For a patient with anal canal squamous cell carcinoma, should definitive chemoradiotherapy be given first rather than proceeding directly to surgery?

Definitive Chemoradiotherapy First for Anal Canal Squamous Cell Carcinoma

For patients with anal canal squamous cell carcinoma, definitive chemoradiotherapy should be given first rather than proceeding directly to surgery, except for very small (<2 cm), well-differentiated T1N0 anal margin tumors without sphincter involvement. 1

Primary Treatment Algorithm

Chemoradiotherapy as Standard of Care

• Combined modality chemoradiation is the recommended first-line treatment for all anal canal cancers except small anal margin lesions, with salvage surgery reserved for treatment failures 1
• This approach preserves anal sphincter function and avoids permanent colostomy while achieving equivalent or superior survival compared to primary surgery 1, 2
• The 2025 ASCO guidelines confirm that definitive CRT has been the standard of care since the landmark 1974 Nigro study, which demonstrated similar cure rates to surgery with sphincter preservation 1

The Only Exception: Small Anal Margin Tumors

• Local excision alone is appropriate only for: T1N0 tumors <2 cm diameter, well-differentiated histology, located at the anal margin (not canal), no nodal involvement on staging, and no sphincter involvement 1, 2
• Even for these small lesions, if margins are inadequate after excision, proceed to chemoradiotherapy rather than re-excision 1

Recommended Chemoradiotherapy Regimen

Radiation Therapy Specifications

• Minimum dose of 45-50 Gy delivered in 25-28 fractions over 5 weeks to the primary tumor, pelvis, perineum, and inguinal nodes 1
• Additional boost of 9-14 Gy (total 54-59 Gy) for T2-T4 tumors, node-positive disease, or residual disease after initial 45 Gy 1
• IMRT is preferred over 3D conformal radiotherapy when available 1
• Uninterrupted treatment without planned gaps is radiobiologically most effective 1, 2

Chemotherapy Regimen

• 5-fluorouracil (5-FU) plus mitomycin C is the standard radiosensitizing regimen 1
• 5-FU: 1000 mg/m² continuous IV infusion days 1-4 during weeks 1 and 5 of radiation 1
• Mitomycin C: 12 mg/m² IV bolus on day 1 (maximum single dose 20 mg) 1
• Alternative regimen: Cisplatin plus 5-FU for patients with contraindications to mitomycin (immunosuppression, renal dysfunction, significant neuropathy, or hearing loss) 1
• Capecitabine may substitute for infusional 5-FU 1

Why Surgery Should NOT Be First-Line

Historical Context and Evidence

• Primary abdominoperineal excision (APE) was associated with local failure rates up to 50% and 5-year survival of only 50-70% before the CRT era 1
• The UKCCCR Anal Cancer Trial I demonstrated that CRT resulted in 25.3% lower locoregional recurrence and 12.5% fewer deaths from anal cancer compared to radiotherapy alone 1
• No randomized trial has directly compared primary surgery versus CRT, but multiple phase III trials have established CRT superiority over radiation alone 1

Quality of Life Considerations

• Chemoradiotherapy preserves anal sphincter function and avoids permanent colostomy, which is the primary quality of life advantage over APE 1, 2
• Complete responders to CRT maintain normal bowel function without the need for colostomy 1
• APE results in permanent colostomy with associated psychosocial and quality of life impacts 1

Role of Surgery: Salvage Only

When Surgery Is Indicated

• Salvage APR is reserved for: persistent disease after CRT (biopsy-proven at 6 months), progressive disease during or after CRT, or local recurrence after initial complete response 1
• Salvage surgery achieves local pelvic control in approximately 60% of cases 2
• The 5-year survival rate after salvage APR is 60-64%, with overall recurrence rate of 43% 1

Assessment Timeline

• Do not biopsy routinely after CRT completion—disease can continue to regress for months, and false-positive rates are high 1
• Perform digital rectal examination at 8-12 weeks post-treatment 1
• Optimal time for complete response assessment is 26 weeks (6 months) rather than earlier timepoints 1, 2
• Only biopsy if clinical suspicion of persistent disease (new hard-edged ulcer, enlarging mass, increasing pain) 1

What NOT to Do: Critical Pitfalls

Avoid Neoadjuvant or Adjuvant Chemotherapy

• Neoadjuvant chemotherapy before CRT has not improved locoregional or distant control and should not be given outside clinical trials 1
• Routine adjuvant chemotherapy after CRT is not recommended for localized anal cancer 1

Avoid Primary Surgery for Anal Canal Tumors

• Surgery is generally contraindicated as primary treatment for anal canal cancers (as opposed to anal margin) 1
• Local excision has not been shown efficacious for small anal canal tumors and is contraindicated 1
• Piecemeal resections make margin assessment impossible and should never be performed 1, 3

Avoid Treatment Interruptions

• Planned treatment gaps during radiotherapy are associated with increased locoregional failure 2
• Uninterrupted treatment delivery is essential for optimal radiobiological effect 1

Special Populations

Immunocompromised Patients

• For patients with HIV/AIDS or on immunosuppressive therapy, cisplatin plus 5-FU is preferable to mitomycin-based regimens due to myelosuppression concerns 1
• These patients may require dose adjustments but should still receive definitive CRT as first-line treatment 1

Previously Irradiated Pelvis

• Primary APE may be offered to patients who have received prior pelvic radiation, as re-irradiation carries significant toxicity risks 1