What is the indication for neoadjuvant chemotherapy in a patient with rectal cancer located 5cm from the anal verge with no evidence of lymph node involvement?

Indications for Neoadjuvant Chemotherapy in Rectal Cancer 5cm from Anal Verge with No Lymph Node Involvement

Total neoadjuvant therapy (TNT) should be offered to patients with rectal cancer located 5cm from the anal verge even without lymph node involvement, as this represents a high-risk location that benefits from tumor regression prior to surgery. 1

Risk Stratification and Treatment Decision Algorithm

The location of the tumor at 5cm from the anal verge places it in the low rectal cancer category, which carries specific considerations:

1. Low rectal location (≤5cm from anal verge):

   • Higher risk of local recurrence
   • Greater challenges for sphincter preservation
   • Increased technical difficulty of achieving negative circumferential resection margins (CRM)

2. T stage considerations:

   • For T3 tumors (regardless of N status): Neoadjuvant therapy is indicated
   • For T1-T2 tumors: Treatment depends on additional risk factors

Treatment Algorithm Based on T Stage:

For T3 tumors at 5cm from anal verge (even N0):

• First choice: Total neoadjuvant therapy (TNT) with either:
  • Long-course chemoradiation followed by chemotherapy 1
  • Short-course radiation followed by chemotherapy (RAPIDO approach) 1

For T2N0 tumors at 5cm from anal verge:

• If sphincter preservation is challenging: Neoadjuvant chemoradiotherapy is recommended 1
• If no difficulties with sphincter preservation: Radical surgery without neoadjuvant therapy may be considered

For T1N0 tumors at 5cm from anal verge:

• If eligible for transanal local excision: Surgery without neoadjuvant therapy
• If sphincter preservation is challenging: Consider neoadjuvant chemoradiotherapy 1

Evidence Supporting Neoadjuvant Therapy for Low Rectal Tumors

The 2024 ASCO guidelines strongly support TNT for locally advanced rectal cancer, with particular emphasis on tumors in the lower rectum (≤5cm from anal verge) 1. This recommendation is based on multiple phase III trials showing improved outcomes:

• PRODIGE-23 trial: 37% of patients had tumors ≤5cm from anal verge, showing benefit with TNT 1
• RAPIDO trial: 24% of patients had tumors <5cm from anal verge, demonstrating improved disease-related treatment failure rates with TNT 1
• POLISH II trial: 56% of patients had tumors ≤5cm from anal verge 1
• STELLAR trial: 49.2% of patients had tumors ≤5cm from anal verge 1

A Japanese study specifically identified distance from anal verge <5cm as an independent risk factor for local recurrence, even after multivariate analysis 2. This study found that patients with rectal cancer located less than 5cm from the anal verge had >10% local recurrence rate, supporting the need for neoadjuvant therapy in this location.

Benefits of Neoadjuvant Therapy for Low Rectal Tumors

1. Improved pathological complete response (pCR): TNT improves pCR compared with standard neoadjuvant chemoradiation (22.4% vs 14.3%) 1

2. Improved overall survival: TNT shows improved 5-year OS compared with standard neoadjuvant chemoradiation (HR 0.78,95% CI 0.62-0.97) 1

3. Improved disease-related treatment failure: TNT may improve the rate of disease-related treatment failure at 5 years 1

4. Potential for sphincter preservation: Downstaging may allow for sphincter-preserving surgery in tumors close to the anal verge 3

5. Possibility of non-operative management: Patients achieving complete clinical response may be candidates for a "watch and wait" approach, avoiding surgery altogether 1

Potential Drawbacks and Considerations

• Increased toxicity: TNT increases grade 3-4 adverse events compared with standard neoadjuvant chemoradiation 1
• Neurotoxicity: Higher rates of grade 1-2 neurotoxicity at 6 and 12 months with TNT 1
• Patient selection: Consider patient's performance status, comorbidities, and ability to tolerate intensive therapy

Special Considerations

1. MMR/MSI status: For patients with dMMR/MSI-H tumors, neoadjuvant immunotherapy may be considered as an alternative approach 1

2. Clinical complete response: Patients achieving complete clinical response after neoadjuvant therapy may be candidates for non-operative management with close surveillance 1

3. Timing of surgery: Optimal timing after completion of neoadjuvant therapy remains under investigation, but typically ranges from 6-12 weeks 4

In conclusion, for a patient with rectal cancer located 5cm from the anal verge without lymph node involvement, neoadjuvant therapy is strongly indicated due to the high-risk location, with total neoadjuvant therapy being the preferred approach according to the most recent guidelines.