J Hepatobiliary Pancreat Sci (2015) 22:669–674 DOI: 10.1002/jhbp.255
ORIGINAL ARTICLE
Phase I study of gemcitabine, cisplatin, and S-1 combination therapy for patients with untreated advanced biliary tract cancer Toshikazu Moriwaki · Hiroyasu Ishida · Masahiro Araki · Shinji Endo · Shigemasa Yoshida · Mariko Kobayashi · Yukako Hamano · Akinori Sugaya · Masahiro Shimoyamada · Naoyuki Hasegawa · Mamiko Imanishi · Yuka Ito · Daiki Sato · Ichinosuke Hyodo Published online: 15 April 2015 © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Abstract Background To develop a triplet regimen containing gemcitabine, cisplatin, and S-1 (GPS), we assessed the recommended dose for patients with untreated advanced biliary tract cancer in this phase I study. Methods Dose-limiting toxicities (DLTs) were evaluated for the following two dose levels: gemcitabine (1000 mg/m2 for level 1 and 1200 mg/m2 for level 2 on day 1), cisplatin (30 mg/m2 fixed dose on day 1), and S-1 (40–60 mg/day fixed dose twice a day for 7 days), every 2 weeks until progression. DLTs for each level were evaluated in six or more patients during the first two cycles. Results A total of 18 patients were enrolled and 16 patients were evaluated. DLTs at level 1 were observed in two of 10 patients. At level 2, a DLT was observed in one of six patients. The main grade 3 or 4 treatment-related adverse events were neutropenia and leukopenia, and a few nonhematological toxicities were observed. Among 14 patients with measurable lesions, the best response rate was 50%. Conclusions GPS with a relative dose intensity corresponding to 90% of the standard gemcitabine plus cisplatin regimen T. Moriwaki (✉) · S. Endo · M. Kobayashi · Y. Hamano · A. Sugaya · N. Hasegawa · M. Imanishi · I. Hyodo Division of Gastroenterology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki 305-8575, Japan e-mail: [email protected] H. Ishida · S. Yoshida · M. Shimoyamada · Y. Ito · D. Sato Department of Gastroenterology, Mito Medical Center, National Hospital Organization, Ibaraki, Japan M. Araki Division of Gastroenterology, Ibaraki Prefectural Central Hospital and Cancer Center, Ibaraki, Japan
could be administered safely, and showed preliminary antitumor activity. Survival benefits will be studied subsequently. Keywords Biliary tract cancer · Cholangiocarcinoma · Cisplatin · Gallbladder carcinoma · Gemcitabine · S-1
Introduction Gemcitabine and fluoropyrimidine (FU) are used widely in patients with advanced biliary tract cancer (ABTC). Recently, gemcitabine plus cisplatin (GP) combination chemotherapy has been recognized as a standard first-line chemotherapy based on the results of a phase III study (ABC-02), which compared GP to gemcitabine alone in patients with ABTC [1]. Since then, FU-containing regimens have been used as second-line chemotherapy for ABTC. S-1, which contains tegafur, gimeracil, and oteracil, has been approved for the treatment of various solid tumors including ABTC in Japan, and S-1 in combination with cisplatin has been approved for gastric cancer therapy in Europe [2]. It showed promising activity against ABTC in several studies [3–10] and is mainly used in gemcitabine-refractory patients in Japan. However, all patients do not receive second-line chemotherapy. The proportion of patients who received second-line chemotherapy after the failure of first-line chemotherapy was reportedly 20 to 70% [1, 11, 12]. It was 60% in our previous study, where we explored prognostic factors for ABTC [13]. This study aimed to develop a triplet regimen, GP plus S-1, using valid drugs in the upfront treatment of patients with ABTC.
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Methods Patient eligibility Eligibility criteria were as follows: pathologically confirmed ABTC including extrahepatic cholangiocarcinoma (EHCC), intrahepatic cholangiocarcinoma (IHCC), or gallbladder carcinoma (GBC); age ≥20 years; Eastern Cooperative Oncology Group performance status 0–2; no prior chemotherapy; presence of measurable or evaluable lesion; adequate bone marrow function (peripheral absolute neutropenia count ≥1,500/mm3, platelet count ≥100,000/mm3, and hemoglobin ≥8.0 g/dL); adequate hepatic and renal functions (total serum bilirubin ≤3.0 mg/dL; this was set so that the patients with the bile drainage for obstructive jaundice can receive treatment as soon as possible, serum transaminases ≤2.5 times upper limit of normal [ULN] or ≤5 times ULN in case of liver metastasis, and serum creatinine within ULN or creatinine clearance ≥50 mL/min). The main exclusion criteria included inability of oral intake, infection with fever, massive ascites or pleural effusion, and uncontrolled intercurrent illness. All patients provided written informed consent before enrollment in the study. This study was conducted in three Japanese institutions and was coordinated by the NPO Tsukuba Cancer Clinical Trial Group. This study was performed in accordance with the Declaration of Helsinki and the Japanese Clinical Research Guidelines, and was approved by the ethics committee of each participating hospital. This study was registered with the University Hospital Medical Information Network (No. UMIN000006123).
Treatment The planned target relative dose intensity (RDI) of gemcitabine, cisplatin, and S-1 (GPS) in this study corresponded to 90% of the dose of the standard GP regimen in the ABC-02 trial [1] or the gemcitabine plus S-1 regimen in a previous phase II study [14]. On the basis of the results of a previously reported phase I study where oxaliplatin, gemcitabine and capecitabine could be combined at a full or nearly full dose of each drug in a biweekly schedule, we adopted this schedule in order to keep the dose intensity high [15]. Cisplatin was administered intravenously over 90 min followed by intravenous gemcitabine over 30 min on day 1. S-1 was administered orally twice a day on days 1–7. The treatment cycle was repeated every 2 weeks. Gemcitabine was administered at a dose of 1,000 mg/m2 in level 1 (corresponding to 75% relative dose intensity of the standard gemcitabine plus cisplatin therapy) and 1,200 mg/m2 in level 2 (corresponding to 90%). The cisplatin dose was fixed at 30 mg/m2 and the daily S-1 dose was defined according to
J Hepatobiliary Pancreat Sci (2015) 22:669–674
the patient’s body surface area as follows: 1.50 m2, 60 mg twice a day. The level 2 dose reached target RDI. No prophylactic granulocyte colony-stimulating factor was administered.
Definition of dose-limiting toxicity Dose-limiting toxicity (DLT) was evaluated during the first two cycles according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0. DLT was defined as grade 4 neutropenia lasting ≥5 days, febrile neutropenia, grade 4 thrombocytopenia, or grade 3 or higher non-hematological toxicities. A next cycle delay of >7 days due to any toxicity was also considered DLT. Dose escalation Six patients were enrolled for each dose level. If DLTs were not observed or were observed in one patient among the first six patients, the dose level was considered tolerable and acceptable. If DLTs occurred in two of six patients, three or more additional patients were enrolled for the same dose level. If no DLTs were observed in at least three additional patients, the dose was acceptable. If DLTs were observed in three or more patients among the first 6–9 patients, the dose was judged to be the maximum tolerated dose.
Dose modification during treatment Chemotherapy was postponed if blood counts before the initiation of each cycle were as follows: neutrophil count
ORIGINAL ARTICLE
Phase I study of gemcitabine, cisplatin, and S-1 combination therapy for patients with untreated advanced biliary tract cancer Toshikazu Moriwaki · Hiroyasu Ishida · Masahiro Araki · Shinji Endo · Shigemasa Yoshida · Mariko Kobayashi · Yukako Hamano · Akinori Sugaya · Masahiro Shimoyamada · Naoyuki Hasegawa · Mamiko Imanishi · Yuka Ito · Daiki Sato · Ichinosuke Hyodo Published online: 15 April 2015 © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Abstract Background To develop a triplet regimen containing gemcitabine, cisplatin, and S-1 (GPS), we assessed the recommended dose for patients with untreated advanced biliary tract cancer in this phase I study. Methods Dose-limiting toxicities (DLTs) were evaluated for the following two dose levels: gemcitabine (1000 mg/m2 for level 1 and 1200 mg/m2 for level 2 on day 1), cisplatin (30 mg/m2 fixed dose on day 1), and S-1 (40–60 mg/day fixed dose twice a day for 7 days), every 2 weeks until progression. DLTs for each level were evaluated in six or more patients during the first two cycles. Results A total of 18 patients were enrolled and 16 patients were evaluated. DLTs at level 1 were observed in two of 10 patients. At level 2, a DLT was observed in one of six patients. The main grade 3 or 4 treatment-related adverse events were neutropenia and leukopenia, and a few nonhematological toxicities were observed. Among 14 patients with measurable lesions, the best response rate was 50%. Conclusions GPS with a relative dose intensity corresponding to 90% of the standard gemcitabine plus cisplatin regimen T. Moriwaki (✉) · S. Endo · M. Kobayashi · Y. Hamano · A. Sugaya · N. Hasegawa · M. Imanishi · I. Hyodo Division of Gastroenterology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki 305-8575, Japan e-mail: [email protected] H. Ishida · S. Yoshida · M. Shimoyamada · Y. Ito · D. Sato Department of Gastroenterology, Mito Medical Center, National Hospital Organization, Ibaraki, Japan M. Araki Division of Gastroenterology, Ibaraki Prefectural Central Hospital and Cancer Center, Ibaraki, Japan
could be administered safely, and showed preliminary antitumor activity. Survival benefits will be studied subsequently. Keywords Biliary tract cancer · Cholangiocarcinoma · Cisplatin · Gallbladder carcinoma · Gemcitabine · S-1
Introduction Gemcitabine and fluoropyrimidine (FU) are used widely in patients with advanced biliary tract cancer (ABTC). Recently, gemcitabine plus cisplatin (GP) combination chemotherapy has been recognized as a standard first-line chemotherapy based on the results of a phase III study (ABC-02), which compared GP to gemcitabine alone in patients with ABTC [1]. Since then, FU-containing regimens have been used as second-line chemotherapy for ABTC. S-1, which contains tegafur, gimeracil, and oteracil, has been approved for the treatment of various solid tumors including ABTC in Japan, and S-1 in combination with cisplatin has been approved for gastric cancer therapy in Europe [2]. It showed promising activity against ABTC in several studies [3–10] and is mainly used in gemcitabine-refractory patients in Japan. However, all patients do not receive second-line chemotherapy. The proportion of patients who received second-line chemotherapy after the failure of first-line chemotherapy was reportedly 20 to 70% [1, 11, 12]. It was 60% in our previous study, where we explored prognostic factors for ABTC [13]. This study aimed to develop a triplet regimen, GP plus S-1, using valid drugs in the upfront treatment of patients with ABTC.
670
Methods Patient eligibility Eligibility criteria were as follows: pathologically confirmed ABTC including extrahepatic cholangiocarcinoma (EHCC), intrahepatic cholangiocarcinoma (IHCC), or gallbladder carcinoma (GBC); age ≥20 years; Eastern Cooperative Oncology Group performance status 0–2; no prior chemotherapy; presence of measurable or evaluable lesion; adequate bone marrow function (peripheral absolute neutropenia count ≥1,500/mm3, platelet count ≥100,000/mm3, and hemoglobin ≥8.0 g/dL); adequate hepatic and renal functions (total serum bilirubin ≤3.0 mg/dL; this was set so that the patients with the bile drainage for obstructive jaundice can receive treatment as soon as possible, serum transaminases ≤2.5 times upper limit of normal [ULN] or ≤5 times ULN in case of liver metastasis, and serum creatinine within ULN or creatinine clearance ≥50 mL/min). The main exclusion criteria included inability of oral intake, infection with fever, massive ascites or pleural effusion, and uncontrolled intercurrent illness. All patients provided written informed consent before enrollment in the study. This study was conducted in three Japanese institutions and was coordinated by the NPO Tsukuba Cancer Clinical Trial Group. This study was performed in accordance with the Declaration of Helsinki and the Japanese Clinical Research Guidelines, and was approved by the ethics committee of each participating hospital. This study was registered with the University Hospital Medical Information Network (No. UMIN000006123).
Treatment The planned target relative dose intensity (RDI) of gemcitabine, cisplatin, and S-1 (GPS) in this study corresponded to 90% of the dose of the standard GP regimen in the ABC-02 trial [1] or the gemcitabine plus S-1 regimen in a previous phase II study [14]. On the basis of the results of a previously reported phase I study where oxaliplatin, gemcitabine and capecitabine could be combined at a full or nearly full dose of each drug in a biweekly schedule, we adopted this schedule in order to keep the dose intensity high [15]. Cisplatin was administered intravenously over 90 min followed by intravenous gemcitabine over 30 min on day 1. S-1 was administered orally twice a day on days 1–7. The treatment cycle was repeated every 2 weeks. Gemcitabine was administered at a dose of 1,000 mg/m2 in level 1 (corresponding to 75% relative dose intensity of the standard gemcitabine plus cisplatin therapy) and 1,200 mg/m2 in level 2 (corresponding to 90%). The cisplatin dose was fixed at 30 mg/m2 and the daily S-1 dose was defined according to
J Hepatobiliary Pancreat Sci (2015) 22:669–674
the patient’s body surface area as follows: 1.50 m2, 60 mg twice a day. The level 2 dose reached target RDI. No prophylactic granulocyte colony-stimulating factor was administered.
Definition of dose-limiting toxicity Dose-limiting toxicity (DLT) was evaluated during the first two cycles according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0. DLT was defined as grade 4 neutropenia lasting ≥5 days, febrile neutropenia, grade 4 thrombocytopenia, or grade 3 or higher non-hematological toxicities. A next cycle delay of >7 days due to any toxicity was also considered DLT. Dose escalation Six patients were enrolled for each dose level. If DLTs were not observed or were observed in one patient among the first six patients, the dose level was considered tolerable and acceptable. If DLTs occurred in two of six patients, three or more additional patients were enrolled for the same dose level. If no DLTs were observed in at least three additional patients, the dose was acceptable. If DLTs were observed in three or more patients among the first 6–9 patients, the dose was judged to be the maximum tolerated dose.
Dose modification during treatment Chemotherapy was postponed if blood counts before the initiation of each cycle were as follows: neutrophil count
