Watch-and-Wait Strategy Shows Safety in Rectal Cancer Responder Population

No differences in oncologic outcomes occurred between mandatory TME or selective WW strategy in rectal cancer responders to neoadjuvant therapy.

A watch and wait (WW) strategy following a complete response (CR) or near CR (nCR) to total neoadjuvant therapy (TNT) displayed safety in patients with stage II/III rectal cancer, according to a pooled analysis of 2 phase 2 trials presented at the 2025 ASCO Gastrointestinal Cancer Symposium.¹ Furthermore, no differences in oncologic outcomes were observed between TNT responders treated with total mesorectal excision (TME) in the phase 2 CAO/ARO/AIO-12 trial (NCT02363374) and the selective WW strategy from the phase 2 OPRA trial (NCT02008656) assessed in the pooled analysis.

Data from the analysis revealed that 3-year disease-free survival (DFS) was similar between patients treated with WW vs TME at 76% (95% CI, 68%-78%) and 73% (95% CI, 71%-81%), respectively. Furthermore, distant recurrence-free survival (DRFS), local recurrence-free survival (LRFS), and overall survival (OS) outcomes were all similar, with WW eliciting respective values of 82% (95% CI, 78%-87%), 95% (95% CI, 92%-97%), and 94% (95% CI, 89%-95%) vs 82% (95% CI, 78%-87%), 95% (95% CI, 92%-98%), and 92% (95% CI, 89%-95%) with TME.

Additional data revealed that tumor response assessed through pathological tumor regression grade among 286 patients treated with TME within 6 weeks of TNT in the CAO/ARO/AIO-12 trial was predominantly intermediate (n = 176), with 64 CRs and 39 poor responses reported. Data from the OPRA trial revealed that 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 were offered a WW strategy, and those who had an iCR were offered TME.

“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,” Hannah Williams, MD, of Memorial Sloan Kettering Cancer Center, stated during the presentation.¹ “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 Study Design

Adult patients with locally advanced rectal cancer (n = 311) in the phase 2 CAO/ARO/AIO-12 trial were randomly assigned 1:1 to receive 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.²

Patients on trial had a median age of 61 years (IQR, 54-68; P < .001); 33% of patients were female, and most had an ECOG performance status of 0 (73%). Furthermore, the most common tumor category was cT3 (82%) or cT4 (15%; P = .002), most patients were node positive at diagnosis (90%; P < .001), and the median tumor distance from the anal verge was 6.00 cm (IQR, 4.00-9.00; P < .001).

A total of 286 patients were given TME within 6 weeks of TNT, and the pathologic complete response (pCR) rate was 17% among those who received induction TNT (INCT-CRT) and 25% among those who received consolidation TNT (CRT-CNCT).

OPRA Study Design

Patients 18 years or older with clinical stage II/III biopsy-proven rectal adenocarcinoma (n = 324) were randomly assigned 1:1 to receive INCT-CRT (n = 158) or CRT-INCT (n = 166).³ 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 over 46 to 48 hours by continuous infusion, repeated on a 14-day cycle, or 5 cycles of 130 mg/m² of capecitabine on day 1 and 1000 g/m² of oxaliplatin (CAPEOX) twice daily on days 1 to 14 repeated on a 21-day cycle before or after CRT.

Those on trial had a median age of 58 years (IQR, 50-67; P < .001); 37% were female, and 72% had an ECOG performance status of 0. Furthermore, the most common tumor category was cT3 (77%) or cT4 (13%; P = .002), most patients were node positive at diagnosis (71%; P < .001), and the median tumor distance from the anal verge was 4.40 cm (IQR, 3.00-6.50; P < .001).

A total of 304 patients were restaged 8 weeks after TNT, and the organ preservation rate was 39% among those who received INCT-CRT and 54% among those who received CRT-CNCT.

The primary end point of the pooled analysis was DFS. Secondary end points included DRFS, LFRS, and OS.

References

1. Williams H, Fokas E, Diefenhardt M, et al. 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. J Clin Oncol. 2025;43(suppl 4):21.
   doi:10.1200/JCO.2025.43.4_suppl.21
2. Fokas E, Schlenska-Lange A, Polat B, et al. Chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for patients with locally advanced rectal cancer: long-term results of the CAO/ARO/AIO-12 randomized clinical trial. JAMA Oncol. 2022;8(1):e215445. doi:10.1001/jamaoncol.2021.5445
3. Garcia-Aguilar J, Patil S, Kim JK, et al. Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin Oncol. 2022;40(23):2546-2556. doi:10.1200/JCO.22.00032