Organ Preservation With Total Neoadjuvant Therapy (OPTNT) for Early Low Rectal Cancer: Short-Term Outcomes of a Nonrandomized Phase 2 Clinical Trial.

BACKGROUND

Total mesorectal excision (TME) is standard for low rectal cancer (≤5cm from anal verge) but causes permanent stomas, functional impairments and surgical risks. Local excision (LE) suits early tumors (cTis-T1N0) but has higher recurrence in cT2+; watch-and-wait (WW) after neoadjuvant chemoradiotherapy risks residual disease. Total neoadjuvant therapy (TNT) improves outcomes, but prior LE trials had limitations.

OBJECTIVE

To evaluate TNT combined with planned LE for organ preservation in selected low rectal adenocarcinoma patients.

DESIGN

Prospective single-arm phase 2 trial (June 2022-March 2024, tertiary center) enrolled 57/60 patients (cT1-3N0M0 nonmucinous adenocarcinoma, etc.). TNT: 50 Gy + 2 cycles of CapoX (standard capecitabine + oxaliplatin) + 4 consolidation CapoX. Clinical complete response (cCR)/near-complete clinical response (ncCR) patients had LE; others got TME. Patients with high-risk residual disease after LE also had additional TME.

RESULTS

Median age was 61 years (28-79); 66.7% were male. cT3 tumors were present in 78.9%, and 78.9% had tumors ≤3 cm from the anal verge. After TNT, 47.4% achieved cCR and 38.6% achieved ncCR. Among surgically treated patients, the pathological complete response (pCR) rate was 68.6%; in the overall population, with WW counted as non-pCR, it was 61.4%. The total complete response rate, including pCR and cCR managed with WW, was 68.4%. Sphincter preservation was 94.7%. LE was associated with lower median blood loss (7 vs 50 mL; P<0.001) and shorter median hospitalization (7 vs 14 days; P=0.001) than TME. Grade 3 adverse events occurred in 22.8%, most commonly lymphocytopenia; no grade 4 or 5 events occurred. Low anterior resection syndrome (LARS) scores were assessed after TNT and at 1, 3, and 6 months postoperatively. At 6 months, LARS outcomes favored LE (80.0% vs 53.8% reporting no LARS; P=0.027). Wexner incontinence scores did not differ significantly between groups at any time point.

CONCLUSION

TNT with planned LE is feasible in cT1-3N0M0 low rectal cancer, yielding a pCR rate of 61.4% in the overall population, 94.7% sphincter preservation, and acceptable toxicity. However, the non-randomized design and immature 3-year organ-preservation endpoint limit this study to a feasibility assessment and do not permit conclusions regarding comparative effectiveness versus WW.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05563922.