Medical Policy

This document addresses neutron beam radiation therapy. Radiobiologic principles suggest that neutron beam radiotherapy (NBT) is associated with a higher linear energy transfer (LET) compared with conventional photon or electrons resulting in a high radiation biological effect (RBE). Certain tumors seem to be more susceptible to the cytotoxic effects of neutrons, including salivary gland tumors. NBT or neutron beam radiation therapy is not to be confused with boron neutron capture therapy (BNCT) for cancer, which is not addressed within this document.

Investigational and Not Medically Necessary:

Neutron beam radiotherapy is considered investigational and not medically necessary for all indications.

Huber and colleagues (2001) compared radiotherapy with neutrons, photons, and a photon/neutron mixed beam in participants with advanced adenoid cystic carcinoma (n=75). Local control, survival, distant failure and complications were analyzed. Follow-up ranged from 1 to 160 months (median, 51 months), and the surviving individuals had a minimum follow-up of 3 years at the time of analysis. The actuarial 5-year local control was 75% for neutrons and 32% for both mixed beam and photons (p=0.015, log-rank). In spite of better local control in the neutron therapy group, there were no significant differences in survival across the groups. Acute toxicity was similar in all 3 radiotherapy groups, although severe late grade 3 and 4 toxicity was significantly more prevalent with neutrons (19%) than with mixed beam (10%) and photons (4%) (p>0.1). While neutron therapy did show improved local control, this did not translate into an improvement in overall survival. In addition, neutron therapy had significant associated toxicities as compared to other treatments.

There have been a few retrospective analyses done evaluating the safety and effectiveness of neutron therapy in salivary gland neoplasms. Local control and toxicity rates were consistent with previously reported outcomes. These studies lack comparison with other treatments (Douglas, 2003; Stannard, 2013).

Maucort-Boulch and colleagues (2010) reported a meta-analysis that included four randomized controlled trials (RCTs; total n=316) evaluating neutron therapy alone, neutron therapy with photon therapy, and photon therapy alone for treatment of glioblastoma. Follow-up at 12 months showed a 7% increase in mortality (range, 5% to 20% increase) and at 24 months, a 6% increase in mortality (range, 3% to 15% increase) in neutron therapy compared with photon therapy. This meta-analysis showed that neutron therapy did not improve survival rate.

Spratt and colleagues (2014) note that much of the data supporting superior local control (LC) in neutron therapy versus photon radiotherapy (RT) is more than 20 years old and there have been many advances in oncological treatment since that time. The researchers reviewed the records of 27 individuals with primary unresectable salivary gland cancer treated with photon RT between 2000 and 2009. These results were compared to results reported in a 1993 randomized controlled trial comparing neutron and photon therapy. The 2- and 5-year LC for photon therapy compared to historical neutron therapy outcomes were similar (65%, 55% versus 67%, 56%, respectively). While the current study data showed lower rates of toxicity in comparison to the historical neutron therapy data, there are limitations associated with comparing current and historical data and additional study is needed with concurrent comparison to alternative treatments to understand relevant clinical outcomes.

Timoshchuk and colleagues (2019) examined the 6- and 10-year locoregional control and survival rates of individuals with salivary gland malignancies who underwent high-energy neutron radiotherapy. A total of 545 individuals were included in the retrospective cohort study. After 6 years, the locoregional control rate was 84% and the survival rate was 72%. Following 10 years, the locoregional control rate was 79% and the survival rate was 62%. The authors suggest that this study provides evidence that, when compared to outcomes reported from previous studies regarding photon radiotherapy, neutron radiotherapy provides favorable outcomes. While this was a large study, the limitations associated with the study reduce the applicability of the results. Of the 559 individuals who met the inclusion criteria, only 473 individuals had data available for survival, recurrence, or metastases analysis. The geographical diversity of the participant base and length of time which had passed since treatment increases the risk of inadequate documentation or identification in the medical records reviewed. Finally, comparisons to photon radiotherapy were limited to statistics published in previous studies.

The Head and Neck Cancer guideline developed by the National Comprehensive Cancer Network^® (NCCN^®) Clinical Practice Guidelines in Oncology removed the recommendation for neutron beam radiotherapy as both a definitive radiation therapy option and a postoperative treatment option for salivary gland tumors in 2015. NCCN noted concern that any potential disease control advantages are offset by the toxicity of neutron therapy. Neutron therapy risks increase with time, with some estimates as high as 20% at 9 years post-treatment. As concerns about toxicity increased, the number of centers offering this treatment in the United States (U.S.) has decreased. At this time, there is only one center in the U.S. which offers neutron therapy (NCCN, 2023).

Neutron beam therapy is a form of external beam radiation therapy. It has been proposed as a treatment of inoperable tumors or tumors that are resistant to conventional radiation therapy. Neutrons have a greater biologic impact on cells than other types of radiation.

Fast neutron beam therapy: A type of external radiation treatment in which neutral charge subatomic particles (neutrons) are precisely targeted to a specific tissue mass by using a sophisticated stereotactic planning and delivery system; an interventional radiologist performs this therapy at a treatment facility equipped with a superconducting accelerator (cyclotron); pretreatment planning usually involves computed tomography (CT) to locate and determine the tumor volume prior to radiation therapy.

Glioblastoma: A fast-growing type of central nervous system tumor that forms from glial (supportive) tissue of the brain and spinal cord. Glioblastoma usually occurs in adults and affects the brain more often than the spinal cord. Glioblastoma is also called grade IV astrocytoma, glioblastoma multiforme and GBM.

Unresectable: Unable to be removed with surgery.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When Services are Investigational and Not Medically Necessary:

Peer Reviewed Publications:

1. Douglas JG, Koh WJ, Austin-Seymour M, Laramore GE. Treatment of salivary gland neoplasms with fast neutron radiotherapy. Arch Otolaryngol Head Neck Surg. 2003; 129(9):944-948.
2. Huber PE, Debus J, Latz D, et al. Radiotherapy for advanced adenoid cystic carcinoma: neutrons, photons or mixed beam?  Radiother Oncol. 2001; 59(2):161-167.
3. Maucort-Boulch D, Baron MH, Pommier P, et al. Rationale for carbon ion therapy in high-grade glioma based on a review and a meta-analysis of neutron beam trials. Cancer Radiother. 2010; 14(1):34-41.
4. Pfister DG, Spencer S, Brizel DM, et al. Head and Neck Cancers, Version 1.2015. J Natl Compr Canc Netw. 2015; 13(7):847-855.
5. Spratt DE, Salgado LR, Riaz N, et al. Results of photon radiotherapy for unresectable salivary gland tumors: is neutron radiotherapy's local control superior? Radiol Oncol. 2014; 48(1):56-61.
6. Stannard C, Vernimmen F, Carrara H, et al. Malignant salivary gland tumours: can fast neutron therapy results point the way to carbon ion therapy? Radiother Oncol. 2013; 109(2):262-268.
7. Timoshchuk MA, Dekker P, Hippe DS, et al. The efficacy of neutron radiation therapy in treating salivary gland malignancies. Oral Oncol. 2019; 88:51-57.

Government Agency, Medical Society, and Other Authoritative Publications:

1. National Cancer Institute (NCI). Salivary Gland Cancer Treatment (PDQ). Updated August 22, 2023. Available at: https://www.cancer.gov/types/head-and-neck/hp/adult/salivary-gland-treatment-pdq. Accessed on September 22, 2023.
2. NCCN Clinical Practice Guidelines in Oncology^® (NCCN). ^© 2023 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 22, 2023.
   • Head and Neck Cancer (V2.2023). Revised May 15, 2023.

1. American Cancer Society (ACS). Radiation Therapy for Salivary Gland Cancer. Last Revised: March 18, 2022. Available at: https://www.cancer.org/cancer/types/salivary-gland-cancer/treating/radiation-therapy.html. Accessed on September 22, 2023.
2. American Society of Clinical Oncology (ASCO). Salivary Gland Cancer Treatment. May 2020. Available at: http://www.cancer.net/cancer-types/salivary-gland-cancer/treatment-options. Accessed on September 22, 2023.

Neutron Beam Radiotherapy
Salivary Gland Tumors