Total Neoadjuvant Therapy for Rectal Cancer
For patients with locally advanced rectal cancer, total neoadjuvant therapy (TNT) should be offered as initial treatment, particularly for those with low rectal tumors and/or high-risk features including T4 tumors, extramural vascular invasion (EMVI), tumor deposits, threatened mesorectal fascia (MRF), or threatened intersphincteric plane. 1
What is Total Neoadjuvant Therapy?
TNT refers to the administration of both systemic chemotherapy and radiation therapy before surgery, rather than the traditional approach of giving some chemotherapy after surgery. This approach offers several advantages:
- Improved treatment compliance
- Better tumor regression
- Potential for organ preservation
- Reduced risk of distant metastases
- Minimized time with temporary ileostomy
Patient Selection for TNT
TNT is most appropriate for:
- Patients with low rectal tumors
- Patients with high-risk features:
- T4 tumors
- EMVI positive
- Tumor deposits on MRI
- Threatened mesorectal fascia
- Threatened intersphincteric plane
For patients with lower-risk locally advanced middle or upper rectal cancer (T3 N0-N1 without threatened MRF), other options may be considered, including neoadjuvant fluoropyrimidine and oxaliplatin-based chemotherapy with selective addition of chemoradiation 1.
Recommended TNT Regimens
Based on current evidence, the optimal TNT approach involves:
Timing of Chemotherapy and Radiation
- Chemotherapy is recommended after radiation rather than before 1
- This sequence demonstrated higher rates of TME-free survival at 3 years in the OPRA phase II RCT 1
Radiation Options
- Long-course chemoradiotherapy (CRT): Typically 45-50.4 Gy with concurrent fluoropyrimidine
- Short-course radiation therapy (SCRT): 5 × 5 Gy followed by chemotherapy 1
Chemotherapy Regimens
- FOLFOX (fluorouracil, leucovorin, and oxaliplatin) - preferred regimen
- CAPOX (capecitabine and oxaliplatin) - alternative regimen
- FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) - may be considered for patients at greater risk of distant metastases 1
Evidence Supporting TNT
Several phase III trials have demonstrated benefits of TNT:
PRODIGE-23 trial: FOLFIRINOX followed by chemoradiotherapy improved 3-year DFS compared to standard approach 1
RAPIDO trial: Short-course radiation followed by FOLFOX/CAPOX reduced disease-related treatment failure compared to standard chemoradiotherapy 1
STELLAR trial: Short-course radiation followed by CAPOX improved 3-year DFS compared to standard approach 1
Meta-analyses: TNT significantly improves pathologic complete response rates (OR 1.77; 95% CI, 1.28-2.45) and reduces risk of distant metastasis (HR 0.81; 95% CI, 0.68-0.95) compared to standard neoadjuvant chemoradiotherapy 2
Important Considerations
Toxicity Management
- TNT with triplet chemotherapy (FOLFIRINOX) carries higher rates of adverse events
- Consider patient factors such as age and comorbidities when selecting regimens
- In the PRODIGE-23 trial, eligibility was limited to patients under 76 years 1
Response Assessment
- Clinical complete response (cCR) should be assessed after TNT
- Definition of cCR includes:
- Digital rectal exam: no palpable tumor
- Rectoscopy: no residual tumor material
- MRI: substantial downsizing with no observable residual tumor or residual fibrosis only 1
Watch-and-Wait Approach
For patients achieving cCR after TNT, a "watch-and-wait" approach (non-operative management) may be considered, especially for low rectal tumors where sphincter preservation is a concern 1.
Conclusion
TNT represents an evolution in the management of locally advanced rectal cancer, offering improved pathologic complete response rates and potential for better disease control. The recommended approach involves radiation (preferably short-course) followed by chemotherapy (preferably FOLFOX or CAPOX), with the specific regimen tailored based on tumor location and risk factors for local and distant recurrence.