title: Large-scale prospective pharmacogenomics study of oxaliplatin-induced neuropathy in colon cancer patients enrolled in the JFMC41-1001-C2 (JOIN Trial).
abstract: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study.
  
  
  
  Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN.
  
  
  
  Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences.
  
  
  
  Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.
authors.affiliation: Department of Clinical Oncology, Pharmacogenomics, and Palliative Medicine. Electronic address: kanai@kuhp.kyoto-u.ac.jp.
authors.forename: M
authors.initials: M
authors.lastname: Kanai
authors.affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto.
authors.forename: T
authors.initials: T
authors.lastname: Kawaguchi
authors.affiliation: Gastrointestinal Cancer Center, Sano Hospital, Kobe.
authors.forename: M
authors.initials: M
authors.lastname: Kotaka
authors.affiliation: Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima.
authors.forename: K
authors.initials: K
authors.lastname: Shinozaki
authors.affiliation: Department of Surgery, Nakagami Hospital, Okinawa.
authors.forename: T
authors.initials: T
authors.lastname: Touyama
authors.affiliation: Department of Surgery, Gastrointestinal Center, Kyoto-Katsura Hospital, Kyoto.
authors.forename: D
authors.initials: D
authors.lastname: Manaka
authors.affiliation: Department of Surgery, Konan Kosei Hospital Konan, Aichi.
authors.forename: K
authors.initials: K
authors.lastname: Ishigure
authors.affiliation: Department of Surgery, Osaka Rosai Hospital, Osaka.
authors.forename: J
authors.initials: J
authors.lastname: Hasegawa
authors.affiliation: Department of Surgery, Fukui-ken Saiseikai Hospital, Fukui.
authors.forename: Y
authors.initials: Y
authors.lastname: Munemoto
authors.affiliation: Department of Gastroenterological Surgery, Aichi Cancer Center Aichi Hospital, Aichi.
authors.forename: T
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Department of Surgery, Hakodate Goryoukaku Hospital, Hokkaido.
authors.forename: A
authors.initials: A
authors.lastname: Takagane
authors.affiliation: Department of Gastrointestinal Surgery, Sasebo City General Hospital, Nagasaki.
authors.forename: H
authors.initials: H
authors.lastname: Ishikawa
authors.affiliation: Department of Clinical Oncology, Graduate School of Medicine, Kyoto University, Kyoto.
authors.forename: S
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo.
authors.forename: J
authors.initials: J
authors.lastname: Sakamoto
authors.affiliation: Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo.
authors.forename: S
authors.initials: S
authors.lastname: Saji
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba.
authors.forename: T
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba.
authors.forename: A
authors.initials: A
authors.lastname: Ohtsu
authors.affiliation: Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto.
authors.forename: F
authors.initials: F
authors.lastname: Matsuda
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects; D006801:Humans; D007564:Japan; D002955:Leucovorin / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil
keywords: FOLFOX; adjuvant chemotherapy; colon cancer; neuropathy; oxaliplatin; pharmacogenomics