Abstract
PURPOSE: To describe the role of hadrontherapy (HT) in treating radioresistant, rare, recurrent, and radio-induced tumors, which can be defined, in assonance with the 4Rs of radiobiology, the "4Rs" of HT indications. MATERIALS AND METHODS: This is a narrative review written by a multidisciplinary team consisting of radiation oncologists, radiobiologists, and physicists on the current literature on HT, particularly carbon ion radiation therapy. To refine HT indications within the context of the "4Rs" framework, we evaluated tumor histologies across different clinical indication settings and emphasized the radiobiological mechanisms contributing to the effectiveness of HT. RESULTS: For rare, radioresistant, recurrent, and radio-induced tumors, HT has proven to be effective and safe, achieving high rates of local response with mild toxicity. The current review shows that the biological parameters can assist clinicians in identifying appropriate cases for HT treatment. CONCLUSION: Biological characteristics of the tumor support the administration of HT in radioresistant, rare, recurrent, and radio-induced tumors and should be considered during multidisciplinary discussions.