Excluding patients who receive preoperative chemotherapy [e.g. patients receiving total neoadjuvant therapy (TNT)], the current consensus is that clinical stage II/III rectal cancer patients who receive neoadjuvant chemoradiotherapy followed by surgery should also receive routine adjuvant chemotherapy. This recommendation is regardless of pathologic stage, applying even to patients with a pathologic complete response. The rationale for recommending routine adjuvant chemotherapy regardless of pathologic stage is based on concerns that the down-staging of node-positive disease by preoperative radiotherapy may result in node-negative pathologic staging among patients who continue to harbor an increased risk for systemic recurrence. In patients with a diverting ileostomy, the adjuvant chemotherapy is typically given prior to ileostomy closure. This is because the benefit of adjuvant therapy may be less if it is significantly delayed, as might occur if there are surgical complications of the ileostomy closure.

The evidence to support this recommendation derives from trials using modern chemotherapy regimens (FOLFOX), which suggest that adjuvant chemotherapy is associated with superior 3-year disease-free survival rates.[1],[2] Thus, recommendations from the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology (ESMO) include routine postoperative adjuvant chemotherapy following preoperative chemoradiotherapy for T3–4 and/or node-positive disease.[3],[4] However, data evaluating the benefit of routine adjuvant chemotherapy are not unanimous. In the phase 3 CHRONICLE trial,[5] rectal cancer patients who received neoadjuvant chemoradiation followed by resection were randomized to either XELOX or observation; adjuvant chemotherapy was not associated with an overall survival or a disease-free survival advantage. The Dutch Colorectal Cancer Group (DCCG) trial[6] used a methodology similar to CHRONICLE, with no survival benefit observed in the adjuvant chemotherapy arm. One potential weakness with these two trials was their use of regimens other than FOLFOX or FOLFIRI. While future trials will continue to clarify the benefit of routine adjuvant chemotherapy, current recommendations are for all patients to receive it if they did not receive it prior to surgery in a TNT regimen.

The duration of adjuvant chemotherapy for rectal cancer is usually six months based on data such as the MOSAIC trial,[7] though when patients receive neoadjuvant chemoradiation, adjuvant chemotherapy can be reduced to a duration of only four months without a change to survival rates.[3]

There is a growing interest in providing total neoadjuvant therapy (TNT), which is now a standard option in clinical practice guidelines.[3] The rationale for this is that many patients do not complete recommended chemotherapy after surgery, or receive an incomplete course.[8],[9] In theory, TNT offers improved compliance with chemotherapy, with the potential for improving disease-free survival by decreasing the incidence of distant disease.[10] Additionally, TNT offers the potential for a higher incidence of complete pathologic response, which may potentially allow a larger number of patients to avoid surgery altogether.[11] Data from the RAPIDO trial[12] suggests that TNT may double the incidence of complete pathologic response, with similar findings noted in the PRODIGE 23 study.[13] Both studies demonstrated a superior 3-year disease-free survival among patients treated with TNT compared to conventional adjuvant chemotherapy; however, longer-term data on overall survival is not yet available.