title: An internally and externally validated nomogram for predicting the risk of irinotecan-induced severe neutropenia in advanced colorectal cancer patients.
abstract: BACKGROUND
  In Asians, the risk of irinotecan-induced severe toxicities is related in part to UGT1A1*6 (UGT, UDP glucuronosyltransferase) and UGT1A1*28, variant alleles that reduce the elimination of SN-38, the active metabolite of irinotecan. We prospectively studied the relation between the UGT1A1 genotype and the safety of irinotecan-based regimens in Japanese patients with advanced colorectal cancer, and then constructed a nomogram for predicting the risk of severe neutropenia in the first treatment cycle.
  
  
  METHODS
  Safety data were obtained from 1312 patients monitored during the first 3 cycles of irinotecan-based regimen in a prospective observational study. In development of the nomogram, multivariable logistic regression analysis was used to test the associations of candidate factors to severe neutropenia in the first cycle. The final nomogram based on the results of multivariable analysis was constructed and validated internally using a bootstrapping technique and externally in an independent data set (n=350).
  
  
  RESULTS
  The UGT1A1 genotype was confirmed to be associated with increased risks of irinotecan-induced grade 3 or 4 neutropenia and diarrhoea. The final nomogram included type of regimen, administered dose of irinotecan, gender, age, UGT1A1 genotype, Eastern Cooperative Oncology Group performance status, pre-treatment absolute neutrophil count, and total bilirubin level. The model was validated both internally (bootstrap-adjusted concordance index, 0.69) and externally (concordance index, 0.70).
  
  
  CONCLUSIONS
  Our nomogram can be used before treatment to accurately predict the probability of irinotecan-induced severe neutropenia in the first cycle of therapy. Additional studies should evaluate the effect of nomogram-guided dosing on efficacy in patients receiving irinotecan.
authors.affiliation: Division of Medical Oncology, Department of Medicine, Showa University, School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Ichikawa
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Uehara
authors.affiliation: Department of Surgery, Mitsui Memorial Hospital, Kanda-Izumi-cho 1, Chiyoda-ku, Tokyo 101-8643, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Minamimura
authors.affiliation: Department of Surgery, Gifu Prefectural General Medical Centre, 4-6-1 Noishiki, Gifu 500-8717, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Tanaka
authors.affiliation: Department of Surgery, Niigata Cancer Centre Hospital, 2-15-3 Kawagishi-cho, Chuo-ku, Niigata 951-8566, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takii
authors.affiliation: Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Miyauchi
authors.affiliation: Department of Surgery, Tokai University, 143 Shimoyasuya, Isehara 259-1193, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Sadahiro
authors.affiliation: Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Division of Gastroenterology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Moriwaki
authors.affiliation: Comprehensive Cancer Centre, Aizawa Hospital, 2-5-1 Honjo, Matsumoto 390-8510, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Division of Medical Oncology, Department of Medicine, Showa University, School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Medical Oncology, Kobe City Medical Centre General Hospital, 2-1-1 Minatojimaminamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Tsuji
authors.affiliation: Division of Clinical Oncology, Hiroshima Prefectural Hospital, 1-5-54 Ujina-Kanda, Minami-ku, Hiroshima 734-8530, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Shinozaki
authors.affiliation: Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Morita
authors.affiliation: Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ando
authors.affiliation: Medical Affairs Department, Daiichi Sankyo, 3-5-1 Nihonbashi-Honcho, Chuo-ku 103-8426, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Okutani
authors.affiliation: Clinical Data & Biostatistics Department, Daiichi Sankyo, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sugihara
authors.affiliation: Department of Obstetrics and Gynaecology, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka 020-8505, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Department of Integrated Science and Engineering for Sustainable Society, Faculty of Science and Engineering, Chuo University, 1-13-27 Kasuga, Tokyo 112-8551, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ohashi
authors.affiliation: CEO, Misawa City Hospital, 164-65, Aza Horiguchi, Oaza Misawa, Misawa, Aomori 033-0022, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sakata
mesh_terms: D000368:Aged; D000483:Alleles; D044466:Asian People / Q000235:genetics; D001663:Bilirubin / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D049451:Nomograms; D011446:Prospective Studies; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme