What is the recommended treatment regimen for an adult patient with anal squamous cell carcinoma (SCC) and good performance status?

Nigro Regimen for Anal Squamous Cell Carcinoma

The standard treatment for anal squamous cell carcinoma is concurrent chemoradiation with 5-fluorouracil (5-FU) and mitomycin-C (MMC), which remains the preferred regimen based on the most recent 2025 ASCO guidelines. 1

Recommended Chemotherapy Regimens

First-Line: 5-FU + Mitomycin-C (Standard Nigro Regimen)

• MMC 10-12 mg/m² IV bolus on day 1 (and possibly day 29) combined with 5-FU continuous infusion (1,000 mg/m²/day for 4 days or 750 mg/m²/day for 5 days) during the first and last weeks of radiation therapy is the preferred regimen. 1
• This combination demonstrated 25.3% lower locoregional recurrence and 12.5% fewer deaths from anal cancer compared to radiation alone in the landmark UKCCCR trial. 1
• The regimen achieves complete response rates of 86% and disease-free survival of 73% at 4 years. 1

Alternative: Capecitabine + Mitomycin-C

• Capecitabine 825 mg/m² orally twice daily on days of radiation (Monday through Friday) can substitute for infusional 5-FU, combined with MMC 15 mg/m² IV on day 1. 1, 2, 3
• This oral alternative demonstrated 86% locoregional control at 6 months with similar efficacy to infusional 5-FU but improved convenience. 3
• Capecitabine is particularly appropriate for patients who cannot manage continuous IV infusion or prefer oral therapy. 1, 2

Second-Line: Cisplatin + 5-FU (Category 2B)

• For patients with contraindications to MMC (particularly immunosuppressed patients including HIV-positive individuals), use cisplatin 60 mg/m² IV on days 1 and 29 with 5-FU continuous infusion. 1, 2
• Do NOT use cisplatin in patients with renal dysfunction, significant neuropathy, or hearing loss. 1
• Carboplatin should NOT be substituted for cisplatin—there is no evidence supporting this substitution. 1
• The RTOG 98-11 trial demonstrated significantly higher colostomy rates with cisplatin compared to MMC (19% vs 10%, P=0.02), making it inferior to the standard regimen. 1

Radiation Therapy Component

• Deliver 45-50 Gy in 1.8-2.0 Gy fractions over 4-5 weeks to the primary tumor with 2-5 cm margins, including presacral, internal iliac, and obturator lymph nodes. 1, 2
• Include inguinal lymph nodes in the radiation field for most patients, even without obvious involvement. 2
• Avoid treatment breaks—uninterrupted radiation is radiobiologically most effective. 2
• For T3-T4 lesions or residual disease, consider boost doses of 4-6 Gy to achieve total doses of 50.4-56 Gy. 1

Critical Treatment Principles

What NOT to Do

• Do NOT use routine induction chemotherapy before chemoradiation—it provides no benefit and increases toxicity. 1, 2
• Do NOT use maintenance chemotherapy after completing chemoradiation—it has shown no significant benefit. 1, 2
• Do NOT rush to surgery for persistent disease—response may continue for up to 26 weeks after treatment initiation. 2

Response Assessment

• Assess clinical response at 8-12 weeks (6-8 weeks per some guidelines) after completing chemoradiation. 2, 4
• For persistent disease without progression, continue observation up to 6 months before considering salvage surgery. 2, 4
• Complete response occurs in 86% of patients, with many achieving response gradually over several months. 5, 6, 3

Special Populations

HIV-Positive Patients

• Treat HIV-positive patients according to standard guidelines—do not modify treatment based solely on HIV status. 1
• Prefer cisplatin + 5-FU over MMC in immunosuppressed patients due to MMC-associated myelosuppression risks. 1, 2
• Outcomes are similar between HIV-positive and HIV-negative patients when treated with standard chemoradiation. 1

Patients with Renal Dysfunction or Neuropathy

• Use MMC + 5-FU regimen instead of cisplatin-based therapy. 1
• Cisplatin is contraindicated in renal dysfunction, significant neuropathy, or hearing loss. 1

Expected Toxicities

• Grade 3 acute toxicities include radiodermitis (23-30%), diarrhea, and hematologic toxicity (leukopenia, thrombocytopenia). 1, 5, 3, 7
• Most acute side effects are reversible and transient. 5
• Counsel patients on infertility risks and consider sperm/oocyte banking before treatment. 1
• Instruct patients on vaginal dilator use and symptoms of vaginal stenosis. 1

Salvage Options

• Reserve abdominoperineal resection for documented persistent/progressive disease after adequate observation (up to 6 months) or for recurrent disease. 2, 4, 6
• Salvage surgery achieves local control in approximately 60% of cases with 5-year survival of 30-60%. 4
• Some patients with residual disease can be salvaged with additional chemoradiation without surgery. 5, 6