From the Guidelines
Total neoadjuvant therapy (TNT) is the preferred approach for stage II-III rectal cancer, as it offers higher rates of pathologic complete response and longer disease-free survival, according to the most recent NCCN guidelines 1.
Key Components of TNT
- Induction chemotherapy using FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) for 3-4 months
- Chemoradiation with either infusional 5-FU (225 mg/m² continuous infusion daily) or oral capecitabine (825 mg/m² twice daily) during radiation therapy (typically 45-50.4 Gy in 25-28 fractions over 5-6 weeks)
- Surgery performed approximately 8-12 weeks after completion of chemoradiation to allow for maximal tumor response
Benefits of TNT
- Ensures early delivery of systemic therapy to address potential micrometastatic disease
- Improves patient compliance with treatment
- Increases the likelihood of pathologic complete response
- May facilitate organ preservation in select patients
Implementation
- Patients should undergo comprehensive baseline staging with MRI, CT, and endoscopic evaluation before starting treatment
- Regular assessments during therapy to monitor response and toxicity
- Dose modifications may be necessary based on patient tolerance
- Close multidisciplinary coordination between medical oncology, radiation oncology, and surgical teams is essential for optimal outcomes, as highlighted in the recent NCCN guidelines update 1.
Recent Updates
- The NCCN guidelines have been updated to include TNT as the preferred approach for stage II-III rectal cancer, based on recent clinical trial data 1.
- The guidelines also emphasize the importance of careful patient selection and sequenced multimodality therapy following a multidisciplinary approach 1.
From the Research
Total Neoadjuvant Therapy for Rectal Cancer Protocol
- Total neoadjuvant therapy (TNT) is a novel strategy for rectal cancer that administers both (chemo)radiotherapy and systemic chemotherapy before surgery 2.
- The goal of TNT is to improve treatment compliance, tumor regression, organ preservation, and oncologic outcomes 2.
- Multiple TNT regimens are currently available, including induction or consolidation chemotherapy, triplet or doublet chemotherapy, and long-course chemoradiotherapy or short-course radiotherapy 2.
Available Regimens and Their Efficacy
- A study compared the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy with the TNT approach for locally advanced rectal cancer (LARC) 3.
- The results showed that patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort 3.
- The complete response (CR) rate was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort 3.
- A phase III randomized clinical trial found that the addition of oxaliplatin to capecitabine or 5-FU did not improve local-regional tumor control, disease-free survival (DFS), or overall survival (OS) 4.
- A systematic review and meta-analysis found that TNT was associated with a significant improvement in overall pathologic complete response rate, DFS, OS, and distant metastasis-free survival compared with standard treatment 5.
Role of Capecitabine in Locally Advanced Rectal Cancer Treatment
- Capecitabine is a rationally designed oral prodrug that is converted into 5-FU by intracellular thymidine phosphorylase 6.
- Capecitabine can safely and effectively replace intravenous continuous infusion of 5-FU in the preoperative chemoradiation setting for rectal cancer management 6.
- The addition of other new antineoplastic agents to a fluoropyrimidine-based regimen remains investigational 6.