Total Neoadjuvant Therapy for Rectal Cancer
Total neoadjuvant therapy (TNT) is the preferred treatment approach for stage II-III locally advanced rectal cancer, particularly for patients with lower rectal tumors and/or high-risk features for local or distant metastases. 1
Definition and Components
TNT delivers both chemoradiotherapy and systemic chemotherapy before surgery, representing a paradigm shift from the traditional approach of postoperative adjuvant chemotherapy 1. This strategy consolidates all systemic and radiation therapy in the neoadjuvant setting.
Evidence-Based Benefits
The TNT approach demonstrates superior outcomes compared to standard therapy:
- Pathologic complete response (pCR): TNT doubles the pCR rate (29.9% vs 14.9%), with an odds ratio of 2.44 2, 3
- Disease-free survival: Improved by 5-10% at 3 years, with hazard ratio of 0.83 2, 4
- Overall survival: Approximately 5% improvement at 7 years 4
- Distant metastases: Significant reduction in risk (HR 0.81) 2
- Treatment completion: Higher chemotherapy compliance rates compared to adjuvant therapy 1
Specific Indications
High-Priority Candidates (TNT Should Be Offered)
TNT is specifically recommended for patients with 1:
- Lower rectal tumors (requiring potential abdominoperineal resection)
- T4 tumors
- Extramural vascular invasion (EMVI) and/or tumor deposits
- Threatened mesorectal fascia or intersphincteric plane
- Patients not eligible for sphincter-sparing surgery
- Node-positive disease (cN2)
- Enlarged lateral lymph nodes
Lower-Risk Patients
For patients without high-risk features, alternative options include neoadjuvant long-course chemoradiotherapy, short-course radiation, or chemotherapy with selective chemoradiotherapy based on response 1.
Optimal TNT Regimen Selection
Chemotherapy Timing
Consolidation chemotherapy (after radiation) is the preferred sequence over induction chemotherapy (before radiation) 1. The OPRA trial demonstrated higher TME-free survival at 3 years with consolidation chemotherapy, though disease-free survival was similar 1.
Exception: Induction chemotherapy may be considered for patients at greater risk of distant metastases, particularly using triplet regimens like FOLFIRINOX 1.
Radiation Approach
Long-course chemoradiotherapy is preferred over short-course radiotherapy for TNT candidates 1. This recommendation is based on the RAPIDO trial's 5-year data showing significantly higher locoregional failure rates with short-course RT (10% vs 6%) 1.
Important caveat: Short-course RT remains a viable option depending on patient circumstances, treatment goals, and institutional factors 1.
The STELLAR trial showed similar 3-year disease-free survival between short-course RT (64.5%) and long-course chemoRT (62.3%), but short-course RT had higher acute grade ≥3 toxicities (26.5% vs 12.6%) 1.
Special Populations
MSI-H/dMMR Tumors
For patients with microsatellite instability-high or mismatch repair-deficient tumors, immunotherapy is the recommended treatment 1. These patients should not routinely receive TNT, as fluorouracil-based chemotherapy has been historically less effective in dMMR tumors 1.
Potential for Non-Operative Management
TNT enables the possibility of avoiding surgery in select patients who achieve a clinical complete response (cCR) 1. Non-operative management may be discussed as an alternative to total mesorectal excision for patients with cCR, particularly those requiring abdominoperineal resection 1.
cCR criteria include 1:
- Digital rectal exam: no palpable tumor
- Rectoscopy: no residual tumor, no erythematous ulcer
- MRI: substantial downsizing with no residual tumor or fibrosis only
- No suspicious lymph nodes
Common Pitfalls
Understaging risk: Thorough staging with pelvic MRI including dedicated rectal sequences is essential before treatment decisions 1. Assessment should include tumor relation to anal verge, sphincter complex, mesorectal fascia, EMVI, and lymph nodes 1.
Toxicity considerations: While TNT improves treatment completion, serious adverse events occur in approximately 38% of patients 1. Triplet chemotherapy regimens like FOLFIRINOX carry higher toxicity and may be inappropriate for patients with significant comorbidities or advanced age 1.
Locoregional recurrence: The RAPIDO trial's 5-year follow-up revealed increased locoregional recurrence with short-course RT-based TNT, emphasizing the importance of long-course chemoradiotherapy when local control is paramount 1.