WW vs TME in patients with rectal cancer with a complete or near-complete response to TNT: Pooled analysis of CAO/ARO/AIO-12 and OPRA trials.
Authors: Hannah Williams, Emmanouil Fokas, Markus Diefenhardt, Sabrina T. Lin, Li-Xuan Qin, Claus Rodel, Julio Garcia-Aguilar
Journal: Journal of Clinical Oncology (2025)

21 Background: Patients with locally advanced rectal cancer (LARC) and a clinical complete response (cCR) or near-complete response (nCR) to total neoadjuvant therapy (TNT) can be offered watch-and-wait (WW) with the intention of achieving organ preservation. However, one third of patients on WW develop tumor regrowth and require total mesorectal excision (TME). Assessing the safety of WW in patients with a cCR or nCR is challenging due to the difficulty of finding an adequate control group. Here we compare the survival outcomes of patients with LARC treated with TNT and either mandatory TME or selective WW stratified by tumor response. Methods: This is a pooled analysis of two multicenter, phase II trials (CAO/ARO/AIO-12 [CAO] and OPRA) that randomized patients with stage II/III rectal cancer to either induction or consolidation TNT. All patients in the CAO trial underwent TME within 6 weeks of TNT. Pathologic tumor regression grade (TRG) was categorized as complete (TRG 4), intermediate (TRG 2,3) or poor (TRG 0,1). Patients in the OPRA trial were restaged by endoscopy and MRI 8±4 weeks after end of TNT. Clinical response was graded as cCR, nCR, or incomplete clinical response (iCR). Patients with a cCR or nCR were offered WW; patients with an iCR were recommended for TME. Survival curves were estimated using the Kaplan-Meier method and the log-rank test. Results: The study included 628 patients ( n =304 CAO; n =324 OPRA). Median follow-up was 3.6 (IQR 1.13) and 5.1 (IQR 2.2) years. Patients in the CAO trial were more likely to have cT3/4 and cN positive disease while patients in the OPRA trial had tumors closer to the anal verge. Compliance with TNT and rates of grade 3+ adverse events were similar between studies. A total of 144 (47%) patients in the OPRA trial achieved long term organ preservation. We found no differences in survival between trials. In addition, we found no differences in DFS between studies for patients with an excellent (TRG4 87% [95% CI, 79-97%], cCR 87% [95% CI, 81-93%]) or intermediate (TRG2-3 69% [95% CI, 62-76%], nCR 71% [95% CI, 68-80%]) response. Conclusions: This pooled analysis demonstrated that almost half of LARC patients treated with TNT can achieve organ preservation and that a selective WW strategy yields similar survival outcomes compared to mandatory TME. In addition, we found no differences in survival based on paired clinical and pathologic tumor response grades following TNT. This data provides further evidence supporting the safety of WW for patients with LARC and a cCR or nCR to TNT. Three-year survival outcomes in the CAO/ARO/AIO-12 and OPRA trials. CAO/ARO/AIO-12(95% CI) OPRA(95% CI) P 3y DFS 73 (71–81)% 76 (68–78)% 0.3 3y DRFS 82 (78–87)% 82 (78–87)% 0.7 3y LRFS 95 (92–98)% 95 (92–97)% 0.4 3y OS 92 (89–95)% 94 (89–95)% 0.5 DFS: disease-free survival, DRFS: distant recurrence-free survival, LRFS: local recurrence-free survival, OS: overall survival.