M E Salem1, J Yin2, R M Goldberg3, L D Pederson2, N Wolmark4, S R Alberts5, J Taieb6, J L Marshall7, S Lonardi8, T Yoshino9, R S Kerr10, G Yothers11, A Grothey12, T Andre13, A De Gramont14, Q Shi15. 1. Levine Cancer Institute, Carolinas HealthCare System, Charlotte, USA. 2. Department of Health Science Research, Mayo Clinic, Rochester, USA. 3. West Virginia University Cancer Institute, Morgantown, USA. 4. National Surgical Adjuvant Breast and Bowel Project (NSABP/NRG Oncology), Pittsburgh, USA. 5. Department of Oncology, Mayo Clinic, Rochester, USA. 6. Department of Gastroenterology and GI Oncology, Georges Pompidou European Hospital, Paris Descartes University, Paris, France. 7. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, USA. 8. Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy. 9. Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. 10. Department of Oncology, University of Oxford, Oxford, UK. 11. Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, USA. 12. West Cancer Center and Research Institute, Germantown, USA. 13. Sorbonne University and Department of Medical Oncology, Hôspital St Antoine, Paris, France. 14. Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France. 15. Department of Health Science Research, Mayo Clinic, Rochester, USA. Electronic address: shi.qian2@mayo.edu.
Abstract
BACKGROUND: Since 2004, adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX or FLOX) have been the standard of care for patients with resected colon cancer. Herein we examine the change of outcomes over a 10-year period in patients with stage III colon cancer who received this regimen. PATIENTS AND METHODS: Individual patient data from the ACCENT database was used to compare the outcomes in older (1998-2003) and newer (2004-2009) treatment eras for patients with stage III colon cancer who received adjuvant FOLFOX or FLOX. The outcomes were compared between the two groups by the multivariate Cox proportional-hazards model adjusting for age, sex, performance score, T stage, N stage, tumor sidedness, and histological grade. RESULTS: A total of 6501 patients with stage III colon cancer who received adjuvant FOLFOX or FLOX in six randomized trials were included in the analysis. Patients enrolled in the new era group experienced statistically significant improvement in time to recurrence [3-year rate, 76.1% versus 73.0%; adjusted hazard ratio (HRadj) = 0.83 (95% CI, 0.74-0.92), P = 0.0008], disease-free survival (DFS) [3-year rate, 74.7% versus 72.3%; HRadj = 0.88 (0.79-0.98), P = 0.024], survival after recurrence (SAR) [median time, 27.0 versus 17.7 months; HRadj = 0.65 (0.57-0.74), P < 0.0001], and overall survival (OS) [5-year rate, 80.9% versus 75.7%; HRadj = 0.78 (0.69-0.88), P < 0.0001]. The improved outcomes remained in patients diagnosed at 45 years of age or older, low-risk patients (T1-3 and N1), left colon, mismatch repair proficient (pMMR), BRAF, and KRAS wild-type tumors. CONCLUSION: Improved outcomes were observed in patients with stage III colon cancer enrolled in clinical trials who received adjuvant FOLFOX/FLOX therapy in 2004 or later compared with patients in the older era. Prolonged SAR calls for revalidation of 3-year DFS as the surrogate endpoint of OS in adjuvant clinical trials and reevaluation of optimal follow-up of OS to confirm the trial findings based on the DFS endpoints. CLINICAL TRIALS NUMBERS: NCT00079274; NCT00096278; NCT00004931; NCT00275210; NCT00265811; NCT00112918.
BACKGROUND: Since 2004, adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX or FLOX) have been the standard of care for patients with resected colon cancer. Herein we examine the change of outcomes over a 10-year period in patients with stage III colon cancer who received this regimen. PATIENTS AND METHODS: Individual patient data from the ACCENT database was used to compare the outcomes in older (1998-2003) and newer (2004-2009) treatment eras for patients with stage III colon cancer who received adjuvant FOLFOX or FLOX. The outcomes were compared between the two groups by the multivariate Cox proportional-hazards model adjusting for age, sex, performance score, T stage, N stage, tumor sidedness, and histological grade. RESULTS: A total of 6501 patients with stage III colon cancer who received adjuvant FOLFOX or FLOX in six randomized trials were included in the analysis. Patients enrolled in the new era group experienced statistically significant improvement in time to recurrence [3-year rate, 76.1% versus 73.0%; adjusted hazard ratio (HRadj) = 0.83 (95% CI, 0.74-0.92), P = 0.0008], disease-free survival (DFS) [3-year rate, 74.7% versus 72.3%; HRadj = 0.88 (0.79-0.98), P = 0.024], survival after recurrence (SAR) [median time, 27.0 versus 17.7 months; HRadj = 0.65 (0.57-0.74), P < 0.0001], and overall survival (OS) [5-year rate, 80.9% versus 75.7%; HRadj = 0.78 (0.69-0.88), P < 0.0001]. The improved outcomes remained in patients diagnosed at 45 years of age or older, low-risk patients (T1-3 and N1), left colon, mismatch repair proficient (pMMR), BRAF, and KRAS wild-type tumors. CONCLUSION: Improved outcomes were observed in patients with stage III colon cancer enrolled in clinical trials who received adjuvant FOLFOX/FLOX therapy in 2004 or later compared with patients in the older era. Prolonged SAR calls for revalidation of 3-year DFS as the surrogate endpoint of OS in adjuvant clinical trials and reevaluation of optimal follow-up of OS to confirm the trial findings based on the DFS endpoints. CLINICAL TRIALS NUMBERS: NCT00079274; NCT00096278; NCT00004931; NCT00275210; NCT00265811; NCT00112918.
Authors: Zhaohui Jin; Jesse G Dixon; Jack M Fiskum; Hiral D Parekh; Frank A Sinicrope; Greg Yothers; Carmen J Allegra; Norman Wolmark; Daniel Haller; Hans-Joachim Schmoll; Aimery de Gramont; Rachel Kerr; Julien Taieb; Eric Van Cutsem; Christopher Tweleves; Michael O'Connell; Leonard B Saltz; Sotaro Sadahiro; Charles D Blanke; Naohiro Tomita; Jean-Francois Seitz; Charles Erlichman; Takayuki Yoshino; Takeharu Yamanaka; Silvia Marsoni; Thierry Andre; Amit Mahipal; Richard M Goldberg; Thomas J George; Qian Shi Journal: J Natl Cancer Inst Date: 2021-08-18 Impact factor: 11.816
Authors: Jeffrey A Meyerhardt; Qian Shi; Charles S Fuchs; Jeffrey Meyer; Donna Niedzwiecki; Tyler Zemla; Priya Kumthekar; Katherine A Guthrie; Felix Couture; Philip Kuebler; Johanna C Bendell; Pankaj Kumar; Dequincy Lewis; Benjamin Tan; Monica Bertagnolli; Axel Grothey; Howard S Hochster; Richard M Goldberg; Alan Venook; Charles Blanke; Eileen M O'Reilly; Anthony F Shields Journal: JAMA Date: 2021-04-06 Impact factor: 56.272
Authors: Jun Yin; Mohamed E Salem; Jesse G Dixon; Zhaohui Jin; Romain Cohen; Aimery DeGramont; Eric Van Cutsem; Julien Taieb; Steven R Alberts; Norman Wolmark; Hans-Joachim Schmoll; Leonard B Saltz; Thomas J George; Richard R M Goldberg; Rachel Kerr; Sara Lonardi; Takayuki Yoshino; Greg Yothers; Axel Grothey; Thierry Andre; Qian Shi Journal: J Natl Cancer Inst Date: 2022-01-11 Impact factor: 11.816
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