Risk of Distant Metastasis After Total Neoadjuvant Therapy: Local Regrowth Versus Surgery After Total Neoadjuvant Therapy With Pathologic Near-Complete Response in Rectal Cancer.

Background: In rectal cancer patients with a clinical complete response managed nonoperatively, local regrowth occurs in up to 35%. Although prior studies suggest a higher metastatic risk after regrowth, most data are derived from conventional chemoradiotherapy cohorts. The risk in a total neoadjuvant therapy setting remains unclear.

Objective: To assess whether local regrowth after clinical complete response in patients treated with total neoadjuvant therapy increases the risk of distant metastasis, and to evaluate if the risk could be reduced by upfront surgery performed after total neoadjuvant therapy.

Design: Retrospective cohort study.

Setting: Single tertiary care center.

Patients: Patients with locally advanced rectal cancer treated with total neoadjuvant therapy between 2018 and 2024 who achieved a clinical complete response, were managed nonoperatively, developed local regrowth, and subsequently underwent salvage total mesorectal excision, compared with those who underwent upfront total mesorectal excision after total neoadjuvant therapy, with final pathology demonstrating a near-complete response.

Intervention: Total neoadjuvant therapy followed by either watch & wait and salvage total mesorectal excision or upfront total mesorectal excision.

Main outcome measures: The primary outcome was distant metastasis. Secondary outcomes included distant metastasis-free survival and independent predictors of distant spread.

Results: Seventy-four patients were included (median age: 58 years [IQR, 51-67]; 58% male): 32 with local regrowth managed by salvage total mesorectal excision and 42 with upfront total mesorectal excision. The distant metastasis-free survival was comparable between groups, and local regrowth was not independently associated with distant metastasis (OR, 0.99; 95% CI, 0.25-4.00). ypT3-4 stage was independently associated with increased risk of distant metastasis (OR, 5.8; 95% CI, 1.3-25.3), while complete mesorectal excision was protective (OR, 0.08; 95% CI, 0.01-0.59).

Limitations: Retrospective design, small sample size, and limited follow-up.

Conclusion: Patients treated with total neoadjuvant therapy who developed local regrowth and underwent salvage total mesorectal excision achieved distant metastasis rates comparable to those who underwent upfront surgery after total neoadjuvant therapy and demonstrated a pathologic near-complete response. High-quality salvage surgery and close surveillance are essential for optimizing oncologic outcomes. See Video Abstract.