What is the schedule of the total neoadjuvant therapy (TNT) regimen for locally advanced rectal adenocarcinoma in a patient who has just completed the full TNT sequence?

Total Neoadjuvant Therapy (TNT) Schedule for Locally Advanced Rectal Cancer

The standard TNT schedule consists of long-course chemoradiotherapy (50.4 Gy over 5-6 weeks with concurrent fluoropyrimidine) followed by consolidation chemotherapy (typically 3-4 cycles of FOLFOX or CAPOX), with surgery performed 6-8 weeks after completing all neoadjuvant treatment. 1, 2

Preferred TNT Regimen Components

Radiation Sequence

• Long-course chemoradiotherapy is strongly preferred over short-course radiotherapy for TNT candidates, based on the RAPIDO trial's 5-year data showing 10% locoregional recurrence with short-course RT versus 6% with long-course CRT (P=0.027). 1, 2
• Long-course CRT delivers 45-50.4 Gy in 1.8-2.0 Gy fractions over 5-6 weeks with concurrent chemotherapy. 3

Chemotherapy Timing

• Consolidation chemotherapy (after radiation) is the recommended sequence over induction chemotherapy (before radiation), based on moderate-quality evidence showing improved treatment compliance and higher pathologic complete response rates. 1, 2
• The CAO/ARO/AIO-12 trial demonstrated 25% pathologic complete response with consolidation versus 17% with induction chemotherapy. 1, 4
• Consolidation chemotherapy after CRT achieved better CRT compliance (97% vs 91% received full-dose radiotherapy) compared to induction approaches. 4

Systemic Chemotherapy Regimen

• Administer 3-4 cycles of FOLFOX (fluorouracil, leucovorin, oxaliplatin) or CAPOX (capecitabine, oxaliplatin) as consolidation chemotherapy following completion of long-course CRT. 2, 3
• Each cycle is typically given every 2 weeks (FOLFOX) or every 3 weeks (CAPOX). 2

Complete TNT Timeline

Week 1-6: Long-Course Chemoradiotherapy

• Deliver 50.4 Gy radiation in 28 fractions (1.8 Gy per fraction) over 5-6 weeks. 3, 4
• Administer concurrent continuous infusion 5-fluorouracil or oral capecitabine throughout radiation. 3
• Oxaliplatin may be added concurrently with radiation (50 mg/m² weekly). 4

Week 7-18: Consolidation Chemotherapy

• Begin consolidation chemotherapy approximately 2-4 weeks after completing CRT. 2
• Deliver 3-4 cycles of FOLFOX or CAPOX over 6-12 weeks. 2, 3
• Total duration of systemic chemotherapy exposure (including concurrent phase) should approach 6 months. 2

Week 19-26: Restaging and Surgery

• Wait 6-8 weeks after completing all TNT before restaging to allow maximal tumor regression. 2
• Perform high-resolution pelvic MRI with dedicated rectal sequences plus endoscopic examination (digital rectal exam and proctoscopy) for response assessment. 2
• Schedule surgery 6-8 weeks after TNT completion for patients requiring resection. 2

Alternative Induction Sequence (Less Preferred)

While consolidation is preferred, induction chemotherapy may be considered in specific circumstances:

• Deliver 3 cycles of FOLFOX chemotherapy first (weeks 1-6). 4
• Follow with long-course CRT with concurrent fluoropyrimidine/oxaliplatin (weeks 7-12). 4
• Proceed to surgery 6-8 weeks after CRT completion (weeks 18-20). 4

Critical caveat: Induction chemotherapy results in lower CRT compliance (91% vs 97% received full-dose radiation) and may be associated with shorter intervals between radiation and response assessment, potentially underestimating treatment effect. 1, 4

Special Considerations for High-Risk Patients

Triplet Chemotherapy (FOLFIRINOX)

• FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, irinotecan) may be considered as induction chemotherapy for patients at highest risk of distant metastases. 1
• Exercise caution: Grade 3+ toxicity occurs in 35.9% with triplet regimens versus 23% with doublet regimens. 2
• PRODIGE-23 trial limited eligibility to patients under 76 years of age due to toxicity concerns. 1

Short-Course RT-Based TNT (Not Recommended as Standard)

• If short-course RT is used (25 Gy in 5 fractions over 1 week), it must be followed by consolidation chemotherapy before surgery. 1
• This approach carries increased locoregional recurrence risk and should be reserved for specific circumstances (elderly patients, severe comorbidities, logistical constraints). 1, 2

Post-TNT Management

Postoperative Adjuvant Therapy

• Complete a total of 6 months of systemic chemotherapy, including the preoperative consolidation period. 2
• For patients with pathologic stage ≤ypII after TNT, fluoropyrimidine monotherapy may be considered. 2
• Begin adjuvant treatment as early as possible and no later than 8 weeks after surgery. 2

Watch-and-Wait for Clinical Complete Response

• Patients achieving clinical complete response on both MRI and endoscopy may be offered non-operative management. 2
• The OPRA trial demonstrated 3-year TME-free survival of 41-53% with organ preservation approaches. 2
• Intensive surveillance is mandatory: MRI and endoscopy every 3-4 months for the first 2 years, as 94-99% of regrowth occurs during this period. 2

Common Pitfalls to Avoid

• Do not perform restaging immediately after TNT—the mandatory 6-8 week interval allows maximal tumor regression and accurate response assessment. 2
• Do not use short-course RT for patients seeking organ preservation—long-course CRT is more appropriate when the goal is achieving clinical complete response. 2
• Do not delay surgery beyond 8-10 weeks after TNT completion in patients requiring resection, as this may permit tumor regrowth. 2
• Do not rely on MRI alone for determining complete response—endoscopic confirmation is mandatory, as MRI detects complete response with only 64% accuracy. 2