External beam radiotherapy has proven highly effective against a wide range of cancers, and in recent decades there have been rapid advances with traditional photon-based (X-ray) radiotherapy and the development of two particle-based techniques, proton and carbon ion radiotherapy (CIRT). There are major cost differences and both physical and biological differences among these modalities that raise important questions about relative treatment efficacy and cost-effectiveness. Randomized clinical trials (RCTs) represent the gold standard for comparing treatments, but there are significant cost and ethical barriers to their wide-spread use. Meta-analysis of non-coordinated clinical trials data is another tool that can be used to compare treatments, and while this approach has recognized limitations, it is argued that meta-analysis represents an early stage of investigation that can help inform the design of future RCTs.