Evolving treatment strategies in anal squamous cell carcinoma: Integrating chemoradiotherapy, immunotherapy, and emerging biomarkers.

BACKGROUND

Anal squamous cell carcinoma (SCAC) is a relatively rare but increasingly prevalent malignancy, largely driven by persistent infection with oncogenic human papillomavirus (HPV). Definitive chemoradiotherapy (CRT) remains the standard of care for locoregional disease; however, a clinically relevant proportion of patients experience persistent or recurrent disease, while outcomes in the metastatic setting remain suboptimal. Recent advances in immune checkpoint inhibition and chemo-immunotherapy combinations are reshaping the therapeutic landscape, raising new questions regarding optimal integration with established treatments and patient selection.

METHODS

This narrative review is based on a structured literature search of PubMed/MEDLINE, Embase, and ClinicalTrials.gov (January 2015-January 2026). Priority was given to phase II-III clinical trials, contemporary international clinical practice guidelines (including updated ESMO and NCCN recommendations), and translational studies addressing HPV-driven tumour biology and biomarker development. The evidence was synthesised using a critical, clinically oriented approach.

RESULTS

Modern CRT with intensity-modulated radiotherapy remains the cornerstone of locoregional SCAC management, with ongoing efforts focusing on treatment de-escalation in low-risk patients and intensification strategies in high-risk disease. In advanced SCAC, carboplatin-paclitaxel represents the established first-line backbone. Recent phase III data (POD1UM-303) demonstrate that the addition of programmed cell death protein 1 (PD-1) blockade improves progression-free survival and response durability, supporting chemo-immunotherapy as a promising first-line strategy in selected patients. In parallel, circulating HPV DNA (ctHPV-DNA) is emerging as a dynamic biomarker with potential applications in response assessment, minimal residual disease detection, and early relapse identification, although prospective validation is required.

CONCLUSIONS

The management of SCAC is evolving toward a more integrated and biologically informed paradigm combining optimised CRT, immunotherapy-based strategies, and biomarker-driven approaches. This review provides a focused synthesis of current evidence, emphasising the interplay between locoregional treatment optimisation, systemic therapy innovation, and the emerging role of ctHPV-DNA in risk-adapted clinical decision-making.