From the Guidelines
Total Neoadjuvant Therapy (TNT) is recommended for patients with locally advanced rectal cancer, as it improves pathological complete response rates and overall survival compared to standard neoadjuvant chemoradiation therapy (CRT). The current evidence, as seen in the 2024 ASCO guideline 1, suggests that TNT increases pathological complete response rates, with a relative risk of 1.74 (95% CI, 1.45 to 2.10), and improves overall survival, with a hazard ratio of 0.78 (95% CI, 0.62 to 0.97).
Key Benefits of TNT
- Improves pathological complete response rates
- Improves overall survival
- May allow for organ preservation in select patients
- Addresses micrometastatic disease earlier
- Improves treatment compliance as patients tolerate therapy better before surgery
- Provides time to assess tumor response which may guide surgical decisions
Patient Selection for TNT
TNT is particularly beneficial for locally advanced rectal cancer (T3-T4 or node-positive disease) and distal tumors where sphincter preservation is a concern. However, not all patients require this intensive approach, and treatment should be individualized based on tumor characteristics, patient factors, and multidisciplinary team assessment.
Typical TNT Regimen
A typical TNT regimen includes induction chemotherapy with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) for 2-3 months, followed by chemoradiation (typically 45-50 Gy of radiation with concurrent 5-fluorouracil or capecitabine), then surgery 8-12 weeks later.
Recent Guidelines and Studies
Recent studies, including the RAPIDO trial 1, have shown that TNT improves disease-related treatment failure at 3 years, including distant metastases, with a relative risk of 0.79 (95% CI, 0.63 to 1.00). The 2024 NCCN guidelines 1 also recommend TNT as an option for patients with locally advanced rectal cancer. The ASCO guideline 1 suggests that TNT should be offered as initial treatment for patients with tumors located in the lower rectum and/or patients who are at higher risk for local and/or distant metastases.
Potential Drawbacks of TNT
While TNT offers several advantages, it also increases grade 3 or 4 adverse events, with a relative risk of 1.56 (95% CI, 1.18 to 2.07) 1, and worsens grade 1 to 2 neurotoxicity at 6 months, with a relative risk of 1.52 (95% CI, 1.19 to 1.95) 1. However, the benefits of TNT in improving overall survival and pathological complete response rates outweigh these potential drawbacks.
From the Research
Total Neoadjuvant Therapy (TNT) for Rectal Cancer
- TNT is a novel approach for locally advanced rectal cancer (LARC), which attempts to deliver both systemic chemotherapy and neoadjuvant chemoradiotherapy prior to surgery 2.
- The efficacy and safety of TNT remain controversial in randomized controlled trials (RCTs), but recent studies suggest that it may improve overall pathologic complete response rate, disease-free survival, overall survival, and distant metastasis-free survival compared to standard treatment 2, 3, 4.
Benefits of TNT
- TNT has been shown to improve the pathologic complete response (pCR) rate, with a statistically significant improvement in pCR rate for TNT treatment (odds ratio, 1.77; 95% confidence interval [CI], 1.28-2.45; p = .0005) 2.
- TNT treatment also shows improvements in disease-free survival (DFS) and overall survival (OS) outcomes compared with standard chemoradiotherapy (hazard ratio [HR], 0.83; 95% CI, 0.72-0.96; p = .03 and HR, 0.88; 95% CI, 0.74-1.05; p = .15) 2.
- TNT may facilitate delivery of planned systemic therapy, with patients in the TNT cohort receiving greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the standard chemoradiotherapy cohort 3.
Organ Preservation
- TNT may facilitate nonoperative treatment strategies aimed at organ preservation, with a higher complete response rate (36% in the TNT cohort compared with 21% in the standard chemoradiotherapy cohort) 3.
- A case report describes a patient with LARC who achieved a clinical complete response following TNT, demonstrating the potential effectiveness of a high-intensity, dose-dense regimen involving synchronous radiotherapy followed by a six-cycle consolidation chemotherapy course aimed at optimizing organ preservation 5.
Current Practices and Future Directions
- TNT is a promising strategy for treating LARC and has started to replace the traditional neoadjuvant chemoradiotherapy (CRT) 6.
- Future directions include integration of immunotherapy, use of TNT in early-stage disease, and determining optimal components of TNT, such as type of chemotherapy and type of radiotherapy 6, 4.