Evolving role of proton therapy in contemporary oncology

Proton therapy offers a distinct physical advantage over photon radiotherapy through the Bragg peak dose concentration in target with both lower integral dose and finite path length, and sharper penumbra as compared to photons, collectively reducing radiation exposure to surrounding normal tissues and potentially improving the therapeutic ratio. However, this advantage is tempered by uncertainties, including range uncertainty and variable relative biological effectiveness. In this review, the authors summarize contemporary evidence supporting proton therapy across pediatric, central nervous system (CNS), head and neck, thoracic, breast, gastrointestinal, genitourinary, and hematologic malignancies, as well as reirradiation. The strength of evidence varies substantially by disease site. Proton therapy is well established in pediatric cancers and selected CNS tumors, where minimizing integral dose and late toxicity is especially important. Randomized trials have demonstrated clinically meaningful benefits in selected settings, including improved disease control and survival with proton craniospinal irradiation for leptomeningeal metastases and reduced toxicity with preserved disease control and survival benefit in oropharyngeal cancer. Conversely, randomized data in localized prostate cancer have not shown improved patient reported outcomes compared with intensity modulated photon therapy. Ongoing phase 3 trials across multiple disease sites are expected to further define the role of protons by clarifying comparative effectiveness, toxicity reduction, and cost-effectiveness relative to advanced photon techniques. Future progress will depend on improved patient selection, robust treatment planning, and emerging technologies including adaptive proton therapy, proton arc therapy, and FLASH radiotherapy.