What is the recommended chemoradiotherapy (CRT) regimen, including dose and schedule, in Total Neoadjuvant Therapy (TNT) for rectal cancer?

Total Neoadjuvant Therapy (TNT) for Rectal Cancer: Chemoradiotherapy Dose and Schedule

For TNT in locally advanced rectal cancer, the standard long-course chemoradiotherapy regimen consists of 45.0-50.4 Gy delivered in 25-28 fractions (1.8-2.0 Gy per fraction) over 5-5.5 weeks, with concurrent capecitabine 825 mg/m² twice daily, 5-7 days per week during radiation, or continuous infusion 5-FU 225 mg/m²/day. 1, 2

Standard Long-Course Chemoradiotherapy Regimens

Radiation Dose and Fractionation

• Total pelvic dose: 45.0-50.4 Gy over 25-28 fractions (1.8-2.0 Gy per fraction), delivered over 5-5.5 weeks 1, 2
• Tumor boost: 4-6 Gy in 2-4 fractions may be added after 45 Gy to the primary tumor bed with a 2 cm margin 1, 2
• For unresectable tumors, dose escalation to 54-56 Gy may be considered if technically feasible 1, 2

Concurrent Chemotherapy Options

Preferred regimens during radiotherapy:

• Capecitabine 825 mg/m² twice daily, administered 5-7 days per week throughout the entire radiation course 1, 2

  • This is the most practical option for TNT as it avoids the need for continuous infusion pumps 2
  • Demonstrated non-inferiority to 5-FU with superior 3-year disease-free survival (75.2% vs 66.6%, P=0.034) 2

• Continuous infusion 5-FU 225 mg/m²/day, administered 7 days per week during the entire radiation period 1, 2

• Bolus 5-FU/leucovorin: 5-FU 400 mg/m² IV bolus + leucovorin 20 mg/m² IV bolus for 4 days during weeks 1 and 5 of radiation 1

  • Reserved only for patients unable to tolerate capecitabine or infusional 5-FU 2

Important: Oxaliplatin NOT Recommended

• Do not add oxaliplatin to concurrent chemoradiotherapy in TNT regimens 2
• Multiple phase III trials (NSABP R-04, ACCORD 12) showed no improvement in pathologic complete response, disease-free survival, or overall survival with oxaliplatin addition, but significantly increased toxicity (grade 3/4 adverse events 24% vs 8%, P<0.001) 2

TNT Sequencing Strategies

Induction Chemotherapy Followed by Chemoradiotherapy (Most Common)

• 6 cycles of modified FOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-FU 400 mg/m² bolus, then 2400 mg/m² continuous infusion over 46 hours, every 2 weeks) 3
• Followed by long-course chemoradiotherapy as described above 3, 4
• Total treatment duration: approximately 20 weeks before surgery 3

Chemoradiotherapy Followed by Consolidation Chemotherapy (Alternative)

• Long-course chemoradiotherapy first (50.4 Gy with capecitabine) 4
• Followed by 4 cycles of CAPOX (capecitabine + oxaliplatin) consolidation chemotherapy 4
• This sequence achieved 23.8% pathologic complete response rate in Japanese patients 4

Short-Course Radiotherapy Option

• 25 Gy in 5 fractions (5 Gy daily for 5 consecutive days) 1, 2
• No concurrent chemotherapy with short-course radiation 1
• For high-risk patients (cT4a/b, EMVI+, cN2, MRF+), consolidation chemotherapy is recommended after short-course RT before surgery 1
• Surgery may proceed within 1 week for low-risk T3 tumors not requiring downstaging 1

Radiation Field Coverage

The clinical target volume must include: 1, 2

• Primary tumor or tumor bed with 2-5 cm margin
• Entire mesorectum (except for very early tumors)
• Presacral lymph nodes along the superior rectal artery up to S1-2 level
• Internal iliac lymph nodes up to below the bifurcation (approximately S1-2 level)
• Obturator lymph nodes
• External iliac lymph nodes for T4 tumors invading anterior structures
• Inguinal lymph nodes may be considered for tumors invading the distal anal canal 1

Technical Delivery

• Use 3D-CRT, VMAT, or IMRT techniques 1, 2
• Employ 3- or 4-field technique 1, 2
• Limit small bowel dose to ≤45-50 Gy 1
• Position patients to minimize small bowel in radiation fields 1

Surgery Timing After Chemoradiotherapy

• Optimal interval: 5-12 weeks after completing full-dose chemoradiotherapy 1
• Longer intervals (>8 weeks) increase pathologic complete response rates but may increase morbidity 1
• The GRECCAR6 trial showed that an 11-week interval versus 7-week interval increased complications (44.5% vs 32%, P=0.04) without improving pathologic complete response (17.4% vs 15.0%, P=0.60) 1
• Recommended: 8-10 weeks balances tumor regression with acceptable morbidity 1

Clinical Outcomes

• TNT achieves pathologic complete response rates of 11.5%-35.7% depending on regimen and patient selection 5, 3, 6, 4
• Meta-analysis demonstrates TNT improves pathologic complete response (OR 1.77,95% CI 1.28-2.45, P=0.0005), disease-free survival (HR 0.83,95% CI 0.72-0.96, P=0.03), and reduces distant metastasis risk (HR 0.81,95% CI 0.68-0.95, P=0.012) compared to standard chemoradiotherapy 6
• Five-year local recurrence rate: 4.5% with excellent local control 5

Common Pitfalls to Avoid

• Do not use IMRT outside clinical trials or unique situations (re-irradiation, unusual anatomy) 1
• Do not add oxaliplatin to concurrent chemoradiotherapy - increases toxicity without benefit 2
• Do not delay surgery beyond 12 weeks unless pursuing non-operative management for clinical complete response 1
• Do not use bolus 5-FU/leucovorin as first-line concurrent chemotherapy when capecitabine or infusional 5-FU are available 2