A pooled analysis of two phase 2 trials presented at the 2025 ASCO Gastrointestinal Cancer Symposium suggests that a watch-and-wait (WW) strategy is safe for patients with stage II/III rectal cancer who achieve a complete response (CR) or near CR (nCR) following total neoadjuvant therapy (TNT). The analysis compared outcomes of patients undergoing WW with those undergoing total mesorectal excision (TME) after TNT.
The data revealed similar 3-year disease-free survival (DFS) rates between the WW group (76%; 95% CI, 68%-78%) and the TME group (73%; 95% CI, 71%-81%). Distant recurrence-free survival (DRFS), local recurrence-free survival (LRFS), and overall survival (OS) outcomes were also comparable. Specifically, WW elicited DRFS, LRFS and OS values of 82% (95% CI, 78%-87%), 95% (95% CI, 92%-97%), and 94% (95% CI, 89%-95%), respectively, versus 82% (95% CI, 78%-87%), 95% (95% CI, 92%-98%), and 92% (95% CI, 89%-95%) with TME.
Tumor Response and Treatment Strategies
The analysis included data from the CAO/ARO/AIO-12 and OPRA trials. In the CAO/ARO/AIO-12 trial, pathological tumor regression grade assessment among 286 patients treated with TME within 6 weeks of TNT showed predominantly intermediate responses (n = 176), with 64 CRs and 39 poor responses. In the OPRA trial, among 304 patients restaged 8 weeks after TNT, CRs and nCRs were observed in 125 and 112 patients, respectively, with 54 reported to have incomplete CRs (iCRs). Responders in the OPRA trial were offered a WW strategy, while those with iCRs were offered TME.
Expert Commentary
"A selective watch-and-wait strategy is a safe treatment option in patients with a [CR] or [nCR] to TNT. We found no differences in oncologic outcomes based on treatment strategy," said Hannah Williams, MD, of Memorial Sloan Kettering Cancer Center, during the presentation. She further noted, "The additional 2.5 months of systemic chemotherapy provided during TNT in the OPRA trial did not improve survival. These results indicate that there may be opportunities to decrease the duration of TNT regimens and avoid potentially unnecessary toxicity for patients. Finally, our results suggest that patients with [nCR] can safely enter non-operative management as long as they remain under close surveillance."
CAO/ARO/AIO-12 and OPRA Trial Designs
The CAO/ARO/AIO-12 trial randomly assigned adult patients with locally advanced rectal cancer (n = 311) to either sequence chemotherapy, preoperative chemoradiotherapy (CRT), and surgery (n = 156) or sequence CRT, chemotherapy, and surgery (n = 150). TNT in this study consisted of 3 cycles of FOLFOX (folinic acid, fluorouracil [FU], and oxaliplatin) for systemic chemotherapy and 5-fluorouracil (5-FU) plus oxaliplatin CRT at 50.4 Gy in 28 fractions across 6-week intervals.
The OPRA trial randomly assigned patients 18 years or older with clinical stage II/III biopsy-proven rectal adenocarcinoma (n = 324) to either INCT-CRT (n = 158) or CRT-INCT (n = 166). Patients received either 825 mg/m2 of oral capecitabine twice daily or a 225 mg/m2 dose of continuous FU during radiotherapy. They were also given 8 cycles of infusional FOLFOX or 5 cycles of CAPEOX before or after CRT.
The primary endpoint of the pooled analysis was DFS. Secondary endpoints included DRFS, LFRS, and OS.
