Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemoradiation for rectal cancer

For patients with high-risk stage II or stage III colon cancer, adjuvant chemotherapy with fluoropyrimidine monotherapy reduces the risk of recurrence and death by approximately 20-30%. Additional improvements have been reported in three phase 3 colon cancer trials when oxaliplatin was added to the chemoradiation regimen, although the effect was mainly on disease-free survival. However, patients with rectal cancer were specifically excluded from these landmark studies because of potential toxicity and the confounding impact of radiotherapy and chemoradiation. Hence, despite evidence from smaller individual postoperative adjuvant phase 3 trials, meta-analyses, retrospective analyses, reviews, and population studies, the precise benefit of adjuvant chemotherapy for patients with rectal cancer following radiotherapy or chemoradiation remains unclear. Consequently, clinical guidelines offer inconsistent recommendations for the management of this patient population. In this Review, we suggest that the available data do not robustly support the routine use of postoperative adjuvant chemotherapy for patients with rectal cancer treated with preoperative chemoradiation. We discuss sources of bias and offer potential reasons to explain this observation, as well as propose a recommended schema for a randomised phase 3 trial that might potentially answer this question definitively.