Overview
This study is a prospective, single-arm, phase II superiority trial to determine whether a selective organ-preserving strategy based on immediate intra-operative frozen-section results can achieve favorable 2-year local control while lowering morbidity in patients with low rectal cancer (tumor ≤5 cm from the anus) who have a near clinical complete response (near-cCR) or partial response (residual tumor \<2 cm) after radiation therapy.
Population: Adults with primary rectal adenocarcinoma located ≤5 cm from the anal verge who, after neoadjuvant radiotherapy, are judged to have near-cCR or partial response (residual tumor \<2 cm).
Intervention: All participants undergo local excision under general anesthesia. The specimen is sent for intra-operative frozen section.
ypT0-1 on frozen section → procedure concluded; patient enters watch-and-wait. ypT2-3 or R1 on frozen section → immediate completion total mesorectal excision (TME).
Frozen-section ypT1-2 but final paraffin section up-staged to ypT2-3 or R1 → elective TME within 8 weeks.
Primary Endpoint: a composite outcome of 2-year local recurrence rate, surgical complications (≤30 days), and long-term functional impairment (anorectal, urogenital, and quality-of-life scales).
Secondary Endpoints: Agreement between intra-operative frozen-section pathology and final paraffin-section pathology, 3-year disease-free survival (DFS), 3-year overall survival (OS), surgery-sparing rate, post-operative recovery metrics, Quality-of-life scores.
Estimated Enrollment: 27 participants.
Description
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.
This study is a prospective, single-arm, phase II superiority trial to determine whether a selective organ-preserving strategy based on immediate intra-operative frozen-section results can achieve favorable 2-year local control while lowering morbidity in patients with low rectal cancer (tumor ≤5 cm from the anus) who have a near clinical complete response (near-cCR) or partial response (residual tumor \<2 cm) after radiation therapy.
Population: Adults with primary rectal adenocarcinoma located ≤5 cm from the anal verge who, after neoadjuvant radiotherapy, are judged to have near-cCR or partial response (residual tumor \<2 cm).
Intervention: All participants undergo local excision under general anesthesia. The specimen is sent for intra-operative frozen section.
ypT0-1 on frozen section → procedure concluded; patient enters watch-and-wait. ypT2-3 or R1 on frozen section → immediate completion total mesorectal excision (TME).
Frozen-section ypT1-2 but final paraffin section up-staged to ypT2-3 or R1 → elective TME within 8 weeks.
Primary Endpoint: a composite outcome of 2-year local recurrence rate, surgical complications (≤30 days), and long-term functional impairment (anorectal, urogenital, and quality-of-life scales).
Secondary Endpoints: Agreement between intra-operative frozen-section pathology and final paraffin-section pathology, 3-year disease-free survival (DFS), 3-year overall survival (OS), surgery-sparing rate, post-operative recovery metrics, Quality-of-life scores.
Estimated Enrollment: 27 participants.
Eligibility
Inclusion Criteria:
- Pathologically confirmed rectal adenocarcinoma.
- Neoadjuvant therapy based on radiotherapy; post-radiotherapy evaluation ≥8 weeks later shows near clinical complete response (near-cCR) or partial response (PR) with residual tumor \<2 cm.
- Tumor distance from the anal verge ≤5 cm.
- Age 18-75 years.
- No synchronous multiple primary cancers.
- No contraindications to pre-operative radiotherapy or chemotherapy.
- Adequate organ function (cardiac, hepatic, renal, hematologic).
- Patient or legally authorized representative able to understand the study protocol, willing to participate, and provide written informed consent.
Exclusion Criteria:
- Age \<18 or \>75 years.
- Concurrent or previous malignancy within the past 5 years (except adequately treated basal-cell or squamous-cell skin carcinoma or carcinoma in situ of the cervix).
- Emergency surgery required for bowel obstruction, perforation, or bleeding.
- Prior colorectal surgery that may compromise intestinal reconstruction.
- Need for en-bloc multivisceral resection.
- ASA physical status IV or V.
- Pregnant or lactating women.
- a) Women of child-bearing potential with a positive serum pregnancy test at baseline or who have not undergone pregnancy testing; post-menopausal women must have been amenorrheic for ≥12 months.
- b) Men or women of reproductive potential unwilling to use effective contraception throughout the study period.
- Severe psychiatric illness precluding informed consent or compliance.
- Severe COPD, interstitial lung disease, or ischemic heart disease precluding safe surgery.
- Continuous systemic corticosteroid therapy within 1 month before enrolment.
- Contraindications to laparoscopic surgery.
- Patient or legally authorized representative unable to understand the study conditions and objectives.