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A Prospective, Randomized Phase II Study of Adjuvant Gemcitabine Versus S-1 After Major Hepatectomy for Biliary Tract Cancer (KHBO 1208)

Kansai Hepato-Biliary Oncology Group

Kobayashi, Shogo MD, PhD*,†,§§§; Nagano, Hiroaki MD, PhD*,***,§§§; Tomokuni, Akira MD, PhD†,§§§; Gotoh, Kunihito MD, PhD*,†,§§§; Sakai, Daisuke MD, PhD‡,§§§; Hatano, Etsuro MD, PhD§,¶,§§§; Seo, Satoru MD, PhD§,§§§; Terajima, Hiroaki MD, PhD||,§§§; Uchida, Yoichiro MD, PhD||,§§§; Ajiki, Tetsuo MD, PhD**,§§§; Satake, Hironaga MD, PhD††,§§§; Kamei, Keiko MD, PhD‡‡,§§§; Tohyama, Taiji MD, PhD§§,§§§; Hirose, Tetsuro MD, PhD¶¶,§§§; Ikai, Iwao MD, PhD||||,§§§; Morita, Satoshi PhD†††,§§§; Ioka, Tatsuya MD‡‡‡,§§§ on behalf of the Kansai Hepato-Biliary Oncology (KHBO) Group

doi: 10.1097/SLA.0000000000002865
RANDOMIZED CONTROLLED TRIALS
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Objective: To evaluate each arm independently and compare adjuvant gemcitabine (GEM) and S-1 chemotherapy after major hepatectomy (hemihepatectomy or trisectionectomy) for biliary tract cancer (BTC).

Background: Standardized adjuvant therapy is not performed after major hepatectomy for BTC, and we determined the recommended dose in the former study (KHBO1003).

Methods: We performed a multicenter, randomized phase II study. The primary measure was 1-year recurrence-free survival (RFS); the secondary measures were other RFS, overall survival (OS), and others. The following 6-month adjuvant chemotherapy was administered within 12 weeks of R0/1: GEM (1000 mg/m2) every 2 weeks; or S-1 (80 mg/m2/d) for 28 days every 6 weeks. Thirty-five patients were assigned to each arm (alpha error, 10%; beta error, 20%).

Results: No patients were excluded for the per-protocol analysis. There were no statistically significant differences in the patient characteristics of the 2 arms. The 1-year RFS and 1-year OS rates of the GEM arm were 51.4% and 80.0%, respectively, whereas those of the S-1 group were 62.9% and 97.1%. The comparison of the 2 arms revealed that 2-year RFS rate, 1 and 2-year OS rates, and OS curve of the S-1 arm were superior to GEM. With regard to OS, the hazard ratio of the S-1 group was 0.477 (90% confidence interval 0.245–0.927).

Conclusion: The comparison of the survival of the 2 groups revealed that adjuvant S-1 therapy may be superior to adjuvant GEM therapy after major hepatectomy for BTC.

*Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan

Department of Surgery, Osaka International Cancer Institute, Osaka, Japan

Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Osaka, Japan

§Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Department of Surgery, Hyogo College of Medicine, Hyogo, Japan

||Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Tazukekofukai Medical Research Institute, Osaka, Japan

**Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Kobe University, Hyogo, Japan

††Department of Medical Oncology, Kobe City Medical Center General Hospital, Hyogo, Japan

‡‡Department of Surgery, Kindai University Faculty of Medicine, Osaka, Japan

§§Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Ehime, Japan

¶¶Department of Surgery, Otsu Red Cross Hospital, Shiga, Japan

||||Department of Surgery, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

***Department of Gastroenterological, Breast and Endocrine Surgery, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan

†††Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

‡‡‡Department of Cancer Survey and Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan

§§§Kansai Hepato-Biliary Oncology Group, Osaka, Japan.

Reprints: Shogo Kobayashi, MD, PhD, Departments of Surgery, Graduate School of Medicine, Osaka University, 2-2 (E2) Yamadaoka, Suita City, Osaka 565-0871, Japan. E-mails: s-kobayashi@umin.ac.jp, kobayasi-si@mc.pref.osaka.jp, skobayashi@gesurg.med.osaka-u.ac.jp.

Funding: This work was supported by JSCO (Japan Society of Clinical Oncology) Clinical Research Grant Program 2012 and 2013.

Disclosures: IT received research funding and a lecture fee from Taiho Pharmaceutical Co. MS received a lecture fee from Taiho Pharmaceutical Co and Eli Lilly Japan K.K. The remaining authors declare no conflicts of interest in association with the present study.

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