The tumor response was evaluated only in 16 patients, but tumor regression had not been recorded. provides low awareness to chemotherapy that’s in great component due to multidrug level of resistance. Immunotherapy for HCC is certainly a new complicated treatment choice and involves immune system checkpoint inhibitors/antibody-based therapy and peptide-based vaccines. Another complicated approach is certainly microRNA-based therapy which involves two strategies. The initial seeks to inhibit oncogenic miRNAs through the use of miRNA antagonists and the next strategy is certainly miRNA replacement, that involves the reintroduction of the tumor-suppressor miRNA mimetic to revive a lack of function. is certainly a metabolic regulator gene owned by the hormone-like FGF category of sign molecules, and NUDT15 works simply because an oncogenic drivers in HCC.58C60 Gao et al discovered that is vital for sorafenib resistance and efficacy in the treating HCC.61 The authors possess confirmed that elevated expression or hyperactivation of FGF19/FGFR4 signaling in HCC cells is among the primary Atrial Natriuretic Factor (1-29), chicken mechanisms of sorafenib resistance.61 In the same research, it had been shown that blocking FGF19/FGFR4 axis by ponatinib, the third-generation tyrosineCkinase inhibitor, can overcome the level of resistance of HCC cells to sorafenib by improving reactive air species-associated apoptosis.61 These and equivalent research may provide the foundation for developing treatment ways of prevent single-drug level of resistance. Inhibition of FGF19/FGFR4 signaling is among the possible approaches for conquering sorafenib level of resistance in HCC. Molecular targeted therapy Sorafenib Sorafenib Atrial Natriuretic Factor (1-29), chicken is certainly a molecular multikinase inhibitor of many tyrosine proteins kinases (VEGFR and PDGFR); Raf kinases (C-Raf and B-Raf); and intracellular serine/threonine kinases (C-Raf, wild-type B-Raf, and mutant B-Raf)62C64 (Desk 1). This is actually the initial molecular targeted agent that confirmed survival advantage in nonresectable HCC sufferers.28,29 Sorafenib induces autophagy which suppresses tumor growth.65 Desk 1 Overview of sorafenib, tivantinib, and regorafenib mechanism of action, impact, and unwanted effects
SorafenibMultikinase inhibitor of:
C several tyrosine protein kinases (VEGFR and PDGFR)
C Raf kinases (C-Raf and B-Raf)
C intracellular serine/threonine kinases (C-Raf, wild-type B-Raf, and mutant B-Raf)Tumor growth suppression by autophagyC Gastrointestinal (diarrhea, increased lipase, increased amylase, nausea, anorexia, vomiting, and constipation)
C Dermatologic (rash/desquamation, handCfoot epidermis reaction, alopecia, pruritus, and dry epidermis)
C Cardiovascular (hypertension, angioedema, and congestive heart failure)
C Hematologic (hypoalbuminemia, hemorrhage, anemia, and thrombocytopenia)
C Nervous program (neuropathy and headache)TivantinibHighly selective inhibitor of c-MET receptor tyrosine kinaseC Promotes apoptosis and cell growth arrest
C Cytotoxic activity, even in cells that absence c-MET
C Activation of cyclin B1 and inhibition of microtubuleC Hematologic toxicity (neutropenia, anemia, and leukopenia)
C Exhaustion, nausea, and vomitingRegorafenibMultikinase inhibitor of VEGFR1-3, c-KIT, Link-2, PDGFR-, FGFR-1, RET, c-RAF, BRAF, and p38 MAP kinaseAnti-angiogenic activityHandCfoot epidermis reaction, diarrhea, fatigue, hypothyroidism, anorexia, hypertension, nausea, and voice shifts Open in another window Both milestone studies established sorafenib, as cure of preference for HCC sufferers with ECOG PS of just one one or two 2 and/or macrovascular invasion or extrahepatic spread based on the EASLCEORTC guidelines.21,28,29 The findings of SHARP/Phase III trial conducted under western culture have demonstrated extended median survival from 7.9 months (placebo group) to 10.7 months (sorafenib group) (hazard rate [HR]=0.69; 95% CI: 0.55C0.87; p=0.00058).28 Sorafenib also improved enough time to radiological development (from 2.8 months to 5.5 months).28 The full total benefits of another Phase III trial, Asia-Pacific trial, have demonstrated a median overall survival of 6.5 months for cure group in comparison to 4.2 months to get a placebo group (HR =0.68; 95% CI: 0.50C0.93; p=0.014)29 (Desk 2). Desk 2 Overview of sorafenib, tivantinib, and regorafenib scientific final results
SorafenibProlonged median success from 7.9 months (placebo group) to 10.7 months (sorafenib group)28 Median overall survival of 6.5 months for sorafenib group in comparison to 4.2 months to get a placebo group29TivantinibSurvival benefit in sufferers with advanced HCC who’ve.Serious immune-mediated AEs weren’t recorded. low awareness to chemotherapy that’s in great component due to multidrug level of resistance. Immunotherapy for HCC is certainly a new complicated treatment choice and involves immune system checkpoint inhibitors/antibody-based Atrial Natriuretic Factor (1-29), chicken therapy and peptide-based vaccines. Another complicated approach is certainly microRNA-based therapy which involves two strategies. The initial seeks to inhibit oncogenic miRNAs through the use of miRNA antagonists and the next strategy is certainly miRNA replacement, that involves the reintroduction of the tumor-suppressor miRNA mimetic to revive a lack of function. is certainly a metabolic regulator gene owned by the hormone-like FGF category of sign molecules, and works simply because an oncogenic drivers in HCC.58C60 Gao et al discovered that is vital for sorafenib efficacy and resistance in the treating HCC.61 The authors possess confirmed that elevated expression or hyperactivation of FGF19/FGFR4 signaling in HCC cells is among the primary mechanisms of sorafenib resistance.61 In the same research, it had been shown that blocking FGF19/FGFR4 axis by ponatinib, the third-generation tyrosineCkinase inhibitor, can overcome the level of resistance of HCC cells to sorafenib by improving reactive air species-associated apoptosis.61 These and equivalent studies might provide the foundation for developing treatment ways of prevent single-drug level of resistance. Inhibition of FGF19/FGFR4 signaling is among the possible approaches for conquering sorafenib level of resistance in HCC. Molecular targeted therapy Sorafenib Sorafenib is certainly a molecular multikinase inhibitor of many tyrosine protein kinases (VEGFR and PDGFR); Raf kinases (C-Raf and B-Raf); and intracellular serine/threonine kinases (C-Raf, wild-type B-Raf, and mutant B-Raf)62C64 (Table 1). This is the first molecular targeted agent that demonstrated survival benefit in nonresectable HCC patients.28,29 Sorafenib induces autophagy which in turn suppresses tumor growth.65 Table 1 Summary of sorafenib, tivantinib, and regorafenib mechanism of action, effect, and side effects
SorafenibMultikinase inhibitor of:
C several tyrosine protein kinases (VEGFR and PDGFR)
C Raf kinases (C-Raf and B-Raf)
C intracellular serine/threonine kinases (C-Raf, wild-type B-Raf, and mutant B-Raf)Tumor growth suppression by autophagyC Gastrointestinal (diarrhea, increased lipase, increased amylase, nausea, anorexia, vomiting, and constipation)
C Dermatologic (rash/desquamation, handCfoot skin reaction, alopecia, pruritus, and dry skin)
C Cardiovascular (hypertension, angioedema, and congestive heart failure)
C Hematologic (hypoalbuminemia, hemorrhage, anemia, and thrombocytopenia)
C Nervous system (neuropathy and headache)TivantinibHighly selective inhibitor of c-MET receptor tyrosine kinaseC Promotes apoptosis and cell growth arrest
C Cytotoxic activity, even in cells that lack c-MET
C Activation of cyclin B1 and inhibition of microtubuleC Hematologic toxicity (neutropenia, anemia, and leukopenia)
C Fatigue, nausea, and vomitingRegorafenibMultikinase inhibitor of VEGFR1-3, c-KIT, TIE-2, PDGFR-, FGFR-1, RET, c-RAF, BRAF, and p38 MAP kinaseAnti-angiogenic activityHandCfoot skin reaction, diarrhea, fatigue, hypothyroidism, anorexia, hypertension, nausea, and voice changes Open in a separate window The two milestone studies have established sorafenib, as a treatment of choice for HCC patients with ECOG PS of 1 1 or 2 2 and/or macrovascular invasion or extrahepatic spread according to the EASLCEORTC guidelines.21,28,29 The findings of SHARP/Phase III trial conducted in the Western world have demonstrated prolonged median survival from 7.9 months (placebo group) to 10.7 months (sorafenib group) (hazard rate [HR]=0.69; 95% CI: 0.55C0.87; p=0.00058).28 Sorafenib also improved the time to radiological progression (from 2.8 months to 5.5 months).28 The results of another Phase III trial, Asia-Pacific trial, have demonstrated a median overall survival of 6.5 months for a treatment group compared to 4.2 months for a placebo group (HR =0.68; 95% CI: 0.50C0.93; p=0.014)29 (Table 2). Table 2 Summary of sorafenib, tivantinib, and regorafenib clinical outcomes
SorafenibProlonged median survival from 7.9 months (placebo group) to 10.7 months (sorafenib group)28 Median overall survival of 6.5 months for sorafenib group compared to 4.2 months for a placebo group29TivantinibSurvival benefit in patients with advanced HCC who have failed or are intolerant to sorafenibRegorafenibOnly systemic treatment found to provide survival benefit in HCC patients progressing on sorafenib treatment106 Open in a separate window Abbreviation: HCC, hepatocellular carcinoma. At the beginning, sorafenib was introduced as.In the upcoming months, data of several ongoing first-line and second-line trials will become available and might further change the care of patients with advanced HCC. Footnotes Disclosure The authors report no conflicts of interest in this work.. miRNA antagonists and the second strategy is miRNA replacement, which involves the reintroduction of a tumor-suppressor miRNA mimetic to restore a loss of function. is a metabolic regulator gene belonging to the hormone-like FGF family of signal molecules, and acts as an oncogenic driver in HCC.58C60 Gao et al found that is essential for sorafenib efficacy and resistance in the treatment of HCC.61 The authors have demonstrated that elevated expression or hyperactivation of FGF19/FGFR4 signaling in HCC cells is one of the main mechanisms of sorafenib resistance.61 In the same study, it was shown that blocking FGF19/FGFR4 axis by ponatinib, the third-generation tyrosineCkinase inhibitor, can overcome the resistance of HCC cells to sorafenib by enhancing reactive oxygen species-associated apoptosis.61 These and similar studies may provide the basis for developing treatment strategies to prevent single-drug resistance. Inhibition of FGF19/FGFR4 signaling is one of the possible strategies for overcoming sorafenib resistance in HCC. Molecular targeted therapy Sorafenib Sorafenib is a molecular multikinase inhibitor of several tyrosine protein kinases (VEGFR and PDGFR); Raf kinases (C-Raf and B-Raf); and intracellular serine/threonine kinases (C-Raf, wild-type B-Raf, and mutant B-Raf)62C64 (Table 1). This is the first molecular targeted agent that demonstrated survival benefit in nonresectable HCC patients.28,29 Sorafenib induces autophagy which in turn suppresses tumor growth.65 Table 1 Summary of sorafenib, tivantinib, and regorafenib mechanism of action, effect, and side effects
SorafenibMultikinase inhibitor of:
C several tyrosine protein kinases (VEGFR and PDGFR)
C Raf kinases (C-Raf and B-Raf)
C intracellular serine/threonine kinases (C-Raf, wild-type B-Raf, and mutant B-Raf)Tumor growth suppression by autophagyC Gastrointestinal (diarrhea, increased lipase, increased amylase, nausea, anorexia, vomiting, and constipation)
C Dermatologic (rash/desquamation, Atrial Natriuretic Factor (1-29), chicken handCfoot skin reaction, alopecia, pruritus, and dry skin)
C Cardiovascular (hypertension, angioedema, and congestive heart failure)
C Hematologic (hypoalbuminemia, hemorrhage, anemia, and thrombocytopenia)
C Nervous system (neuropathy and headache)TivantinibHighly selective inhibitor of c-MET receptor tyrosine kinaseC Promotes apoptosis and cell growth arrest
C Cytotoxic activity, even in cells that lack c-MET
C Activation of cyclin B1 and inhibition of microtubuleC Hematologic toxicity (neutropenia, anemia, and leukopenia)
C Fatigue, nausea, and vomitingRegorafenibMultikinase inhibitor of VEGFR1-3, c-KIT, TIE-2, PDGFR-, FGFR-1, RET, c-RAF, BRAF, and p38 MAP kinaseAnti-angiogenic activityHandCfoot skin reaction, diarrhea, fatigue, hypothyroidism, anorexia, hypertension, nausea, and voice changes Open in a separate window The two milestone studies have established sorafenib, as a treatment of choice for HCC patients with ECOG PS of 1 1 or 2 2 and/or macrovascular invasion or extrahepatic spread according to the EASLCEORTC guidelines.21,28,29 The findings of SHARP/Phase III trial conducted in the Western world have demonstrated prolonged median survival from 7.9 months (placebo group) to 10.7 months (sorafenib group) (hazard rate [HR]=0.69; 95% CI: 0.55C0.87; p=0.00058).28 Sorafenib also improved the time to radiological progression (from 2.8 months to 5.5 months).28 The results of another Phase III trial, Asia-Pacific trial, have demonstrated a median overall survival of 6.5 months for a treatment group compared to 4.2 months for a placebo group (HR =0.68; 95% CI: 0.50C0.93; p=0.014)29 (Table 2). Table 2 Summary of sorafenib, tivantinib, and regorafenib clinical outcomes
SorafenibProlonged median success from 7.9 months (placebo group) to 10.7 months (sorafenib group)28 Median overall survival of 6.5 months for sorafenib group in comparison to 4.2 months for the placebo group29TivantinibSurvival benefit in sufferers with advanced HCC who’ve failed or are intolerant to sorafenibRegorafenibOnly systemic treatment found to supply survival benefit in HCC sufferers progressing on sorafenib treatment106 Open up in another window Abbreviation: HCC, hepatocellular carcinoma. At the start, sorafenib was presented being a well-tolerated medication. However, a subanalysis from the Asia-Pacific and Clear studies and outcomes of various other research show suboptimal tolerability of sorafenib; it had been down-dosed in >50% sufferers and interrupted in 45% of sufferers due to serious adverse occasions (AEs) or affected liver organ function.28,29,66C68 Based on the outcomes of several research, the main unwanted effects are gastrointestinal (diarrhea 43%, increased lipase 41%, increased amylase 30%, nausea 23%, anorexia 16%, vomiting 16%, and constipation 15%), dermatologic (rash/desquamation 40%,.These total results suggest feasible resistance to sorafenib in metformin-treated patients.82 The possible usage of sorafenib in adjuvant settings was assessed in the Surprise trial. using miRNA antagonists and the next strategy is normally miRNA replacement, that involves the reintroduction of the tumor-suppressor miRNA mimetic to revive a lack of function. is normally a metabolic regulator gene owned by the hormone-like FGF category of indication molecules, and serves simply because an oncogenic drivers in HCC.58C60 Gao et al discovered that is vital for sorafenib efficacy and resistance in the treating HCC.61 The authors possess confirmed that elevated expression or hyperactivation of FGF19/FGFR4 signaling in HCC cells is among the primary mechanisms of sorafenib resistance.61 In the same research, it had been shown that blocking FGF19/FGFR4 axis by ponatinib, the third-generation tyrosineCkinase inhibitor, can overcome the level of resistance of HCC cells to sorafenib by improving reactive air species-associated apoptosis.61 These and very similar studies might provide the foundation for developing treatment ways of prevent single-drug level of resistance. Inhibition of FGF19/FGFR4 signaling is among the possible approaches for conquering sorafenib level of resistance in HCC. Molecular targeted therapy Sorafenib Sorafenib is normally a molecular multikinase inhibitor of many tyrosine proteins kinases (VEGFR and PDGFR); Raf kinases (C-Raf and B-Raf); and intracellular serine/threonine kinases (C-Raf, wild-type B-Raf, and mutant B-Raf)62C64 (Desk 1). This is actually the initial molecular targeted agent that showed survival advantage in nonresectable HCC sufferers.28,29 Sorafenib induces autophagy which suppresses tumor growth.65 Desk 1 Overview of sorafenib, tivantinib, and regorafenib mechanism of action, impact, and unwanted effects
SorafenibMultikinase inhibitor of:
C several tyrosine protein kinases (VEGFR and PDGFR)
C Raf kinases (C-Raf and B-Raf)
C intracellular serine/threonine kinases (C-Raf, wild-type B-Raf, and mutant B-Raf)Tumor growth suppression by autophagyC Gastrointestinal (diarrhea, increased lipase, increased amylase, nausea, anorexia, vomiting, and constipation)
C Dermatologic (rash/desquamation, handCfoot epidermis reaction, alopecia, pruritus, and dry epidermis)
C Cardiovascular (hypertension, angioedema, and congestive heart failure)
C Hematologic (hypoalbuminemia, hemorrhage, anemia, and thrombocytopenia)
C Nervous program (neuropathy and headache)TivantinibHighly selective inhibitor of c-MET receptor tyrosine kinaseC Promotes apoptosis and cell growth arrest
C Cytotoxic activity, even in cells that absence c-MET
C Activation of cyclin B1 and inhibition of microtubuleC Hematologic toxicity (neutropenia, anemia, and leukopenia)
C Exhaustion, nausea, and vomitingRegorafenibMultikinase inhibitor of VEGFR1-3, c-KIT, Link-2, PDGFR-, FGFR-1, RET, c-RAF, BRAF, and p38 MAP kinaseAnti-angiogenic activityHandCfoot epidermis reaction, diarrhea, fatigue, hypothyroidism, anorexia, hypertension, nausea, and voice shifts Open in another window Both milestone studies established sorafenib, as cure of preference for HCC sufferers with ECOG PS of just one one or two 2 and/or macrovascular invasion or extrahepatic spread based on the EASLCEORTC guidelines.21,28,29 The findings of SHARP/Phase III trial conducted under western culture have demonstrated extended median survival from 7.9 months (placebo group) to 10.7 months (sorafenib group) (hazard rate [HR]=0.69; 95% CI: 0.55C0.87; p=0.00058).28 Sorafenib also improved enough time to radiological development (from 2.8 months to 5.5 months).28 The benefits of another Phase III trial, Asia-Pacific trial, have demonstrated a median overall survival of 6.5 months for cure group in comparison to 4.2 months for the placebo group (HR =0.68; 95% CI: 0.50C0.93; p=0.014)29 (Desk 2). Desk 2 Overview of sorafenib, tivantinib, and regorafenib scientific final results
SorafenibProlonged median survival from 7.9 months (placebo group) to 10.7 months (sorafenib group)28 Median overall survival of 6.5 months for sorafenib group in comparison to 4.2 months for the placebo group29TivantinibSurvival benefit in patients with advanced HCC who’ve failed or are intolerant to sorafenibRegorafenibOnly systemic treatment found to supply survival benefit in HCC patients progressing on sorafenib treatment106 Open in another window Abbreviation: HCC, hepatocellular carcinoma. At the start, sorafenib was introduced being a well-tolerated drug. However, a subanalysis from the SHARP and Asia-Pacific trials and results of other studies show suboptimal tolerability of sorafenib; it had been down-dosed in >50% patients and interrupted in 45% of patients because of severe adverse events (AEs) or compromised liver function.28,29,66C68 Based on the results of several studies, the main unwanted effects are gastrointestinal (diarrhea 43%, increased lipase 41%, increased amylase 30%, nausea 23%, anorexia 16%, vomiting 16%, and constipation 15%), dermatologic (rash/desquamation 40%, handCfoot skin reaction 30%, alopecia 27%, pruritus 19%, and dry skin 11%),.Median time for you to progression for patients receiving sorafenib plus drug-eluting bead (DEB)-TACE or placebo plus DEB-TACE was similar (169 vs 166 days, respectively; HR =0.797, p=0.072).84 Tivantinib Tivantinib (ARQ 197) is a little, mouth, highly selective inhibitor of c-MET receptor tyrosine kinase85 (Desk 1). multidrug level of resistance. Immunotherapy for HCC is normally a new complicated treatment choice and involves immune system checkpoint inhibitors/antibody-based therapy and peptide-based vaccines. Another complicated approach is normally microRNA-based therapy which involves two strategies. The initial aspires to inhibit oncogenic miRNAs through the use of miRNA antagonists and the next strategy is normally miRNA replacement, which involves the reintroduction of a tumor-suppressor miRNA mimetic to restore a loss of function. is usually a metabolic regulator gene belonging to the hormone-like FGF family of transmission molecules, and functions as an oncogenic driver in HCC.58C60 Gao et al found that is essential for sorafenib efficacy and resistance in the treatment of HCC.61 The authors have demonstrated that elevated expression or hyperactivation of FGF19/FGFR4 signaling in HCC cells is one of the main mechanisms of sorafenib resistance.61 In the same study, it was shown that blocking FGF19/FGFR4 axis by ponatinib, the third-generation tyrosineCkinase inhibitor, can overcome the resistance of HCC cells to sorafenib by enhancing reactive oxygen species-associated apoptosis.61 These and similar studies may provide the basis for developing treatment strategies to prevent single-drug resistance. Inhibition of FGF19/FGFR4 signaling is one of the possible strategies for overcoming sorafenib resistance in HCC. Molecular targeted therapy Sorafenib Sorafenib is a molecular multikinase inhibitor of several tyrosine protein kinases (VEGFR and PDGFR); Raf kinases (C-Raf and B-Raf); and intracellular serine/threonine kinases (C-Raf, wild-type B-Raf, and mutant B-Raf)62C64 (Table 1). This is the first molecular targeted agent that demonstrated survival benefit in nonresectable HCC patients.28,29 Sorafenib induces autophagy which in turn suppresses tumor growth.65 Table 1 Summary of sorafenib, tivantinib, and regorafenib mechanism of action, effect, and side effects
SorafenibMultikinase inhibitor of:
C several tyrosine protein kinases (VEGFR and PDGFR)
C Raf kinases (C-Raf and B-Raf)
C intracellular serine/threonine kinases (C-Raf, wild-type B-Raf, and mutant B-Raf)Tumor growth suppression by autophagyC Gastrointestinal (diarrhea, increased lipase, increased amylase, nausea, anorexia, vomiting, and constipation)
C Dermatologic (rash/desquamation, handCfoot skin reaction, alopecia, pruritus, and dry skin)
C Cardiovascular (hypertension, angioedema, and congestive heart failure)
C Hematologic (hypoalbuminemia, hemorrhage, anemia, and thrombocytopenia)
C Nervous system (neuropathy and headache)TivantinibHighly selective inhibitor of c-MET receptor tyrosine kinaseC Promotes apoptosis and cell growth arrest
C Cytotoxic activity, even in cells that lack c-MET
C Activation of cyclin B1 and inhibition of microtubuleC Hematologic toxicity (neutropenia, anemia, and leukopenia)
C Fatigue, nausea, and vomitingRegorafenibMultikinase inhibitor of VEGFR1-3, c-KIT, TIE-2, PDGFR-, FGFR-1, RET, c-RAF, BRAF, and p38 MAP kinaseAnti-angiogenic activityHandCfoot skin reaction, diarrhea, fatigue, hypothyroidism, anorexia, hypertension, nausea, and voice changes Open in a separate window The two milestone studies have established sorafenib, as a treatment of choice for HCC patients with ECOG PS of 1 1 or 2 2 and/or macrovascular invasion or extrahepatic spread according to the EASLCEORTC guidelines.21,28,29 The findings of SHARP/Phase III trial conducted in the Western world have demonstrated prolonged median survival from 7.9 months (placebo group) to 10.7 months (sorafenib group) (hazard rate [HR]=0.69; 95% CI: 0.55C0.87; p=0.00058).28 Sorafenib also improved the time to radiological progression (from 2.8 months to 5.5 months).28 The results of another Phase III trial, Asia-Pacific trial, have demonstrated a median overall survival of 6.5 months for a treatment group compared to 4.2 months for any placebo group (HR =0.68; 95% CI: 0.50C0.93; p=0.014)29 (Table 2). Table 2 Summary of sorafenib, tivantinib, and regorafenib clinical outcomes
SorafenibProlonged median survival from 7.9 months (placebo group) to 10.7 months (sorafenib group)28 Median overall survival of 6.5 months for sorafenib group compared to 4.2 months for a placebo group29TivantinibSurvival benefit in patients with advanced HCC who have failed or are intolerant to sorafenibRegorafenibOnly systemic treatment found to provide survival benefit in HCC patients progressing on sorafenib treatment106 Open in a separate window Abbreviation: HCC, hepatocellular carcinoma. At the beginning, sorafenib was introduced as a well-tolerated drug. However, a subanalysis of the SHARP and Asia-Pacific trials and results of other studies have shown suboptimal tolerability of sorafenib; it was down-dosed in >50% patients and interrupted in 45% of patients due to severe adverse events (AEs) or compromised liver function.28,29,66C68 According to the results of several studies, the most important side effects are gastrointestinal (diarrhea 43%, increased lipase 41%, increased amylase 30%, nausea 23%, anorexia 16%, vomiting 16%, and constipation 15%), dermatologic (rash/desquamation 40%, handCfoot skin reaction 30%,.