Influence of initial dose intensity on efficacy of FOLFIRINOX in patients with advanced pancreatic cancer

// Satoshi Kobayashi 1 , Makoto Ueno 1 , Katsuhiro Omae 2 , Hidekazu Kuramochi 3 , Masato Terao 4 , Nobumasa Mizuno 5 , Masato Ozaka 6 , Hideki Ueno 7 , Kazuhiro Uesugi 8 , Noritoshi Kobayashi 9 , Marina Kobayashi 10 , Akiko Todaka 11 and Akira Fukutomi 11 1 Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama, 241-0815, Japan 2 Clinical Research Center, Clinical Research Promotion Unit, Shizuoka Cancer Center, Shuntogun, 411-8777, Japan 3 Department of Medical Oncology, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, 276-8524, Japan 4 Department of Medical Oncology, Fukuyama City Hospital, Fukuyama, 721-8511, Japan 5 Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, 464-8681, Japan 6 Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan 7 Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, 104-0045, Japan 8 Department of Gastroenterology, National Hospital Organization Shikoku Cancer Center, Matsuyama, 791-0280, Japan 9 Department of Oncology, Yokohama City University, Yokohama, 236-0004, Japan 10 Clinical Trial Promotion Section, Shizuoka Industrial Foundation Pharma Valley Center, Shuntogun, 411-0934, Japan 11 Department of Gastrointestinal Oncology, Shizuoka Cancer Center, Shuntogun, 411-8777, Japan Correspondence to: Satoshi Kobayashi, email: kobayashis@kcch.jp Keywords: irinotecan; fluorouracil; oxaliplatin; leucovorin; dose response relationship Received: August 11, 2018      Accepted: January 17, 2019      Published: March 05, 2019 ABSTRACT The combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is the standard of care for advanced pancreatic cancer, but causes hematological and gastrointestinal toxicities, leading to treatment delay and dose reduction; optimal modification based on toxicities is needed. Therefore, we evaluated the effect of initial relative dose intensity (RDI) on FOLFIRINOX efficacy by conducting a Japanese nationwide survey. We evaluated overall survival (OS) and progression-free survival (PFS) of patients administered two or more cycles of FOLFIRINOX, and determined RDIs for each drug within the first two cycles. RDI’s effect on efficacy was evaluated using a multivariate analysis with a Cox regression hazard model. Of 399 patients enrolled, 359 and 346 were evaluated for OS and PFS, respectively. Median RDI was 71.8%, 64.7%, 23.4%, and 76.9% for oxaliplatin, irinotecan, and bolus and continuous infusions of 5-FU, respectively. A high RDI for 5-FU bolus resulted in poor prognosis in terms of PFS (hazard ratio: 1.34; p = 0.022) and negatively correlated with objective response (coefficient: −0.70; p = 0.021), and a high RDI for CPT-11 positively correlated with objective response (coefficient: 1.02; p = 0.031). In conclusion, low and high RDIs for irinotecan and 5-FU bolus, respectively, resulted in poor FOLFIRINOX efficacy.