Abstract

A B S T R A C T Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy. © 2018 by American Society of Clinical Oncology.
Original languageEnglish
Pages (from-to)1478-1485
Number of pages8
JournalJournal of Clinical Oncology
Volume36
Issue number15
DOIs
Publication statusPublished - 2018

Fingerprint

oxaliplatin
Colonic Neoplasms
Colon
Recurrence
Leucovorin
Therapeutics
Fluorouracil
Multicenter Studies
Capecitabine
Patient Care

Keywords

  • capecitabine
  • fluorouracil
  • folinic acid
  • oxaliplatin
  • adult
  • aged
  • Article
  • cancer combination chemotherapy
  • cancer mortality
  • cancer recurrence
  • cancer staging
  • cancer survival
  • clinical outcome
  • colon cancer
  • comparative study
  • controlled study
  • drug efficacy
  • female
  • follow up
  • high risk patient
  • human
  • major clinical study
  • male
  • multicenter study
  • open study
  • phase 3 clinical trial
  • priority journal
  • recurrence free survival
  • relapse
  • treatment duration

Cite this

FOLFOX or CAPOX in stage II to III colon cancer: Efficacy results of the italian three or six colon adjuvant trial. / Sobrero, A.; Lonardi, S.; Rosati, G.; Di Bartolomeo, M.; Ronzoni, M.; Pella, N.; Scartozzi, M.; Banzi, M.; Zampino, M.G.; Pasini, F.; Marchetti, P.; Cantore, M.; Zaniboni, A.; Rimassa, L.; Ciuffreda, L.; Ferrari, D.; Zagonel, V.; Maiello, E.; Barni, S.; Rulli, E.; Labianca, R.

In: Journal of Clinical Oncology, Vol. 36, No. 15, 2018, p. 1478-1485.

Research output: Contribution to journalArticle

Sobrero, A. ; Lonardi, S. ; Rosati, G. ; Di Bartolomeo, M. ; Ronzoni, M. ; Pella, N. ; Scartozzi, M. ; Banzi, M. ; Zampino, M.G. ; Pasini, F. ; Marchetti, P. ; Cantore, M. ; Zaniboni, A. ; Rimassa, L. ; Ciuffreda, L. ; Ferrari, D. ; Zagonel, V. ; Maiello, E. ; Barni, S. ; Rulli, E. ; Labianca, R. / FOLFOX or CAPOX in stage II to III colon cancer: Efficacy results of the italian three or six colon adjuvant trial. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 15. pp. 1478-1485.
@article{ad9efb4af30b4d8d89d6de9b6eecca1f,
title = "FOLFOX or CAPOX in stage II to III colon cancer: Efficacy results of the italian three or six colon adjuvant trial",
abstract = "A B S T R A C T Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64{\%} receiving FOLFOX and 36{\%} CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95{\%} CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9{\%} (95{\%} CI, -0.7{\%} to 4.4{\%}). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95{\%} CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95{\%} CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95{\%} CI, 1.05 to 1.89) and 1.23 (95{\%} CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20{\%} relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy. {\circledC} 2018 by American Society of Clinical Oncology.",
keywords = "capecitabine, fluorouracil, folinic acid, oxaliplatin, adult, aged, Article, cancer combination chemotherapy, cancer mortality, cancer recurrence, cancer staging, cancer survival, clinical outcome, colon cancer, comparative study, controlled study, drug efficacy, female, follow up, high risk patient, human, major clinical study, male, multicenter study, open study, phase 3 clinical trial, priority journal, recurrence free survival, relapse, treatment duration",
author = "A. Sobrero and S. Lonardi and G. Rosati and {Di Bartolomeo}, M. and M. Ronzoni and N. Pella and M. Scartozzi and M. Banzi and M.G. Zampino and F. Pasini and P. Marchetti and M. Cantore and A. Zaniboni and L. Rimassa and L. Ciuffreda and D. Ferrari and V. Zagonel and E. Maiello and S. Barni and E. Rulli and R. Labianca",
note = "Cited By :2 Export Date: 5 February 2019 CODEN: JCOND Correspondence Address: Sobrero, A.; Ospedale Policlinico San Martino, Largo Benzi 10, Italy; email: alberto.sobrero@hsanmartino.it Chemicals/CAS: capecitabine, 154361-50-9; fluorouracil, 51-21-8; folinic acid, 58-05-9; oxaliplatin, 61825-94-3 Funding details: Agenzia Italiana del Farmaco, Ministero della Salute, AIFA Funding details: Agenzia Italiana del Farmaco, Ministero della Salute, AIFA, NCT0064660 Funding text 1: This study was sponsored by GISCAD Foundation and supported by a grant from AIFA (Agenzia Italiana del Farmaco). The trial is registered with ClinicalTrials.gov, registration number: NCT0064660. References: Andr{\'e}, T., Boni, C., Mounedji-Boudiaf, L., Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer (2004) N Engl J Med, 350, pp. 2343-2351; Andr{\'e}, T., Boni, C., Navarro, M., Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial (2009) J Clin Oncol, 27, pp. 3109-3116; Moertel, C.G., Fleming, T.R., Macdonald, J.S., Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma (1990) N Engl J Med, 322, pp. 352-358; Haller, D.G., Catalano, P.J., Macdonald, J.S., Phase III study of fluorouracil, leucovorin, and leva-misole in high-risk stage II and III colon cancer: Final report of Intergroup 0089 (2005) J Clin Oncol, 23, pp. 8671-8678; Andre, T., Colin, P., Louvet, C., Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: Results of a randomized trial (2003) J Clin Oncol, 21, pp. 2896-2903; Chau, I., Norman, A.R., Cunningham, D., A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer (2005) Ann Oncol, 16, pp. 549-557; Shi, Q., Sobrero, A., Shields, A., Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration (2017) J Clin Oncol, 35. , abstr LBA1; Lonardi, S., Sobrero, A., Rosati, G., Phase III trial comparing 3-6 months of adjuvant FOLFOX4/ XELOX in stage II-III colon cancer: Safety and compliance in the TOSCA trial (2016) Ann Oncol, 27, pp. 2074-2081; Royston, P., Parmar, M.K.B., Flexible parametric proportional-hazards and proportional-odds models for censored survival data, with application to prognostic modelling and estimation of treatment effects (2002) Stat Med, 21, pp. 2175-2197; Chapman, J.W., O’Callaghan, C.J., Hu, N., Innovative estimation of survival using log-normal survival modelling on ACCENT database (2013) Br J Cancer, 108, pp. 784-790; Iveson, T., Kerr, R., Saunders, M.P., Final DFS results of the SCOT study: An international phase III randomised (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer (2017) J Clin Oncol, 35. , abstr 3502; Sargent, D.J., Marsoni, S., Monges, G., Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer (2010) J Clin Oncol, 28, pp. 3219-3226; Naxerova, K., Reiter, J.G., Brachtel, E., Origins of lymphatic and distant metastases in human colorectal cancer (2017) Science, 357, pp. 55-60",
year = "2018",
doi = "10.1200/JCO.2017.76.2187",
language = "English",
volume = "36",
pages = "1478--1485",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
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}

TY - JOUR

T1 - FOLFOX or CAPOX in stage II to III colon cancer: Efficacy results of the italian three or six colon adjuvant trial

AU - Sobrero, A.

AU - Lonardi, S.

AU - Rosati, G.

AU - Di Bartolomeo, M.

AU - Ronzoni, M.

AU - Pella, N.

AU - Scartozzi, M.

AU - Banzi, M.

AU - Zampino, M.G.

AU - Pasini, F.

AU - Marchetti, P.

AU - Cantore, M.

AU - Zaniboni, A.

AU - Rimassa, L.

AU - Ciuffreda, L.

AU - Ferrari, D.

AU - Zagonel, V.

AU - Maiello, E.

AU - Barni, S.

AU - Rulli, E.

AU - Labianca, R.

N1 - Cited By :2 Export Date: 5 February 2019 CODEN: JCOND Correspondence Address: Sobrero, A.; Ospedale Policlinico San Martino, Largo Benzi 10, Italy; email: alberto.sobrero@hsanmartino.it Chemicals/CAS: capecitabine, 154361-50-9; fluorouracil, 51-21-8; folinic acid, 58-05-9; oxaliplatin, 61825-94-3 Funding details: Agenzia Italiana del Farmaco, Ministero della Salute, AIFA Funding details: Agenzia Italiana del Farmaco, Ministero della Salute, AIFA, NCT0064660 Funding text 1: This study was sponsored by GISCAD Foundation and supported by a grant from AIFA (Agenzia Italiana del Farmaco). The trial is registered with ClinicalTrials.gov, registration number: NCT0064660. References: André, T., Boni, C., Mounedji-Boudiaf, L., Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer (2004) N Engl J Med, 350, pp. 2343-2351; André, T., Boni, C., Navarro, M., Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial (2009) J Clin Oncol, 27, pp. 3109-3116; Moertel, C.G., Fleming, T.R., Macdonald, J.S., Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma (1990) N Engl J Med, 322, pp. 352-358; Haller, D.G., Catalano, P.J., Macdonald, J.S., Phase III study of fluorouracil, leucovorin, and leva-misole in high-risk stage II and III colon cancer: Final report of Intergroup 0089 (2005) J Clin Oncol, 23, pp. 8671-8678; Andre, T., Colin, P., Louvet, C., Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: Results of a randomized trial (2003) J Clin Oncol, 21, pp. 2896-2903; Chau, I., Norman, A.R., Cunningham, D., A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer (2005) Ann Oncol, 16, pp. 549-557; Shi, Q., Sobrero, A., Shields, A., Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration (2017) J Clin Oncol, 35. , abstr LBA1; Lonardi, S., Sobrero, A., Rosati, G., Phase III trial comparing 3-6 months of adjuvant FOLFOX4/ XELOX in stage II-III colon cancer: Safety and compliance in the TOSCA trial (2016) Ann Oncol, 27, pp. 2074-2081; Royston, P., Parmar, M.K.B., Flexible parametric proportional-hazards and proportional-odds models for censored survival data, with application to prognostic modelling and estimation of treatment effects (2002) Stat Med, 21, pp. 2175-2197; Chapman, J.W., O’Callaghan, C.J., Hu, N., Innovative estimation of survival using log-normal survival modelling on ACCENT database (2013) Br J Cancer, 108, pp. 784-790; Iveson, T., Kerr, R., Saunders, M.P., Final DFS results of the SCOT study: An international phase III randomised (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer (2017) J Clin Oncol, 35. , abstr 3502; Sargent, D.J., Marsoni, S., Monges, G., Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer (2010) J Clin Oncol, 28, pp. 3219-3226; Naxerova, K., Reiter, J.G., Brachtel, E., Origins of lymphatic and distant metastases in human colorectal cancer (2017) Science, 357, pp. 55-60

PY - 2018

Y1 - 2018

N2 - A B S T R A C T Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy. © 2018 by American Society of Clinical Oncology.

AB - A B S T R A C T Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy. © 2018 by American Society of Clinical Oncology.

KW - capecitabine

KW - fluorouracil

KW - folinic acid

KW - oxaliplatin

KW - adult

KW - aged

KW - Article

KW - cancer combination chemotherapy

KW - cancer mortality

KW - cancer recurrence

KW - cancer staging

KW - cancer survival

KW - clinical outcome

KW - colon cancer

KW - comparative study

KW - controlled study

KW - drug efficacy

KW - female

KW - follow up

KW - high risk patient

KW - human

KW - major clinical study

KW - male

KW - multicenter study

KW - open study

KW - phase 3 clinical trial

KW - priority journal

KW - recurrence free survival

KW - relapse

KW - treatment duration

U2 - 10.1200/JCO.2017.76.2187

DO - 10.1200/JCO.2017.76.2187

M3 - Article

VL - 36

SP - 1478

EP - 1485

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 15

ER -