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Distributed under the mucosa of the oral cavity, pharynx, larynx, and contralateral salivary glands, leading
Creative Commons CC-BY to acute toxicities, including mucositis, dysguesia, xerostoma, and dysphagia. Such
OPEN ACCESS toxicities result in decreased quality of life (QOL) and longer duration of recovery due to
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GI Toxicity from Proton Therapy
malnutrition and dehydration; furthermore, with concurrent chemoradiotherapy, toxicities can lead to complications like renal
insufficiency, hypotension, and hospitalization [4].
The parotid region represents an ideal target volume for harnessing the unique dosimetric properties of proton therapy.
Because the depth of the target volume is shallow with these tumors, proximal non-conformity and entry radiation are less
concerning, and all critical organs at risk, such as the oral cavity, pharynx, larynx, spinal cord, temporal lobe, brainstem, and
contralateral salivary glands, lie distal to the target volume. Given the sharp distal dose fall-off generated by the properties of
the proton’s Bragg peak, these critical structures will receive either very little or no dose from most proton therapy plans.
We hypothesized that the dosimetric advantages of proton therapy would result in negligible acute mucosal toxicity, diet
modifications, and weight loss. Herein we report prospectively collected data in these domains for patients treated with proton
therapy to the parotid target.
Results
Table 2 demonstrates the average minimum, mean, and maximum doses delivered to relevant organs at risk associated with
acute mucosal toxicities. The results are summarized in Figure 2A-D. At baseline, no patient had mucositis, 13% had
dysphagia (4% grade 1 and 9% grade 2), 8% had dysgeusia (4% grade 1 and 4% grade 2), and 19% had xerostomia (14%
grade 1 and 5% grade 2). During radiotherapy, toxicities were minimal, typically emerging in weeks 2 and 3 and then
stabilizing. Most patients experienced either no toxicity or grade1 toxicity throughout therapy. Weight loss (Figure 3) was
minimal with a median percentage weight loss of 3% through therapy and holding steady at the first follow-up. Only 1 patient
experienced greater than 10% weight loss, 74% experienced less than 5% weight loss, and 17% gained weight during
radiotherapy. No patient required a feeding tube, intermittent intravenous hydration, or significant diet modification, such as the
use of a soft/liquid diet or reliance on nutritional supplements. There were no occurrences of grade 4 toxicity and only 1
transient grade 3 dysphagia. This dysphagia occurred during only one week in a patient with baseline grade 2 dysphagia. Prior
to radiotherapy, this patient underwent parotidectomy, mandible resection, and full-mouth extractions, and a percutaneous
gastrostomy tube was placed. The grade 3 toxicity was recorded during week 4 of therapy and returned to baseline the
following week. Upon completing therapy, the gastrostomy tube was removed when dysphagia improved to grade 1.
The worst mucositis recorded was grade 2 (patchy ulceration or pseudomembranes), ranging from 35 to 43% per week.
Thus, most patients either experienced no mucositis (35-43%) or grade 1 mucositis (17-30%, mucosal erythema without
ulceration or pseudomembranes) throughout their entire treatment course. Approximately 50% of patients had no dysphagia
with 17-26% experiencing grade 1 dysphagia (symptomatic but able to eat a regular diet) per week and 26-30% experiencing
grade 2 dysphagia (symptomatic with altered eating/swallowing requiring oral supplements, altered dietary habits, or less than
24 hours of intravenous hydration) per week. Dysgeusia was absent in 40-50% of patients each week throughout therapy; 22-
40% had grade 1 dysgeusia (altered taste but no change in diet) each week and 9-26% developed grade 2 dysgeusia (altered
taste requiring altered dietary habits) each week. Xerostomia was the most commonly reported toxicity. During the course of
Structure Average mean dose Gy (RBE) Average min dose Gy (RBE) Average max dose Gy (RBE)
Oral cavity 7.5 2.6 45.6
Larynx 7.2 0.4 37.0
Pharyngeal constrictor muscles 19.5 0.4 64.0
Contralateral parotid gland 1 0.1 2
Contralateral submandibular gland 1.8 0.5 6.2
radiotherapy, the rate of xerostomia fluctuated slightly with 17-36% of patients experiencing no xerostomia each week, 55-64%
experiencing grade 1 xerostomia (symptomatic with dry or thick saliva, but no change in diet) each week, and 9-25%
Discussion
The dosimetric advantages of advanced radiotherapy techniques such as proton therapy can improve the therapeutic ratio in
one of two ways: by improving the probability of tumor control through treatment intensification or by reducing treatment-
associated toxicities. When considering the potential advantages of proton therapy, physicians and patients often focus on
reducing late toxicities, such as blindness, brainstem injury, cardiac injury, or second malignancies; however, reducing acute
toxicities is also an important goal. In regards to head-and-neck cancer patients, acute mucosal toxicities represent a major
burden for patients and caregivers, often requiring aggressive pain management, intravenous hydration, expensive nutritional
support, and potential hospitalizations. Following therapy, these toxicities can linger, severely impacting QOL, time to
functional recovery, and lost productivity in working-age patients. Weight loss in particular has been associated with
decreased survival [6]. The parotid target volume is ideal for proton therapy, which can nearly eliminate the exit radiation to
organs at risk, such as the mucosa of the oral cavity and pharynx, contralateral major salivary glands, and swallowing
patient population that is expected to develop these symptoms when treated with conventional radiotherapy techniques. The
overall impact of this toxicity reduction with regards to QOL, recovery of potentially lost productivity, or cost-effectiveness is yet
to be determined.
Conclusion
In our cohort of 23 patient treated with ipsilateral radiotherapy to tumors of the parotid region, proton therapy resulted in very
minimal acute mucosal toxicity. The majority of patients experienced either no or only grade 1 dysgeusia, mucositis,
dysphagia, and xerostomia. The median percent weight loss was 3% throughout therapy and at first follow-up. Only 1 patient
experienced transient grade 3 dysphagia. These findings should be validated in a larger prospective multi-institutional cohort
with comparisons to similar patients treated with conventional radiotherapy and additional focus on the impact on patient-
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