Response to Koulaouzidis et al and Sharma et al

We thank Koulaouzidis et al. and Sharma et al. for their interest in our study “Impact of Beta-Blockers on Prognostic Outcomes in Solid Cancers: A Systematic Review and Meta-Analysis.”3

The authors highlight the risk of time-related bias, residual confounding, and heterogeneity. These are important considerations, and they are acknowledged and discussed in our article. We emphasized the potential for immortal time bias, exposure misclassification, and confounding by indication, particularly in analyses of postdiagnostic beta-blocker exposure. Accordingly, our findings were explicitly framed as associative rather than causal, and these limitations were incorporated into the interpretation of our results.

With respect to biological specificity and differences across tumor types, we sought to explore potential cancer subtype-specific signals through subgroup analyses where data permitted. However, these analyses were constrained by the available literature. Our intention in undertaking a broad pooled meta-analysis was to provide a comprehensive synthesis of existing evidence, define the overall signal and its limitations, and thereby inform the design of future studies, including randomized clinical trials and target trial emulations on beta-blocker exposure and cancer-related outcomes.