Randomized phase III trial of gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer, the short-term safety and surgical results: Japan Clinical Oncology Group Study (JCOG0501)
- 1.3k Downloads
The prognosis of patients with linitis plastica (type 4) and large (≥ 8 cm) ulcero-invasive-type (type 3) gastric cancer is extremely poor, even after extended surgery and adjuvant chemotherapy. Given the promising results of our previous phase II study evaluating neoadjuvant chemotherapy (NAC) with S-1 plus cisplatin (JCOG0210), we performed a phase III study to confirm the efficacy of NAC in these patients, with the safety and surgical results are presented here.
Eligible patients were randomized to gastrectomy plus adjuvant chemotherapy with S-1 (Arm A) or NAC followed by gastrectomy + adjuvant chemotherapy (Arm B). The primary endpoint was the overall survival (OS). This trial is registered at the UMIN Clinical Trials Registry as C000000279.
From February 2007 to July 2013, 300 patients were randomized (Arm A 149, Arm B 151). NAC was completed in 133 patients (88%). Major grade 3/4 adverse events during NAC were neutropenia (29.3%), nausea (5.4%), diarrhea (4.8%), and fatigue (2.7%). Gastrectomy was performed in 147 patients (99%) in Arm A and 139 patients (92%) in Arm B. The operation time was significantly shorter in Arm B than in Arm A (median 255 vs. 240 min, respectively; p = 0.024). There were no significant differences in Grade 2–4 morbidity and mortality (25.2% and 1.3% in Arm A and 15.8% and 0.7% in Arm B, respectively).
NAC for type 4 and large type 3 gastric cancer followed by D2 gastrectomy can be safely performed without increasing the morbidity or mortality.
KeywordsLinitis plastica Neoadjuvant chemotherapy Large type 3
The authors are grateful to the members of the JCOG Data Center and JCOG Operations Office for their support in this study.
Stomach Cancer Study Group, Japan Clinical Oncology Group: Akinori Takagane, Hakodate Goryokaku Hospital; Keisuke Koeda, Iwate Medical University; Shin Teshima, National Hospital Organization, Sendai Medical Center; Tsuneaki Fujitani, Miyagi Cancer Center; Norimasa Fukushima, Yamagata Prefectural Central Hospital; Naoyuki Matsushita, Tochigi Cancer Center; Hase Kazuo, National Defense Medical College; Yoshiyuki Kawashima, Saitama Cancer Center; Takahiro Kinoshita, National Cancer Center Hospital East; Hitoshi Katai, National Cancer Center Hospital; Yoshiaki Iwasaki, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital; Mikito Inokuchi, Tokyo Medical and Dental University Hospital; Takeshi Sano, Cancer Institute Hospital of Japanese Foundation for Cancer Research; Masanori Ueno, Toranomon Hospital; Ikuo Wada, Tokyo Metropolitan Bokutoh Hospital; Takaki Yoshikawa, Kanagawa Cancer Center; Hiroshi Yabusaki, Niigata Cancer Center Hospital; Yasuyuki Kawauchi, Nagaoka Chuo General Hospital; Kaoru Miyashita, Tsubame Rosai Hospital; Masahide Kaji, Toyama Prefectural Central Hospital; Makoto Yamada, Gifu Municipal Hospital; Masakazu Takagi, Shizuoka General Hospital; Masanori Terashima, Shizuoka Cancer Center; Seiji Ito, Aichi Cancer Center Hospital; Hiroaki Hata, National Hospital Organization Kyoto Medical Center Hiroki Taniguchi, Kyoto Second Red Cross Hospital; Yuichiro Doki, Osaka University Graduate School of Medicine; Takushi Yasuda, Kinki University Faculty of Medicine; Ken Omori, Osaka Prefectural Hospital Organization Osaka Medical Center for Cancer and Cardiovascular Diseases; Motohiro Hirao, National Hospital Organization Osaka National Hospital; Masahiro Goto, Osaka Medical College; Hiroshi Imamura, Toyonaka Municipal Hospital.
The study was supported in part by the National Cancer Center Research and Development Funds (23-A-19, and 26-A-4, 29-A-3) and a Grant-in-Aid for Clinical Cancer Research (H19-15, H22-027, H22-23) from the Ministry of Health, Labour and Welfare of Japan.
Compliance with ethical standards
Conflict of interest
Author MT has received personal fees from Taiho, Ono, Chugai, Eli Lilly Japan, Bristol Myers Squib, and Yakult Honsha outside the submitted work. Author MS received personal fees from Taiho, Chugai, Lilly, and Ono outside the submitted work. Author TS has received personal fees from Taiho. Author NB has received grant from Taiho, Ono and Bristol Myer-Squibb, and honorarium form Taiho, Ono, Chugai, Eli Lilly and Bristol Myer-Squibb. Author KN has received personal fees from Bayer, Chugai, Merck, and Eisai outside the submitted work. Author TY has received grants and personal fees from Taiho, Chugai, Yakult, personal fees from Ono, Bristol, Lilly, Terumo, Abbott, Johnson and Johnson, Covidien, Olympus, Nihon Kayaku, Daiichi Sankyo outside the submitted work. Author HK has received personal fees from Johnson & Johnson outside the submitted work.
Human rights statement
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the 1964 Declaration of Helsinki and later versions.
Informed consent was obtained from all patients for inclusion in the study.
- 6.Tsuburaya A, Mizusawa J, Tanaka Y, Fukushima N, Nashimoto A, Sasako M, et al. Neoadjuvant chemotherapy with S-1 and cisplatin followed by D2 gastrectomy with para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis. Br J Surg. 2014;101:653–60.CrossRefPubMedGoogle Scholar
- 7.Sasako M, Maruyama K, Kinoshita T, et al. Neoadjuvant chemotherapy for gastric cancer: Indication and trial setting (in Japanese). Shokakigeka. 1992;15:159–67.Google Scholar
- 12.Japanese Research Society for Gastric Cancer. Japanese Classification of Gastric Carcinoma. First ed. Tokyo: Kanehara & Co. Ltd.; 1995.Google Scholar
- 16.Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, et al. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016;17:1697–708.CrossRefPubMedGoogle Scholar
- 17.Al-Batran SE, Homann N, Pauligk C, Illerhaus G, Martens UM, Stoehlmacher J, et al. Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: the AIO-FLOT3 trial. JAMA Oncol. 2017;3:1237–44.CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Al-Batran SE, Homann N, Schmalenberg H, Kopp HG, Haag GM, Luley KB. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicentre, randomized phase 3 trial. J Clin Oncol. 2017;35(suppl 15):4004.CrossRefGoogle Scholar
- 22.Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, et al. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010;28:1547–53.CrossRefPubMedGoogle Scholar
- 23.Bodoky G, Scheulen ME, Rivera F, Jassem J, Carrato A, Moiseyenko V, et al. Clinical benefit and health-related quality of life assessment in patients treated with cisplatin/S-1 versus cisplatin/5-FU: secondary end point results from the first-line advanced gastric cancer study (FLAGS). J Gastrointest Cancer. 2015;46:109–17.CrossRefPubMedGoogle Scholar
- 24.Ito S, Sano T, Mizusawa J, Takahari D, Katayama H, Katai H, et al. A phase II study of preoperative chemotherapy with docetaxel, cisplatin, and S-1 followed by gastrectomy with D2 plus para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis: JCOG1002. Gastric Cancer. 2017;20:322–31.CrossRefPubMedGoogle Scholar