Adjuvant Therapy for Rectal Adenocarcinoma
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, 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 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 significantly delayed, as might occur if there are surgical complications related to ileostomy closure. One advantage of consolidated (FOLFOX chemotherapy following chemoradiation) and induction (FOLFOX chemotherapy prior to chemoradiation) total neoadjuvant therapy in patients without metastatic disease is that all chemotherapy is administered prior to surgery. These patients do not receive adjuvant chemotherapy unless they develop locally recurrent (regrowth) or metastatic disease.
The evidence to support this recommendation is from trials using modern chemotherapy regimens (FOLFOX) which suggest that adjuvant chemotherapy is associated with superior 3-year disease-free survival rates.Therefore, 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.However, studies do not consistently demonstrate the benefit of routine adjuvant chemotherapy. In the phase 3 CHRONICLE trial, 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 used a methodology similar to CHRONICLE and no survival benefit was observed in the adjuvant chemotherapy arm. One potential weakness with these two trials was the use of regimens other than FOLFOX or FOLFIRI. While 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 chemotherapy prior to surgery in a total neoadjuvant therapy (TNT) regimen.
The duration of adjuvant chemotherapy for rectal cancer is usually six months based on data such as the MOSAIC trial, though when patients receive neoadjuvant chemoradiation, adjuvant chemotherapy can be reduced to a duration of four months without a change in survival rates.
Total neoadjuvant therapy (TNT) strategies are now standard options in clinical practice guidelines. The rationale is that many patients do not complete recommended adjuvant chemotherapy after surgery or receive an incomplete course due to frailty or surgical complications. TNT is associated with improved compliance with chemotherapy, with the potential for improving disease-free survival by decreasing the incidence of distant disease. Additionally, TNT offers the potential for a higher complete clinical response rate, which may potentially allow a larger number of patients to avoid surgery in a nonoperative surveillance strategy. Data from the RAPIDO trial suggests that TNT may double complete pathologic response rate, with similar findings noted in the PRODIGE 23 study. Both studies demonstrated superior 3-year disease-free survival among patients treated with TNT compared to conventional adjuvant chemotherapy. Long-term survival data are not yet mature. Patients found to be MMR-deficient (dMMR) or microsatellite instability-high (MSI-H) at initial endoscopic biopsies do not respond as well to standard neoadjuvant and adjuvant chemotherapy regimens and may be candidates for neoadjuvant immunotherapy with immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1). One review showed that neoadjuvant treatment of dMMR/MSI-H rectal cancers with ICIs are associated with a complete clinical response (cCR) rate of 40-100%, though follow up was < 2 years.
TNT = total neoadjuvant therapy
CRT = chemoradiation therapy
cCR = clinical complete response
W&W = watch and wait (nonoperative management)
TME = total mesorectal excision
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