), and is preferred when patients present with risk factors.6–9 SBRT coupled with targeted therapy might provide additional benefit given their synergetic action. A previous study demonstrated that concurrent targeted therapy and SBRT is safe and offers superior LC compared with SBRT or targeted therapy alone.10 Previous studies have primarily focused on LC after SBRT; therefore, there is a lack of data regarding the survival benefits and the timing of SBRT when combined with targeted therapy. Therefore, we conducted this study to investigate the survival outcomes and the potential efficacy of the combination strategy.

Radiotherapy was reserved for symptom relief because of the dogma that renal cell carcinoma is radioresistant. Stereotactic body radiotherapy (SBRT) could overcome radioresistance by intensified dose delivery, emphasizing long-term local control (LC) rather than short-term palliation. Previous studies suggested that SBRT could yield a noninferior LC compared with surgical resection (1-year LC, 80% to 90%), and is preferred when patients present with risk factors.6–9 SBRT coupled with targeted therapy might provide additional benefit given their synergetic action. A previous study demonstrated that concurrent targeted therapy and SBRT is safe and offers superior LC compared with SBRT or targeted therapy alone.10 Previous studies have primarily focused on LC after SBRT; therefore, there is a lack of data regarding the survival benefits and the timing of SBRT when combined with targeted therapy. Therefore, we conducted this study to investigate the survival outcomes and the potential efficacy of the combination strategy. METHODS AND MATERIALS Patient Eligibility The medical records of 350 consecutive patients with mRCC treated with tyrosine kinase inhibitor (TKI) between 2013 and 2018 were reviewed retrospectively. Eligible patients were adults (≥18 y of age) who underwent SBRT for at least 1 unresectable metastatic lesion at the discretion of the genitourinary multidisciplinary team. SBRT was indicated in patients with oligometastases or oligoprogression, or in patients with multiple metastases who required local therapy for symptom relief or tumor burden reduction. Those with spinal instability or rapidly progressive neurological deficit who received SBRT after surgical intervention were also included. Patients were excluded if they were followed up for <2 months, received TKI after SBRT for systemic disease progression or were treated with conventionally fractionated radiotherapy. Finally, 56 patients were included in the analysis.

eurological deficit who received SBRT after surgical intervention were also included. Patients were excluded if they were followed up for <2 months, received TKI after SBRT for systemic disease progression or were treated with conventionally fractionated radiotherapy. Finally, 56 patients were included in the analysis. TKI Administration All patients were treated systemically with TKI for mRCC. Sunitinib, sorafenib, and axitinib were the most frequently chosen TKI. Suntinib was administered orally in a 6-week cycle at 50 mg daily for 4 weeks. Sorafenib was given orally at a dose of 400 mg twice daily, and axitinib was given at 5 mg twice daily. The TKI dose was not withheld or reduced during SBRT. SBRT Procedure SBRT was indicated for curative intent, major tumor burden, or symptom relief. For patients treated with curative intent, all metastatic sites at the time of SBRT were irradiated. Tumor burden was defined as the sum of the longest unidimensional diameter of target lesions according to Response Evaluation and Criteria in Solid Tumors (RECIST) version 1.1. Major tumor burden was defined as the largest lesion accounting for at least 50% of the tumor burden in each patient. Symptom relief was performed in frail patients with disseminated metastases to relieve pain, spinal cord compression, or bleeding. A total of 103 unresectable lesions were irradiated.

CIST) version 1.1. Major tumor burden was defined as the largest lesion accounting for at least 50% of the tumor burden in each patient. Symptom relief was performed in frail patients with disseminated metastases to relieve pain, spinal cord compression, or bleeding. A total of 103 unresectable lesions were irradiated. SBRT was performed using Volumetric Intensity Modulated Arc Therapy planning. All patients underwent 3 mm slice thickness contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging simulation scanning with site-specific immobilization. Four-dimensional CT simulation scans were performed in lung metastatic lesions, allowing for visualization of tumor motion. Biologically effective dose (BED) was calculated using linear-quadratic model with α/β=5.9 The most common fractionation scheme was 35 to 45 Gy delivered in 5 fractions, which was prescribed in 84% patients (Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/AJCO/A296). Normal tissue dose constraints were in accordance with the United Kingdom consensus since 2018. Before that, BED was calculated for dose constraints. Prescription dose was required to cover >95% of the target; however, normal tissue protection had priority over target coverage. Cone beam CT was mandatory for daily image-guided radiation therapy during SBRT.

accordance with the United Kingdom consensus since 2018. Before that, BED was calculated for dose constraints. Prescription dose was required to cover >95% of the target; however, normal tissue protection had priority over target coverage. Cone beam CT was mandatory for daily image-guided radiation therapy during SBRT. Outcomes and Statistical Analysis Clinical examination and follow-up scans were recommended every 3 months for the first 2 years; however, early scans might be ordered for patients’ complaints. OS was defined as the time from the diagnosis of metastatic disease until last follow-up or death from any cause. Progression-free survival (PFS) was measured from the initiation of SBRT until disease progression or death. LC and distant PFS were defined as freedom from in-field and out-field progression after SBRT, respectively. Irradiated sites were independently assessed for treatment response. Bone metastases were evaluated using The University of Texas MD Anderson Cancer Center (MDA) criteria,11 and the rest were evaluated using Response Evaluation and Criteria in Solid Tumors version 1.1. Toxicities were graded according to Common Terminology Criteria for Adverse Events rating scale (CTCAE 4.0). Categorical data were compared using a χ2 test. Survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test. A hazard ratio with a 95% confidence interval for univariate and multivariate analyses was calculated using the Cox proportional hazard model. A P-value <0.05 was considered significant. SPSS version 23 (IBM Corp., Armonk, NY) was used for the statistical analyses.

lan-Meier method and compared using the log-rank test. A hazard ratio with a 95% confidence interval for univariate and multivariate analyses was calculated using the Cox proportional hazard model. A P-value <0.05 was considered significant. SPSS version 23 (IBM Corp., Armonk, NY) was used for the statistical analyses. RESULTS Patient Characteristics The clinical features of the patients are summarized in Table 1. Among the 56 patients, 26 (46%) had synchronous metastases. Ten (18%), 32 (57%), and 12 (21%) patients were categorized as International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable, intermediate, and poor risk, respectively at the diagnosis of mRCC. Patients had predominantly clear-cell type disease, with >5 metastatic lesions before SBRT. Bone was the most common metastatic site, followed by the lungs and lymph nodes. Only 4 patients presented with brain metastases. TABLE 1 Patient Characteristics (N=56)

RESULTS Patient Characteristics The clinical features of the patients are summarized in Table 1. Among the 56 patients, 26 (46%) had synchronous metastases. Ten (18%), 32 (57%), and 12 (21%) patients were categorized as International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable, intermediate, and poor risk, respectively at the diagnosis of mRCC. Patients had predominantly clear-cell type disease, with >5 metastatic lesions before SBRT. Bone was the most common metastatic site, followed by the lungs and lymph nodes. Only 4 patients presented with brain metastases. TABLE 1 Patient Characteristics (N=56) Treatment Characteristics The treatment characteristics of the patients were summarized in Table 2. First-line targeted therapy comprised sunitinib, axitinib, or sorafenib in 91% of the patients. Thirty-eight (68%) patients switched to second-line therapy after systemic disease progression. Two patients changed to second-line TKI because of drug intolerance, and 2 patients discontinued systemic treatment because of intolerable toxicity caused by the first-line TKI. All of these patients were treated with first-line sunitinib. Nephrectomy was performed in 84% of the patients, and ~38% of the patients underwent incomplete metastasectomy. The sequence of systemic and local therapy for each patient was presented in Figure 1. TABLE 2 Therapeutic Characteristics (N=56)

Treatment Characteristics The treatment characteristics of the patients were summarized in Table 2. First-line targeted therapy comprised sunitinib, axitinib, or sorafenib in 91% of the patients. Thirty-eight (68%) patients switched to second-line therapy after systemic disease progression. Two patients changed to second-line TKI because of drug intolerance, and 2 patients discontinued systemic treatment because of intolerable toxicity caused by the first-line TKI. All of these patients were treated with first-line sunitinib. Nephrectomy was performed in 84% of the patients, and ~38% of the patients underwent incomplete metastasectomy. The sequence of systemic and local therapy for each patient was presented in Figure 1. TABLE 2 Therapeutic Characteristics (N=56) FIGURE 1 Swimmer plot of time since metastases (N=56). Individual patients are depicted as lines. Two patients who discontinued TKI due to toxicity are demonstrated as blue lines. SBRT indicates stereotactic body radiotherapy; TKI, tyrosine kinase inhibitor. The median number of irradiated metastases was 1 (range, 1 to 6), and the median BED was 104 Gy (range, 50 to 165 Gy) (Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/AJCO/A296). The majority of irradiated lesions were located in bones, accounting for 71% of cases. The median time between the initiation of first-line TKI and SBRT was 5.3 months (range, 0 to 58.9 mo). Twenty-four (43%) patients received SBRT before TKI failure, whereas 32 (57%) patients received SBRT after TKI failure.

CO/A296). The majority of irradiated lesions were located in bones, accounting for 71% of cases. The median time between the initiation of first-line TKI and SBRT was 5.3 months (range, 0 to 58.9 mo). Twenty-four (43%) patients received SBRT before TKI failure, whereas 32 (57%) patients received SBRT after TKI failure. Response and Disease Control CR, partial response, stable disease, and progressive disease were observed in 20 (19%), 67 (65%), 13 (13%), and 3 (3%) lesions after SBRT, leading to an ORR of 84%. In patients irradiated before TKI failure, 16 (34%) lesions achieved CR, whereas only 4 (7%) lesions yielded CR in patients irradiated after TKI failure (P=0.001). At last follow-up, 3 lesions (located on the vertebra, pleura, and adrenal gland, respectively) developed progressive disease. The 1-year and 2-year LC rates were 98% and 94%, respectively. The median BED was not different between the CR (104 Gy; range, 50 to 165 Gy) and the non-CR (104 Gy; range, 59 to 134 Gy; P=0.099) lesions.

llow-up, 3 lesions (located on the vertebra, pleura, and adrenal gland, respectively) developed progressive disease. The 1-year and 2-year LC rates were 98% and 94%, respectively. The median BED was not different between the CR (104 Gy; range, 50 to 165 Gy) and the non-CR (104 Gy; range, 59 to 134 Gy; P=0.099) lesions. Survival and Prognostic Factors At a median follow-up of 21.7 months (range, 5.1 to 110.6 mo), 18 patients died. All deaths were tumor-related. The median OS was 61.2 months, with 2-year and 5-year OS rates of 71% and 58%, respectively. The median PFS was 11.5 months, mainly for out-field progression. Thirty-two patients had out-field progression after SBRT, and the median distant PFS was 5.0 months (Fig. 2). The 2-year OS of patients treated for curative intent, major tumor burden, and symptom relief were 93%, 68%, and 58%, respectively (P=0.032). Patients who achieved CR at irradiated sites after SBRT had a more favorable prognosis. The median PFS in CR group was significantly longer than that of non-CR group (18.9 vs. 7.1 mo; P=0.003). The 5-year OS in CR group was 86%, compared with 48% in non-CR group (P=0.010; Fig. 2).

68%, and 58%, respectively (P=0.032). Patients who achieved CR at irradiated sites after SBRT had a more favorable prognosis. The median PFS in CR group was significantly longer than that of non-CR group (18.9 vs. 7.1 mo; P=0.003). The 5-year OS in CR group was 86%, compared with 48% in non-CR group (P=0.010; Fig. 2). FIGURE 2 Survival outcomes of metastatic renal cell carcinoma patients treated with SBRT combined with TKI (N=56). A, Overall survival. B, Progression-free survival. C, Local progression-free survival. D, Distant progression-free survival of all patients. Overall survival (E) and progression-free survival of patients who achieved local CR and non-CR after SBRT (F). CR indicates complete response; SBRT, stereotactic body radiotherapy; TKI, tyrosine kinase inhibitors. In univariate analysis, IMDC high-risk group, sarcomatoid features, CR after SBRT, ECOG >1 were significant prognostic factors for OS. No difference in OS was found between the concurrent first-line TKI and the concurrent second-line TKI group (P=0.249). In multivariate analysis, only CR after SBRT was associated with OS (hazard ration 0.08; 95% confidence interval, 0.01-0.70; P=0.023; Table 3). TABLE 3 Prognostic Factors of Overall Survival

In univariate analysis, IMDC high-risk group, sarcomatoid features, CR after SBRT, ECOG >1 were significant prognostic factors for OS. No difference in OS was found between the concurrent first-line TKI and the concurrent second-line TKI group (P=0.249). In multivariate analysis, only CR after SBRT was associated with OS (hazard ration 0.08; 95% confidence interval, 0.01-0.70; P=0.023; Table 3). TABLE 3 Prognostic Factors of Overall Survival Toxicity Treatment-related toxicities are presented in Table 4. Toxicity occurred in 30 (54%) patients. There were 5 cases of Grade 3 toxicity in 4 patients, and 60% were Grade 3 anemia. One patient with neural invasion before radiotherapy suffered from late radiation-related neuropathy. One patient with pretreatment skin invasion developed skin perforation in addition to Grade 3 anemia, and received skin flap surgery after radiotherapy. One patient with a prior history of multiple pulmonary bullae developed bronchopleural fistula 7 months after radiotherapy. Among the patients with Grade 3 toxicity, half were treated concurrently with axitinib, and the others received concurrent sunitinib. TABLE 4 Treatment-related Toxicity

Toxicity Treatment-related toxicities are presented in Table 4. Toxicity occurred in 30 (54%) patients. There were 5 cases of Grade 3 toxicity in 4 patients, and 60% were Grade 3 anemia. One patient with neural invasion before radiotherapy suffered from late radiation-related neuropathy. One patient with pretreatment skin invasion developed skin perforation in addition to Grade 3 anemia, and received skin flap surgery after radiotherapy. One patient with a prior history of multiple pulmonary bullae developed bronchopleural fistula 7 months after radiotherapy. Among the patients with Grade 3 toxicity, half were treated concurrently with axitinib, and the others received concurrent sunitinib. TABLE 4 Treatment-related Toxicity DISCUSSION Local treatment has become increasingly popular to treat patients with oligometastatic mRCC; however, its role in patients with nonoligometastatic disease remains controversial.12 Our study focused exclusively on the survival benefit of patients treated with combined TKI and SBRT in both the oligometastatic setting and nonoligometastatic setting. SBRT combined with TKI was safe and there was no need to pause the targeted therapy several weeks before SBRT. We also observed superior local treatment response in patients irradiated before TKI failure, and better local treatment response was associated with improved OS. Thus, we suggest the adoption of SBRT early in the course of systemic treatment, preferably before TKI failure.

e targeted therapy several weeks before SBRT. We also observed superior local treatment response in patients irradiated before TKI failure, and better local treatment response was associated with improved OS. Thus, we suggest the adoption of SBRT early in the course of systemic treatment, preferably before TKI failure. Acquired resistance will inevitably occur at a median of 6 to 12 months in patients treated with TKI.1–3,13,14 Sequential targeted therapy has prolonged the median OS of patients with mRCC to about 30 months; however, cross-resistance after first-line TKI failure creates a bottleneck to further improve survival outcomes.15–17 Thus, systemic therapy alone is insufficient for optimal mRCC management. When assessing the survival outcomes, the median OS of our patients (61.2 mo) was unexpectedly high compared with patients treated with targeted agents alone. Previous studies in patients treated with TKI combined with complete metastasectomy or SBRT demonstrated similar survival benefit (median OS 51 to 66 mo).9,18,19 Although the result is only exploratory, we believe that the clear survival improvement was realized by the incorporation of local treatment. Complete metastasectomy, a well-recognized local therapy, could reduce the risk of mortality by 51%, even in the era of targeted therapy.19 However, up to 25% of patients receiving metastasectomy suffered from major postoperative complications, and perioperative discontinuation of targeted agents would lead to a rapid increase in angiogenesis.20,21 SBRT has been shown to be noninferior to metastasectomy, especially in patients with risk factors.9 In addition, there was no need no pause TKI during SBRT, ensuring uninterrupted benefit from the combined therapy. Therefore, with improved systemic control and advanced treatment techniques, SBRT might be considered in patients with less favorable risk profiles.

tastasectomy, especially in patients with risk factors.9 In addition, there was no need no pause TKI during SBRT, ensuring uninterrupted benefit from the combined therapy. Therefore, with improved systemic control and advanced treatment techniques, SBRT might be considered in patients with less favorable risk profiles. Our study considered sites with major tumor burden as target for SBRT, based on the evidence that tumor burden is a significant prognostic factor.22–24 Heterogenous responses of different metastatic sites within individual patients are frequently observed during TKI treatment, among which larger lesions exhibit inferior response rates.25 Furthermore, the development of local resistance is the initial step for systemic progression in most cases, and bulky lesions have a higher proportion of clonal and subclonal alterations that might drive TKI resistance.26,27 Theoretically, irradiation to the major tumor burden could reduce the chance of developing resistant clones or subclones and could maintain TKI sensitivity. A previous study suggested that a 1 cm increase in the tumor burden elevates the risk of progression by 4.5% and death by 5%.23 A greater percentage of tumor burden removal is associated with improved PFS.28 Indeed, our study suggests that those who yielded CR at irradiated sites had more favorable survival outcomes. Thus, cytoreductive radiotherapy for nonoligometastatic patients is promising, and the site and extent of tumor burden removal is worthy of further investigation.

den removal is associated with improved PFS.28 Indeed, our study suggests that those who yielded CR at irradiated sites had more favorable survival outcomes. Thus, cytoreductive radiotherapy for nonoligometastatic patients is promising, and the site and extent of tumor burden removal is worthy of further investigation. For patients treated with the combined therapy, SBRT delivered before TKI failure resulted in superior PFS, OS, and CR rates. Multivariate analyses revealed that SBRT timing was an independent prognostic factor for survival outcome. Consideration of the use of SBRT early in the course of treatment is encouraged29; however, the use SBRT before TKI requires further discussion. mRCC has a variable spectrum of biological behavior, and patients with certain driver events show rapid systemic progression and extremely short survival.27 On the one hand, TKI could sift out resistant lesions that may benefit from local intervention in patients with multiple metastases. On the other hand, initial TKI could identify patients with rapid progression, who require intensive systemic treatment, rather than local treatment. As observed in the SURTIME and CARMENA trials, cytoreductive nephrectomy (CN) before TKI had a significantly inferior survival outcome compared with sunitinib followed by CN (32.4 vs. 15 mo); however, delaying CN for symptom control could only achieve a median OS of 18.4 months.13,30 Thus, TKI followed by SBRT before systemic progression is likely to be the ideal temporal combination.

ctomy (CN) before TKI had a significantly inferior survival outcome compared with sunitinib followed by CN (32.4 vs. 15 mo); however, delaying CN for symptom control could only achieve a median OS of 18.4 months.13,30 Thus, TKI followed by SBRT before systemic progression is likely to be the ideal temporal combination. All of the patients in the present study received concurrent TKI during SBRT, and treatment was well tolerated, despite common concerns about severe toxicity. Only 5 Grade 3 events were observed, 4 of which were myelosuppression. Previous studies suggested that Grade 3 toxicity after SBRT is 0% to 7% in mRCC, and the few studies focusing on combined modality therapy in mRCC found 0% to 7% Grade 3 toxicities following concurrent treatment.6,9,29,31 Meta-analyses showed that the vast majority of evaluated TKI do not alter the adverse effect profile of SBRT when administered concurrently; however, liver SBRT in conjunction with sorafenib should be administered with caution.32 Our study is limited by its retrospective nature and the relatively small sample size. However, in the absence of prospective randomized trials, our study contributes useful information regarding combined modality therapy for mRCC. In addition, patients with oligometastatic mRCC comprised a relatively small proportion of the series, which might represent a more real-world clinical situation. Thirdly, our patients were treated at a large academic center that has more access to investigational drugs. Thus, results might be difficult to replicate in small centers.

tients with oligometastatic mRCC comprised a relatively small proportion of the series, which might represent a more real-world clinical situation. Thirdly, our patients were treated at a large academic center that has more access to investigational drugs. Thus, results might be difficult to replicate in small centers. CONCLUSIONS The present study evaluated survival outcomes and toxicity profiles after combining SBRT with TKI. Our findings suggest that adding SBRT to TKI is safe and seems to improve survival in patients with mRCC. Patients irradiated before TKI failure have higher CR rate, and the favorable local treatment response might turn info survival benefit. Supplementary Material SUPPLEMENTARY MATERIAL Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.amjclinicaloncology.com. L.H. and Y.L. contributed equally to the work. The authors declare no conflicts of interest.

Colorectal cancer remains the third most common cancer and the third leading cause of cancer-related deaths in the United States for both men and women. For colon cancer alone, 101,220 new cases were projected to occur in 2019, causing 51,020 deaths.1 Despite significant improvements in both prevention and screening over the last twenty years, about 36,500 (36%) of such cases are still being diagnosed in stage III, with regional lymph node involvement (LN+, N1a-b, N2a-b) or tumor deposits (TD+, N1c). Adjuvant chemotherapy is generally advised after adequate surgical resection, with only slight variations in the choice of agents and duration of therapy. In its October 2018 edition, the National Comprehensive Cancer Network (NCCN) Guidelines recommend 3 months of capecitabine plus oxaliplatin (CAPEOX) or 3 to 6 months of 5-fluorouracil, leucovorin plus oxaliplatin (FOLFOX) for low-risk patients (T1-T3, N1); and 3 to 6 months of CAPEOX or 6 months of FOLFOX for high-risk patients (T4, N2). Single-agent capecitabine or 5-fluorouracil//leucovorin maybe used in patients in both risk groups when oxaliplatin therapy is contraindicated.2

s of 5-fluorouracil, leucovorin plus oxaliplatin (FOLFOX) for low-risk patients (T1-T3, N1); and 3 to 6 months of CAPEOX or 6 months of FOLFOX for high-risk patients (T4, N2). Single-agent capecitabine or 5-fluorouracil//leucovorin maybe used in patients in both risk groups when oxaliplatin therapy is contraindicated.2 TDs, also called extranodal TDs, peritumoral deposits, or satellite nodules, are defined as discrete tumor foci in the mesocolic (or perirectal) fat, within the lymphatic drainage space of the primary tumor, but without identifiable residual LN tissue or vascular structures.3 They were first listed in the seventh edition of the American Joint Committee on Cancer (AJCC) Staging Manual, effective January 1, 2010, under “Regional Lymph Nodes” as N1c, in the absence of LN involvement, indicative of stage III disease.4 This listing was maintained without changes in the eighth edition in 2018.5 A few retrospective, mostly single-institution, studies with a limited number of patients had associated the presence of TDs in colorectal cancer with an adverse prognosis, even before such AJCC staging modifications were implemented, and likely prompted such changes.6–9 Although it is recommended that the number of TD be recorded in the pathology report, AJCC has not correlated a higher number of TD with staging, unlike LNs (ie, N1=metastasis in 1 to 3 regional LNs, N2=metastasis in ≥4 regional LNs). In addition, in cases with positive LN, AJCC does not offer a staging option different than number of positive LN alone, regardless of the presence or absence and number of positive TD found in the mesocolon.

er of TD with staging, unlike LNs (ie, N1=metastasis in 1 to 3 regional LNs, N2=metastasis in ≥4 regional LNs). In addition, in cases with positive LN, AJCC does not offer a staging option different than number of positive LN alone, regardless of the presence or absence and number of positive TD found in the mesocolon. Even though the presence of TD in the pathology report for colorectal cancer specimens, even in the absence of positive regional LN, should be classified and treated as stage III,10 2 recent larger retrospective studies have shown that TD+LN− patients are less likely to receive adjuvant chemotherapy than LN+ patients.11,12 Such findings appear indicative of an opportunity to improve awareness and understanding of the clinical significance of TDs in colorectal cancer, especially with respect to appropriate risk stratification, choices for adjuvant treatment and more diversified survivorship strategies. The objectives of this study were multiple:Assess the incidence of TD+ in stage III colon cancer, alone (TD+LN−) and in combination with positive LNs (TD+LN+). Analyze the association of TD with T and N status, as well as other known adverse histopathologic features, ie, poor differentiation (PD+), perineural invasion (PNI+), and lymphovascular invasion (LVI+). Assess 5-year survival probability for LN+TD−, LN−TD+, and LN+TD+ patients. Determine the hazard ratio of TD+ and other adverse histopathologic variables. Determine if a higher number of TD+ correlates with a worse prognosis, as is the case for a higher number of LN+.

Analyze the association of TD with T and N status, as well as other known adverse histopathologic features, ie, poor differentiation (PD+), perineural invasion (PNI+), and lymphovascular invasion (LVI+). Assess 5-year survival probability for LN+TD−, LN−TD+, and LN+TD+ patients. Determine the hazard ratio of TD+ and other adverse histopathologic variables. Determine if a higher number of TD+ correlates with a worse prognosis, as is the case for a higher number of LN+. Stratify survival probability for stage III colon cancer patients into low-risk, intermediate-risk, and high-risk categories, on the basis of presence or absence of adverse histopathologic features. MATERIALS AND METHODS Data Source The National Cancer Database (NCDB) is a joint project of the American Cancer Society and the Commission on Cancer (CoC) of the American College of Surgeons (ACS), dedicated to the evaluation, management, and surveillance of cancer patients in the United States. The ACS has executed a Business Associate Agreement that includes a data use agreement with each of its CoC-accredited hospitals. The NCDB was established in 1989 as a nationwide, facility-based, comprehensive clinical surveillance resource oncology dataset that currently captures information on ∼70% of all newly diagnosed malignancies annually in the United States. The database is populated by information entered by certified tumor registrars from CoC-accredited cancer programs.

s a nationwide, facility-based, comprehensive clinical surveillance resource oncology dataset that currently captures information on ∼70% of all newly diagnosed malignancies annually in the United States. The database is populated by information entered by certified tumor registrars from CoC-accredited cancer programs. For this study, we obtained a participant user file to query datasets limited to stage III adenocarcinoma of the colon. We elected to exclude cases of rectal or “rectosigmoid” cancer, which are often managed with neoadjuvant chemotherapy and radiation in stage III disease, with the added variable of the tumor and nodal regression affecting the review of histopathologic features in the resected specimen. Also, we limited our investigation to patients treated with both surgical resection and chemotherapy, to compare more homogeneous groups. The time frame for data collection ranged from January 1, 2010 (the year in which the N1c designation was implemented) through December 31, 2015, to ensure adequate long-term survival in a sizable number of patients available for statistical analysis. Patient characteristics included sex, age at diagnosis, race/ethnicity, health insurance status, and comorbidities (Charlson-Deyo Score).13 Charlson-Deyo Score is based on comorbid conditions from listed ICD-9 codes, with a score of 0 indicating no comorbidities, and point values of 1 or 2 being assigned on the basis of number and severity of comorbid conditions.

diagnosis, race/ethnicity, health insurance status, and comorbidities (Charlson-Deyo Score).13 Charlson-Deyo Score is based on comorbid conditions from listed ICD-9 codes, with a score of 0 indicating no comorbidities, and point values of 1 or 2 being assigned on the basis of number and severity of comorbid conditions. Hospital characteristics included cancer facility type providing care, according to the CoC accreditation criteria, based on the total number of yearly new cancer diagnoses, diagnostic and treatment services, research participation, and residency educational programs (Academic/Research, Community, Comprehensive Community, and Integrated Network Cancer Centers). Tumor variables included T and N status, histologic grade, LVI, PNI, presence or absence of TD, alone or in combination with LN+ status. Vital status at last contact provided survival information. Statistical Analysis The primary outcome of the study was overall survival. Patients were divided into 3 groups according to TD and LN status. Demographic data was stratified into 3 groups: LN+TD−, LN−TD+, and LN+TD+. A χ2 test was used to compare whether the distribution of the demographic factors was different between the 3 groups. For the distribution of tumor-related characteristics grouped by LN+TD− or LN−TD+ versus LN+TD+, the P-values were calculated using a test of proportions. All plots of survival curves were created using group-specific Kaplan-Meier estimators, and all tests of equality of survival curves between groups were performed using a log-rank test.

of tumor-related characteristics grouped by LN+TD− or LN−TD+ versus LN+TD+, the P-values were calculated using a test of proportions. All plots of survival curves were created using group-specific Kaplan-Meier estimators, and all tests of equality of survival curves between groups were performed using a log-rank test. Five-year survival estimators and associated confidence intervals were calculated using the Kaplan-Meier curves. Hazard ratios were estimated using a main effect multivariable Cox proportional hazards model. RESULTS A total of 42,901 patients, who had all the required information in the database, were found eligible and were analyzed in the study. The mean follow-up time was 40.7 months. Patient demographic factors are listed in Table 1. There was a difference in the age distribution and insurance status categories among the 3 groups. TABLE 1 Patient Demographics and Facility Types A comparison of histopathologic variables is presented in Table 2, showing that LN+TD+ tumors were associated with other adverse features such as T4 status, PD, PNI, LVI, significantly more often than either LN+TD− or LN−TD+ tumors. LN+TD+ tumors were also associated with N2 status more often than LN+TD− tumors. TABLE 2 Histopathologic Variables Comparing LN+TD− With LN−TD+ and LN+TD+ Estimated hazard ratios, calculated to quantify the contribution to the prognosis of each adverse histopathologic factors, are presented in Table 3. TABLE 3 HRs of Different Adverse Histopathologic Variables

A comparison of histopathologic variables is presented in Table 2, showing that LN+TD+ tumors were associated with other adverse features such as T4 status, PD, PNI, LVI, significantly more often than either LN+TD− or LN−TD+ tumors. LN+TD+ tumors were also associated with N2 status more often than LN+TD− tumors. TABLE 2 Histopathologic Variables Comparing LN+TD− With LN−TD+ and LN+TD+ Estimated hazard ratios, calculated to quantify the contribution to the prognosis of each adverse histopathologic factors, are presented in Table 3. TABLE 3 HRs of Different Adverse Histopathologic Variables Survival probability graphs according to LN and TD status combinations in the 3 groups are shown in Figure 1. Five-year survivals are shown in parentheses. Overall and 5-year survival was significantly worse for LN+TD+ patients (41.5%), than either LN+TD− (59.8%) or LN−TD+ patients (58.2%) (P<0.001). FIGURE 1 Kaplan-Meier curves comparing survival for LN+TD−, LN−TD+, and TD+LN+. Overall and 5-year survival was similar for LN+TD− (0.598; 95% CI: 0.593-0.604) and LN−TD+ (0.582; 95% CI: 0.556-0.609), but significantly worse for LN+TD+ (0.415; 95% CI: 0.403-0427) compared with each of the other 2 groups (P<0.001). CI indicates confidence interval; LN, lymph node; TD, tumor deposit.

D+, and TD+LN+. Overall and 5-year survival was similar for LN+TD− (0.598; 95% CI: 0.593-0.604) and LN−TD+ (0.582; 95% CI: 0.556-0.609), but significantly worse for LN+TD+ (0.415; 95% CI: 0.403-0427) compared with each of the other 2 groups (P<0.001). CI indicates confidence interval; LN, lymph node; TD, tumor deposit. A subset analysis to address the question of a higher number of TD+ possibly having a worse prognosis, as it is the case for a higher number of LNs, is shown in Figure 2. In fact, LN− patients with ≥3 TD+ (currently staged as N1c), had an overall survival of 51.4%, worse than those with 1 to 2 TD+ (60.6%), but similar to ≥4 LN+TD− (currently staged as N2) (48.9%) and 1 to 3LN+TD+ (currently staged as N1a-b) (50.7%) (P<0.01). FIGURE 2 Kaplan-Meier survival curves for subgroups of patients. LN−, ≥3 TD+ (N1c) had worse overall survival (0.504; 95% CI: 0.426-0.597) than LN−, 1 to 2 TD+ (N1c) (0.623; 95% CI: 0.591-0.657), similar to ≥4 LN+, TD− (N2) (0.489; 95% CI: 0.478-0.500) and 1 to 3 LN+, TD+ (N1a-b) (0.507; 95% CI: 0.489-0.526) (P<0.01). CI indicates confidence interval; LN, lymph node; TD, tumor deposit.

, ≥3 TD+ (N1c) had worse overall survival (0.504; 95% CI: 0.426-0.597) than LN−, 1 to 2 TD+ (N1c) (0.623; 95% CI: 0.591-0.657), similar to ≥4 LN+, TD− (N2) (0.489; 95% CI: 0.478-0.500) and 1 to 3 LN+, TD+ (N1a-b) (0.507; 95% CI: 0.489-0.526) (P<0.01). CI indicates confidence interval; LN, lymph node; TD, tumor deposit. Finally, a prognostic stratification into low, intermediate, and high-risk groups was done to assess the cumulative impact of adverse histopathologic variables on survival. Patients with T1-T2 tumors; N1a-b with TD−, or LN− with 1 to 2 TD+; and negative PD, PNI, and LVI, were assigned to the low-risk group. Patients with T3 tumors; N2 TD−, or LN− with ≥3 TD+; and only 1 positive either PD, PNI, or LVI, were assigned to the intermediate-risk group. Patients with T4 tumors; N2 TD+; and 2 to 3 positive PD, PNI, and LVI, were assigned to the high-risk group. Five-year survival was 78.1% for the low-risk group, 57.2% for the intermediate-risk group, and 23.4% for the high-risk group (P-values comparing overall and 5-year survival for all 3 groups <0.001) (Fig. 3).

p. Patients with T4 tumors; N2 TD+; and 2 to 3 positive PD, PNI, and LVI, were assigned to the high-risk group. Five-year survival was 78.1% for the low-risk group, 57.2% for the intermediate-risk group, and 23.4% for the high-risk group (P-values comparing overall and 5-year survival for all 3 groups <0.001) (Fig. 3). FIGURE 3 Kaplan-Meier survival curves for low-risk, intermediate-risk, and high-risk groups, on the basis of histopathologic variables T, N, TD, PD, PNI, and LVI. Overall and 5-year survival was significantly higher (0.781; 95% CI: 0.762-0.801) for low-risk patients; average (0.572; 95% CI: 0.524-0.625) for intermediate-risk patients; and significantly lower (0.234; 95% CI: 0.211-0.259) for high-risk patients (P<0.001 for all 3 groups). CI indicates confidence interval; LVI, lymphovascular invasion; PD, poor differentiation; PNI, perineural invasion; TD, tumor deposit. CONCLUSIONS The addition of N1c in the AJCC classification of colon cancer staging was prompted by several publications, before 2010. Some investigators focused on appropriate histologic differentiation of TD from LN metastases at the time of histologic evaluation,8,12,14 while noting that interobserver variability among pathologists may at times affect consistent interpretation and reporting.15 Other authors reported on mostly single-institution data on the adverse prognosis of TD in colorectal cancer,16,17 contributing to the AJCC Staging Manual classification changes implemented in its seventh edition.

nterobserver variability among pathologists may at times affect consistent interpretation and reporting.15 Other authors reported on mostly single-institution data on the adverse prognosis of TD in colorectal cancer,16,17 contributing to the AJCC Staging Manual classification changes implemented in its seventh edition. In a pathology study, the authors opined that “despite the apparent adverse prognosis of TDs, it should be noted that the N1c category does not necessarily imply a worse prognosis than N1a or N1b.”15 However, additional publications in pathology, oncology and surgery journals from larger databases (eg, Surveillance, Epidemiology, and End Results [SEER] and NCDB), provided evidence that the presence of TD in colorectal cancer should be considered a significant adverse prognostic factor for overall survival.18–24 A recent study has shown the presence of TD in patients with stage III colon cancer to be associated with a 2.2-fold increased risk of developing disease recurrence.25

, provided evidence that the presence of TD in colorectal cancer should be considered a significant adverse prognostic factor for overall survival.18–24 A recent study has shown the presence of TD in patients with stage III colon cancer to be associated with a 2.2-fold increased risk of developing disease recurrence.25 After the eighth edition of the AJCC Staging Manual for colorectal cancer in 2018, which left the N1c classification unchanged, the issue of appropriately assessing the increased risks posed by TD+ remains incompletely addressed. The current classification includes only LN−TD+ as “low-risk” stage III as N1c, comparable to N1a (1LN+), and N1b (2 to 3 LN+). “High-risk” is limited to N2a (4 to 6 LN+) and N2b (>6 LN+). Over one fourth of stage III colon cancers are TD+. About 20% of stage III colon cancer patients are LN+TD+; yet only the number of LN+ is used for staging purposes, completely disregarding the additional presence of TDs and their “additional” adverse prognostic value. For example, had the TD+ lesions been read as LN+, their combined total number may well have made the difference between N1a-b and N2a-b. Finally, in the roughly 7% of stage III colon cancer cases that are LN−TD+, the possible increased risk posed by a higher number of TD+, as it is the case for a higher number of LN+, is currently not addressed by AJCC staging.

s LN+, their combined total number may well have made the difference between N1a-b and N2a-b. Finally, in the roughly 7% of stage III colon cancer cases that are LN−TD+, the possible increased risk posed by a higher number of TD+, as it is the case for a higher number of LN+, is currently not addressed by AJCC staging. Our study’s purpose was to conduct a deeper and more focused analysis of the available NCDB data to assess the relevance of those 2 outstanding issues. This study represents the largest NCDB analysis of the impact of TD in the prognosis of stage III colon cancer patients treated with both surgery and chemotherapy, with the longest accrual time (6 years) and longest follow-up for survival figures (up to over 80 mo). A previously published 2010-2014 NCDB review study had evidenced the high incidence of TDs, in ∼25% of all stage III colon cancers, of which 6.8% were LN−TD+, with only 52% of LN−TD+ receiving adjuvant chemotherapy.12 Our patient cohort has a lower incidence of TD+LN− (3.9%), because we limited our analysis to patients who received both surgery and chemotherapy, to have more homogeneous comparison groups, as there is no question about the survival improvement provided by the addition of chemotherapy for all stage III colon cancer patients. In our data, there was no difference in demographics between the 3 comparison groups (LN+TD−, LN−TD+, and LN+TD+), with only variations in age at diagnosis and insurance status showing changes in various groups, not clinically relevant to our study purpose (Table 1).

Our study’s purpose was to conduct a deeper and more focused analysis of the available NCDB data to assess the relevance of those 2 outstanding issues. This study represents the largest NCDB analysis of the impact of TD in the prognosis of stage III colon cancer patients treated with both surgery and chemotherapy, with the longest accrual time (6 years) and longest follow-up for survival figures (up to over 80 mo). A previously published 2010-2014 NCDB review study had evidenced the high incidence of TDs, in ∼25% of all stage III colon cancers, of which 6.8% were LN−TD+, with only 52% of LN−TD+ receiving adjuvant chemotherapy.12 Our patient cohort has a lower incidence of TD+LN− (3.9%), because we limited our analysis to patients who received both surgery and chemotherapy, to have more homogeneous comparison groups, as there is no question about the survival improvement provided by the addition of chemotherapy for all stage III colon cancer patients. In our data, there was no difference in demographics between the 3 comparison groups (LN+TD−, LN−TD+, and LN+TD+), with only variations in age at diagnosis and insurance status showing changes in various groups, not clinically relevant to our study purpose (Table 1). Other variables, such as T4 and N2, which have been definitively associated with worse survival expectations, have been found to occur more frequently in LN+TD+ patients in previous publications.11,12,26 Our data confirmed such association as well: 55.1% for N2 in LN+TD+ patients, versus 31.1% in LN+TD− patients; and 36.9% for T4 in LN+TD+ patients, versus 19.2% in LN+TD− and 23.5% in LN−TD+ patients (P<0.001). In addition, we found a significant association between LN+TD+ patients and other adverse histopathologic features, especially LVI (69.1%), but also PD (37.4%), and PNI (34.5%), prognostic factors known to contribute to poorer long-term survival figures (Table 2). The frequent association between TD+ and LVI+ may provide additional insight as to the nature and origin of TDs.

N+TD+ patients and other adverse histopathologic features, especially LVI (69.1%), but also PD (37.4%), and PNI (34.5%), prognostic factors known to contribute to poorer long-term survival figures (Table 2). The frequent association between TD+ and LVI+ may provide additional insight as to the nature and origin of TDs. We found that each adverse variable carried a significant hazard ratio, which we quantified individually as well as in combination, for a cumulative effect on the mortality probability (Table 3). When analyzing our survival graphs (Figs. 1–3), it is also apparent that, in poorer risk patients, a rapid decline occurs within 2 years of diagnosis, emphasizing the need for timely systemic treatment of adequate duration.27 In subsets of TD+ patients, survival figures may actually be so poor they resemble stage IV colon cancer, as noted recently by other authors, advocating staging classification changes.28

ients, a rapid decline occurs within 2 years of diagnosis, emphasizing the need for timely systemic treatment of adequate duration.27 In subsets of TD+ patients, survival figures may actually be so poor they resemble stage IV colon cancer, as noted recently by other authors, advocating staging classification changes.28 In recent years “survival calculators” and “prognostic calculators” have been developed for different cancer sites at some cancer centers in the United States, based on regional as well as NCDB data.29 The availability of prognostic indicators and risk calculators is becoming part of the assessment and decision-making progress for physicians and patients as well, who increasingly seek more information and involvement in a personalized approach to their care for a variety of medical conditions.30,31 Interestingly, the variables utilized differed widely among 3 programs evaluated in 1 study. Age, sex, grade, and a number of total positive/examined nodes were common to all 3 programs, but the total number of items analyzed varied from as few as 5 to as many as 15 out of a possible total of 18. The predicted survival was different among programs, with 1 program being defined as clearly more “optimistic,” while the more comprehensive program was more “realistic.” The authors concluded that a more comprehensive list of variables would provide a more accurate tool.32 Of note, to date no survival calculator for colon cancer has included TD status. Data from our study and from other publications addressing the role of TD+ in colon cancer would add valuable information for practitioners and patients and maybe considered for inclusion in such “risk calculators.”

a more accurate tool.32 Of note, to date no survival calculator for colon cancer has included TD status. Data from our study and from other publications addressing the role of TD+ in colon cancer would add valuable information for practitioners and patients and maybe considered for inclusion in such “risk calculators.” Some authors had hypothesized that a prognostic relationship existed between the number of positive LNs and TD positivity,33 whereas others proposed that TD+ be counted as LN+, to obtain a larger total number.34 A higher number of TD+ maybe associated with a worse prognosis, as it is the case for a higher number of LN+. Therefore, we compared survival probability in certain subsets of patients currently staged as N1 (a, b, or c) and found that to be similar to patients currently staged as N2, depending on TD status. In fact, LN− patients with ≥3 TD+ (currently staged as N1c) had worse overall survival than those with only 1or 2 TD+ (also currently staged as N1c), but similar survival to ≥4 LN+TD− (currently staged as N2) and 1 to 3 LN+TD+ (currently staged as N1a-b) (Fig. 2). These observations may prompt consideration of AJCC classification changes, to accurately reflect the additional risk of a higher number of TD+, alone and in combination with number of LN+.

staged as N1c), but similar survival to ≥4 LN+TD− (currently staged as N2) and 1 to 3 LN+TD+ (currently staged as N1a-b) (Fig. 2). These observations may prompt consideration of AJCC classification changes, to accurately reflect the additional risk of a higher number of TD+, alone and in combination with number of LN+. Finally, the survival probability curves that the study generated, on the basis of the type and number of adverse variables, demonstrate the wide range of survival in stage III colon cancer. In patients with the worst possible T, N, TD, PD, PNI, and LVI status (high risk), according to our model, the estimated 5-year survival is only 23.4%, even after receiving chemotherapy at CoC-accredited cancer programs. In the “best-case scenario” stage III, with T1-T2, favorable LN and TD combinations, and no PD, PNI, or LVI (low risk), the survival estimate is as high as 78.1%. The intermediate-risk group was found to have an estimated 5-year survival of 57.2% (Fig. 3). Such data provide validation of the accuracy of our tumor-related prognostic assessment, which could be combined with clinical individual patient data (eg, age and Charlson-Deyo Score) to better tailor therapeutic strategies in patients with different risk profiles. It appears obvious that such a wide difference in prognosis would warrant a more diversified approach. Particularly for the high-risk patients, with such low survival expectations, a much more vigorous systemic therapy regimens may need to be considered, even in an adjuvant setting. Such a wide prognostic variability should prompt a reconsideration of not only adjuvant therapy regimens but also more diversified survivorship plans, tailored to each subset of patients.

ch low survival expectations, a much more vigorous systemic therapy regimens may need to be considered, even in an adjuvant setting. Such a wide prognostic variability should prompt a reconsideration of not only adjuvant therapy regimens but also more diversified survivorship plans, tailored to each subset of patients. Limitations of this study include its retrospective design, necessary to access such a large multi-institutional database. Also, survival data do not account for disease-free or disease-specific survival figures, nor do they include disease recurrence or progression. However, a large number of patients evaluated should minimize variation from other causes of death. In addition, no information was available with respect to TD incidence in patients with hereditary or genetic colorectal cancer syndromes. Finally, no detailed information was available about specific chemotherapeutic medications used, other than single or multiple agents. In conclusion, the incidence of TD+ in stage III colon cancer, about 1 in 4 cases, makes it a relevant cancer variable. TD+ tumors, when LN+, are frequently associated with other adverse histopathologic features (T4, N2, PD, PNI, LVI). The variability in prognosis for stage III colon cancer is wide enough to merit a more diversified approach in management. The association of TD+ and LN+ is indicative of poor prognosis, currently not addressed by AJCC staging, A high number of TDs (≥3), even in the LN− patients, is indicative of poor prognosis, currently not addressed by AJCC staging.

tage III colon cancer is wide enough to merit a more diversified approach in management. The association of TD+ and LN+ is indicative of poor prognosis, currently not addressed by AJCC staging, A high number of TDs (≥3), even in the LN− patients, is indicative of poor prognosis, currently not addressed by AJCC staging. Therefore, we propose an amendment to the AJCC classification of stage III colon cancer, which would appropriately reflect LN+TD+ or LN− ≥3 TD+ into a new subset category which could be named “N2c.” Only patients with LN−, 1 to 2 TD+ would remain staged as N1c. Such modifications should draw greater attention to the issue of TD positivity and prompt appropriate risk stratification, consideration of a more vigorous therapeutic approach and closer survivorship planning for this subset of high-risk stage III colon cancer patients. Presented at the 100th Meeting of the New England Surgical Society, September 14, 2019, Montreal, PQ, Canada. The authors declare no conflicts of interest.