Journal Review in Colorectal Surgery: Total Neoadjuvant Therapy in Rectal Cancer

Nov 24, 2025

Guest

Emmanouil Fokas

Guest

Julio Garcia-Aguilar

Guest

Benjamin Schlechter

Join leading experts in the field as Benjamin Schlechter, a Senior Physician at Dana-Farber, dives into the evolution of Total Neoadjuvant Therapy (TNT) in rectal cancer treatment. Julio Garcia-Aguilar, from MSK, shares insights from the impactful OPRA trial on organ preservation strategies. Emmanouil Fokas reveals findings from German trials on radiation scheduling. They explore benefits of preoperative chemotherapy, survival outcomes, and how emerging trials and research are shaping future treatment options.

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INSIGHT

Definition And Guideline Differences For LARC

Locally advanced rectal cancer (LARC) includes cT3-4 or node-positive tumors and some cT3N0 cases.
NCCN favors TNT for all non-metastatic LARC while ESMO limits TNT to high-risk features like cT4 or threatened mesorectal fascia.

INSIGHT

Why TNT Replaces Postop Chemotherapy

Historic trials established neoadjuvant radiation and chemoradiation to lower local recurrence and improve sphincter preservation.
Moving chemo before surgery (TNT) raises pathCR rates and addresses micrometastatic disease that adjuvant therapy often missed.

INSIGHT

Key Trial Outcomes: RAPIDO vs PRODIGE-23

RAPIDO (short-course TNT) and PRODIGE-23 (FOLFIRINOX-based TNT) both increased pathologic complete response rates.
PRODIGE-23 showed durable DFS and OS benefits with triplet chemotherapy, while RAPIDO raised concerns about higher locoregional failure with short-course RT.

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The treatment for locally advanced rectal cancer has undergone numerous changes and is now used routinely in clinical practice. Please join us in a thorough discussion of current evidence and ongoing research of total neoadjuvant therapy in locally advanced rectal cancer with leaders in the field including Drs J. Joshua Smith, Julio Garcia-Aguilar, Emmanouil Fokas, and Benjamin Schlechter

Hosts:
· Dr. Janet Alvarez - General Surgery Resident at New York Medical College/Metropolitan Hospital Center
· Dr. Wini Zambare – General Surgery Resident at Weill Cornell Medical Center/New York Presbyterian
· Dr. Phil Bauer, Graduating Colorectal Surgical Oncology Fellow at Memorial Sloan Kettering Cancer Center
· Dr. J. Joshua Smith MD, PhD, Chair, Department of Colon and Rectal Surgery at MD Anderson Cancer Center

Guests:
1. Julio Garcia-Aguilar, MD, PhD
Benno C. Schmidt Chair in Surgical Oncology
Chief, Colorectal Service, Department of Surgery
Director, Colorectal Cancer Research Center, Memorial Sloan Kettering Cancer Center
Professor of Surgery, Weill Cornell Medical College
2. Benjamin Schlechter, MD
Senior Physician in the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute
Assistant Professor of Medicine, Medicine, Harvard Medical School
3. Emmanouil Fokas, MD, DPhil
Professor and Chairman | Department of Radiation Oncology, Cyberknife and Radiotherapy | Faculty of Medicine, University Hospital Cologne

Learning objectives:
· Define locally advanced rectal cancer (LARC) and describe the clinical staging that qualifies patients for total neoadjuvant therapy (TNT).
· Explain the rationale for transitioning from traditional chemoradiotherapy (CRT) plus surgery to total neoadjuvant therapy in rectal cancer management.
· Compare the designs, treatment regimens, and long-term outcomes of major TNT trials including RAPIDO, PRODIGE-23, OPRA, and CAO/ARO/AIO-12/16.
· Evaluate organ preservation strategies—such as the watch-and-wait approach—after TNT and identify which patients are appropriate candidates based on clinical or near-complete response.
· Summarize emerging research directions including:
· Integration of circulating tumor DNA (ctDNA) in surveillance and response prediction.
· The role of immunotherapy in mismatch repair proficient (MSS) and deficient (dMMR) tumors.

References:
1. Garcia-Aguilar, J. et al. Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy. JCO 40, 2546–2556 (2022). https://pubmed.ncbi.nlm.nih.gov/35483010/

2. Verheij, F. S. et al.Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial. JCO 42, 500–506 (2024). https://pubmed.ncbi.nlm.nih.gov/37883738/

3. Fokas, E. et al. Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12. JCO 37, 3212–3222 (2019). https://pubmed.ncbi.nlm.nih.gov/31150315/

4. Fokas, E. et al. Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial. JAMA Oncol 8, e215445–e215445 (2022). https://pubmed.ncbi.nlm.nih.gov/34792531/

5. Williams H*, Fokas E*, et al. Survival among patients treated with total mesorectal excision or selective watch-and-wait after total neoadjuvant therapy: a pooled analysis of the CAO/ARO/AIO-12 and OPRA randomized phase II trials. Ann Oncol 2025 May;36(5):543-547. https://pubmed.ncbi.nlm.nih.gov/39848335/

6. Gani, C. et al. Organ preservation after total neoadjuvant therapy for locally advanced rectal cancer (CAO/ARO/AIO-16): an open-label, multicentre, single-arm, phase 2 trial. The Lancet Gastroenterology & Hepatology 10, 562–572 (2025). https://pubmed.ncbi.nlm.nih.gov/40347958/