title: Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials.
abstract: BACKGROUND
  Oxaliplatin-based adjuvant therapy is the standard of care for stage III colon cancer. Adjuvant capecitabine with or without oxaliplatin versus leucovorin and fluorouracil with or without oxaliplatin has not been directly compared; therefore, we aimed to analyse the efficacy and safety of these treatments using individual patient data pooled from four randomised controlled trials. We also assessed post-relapse survival, which has been postulated to be worse in patients receiving adjuvant oxaliplatin.
  
  
  METHODS
  Patients with resected stage III colon cancer who were 18 years of age or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from four randomised controlled trials (NSABP C-08, XELOXA, X-ACT, and AVANT; 8734 patients in total) were pooled and analysed. The treatment regimens included in our analyses were: XELOX (oxaliplatin and capecitabine); leucovorin and fluorouracil; capecitabine; FOLFOX-4 (leucovorin, fluorouracil, and oxaliplatin); and modified FOLFOX-6 (mFOLFOX-6). Disease-free survival was the primary endpoint for all trials that supplied patients for this analysis. Here, we compared disease-free, relapse-free, and overall survival between the patient groups who received capecitabine with or without oxaliplatin and those who received leucovorin and fluorouracil with or without oxaliplatin. Post-relapse survival was compared between the combined XELOX and FOLFOX groups, and the leucovorin and fluorouracil groups. Post-relapse survival was also compared between the capecitabine with or without oxaliplatin and leucovorin and fluorouracil with or without oxaliplatin groups.
  
  
  RESULTS
  Disease-free survival did not differ significantly between patients who received leucovorin and fluorouracil versus those who received capecitabine in adjusted analyses (hazard ratio [HR] 1·02 [0·93-1·11; p=0·72]) or in unadjusted analyses (HR 1·01 [95% CI 0·92-1·10; p=0·86]). Relapse-free survival was similar (adjusted HR 1·02 [0·93-1·12; p=0·72] and unadjusted HR 1·01 [95% CI 0·92-1·11; p=0·86]), as was overall survival (adjusted HR 1·04 [95% CI 0·93-1·15; p=0·50] and unadjusted HR 1·02 [0·92-1·14]; p=0·65). For overall survival, a significant interaction between oxaliplatin and fluoropyrimidine was recorded in the multiple Cox regression analysis (p=0·014). Post-relapse survival was similar in adjusted (p=0·23) and unadjusted analyses (p=0·33) for the comparison of XELOX or FOLFOX versus leucovorin and fluorouracil, and was also similar for capecitabine-based regimens versus leucovorin and fluorouracil-based regimens (unadjusted p=0·26).
  
  
  CONCLUSIONS
  Combination therapy with oxaliplatin provided consistently improved outcomes without adversely affecting post-relapse survival in the adjuvant treatment of stage III colon cancer, irrespective of whether the fluoropyrimidine backbone was capecitabine or leucovorin and fluorouracil. These data add to the existing evidence that oxaliplatin plus capecitabine or leucovorin and fluorouracil is the standard of care for the adjuvant treatment of stage III colon cancer, and offers physicians flexibility to treat patients according to the patients' overall physical performance and preference.
  
  
  BACKGROUND
  Genentech Inc.
authors.affiliation: University Clinic, Martin Luther University, Halle (Saale), Germany. Electronic address: hans-joachim.schmoll@uk-halle.de.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schmoll
authors.affiliation: Leeds Institute of Cancer and Pathology and St James's University Hospital, Leeds, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Twelves
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Weijing
authors.initials: W
authors.lastname: Sun
authors.affiliation: National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Connell
authors.affiliation: Florida Cancer Affiliates, New Port Richey, FL, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cartwright
authors.affiliation: Genentech Inc, South San Francisco, CA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: McKenna
authors.affiliation: Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Saif
authors.affiliation: Genentech Inc, South San Francisco, CA, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Lee
authors.affiliation: NSABP Biostatistical Center and University of Pittsburgh Graduate School of Public Health Department of Biostatistics, Pittsburgh, PA, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Yothers
authors.affiliation: Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Haller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069287:Capecitabine; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil