Anal Cancer (Squamous Cell Carcinoma of the Anal Canal)

HPV-driven biology, organ-preserving definitive chemoradiation, and the emergence of checkpoint immunotherapy in advanced squamous cell carcinoma of the anal canal

Key Points

• The overwhelming majority of anal canal cancers are squamous cell carcinoma (SCAC), driven by persistent high-risk human papillomavirus (HPV) infection — HPV-16 accounts for the largest share.
• Key risk factors include HPV infection, HIV / immunosuppression, receptive anal intercourse, a history of HPV-related cervical, vulvar, or vaginal dysplasia, and smoking.
• Diagnosis requires biopsy of the primary with digital rectal exam and anoscopy; staging uses pelvic MRI, PET/CT, inguinal nodal assessment, and HIV testing.
• Definitive concurrent chemoradiation with fluorouracil plus mitomycin (the Nigro-derived regimen) is the curative, organ-preserving standard of care for localized disease — abdominoperineal resection is reserved for salvage of residual or recurrent disease.
• For metastatic disease, first-line carboplatin plus paclitaxel (InterAAct) is the preferred chemotherapy backbone over cisplatin plus fluorouracil.
• Checkpoint immunotherapy has transformed advanced disease: retifanlimab added to carboplatin/paclitaxel (POD1UM-303 / InterAACT 2) is an approved first-line option, and retifanlimab, nivolumab, and pembrolizumab all have activity in previously treated disease.
• Investigational strategies — including the oncolytic reovirus pelareorep plus checkpoint blockade (GOBLET), which holds FDA Fast Track designation for second-line and later SCAC — aim to convert immunologically 'cold' tumors into responders.

Epidemiology & HPV-Driven Biology

Anal cancer is uncommon but its incidence has been rising steadily over recent decades. More than 85–90% of anal canal malignancies are squamous cell carcinoma (SCAC); less common histologies include adenocarcinoma (which behaves more like rectal cancer), neuroendocrine carcinoma, and melanoma. This article focuses on squamous cell carcinoma of the anal canal. Persistent infection with high-risk human papillomavirus (HPV) — most often HPV-16 — is the dominant carcinogenic driver, present in the large majority of tumors. HPV oncoproteins E6 and E7 inactivate the p53 and retinoblastoma (Rb)…

Clinical Presentation & Diagnostic Work-up

The most common presenting symptoms are rectal bleeding, a palpable anal mass, anal pain or discomfort, pruritus, and a sensation of fullness; advanced disease may cause fecal incontinence or fistula formation. Symptoms are frequently attributed to hemorrhoids, contributing to diagnostic delay. Work-up begins with digital rectal examination and anoscopy with biopsy to establish the histologic diagnosis, plus palpation of the inguinal nodes with biopsy or fine-needle aspiration of suspicious nodes. Locoregional staging is best assessed with pelvic MRI, while FDG-PET/CT is recommended to…

Definitive Treatment of Localized Disease: Chemoradiation

Localized anal squamous cell carcinoma is one of oncology's landmark organ-preservation success stories. Concurrent chemoradiation — derived from the Nigro protocol — is curative for most patients and avoids permanent colostomy. The standard regimen combines external-beam radiotherapy with concurrent fluorouracil plus mitomycin delivered during radiation. The ACT II trial established mitomycin-based chemoradiation as the standard and showed no benefit from cisplatin substitution or maintenance chemotherapy; the RTOG 98-11 trial similarly supported the fluorouracil/mitomycin backbone over an…

Systemic Therapy for Advanced & Metastatic Disease

For metastatic or unresectable recurrent SCAC, first-line carboplatin plus paclitaxel is the preferred chemotherapy backbone, established by the InterAAct trial, which found it better tolerated and associated with more favorable survival than cisplatin plus fluorouracil. Checkpoint immunotherapy has since reshaped the field: in the POD1UM-303 / InterAACT 2 trial, adding the anti-PD-1 antibody retifanlimab to carboplatin/paclitaxel significantly improved progression-free survival, supporting a first-line chemo-immunotherapy standard. In previously treated disease, single-agent PD-1 blockade…

Immunotherapy Frontiers & Investigational Directions

Because anal cancer is virally driven and carries a substantial neoantigen and immune-infiltrate burden, it is a rational target for immune-based therapy. Beyond approved PD-1 agents, active investigation includes dual checkpoint blockade (for example botensilimab, an Fc-enhanced anti-CTLA-4 antibody, combined with the anti-PD-1 antibody balstilimab) and HPV-directed strategies such as therapeutic vaccines and adoptive T-cell therapies targeting HPV-16 E6/E7. Oncolytic virotherapy is a further frontier. Pelareorep, an intravenously delivered oncolytic reovirus, preferentially replicates in…