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Asia-Pacific Journal of Clinical Oncology 2014; 10: 255–260
doi: 10.1111/ajco.12191
ORIGINAL ARTICLE
Efficacy and safety of sorafenib in combination with gemcitabine in patients with advanced hepatocellular carcinoma: A multicenter, open-label, single-arm phase II study Vichien SRIMUNINNIMIT,1 Virote SRIURANPONG2 and Suthida SUWANVECHO3 1 Department of Medicine, Faculty of Medicine, Siriraj Hospital, 2Department of Medicine, Faculty of Medicine, Chulalongkorn University, and 3Bumrungrad International Hospital, Bangkok, Thailand
Abstract Aims: Currently, the only standard systemic treatment for advanced hepatocellular carcinoma is sorafenib monotherapy. The study was conducted to assess the efficacy and safety of the novel combination of sorafenib and gemcitabine in the treatment of advanced hepatocellular carcinoma. Methods: Between March 2008 and October 2010, patients with advanced pathologically proven hepatocellular carcinoma who had not received previous systemic therapy and had Child–Pugh liver function class A or B received sorafenib plus gemcitabine. Treatment included 4-week cycle of gemcitabine (1000 mg/m2 days 1, 8, 15) to the maximum of six cycles together with sorafenib (400 mg twice daily). Patient continued sorafenib until disease progression or withdrawal from other reasons. The primary end point is progressionfree survival. Results: Forty-five patients were enrolled in this study. The median progression-free survival was 3.7 months (95% CI 3.5–3.8). The overall response rate was 4% with no complete responses and the disease control rate was 66%. The median overall survival (OS) was 11.6 months (95% CI 7.4–15.9). The median time to progression was 3.6 months (95% CI 3.4–3.7). The most frequently reported grade 3/4 treatmentrelated adverse events included thrombocytopenia 33%, neutropenia 16% and hand-foot skin reaction 13%. The study regimen was well tolerated. Conclusion: The combination of sorafenib and gemcitabine in advanced hepatocellular carcinoma is generally well tolerated and has modest clinical efficacy. The median OS is up to 1 year. However, well-designed randomized controlled trials with a sorafenib alone comparator arm are needed to confirm this finding. Key words: gemcitabine, hepatoma, sorafenib.
INTRODUCTION Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, accounting for more than Correspondence: Dr Vichien Srimuninnimit MD, Division of Medical Oncology, Department of Medicine, 13th Fl. Chalerm-Prakiat Building, Faculty of Medicine, Siriraj Hospital, Bangkok-noi, Bangkok 10700, Thailand. Email: [email protected] Conflicts of interest: none Accepted for publication 16 February 2014.
© 2014 Wiley Publishing Asia Pty Ltd
600 000 deaths each year.1 The HCC is more common in sub-Saharan Africa and Southeast Asian countries than in the United States.1 More than 667 000 cases of HCC were expected worldwide in 20052,3 and in 80% of cases it occurs in patients with cirrhosis. According to National Cancer Institute’s Surveillance, Epidemiology, and End Results, the relative survival rate at 5 years is no better than 6% among patients with advanced-stage disease.4 Potential curative treatments such as orthotopic liver transplantation, complete surgical resection and percutaneous ablation are feasible in only 20–25%
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of patients, primarily due to early dissemination.5 There is no consensus on the treatment of patients with advanced-stage HCC. Locoregional approaches (embolization, intra-arterial chemotherapy [TACE] and chemoembolization) and systemic treatments (interferon, hormone therapy and chemotherapy) offered a marginal survival benefit in most clinical trials.6 New therapeutic approaches are therefore needed to improve the survival of patients with advanced HCC. The development of effective systemic therapies for HCC has been challenging.7 For advanced HCC, sorafenib is now the new standard of care. Sorafenib is a multikinase inhibitor with activity against c-Raf, b-Raf, vascular endothelial growth factor receptor, c-KIT and platelet-derived growth factor receptor beta, which are important in tumor cell proliferation and angiogenesis. A double-blind randomized phase III trial involving patients with advanced HCC demonstrated a statistically significant increase in overall survival (OS) over placebo (10.7 months vs 7.9 months; P < 0.001).8 Combinational therapies with sorafenib have the potential to further improved therapeutic options for patients suffering from advanced HCC.9 Gemcitabine is a classical chemotherapeutic substance that has modest anticancer activity in HCC.10 However, its anticancer activity seems to be improved when combined with other anticancer drugs including drugs interfering with the vascular endothelial growth factor pathway.11,12 Both substances, sorafenib and gemcitabine, have a favorable safety profile with a minimal overlap of side effects. Further, the mode of actions of sorafenib and gemcitabine is likely to result in synergistic antitumor effects. The present open-label, single-arm, multicenter phase II study was conducted to determine the progressionfree survival (PFS) of patients with advanced HCC treated with sorafenib in combination with gemcitabine.
METHODS Study design and patients This was an open-label, single-arm and multicenter phase II study involving patients at least 18 years old with advanced (unresectable or metastatic) HCC who had not received previous systemic anticancer, chemotherapy, immunotherapy or targeted therapy. The patient must have completed local treatments at least 4 weeks, or completed radiotherapy at least 3 weeks before study entry. The term, advanced HCC, was defined as localized unresectable HCC with ineligibility for TACE, or progression after TACE, or HCC with extrahepatic spread. The eligibility criteria also included
© 2014 Wiley Publishing Asia Pty Ltd
V Srimuninnimit et al.
histologically or cytologically proven HCC, an Eastern Cooperative Oncology Group Performance Status score of 0–2, Child–Pugh liver function class A or B, a life expectancy of 12 weeks or more, adequate hematologic function (hemoglobin ≥9 g/dL; absolute neutrophil count ≥1500/μL; platelet count ≥100 000 μL), adequate hepatic function (total bilirubin ≤3 mg/dL; alanine aminotransferase and aspartate aminotransferase ≤5 times the upper limit of the normal range) and adequate renal function (serum creatinine ≤1.5 times the upper limit of the normal range). Patients were required to have at least one untreated target lesion that could be measured in one dimension, according to the Response Evaluation Criteria in Solid Tumors (RECIST). All patients provided written informed consent before enrollment in the study. The study was approved by the institutional review board or ethics committee at each center and complied with the provisions of the Good Clinical Practice guidelines and the Declaration of Helsinki and local laws.
Treatment and assessment Treatment included 4-week cycles of gemcitabine (1000 mg/m2 days 1, 8, 15) to the maximum of six cycles together with sorafenib (400 mg twice daily). Patients continued taking sorafenib until they were dropped from the study because of progression of disease and intolerable toxicity, or until they wished to withdraw. As per protocol, evaluation of response was performed every 6 weeks according to RECIST version 1.0. The objectives of the study were to investigate the efficacy and adverse events (AEs) by use of the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 of sorafenib in combination with gemcitabine. The primary end point was PFS and the secondary end points were OS, overall response rate, time to progression (TTP) and disease control rate (DCR). PFS was calculated from the date of the first dose of study medication to disease progression either radiologic or clinical or death, and OS was calculated from the date of the first dose of study medication until the date of death of any cause. TTP was defined as the time from the first dose of study medication to disease progression.
Statistical analysis We calculated the number of patients needed for the study based on the assumption of a median PFS for gemcitabine monotherapy of 4 months and expected a median PFS of 6 months when treated with sorafenib and gemcitabine combination therapy with the risk
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alpha of 15% (one sided) and a power of 85%. In these conditions, the number of evaluable patients to be included was 42. If we took into account a dropout of 5%, the number of enrolled patients was 45. Timeto-event data (PFS, OS, TTP) were calculated using Kaplan–Meier survival curves.
RESULTS Patients and treatment Between March 2008 and October 2010, 45 patients were recruited in the study. The summary of baseline demographic and disease characteristics was presented in Table 1. Almost all patients had Child–Pugh class A (93%). There were 67% of patients with hepatitis B virus (HBV) infection, 11% with hepatitis C virus (HCV) infection, 2% with both HBV and HCV infection, 76% with elevated alpha-fetoprotein (AFP) and
Table 1
Demography and baseline characters
Characteristic Gender, n (%) Male Mean age (years) ± SD ECOG performance status, n (%) 0 1 2 Child–Pugh status, n (%) A B AFP > ULN, n (%) Yes No Missing Prior therapy, n (%) No prior therapy Surgery TACE/TOCE Surgery + TACE/TOCE RFA + Surgery + TACE/TOCE Extrahepatic spread, n (%) Present Absent Viral hepatitis, n (%) HBV HCV HBV + HCV Negative
(n = 45) 41 (91) 50.2 ± 10.5 16 (36) 28 (62) 1 (2) 42 (93) 3 (7) 34 (76) 9 (20) 2 (4) 12 (27) 5 (11) 18 (40) 8 (18) 2 (4) 23 (51) 22 (49) 30 (67) 5 (11) 1 (2) 9 (20)
AFP, alpha-fetoprotein; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ULN, upper limit of normal.
Asia-Pac J Clin Oncol 2014; 10: 255–260
51% with extrahepatic spread. Out of 45 patients, five (11%) lost to follow-up, 14 (31%) were alive, 25 (56%) died and one (2%) had ongoing treatment. The median duration of the study was 32.2 weeks.
Clinical efficacy Across efficacy population, median PFS was 3.7 months ([95% CI 3.5–3.8] [N = 41]) and median OS was 11.6 months ([95% CI 7.4–15.9] [N = 45]) (Fig. 1). At normal AFP (N = 7), median PFS was 8.3 months (95% CI 3.2–13.4) and at AFP > upper limit of normal (N = 32) median PFS was 3.5 months (95% CI 3.4–3.7) (Fig. 2). In the analysis for best response, 4% of the patients achieved a partial response (PR), no complete response, and 62% of the patients had stable disease (SD). The DCR was 66%.
Safety data As of 31 October 2010, all the study population reported with at least one of the AEs (Table 2). The most frequently reported AEs with 3/4 safety grade were thrombocytopenia (33%), neutropenia (16%), handfoot syndrome (HFS, 13%) and diarrhea (11%). All the AEs reported were assessed drug related by the investigator. Dose adjustment for sorafenib was required in 47% of patients and dose adjustment for gemcitabine was required in 73% of patients. Furthermore, dose interruption for sorafenib and gemcitabine was required in 51 and 73% of patients, respectively. However, there were only three patients (7%) whose treatment was discontinued permanently due to treatment-related AEs, while 36 (80%) discontinued due to disease progression, two (4%) lost to follow-up, one (2%) discontinued from treatment-unrelated AE, one (2%) died, one (2%) violated the protocol, and one had treatment continued at the cutoff date.
DISCUSSION The combination of sorafenib and gemcitabine therapy was generally well tolerated and demonstrated antitumor activity in advanced HCC patients. There is strong evidence that sorafenib can be combined successfully with other agents in HCC on the basis of a strong preclinical rationale and a favorable toxicity profile.13 In this trial designed to explore the benefit of gemcitabine plus sorafenib, sorafenib combined with gemcitabine achieved PR of 4% and SD of 62% compared with sorafenib alone in SHARP trial with 2% PR and 71% SD, or in Asia-Pacific study with 3.3% PR and
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258
Figure 1
V Srimuninnimit et al.
Progression-free survival (PFS) (a) and overall survival (b).
Table 2
Summary of adverse events (AEs)
Adverse events†
Figure 2 Progression-free survival (PFS): normal AFP versus AFP > ULN.
Hematological event Thrombocytopenia Neutropenia Anemia Non-hematological event Diarrhea HFS Alopecia Mucositis Nausea/vomiting Rash †
54% SD.8,14 As presented in the Table 3, our study demonstrated a median TTP of 3.6 months, the same result as sorafenib alone from SHARP study (5.5 months) and from Asia-Pacific study (2.8 months).8,14 In addition, as presented in Table 3, our study also showed the similar OS (11.6 months) when compared with sorafenib alone in SHARP study (10.7 months) and in Asia-Pacific study (6.5 months).8,14 The OS in Asia-Pacific study was lower than in the SHARP study due to poorer performance status, more frequent infection with hepatitis B, more major vascular involvement and extrahepatic spread. In a phase II trial conducted at a single institution in Hong
© 2014 Wiley Publishing Asia Pty Ltd
All No. of patients (%)
Grades 3 and 4 No. of patients (%)
33 (73) 20 (44) 17 (38)
15 (33) 7 (16) 1 (2)
32 (71) 32 (71) 28 (62) 20 (44) 19 (42) 18 (40)
5 (11) 6 (13) 0 (0) 1 (2) 0 (0) 1 (2)
Table shows only the top 10 adverse events.
Kong, the median OS was 5 months in patients with more advanced disease, including Child–Pugh class B (26%) and class C (3%).15 However, our findings compare favorably with singlearm studies evaluating combination therapy (cisplatin, interferon, doxorubicin and fluorouracil [PIAF] or doxorubicin plus cisplatin) in HCC patients.16,17 In the present study, the median PFS was 3.7 months. Patients with normal AFP had longer PFS when compared with patients with elevated AFP (P = 0.027).
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Table 3
Sorafenib-SHARP versus ORIENTAL study and our study SHARP study 8
Cheng et al.14
Llovet et al. Outcome HBV infection (%) Extrahepatic spread (%) Time to progression (months)† Overall survival (months)† Response rate (%) †
ORIENTAL study Our study
Sorafenib (n = 226)
Placebo (n = 246)
Sorafenib (n = 150)
Placebo (n = 76)
Sorafenib plus gemcitabine (n = 45)
19 53 5.5 10.7 2
18 50 2.8 7.9 2
70.7 68.7 2.8 6.5 3
77.6 68.4 1.4 4.2 1
67 51 3.6 11.6 4
Median.
Our study showed that the combination of sorafenib with gemcitabine achieved the same efficacy as the combination of sorafenib with doxorubicin in terms of response rate (4% vs 4%) and OS (11.6 months vs 13.7 months) but less grade 3/4 neutropenia (16% vs 38%).9 The most common grade 3/4 drug-related AEs included thrombocytopenia, neutropenia, HFS and diarrhea. Our study demonstrated that the combination of sorafenib and gemcitabine had more thrombocytopenia and neutropenia but same incidence of HFS and diarrhea when compared with sorafenib alone in the SHARP study and Asia-Pacific study.8,14 The higher thrombocytopenia (33%) and neutropenia (16%) were consistent with the expected gemcitabine profiles. However, the combination of sorafenib and gemcitabine was generally well tolerated and had manageable side effects, as there were only three patients (7%) whose treatment was discontinued permanently due to treatment-related AEs. Because this is a single-arm cohort study, interpretation of outcome value from this study should be done with caution, especially when comparing the results of this study with the results from studies of sorafenib alone or gemcitabine alone.
Conclusion Combination of sorafenib and gemcitabine in advanced HCC was generally well tolerated. It has the modest clinical efficacy but more toxicities when compared with sorafenib alone in the pivotal studies. However, the lack of a comparative sorafenib standard arm precludes any assessment of different efficacy between sorafenib alone and the combination between gemcitabine and sorafenib. Large-scale randomized controlled trials with a comparator arm with sorafenib alone are needed to confirm this finding.
Asia-Pac J Clin Oncol 2014; 10: 255–260
ACKNOWLEDGMENTS We extend our sincere thanks to Dr Peter Pothula, BioQuest, for his valuable editorial guidance in the generation of this report. Bayer (Thailand) sponsored sorafenib and statistical analysis of the trial. Lilly (Thailand) sponsored gemcitabine.
REFERENCES 1 American Cancer Society. Cancer Facts & Figures 2010. American Cancer Society, Atlanta 2010. 2 Remontet L, Esteve J, Bouvier AM et al. Cancer incidence and mortality in France over the period 1978–2000. Rev Epidemiol Sante Publique 2003; 51: 3–30. 3 Jemal A, Murray T, Ward E et al. Cancer statistics, 2005. CA Cancer J Clin 2005; 55: 10–30. 4 National Cancer Institute. SEER Stat Fact Sheets: Liver and Intrahepatic Bile Duct Cancer [Internet]. 2009. [Cited 30 Nov 2011.] Available from URL: http://seer.cancer.gov/ statfacts/html/livibd.html. 5 Llovet JM, Di Bisceglie AM, Bruix J et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 698–711. 6 Bruix J, Sherman M, Llovet JM et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona2000 EASL Conference. European Association for the Study of the Liver. J Hepatol 2001; 35: 421–43. 7 Giglia JL, Antonia SJ, Berk LB et al. Systemic therapy for advanced hepatocellular carcinoma: past, present, and future. Cancer Control 2010; 17: 120–9. 8 Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N Eng J Med 2008; 359: 378–90. 9 Abou-Alfa GK, Johnson P, Knox JJ et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 2010; 304: 2154–60.
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10 Matsumoto K, Nagahara T, Okano J et al. The growth inhibition of hepatocellular and cholangiocellular carcinoma cells by gemcitabine and the roles of extracellular signal-regulated and checkpoint kinases. Oncol Rep 2008; 20: 863–72. 11 Louafi S, Boige V, Ducreux M et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer 2007; 109: 1384–90. 12 Taïeb J, Bonyhay L, Golli L et al. Gemcitabine plus oxaliplatin for patients with advanced hepatocellular carcinoma using two different schedules. Cancer 2003; 98: 2664–70. 13 Richly H, Kupsch P, Passage K et al. Results of a phase I trial of BAY 43-9006 in combination with doxorubicin in patients with primary hepatic cancer. Int J Clin Pharmacol Ther 2004; 42: 650–1.
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14 Cheng AL, Kang YK, Chen Z et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10: 25–34. 15 Yau T, Chan P, Ng KK et al. Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: presence of lung metastasis predicts poor response. Cancer 2009; 115: 428–36. 16 Leung TW, Patt YZ, Lau WY et al. Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res 1999; 5: 1676–81. 17 Lee J, Park JO, Kim WS et al. Phase II study of doxorubicin and cisplatin in patients with metastatic hepatocellular carcinoma. Cancer Chemother Pharmacol 2004; 54: 385–90.
Asia-Pac J Clin Oncol 2014; 10: 255–260
Asia-Pacific Journal of Clinical Oncology 2014; 10: 255–260
doi: 10.1111/ajco.12191
ORIGINAL ARTICLE
Efficacy and safety of sorafenib in combination with gemcitabine in patients with advanced hepatocellular carcinoma: A multicenter, open-label, single-arm phase II study Vichien SRIMUNINNIMIT,1 Virote SRIURANPONG2 and Suthida SUWANVECHO3 1 Department of Medicine, Faculty of Medicine, Siriraj Hospital, 2Department of Medicine, Faculty of Medicine, Chulalongkorn University, and 3Bumrungrad International Hospital, Bangkok, Thailand
Abstract Aims: Currently, the only standard systemic treatment for advanced hepatocellular carcinoma is sorafenib monotherapy. The study was conducted to assess the efficacy and safety of the novel combination of sorafenib and gemcitabine in the treatment of advanced hepatocellular carcinoma. Methods: Between March 2008 and October 2010, patients with advanced pathologically proven hepatocellular carcinoma who had not received previous systemic therapy and had Child–Pugh liver function class A or B received sorafenib plus gemcitabine. Treatment included 4-week cycle of gemcitabine (1000 mg/m2 days 1, 8, 15) to the maximum of six cycles together with sorafenib (400 mg twice daily). Patient continued sorafenib until disease progression or withdrawal from other reasons. The primary end point is progressionfree survival. Results: Forty-five patients were enrolled in this study. The median progression-free survival was 3.7 months (95% CI 3.5–3.8). The overall response rate was 4% with no complete responses and the disease control rate was 66%. The median overall survival (OS) was 11.6 months (95% CI 7.4–15.9). The median time to progression was 3.6 months (95% CI 3.4–3.7). The most frequently reported grade 3/4 treatmentrelated adverse events included thrombocytopenia 33%, neutropenia 16% and hand-foot skin reaction 13%. The study regimen was well tolerated. Conclusion: The combination of sorafenib and gemcitabine in advanced hepatocellular carcinoma is generally well tolerated and has modest clinical efficacy. The median OS is up to 1 year. However, well-designed randomized controlled trials with a sorafenib alone comparator arm are needed to confirm this finding. Key words: gemcitabine, hepatoma, sorafenib.
INTRODUCTION Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, accounting for more than Correspondence: Dr Vichien Srimuninnimit MD, Division of Medical Oncology, Department of Medicine, 13th Fl. Chalerm-Prakiat Building, Faculty of Medicine, Siriraj Hospital, Bangkok-noi, Bangkok 10700, Thailand. Email: [email protected] Conflicts of interest: none Accepted for publication 16 February 2014.
© 2014 Wiley Publishing Asia Pty Ltd
600 000 deaths each year.1 The HCC is more common in sub-Saharan Africa and Southeast Asian countries than in the United States.1 More than 667 000 cases of HCC were expected worldwide in 20052,3 and in 80% of cases it occurs in patients with cirrhosis. According to National Cancer Institute’s Surveillance, Epidemiology, and End Results, the relative survival rate at 5 years is no better than 6% among patients with advanced-stage disease.4 Potential curative treatments such as orthotopic liver transplantation, complete surgical resection and percutaneous ablation are feasible in only 20–25%
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of patients, primarily due to early dissemination.5 There is no consensus on the treatment of patients with advanced-stage HCC. Locoregional approaches (embolization, intra-arterial chemotherapy [TACE] and chemoembolization) and systemic treatments (interferon, hormone therapy and chemotherapy) offered a marginal survival benefit in most clinical trials.6 New therapeutic approaches are therefore needed to improve the survival of patients with advanced HCC. The development of effective systemic therapies for HCC has been challenging.7 For advanced HCC, sorafenib is now the new standard of care. Sorafenib is a multikinase inhibitor with activity against c-Raf, b-Raf, vascular endothelial growth factor receptor, c-KIT and platelet-derived growth factor receptor beta, which are important in tumor cell proliferation and angiogenesis. A double-blind randomized phase III trial involving patients with advanced HCC demonstrated a statistically significant increase in overall survival (OS) over placebo (10.7 months vs 7.9 months; P < 0.001).8 Combinational therapies with sorafenib have the potential to further improved therapeutic options for patients suffering from advanced HCC.9 Gemcitabine is a classical chemotherapeutic substance that has modest anticancer activity in HCC.10 However, its anticancer activity seems to be improved when combined with other anticancer drugs including drugs interfering with the vascular endothelial growth factor pathway.11,12 Both substances, sorafenib and gemcitabine, have a favorable safety profile with a minimal overlap of side effects. Further, the mode of actions of sorafenib and gemcitabine is likely to result in synergistic antitumor effects. The present open-label, single-arm, multicenter phase II study was conducted to determine the progressionfree survival (PFS) of patients with advanced HCC treated with sorafenib in combination with gemcitabine.
METHODS Study design and patients This was an open-label, single-arm and multicenter phase II study involving patients at least 18 years old with advanced (unresectable or metastatic) HCC who had not received previous systemic anticancer, chemotherapy, immunotherapy or targeted therapy. The patient must have completed local treatments at least 4 weeks, or completed radiotherapy at least 3 weeks before study entry. The term, advanced HCC, was defined as localized unresectable HCC with ineligibility for TACE, or progression after TACE, or HCC with extrahepatic spread. The eligibility criteria also included
© 2014 Wiley Publishing Asia Pty Ltd
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histologically or cytologically proven HCC, an Eastern Cooperative Oncology Group Performance Status score of 0–2, Child–Pugh liver function class A or B, a life expectancy of 12 weeks or more, adequate hematologic function (hemoglobin ≥9 g/dL; absolute neutrophil count ≥1500/μL; platelet count ≥100 000 μL), adequate hepatic function (total bilirubin ≤3 mg/dL; alanine aminotransferase and aspartate aminotransferase ≤5 times the upper limit of the normal range) and adequate renal function (serum creatinine ≤1.5 times the upper limit of the normal range). Patients were required to have at least one untreated target lesion that could be measured in one dimension, according to the Response Evaluation Criteria in Solid Tumors (RECIST). All patients provided written informed consent before enrollment in the study. The study was approved by the institutional review board or ethics committee at each center and complied with the provisions of the Good Clinical Practice guidelines and the Declaration of Helsinki and local laws.
Treatment and assessment Treatment included 4-week cycles of gemcitabine (1000 mg/m2 days 1, 8, 15) to the maximum of six cycles together with sorafenib (400 mg twice daily). Patients continued taking sorafenib until they were dropped from the study because of progression of disease and intolerable toxicity, or until they wished to withdraw. As per protocol, evaluation of response was performed every 6 weeks according to RECIST version 1.0. The objectives of the study were to investigate the efficacy and adverse events (AEs) by use of the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 of sorafenib in combination with gemcitabine. The primary end point was PFS and the secondary end points were OS, overall response rate, time to progression (TTP) and disease control rate (DCR). PFS was calculated from the date of the first dose of study medication to disease progression either radiologic or clinical or death, and OS was calculated from the date of the first dose of study medication until the date of death of any cause. TTP was defined as the time from the first dose of study medication to disease progression.
Statistical analysis We calculated the number of patients needed for the study based on the assumption of a median PFS for gemcitabine monotherapy of 4 months and expected a median PFS of 6 months when treated with sorafenib and gemcitabine combination therapy with the risk
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alpha of 15% (one sided) and a power of 85%. In these conditions, the number of evaluable patients to be included was 42. If we took into account a dropout of 5%, the number of enrolled patients was 45. Timeto-event data (PFS, OS, TTP) were calculated using Kaplan–Meier survival curves.
RESULTS Patients and treatment Between March 2008 and October 2010, 45 patients were recruited in the study. The summary of baseline demographic and disease characteristics was presented in Table 1. Almost all patients had Child–Pugh class A (93%). There were 67% of patients with hepatitis B virus (HBV) infection, 11% with hepatitis C virus (HCV) infection, 2% with both HBV and HCV infection, 76% with elevated alpha-fetoprotein (AFP) and
Table 1
Demography and baseline characters
Characteristic Gender, n (%) Male Mean age (years) ± SD ECOG performance status, n (%) 0 1 2 Child–Pugh status, n (%) A B AFP > ULN, n (%) Yes No Missing Prior therapy, n (%) No prior therapy Surgery TACE/TOCE Surgery + TACE/TOCE RFA + Surgery + TACE/TOCE Extrahepatic spread, n (%) Present Absent Viral hepatitis, n (%) HBV HCV HBV + HCV Negative
(n = 45) 41 (91) 50.2 ± 10.5 16 (36) 28 (62) 1 (2) 42 (93) 3 (7) 34 (76) 9 (20) 2 (4) 12 (27) 5 (11) 18 (40) 8 (18) 2 (4) 23 (51) 22 (49) 30 (67) 5 (11) 1 (2) 9 (20)
AFP, alpha-fetoprotein; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ULN, upper limit of normal.
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51% with extrahepatic spread. Out of 45 patients, five (11%) lost to follow-up, 14 (31%) were alive, 25 (56%) died and one (2%) had ongoing treatment. The median duration of the study was 32.2 weeks.
Clinical efficacy Across efficacy population, median PFS was 3.7 months ([95% CI 3.5–3.8] [N = 41]) and median OS was 11.6 months ([95% CI 7.4–15.9] [N = 45]) (Fig. 1). At normal AFP (N = 7), median PFS was 8.3 months (95% CI 3.2–13.4) and at AFP > upper limit of normal (N = 32) median PFS was 3.5 months (95% CI 3.4–3.7) (Fig. 2). In the analysis for best response, 4% of the patients achieved a partial response (PR), no complete response, and 62% of the patients had stable disease (SD). The DCR was 66%.
Safety data As of 31 October 2010, all the study population reported with at least one of the AEs (Table 2). The most frequently reported AEs with 3/4 safety grade were thrombocytopenia (33%), neutropenia (16%), handfoot syndrome (HFS, 13%) and diarrhea (11%). All the AEs reported were assessed drug related by the investigator. Dose adjustment for sorafenib was required in 47% of patients and dose adjustment for gemcitabine was required in 73% of patients. Furthermore, dose interruption for sorafenib and gemcitabine was required in 51 and 73% of patients, respectively. However, there were only three patients (7%) whose treatment was discontinued permanently due to treatment-related AEs, while 36 (80%) discontinued due to disease progression, two (4%) lost to follow-up, one (2%) discontinued from treatment-unrelated AE, one (2%) died, one (2%) violated the protocol, and one had treatment continued at the cutoff date.
DISCUSSION The combination of sorafenib and gemcitabine therapy was generally well tolerated and demonstrated antitumor activity in advanced HCC patients. There is strong evidence that sorafenib can be combined successfully with other agents in HCC on the basis of a strong preclinical rationale and a favorable toxicity profile.13 In this trial designed to explore the benefit of gemcitabine plus sorafenib, sorafenib combined with gemcitabine achieved PR of 4% and SD of 62% compared with sorafenib alone in SHARP trial with 2% PR and 71% SD, or in Asia-Pacific study with 3.3% PR and
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Figure 1
V Srimuninnimit et al.
Progression-free survival (PFS) (a) and overall survival (b).
Table 2
Summary of adverse events (AEs)
Adverse events†
Figure 2 Progression-free survival (PFS): normal AFP versus AFP > ULN.
Hematological event Thrombocytopenia Neutropenia Anemia Non-hematological event Diarrhea HFS Alopecia Mucositis Nausea/vomiting Rash †
54% SD.8,14 As presented in the Table 3, our study demonstrated a median TTP of 3.6 months, the same result as sorafenib alone from SHARP study (5.5 months) and from Asia-Pacific study (2.8 months).8,14 In addition, as presented in Table 3, our study also showed the similar OS (11.6 months) when compared with sorafenib alone in SHARP study (10.7 months) and in Asia-Pacific study (6.5 months).8,14 The OS in Asia-Pacific study was lower than in the SHARP study due to poorer performance status, more frequent infection with hepatitis B, more major vascular involvement and extrahepatic spread. In a phase II trial conducted at a single institution in Hong
© 2014 Wiley Publishing Asia Pty Ltd
All No. of patients (%)
Grades 3 and 4 No. of patients (%)
33 (73) 20 (44) 17 (38)
15 (33) 7 (16) 1 (2)
32 (71) 32 (71) 28 (62) 20 (44) 19 (42) 18 (40)
5 (11) 6 (13) 0 (0) 1 (2) 0 (0) 1 (2)
Table shows only the top 10 adverse events.
Kong, the median OS was 5 months in patients with more advanced disease, including Child–Pugh class B (26%) and class C (3%).15 However, our findings compare favorably with singlearm studies evaluating combination therapy (cisplatin, interferon, doxorubicin and fluorouracil [PIAF] or doxorubicin plus cisplatin) in HCC patients.16,17 In the present study, the median PFS was 3.7 months. Patients with normal AFP had longer PFS when compared with patients with elevated AFP (P = 0.027).
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Sorafenib and gemcitabine in hepatoma
Table 3
Sorafenib-SHARP versus ORIENTAL study and our study SHARP study 8
Cheng et al.14
Llovet et al. Outcome HBV infection (%) Extrahepatic spread (%) Time to progression (months)† Overall survival (months)† Response rate (%) †
ORIENTAL study Our study
Sorafenib (n = 226)
Placebo (n = 246)
Sorafenib (n = 150)
Placebo (n = 76)
Sorafenib plus gemcitabine (n = 45)
19 53 5.5 10.7 2
18 50 2.8 7.9 2
70.7 68.7 2.8 6.5 3
77.6 68.4 1.4 4.2 1
67 51 3.6 11.6 4
Median.
Our study showed that the combination of sorafenib with gemcitabine achieved the same efficacy as the combination of sorafenib with doxorubicin in terms of response rate (4% vs 4%) and OS (11.6 months vs 13.7 months) but less grade 3/4 neutropenia (16% vs 38%).9 The most common grade 3/4 drug-related AEs included thrombocytopenia, neutropenia, HFS and diarrhea. Our study demonstrated that the combination of sorafenib and gemcitabine had more thrombocytopenia and neutropenia but same incidence of HFS and diarrhea when compared with sorafenib alone in the SHARP study and Asia-Pacific study.8,14 The higher thrombocytopenia (33%) and neutropenia (16%) were consistent with the expected gemcitabine profiles. However, the combination of sorafenib and gemcitabine was generally well tolerated and had manageable side effects, as there were only three patients (7%) whose treatment was discontinued permanently due to treatment-related AEs. Because this is a single-arm cohort study, interpretation of outcome value from this study should be done with caution, especially when comparing the results of this study with the results from studies of sorafenib alone or gemcitabine alone.
Conclusion Combination of sorafenib and gemcitabine in advanced HCC was generally well tolerated. It has the modest clinical efficacy but more toxicities when compared with sorafenib alone in the pivotal studies. However, the lack of a comparative sorafenib standard arm precludes any assessment of different efficacy between sorafenib alone and the combination between gemcitabine and sorafenib. Large-scale randomized controlled trials with a comparator arm with sorafenib alone are needed to confirm this finding.
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ACKNOWLEDGMENTS We extend our sincere thanks to Dr Peter Pothula, BioQuest, for his valuable editorial guidance in the generation of this report. Bayer (Thailand) sponsored sorafenib and statistical analysis of the trial. Lilly (Thailand) sponsored gemcitabine.
REFERENCES 1 American Cancer Society. Cancer Facts & Figures 2010. American Cancer Society, Atlanta 2010. 2 Remontet L, Esteve J, Bouvier AM et al. Cancer incidence and mortality in France over the period 1978–2000. Rev Epidemiol Sante Publique 2003; 51: 3–30. 3 Jemal A, Murray T, Ward E et al. Cancer statistics, 2005. CA Cancer J Clin 2005; 55: 10–30. 4 National Cancer Institute. SEER Stat Fact Sheets: Liver and Intrahepatic Bile Duct Cancer [Internet]. 2009. [Cited 30 Nov 2011.] Available from URL: http://seer.cancer.gov/ statfacts/html/livibd.html. 5 Llovet JM, Di Bisceglie AM, Bruix J et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 698–711. 6 Bruix J, Sherman M, Llovet JM et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona2000 EASL Conference. European Association for the Study of the Liver. J Hepatol 2001; 35: 421–43. 7 Giglia JL, Antonia SJ, Berk LB et al. Systemic therapy for advanced hepatocellular carcinoma: past, present, and future. Cancer Control 2010; 17: 120–9. 8 Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N Eng J Med 2008; 359: 378–90. 9 Abou-Alfa GK, Johnson P, Knox JJ et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 2010; 304: 2154–60.
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10 Matsumoto K, Nagahara T, Okano J et al. The growth inhibition of hepatocellular and cholangiocellular carcinoma cells by gemcitabine and the roles of extracellular signal-regulated and checkpoint kinases. Oncol Rep 2008; 20: 863–72. 11 Louafi S, Boige V, Ducreux M et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer 2007; 109: 1384–90. 12 Taïeb J, Bonyhay L, Golli L et al. Gemcitabine plus oxaliplatin for patients with advanced hepatocellular carcinoma using two different schedules. Cancer 2003; 98: 2664–70. 13 Richly H, Kupsch P, Passage K et al. Results of a phase I trial of BAY 43-9006 in combination with doxorubicin in patients with primary hepatic cancer. Int J Clin Pharmacol Ther 2004; 42: 650–1.
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V Srimuninnimit et al.
14 Cheng AL, Kang YK, Chen Z et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10: 25–34. 15 Yau T, Chan P, Ng KK et al. Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: presence of lung metastasis predicts poor response. Cancer 2009; 115: 428–36. 16 Leung TW, Patt YZ, Lau WY et al. Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res 1999; 5: 1676–81. 17 Lee J, Park JO, Kim WS et al. Phase II study of doxorubicin and cisplatin in patients with metastatic hepatocellular carcinoma. Cancer Chemother Pharmacol 2004; 54: 385–90.
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