A systematic review of heterogeneity in clinical trial design for anal cancer radiotherapy-immunotherapy combinations

Localised anal squamous cell carcinoma (ASCC) is treated with radical chemoradiotherapy, which achieves durable disease control in most patients. However, treatment failure is stage-dependent, with approximately 25–30% of patients with locally advanced disease relapsing after treatment, supporting investigation of novel approaches such as radiotherapy-immunotherapy (RT-IO) combinations. Combining radiotherapy (RT) with immunotherapy (IO) shows promise, with multiple trials investigating different combinations. This review evaluates trial design for RT-IO trials in ASCC. A systematic review was conducted on PubMed, ClinicalTrials.gov, and EudraCT databases to identify interventional clinical trials evaluating RT combined with immune-modulating treatments for ASCC. The review was prospectively registered on PROSPERO (CRD42023384068). Information on trial design, patient selection, and treatment regimens was collected. Twelve trials were identified, with three reporting results for a combined total of 69 patients. Across all trials, 14 different IO regimens were used before, during, and after RT. Substantial heterogeneity was observed in patient selection, statistical design, chemotherapy, and RT regimens. Data on exploratory and translational analyses was available for six trials. No trials used biomarkers for enrolment, although INTERACT-ION used cHPV-DNA to guide post-induction treatment allocation. Full trial comparisons were hindered by protocol publication and commercial sensitivities. The diversity in IO regimens and timing relative to RT offers valuable data on RT-IO combinations for ASCC. However, heterogeneity in trial design and translational analysis will limit comparisons between trials. Two possible solutions to improve comparisons are a core minimal translational component and federated learning.