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Core tip: Hepatocellular carcinoma (HCC) is an aggressive and invasive malignancy. Curative options, such as resection and liver transplantation, are limited to only a few patients, who are suitable candidates. Sorafenib is the only approved systemic treatment in HCC, especially for advanced tumor stage and early stage liver disease. Recent findings suggest that it may also be helpful in carefully selected decompensated patients. Its adjuvant role is yet to be proven with more promising results. The combination of Sorafenib with other chemotherapy agents has shown improved efficacy and safety. We aim to present the evolution of Sorafenib’s use over the last decade. INTRODUCTION Hepatocellular carcinoma (HCC), the most common primary malignant neoplasm of the liver (85%-90%)[1], is the sixth most frequent cancer in the world and the third cause of cancer-related[2]. Cirrhosis is the stage of chronic liver disease characterized by disrupted architecture of the liver, therefore resulting in its dysfunction over the time. Regardless of the cause leading to cirrhosis, it is a major condition predisposing to a malignant transformation of the liver eventually leading to HCC[3]. Nowadays, the incidence of HCC is increasing rapidly owing to the large number of people suffering from cirrhosis, mainly caused by hepatitis B and C virus infection, as well as due to longer survival among cirrhotic patients[1].

tion predisposing to a malignant transformation of the liver eventually leading to HCC[3]. Nowadays, the incidence of HCC is increasing rapidly owing to the large number of people suffering from cirrhosis, mainly caused by hepatitis B and C virus infection, as well as due to longer survival among cirrhotic patients[1]. Equally important to the presence and stage of cirrhosis, is the stage of the HCC, as any treatment that will follow will be in accordance to that. Specifically, surgical resection, ablation and liver transplantation are the only acceptable potentially curative options, but as it turns out, despite screening and frequent follow-ups, only 40%-60% of cirrhotic patients are diagnosed with very early or early stage HCC, therefore being eligible for curative treatment[4,5]. Unfortunately, most patients are diagnosed with more advanced stage HCC, i.e., portal vein invasion and/or extrahepatic spread or general symptoms attributed to cancer, unresponsive to such modalities. As a result alternative treatment combinations and algorithms including embolization, chemotherapy, radiotherapy, molecular target therapy or immunotherapy are constantly being generated in order to improve the overall survival (OS) of such patients[4,6,7].

ymptoms attributed to cancer, unresponsive to such modalities. As a result alternative treatment combinations and algorithms including embolization, chemotherapy, radiotherapy, molecular target therapy or immunotherapy are constantly being generated in order to improve the overall survival (OS) of such patients[4,6,7]. In particular, an aspect of systemic therapy tends to focus on an important characteristic of HCC, its angiogenesis, by developing antiangiogenic drugs that impede the formation of new blood vessels, thus inhibiting the proliferation and growth of the liver tumor[8]. Sorafenib, an antiangiogenic drug, is the first and currently the only chemotherapeutic regimen approved as a palliative type of treatment in advanced stage HCC[9]. This review describes the general characteristics of Sorafenib, its current place in the clinician’s therapeutic armamentarium, as well as the clinical results of the evolving role of Sorafenib when combined or compared to other treatment modalities.

approved as a palliative type of treatment in advanced stage HCC[9]. This review describes the general characteristics of Sorafenib, its current place in the clinician’s therapeutic armamentarium, as well as the clinical results of the evolving role of Sorafenib when combined or compared to other treatment modalities. GENERAL PRINCIPLES Molecular mechanisms As stated above, HCC is a tumor with abundant vasculature and high heterogeneity, especially when it comes to the various signaling pathways involved[10]. One of the key pathways involved in the growth and proliferation of HCC is the Raf/MEK/ERK mitogen-activated protein (MAP) kinase cascade, which shows particularly increased activity[11]. This over-activation is mainly achieved by the combined action of hepatitis virus proteomics and growth factors, with platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) playing a critical role and highlighting the linkage between angiogenesis and HCC development[12-14]. Sorafenib (Nexavar, BAY 43-9006), a biaryl urea, is an oral multikinase inhibitor of the serine/threonine-kinases (c-RAF and BRAF), therefore blocking the Raf/MEK/ERK pathway, and of the vascular endothelial growth factor receptor 2 (VEGFR2), VEGFR3, platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-KIT[15]. Moreover, it has been shown to result in apoptosis in various human tumor cell lines, independently of its involvement in the Raf/MEK/ERK pathway, by: (1) down-regulating an anti-apoptotic protein, the myeloid cell leukemia-1 (Mcl-1), member of the Bcl-2 family; and (2) inhibiting the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), which normally, when phosphorylated, promotes the expression of oncogenic genes[16]. According to this rationale, Sorafenib is an effective drug against not only the tumor compartment, but also the formation of new vessels[17,18]. It’s mechanism of action is illustrated in Figure 1.

lation initiation factor 4E (eIF4E), which normally, when phosphorylated, promotes the expression of oncogenic genes[16]. According to this rationale, Sorafenib is an effective drug against not only the tumor compartment, but also the formation of new vessels[17,18]. It’s mechanism of action is illustrated in Figure 1. Figure 1 Sorafenib’s mechanism of action. In tumor cells sorafenib blocks the Raf/MEK/ERK cascade and can lead to apoptosis through various mechanisms, such as inhibition of eukaryotic translation initiation factor 4E phosphorylation. In vascular endothelial cells, it inhibits receptor tyrosine kinases, such as VEGFR and PDGFR. PDGFR: Platelet-derived growth factor receptor; VEGFR: Vascular endothelial growth factor receptor. Sorafenib’s history This therapeutic action was firstly assessed in an uncontrolled phase 2 clinical trial of 137 patients with advanced and unresectable HCC, not having received any prior systemic therapy and with Child Pugh (CP) A or B cirrhosis[19]. The dosage administered was 400 mg orally twice a day in 4-wk cycles with a partial response of 2.2%, a minor response of 5.8% and a 33.6% of the patients reporting non progressive disease for at least 16 wk. Some other major data reported were the 4.2-mo median time to progression (TTP) and the 9.2-mo OS, while CP A and B patients showed only negligible differences regarding the pharmacokinetics[19].

response of 2.2%, a minor response of 5.8% and a 33.6% of the patients reporting non progressive disease for at least 16 wk. Some other major data reported were the 4.2-mo median time to progression (TTP) and the 9.2-mo OS, while CP A and B patients showed only negligible differences regarding the pharmacokinetics[19]. Such positive results could not but be followed by the international phase 3, randomized, double-blind, placebo-controlled “Sorafenib HCC Assessment Randomized Protocol” (SHARP) clinical trial[9]. For this purpose, 602 patients with advanced stage HCC, Eastern Cooperative Oncology Group (ECOG) performance status from 0 to 2, CP A liver disease and without any preceding systemic treatment, were randomized either for Sorafenib, same dosage as in phase 2, or for placebo. According to the data reported, Sorafenib resulted in a median OS of 10.7 mo vs the 7.9 mo of the placebo, as well as in a median TTP of 24 wk compared to 12 wk of the placebo. Also, although the median TTP based on radiologic findings was 5.5 mo in the Sorafenib arm compared to 2.8 mo in the placebo arm, there was again no complete response, while the partial response was limited[9]. In spite of the positive clinical effects and the improvement in OS, Sorafenib was assessed within the frontiers of advanced stage HCC, but very early stage liver disease. This leads to many questions regarding its potential place in the treatment of patients with both advanced HCC and liver disease.

se was limited[9]. In spite of the positive clinical effects and the improvement in OS, Sorafenib was assessed within the frontiers of advanced stage HCC, but very early stage liver disease. This leads to many questions regarding its potential place in the treatment of patients with both advanced HCC and liver disease. Adverse effects On the other hand, nobody claimed that Sorafenib was harmless. The SHARP trial, as a phase 3 study, except for the effectiveness, also reported details about some possible adverse effects, which were more frequent in the Sorafenib group compared to the placebo one (80% vs 52%, respectively). The most commonly described toxicities were grade 1 and 2 regarding the severity, i.e., weight loss, anorexia, diarrhea, changes in voice, hand-foot skin reaction, rash or desquamation and hair loss[9]. Some of these toxicities led to drug discontinuation (Sorafenib 11% vs placebo 5%)[9]. Another important study, the Sorafenib Italian Assessment (SOFIA) trial, showed that intervening by down-dosing at the appropriate time might be beneficial regarding an improved toxicity-tolerance rate and an increased OS[20].

ss[9]. Some of these toxicities led to drug discontinuation (Sorafenib 11% vs placebo 5%)[9]. Another important study, the Sorafenib Italian Assessment (SOFIA) trial, showed that intervening by down-dosing at the appropriate time might be beneficial regarding an improved toxicity-tolerance rate and an increased OS[20]. Moreover, significant findings from the routine clinical practice were presented by Sacco et al[21], who stated that when Sorafenib is administered early at a low dose, especially in patients characterized as high-risk, it may be easier to render the patients compliant to the continuation of the therapy and for the drug to be well-tolerated. As a result, Sorafenib may induce some harmful events, mostly minor, which can be better tolerated by adjusting the dosage.

early at a low dose, especially in patients characterized as high-risk, it may be easier to render the patients compliant to the continuation of the therapy and for the drug to be well-tolerated. As a result, Sorafenib may induce some harmful events, mostly minor, which can be better tolerated by adjusting the dosage. FOOD AND DRUG ADMINISTRATION APPROVAL According to the European Association for the Study of the Liver (EASL) - European Organisation for Research and Treatment of Cancer (EORTC) guidelines (2012), Sorafenib is currently the only standard systemic treatment for HCC[6]. Its use is approved since 2007 upon the publication of the results of two studies: (1) the SHARP trial[9], conducted in the United States of America and Europe; and (2) the Sorafenib Asia-Pacific (Sorafenib-AP) trial[22], conducted in South Korea, China and Taiwan, which both showed an increased OS and a reduced risk of mortality in patients treated with Sorafenib. However, the aforementioned guidelines[6] highlight that Sorafenib is recommended only in patients with early stage liver disease - Child-Pugh A - and advanced stage HCC - Barcelona - Clinic Liver Cancer (BCLC) stage C - or as an adjuvant therapy combined with loco-regional treatment options. Sorafenib’s current place in the treatment algorithm, in accordance with the BCLC staging system for HCC, is presented in Figure 2[4,23]. Figure 2 Barcelona clinic liver cancer staging system and treatment algorithm. PS: Performance status; N: Nodules; M: Metastases; HCC: Hepatocellular carcinoma.

FOOD AND DRUG ADMINISTRATION APPROVAL According to the European Association for the Study of the Liver (EASL) - European Organisation for Research and Treatment of Cancer (EORTC) guidelines (2012), Sorafenib is currently the only standard systemic treatment for HCC[6]. Its use is approved since 2007 upon the publication of the results of two studies: (1) the SHARP trial[9], conducted in the United States of America and Europe; and (2) the Sorafenib Asia-Pacific (Sorafenib-AP) trial[22], conducted in South Korea, China and Taiwan, which both showed an increased OS and a reduced risk of mortality in patients treated with Sorafenib. However, the aforementioned guidelines[6] highlight that Sorafenib is recommended only in patients with early stage liver disease - Child-Pugh A - and advanced stage HCC - Barcelona - Clinic Liver Cancer (BCLC) stage C - or as an adjuvant therapy combined with loco-regional treatment options. Sorafenib’s current place in the treatment algorithm, in accordance with the BCLC staging system for HCC, is presented in Figure 2[4,23]. Figure 2 Barcelona clinic liver cancer staging system and treatment algorithm. PS: Performance status; N: Nodules; M: Metastases; HCC: Hepatocellular carcinoma. MONOTHERAPY As mentioned above, the results of systemic monotherapy with Sorafenib were encouraging according to a phase 2 trial[19] and two phase 3 trials (SHARP[9] and Sorafenib-AP[22]). There was general agreement that Sorafenib has a great impact in increasing the OS, even though in the phase 2 study 28% of the patients, who had CP B cirrhosis, showed a shorter median OS of 3.2 mo and could tolerate the treatment for only 1.8 mo. Also the incidence of ascites, encephalopathy and advanced hyperbilirubinemia is higher in advanced liver disease[24]. Interestingly, a phase 1 study, assessing the use of Sorafenib in patients with higher Child-Pugh class, underlined its link with the dose-limiting rises in serum bilirubin concentration[25]. Therefore, treatment guidelines[7] recommend taking bilirubin into consideration when adjusting the dose of Sorafenib. In addition, a post-marketing trial (GIDEON)[26] has shown equivalent results regarding safety and dosing strategy regardless of the Child-Pugh score. On the other hand, several studies evaluating the role of Sorafenib among the different stages of liver function reserve, reported a decreased response in advanced CP class, while liver-specific toxicities were independent of the liver cirrhosis stage[27-29].

fety and dosing strategy regardless of the Child-Pugh score. On the other hand, several studies evaluating the role of Sorafenib among the different stages of liver function reserve, reported a decreased response in advanced CP class, while liver-specific toxicities were independent of the liver cirrhosis stage[27-29]. On the whole, a systematic review has shown that in a male elderly population with advanced HCC and CP A cirrhosis, Sorafenib monotherapy can yield a statistically significant, yet clinically insignificant, increase in OS, time to tumor progression and disease control rate[30]. Besides, the cumulative data underline the decrease response of HBV-infected patients when compared to HCV, while patients with worse level of cirrhosis tend to display a more prominent Sorafenib-driven toxicity[30].

, yet clinically insignificant, increase in OS, time to tumor progression and disease control rate[30]. Besides, the cumulative data underline the decrease response of HBV-infected patients when compared to HCV, while patients with worse level of cirrhosis tend to display a more prominent Sorafenib-driven toxicity[30]. A study published in 2017 analysing the SEER-Medicare database, reported that elderly patients with advanced stage HCC may survive longer if treated with Sorafenib vs placebo (150.5 d vs 62 d, respectively), while the most remarkable factor associated with increased mortality was treatment taking place in an urban setting, although this survival effect was found to be neither prolonged, nor cost-effective in decompensated patients[31]. Currently, a randomized controlled phase 3 study - the B Child Patient-Optimization of Sorafenib Treatment (BOOST) study - is ongoing so as to evaluate the safety and efficacy of Sorafenib in CP B patients and is going to provide helpful information regarding the treatment of patients with decompensated disease[32]. However, reality is that for most patients Sorafenib is only one of the treatments that they receive, thus rendering it essential to review the adjuvant role of Sorafenib within the spectrum of other therapies.

d is going to provide helpful information regarding the treatment of patients with decompensated disease[32]. However, reality is that for most patients Sorafenib is only one of the treatments that they receive, thus rendering it essential to review the adjuvant role of Sorafenib within the spectrum of other therapies. SORAFENIB AND SURGICAL RESECTION Currently, surgical resection remains the treatment of choice for HCC, when it is associated with solitary masses and the hepatic remnant can maintain liver function[6]. Recently, there has been great interest concerning the down-staging of advanced HCC in order to make surgical resection even more efficient. One way to accomplish that is by taking advantage of Sorafenib’s use as a neoadjuvant treatment. In fact, a study has reported the incidence of Sorafenib-driven tumor necrosis, when used pre-operatively, therefore making resection an applicable treatment modality for a previously unresectable HCC tumor[33]. Moreover, the use of Sorafenib before surgery was not found to lead to any intra- or post-operative side-effects[34].

a study has reported the incidence of Sorafenib-driven tumor necrosis, when used pre-operatively, therefore making resection an applicable treatment modality for a previously unresectable HCC tumor[33]. Moreover, the use of Sorafenib before surgery was not found to lead to any intra- or post-operative side-effects[34]. However, it is unclear whether Sorafenib could also be efficacious as an adjuvant therapy post-operatively. Specifically, a phase 3 study (STORM) evaluating its use after resection or ablation showed that Sorafenib is not superior to placebo when it comes to OS, recurrence-free survival or time to recurrence[35]. Unfortunately, many patients enrolled in this study could not tolerate the standard dose used[35]. These results are against incorporating Sorafenib in the guidelines as an appropriate adjuvant treatment option after resection[6].

erior to placebo when it comes to OS, recurrence-free survival or time to recurrence[35]. Unfortunately, many patients enrolled in this study could not tolerate the standard dose used[35]. These results are against incorporating Sorafenib in the guidelines as an appropriate adjuvant treatment option after resection[6]. SORAFENIB AND LIVER TRANSPLANTATION Another curative treatment, especially for patients within the Milan criteria is orthotopic liver transplantation[36]. The challenges involved in liver transplantation, such as graft availability, have led to the increased use of grafts, including split grafts or those from living donors or from marginal donors. However, sometimes the delay between joining the waiting list and actually having a liver transplant may be quite significant, leading to patients dropping off the list[37]. Consequently, those patients with HCC waiting for a liver donor for at least six months are recommended to receive the so called “bridging therapy”, which mainly consists of locoregional treatment approaches, such as radiofrequency ablation (RFA) or transarterial chemoembolization (TACE)[6]. The rationale of “bridging” is entirely understandable when trying to prevent tumor progression in cirrhotic patients with HCC, who patiently wait a suitable donor organ to become available. An alternative strategy is down-staging of HCC patients outside the Milan criteria, in an effort to make them eligible for transplantation. A legitimate question is whether Sorafenib has an adjuvant role in this endeavor.

ion in cirrhotic patients with HCC, who patiently wait a suitable donor organ to become available. An alternative strategy is down-staging of HCC patients outside the Milan criteria, in an effort to make them eligible for transplantation. A legitimate question is whether Sorafenib has an adjuvant role in this endeavor. This neoadjuvant use of Sorafenib for down-staging comes with little evidence not demonstrating any significant advantages, even though some cases seem to accomplish reduction in the tumor boarder, down-staging and therefore allowing the patient to be added to the waiting list[38,39]. All-in-all, Sorafenib has shown a safe profile, when used before transplantation, with insignificant post-operative negative events[40,41]. Besides, the Sorafenib-driven hypoxia, because of its antiangiogenic effects, is thought to result in alterations in molecular mechanisms and growth factors, thus allowing the tumor to develop resistance and become more invasive or even metastatic[42]. Until more convincing data is reported from large clinical trials, the use of Sorafenib in this setting should be limited to investigational protocols.

ught to result in alterations in molecular mechanisms and growth factors, thus allowing the tumor to develop resistance and become more invasive or even metastatic[42]. Until more convincing data is reported from large clinical trials, the use of Sorafenib in this setting should be limited to investigational protocols. On the other hand, the post-operative adjuvant use of Sorafenib has proven to be inefficient (STORM trial)[35], but when it comes to post-transplantation, results may be different. Specifically, a lot of studies agree with the fact that the use of Sorafenib, either concomitantly with mammalian target of rapamycin (mTOR) inhibitors or without them, can improve the survival when used for recurrent disease after liver transplantation, with the disadvantage of some drug-induced toxicity leading to a decrease in the dosage or even cessation of treatment[43-50]. As a matter of fact, Sorafenib has also resulted in complete remission of recurrent HCC after liver transplantation[51]. In general its use in this setting is thought to be safe[52]. Alltogether, current evidence is not favorable regarding the adjuvant use of sorafenib either pre- or post-transplantation and more research on this particular topic needs to take place, especially in the form of randomized controlled trials[53].

On the other hand, the post-operative adjuvant use of Sorafenib has proven to be inefficient (STORM trial)[35], but when it comes to post-transplantation, results may be different. Specifically, a lot of studies agree with the fact that the use of Sorafenib, either concomitantly with mammalian target of rapamycin (mTOR) inhibitors or without them, can improve the survival when used for recurrent disease after liver transplantation, with the disadvantage of some drug-induced toxicity leading to a decrease in the dosage or even cessation of treatment[43-50]. As a matter of fact, Sorafenib has also resulted in complete remission of recurrent HCC after liver transplantation[51]. In general its use in this setting is thought to be safe[52]. Alltogether, current evidence is not favorable regarding the adjuvant use of sorafenib either pre- or post-transplantation and more research on this particular topic needs to take place, especially in the form of randomized controlled trials[53]. SORAFENIB AND LOCOREGIONAL THERAPIES Current guidelines suggest the implementation of transarterial TACE in patients with intermediate stage HCC, consisting of multiple nodules, presenting without symptoms, invasion of the vessels or metastases and without advanced liver disease[6]. Although TACE can be helpful and efficient in this particular group of patients by improving survival[4], it is classified as a palliative option because it cannot achieve complete necrosis of the tumor and is associated with increased recurrent disease and tumor proliferation[54]. This tumor growth is also promoted by the ischemic area appearing after treatment with TACE, and owes its existence to the overexpression of certain growth factors, with VEGF playing a major role[55,56]. VEGF’s place in this equation lies on the side of tumor progression and metastasis and thus Sorafenib can be the ideal agent to deal with this process and impede angiogenesis, while simultaneously supplementing the promising action of TACE by eliminating the possibilities of future proliferation or recurrence[57].

56]. VEGF’s place in this equation lies on the side of tumor progression and metastasis and thus Sorafenib can be the ideal agent to deal with this process and impede angiogenesis, while simultaneously supplementing the promising action of TACE by eliminating the possibilities of future proliferation or recurrence[57]. Some phase 2 studies[58,59] evaluating the concurrent use of TACE and Sorafenib in patients with HCC not amenable to resection have shown a fairly safe profile for this combination with encouraging results regarding the efficacy and toxicity. When this duet was compared to TACE plus placebo in intermediate stage HCC on the background of HCV infection, it greatly improved time to tumor progression, without any unforeseen adverse events[60]. The comparison mentioned above was also assessed in a meta-analysis of six studies (1254 patients) reassuring that TACE plus sorafenib in either intermediate or advanced stage HCC patients can increase OS, time to tumor progression, as well as objective response rate, while the risk of side effects is also high[61]. Other recent meta-analyses, however, evaluating the marriage of Sorafenib and TACE for unresectable HCC showed an improvement in time to tumor progression, but not in OS[62,63]. It should also be mentioned that Sorafenib has been assessed in combination with drug-eluting beads (DEB)-TACE, an alternative method of delivering regional chemotherapy with minimal systemic exposure, for the management of both intermediate and advanced stage HCC. The results proved the increased efficacy and safety of this strategy[57].

ntioned that Sorafenib has been assessed in combination with drug-eluting beads (DEB)-TACE, an alternative method of delivering regional chemotherapy with minimal systemic exposure, for the management of both intermediate and advanced stage HCC. The results proved the increased efficacy and safety of this strategy[57]. Another important issue is that of the time of TACE and Sorafenib administration, for which three different options have been suggested: (1) TACE is followed by antiangiogenic therapy; (2) continuous antiangiogenic treatment interrupted only for the moment of TACE administration; and (3) continuous antiangiogenic therapy with no interruption at the moment of TACE administration[64]. Although the first two options are superior regarding the risk of bleeding, which is reduced, the third eliminates the possibilities of VEGF increase after TACE. In general, it appears that Sorafenib plus TACE can lead to improved clinical results, especially regarding the intermediate stage HCC, mainly consisting of a highly heterogeneous group of patients for whom the overall approach is still to be defined based on several ongoing studies[57,65].

Another important issue is that of the time of TACE and Sorafenib administration, for which three different options have been suggested: (1) TACE is followed by antiangiogenic therapy; (2) continuous antiangiogenic treatment interrupted only for the moment of TACE administration; and (3) continuous antiangiogenic therapy with no interruption at the moment of TACE administration[64]. Although the first two options are superior regarding the risk of bleeding, which is reduced, the third eliminates the possibilities of VEGF increase after TACE. In general, it appears that Sorafenib plus TACE can lead to improved clinical results, especially regarding the intermediate stage HCC, mainly consisting of a highly heterogeneous group of patients for whom the overall approach is still to be defined based on several ongoing studies[57,65]. SORAFENIB AND OTHER CHEMOTHERAPEUTIC DRUGS Sorafenib and hypoxia-inducible factor-1a inhibitors Locoregional treatment modalities can be efficient when it comes to HCC, but up to a point. Radiofrequency and microwave ablation trigger hypoxia and consequently hypoxia-induced angiogenesis, thus increasing the possibility of HCC recurrence. This process is primarily mediated by the hypoxia-inducible factor (HIF)-1a/vascular endothelial growth factor-A (VEGF-A) pathway, which can be impeded by Sorafenib[66]. Therefore, Sorafenib has been shown to limit the tumor’s invasive nature in vitro, a result of the cobalt chloride’s increase of the expression of HIF-1a, and to reduce proliferation and promote apoptosis in HCC cells[66].

-1a/vascular endothelial growth factor-A (VEGF-A) pathway, which can be impeded by Sorafenib[66]. Therefore, Sorafenib has been shown to limit the tumor’s invasive nature in vitro, a result of the cobalt chloride’s increase of the expression of HIF-1a, and to reduce proliferation and promote apoptosis in HCC cells[66]. 2-Methoxyestradiol (2ME2), an inactive end product of estrogen metabolism, has recently been proven to have an antitumor effect by inhibiting proliferation and angiogenesis and by promoting apoptosis in many cancer types and especially in HCC[67]. The most important mechanism 2ME2 acts is through the inhibition of HIF-1 and the down-regulation of the HIF-driven VEGF expression[68]. It has been shown that 2ME2 comes up with synergistic effects in combination with Sorafenib in accordance to HCC suppression and antiangiogenesis, effects mostly driven be HIF-1 and -2 deregulation[69]. Sorafenib and mTOR inhibitors mTOR, a protein kinase, plays a key role in cell growth, proliferation, angiogenesis and metabolism in several cancers, including HCC[70]. It represents the target of rapamycin and its analogues, as well as Everolimus and Sirolimus, which present with an antitumor profile through the down-regulation of hypoxia-inducible factor, thus resulting in low VEGF and PDGF expression.

proliferation, angiogenesis and metabolism in several cancers, including HCC[70]. It represents the target of rapamycin and its analogues, as well as Everolimus and Sirolimus, which present with an antitumor profile through the down-regulation of hypoxia-inducible factor, thus resulting in low VEGF and PDGF expression. Everolimus has been evaluated in a phase 1/2 study in patients with advanced stage HCC, who were previously treated with systemic therapy, and has shown encouraging results in terms of tolerability and efficacy[71]. However, when Everolimus was combined with Sorafenib, again in a phase 1 trial, so that its maximum tolerated dose (MTD) could be determined, the results were disappointing regarding its efficacy in the MTD[72]. In addition, a randomized clinical trial (EVOLVE-1)[73] assessing the use of Everolimus in patients with advanced HCC, who presented with tumor progression during or after taking Sorafenib or who showed limited tolerability towards Sorafenib, reported no increase in OS. On the other hand, the significant immunosuppressive role of mTOR inhibitors has been used in combination with Sorafenib vs Sorafenib alone in cases of post-transplantation late recurrent HCC, thus highlighting the broadening of the horizons in the treatment options against HCC towards the direction of personalized molecular targeted therapy[74]. Besides, cohort studies[46,49] assessing the combination of Sorafenib and mTOR inhibitors in the same disease context showed improved survival, but with some serious adverse events.

the broadening of the horizons in the treatment options against HCC towards the direction of personalized molecular targeted therapy[74]. Besides, cohort studies[46,49] assessing the combination of Sorafenib and mTOR inhibitors in the same disease context showed improved survival, but with some serious adverse events. As a result, it is suggested that further studies are carried out, so as to evaluate the combination of mTOR inhibitors with Sorafenib in terms of achieving the maximum possible synergy and the minimum possible toxicity overlap. Sorafenib and PI3K/AKT inhibitors Despite the blockade of the Raf/MEK/ERK cascade by Sorafenib, HCC has remarkable compensation through the over-expression of several other pro-survival pathways. The phosphoinositide 3-kinase (PI3K)/AKT pathway comes into play here as one of those and data state that it can render the tumor less susceptible to Sorafenib[75]. Thus, synergy may result from the combination of Sorafenib with a PI3K/AKT inhibitor, such as PKI-587 which simultaneously blocks the mTOR pathway, and this significant additive inhibitory effect has been proven in liver cancer stem cell patterns[76].

tate that it can render the tumor less susceptible to Sorafenib[75]. Thus, synergy may result from the combination of Sorafenib with a PI3K/AKT inhibitor, such as PKI-587 which simultaneously blocks the mTOR pathway, and this significant additive inhibitory effect has been proven in liver cancer stem cell patterns[76]. Sorafenib and WNT/B-catenin inhibitors The complexity of the molecular mechanisms involved in the multistep process of tumor growth in HCC has been shown to incorporate mutations in the Wnt/β-catenin pathway as well[77]. Therefore, it is possible that the Wnt/β-catenin pathway represents a novel target for systemic treatment in HCC and as such it may also show an additive effect when used concurrently with Sorafenib. Indeed, not only has Sorafenib been able to down-regulate this pathway in different models[78], but also FH535, a Wnt/β-catenin inhibitor, was found to impede tumor growth of HCC and hepatoblastoma[79,80]. Moreover, when Sorafenib was combined with FH535, their synergistic effect on inhibiting the proliferation of HCC was more significant[81,82].

ib been able to down-regulate this pathway in different models[78], but also FH535, a Wnt/β-catenin inhibitor, was found to impede tumor growth of HCC and hepatoblastoma[79,80]. Moreover, when Sorafenib was combined with FH535, their synergistic effect on inhibiting the proliferation of HCC was more significant[81,82]. Sorafenib and MEK inhibitors The MAPK/ERK kinases (MEK) 1 and 2 can be consequently activated if a Ras mutation shows up, as they are found downstream in the RAS cascade, the activation of which can therefore provide proliferative and antiapoptotic capabilities to the tumor. This “vertical” type of inhibition totally differs from the “parallel” blockade previously described in the mTOR inhibition, in which two unconnected cascades are concurrently inhibited[83]. Interestingly, MEK inhibitors, such as Refametinib (BAY 869766) which is an allosteric MEK 1/2 inhibitor, have proven their efficacy in preclinical HCC models[84]. When combined with Sorafenib in a phase 2 trial, Refametinib was found efficacious, especially in case of Ras mutations, and was well-tolerated[85].

ed[83]. Interestingly, MEK inhibitors, such as Refametinib (BAY 869766) which is an allosteric MEK 1/2 inhibitor, have proven their efficacy in preclinical HCC models[84]. When combined with Sorafenib in a phase 2 trial, Refametinib was found efficacious, especially in case of Ras mutations, and was well-tolerated[85]. Sorafenib and JAK/STAT inhibitors The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway plays an important part as a signal transduction cascade, with several proteins of the STAT family participating in cell growth, immunity and survival[86]. The one with the most significant role in oncogenesis is STAT3[87]. This STAT3 protein is key in modulating sensitization of HCC in recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), an antitumor drug with encouraging efficacy[88]. When Sorafenib was combined with TRAIL, it decreased the expression of STAT3 and proteins involved in its actions, thus rendering, the previously resistant to TRAIL, HCC susceptible to TRAIL-induced apoptosis[88]. Besides, Sorafenib targets STAT3 in a kinase-independent manner in patients with HCC[88,89].

efficacy[88]. When Sorafenib was combined with TRAIL, it decreased the expression of STAT3 and proteins involved in its actions, thus rendering, the previously resistant to TRAIL, HCC susceptible to TRAIL-induced apoptosis[88]. Besides, Sorafenib targets STAT3 in a kinase-independent manner in patients with HCC[88,89]. In addition, the SH2 domain-containing tyrosine phosphatases family (SHP-1 and SHP-2), which are included in the family of protein tyrosine phosphatases (PTP), consist of two Src Homology (SH) 2 domains just as their name indicates[90]. These phosphatases dephosphorylate STAT3, leading to a significant decrease in its activation[91] and as a result they represent a potential target for systemic treatment of HCC. In fact, SHP-1 is a target of Sorafenib and through conformational modifications and signaling pathways, in which STAT3 is also involved, Sorafenib can also exhibit its anti-HCC effect[92]. However, we have already experienced the evolution of Sorafenib through its derivatives, such as SC-43 and SC-40, which are potent SHP-1 agonists and have proven to be superior to Sorafenib for the management of HCC[92]. Another novel derivative of Sorafenib, SC-59, when combined with radiotherapy has also shown to be superior to Sorafenib for treating HCC and its actions are mediated through STAT3 inhibition[93]. Last but not least, the synergistic combination of Sorafenib with SC-43, through their SHP-1 agonist effects, has been found efficacious, as it decreased tumor size and improved survival in preclinical models[94].

wn to be superior to Sorafenib for treating HCC and its actions are mediated through STAT3 inhibition[93]. Last but not least, the synergistic combination of Sorafenib with SC-43, through their SHP-1 agonist effects, has been found efficacious, as it decreased tumor size and improved survival in preclinical models[94]. Sorafenib and phytochemicals Data from preclinical models indicate that dietary phytochemicals with anti-inflammatory, antioxidant and antineoplastic characteristics may reduce the risk of HCC. Curcumin is a yellow polyphenol derived from turmeric and has been shown to be protective against HCC caused by aflatoxins in mice[95]. Due to its solubility issues, polymeric nanoparticle formations of curcumin (NFC) have been developed and it is reported that the use of NFC alone or in combination with Sorafenib presents with remarkable findings regarding the suppression of tumor proliferation and invasiveness of HCC, as well as that of lung metastases[96]. Resveratrol is also a dietary polyphenol, mostly present in grapes, berries, peanuts and red wine, and has appeared as a promising chemopreventive agent against liver cancer[97]. The combination of Resveratrol and Sorafenib can lead to apoptosis and reduced tumor growth in HCC mice by fighting the diverted metabolic phenotype of aerobic glycolysis[98].

phenol, mostly present in grapes, berries, peanuts and red wine, and has appeared as a promising chemopreventive agent against liver cancer[97]. The combination of Resveratrol and Sorafenib can lead to apoptosis and reduced tumor growth in HCC mice by fighting the diverted metabolic phenotype of aerobic glycolysis[98]. Indole-3-carbinol (I3C), found in cruciferous vegetables, is also one of the phytochemicals that have recently emerged with antineoplastic and antiangiogenic properties[99]. Specifically, its combined use with sorafenib has shown synergy by increasing the latter’s cytotoxicity and antiangiogenic properties, by promoting cell cycle arrest and apoptosis, as well as by reducing the expression of p-Akt, HIF-1a, VEGF and EGFR in HCC cells[99]. Regorafenib: A new era Several antiangiogenic drugs with the same antiangiogenic capabilities as Sorafenib have been developed over time for the management of HCC, mostly as second-line systemic therapy agents.

Indole-3-carbinol (I3C), found in cruciferous vegetables, is also one of the phytochemicals that have recently emerged with antineoplastic and antiangiogenic properties[99]. Specifically, its combined use with sorafenib has shown synergy by increasing the latter’s cytotoxicity and antiangiogenic properties, by promoting cell cycle arrest and apoptosis, as well as by reducing the expression of p-Akt, HIF-1a, VEGF and EGFR in HCC cells[99]. Regorafenib: A new era Several antiangiogenic drugs with the same antiangiogenic capabilities as Sorafenib have been developed over time for the management of HCC, mostly as second-line systemic therapy agents. In case of failure to respond to Sorafenib, patients with HCC can be treated with another multikinase inhibitor, Regorafenib[100]. The addition of a fluorine atom in the central phenyl ring of Sorafenib transforms Regorafenib into an agent with increased potency[101]. A phase 2 study evaluating Regorafenib for intermediate or advanced HCC in patients that had previously received Sorafenib reported encouraging results, such as an OS of 13.8 mo, a safety profile similar to Sorafenib and no deaths attributed to Regorafenib[102]. Recently, in July 2016, at the ESMO World Congress on Gastrointestinal Cancer in Barcelona findings from a phase 3 trial (RESORCE, NCT01774344) assessing Regorafenib in HCC patients, who received prior therapy with Sorafenib, exhibited a remarkable increase in median OS for those treated with Regorafenib vs those receiving placebo as a second-line agent after radiologic progression under Sorafenib (10.6 vs 7.8)[103].

from a phase 3 trial (RESORCE, NCT01774344) assessing Regorafenib in HCC patients, who received prior therapy with Sorafenib, exhibited a remarkable increase in median OS for those treated with Regorafenib vs those receiving placebo as a second-line agent after radiologic progression under Sorafenib (10.6 vs 7.8)[103]. Almost a decade has passed with numerous clinicians and scientists getting negative results in trials for systemic therapy in HCC patients, while the RESORCE trial is the only one after the SHARP trial to come forward with positive findings. The most important causes of those negative results are: (1) the heterogeneity among the HCC patients recruited and the lack of selection criteria based on molecular patterns; and (2) the imbalance between adverse events and tolerable dosage vs anticancer efficiency and drug potency of the tested agents. Current advances in medicine and biology will improve our knowledge regarding the different and complex molecular mechanisms and driving mutations involved in this vast heterogeneity of this unique and multidimensional type of cancer and will guide us towards the right direction of conducting successful trials in the near future [104].

in medicine and biology will improve our knowledge regarding the different and complex molecular mechanisms and driving mutations involved in this vast heterogeneity of this unique and multidimensional type of cancer and will guide us towards the right direction of conducting successful trials in the near future [104]. CONCLUSION Sorafenib represents a type of medicinal revolution, therefore making antiangiogenesis drugs a feasible choice when it comes to dealing with cancer and opening the road for personalized targeted therapy. Currently, Sorafenib is the only accepted treatment for systemic therapy, as it has shown to increase the OS in patients suffering from advanced HCC, but with liver disease of early stage with tolerable adverse effects. Recently, studies show that Sorafenib is also safe in patients with advanced liver disease as well, but neither adequately efficient, nor cost-effective. Thus, ongoing studies (i.e., BOOST trial) are going to define its role in decompensated population in the future and up until then, patient selection in patients treated with Sorafenib is critical.

afenib is also safe in patients with advanced liver disease as well, but neither adequately efficient, nor cost-effective. Thus, ongoing studies (i.e., BOOST trial) are going to define its role in decompensated population in the future and up until then, patient selection in patients treated with Sorafenib is critical. All-in-all, Sorafenib has evolved through time by being evaluated in several treatment protocols either as a neoadjuvant or as an adjuvant agent. Its use prior to or after liver transplantation has demonstrated a range of some minor advantages to even complete remission of recurrence, while preserving an acceptable safety profile. Still, a lot of research is needed in this field, as Sorafenib’s role post-resection was not that much promising, while its combination with TACE showed encouraging results. Overall, understanding the molecular mechanisms of HCC and Sorafenib, as well as those resulting from the implementation of other treatment methods, will guide us to the future development of combinations involving Sorafenib, agents with higher efficacy that derive from Sorafenib or even second-line agents that will complement the therapeutic role that Sorafenib could not accomplish by itself. Conflict-of-interest statement: Authors declare no conflict of interests for this article. Manuscript source: Invited manuscript Specialty type: Oncology Country of origin: Greece Peer-review report classification Grade A (Excellent): A, A, A Grade B (Very good): B Grade C (Good): 0 Grade D (Fair): 0 Grade E (Poor): 0 Peer-review started: February 10, 2017 First decision: March 27, 2017

Conflict-of-interest statement: Authors declare no conflict of interests for this article. Manuscript source: Invited manuscript Specialty type: Oncology Country of origin: Greece Peer-review report classification Grade A (Excellent): A, A, A Grade B (Very good): B Grade C (Good): 0 Grade D (Fair): 0 Grade E (Poor): 0 Peer-review started: February 10, 2017 First decision: March 27, 2017 Article in press: April 25, 2017 P- Reviewer: El-Shemi AG, Ungtrakul T, Vetvicka V, Yamagata M S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ