Original Article Dig Dis 2014;32:705–710 DOI: 10.1159/000368006
Duration of Stable Disease Is Associated with Overall Survival in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib Tadaaki Arizumi Kazuomi Ueshima Hirokazu Chishina Masashi Kono Mashiro Takita Satoshi Kitai Tatsuo Inoue Norihisa Yada Satoru Hagiwara Yasunori Minami Toshiharu Sakurai Naoshi Nishida Masatoshi Kudo Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan
Abstract Background: Sorafenib is a molecular-targeting agent showing improved overall survival (OS) for advanced hepatocellular carcinoma (HCC). Although tumor dormancy, characterized by stable tumor status or stable disease (SD) without tumor regression, is a unique feature of sorafenib treatment, the contribution of SD to OS remains debatable. This study aimed to clarify the correlation between SD periods and OS in patients with HCC treated with sorafenib. Methods: From May 2009 to January 2013, 269 patients with advancedstage HCC were treated with sorafenib at the Kinki University Hospital. The antitumor response of sorafenib was evaluated in 158 patients using the modified Response Evaluation Criteria in Solid Tumors, and patients with SD were divided into two subgroups according to the median duration of SD: short SD (1 month, (3) performance status of 0 or 1 and (4) ChildPugh class A or B. Exclusion criteria were: (1) concomitant anti-
706
Dig Dis 2014;32:705–710 DOI: 10.1159/000368006
neoplastic treatment, (2) TACE or radiofrequency ablation performed within 3 months of initiation of sorafenib and (3) lack of response evaluation using CE-CT or dynamic MRI during the follow-up period. Patient characteristics are summarized in online supplementary table 1 (for all online suppl. material, see www. karger.com/doi/10.1159/000368006). Initial and Follow-Up Assessments Liver function and tumor stage were evaluated before the initiation of sorafenib therapy using the Child-Pugh, Barcelona Clinic for Liver Cancer (BCLC) and Cancer of the Liver Italian Program classifications. CE-CT images were obtained during the arterial (40 s) and portal (70 s) phases using 120 ml of iomeprol at a flow rate of 3 ml/s. Dynamic MRI was performed using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOBDTPA) enhancement during the arterial (22–35 s after injection) and portal venous (70 s after injection) phases. A T1-weighted high-resolution sequence was obtained during a single breath hold. CE-CT and Gd-EOB-DTPA-MRI were reviewed by two independent radiologists. The response to sorafenib was assessed every 4–6 weeks using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) according to the interval change in tumor size and vascularity after the initiation of treatment. Two experienced radiologists retrospectively reviewed each CE-CT and Gd-EOB-DTPA-MRI, and tumor response was evaluated in a nonblinded fashion [22]. For all patients, the target lesions were defined by two experienced hepatologists using the CT and/or MRI scans before treatment. Extrahepatic lesions were assessed as required by chest X-ray, bone scintigraphy or fluorodeoxyglucose positron emission tomography, and tumor markers were measured at 4- to 12-week intervals to assess the tumor status. The criteria for discontinuing sorafenib were (1) detection of progressive disease (PD), such as obvious tumor progression and/or onset of a new lesion (based on the mRECIST criteria); (2) grade 3 or higher adverse reactions that could not be well controlled by dose reduction or interruption (based on the Common Terminology Criteria for Adverse Events, version 4.0; http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ctcaev3.pdf), and (3) noncompliance to oral drug treatment and/or follow-up visits. Definitions of Tumor Response Complete response (CR) was defined as the disappearance of any arterial enhancement within all target lesions. PR was defined as ≥30% reduction in tumor size. Tumor size was determined by the sum of the diameters of target lesions, which were estimated using unidirectional measurement. PD was defined as ≥20% increase in tumor size determined by the sum of the maximal dimensions of the target lesions. mRECIST defines SD as the absence of either PR or PD; it defines response rate (PR) as the percentage of CR + PR among all cases, and disease control rate as the percentage of cases achieving CR, PR or SD. We further classified patients with SD into two subgroups: the long SD group was defined as continuous SD for ≥3 months, and the short SD group was defined as SD periods
Duration of Stable Disease Is Associated with Overall Survival in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib Tadaaki Arizumi Kazuomi Ueshima Hirokazu Chishina Masashi Kono Mashiro Takita Satoshi Kitai Tatsuo Inoue Norihisa Yada Satoru Hagiwara Yasunori Minami Toshiharu Sakurai Naoshi Nishida Masatoshi Kudo Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan
Abstract Background: Sorafenib is a molecular-targeting agent showing improved overall survival (OS) for advanced hepatocellular carcinoma (HCC). Although tumor dormancy, characterized by stable tumor status or stable disease (SD) without tumor regression, is a unique feature of sorafenib treatment, the contribution of SD to OS remains debatable. This study aimed to clarify the correlation between SD periods and OS in patients with HCC treated with sorafenib. Methods: From May 2009 to January 2013, 269 patients with advancedstage HCC were treated with sorafenib at the Kinki University Hospital. The antitumor response of sorafenib was evaluated in 158 patients using the modified Response Evaluation Criteria in Solid Tumors, and patients with SD were divided into two subgroups according to the median duration of SD: short SD (1 month, (3) performance status of 0 or 1 and (4) ChildPugh class A or B. Exclusion criteria were: (1) concomitant anti-
706
Dig Dis 2014;32:705–710 DOI: 10.1159/000368006
neoplastic treatment, (2) TACE or radiofrequency ablation performed within 3 months of initiation of sorafenib and (3) lack of response evaluation using CE-CT or dynamic MRI during the follow-up period. Patient characteristics are summarized in online supplementary table 1 (for all online suppl. material, see www. karger.com/doi/10.1159/000368006). Initial and Follow-Up Assessments Liver function and tumor stage were evaluated before the initiation of sorafenib therapy using the Child-Pugh, Barcelona Clinic for Liver Cancer (BCLC) and Cancer of the Liver Italian Program classifications. CE-CT images were obtained during the arterial (40 s) and portal (70 s) phases using 120 ml of iomeprol at a flow rate of 3 ml/s. Dynamic MRI was performed using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOBDTPA) enhancement during the arterial (22–35 s after injection) and portal venous (70 s after injection) phases. A T1-weighted high-resolution sequence was obtained during a single breath hold. CE-CT and Gd-EOB-DTPA-MRI were reviewed by two independent radiologists. The response to sorafenib was assessed every 4–6 weeks using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) according to the interval change in tumor size and vascularity after the initiation of treatment. Two experienced radiologists retrospectively reviewed each CE-CT and Gd-EOB-DTPA-MRI, and tumor response was evaluated in a nonblinded fashion [22]. For all patients, the target lesions were defined by two experienced hepatologists using the CT and/or MRI scans before treatment. Extrahepatic lesions were assessed as required by chest X-ray, bone scintigraphy or fluorodeoxyglucose positron emission tomography, and tumor markers were measured at 4- to 12-week intervals to assess the tumor status. The criteria for discontinuing sorafenib were (1) detection of progressive disease (PD), such as obvious tumor progression and/or onset of a new lesion (based on the mRECIST criteria); (2) grade 3 or higher adverse reactions that could not be well controlled by dose reduction or interruption (based on the Common Terminology Criteria for Adverse Events, version 4.0; http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ctcaev3.pdf), and (3) noncompliance to oral drug treatment and/or follow-up visits. Definitions of Tumor Response Complete response (CR) was defined as the disappearance of any arterial enhancement within all target lesions. PR was defined as ≥30% reduction in tumor size. Tumor size was determined by the sum of the diameters of target lesions, which were estimated using unidirectional measurement. PD was defined as ≥20% increase in tumor size determined by the sum of the maximal dimensions of the target lesions. mRECIST defines SD as the absence of either PR or PD; it defines response rate (PR) as the percentage of CR + PR among all cases, and disease control rate as the percentage of cases achieving CR, PR or SD. We further classified patients with SD into two subgroups: the long SD group was defined as continuous SD for ≥3 months, and the short SD group was defined as SD periods
