The standard treatment for patients with locally advanced (LA) rectal adenocarcinoma is neoadjuvant chemoradiotherapy (CRT), total mesorectal excision (TME), and adjuvant chemotherapy. While this multidisciplinary treatment approach is effective in achieving tumor control, it may permanently compromise patients’ quality of life. Since most of the sequelae from this strategy are related to surgical treatment, non-surgical treatment options, such as total neoadjuvant therapy (TNT), are being explored extensively. TNT consists of delivering chemotherapy before surgery, either before or after CRT. The Organ Preservation for Rectal Adenocarcinoma (OPRA) Trial was a prospective, randomized, multicenter phase II clinical trial conducted at 18 US centers. The trial’s key objective was to evaluate whether a potential rectum-preserving treatment approach, using TNT and watch-and-wait (WW), can achieve better outcomes than standard-resection based treatment.

In total, 324 eligible patients with stage II or III locally advanced rectal adenocarcinoma were randomized to receive TNT with either induction chemotherapy followed by CRT (INCT-CRT) or CRT followed by consolidation therapy (CRT-CNCT). Patients in both groups received 4 months of FOLFOX or CAPOX and 50-56Gy of radiation combined with either continuous fluorouracil or capecitabine during radiotherapy. Within 8 (± 4) weeks following the completion of TNT, all patients underwent tumor restaging. For patients who achieved incomplete clinical response, TME was recommended, while for patients with clinical complete response (cCR) or near-complete response, a standardized WW approach was offered, consisting of digital rectal examination and flexible sigmoidoscopy every 4 months for the first 2 years from the time of first assessment of response, and every 6 months for the following 3 years. Rectal MRI was performed every 6 months for the first 2 years and yearly for the following 3 years, or more frequently if considered necessary by the investigators. For patients with a sustained clinical response, WW follow-up was recommended, while for patients with lack of ongoing response (compared with previous evaluation) or with signs of tumor regrowth on MRI or endoscopy, TME was advised. The median follow-up was three years. The primary endpoint of the study was disease-free survival (DFS). The 3-year DFS rate was 76% for patients receiving INCT-CRT and 76% for the CRT-CNCT group, which is in line with the 3-year DFS rate of 75% from historical control patients treated with neoadjuvant CRT, TME and adjuvant chemotherapy. The proportion of patients who preserved the rectum (TME-free survival) at 3 years was 41% in the INCT-CRT group and 53% in the CRT-CNCT group (P = 0.01). There was no difference in local recurrence-free survival, distant metastasis-free survival, or overall survival between groups. DFS rates were similar for patients who underwent TME after restaging and patients who underwent TME after regrowth. The rates of sphincter-saving surgery were numerically higher in patients having TME at restaging compared with patients having TME after regrowth; however, this difference was not statistically significant.

In their discussion, the authors highlighted that although the trial did not meet the primary endpoint of 3-year DFS improvement with TNT, the results are in line with historical controls and with recently reported trials. They concluded from the trial results that a treatment strategy that includes TNT and selective WW on the basis of tumor response, allows organ preservation in almost half of the patients with LA rectal cancer, without specific adverse events impacting oncological outcomes. They also noted that although the sequence of CRT and systemic chemotherapy did not affect DFS, the delivery of CRT before chemotherapy appears to be associated with a higher rate of organ preservation.

Reference:
Garcia-Aguilar J, et al. J Clin Oncol. 2022 April 28. [Online ahead of print].