A Combined Neutron and Proton Regimen for Advanced Salivary Tumors: Early Clinical Experience

Background and objective Fast neutron radiotherapy (NRT) is a high linear energy transfer (LET) particle therapy that offers a local control (LC) advantage over low-LET X-rays in the treatment of advanced and unresectable salivary gland malignancies. However, in tumors approximating the base of skull (BOS), target volumes may be underdosed to minimize toxicity to the central nervous system (CNS). In this setting, a proton beam boost to the underdosed part of the tumor may improve LC. We report our early experience with a hybrid neutron-proton approach in patients with BOS involvement. Materials and methods We retrospectively reviewed 29 patients with locally advanced and unresectable salivary gland tumors involving the BOS between 2014-2018. The median age of the patients was 56 years, with the majority of them having adenoid cystic carcinomas (ACC) (79%) with advanced T4a/b disease (86%), pathologic perineural invasion (PNI) (55.2%), and orbital invasion (34.5%). Five patients (17.2%) were cases of re-irradiation. Surgical resection was attempted in 15 patients (51.7%), of which none achieved negative margins. The median neutron dose was 18.4 neutron Gray (nGy) with a sequential proton boost (PB) with a median dose of 25 Gy [relative biological effectiveness (RBE)] (range: 16-45 Gy). Toxicity was graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Descriptive statistics and the Kaplan-Meier method were used. Results At a median follow-up of 18.9 months [interquartile range (IQR): 6.1-32.5], the entire cohort's overall survival (OS) was 93.1%, progression-free survival (PFS) was 79.3%, and LC was 89.7%. Among patients who were not re-irradiated (n=24), the most commonly recorded acute grade 3 toxicities were mucositis (50%) and dermatitis (37.5%). There was no documented acute grade 4/5 events. Late grade 3/4 events included trismus (n=1), hearing loss (n=2), visual loss (n=6), and bone necrosis (n=1). There were no reported late grade 5 events in de novo patients. Conclusion In this challenging cohort with a poor prognosis, early outcomes for a hybrid neutron-proton approach were found to be promising. Further studies involving longer follow-ups with a larger cohort of patients are required to validate our findings.