This is a comprehensive review of toxicities associated with proton therapy focusing on the underreported and/or unexpected side effects, with data from 82 primary reports. These toxicities include neurotoxicity (radiation necrosis, moyamoya syndrome, neurosensory toxicities, brain edema, neuromuscular toxicities, and neurocognitive toxicities), pulmonary toxicities (pneumonitis and fibrosis, pleural e9usions, and bronchial toxicities), cardiac side effects (pericarditis, pericardial effusions, and atrial fibrillations), gastrointestinal and hematological toxicities, genitourinary and reproductive-related toxicities, as well as osteological, oral, endocrine toxicities.

In discussion, the authors have remarked that almost all mentioned proton-related toxicities are underreported when compared to conventional radiation toxicities. The term underreported is indicating that far less information found in association with proton radiotherapy in comparison to photon radiotherapy.

In conclusion, the authors have stated that unexpected toxicities are more likely to happen with proton RT, mostly due to RBE and range uncertainties. These unexpected toxicities are usually serious (grade 3+), and occur despite meeting dose constraints. The authors call for a more comprehensive large-scale reporting of PBT toxicities to further characterize the toxicity profiles associated with proton RT, including unexpected and underreported toxicities.