Purpose: High linear energy transfer (LET) radiotherapy may cause unexpected adverse events (AEs) in head and neck (H&N) cancer patients treated by intensity-modulated proton therapy (IMPT). In this exploratory study, we propose to investigate the effects of LET upon AEs in IMPT using dose-linear-energy-transfer volume histograms (DLVHs) and seed spots analysis.
Methods: We included 14 H&N patients with unanticipated CTCAEv4.0 grade≥3 AEs for analysis. The AE regions were contoured and the corresponding DLVHs of the AE regions were generated. DLVH was constructed with physical dose (Gy) and LET (keV/µm) as independent variables. The normalized volume of the structure was contoured as iso-volume lines in the dose-LET plane. All voxels in the structure were mapped into the dose-LET plane as dots to see how the dots with similar dose and LET were clustered. For seed spot analysis, we selected voxels at the top edge of the DLVH plots as critical voxels. Individually clustered critical voxels that are geometrically apart were considered as independent seed spots. Median dose/LET from seed spots were extracted. Bivariate-linear-regression models were established for all AEs. The dose and LET product (xBD) volume constraint of osteoradionecrosis was obtained using the receiver operating characteristic curve of 4 osteoradionecrosis patients and 15 additional independent control patients.
Results: Dose played a dominant role for in-field AEs such as hemorrhage and ulceration, while LET played an important role in out-of-field AEs such as osteoradionecrosis and mucositis. Intercept-free linear models between the reciprocal of dose and LET were found for different AEs. The xBD volume constraint of osteoradionecrosis was derived, V(xBD≥275.18 Gy∙keV/μm)<0.0612cc, with an area under curve of 0.85.
Conclusion: A potentially important LET-enhancing effect to induce AEs in H&N cancer treated with IMPT was observed. Voxel-based DLVH and seed spots analysis are powerful tools to study AEs in IMPT.
Funding Support, Disclosures, and Conflict of Interest: This research was supported by Arizona Biomedical Research Commission Investigator Award, the Lawrence W. and Marilyn W. Matteson Fund for Cancer Research, and the Kemper Marley Foundation.