Proton therapy tied to increased risk of osteoradionecrosis

A study on patients with oropharyngeal squamous cell carcinoma (OPSCC) shows an association between proton therapy (PT) and a higher rate of osteoradionecrosis (ORN).

“In this large, relatively homogeneous cohort of patients with OPSCC who underwent curative-intent RT for 10 years, PT was associated with a higher rate of ORN compared with intensity-modulated radiation therapy (IMRT), particularly in the definitive setting,” the investigators said.

The study included 1,564 patients (mean age 61.5 years, 86.7 percent men) who had undergone IMRT (n=1,389) or proton-based treatment (n=175). A majority of participants in the proton-based group received IMPT (n=168), while the remaining seven underwent a uniform scanning technique. [JAMA Otolaryngol Head Neck Surg 2025:doi:10.1001/jamaoto.2025.4179]

Overall, 68 participants developed ORN of any grade during the study period, corresponding to a 3-year rate of 3 percent. Approximately three-quarters (73.5 percent) of the ORN cases were grade 2.

The median time to ORN was similar between the PT and IMRT modalities (23.5 vs 25 months), but the former was associated with a higher ORN incidence than the latter (6.36 percent vs 2.69 percent; hazard ratio [HR], 2.62, 95 percent confidence interval [CI], 1.39–4.93), primarily in patients treated in the definitive setting (7.47 percent vs 2.38 percent; HR, 3.62, 95 percent CI, 1.85–7.09).

The researchers attributed the higher incidence in the definitive setting to the higher total RT dose received by participants, compared with those who received treatment in the postoperative setting. “Indeed, most patients received 7,000 centi-Gray,” they said.

Moreover, the 3-year ORN rates were higher with IMPT than with IMRT in the sensitivity analyses by treatment year: 7.6 percent vs 2.5 percent; HR, 3.17; 95 percent CI, 1.22–8.21 (from 2016 to 2019) and 7.8 percent vs 1.9 percent; HR, 3.27; 95 percent CI, 1.14–9.36 (from 2020 to 2023).

“The robustness of the association between IMPT and greater hazard of ORN in two separate time ranges … strengthens support for the increased risk of ORN associated with PT vs IMRT,” the researchers noted.

Mandibular complications

Six patients had mandibular fractures, three had exposed bone, and one had a mandibular abscess and an imminent fracture. Nine patients have undergone surgical debridement and/or flap reconstruction. One of the patients with a mandibular fracture received conservative treatment due to comorbidities that preclude surgery. None developed grade ≥4 ORN.

The risk of ORN in the mandible may be attributed to its relatively poor blood supply. The subsequent bone exposure may be associated with pain and/or superimposed infection. [Front Oral Health 2022;3:980786]

Despite modern treatment and improved dental care, the reported rates of ORN range from 4 to 11 percent, the researchers noted. “Such heterogeneity may result from variability in diagnostic criteria and grading, as well as pooling multiple subsites, complicating comparison across different series. Therefore, reporting both overall and high-grade ORN rates may guide patient counselling and management.”

A potentially debilitating complication

ORN is a late complication of RT for head and neck cancer that could be debilitating and eventually impair quality of life. [Int J Oral Maxillofac Surg 2013;42:1121-1128] “PT canonically offers superior normal tissue sparing due to increased dosimetric conformality … [However,] its impact on ORN risk remains uncertain, particularly in patients with OPSCC,” they said.

This study shows that, despite superior dose conformality, PT for OPSCC was associated with an increased risk of ORN, highlighting the need for hypothesis-driven studies to refine dose constraints and optimize treatment planning to mitigate late effects, the researchers said.

However, they noted that the retrospective results should be deemed exploratory and called for prospective studies to elucidate risk factors and inform strategies to mitigate ORN while preserving the therapeutic advantages of advanced RT modalities.