What is the role of the TNT (chemotherapy, radiation therapy, and surgery) regimen in treating rectal cancer?

Total Neoadjuvant Therapy (TNT) for Rectal Cancer

Total Neoadjuvant Therapy (TNT) is now the preferred treatment approach for locally advanced (stage II/III) rectal cancer, delivering both chemoradiotherapy and systemic chemotherapy before surgery to maximize tumor regression, improve pathologic complete response rates, and potentially allow organ preservation. 1, 2

What is TNT and Why Use It?

TNT represents an evolution from traditional neoadjuvant chemoradiotherapy by intensifying systemic chemotherapy delivery before surgery rather than after. The TNT model prioritizes concurrent chemoradiotherapy followed by sequential systemic chemotherapy, which is more conducive to tumor regression and can help avoid total mesorectal excision (TME) surgery. 1

The rationale for TNT includes:

• Higher pathologic complete response (pCR) rates compared to standard chemoradiotherapy alone 1
• Improved disease-free survival as demonstrated in the PRODIGE-23 trial, which showed that FOLFIRINOX followed by capecitabine-based long-course chemoradiotherapy improved pCR rates and 3-year disease-free survival compared to standard treatment 2
• Better treatment compliance since chemotherapy is delivered when patients are healthier, before surgery 1
• Potential for organ preservation through watch-and-wait strategies in patients achieving complete clinical response 1, 2

TNT Treatment Sequence

Step 1: Long-Course Chemoradiotherapy

Preoperative chemoradiotherapy (50 Gy, 2 Gy/day with concurrent 5-FU continuous infusion during the first and fifth weeks) is preferred over postoperative chemoradiotherapy due to decreased toxicity. 1

• Radiation dose: 45-50.4 Gy delivered over 5-6 weeks 1, 2
• Concurrent chemotherapy: fluoropyrimidine-based (5-FU continuous infusion or capecitabine) 1, 3, 4
• Oxaliplatin should NOT be used concurrently with radiotherapy due to increased toxicity 2, 5

Step 2: Consolidation Chemotherapy

After completing chemoradiotherapy, consolidation chemotherapy with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) should be administered for 12-16 weeks, with FOLFOX being preferred based on robust trial evidence. 1, 2

Specific regimens:

• FOLFOX: administered every 2 weeks for 4-6 cycles 2
• CAPOX: administered for 6-8 cycles in the consolidation phase 2
• Consolidation chemotherapy regimens may include FOLFOX, CAPEOX, 5-FU/LV, or capecitabine 1

The STELLAR trial confirmed that consolidation CAPOX after chemoradiotherapy achieved 3-year disease-free survival of 64.5% with manageable toxicity. 2

Step 3: Reassessment and Surgery

Surgery should be performed 2-4 weeks after completion of consolidation chemotherapy, following MRI reassessment. 1

• Timing allows for maximal tumor response assessment 2
• Total mesorectal excision (TME) is strongly recommended as the surgical method, giving a low local recurrence rate (<10%) and good quality of life 1
• Sphincter-sparing procedures should be performed whenever technically feasible 1

Step 4: Watch-and-Wait Option

For patients achieving complete clinical response (cCR) after TNT based on digital rectal examination, rectal MRI, and direct endoscopic evaluation, a "watch and wait" strategy may be considered as an alternative to surgery. 1, 2

This non-surgical approach should be:

• Conducted only in experienced multidisciplinary centers 1
• Particularly considered for patients requiring abdominoperineal resection with permanent colostomy 2
• Reserved for elderly patients or those with significant comorbidities 2
• Offered to patients strongly motivated to avoid permanent stoma 2

Post-Operative Adjuvant Chemotherapy

Patients receiving preoperative TNT should still undergo postoperative adjuvant chemotherapy, with a recommended total treatment duration of 6 months including the preoperative consolidation period. 1

• For patients with pathological stage ≤ypII after preoperative TNT, fluoropyrimidine monotherapy may be considered 1
• Postoperative treatment should start as early as possible, no later than 8 weeks after surgery 1

Special Populations

For MSI-high or dMMR stage III rectal cancer, immunotherapy with dostarlimab is preferred over standard TNT, achieving clinical complete response in 100% of evaluable patients without grade 3+ adverse events. 2

Important Toxicity Monitoring

• Oxaliplatin-induced peripheral neuropathy is cumulative and dose-limiting; monitor closely and consider dose reduction or discontinuation if grade 2-3 neuropathy develops 2, 5
• Patients taking warfarin require close INR and prothrombin time monitoring, as fluorouracil can cause clinically significant increases in coagulation parameters 3, 4
• Elderly patients and those with significant comorbidities may require dose modifications 2

Common Pitfalls to Avoid

• Never administer oxaliplatin concurrently with radiation therapy - this significantly increases toxicity without proven benefit 2, 5
• Do not skip postoperative adjuvant chemotherapy even if pathologic complete response is achieved, unless pathological stage is ≤ypII 1
• Ensure adequate interval (2-4 weeks) between completion of consolidation chemotherapy and surgery for proper tumor regression assessment 1
• Watch-and-wait should only be offered in experienced centers with rigorous follow-up protocols 1