Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Real-World Insights from an International Consortium

Highlight

– Total neoadjuvant therapy (TNT) for stage II/III rectal cancer shows consistent efficacy across various chemotherapy and radiotherapy regimens in a large international real-world cohort.
– The study demonstrated a 23.2% pathological or clinical complete response rate, with 3-year event-free survival at 68% and 5-year overall survival at 79%.
– PRODIGE 23-like regimens showed higher serious adverse events but potential for improved local control and survival, though matched analyses revealed no survival differences between TNT regimens.
– Practice patterns varied substantially globally, highlighting individualized TNT application and reinforcing TNT’s role outside clinical trial settings.

Study Background and Disease Burden

Locally advanced rectal cancer (stage II/III) presents a significant clinical challenge due to risks of local recurrence and distant metastasis. Multimodal treatment combining surgery, radiotherapy, and chemotherapy is standard, aiming to improve oncological outcomes and preserve organ function. Total neoadjuvant therapy (TNT), which involves delivering all systemic and radiation treatments prior to surgery or definitive nonoperative management, promises better tumor downstaging, increased complete response rates, and potential survival benefits. However, evidence from large-scale clinical trials needed confirmation in real-world clinical practice, especially concerning regimen variation, safety profiles, and long-term outcomes.

Study Design

This international, multicenter observational study involved 1585 consecutive patients treated off-trial with TNT for stage II/III rectal adenocarcinoma between September 2012 and December 2023 at 61 centers across 21 countries. The definition of TNT included administration of both radiotherapy and nonradiosensitizing chemotherapy before surgical resection or observation strategies such as watch and wait. The primary objective was to identify types of TNT regimens administered in practice.

Secondary objectives evaluated patient characteristics, treatment adherence, safety, and treatment efficacy. Outcomes were analyzed overall and stratified by TNT regimen types using propensity vector matching to reduce confounding. The main regimen categories were:
– PRODIGE 23-like: FOLFIRINOX or FOLFOXIRI induction chemotherapy followed by long-course chemoradiotherapy.
– RAPIDO-like: short-course radiotherapy followed by consolidation systemic chemotherapy (FOLFOX or CAPOX).
– OPRA induction-like: induction chemotherapy before long-course chemoradiotherapy.
– OPRA consolidation-like: chemoradiotherapy followed by consolidation chemotherapy.
– Other unclassified regimens.

Endpoints included response rates (pathological and clinical complete responses), rates of watch and wait and local excision strategies, local and distant progression, event-free survival (EFS), overall survival (OS), and safety profiles including serious adverse events.

Key Findings

The cohort had a median age of 61 years, with 37.1% female patients, and 79.5% exhibited at least one high-risk feature (cT4, cN2, extramural venous invasion, threatened/involved mesorectal fascia, or lateropelvic lymphadenopathy). Distribution of TNT regimens was 17.7% PRODIGE 23-like, 33.4% RAPIDO-like, 12% OPRA induction-like, 16.2% OPRA consolidation-like, and 22.7% other regimens.

– Response and Management: The overall pathological or clinical complete response (pCR or cCR) rate was 23.2%. Watch and wait was adopted in 12.1% of patients, reflecting a nonoperative management approach when applicable, and 1.9% underwent local excision.

– Recurrence: Local failure occurred in 8.5%, and distant progression in 16.4%, indicating disease control challenges despite TNT.

– Survival Outcomes: The 3-year event-free survival rate was 68% (95% CI, 64-71%), while 5-year overall survival reached 79% (95% CI, 75-83%), supportive of long-term benefits from TNT.

– Safety: The PRODIGE 23-like regimen had the highest frequency of serious adverse events (23.5%), consistent with its more intensive chemotherapy backbone.

– Comparative Outcomes: In unadjusted analyses, PRODIGE 23-like therapy showed superior local control and survival outcomes compared with RAPIDO-like, OPRA induction-like, and OPRA consolidation-like regimens, with hazard ratios ranging approximately between 0.35 to 0.68 for event-free and overall survival benefit (all statistically significant).

– Matched Analysis: After propensity score matching of 928 patients, no statistically significant survival differences were observed among the various TNT regimens, indicating comparable efficacy across different TNT strategies when patient factors were balanced.

Expert Commentary

This comprehensive real-world investigation substantiates TNT as an effective strategy for managing locally advanced rectal cancer outside of clinical trials. The study highlighted the heterogeneity of TNT regimens used globally, reflecting differing institutional preferences and patient characteristics. The higher adverse event rate with PRODIGE 23-like regimens suggests caution and need for patient selection when using intensified chemotherapy. However, its association with improved unadjusted outcomes should prompt further exploration.

Importantly, matched analyses revealed no significant survival disparities, emphasizing that multiple TNT regimen approaches can yield comparable long-term outcomes when adapted to patient profiles. This aligns with current guideline directions that endorse TNT for appropriate candidates but recognize no single optimal regimen universally.

Limitations include the observational off-trial design susceptible to residual confounding despite matching and potential variability in assessment methodologies across centers. Additionally, longer follow-up is warranted to consolidate survival and late toxicity data.

Mechanistically, TNT capitalizes on early micrometastases eradication and enhancement of tumor radiosensitivity through combined systemic and local therapy, rationalizing its integration before surgery or nonoperative management.

Conclusion

The International Real-World TNT Study Consortium’s findings demonstrate that total neoadjuvant therapy is widely utilized across diverse practice settings for stage II/III rectal cancer with favorable efficacy and manageable safety profiles. Substantial regimen variation did not compromise overall survival or event-free survival when comparing propensity matched cohorts, endorsing TNT as a flexible, effective approach in clinical practice.

Ongoing research should aim to refine patient selection, optimize TNT sequencing and components, and integrate biomarkers predictive of response. Clinicians may confidently incorporate TNT strategies tailored to individual patient risk and tolerance, reinforcing its role as a cornerstone for locally advanced rectal cancer management.

References

1. Audisio A, Gallio C, Velenik V, et al; International Real-World TNT Study Consortium. Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer. JAMA Oncol. 2025 Jul 10:e252026. doi:10.1001/jamaoncol.2025.2026.
2. Bahadoer RR, Dijkstra EA, van Etten B, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):29-42.
3. Cercek A, Goodman KA, Humm J, et al. Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: A Single-Institution Experience and Review of Current Evidence. J Clin Oncol. 2020 Jan;38(21):2435-2446.
4. Smith JD, Ruby JA, Goodman KA, et al. Organ Preservation in Rectal Adenocarcinoma: Seminal Expert Analyses and Clinical Perspectives. J Natl Compr Canc Netw. 2021 Apr;19(4):462-470.