Duration of Adjuvant Doublet Chemotherapy (3 or 6 months) in Patients With High-Risk Stage II Colorectal Cancer
Timothy J Iveson, Alberto F Sobrero, Takayuki Yoshino, Ioannis Souglakos, Fang-Shu Ou, Jeffrey P Meyers, Qian Shi, Axel Grothey, Mark P Saunders, Roberto Labianca, Takeharu Yamanaka, Ioannis Boukovinas, Niels H Hollander, Fabio Galli, Kentaro Yamazaki, Vassilis Georgoulias, Rachel Kerr, Eiji Oki, Sara Lonardi, Andrea Harkin, Gerardo Rosati, James Paul, Timothy J Iveson, Alberto F Sobrero, Takayuki Yoshino, Ioannis Souglakos, Fang-Shu Ou, Jeffrey P Meyers, Qian Shi, Axel Grothey, Mark P Saunders, Roberto Labianca, Takeharu Yamanaka, Ioannis Boukovinas, Niels H Hollander, Fabio Galli, Kentaro Yamazaki, Vassilis Georgoulias, Rachel Kerr, Eiji Oki, Sara Lonardi, Andrea Harkin, Gerardo Rosati, James Paul
Abstract
Purpose: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers.
Patients and methods: Four of the six studies in the International Duration of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required.
Results: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68).
Conclusion: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.
Trial registration: ClinicalTrials.gov NCT00749450 NCT00646607 NCT01308086.
Figures
References
- Andre T Boni C Mounedji-Boudiaf L, et al. : Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004
- Kuebler JP Wieand HS O'Connell MJ, et al. : Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: Results from NSABP C-07. J Clin Oncol 25:2198-2204, 2007
- Schmoll HJ Tabernero J Maroun J, et al. : Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III Colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol 33:3733-3740, 2015
- Grothey A Sobrero AF Shields AF, et al. : Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med 378:1177-1188, 2018
- Tournigand C Andre T Bonnetain F, et al. : Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: Subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer trial. J Clin Oncol 30:3353-3360, 2012
- Dienstmann R, Salazar R, Tabernero J: Personalizing colon cancer adjuvant therapy: Selecting optimal treatments for individual patients. J Clin Oncol 33:1787-1796, 2015
- Andre T Boni C Navarro M, et al. : Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27:3109-3116, 2009
- Sargent D Sobrero A Grothey A, et al. : Evidence for cure by adjuvant therapy in colon cancer: Observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 27:872-877, 2009
- Quasar Collaborative G Gray R Barnwell J, et al. : Adjuvant chemotherapy versus observation in patients with colorectal cancer: A randomised study. Lancet 370:2020-2029, 2007
- Sargent DJ Marsoni S Monges G, et al. : Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28:3219-3226, 2010
- Sargent D Shi Q Yothers G, et al. : Two or three year disease-free survival as a primary end-point in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: Data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803. Eur J Cancer 47:990-996, 2011.
- Iveson TJ Kerr RS Saunders MP, et al. : 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): An international, randomised, phase 3, non-inferiority trial. Lancet Oncol 19:562-578, 2018
- Yoshino T Yamanaka T Oki E, et al. : Efficacy and long-term peripheral sensory neuropathy of 3 vs 6 months of oxaliplatin-based adjuvant chemotherapy for colon cancer: The ACHIEVE phase 3 randomized clinical trial. JAMA Oncol 5:1574-1581, 2019
- Gunderson LL Jessup JM Sargent DJ, et al. : Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol 28:264-271, 2010
- Tie J Cohen JD Wang Y, et al. : Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer. JAMA Oncol 5:1710-1717, 2019
Source: PubMed