title: Relationship of baseline serum bilirubin to efficacy and toxicity of single-agent irinotecan in patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  To examine the predictive value of baseline serum bilirubin measurement for chemotherapy-related toxicity or efficacy among patients receiving irinotecan for metastatic colorectal cancer.
  
  
  METHODS
  We performed a secondary analysis of a cohort of 287 patients treated in a multicenter, phase III study with single-agent irinotecan administered either weekly or once every 3 weeks. Patients were grouped into three categories of baseline bilirubin measurements (0 to 0.4, 0.5 to 0.9, and 1.0 to 1.5 mg/dL). We performed analyses of overall survival, time to progression, and treatment-related toxicity based on bilirubin category, as well as using bilirubin as a continuous variable.
  
  
  RESULTS
  With a median follow-up of 15.8 months, baseline serum bilirubin was not predictive of 1-year survival (42.4%, bilirubin 0 to 0.4; 42.3%, bilirubin 0.5 to 0.9; 48.1%, bilirubin 1.0 to 1.5 mg/dL), median overall survival (10.1, 9.7, and 15.6 months, respectively; P =.5), or median time to progression (2.8, 3.0, and 4.1 months, respectively; P =.5). Patients with elevated bilirubin had a significantly greater risk grade 3 to 4 neutropenia; however, this was limited to patients treated on a weekly schedule (P trend =.03) and not once every 3 weeks (P trend =.8). Other toxicities were not significantly different by initial bilirubin measurement.
  
  
  CONCLUSIONS
  Although modest elevations of bilirubin (1.0 to 1.5 mg/dL) are associated with increased grade 3 to 4 neutropenia in patients treated with weekly irinotecan, baseline serum bilirubin does not reliably predict overall irinotecan-related toxicity or efficacy. Additional methods, including potential application of pharmacogenetic information, are needed to optimize irinotecan dosing and tailor therapy to individual patients.
authors.affiliation: Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. jmeyerhardt@partners.org
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Ambrose
authors.initials: A
authors.lastname: Kwok
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: J Patrick
authors.initials: JP
authors.lastname: McGovren
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
mesh_terms: D000368:Aged; D000972:Antineoplastic Agents, Phytogenic; D001663:Bilirubin / Q000097:blood*; D002166:Camptothecin / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D001663:Bilirubin; D002166:Camptothecin