Inflammatory signatures across four photon radiotherapy and proton radiotherapy: mechanisms, mitigation, and quality of life impact.

Cancer is the second leading cause of death globally and in the United States, second only to cardiovascular disease. Unlike many cardiovascular conditions, cancer is often less preventable, manageable, and curable-even with ongoing technological advancements in medicine. The adverse effects of cancer treatments on cancer patients remain profound due to shared cellular characteristics between cancerous and normal cells; one of the primary adverse effects is treatment-induced inflammation. These inflammatory responses aim to eliminate cancerous cells but often damage normal tissues. Notably, inflammatory side effects vary considerably across the growing diversity of therapeutic approaches. This study reviewed studies between 2007 and 2024, comparing the inflammatory profiles associated with five major radiation therapies (RTs): Three-Dimensional Conformal Radiation Therapy (3D-CRT), Intensity-Modulated Radiation Therapy (IMRT), Image-Guided Radiation Therapy (IGRT), Stereotactic Body Radiation Therapy (SBRT), and Proton Beam Therapy (PBT)-each characterized by distinct mechanistic and therapeutic features. In addition to each radiation modality eliciting distinct inflammatory responses, tissue-specific variability further complicates clinical outcomes. Accordingly, this review also undertakes a cross-tissue comparison of radiation-induced inflammation, with a focus on the gastrointestinal (GI) system, central nervous system (CNS), and skin. However, the variation in treatment modalities and organ-specific inflammatory biomarkers greatly hinders direct comparison across studies. Finally, this review highlights potential inflammatory mitigations, including ambroxol, that may be employed synergistically with RTs, minimizing side effects and enhancing patient outcomes. Taken together, while all modalities offer therapeutic value alongside certain limitations, proton-based therapy demonstrates the greatest potential for minimizing toxicity though its broader adoption remains limited by cost-effectiveness concerns.