ANTICANCER RESEARCH 37 : 2663-2671 (2017) doi:10.21873/anticanres.11614 Efficacy and Safety Analysis of Oxaliplatin-based Chemotherapy for Advanced Gastric Cancer KYOKO INADOMI 1, HITOSHI KUSABA 1, YUZO MATSUSHITA 2, RISA TANAKA 2, KENJI MITSUGI 2, KOHEI ARIMIZU 3, GEN HIRANO 3, AKITAKA MAKIYAMA 3, HIROFUMI OHMURA 4, KEITA UCHINO 4, FUMIYASU HANAMURA 5, YOSHIHIRO SHIBATA 5, MIYUKI KUWAYAMA 6, TAITO ESAKI 6, KOTOE TAKAYOSHI 1, SHUJI ARITA 7, HIROSHI ARIYAMA 1, KOICHI AKASHI 1 and EISHI BABA 7 1Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; 2Department of Medical Oncology, Hamanomachi Hospital, Fukuoka, Japan; 3Department of Hematology and Oncology, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushu, Japan; 4Department of Medical Oncology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan; 5Department of Medical Oncology, Fukuoka Wajiro Hospital, Fukuoka, Japan; 6Department of Gastrointestinal and Medical Oncology, National Kyushu Cancer Center, Fukuoka, Japan; 7Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan Abstract. Background: Significant efficacy of oxaliplatin- increase with oxaliplatin at 130 mg/m 2. A total of 10 patients based chemotherapy has been demonstrated for advanced (18%) had a prior cisplatin-based therapy. The ORR of the gastric cancer (AGC). However, the appropriate dose of patients pretreated with cisplatin was 14% and the mPFS was oxaliplatin, and the efficacy and toxicity of administration of 6.1 months. Conclusion: An initial oxaliplatin dose of 130 oxaliplatin subsequent to cisplatin therapy still remain mg/m 2 resulted in a good response, but tended to increase the unclear. Patients and Methods: In total, 55 patients with AGC risk of toxicity. Subsequent oxaliplatin-based therapy after that were scheduled to receive oxaliplatin-based chemotherapy cisplatin exhibited modest efficacy, especially in cases with were prospectively examined. Results: The median age was 67 cisplatin intolerance. years and oxaliplatin was administered to 39 (71%) patients as first-line and in 16 (29%) patients as second-line therapy. Gastric cancer (GC) is the fourth most frequent malignant tumor An initial dose of 130 or 100 mg/m 2 of oxaliplatin was and the second most common cause of tumor death in the world administered to 11 and 36 patients, respectively. The overall (1). Recurrent GC after curative resection and initially response rates (ORR) and median progression free survival unresectable metastatic GC (advanced GC; AGC) are treated (mPFS) were 86 and 33%, and 7.2 and 7.8 months, with systemic chemotherapy (CT), that can prolong survival and respectively. Compared to 100 mg/m 2, the relative dose maintain quality of life. For the initial CT, combination intensity was significantly lower and severe toxicity tended to consisting of fluorouracil or fluoropyrimidine and platinum has been demonstrated to be effective. The triplet regimen including fluoropyrimidine, platinum and epirubicin is often used in European countries (2). Effectiveness of a triplet of docetaxel, This article is freely accessible online. cisplatin and fluorouracil has been shown in the United States (3). The standard therapy for patients with AGC in Japan has Correspondence to: Eishi Baba, MD, Ph.D., Department of been a combination of the oral fluoropyrimidine S-1 and Comprehensive Clinical Oncology, Faculty of Medical Sciences, cisplatin (SP) based on the results of the phase 3 SPIRITS study Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan. Tel: +81 926426921, Fax +81 926426922, e-mail: e-baba@c- (4). Another fluoropyrimidine, capecitabine, has also been shown oncology.med.kyushu-u.ac.jp to be effective for AGC in combination with cisplatin (5). Oxaliplatin has also been employed for systemic CT for Key Words: Gastric cancer, oxaliplatin, cisplatin, chemotherapy. AGC in combination with fluorouracil or fluoropyrimidine 2663 ANTICANCER RESEARCH 37 : 2663-2671 (2017) (2, 5, 6). Non-inferiority of oxaliplatin over cisplatin in terms Medical Oncology Group with written informed consent were of overall survival (OS) was demonstrated in the randomized assessed. The eligibility criteria were: 20 years or older, phase III REAL-2 study, in which the dosage of oxaliplatin histologically proven metastatic or recurrent gastric adenocarcinoma or esophagogastric junction adenocarcinoma, patients who were was 130 mg/m 2 (2). A phase II study that examined a planned to receive oxaliplatin-based chemotherapy at any treatment combination CT of S-1 plus oxaliplatin (SOX) exhibited line. This study was approved by the Ethics Committee of Kyushu efficacy for AGC (7). Subsequently, a phase III G-SOX study University Hospital (Approval No. 27-80) and was performed aimed at confirming the effectiveness of SOX for Japanese according to the guidelines for biomedical research specified in the patients with AGC demonstrated similar progression-free Declaration of Helsinki. survival (PFS) and OS by using a dose of oxaliplatin of 100 mg/m 2. This lower dose of oxaliplatin was used because of Treatment. All patients were treated with systemic CT consisting of a combination of SOX, oxaliplatin plus capecitabine (CapeOX), SOX frequent thrombocytopenia induced by oxaliplatin in the plus trastuzumab, or oxaliplatin, S-1 plus leucovorin. In the SOX previous phase II study (7, 8). Therefore, different doses of regimen, 40-60 mg of S-1 was orally administered twice-daily on days oxaliplatin have been used in individual regimens in Japanese 1-14, depending on the patient's body surface area, and 100 mg/m 2 or clinical practice; however, it remains to be clarified which of 130 mg/m 2 oxaliplatin was administered intravenously on day 1 every these doses are the most effective and the safest. 3 weeks. In the CapeOX regimen, 1,000 mg/m 2 capecitabine was 2 Both cisplatin and oxaliplatin are forms of platinum and orally administered twice-daily on days 1-14 and 100 mg/m or 130 2 can inhibit DNA-duplication by cross-linking double-stranded mg/m oxaliplatin was administered intravenously on day 1 every 3 weeks. Trastuzumab was administered at a dose of 8 mg/kg for the DNA. Cross-resistance between the two drugs is thought to initial course and at a dose of 6 mg/kg from the second course on day be unlikely because of the different repair mechanisms for the 1 every 3 weeks. In the combination regimen of oxaliplatin, S-1 plus DNA damage induced by each drug (9-15). Several clinical leucovorin, 85 mg/m 2 of oxaliplatin was administered on day 1 every studies have been conducted to address the efficacy of 2 weeks, and 60 mg S-1 and 25 mg leucovorin were administered oxaliplatin-based CT against cisplatin-resistant cancer (16- twice daily on days 1-7 every 2 weeks. These treatments were 18). A phase I study that examined a combination of continued until disease progression, unacceptable toxicity or the fluorouracil, leucovorin, mitomycin C and oxaliplatin for decision to discontinue by the patient or the investigator. Dose reduction and treatment delay were performed basically following the cisplatin-resistant AGC demonstrated a response rate (RR) of dose modification and interruption protocol of the G-SOX study (8). 35%, PFS of 4.1 months and OS of 8 months (17). A phase II study that employed FOLFOX4 (fluorouracil, leucovorin Assessments. Assessment of tumor lesions was basically performed and oxaliplatin) showed an RR of 26% and a median OS of by computed tomographic scan. Gastrointestinal endoscopy, 7.3 months (18). Although these studies suggested efficacy of magnetic resonance imaging and positron-emission tomography oxaliplatin-based CT against cisplatin-resistant AGC, were also utilized for examination of lesions if necessary. Tumor sequential usage of cisplatin- and oxaliplatin-based CTs has responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (21). PFS was not been well determined, especially in prospective studies. defined as the period from the initiation of oxaliplatin-based CT to The use of oxaliplatin for AGC was approved in Japan in the day of tumor progression or the day of death from any cause. 2015. Some patients with cisplatin-resistant AGC have been Additionally, for patients who had first-line cisplatin therapy and treated with oxaliplatin-based CT, and patients intolerant to were then administered oxaliplatin-based therapy as a second line, cisplatin have continued their platinum-based CT by the period from the initiation of cisplatin therapy to the termination switching from cisplatin to oxaliplatin in clinical practice in of oxaliplatin-based CT was also examined, which was defined as Japan. However, the efficacy and safety of administration of whole-platinum PFS. All adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology oxaliplatin subsequent to cisplatin therapy are poorly Criteria for Adverse Events (CTCAE) version 4.0 (22). The most understood. In addition, clinical studies of pre-operative SP severe grades of AE in the period of chemotherapy were recorded. therapy were recently conducted (19, 20). Conservation of the efficacy and safety of oxaliplatin-based CT in patients Statistics. PFS was estimated using the Kaplan–Meier method. who were treated with perioperative cisplatin-based CT in Comparison of tumor responses and the survival of patient groups cases of recurrence is an important issue. This study according to the dose of oxaliplatin was performed using Fisher’s prospectively examined the efficacy and safety of exact test and the log-rank test, respectively. Comparison of baseline characteristics before the initiation of oxaliplatin-based CT was oxaliplatin-based CT in Japanese clinical practice, especially performed using Student’s t-test. Values of p< 0.05 were considered in terms of differences in doses of oxaliplatin and the statistically significant. All statistical analyses were carried out subsequent use of oxaliplatin after cisplatin therapy. using JMP software (SAS Institute Japan, Tokyo, Japan).