What is the recommended chemotherapy regimen for stage 3 rectal cancer after long course radiotherapy as part of the Total Neoadjuvant Therapy (TNT) protocol?

Recommended Chemotherapy Regimen for Stage 3 Rectal Cancer After Long-Course Radiotherapy (TNT Protocol)

For stage 3 rectal cancer following long-course chemoradiotherapy as part of Total Neoadjuvant Therapy, consolidation chemotherapy with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) is the recommended regimen, with FOLFOX being preferred based on the most robust trial evidence. 1

Specific Chemotherapy Regimens

FOLFOX (Preferred Option)

• Modified FOLFOX6 (mFOLFOX6) is the standard consolidation regimen after long-course chemoradiotherapy 1
• Dosing consists of oxaliplatin 85 mg/m² on day 1, leucovorin 200 mg/m² on day 1,5-FU 400 mg/m² IV bolus on day 1, followed by 5-FU 1600 mg/m² as 46-hour continuous infusion 2
• Administer every 2 weeks for 4-6 cycles after completion of long-course chemoradiotherapy 1

CAPOX (Alternative Option)

• Capecitabine and oxaliplatin combination is an acceptable alternative 1
• Typically administered for 6-8 cycles in the consolidation phase 1
• This regimen offers the convenience of oral capecitabine administration 3, 4

Timing and Sequencing

Surgery should be performed 6-8 weeks after completion of the consolidation chemotherapy 1, 5, allowing adequate time for maximal tumor response assessment.

The preferred sequence in TNT is:

1. Long-course chemoradiotherapy (45-50.4 Gy with concurrent fluoropyrimidine) 1
2. Consolidation chemotherapy with FOLFOX or CAPOX (4-6 cycles) 1
3. Surgery or watch-and-wait assessment 1

This consolidation-after-radiation approach achieved higher 3-year TME-free survival (41.1% vs 30.6%) compared to induction chemotherapy before radiation in the OPRA trial 1.

Evidence Supporting This Approach

The PRODIGE-23 trial demonstrated that FOLFIRINOX followed by capecitabine-based long-course chemoradiotherapy improved pathologic complete response rates (27.5% vs 11.7%) and 3-year disease-free survival compared to standard treatment 1. However, for consolidation chemotherapy specifically after long-course chemoradiotherapy, doublet therapy (FOLFOX or CAPOX) is recommended rather than triplet therapy to balance efficacy with tolerability 1.

The STELLAR trial confirmed that consolidation CAPOX after chemoradiotherapy achieved 3-year disease-free survival of 64.5% with manageable toxicity 1.

Important Toxicity Considerations

Expected Grade 3-4 Toxicities with FOLFOX:

• Neutropenia: 9.1% 2
• Diarrhea: 21.8% 2
• Peripheral neuropathy: 9.1% 2
• Hepatotoxicity: 5.5% 2

Oxaliplatin-induced peripheral neuropathy is cumulative and dose-limiting 1. Monitor closely and consider dose reduction or discontinuation if grade 2-3 neuropathy develops. Elderly patients and those with significant comorbidities may require dose modifications 1.

Chemotherapy Completion Rates:

• 92.7% of patients completed planned chemotherapy cycles when given as consolidation after chemoradiotherapy 2
• This high completion rate supports the consolidation approach over adjuvant chemotherapy after surgery

Triplet Chemotherapy: Not Currently Recommended

FOLFIRINOX (adding irinotecan to FOLFOX) is NOT recommended as consolidation chemotherapy after long-course chemoradiotherapy 1. While FOLFIRINOX showed promise when given as induction therapy before chemoradiotherapy in PRODIGE-23, it carries significantly higher toxicity (23.5% serious adverse events) 6 and is reserved for:

• Induction TNT protocols (chemotherapy given before radiation) 1
• Patients at very high risk of distant metastases 1
• Younger patients (<76 years) without significant comorbidities 1

The ongoing JANUS and ENSEMBLE trials are investigating whether triplet chemotherapy after long-course chemoradiotherapy improves outcomes, but results are not yet available 1.

Special Populations

MSI-High or dMMR Tumors (5-10% of rectal cancers):

Immunotherapy with dostarlimab is preferred over standard TNT for MSI-high or dMMR stage 3 rectal cancer, achieving clinical complete response in 100% of evaluable patients without grade 3+ adverse events 1. If immunotherapy is contraindicated, proceed with standard FOLFOX/CAPOX consolidation as outlined above 1.

Patients Achieving Clinical Complete Response:

If clinical complete response is documented after consolidation chemotherapy (no palpable tumor on digital rectal exam, no residual tumor on MRI with limited diffusion-weighted imaging signal, no residual tumor on rectoscopy) 1, nonoperative management (watch-and-wait) may be discussed as an alternative to surgery, particularly for patients requiring abdominoperineal resection with permanent colostomy 1, 5.

Common Pitfalls to Avoid

• Do NOT add oxaliplatin concurrently with radiation therapy – this increases toxicity without improving outcomes 1, 4
• Do NOT use capecitabine monotherapy as consolidation chemotherapy – doublet therapy with oxaliplatin is required for adequate systemic control 7
• Do NOT delay surgery beyond 12 weeks after completing consolidation chemotherapy – optimal timing is 6-8 weeks to balance maximal tumor response with avoiding tumor regrowth 1, 5
• Do NOT omit consolidation chemotherapy even if planning watch-and-wait – the chemotherapy itself contributes to achieving complete response 1