Teaching pack: Anal cancer (squamous cell carcinoma)

Anal squamous cell carcinoma is an HPV-driven cancer (HPV16 in most), biologically closer to cervical cancer than to rectal adenocarcinoma. Risk factors are HPV persistence, HIV, immunosuppression, receptive anal intercourse and smoking; high-grade anal intraepithelial neoplasia is the precursor, and the ANCHOR trial (2022) showed treating it in people with HIV cuts progression to cancer by more than half.

Definitive chemoradiation with mitomycin and 5-fluorouracil (Nigro regimen 1974; ACT II confirmed mitomycin-5-FU and no benefit of maintenance) cures ~70-80% and preserves the sphincter; salvage abdominoperineal resection is reserved for persistent or recurrent disease. Metastatic disease was treated with carboplatin-paclitaxel (InterAAct, 2020); PD-1 blockade showed activity in refractory disease (nivolumab NCI9673, pembrolizumab KEYNOTE-158), and POD1UM-303 (2024) established retifanlimab plus carboplatin-paclitaxel as first-line standard (FDA approval 2025). Response-adapted radiotherapy dose (PLATO trials) and ctHPV DNA monitoring are being developed.

• Chemoradiation cures most patients with sphincter preservation; the 1974 Nigro insight still holds.
• ANCHOR proved that anal cancer is preventable in the highest-risk group by screening and treating precancer.
• Retifanlimab-chemotherapy is the first immunotherapy standard in first-line metastatic disease.
• Radiotherapy dose de-escalation for small tumours and escalation for bulky disease (PLATO) is under test.

1. 1974Nigro: chemoradiation instead of surgery
2. 1996UKCCCR ACT I and EORTC: chemoradiation beats radiation alone
3. 2013ACT II: mitomycin-5-FU standard; no maintenance benefit
4. 2017Nivolumab active in refractory disease (NCI9673)
5. 2020InterAAct: carboplatin-paclitaxel first-line standard
6. 2022ANCHOR: treating HSIL prevents anal cancer in people with HIV
7. 2024POD1UM-303: retifanlimab + chemotherapy improves PFS/OS

• Retifanlimab (treatment)
• Circulating tumour HPV DNA (ctHPV-DNA) (technology)
• HPV & HBV vaccination (technology)

• ANCHOR (phase 3, n=4,446): Incidence of anal cancer: 173 cases per 100,000 person-years vs 402 cases per 100,000 person-years
• POD1UM-303/InterAACT-2 (phase 3, n=308): Progression-free survival (blinded independent central review): 9.3 months vs 7.4 months, HR 0.63
• ACT II (phase 3, n=940): Complete response at 26 weeks: 90.5% vs 89.6%
• NHS-Galleri (phase 3, n=142,250): Stage III to IV incidence, 12 prespecified cancers (primary): Not met, per the Nature Medicine test-performance paper (22 September 2026), which states the primary endpoint was not met and reported elsewhere; no peer-reviewed primary-endpoint paper was on Europe PMC by 23 September 2026, so no figures are recorded here.
• InterAACT (phase 2, n=91): Best overall response rate by 24 weeks: 59% vs 57%
• NCI9673 (phase 2, n=143): Objective response rate, part A: 24%

• Screening programmes for high-risk groups exist almost nowhere despite ANCHOR.
• Late toxicity of pelvic chemoradiation (bowel, sexual, bone).
• HPV-negative anal cancer does poorly.
• Stigma and delayed diagnosis.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. What fraction of advanced melanoma patients on nivolumab plus ipilimumab are alive at ten years?
   Answer

   About 43% overall survival (CheckMate 067), with melanoma-specific survival around 52%.
3. What is the Galleri test and where does it stand with the FDA?
   Answer

   GRAIL's methylation-based multi-cancer early detection blood test for more than 50 cancers; PMA submitted January 2026 on PATHFINDER 2 and NHS-Galleri data, FDA advisory committee 23 September 2026. NHS-Galleri missed its primary stage III-IV reduction endpoint (stage IV fell ~14%).
4. Which cooperative group ran the trial that put nivolumab into first-line Hodgkin lymphoma?
   Answer

   SWOG (S1826, nivolumab-AVD vs BV-AVD), leading to FDA approval in March 2026 for ages 12 and over.
5. What single change would most improve outcomes across all cancers, and what evidence supports it?
   Answer

   Prevention and early detection: HPV vaccination has driven cervical cancer toward elimination in vaccinated cohorts, tobacco control and screening (mammography, colonoscopy, low-dose CT) have proven mortality benefits, and early-stage disease is where surgery cures; MCED blood tests aim to extend this but are unproven.

• NCCN Guidelines: Anal Carcinoma: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414
• ANCHOR (NEJM 2022): https://doi.org/10.1056/NEJMoa2201048
• NCI PDQ: anal cancer: https://www.cancer.gov/types/anal/patient/anal-treatment-pdq
• Wikipedia: https://en.wikipedia.org/wiki/Anal_cancer
• Guideline: https://doi.org/10.1056/NEJMoa2201048
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414