Background:

Oxaliplatin and fluoropyrimidine chemotherapy administered over 6 months is the standard adjuvant regimen for patients with high-risk stage II or III colorectal cancer. However, the regimen is associated with cumulative toxicity, characterised by chronic and often irreversible neuropathy.

Objectives:

To assess the efficacy of 3-month versus 6-month adjuvant chemotherapy for colorectal cancer and to compare the toxicity, health-related quality of life and cost-effectiveness of the durations.

Design:

An international, randomised, open-label, non-inferiority, Phase III, parallel-group trial.

Setting:

A total of 244 oncology clinics from six countries: UK (England, Scotland, Wales and Northern Ireland), Denmark, Spain, Sweden, Australia and New Zealand.

Participants:

Adults aged ≥ 18 years who had undergone curative resection for high-risk stage II or III adenocarcinoma of the colon or rectum.

Interventions:

The adjuvant treatment regimen was either oxaliplatin and 5-fluorouracil or oxaliplatin and capecitabine, randomised to be administered over 3 or 6 months.

Main outcome measures:

The primary outcome was disease-free survival. Overall survival, adverse events, neuropathy and health-related quality of life were also assessed. The main cost categories were chemotherapy treatment and hospitalisation. Cost-effectiveness was assessed through incremental cost comparisons and quality-adjusted life-year gains between the options and was reported as net monetary benefit using a willingness-to-pay threshold of £30,000 per quality-adjusted life-year per patient.

Results:

Recruitment is closed. In total, 6088 patients were randomised (3044 per group) between 27 March 2008 and 29 November 2013, with 6065 included in the intention-to-treat analyses (3-month analysis, n = 3035; 6-month analysis, n = 3030). Follow-up for the primary analysis is complete. The 3-year disease-free survival rate in the 3-month treatment group was 76.7% (standard error 0.8%) and in the 6-month treatment group was 77.1% (standard error 0.8%), equating to a hazard ratio of 1.006 (95% confidence interval 0.909 to 1.114; p-value for non-inferiority = 0.012), confirming non-inferiority for 3-month adjuvant chemotherapy. Frequent adverse events (alopecia, anaemia, anorexia, diarrhoea, fatigue, hand–foot syndrome, mucositis, sensory neuropathy, neutropenia, pain, rash, altered taste, thrombocytopenia and watery eye) showed a significant increase in grade with 6-month duration; the greatest difference was for sensory neuropathy (grade ≥ 3 was 4% for 3-month vs.16% for 6-month duration), for which a higher rate of neuropathy was seen for the 6-month treatment group from month 4 to ≥ 5 years (p < 0.001). Quality-of-life scores were better in the 3-month treatment group over months 4–6. A cost-effectiveness analysis showed 3-month treatment to cost £4881 less over the 8-year analysis period, with an incremental net monetary benefit of £7246 per patient.

Conclusions:

The study achieved its primary end point, showing that 3-month oxaliplatin-containing adjuvant chemotherapy is non-inferior to 6 months of the same regimen; 3-month treatment showed a better safety profile and cost less. For future work, further follow-up will refine long-term estimates of the duration effect on disease-free survival and overall survival. The health economic analysis will be updated to include long-term extrapolation for subgroups. We expect these analyses to be available in 2019–20. The Short Course Oncology Therapy (SCOT) study translational samples may allow the identification of patients who would benefit from longer treatment based on the molecular characteristics of their disease.

Trial registration:

Current Controlled Trials ISRCTN59757862 and EudraCT 2007-003957-10.

Funding:

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 64. See the NIHR Journals Library website for further project information. This research was supported by the Medical Research Council (transferred to NIHR Evaluation, Trials and Studies Coordinating Centre – Efficacy and Mechanism Evaluation; grant reference G0601705), the Swedish Cancer Society and Cancer Research UK Core Clinical Trials Unit Funding (funding reference C6716/A9894).

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 14/140/84. The contractual start date was in December 2015. The draft report began editorial review in August 2018 and was accepted for publication in June 2019. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Timothy Iveson reports honoraria from Amgen Inc. (Thousand Oaks, CA, USA), Bayer AG (Leverkusen, Germany), Bristol-Myers Squibb (New York, NY, USA), Celgene Corporation (Summit, NJ, USA), Pierre-Fabre (Paris, France), Roche (Roche Holding AG, Basel, Switzerland) and Servier (Laboratories Servier, Suresnes, France). Kathleen A Boyd reports grants from the Medical Research Council during the conduct of the study. Mark P Saunders reports personal fees from Servier, Amgen, Merck (Merck and Co., Kenilworth, New Jersey, USA), Eisai (Eisai Co., Ltd., Tokyo, Japan) and Roche outside the submitted work. Jim Cassidy reports grants from the Medical Research Council during the conduct of the study and is currently an employee of Celgene Corporation. Josep Tabernero reports personal fees from Array Biopharma (Boulder, CO, USA), AstraZeneca (Cambridge, UK), Bayer AG (Leverkusen, Germany), BeiGene (Beijing, China), Boehringer Ingelheim (Ingelheim am Rhein, Germany), Chugai (Chugai Pharmaceutical Co., Tokyo, Japan), Genentech, Inc. (South San Francisco, CA, USA), Genmab A/S (Copenhagen, Denmark), Halozyme (Halozyme Therapeutics, San Diego, CA, USA), Imugene Limited (Sydney, NSW, Australia), Inflection Biosciences Limited (Blackrock, Dublin), Ipsen (Paris, France), Kura Oncology (San Diego, CA, USA), Eli Lilly and Company (Indianapolis, IN, USA), Merck, Menarini (The Menarini Group, Florence, Italy), Merck Serono (Rockland, MA, USA), Merrimack Pharmaceuticals (MA, USA), Merus (Utrecht, the Netherlands), Molecular Partners (Molecular Partners AG, Zurich, Switzerland), Novartis (Novartis International AG, Basel, Switzerland), Peptomyc, Pfizer Inc. (New York, NY, USA), Pharmacyclics (Pharmacyclics LLC, Sunnyvale, CA, USA), ProteoDesign SL (Barcelona, Spain), Rafael Pharmaceuticals (Stony Brook, NY, USA), F. Hoffmann-La Roche Ltd, Sanofi (Sanofi S. A., Paris, France), Seattle Genetics (Bothwell, WA, USA), Servier, Symphogen (Symphogen A/S, Ballerup, Denmark), Taiho Pharmaceutical (Tokyo, Japan), VCN Biosciences (Barcelona, Spain), Biocartis (Biocartis Group, Mechelen, Belgium), Foundation Medicine (Cambridge, MA, USA), HalioDX (Marseille, France), SAS Pharmaceuticals (Delhi, India) and Roche Diagnostics outside the submitted work. Bengt Glimelius reports support from PledPharma AB for being on advisory boards. Sherif Raouf reports grants, personal fees and non-financial support from Roche, grants and personal fees from Amgen, and grants and personal fees from Merck outside the submitted work. David Farrugia reports that he received honoraria for speaking in educational events and support for meeting attendance from Bristol-Myers Squibb, Novartis, Ipsen, Amgen, AstraZeneca and Merck. David Cunningham reports grants from 4SC (4SC AG, Planegg, Germany), AstraZeneca, Bayer, Amgen, Celgene, Clovis Oncology (Boulder, CO, USA), Eli Lilly and Company, Janssen Pharmaceuticals (Beerse, Belgium), MedImmune (Gaithersburg, MD, USA), Merck, Merrimack and Sanofi, outside the submitted work. Tamish Hickish reports grants from Pfizer, Roche, Pierre Fabre (Paris, France) and personal fees from Eli Lilly and Company during the conduct of the study. John Bridgewater reports funding from the University College London Hospitals NHS Foundation Trust/University College London Biomedical Research Centre. David Cunningham reports funding from the National Institute for Health Research Biomedical Research Centres at the Royal Marsden.