Proton beam radiation therapy treatment for head and neck cancer

Proton beam therapy has gained popularity over recent years. This is likely due to improved affordability; that is, lower cost, and increasing reports on excellent patient‐reported outcomes. Protons’ physical properties provide dosimetric advantages over photon therapy due to the unique ability to have little‐to‐no “exit” dose, potentially translating to reduced toxicities and improved patient quality of life. The increased delivery of proton beam therapy to treat numerous head and neck cancers, including oropharynx, nasopharynx, sinonasal, in the re‐irradiation setting, and unilateral malignancies, has led to more studies elucidating the clinical risks and benefits. In this review, we aim to summarize the recent literature on proton beam therapy utilization in head and neck cancer. In addition, we discuss the process of treatment and planning, clinical treatment toxicities and outcomes, limitations, and future directions.

F I G U R E 1 Depth-dose curves for photon and proton beams. The proton Bragg peak allows for precise dose delivery to the tumor target and a relative dose elimination compared with photon exit dose. Modulated proton beams allow for spread out Bragg peak (SOBP), covering the tumor target at various depths ( Figure 1. created with BioRender.com. Accessed 2021.) In this review, we aim to summarize the recent literature on PBT utilization in head and neck cancer. In addition, we discuss the process of treatment and planning, clinical treatment toxicities and outcomes, limitations, and future directions.

REFERENCES SEARCH
We did not attempt a systematic review of PBT; instead, we comprehensively summarized the literature on PBT in head and neck cancer. A review of PubMed and Web of Science was conducted using a search syntax with the keywords ("proton therapy" OR "proton beam therapy" OR "proton radiation" OR "proton beam radiation AND "head and neck cancer"). Terms were included to specify individual anatomical sites.
Articles that reported clinical results were included in this review. We identified ongoing interventional clinical trials by searching ClinicalTrials.gov using the terms "proton therapy" and "head and neck cancer," and excluded trials that are terminated, completed, withdrawn, or have an unknown status.

TREATMENT PLANNING AND DELIVERY
Radiation planning for PBT differs from IMRT due to its inherent physical properties. On an atomic level, protons' heavier mass decreases the scattering angle and the dose distribution, allowing for a more finite and defined range of radiation. In addition, the localization of the Bragg peak to the designated tumor volume and the virtually non-existent exit dose favors a more precise dose delivery. However, tumors are complex targets with varying thickness and depths, requiring a spreadout Bragg peak to cover the entire selected volume (Figure 1). This method can eliminate the skin-sparing effects of the entrance dose and lead to skin toxicities, especially in more superficial tumors. 5 Relative to photons, protons are more sensitive to the varying densities it travels through. A considerable challenge for PBT planning is considering the factors that can shift the Bragg peak location, potentially leading to poor treatment and inappropriate radiation to healthy tissue. Some of the uncertainties that need to be considered to avoid this dilemma are artifacts (e.g. dental or surgical hardware), anatomical variations due to tumor response or weight change, and daily changes in patient position. 5,6 To circumnavigate the issue of artifacts and other heterogeneous structures interfering with Bragg peak localization, a short and reliable beam path needs to be selected that avoids areas such as the mouth, spinal cord, and other hollow structures.
Implementation of automated adaptive replanning is highly recommended to account for the anatomical variations and patient's weight change. [7][8][9] The two primary modes of PBT delivery are passive-scatter protons therapy or intensity-modulated proton therapy (IMPT). Similar to three-dimensional photon therapy, passive-scatter protons therapy uses scattering foils to spread the proton beam, which is less flexible than active scanning. The utilization of apertures in passive-scatter protons therapy allows for impressive lateral conformality. Conversely, IMPT -the most recent advancement of PBT -utilizes pencil-beam scanning, which uses two pairs of scanning magnets that guide the proton beam to varying directions and depth. The modulation of the proton beamline allows for more precise coverage of the 3-D, irregular targets, improving proximal and distal conformality. In IMPT planning, single-field optimization (i.e. each proton beam separately covers the target volume) or multiple-field optimization (i.e. the proton beams collectively cover the target volume) can be utilized to personalize patients' treatments. Multiple-field optimization allows for a higher degree of conformality and intensity modulation and is more sensitive to treatment uncertainties than single-field optimization. Overall, IMPT provides for an increased relative biological effectiveness and decreased radiation to healthy surrounding tissue.

Oropharyngeal cancer
Alongside surgery and chemotherapy, radiation therapy is an essential component in the definitive and adjuvant treatment of oropharyngeal carcinoma (OPC). IMRT is commonly used to treat oropharyngeal carcinoma with limited toxicities, such as dysphagia and xerostomia; however, these adverse effects significantly impact patient QoL. 10 The incidence of young, human papilloma virus-positive patients is on the rise, 11 so further efforts are required to reduce radiation-related toxicities due to the longer lives these patients will live after treatment.
The physical properties of photon therapy lead to incidental radiation of healthy oropharyngeal and nasopharyngeal tissue. PBT is an emerging modality to reduce toxicities and improve patient QoL. Given the virtually non-existent exit dose of PBT, there is potentially a dosimetric advantage in using PBT compared with IMRT because of the minimal radiation to nearby major organs, which can translate to minimal toxicities in OPC treatment. 12

Nasopharyngeal cancer
The standard of care for locoregionally advanced nasopharyngeal carcinoma (NPC) consists of radiation and chemotherapy in the definitive setting. The challenge of radiating the nasopharynx is limiting the radiation dose to nearby integral structures, such as the major salivary glands, pharyngeal constrictors, brain stem, optic chiasm, cranial nerves, and spinal cord. IMRT is utilized for optimal tumor coverage while limiting radiation to critical tissue, leading to reductions in toxicity and better QoL than conventional radiotherapy in NPC. 22

Sinonasal cancer
Most primary sinonasal cancers have acceptable treatment outcomes with surgical resection followed by radiation with or without chemotherapy. However, in advanced cancers, surgery can potentially result in facial disfiguration and neurovascular injury due to the proximity of the paranasal sinuses and nasal cavity to critical structures. 33 Patients with unresectable sinonasal tumors are treated with radiation with or without chemotherapy, but this treatment results in suboptimal outcomes, because the radiation dose is limited to preserve nearby critical structures and prevent radiation-induced hypopituitarism. 34 Dosimetry studies showed that dose escalation could be achieved safely with PBT compared with photon therapy. [35][36][37] In a clinical setting, PBT has been shown to reduce the radiation dose to nearby tissue, such as optic structures and brain stem, thereby reducing toxicities. 38 In summary, these studies support the use of PBT for its improved local control, overall survival, and reduced toxicities among sinonasal cancer patients. Ongoing clinical trials will further support the benefits of PBT delivery among sinonasal cancer patients (Table 1).

Re-irradiation for recurrent head and neck cancer
When head and neck cancer patients develop recurrence of disease after radiation treatment, they require salvage therapy to control the tumor and prevent severe declines in QoL and painful death. Salvage therapy may consist of surgery and subsequent re-irradiation or re-irradiation without surgery. High doses of radiation would be required to control the radioresistant tumors; however, delivering high doses is limited by the surrounding tissue previously exposed to radiation from prior treatment. Re-irradiation carries the risk of damaging surrounding tissue, leading to irreversible toxicity. This challenge limits the dose delivered and occasionally limits the dose given in the re-irradiation setting. Given the near absence of an exit dose, PBT has been used to overcome the obstacle of limiting radiation to spare nearby structures and allows for dose escalation, resulting in reduced toxicity to surrounding tissue and improve disease control.
Based on a review of re-irradiation of head and neck cancer, the 1-2-year LRC rates are approximately 50-60%. 47  65.2%, respectively. The acute grade 3 toxicities were dysphagia (n = 6, 9.1%), mucositis (n = 9, 9.9%), esophagitis (n = 6, 9.1%), and dermatitis (n = 3, 3.3%). Compared with IMRT, PBT had lower grade 3 or 4 late toxicities rates, including skin complications (n = 6, 8.7%) and dysphagia (n = 4, 7.1%). Two deaths occurred from bleeding. 50 These studies suggest re-irradiation with PBT has a relatively safe toxicity profile with acceptable outcomes, but it is important to note the small percentage of patient deaths, and for practitioners to be mindful of reducing toxicity. Predictive factors for severe late toxicity include shorter intervals to re-irradiation (<20 months) and larger re-irradiated planning tumor volumes (PTVs >100 cm 3 ). 51 A retrospective study of recurrent NPC patients treated with PBT showed OS and LC rates of 54.4% and 66.6%, respectively. No acute grade ≥3 toxicities were observed, and late grade ≥3 toxicities were observed in 23.5%, with hearing impairment (17.6%) being the most frequent. 52 In another disease-specific retrospective review, recurrent oral cancer patients treated with PBT were reported to have 1-year OS and LC rates of 62% and 77%, respectively, and 2-year OS and LC rates of 42% and 60%, respectively. No treatment-related deaths were observed. 53 Despite the challenges of re-irradiating recurrent tumors, PBT appears to have a relatively safe toxicity profile with acceptable outcomes compared with historical photon use. Of note, the frequencies of acute and late adverse events are still high. Re-irradiation treatment planning needs to be personalized for patients because of the heterogeneity in cases to limit toxicities and improve disease control.
Prospective clinical trials are required to further assess the advantages of PBT compared with traditional photon radiotherapy. Ongoing prospective clinical trials with recurrent head and neck cancer patients will continue to evaluate PBT's efficacy in the re-irradiation setting (Table 1). An on-going randomized trial, NCT02923570, aims to compare PBT and IMRT for unilateral radiation, while primarily assessing acute toxicities (Table 1). RTOG 1008 (NCT01220583), a phase II/III randomized trial assessing radiation therapy with or without chemotherapy treatment for resected malignant salivary gland tumors, has permitted proton therapy.

LIMITATIONS
PBT has been used clinically for over two decades, but the costly PBT. These findings suggest that patients from more affluent backgrounds are more likely to receive PBT. 65 This trend is noteworthy to recognize early to ensure the inclusion of economically disadvantaged patients in future studies. These patients are necessary to acquire an accurate representation of both the beneficial outcomes and the toxicities. More importantly, providing marginalized patients with this potentially superior radiotherapy will be one step closer to narrowing the disparities gap.

FUTURE DIRECTIONS
The rise in proton facilities and increase in PBT delivery has expanded the literature, providing more insight into the benefits and areas of improvement. Efforts to strengthen techniques, including on-board imaging and automating proton plan adaption, will establish a system to precisely deliver protons, thereby permitting an even wider adoption of this radiotherapy. 66,67 Furthermore, these technological improvements and increased availability of sites offering this radiotherapy may reduce treatment costs. The reduction in adverse effects will lead to decreased expenses on toxicity management, which can minimize the total costs spent throughout the entire duration of care.
Prospective, randomized studies are required to directly compare the clinical benefits and adverse effects of PBT to photon therapy.
Reports from these trials will provide more robust evidence supporting the clinical benefits, leading to increased adoption of protons as a treatment option. Current trials are evaluating the cost-effectiveness, toxicities, QoL, and suitable patient populations ( Table 1). As these factors will vary among head and neck cancer patients, the decision to pursue PBT needs to be personalized, based on the individual characteristics of each patient. Other factors to consider are the proton interactions with other treatment modalities, such as immunotherapy. 68 Investigating the relationship between proton radiotherapy and immunotherapy will provide insight into the immunological response to cancer cells. Furthermore, the effect of proton radiation on different biological mechanisms needs to be continuously studied, as it has been shown that RNA and protein expression varies in (lymph) angiogenic, inflammatory, proliferative, and anti-tumor immune responses. 69,70 Besides the superior physical characteristics that protons have over photons, these findings elucidate the biological advantages of protons and their potential to be supplemented with anti-angiogenic or anti-immune checkpoint drugs to improve the therapeutic window. 70

CONCLUSION
Given the physical properties of protons to maximize radiation dose to target volume with minimal dose to normal tissue, PBT is theoretically advantageous over IMRT. The clinical evidence summarized in this review suggests PBT is a favorable radiotherapy option for head and neck cancer treatment. Improvements in its technologies and increased proton therapy sites will allow for more accessible treatment. With more patients receiving protons, we can further conduct clinical trials to improve our understanding of proton radiotherapy, increasing the therapeutic ratio. As prospective studies are underway to highlight its benefits, and proton radiotherapy becomes more accessible and effective, practitioners will provide better quality of life and health outcomes to head and neck cancer patients.

CONFLICTS OF INTEREST
The authors declare that they have no conflicts of interest to disclose.

FUNDING
The research is funded by P30 Cancer Center Support Grant (P30 CA008748).