What types of treatments are involved in total neoadjuvant therapy?

Total Neoadjuvant Therapy: Treatment Components and Regimens

Total neoadjuvant therapy (TNT) combines both chemoradiotherapy and systemic chemotherapy delivered entirely before surgery, representing the preferred treatment approach for locally advanced rectal cancer (stage II-III) with high-risk features. 1, 2

Core Treatment Components

TNT consists of two fundamental elements delivered in the neoadjuvant setting:

• Radiation therapy component: Either long-course chemoradiotherapy (45-50.4 Gy with concurrent fluoropyrimidine over 5-6 weeks) or short-course radiotherapy (25 Gy over 5 days) 1, 2
• Systemic chemotherapy component: Multi-agent chemotherapy regimens (typically FOLFOX, CAPOX, or FOLFIRINOX) administered for 3-6 months 2, 3

Optimal Sequencing Strategies

Consolidation chemotherapy (administered after radiation) is the preferred sequence over induction chemotherapy (given before radiation) based on superior outcomes. 1, 2

The two main sequencing approaches include:

• Consolidation approach: Chemoradiotherapy → systemic chemotherapy → surgery (preferred) 1, 2
• Induction approach: Systemic chemotherapy → chemoradiotherapy → surgery (alternative) 3, 4

Radiation Therapy Selection

Long-course chemoradiotherapy is preferred over short-course radiotherapy for TNT candidates due to superior local control. 1, 2

Critical evidence supporting this recommendation:

• The RAPIDO trial's 5-year data revealed 10% locoregional recurrence with short-course RT-based TNT versus 6% with long-course chemoradiotherapy (RR 1.45,95% CI 0.97-2.17) 2
• Long-course chemoradiotherapy achieves higher pathologic complete response rates (25% vs 17%) when given before chemotherapy 5
• Short-course RT should be reserved for patients requiring rapid treatment initiation or those with contraindications to prolonged concurrent chemoradiotherapy 2, 3

Chemotherapy Regimen Options

The systemic chemotherapy component typically employs:

• Doublet regimens: FOLFOX (5-FU/leucovorin/oxaliplatin) or CAPOX (capecitabine/oxaliplatin) for standard-risk patients 3, 4
• Triplet regimens: FOLFIRINOX (5-FU/leucovorin/oxaliplatin/irinotecan) for high-risk patients who can tolerate intensive therapy 3, 4
• Duration: Typically 4-6 cycles (approximately 3-4 months) of systemic chemotherapy 2, 3

Special Population Considerations

For patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, immunotherapy is the recommended treatment instead of conventional TNT. 1, 2

• Checkpoint inhibitor monotherapy (pembrolizumab or dostarlimab) has demonstrated exceptional response rates in this molecular subtype 1, 2
• Conventional chemoradiotherapy should be avoided in MSI-H/dMMR tumors due to inferior outcomes with cytotoxic therapy 4

Beyond Rectal Cancer Applications

While TNT is most established in rectal cancer, neoadjuvant approaches incorporating multiple treatment modalities are emerging in other malignancies:

• Melanoma: Neoadjuvant immunotherapy (pembrolizumab, nivolumab/ipilimumab) or targeted therapy (dabrafenib/trametinib for BRAF-mutant disease) for resectable stage III disease 1
• Breast cancer: Neoadjuvant chemotherapy ± targeted agents (trastuzumab for HER2-positive, pertuzumab combinations) for locally advanced disease 1, 6
• Lung cancer: Neoadjuvant chemotherapy or chemoimmunotherapy combinations for resectable stage II-III non-small cell lung cancer 1

Critical Implementation Pitfalls

Thorough staging with high-resolution pelvic MRI including dedicated rectal sequences is mandatory before initiating TNT to identify appropriate candidates. 2, 5

Essential pre-treatment assessments include:

• Tumor distance from anal verge and relationship to sphincter complex 2
• Mesorectal fascia involvement, extramural vascular invasion (EMVI), and tumor deposits 2, 5
• Clinical nodal stage and lateral lymph node assessment 2
• MSI/MMR status determination to identify patients requiring immunotherapy instead 1, 2

Serious adverse events occur in approximately 38% of patients undergoing TNT, requiring careful patient selection. 2

• Triplet chemotherapy regimens (FOLFIRINOX) carry substantially higher toxicity and may be inappropriate for elderly patients or those with significant comorbidities 2
• Long-course chemoradiotherapy demonstrates more favorable acute toxicity (23% grade 3+ events) compared to short-course RT-based TNT (35.9% grade 3+ events) 2