Selective Total Mesorectal Excision Based on Intra-Operative Frozen Section From Local Excision in Rectal Cancer Undergoing Neoadjuvant Chemoradiotherapy: A Prospective, Single-arm, Phase II Superiority Trial

Rectal cancer is a major global health burden with high morbidity and mortality. Its prognosis is generally worse than that of colon cancer, largely because of a higher risk of local recurrence. In 1982, Bill Heald introduced total mesorectal excision (TME), which has since proven to markedly reduce local recurrence. Peri-operative radiotherapy and chemotherapy further improve outcomes; pre-operative chemoradiotherapy (CRT) is superior to post-operative CRT, cutting local relapse by ~50%. Current National Comprehensive Cancer Network (NCCN) guidelines therefore recommend "pre-operative concurrent CRT followed by radical surgery" for locally advanced (stage II/III) rectal cancer. More recently, total neoadjuvant therapy (TNT) has refined this strategy, increasing pathologic complete response (pCR) rates to 20-40 %, and up to 60 % when combined with immunotherapy.

After neoadjuvant treatment, approximately 20 % of tumors achieve complete regression with pCR. If pre-operative assessment shows a clinical complete response (cCR), these patients may be offered an organ-preserving "watch-and-wait" approach instead of immediate TME, preserving sphincter function and quality of life. Since Habr-Gama's first report, multiple studies have confirmed the safety of this strategy: among patients managed by watch-and-wait, 15-20 % develop regrowth, 95 % of which are local and salvageable; 3-year distant-metastasis rates are only 8 % and 5-year cancer-specific survival is 94 %. Consequently, watch-and-wait is now standard for patients with cCR after CRT.

However, only 10-20 % of patients who ultimately achieve pCR are judged cCR pre-operatively. Imaging or endoscopic uncertainties (e.g., minimal ulceration) often lead to classification as partial response (PR) or near-cCR, depriving these patients of organ preservation. Traditionally, such patients proceed directly to TME. An emerging alternative is "local excision ± salvage TME": trans-anal full-thickness excision is performed first; if final pathology shows ypT0-1, no further surgery is required, whereas ypT2-3 or R1 margins trigger elective salvage TME. This risk-stratified approach aims to preserve organs in good responders while ensuring oncologic safety in poor responders.

Yet the GRECCAR-2 trial raised concerns: prior local excision may complicate subsequent TME, compromise sphincter preservation, and increase peri-operative morbidity (bleeding, infection, anorectal dysfunction) and long-term functional impairment. For patients with excellent tumor regression after CRT, these risks pose a dilemma.

To address this challenge, we propose the present clinical study, evaluating whether intra-operative frozen-section guidance during local excision can maintain diagnostic accuracy and oncologic safety while reducing the surgical complications and long-term functional sequelae associated with deferred TME.