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Hepatology Research 2015; 45: 279–287
doi: 10.1111/hepr.12354
Original Article
Field practice study of half-dose sorafenib treatment on safety and efficacy for hepatocellular carcinoma: A propensity score analysis Manabu Morimoto,1,2 Kazushi Numata,1 Masaaki Kondo,1 Satoshi Kobayashi,2 Shinichi Ohkawa,2 Hisashi Hidaka,3 Takahide Nakazawa,3 Yusuke Okuwaki,3 Chiaki Okuse,4 Kotaro Matsunaga,4 Michihiro Suzuki,4 Satoshi Morita,5 Masataka Taguri5 and Katsuaki Tanaka1 1 Gastroenterological Center, 5Department of Biostatistics and Epidemiology, Yokohama City University Medical Center, 2Department of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama, 3 Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, and 4 Division of Gastroenterology and Hepatology, Department of Internal Medicine, St Marianna University School of Medicine, Kawasaki, Japan
Aim: Patients with hepatocellular carcinoma (HCC) who receive an initial full dose of sorafenib (800 mg/day) often require a decreased dose (400 mg/day) or discontinuation of therapy because of severe adverse events. We conducted a retrospective analysis of patients with HCC to compare the safety and efficacy of full- to half-dose sorafenib. Methods: We reviewed the medical records of 218 consecutive patients with intermediate or advanced stage HCC who received half (n = 73) or full-dose sorafenib (n = 145) between 2009 and 2012 at four institutions. A propensity scorematching analysis was used to adjust for potential bias. Results: Multivariate logistic regression analysis showed that increased age was an independent factor for the selection of initial half-dose sorafenib (odds ratio, 1.10; 95% confidence interval, 1.05–1.15; P < 0.001). Fifty-eight patients each in the half-dose and full-dose groups were selected for pro-
INTRODUCTION
H
EPATOCELLULAR CARCINOMA (HCC) is the fifth most common malignancy worldwide, and its incidence is increasing in several countries.1 Patients
Correspondence: Dr Manabu Morimoto, Department of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama City 241-8515, Japan. Email: [email protected] Conflict of interest: The authors declare that they have no conflict of interest. Received 14 January 2014; revision 30 April 2014; accepted 30 April 2014.
© 2014 The Japan Society of Hepatology
pensity score matching. The incidence of grade 3–4 severe adverse effects was lower in the half-dose group (47.4% vs 66.7%, P = 0.037). In contrast, the median progression-free survival (PFS) and overall survival (OS) rates were not significantly different (half-dose group, 3.8 and 10.2 months; fulldose group, 2.5 and 8.8 months; P = 0.143 and 0.911, respectively).
Conclusion: Propensity score-matched analyses indicate that initial half-dose sorafenib treatment led to fewer severe adverse effects and a comparable survival benefit compared with a full dose in select patients with HCC, particularly for those of advanced age. Key words: adverse drug reaction, age, dose, hepatocellular carcinoma, propensity score, sorafenib
with early-stage HCC are generally administrated curative treatments such as surgery or local ablation, patients with intermediate-stage HCC usually receive transarterial chemoembolization, and patients with advanced-stage disease are candidates for systemic therapies.2 Sorafenib is a small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors, platelet-derived growth factor receptor-β and Raf kinase.3 Sorafenib is administrated p.o. and is the only systemic agent that provides a survival benefit for patients with advanced HCC.4,5 In global phase III trials, sorafenib was generally well tolerated;4,5 however, studies of general practice reported
279
280 M. Morimoto et al.
that treatment was interrupted in 22–40% of patients because of adverse drug reactions.6,7 The reason for this difference is unknown; however, differences in the ages of patients treated in practice and those studied in phase III trials may represent a contributing factor. Some case series reported the efficacy and safety of sorafenib using a reduced initial dose.8–10 However, no prior published study compared the safety and efficacy between different initial doses of sorafenib administrated to patients with HCC. In the present study, we aimed to evaluate the safety and efficacy of half-dose sorafenib treatment using a multicenter cohort. To minimize the potential effects of selection bias on patient characteristics treated with initial half or full doses, we used a model adjusted for propensity score.11
METHODS Patient selection
W
E ANALYZED RETROSPECTIVELY the medical records of 218 patients with histopathologically or radiographically proven HCC, or both, who were treated at four member institutes of the Kanagawa Liver Study Group between May 2009 and May 2012. All patients had Barcelona Clinic Liver Cancer intermediate or advanced stage HCC12 that was diagnosed at baseline according to the Response Evaluation Criteria in Solid Tumors.13 All patients provided written informed consent. The institutional review board or ethics committee at each institution approved the study protocol, which complied with Good Clinical Practice guidelines, the Declaration of Helsinki and local laws. The inclusion criteria were defined as Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less, Child–Pugh liver function class A, adequate hematological function (platelet count, >5.0 × 104/μL; hemoglobin level, >8.0 g/dL), adequate hepatic function (albumin level, >2.5 g/dL; total bilirubin level,
Hepatology Research 2015; 45: 279–287
doi: 10.1111/hepr.12354
Original Article
Field practice study of half-dose sorafenib treatment on safety and efficacy for hepatocellular carcinoma: A propensity score analysis Manabu Morimoto,1,2 Kazushi Numata,1 Masaaki Kondo,1 Satoshi Kobayashi,2 Shinichi Ohkawa,2 Hisashi Hidaka,3 Takahide Nakazawa,3 Yusuke Okuwaki,3 Chiaki Okuse,4 Kotaro Matsunaga,4 Michihiro Suzuki,4 Satoshi Morita,5 Masataka Taguri5 and Katsuaki Tanaka1 1 Gastroenterological Center, 5Department of Biostatistics and Epidemiology, Yokohama City University Medical Center, 2Department of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama, 3 Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, and 4 Division of Gastroenterology and Hepatology, Department of Internal Medicine, St Marianna University School of Medicine, Kawasaki, Japan
Aim: Patients with hepatocellular carcinoma (HCC) who receive an initial full dose of sorafenib (800 mg/day) often require a decreased dose (400 mg/day) or discontinuation of therapy because of severe adverse events. We conducted a retrospective analysis of patients with HCC to compare the safety and efficacy of full- to half-dose sorafenib. Methods: We reviewed the medical records of 218 consecutive patients with intermediate or advanced stage HCC who received half (n = 73) or full-dose sorafenib (n = 145) between 2009 and 2012 at four institutions. A propensity scorematching analysis was used to adjust for potential bias. Results: Multivariate logistic regression analysis showed that increased age was an independent factor for the selection of initial half-dose sorafenib (odds ratio, 1.10; 95% confidence interval, 1.05–1.15; P < 0.001). Fifty-eight patients each in the half-dose and full-dose groups were selected for pro-
INTRODUCTION
H
EPATOCELLULAR CARCINOMA (HCC) is the fifth most common malignancy worldwide, and its incidence is increasing in several countries.1 Patients
Correspondence: Dr Manabu Morimoto, Department of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama City 241-8515, Japan. Email: [email protected] Conflict of interest: The authors declare that they have no conflict of interest. Received 14 January 2014; revision 30 April 2014; accepted 30 April 2014.
© 2014 The Japan Society of Hepatology
pensity score matching. The incidence of grade 3–4 severe adverse effects was lower in the half-dose group (47.4% vs 66.7%, P = 0.037). In contrast, the median progression-free survival (PFS) and overall survival (OS) rates were not significantly different (half-dose group, 3.8 and 10.2 months; fulldose group, 2.5 and 8.8 months; P = 0.143 and 0.911, respectively).
Conclusion: Propensity score-matched analyses indicate that initial half-dose sorafenib treatment led to fewer severe adverse effects and a comparable survival benefit compared with a full dose in select patients with HCC, particularly for those of advanced age. Key words: adverse drug reaction, age, dose, hepatocellular carcinoma, propensity score, sorafenib
with early-stage HCC are generally administrated curative treatments such as surgery or local ablation, patients with intermediate-stage HCC usually receive transarterial chemoembolization, and patients with advanced-stage disease are candidates for systemic therapies.2 Sorafenib is a small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors, platelet-derived growth factor receptor-β and Raf kinase.3 Sorafenib is administrated p.o. and is the only systemic agent that provides a survival benefit for patients with advanced HCC.4,5 In global phase III trials, sorafenib was generally well tolerated;4,5 however, studies of general practice reported
279
280 M. Morimoto et al.
that treatment was interrupted in 22–40% of patients because of adverse drug reactions.6,7 The reason for this difference is unknown; however, differences in the ages of patients treated in practice and those studied in phase III trials may represent a contributing factor. Some case series reported the efficacy and safety of sorafenib using a reduced initial dose.8–10 However, no prior published study compared the safety and efficacy between different initial doses of sorafenib administrated to patients with HCC. In the present study, we aimed to evaluate the safety and efficacy of half-dose sorafenib treatment using a multicenter cohort. To minimize the potential effects of selection bias on patient characteristics treated with initial half or full doses, we used a model adjusted for propensity score.11
METHODS Patient selection
W
E ANALYZED RETROSPECTIVELY the medical records of 218 patients with histopathologically or radiographically proven HCC, or both, who were treated at four member institutes of the Kanagawa Liver Study Group between May 2009 and May 2012. All patients had Barcelona Clinic Liver Cancer intermediate or advanced stage HCC12 that was diagnosed at baseline according to the Response Evaluation Criteria in Solid Tumors.13 All patients provided written informed consent. The institutional review board or ethics committee at each institution approved the study protocol, which complied with Good Clinical Practice guidelines, the Declaration of Helsinki and local laws. The inclusion criteria were defined as Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less, Child–Pugh liver function class A, adequate hematological function (platelet count, >5.0 × 104/μL; hemoglobin level, >8.0 g/dL), adequate hepatic function (albumin level, >2.5 g/dL; total bilirubin level,
