Sex-specific differences in abscopal responses to combined radiotherapy and immune checkpoint inhibition–insights from a multicenter study

TL;DR

This study finds sex-specific differences in abscopal responses to combined radiotherapy and immune checkpoint inhibition, suggesting personalized treatment strategies may be needed.

Contribution

The study is the first to systematically explore sex-specific patterns in abscopal effects and their prognostic factors in RT-ICI treatment.

Findings

Abscopal responses and control occurred more frequently in female patients compared to males.

A longer ICI-to-RT interval and higher BMI were associated with better survival in both sexes.

Elevated C-reactive protein was a male-specific prognostic factor for worse survival.

Abstract

Abscopal effects (AbE) during combined radiotherapy (RT) and immune checkpoint inhibition (ICI) represent a potential mechanism for systemic tumor control, yet sex-specific differences in these responses remain largely unexplored. We investigated sex-associated signals in outcomes of combined RT-ICI in a multicenter cohort. We analyzed the incidence of AbE and survival outcomes with respect to clinical and biomedical markers.

In this observational multicenter study, patients with metastatic solid tumors receiving RT-ICI and showing at least one non-irradiated lesion (NIL), assessed using iRECIST criteria, were analyzed. Abscopal response (AR) was defined as ≥30% reduction in NIL size, abscopal progression (AP) as ≥20% increase, and abscopal control (AC) as changes within this range.

Among 3,773 screened patients, 142 met the inclusion criteria (62% male, median age 62 years; 38% female, median age 58 years). AR and AC occurred more frequently in females (24% vs. 14%, 35% vs. 31%). While OS showed no significant difference (p=0.81), Cox regression analyses revealed significant associations of a longer ICI-to-RT-interval (males: HR = 0.903 [0.833–0.978], p=0.012; females: HR = 0.748 [0.621–0.900], p=0.002) and a BMI ≥25 kg/m² with survival in both sexes (males: HR = 4.282 [1.473–12.446], p=0.008; females: HR = 4.801 [1.182–19.502], p=0.028 with survival in both sexes). Elevated C-reactive protein (CRP) (≥5 mg/L) showed prognostic significance only in males (HR = 4.764 [1.184–19.170], p=0.028).

Our findings suggest the possibility of sex-specific patterns in AbE occurrence. Additionally, our analyses identified sex-associated prognostic factors, including the importance of ICI-to-RT interval and BMI in both sexes and the male-specific prognostic value of CRP. These observations warrant further research and consideration in designing personalized RT-ICI combination strategies.

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