Assessing the OPRA Trial for surgical oncologists: Safety and feasibility of a total neoadjuvant therapy approach in patients with rectal cancer

The Organ Preservation in patients with Rectal Adenocarcinoma (OPRA) trial was a randomized, non-blinded, phase II prospective study investigating total neoadjuvant therapy (TNT) and a selective “watch-and-wait” (WW) approach in locally advanced rectal cancer (LARC). It compared two TNT regimens: induction chemotherapy-chemoradiotherapy (INCT-CRT) and chemoradiotherapy-consolidation chemotherapy (CRT-CNCT). Depending on tumor response, patients were offered WW or surgery. The primary endpoint was disease-free survival (DFS), hypothesizing that patients who underwent TNT with selective WW would have improved DFS compared to historical rates. Secondary endpoints included organ preservation (OP) and overall survival, hypothesizing that differences between INCT-CRT and CRT-CNCT could indicate a superior regimen.Results demonstrated treatment of LARC with TNT and selective WW allows for OP in approximately half of patients without negatively impacting oncologic outcomes such as DFS. The data show that a CRT-CNCT regimen had higher rates of OP, lower rates of tumor regrowth, and similar DFS compared to INCT-CRT. Lastly, DFS does not differ between patients who undergo immediate TME versus TME after regrowth. Thus, patients treated with TNT who achieve a clinical complete response (cCR) can safely undergo WW with the potential for OP.Current research to improve TNT and enhance cCR will expand the utility of the WW approach, including the intensification of neoadjuvant chemotherapy (Janus trial), comparing short-course and long-course CRT prior to CNCT (ENSEMBLE and German trials), utilizing fluoropyrimidine-chemotherapy with and without oxaliplatin in the context of WW (CHOW trial), and exploring less invasive operative approaches for early-stage tumors (NEO and NEO II trials). Synopsis The OPRA trial demonstrates treatment of locally advanced rectal cancer using total neoadjuvant therapy with selective “watch-and-wait” allows organ preservation in approximately half of patients without negatively impacting oncologic outcomes. For widespread adoption of “watch-and-wait”, data from accruing prospective trials are needed to demonstrate its viability across diverse clinical settings.