Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.To assess long-term risk of local tumor regrowth, we report updated organ preservation rate and oncologic outcomes of the OPRA trial (ClinicalTrials.gov identifier: NCT02008656). Patients with stage II/III rectal cancer were randomly assigned to receive induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients who achieved a complete or near-complete response after finishing treatment were offered watch-and-wait (WW). Total mesorectal excision (TME) was recommended for those who achieved an incomplete response. The primary end point was disease-free survival (DFS). The secondary end point was TME-free survival. In total, 324 patients were randomly assigned (INCT-CRT, n = 158; CRT-CNCT, n = 166). Median follow-up was 5.1 years. The 5-year DFS rates were 71% (95% CI, 64 to 79) and 69% (95% CI, 62 to 77) for INCT-CRT and CRT-CNCT, respectively (P = .68). TME-free survival was 39% (95% CI, 32 to 48) in the INCT-CRT group and 54% (95% CI, 46 to 62) in the CRT-CNCT group (P = .012). Of 81 patients with regrowth, 94% occurred within 2 years and 99% occurred within 3 years. DFS was similar for patients who underwent TME after restaging (64% [95% CI, 53 to 78]) and patients in WW who underwent TME after regrowth (64% [95% CI, 53 to 78]; P = .94). Updated analysis continues to show long-term organ preservation in half of the patients with rectal cancer treated with total neoadjuvant therapy. In patients who enter WW, most cases of tumor regrowth occur in the first 2 years.

Figure 1:

Kaplan Meier estimates of (A) disease-free survival, (B) overall survival, (C) local recurrence-free survival and (D) distant metastases-free survival in the intention-to-treat population by treatment group. CRT-CNCT, chemoradiation followed by chemotherapy; INCT-CRT, chemotherapy followed by chemoradiation.

Figure 2:

Kaplan Meier estimates of (A) time to regrowth in watch-and-wait patients and (B) TME-free survival by intention-to-treat, (C) disease-free survival for patients who were recommended TME after restaging and patients who were recommended TME after regrowth and (D) disease-free survival for patients who were recommended TME after restaging and patients who were recommended TME after regrowth by intention-to-treat. Patients who developed distant metastasis before TME was recommended (three at restaging and six at regrowth) and patients in whom TME was not performed because of disease progression found at surgery (one at restaging and two at regrowth) are not included in the analysis. Three patients were lost to follow-up after TME (two patients with TME after restaging and one patient with TME after regrowth). A total of 11 patients refused TME and were censored as having an event at time of refusal in the intention-to-treat analysis. CRT-CNCT, chemoradiation followed by chemotherapy; INCT-CRT, chemotherapy followed by chemoradiation; NAT, neoadjuvant therapy; TME, total mesorectal excision.