As confirmed by the National Comprehensive Cancer Network (NCCN^®), the current consensus is that patients with clinical stage II/III rectal cancer who receive neoadjuvant chemoradiation therapy (CRT) followed by surgery also should receive routine adjuvant chemotherapy. This recommendation is regardless of the patient’s pathologic stage, even for patients with a pathologic complete response (pCR). The rationale for recommending routine adjuvant chemotherapy regardless of pathologic stage is based on concerns that the downstaging 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, adjuvant chemotherapy is typically given prior to ileostomy closure, because the benefit of adjuvant therapy may be less if significantly delayed. For instance, surgical complications related to ileostomy closure may delay adjuvant therapy. One advantage of consolidated (folinic acid, fluorouracil and oxaliplatin [FOLFOX] chemotherapy following chemoradiation) and induction (FOLFOX chemotherapy prior to chemoradiation) total neoadjuvant therapy (TNT) in patients without metastatic disease is that all chemotherapy is administered prior to surgery. These patients do not receive postoperative chemotherapy unless they develop locally recurrent (regrowth) or metastatic disease.[1] Figure 1 shows a flow chart of recommended treatment with neoadjuvant and adjuvant therapy for rectal cancer.

Figure 1. Flow Chart of Recommended Neoadjuvant and Adjuvant Therapy for Rectal Cancer

Abbreviations: TNT, total neoadjuvant therapy; CRT, chemoradiation therapy; cCR, clinical complete response; W&W, watch and wait (nonoperative management); TME, total mesorectal excision

The evidence to support this recommendation is from trials using modern chemotherapy regimens (e.g., FOLFOX) that suggest that adjuvant chemotherapy is associated with superior 3-year disease-free survival rates.[2][3] Therefore, recommendations from NCCN and the European Society of Medical Oncology include routine postoperative adjuvant chemotherapy following preoperative CRT for T3–4 and/or node-positive disease.[1][4] However, studies do not consistently demonstrate the benefit of routine adjuvant chemotherapy. In the phase 3 Chronicle trial, patients with rectal cancer who received neoadjuvant CRT followed by resection were randomized to either FOLFOX with capecitabine or observation. The study found that adjuvant chemotherapy was not associated with an overall survival or a disease-free survival advantage.[5] The Dutch Colorectal Cancer Group trial used a methodology similar to the Chronicle trial, and no survival benefit was observed in the adjuvant chemotherapy arm.[6] One potential weakness with these two trials was the use of regimens other than FOLFOX or folinic acid), fluorouracil, and irinotecan hydrochloride (FOLFIRI).[7] Although future trials will continue to clarify the role of routine adjuvant chemotherapy, current recommendations are for all patients to receive adjuvant chemotherapy if they did not receive a TNT regimen preoperatively.[1]

The duration of adjuvant chemotherapy for rectal cancer is usually 6 months based on data, such as those from the MOSAIC trial. For patients who received neoadjuvant CRT, adjuvant chemotherapy can be reduced to a duration of 4 months without a change in survival rates.[1]

Because TNT strategies are now standard options in clinical practice guidelines,[1] adjuvant therapy use is decreasing.