Adjuvant therapy in colon cancer: less is more
Authors: David H Ilson
Journal: The Lancet Oncology (2018)

The results of the SCOT trial reported by Timothy Iveson and colleagues1Iveson 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. 2018; 19: 562-578Summary Full Text Full Text PDF PubMed Scopus (107) Google Scholar in The Lancet Oncology establish a new standard of care in the adjuvant treatment of stage III colon cancer. The investigators showed the non-inferiority of treatment with 3 months of adjuvant chemotherapy versus 6 months of the same treatment in terms of 3 year disease-free survival. These results endorse the adoption of a shorter duration of adjuvant chemotherapy. Patients treated with the shorter duration of therapy had significant reductions in adverse events, including a more than halving in the number of grade 2 or worse sensory neuropathy events. These results were robust in patients with low-risk stage III (T3 or N1) disease who received 3 months of capecitabine and oxaliplatin. However, the non-inferiority of 3 months of therapy versus 6 months could not be shown in higher risk T4 or N2 disease. The small difference in 3 year disease-free survival in these patients led the authors to suggest that 3 months of therapy with capecitabine and oxaliplatin could still be considered for all patients with stage III disease. The practice-changing results from SCOT need to be taken in the context of the IDEA trial, a pooled analysis of more than 10 000 patients enrolled in six global adjuvant therapy trials, including SCOT.2Shi Q Sobrero AF Shields AF et al.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.Proc Am Soc Clin Oncol. 2017; 35: LBA1Google Scholar There is consistency in the results of IDEA3Grothey A, Sobrero AF, Shields AF, et al. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med (in press).Google Scholar and the individual trials), which supports the adoption of 3 months of capecitabine and oxaliplatin as the preferred adjuvant therapy in patients with low-risk stage III disease.2Shi Q Sobrero AF Shields AF et al.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.Proc Am Soc Clin Oncol. 2017; 35: LBA1Google Scholar, 4Sobrero AF Lonardi S Rosati G et al.FOLFOX4/XELOX in stage II–III colon cancer: efficacy results of the Italian three or six colon adjuvant (TOSCA) trial.Proc Am Soc Clin Oncol. 2017; 35: 3501Google Scholar, 5Andre T Bonnetain F Mineur L et al.Three versus six months adjuvant oxaliplatin-based chemotherapy for patients with stage III colon cancer: the French participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project.Proc Am Soc Clin Oncol. 2017; 35: 3500Google Scholar Similar to SCOT, a small difference favouring 6 months of therapy over 3 months in higher risk patients was also seen in IDEA. Like SCOT, non-inferiority could not be shown for the shorter duration of therapy with capecitabine and oxaliplatin in the higher risk patients. For higher risk stage III disease, clinicians will now need to discuss with patients the risks and likely small benefit of continuing therapy to 6 months. What about the use of adjuvant FOLFOX (leucovorin, fluorouracil, and oxaliplatin)? In SCOT, those receiving FOLFOX represented a minority of patients. FOLFOX for 3 months was not shown to be non-inferior to FOLFOX for 6 months, irrespective of risk status. Arguably, capecitabine and oxaliplatin should replace FOLFOX as the regimen of choice in the adjuvant setting. The potential exception would be clinicians choosing to administer 6 months of therapy in higher risk T4 or N2 patients. What are the implications for changing practice to 3 months of adjuvant chemotherapy? A shorter duration of adjuvant therapy could permit the earlier introduction of investigational therapies to be used sequentially or combined with chemotherapy, particularly in higher risk patients. Furthermore, it will be necessary to await the impact of findings from correlative studies done in SCOT and the other IDEA trials, given the now recognised prognostic importance of factors such as tumour sidedness, microsatellite instability, and BRAF or RAS mutation. Less might also be more in therapy for other gastrointestinal malignancies. In anal cancer treated with definitive chemoradiotherapy, the addition of extra cycles of chemotherapy either before or after chemoradiotherapy has been shown not to improve survival compared with chemoradiotherapy alone.6James RD Glynne-Jones R Meadows HM et al.Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.Lancet Oncol. 2013; 14: 516-524Summary Full Text Full Text PDF PubMed Scopus (474) Google Scholar, 7Ajani JA Winter KA Gunderson LL et al.Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial.JAMA. 2008; 299: 1914-1921Crossref PubMed Scopus (647) Google Scholar An argument for less chemotherapy is also seen in results from trials investigating neoadjuvant or preoperative therapy in oesophageal and gastric cancers. In a randomised trial8Ajani JA Xiao L Roth JA et al.A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer.Ann Oncol. 2013; 24: 2844-2849Crossref PubMed Scopus (75) Google Scholar of oesophageal and gastro-oesophageal junction cancers reported by Ajani and colleagues, the addition of 2 months of fluorouracil and oxaliplatin before preoperative fluorouracil plus oxaliplatin and radiotherapy did not improve survival compared with chemotherapy given only during radiotherapy. In the OEO5 trial,9Alderson D Cunningham D Nankivell M et al.Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial.Lancet Oncol. 2017; 18: 1249-1260Summary Full Text Full Text PDF PubMed Scopus (142) Google Scholar which enrolled patients with oesophageal and gastro-oesophageal junction adenocarcinoma, Alderson and colleagues also reported no survival benefit with four cycles of the ECX regimen (epirubicin, cisplatin, and capecitabine) beyond that achieved with two cycles of fluorouracil and cisplatin. These results support the use of a shorter duration of preoperative chemotherapy as well as the discontinuation of the use of epirubicin. Al-Batran and colleagues have reported that the addition of docetaxel to infused fluorouracil and oxaliplatin, using the FLOT regimen (fluorouracil, leucovorin, oxaliplatin, and docetaxel) as preoperative therapy, resulted in a significant survival benefit compared with preoperative ECX in patients with gastric and gastro-oesophageal junction cancers.10Al-Batran S-E Homann N Schmalenberg H et al.Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.Proc Am Soc Clin Oncol. 2017; 35: 4004Google Scholar If a third chemotherapy agent is to be added to preoperative fluorinated pyrimidine platinum chemotherapy, it should be docetaxel and not epirubicin. The SCOT investigators deserve congratulations for their practice-changing trial that can directly improve the lives of patients receiving adjuvant chemotherapy for stage III colon cancer. In this case, less clearly is more. I declare no competing interests. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trialIn the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care. Full-Text PDF Open Access