KEY POINTS
- The PROSPERO-registered systematic review searched PubMed, ClinicalTrials.gov, and EudraCT through November 2025 and identified 12 interventional trials combining radiotherapy with immune-modulating treatment for anal squamous cell carcinoma.
- Only three trials had reported results, covering a combined 69 patients. INTERACT-ION was the only study with mature efficacy data, reporting a 40-week clinical complete response rate of 77.8% (90% CI 66.5–86.7).
- Trial maturity and design varied widely: two studies were phase I or I/II, seven were phase II, two were phase III, and one was an observational cohort. Five trials were randomized, but only one randomized phase II study was clearly designed for a formal arm-to-arm efficacy comparison.
- Across the 12 trials, investigators used 14 different immunotherapy regimens before, during, or after radiotherapy. Ten trials evaluated checkpoint inhibition—eight anti-PD-1 regimens, one anti-PD-L1 regimen, and one PD-L1 plus TIGIT combination—while others tested an HPV-directed vaccine or prebiotic/probiotic treatment.
- Chemoradiotherapy backbones also differed. Nine trials used concurrent chemotherapy, with variable fluorouracil or capecitabine selection, mitomycin or cisplatin use and dosing, while GI22-588 combined carboplatin–paclitaxel, pembrolizumab, and radiotherapy.
- Eight trials used five different definitions of locally advanced disease, and radiotherapy doses, elective volumes, contouring guidance, and staging systems differed across eight countries. At least three trials incorporated formal radiotherapy quality assurance.
- Translational plans were available for only six trials, with collection time points reported for four. No molecular biomarker was used for enrolment; at least five trials assessed circulating HPV DNA, and INTERACT-ION used its clearance within a composite response definition to determine subsequent radiotherapy intensity.
CLINICAL TAKEAWAY
The current trial portfolio may establish whether individual radiotherapy–immunotherapy strategies are active, but its heterogeneity could prevent reliable comparison between positive and negative studies. Future trials need more consistent risk definitions, radiotherapy reporting, core outcomes, quality assurance, and a minimum shared translational dataset.