Neoadjuvant Therapy Sequencing May Improve Outcome in Rectal Cancer

There has been a move to total neoadjuvant therapy for patients with locally advanced rectal cancer both to optimize therapy delivery and potentially improve response, leading to nonoperative management and organ preservation in patients who achieve a clinical complete response. Investigators now report results of the open-label, multicenter, phase 2 Organ Preservation for Rectal Adenocarcinoma (OPRA) trial, which randomized patients to either induction chemotherapy with FOLFOX or capecitabine/oxaliplatin for 4 months followed by capecitabine and radiotherapy (INCT-CRT) or the reverse sequence of CRT followed by consolidation chemotherapy (CRT-CNCT). Total mesorectal excision (TME) was performed in patients not achieving a clinical complete response.

Of 324 patients, most were men (63%) with stage III cancers that were T3 (77%), node positive (71%), and less than 5 cm from the anal verge. At a median follow-up of 3 years, disease-free survival, the primary endpoint, was similar for the INCT-CRT and CRT-CNCT arms (76% and 76%) and was not superior to an historical rate of 75% in patients undergoing conventional chemoradiotherapy followed by surgery. Local recurrence-free survival (94% and 94%) and distant metastasis free survival (84% and 82%) were also similar in the two treatment arms. A watch-and-wait approach was offered to 71% of the INCT-CRT patients and 76% of the CRT-CNCT patients, with 40% and 27%, respectively, developing local tumor regrowth. The CRT-CNCT group had a higher rate of TME-free survival at 3 years than the INCT-CRT group (60% vs. 47%; P=0.02).