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Primary chondrosarcomas of the larynx treated with proton radiotherapy: A single institutional experience

Primary laryngeal chondrosarcomas are rare entities whose excellent survival rates following resection promote conservative surgical approaches to maintain quality of life without compromising outcomes. There are excellent outcomes in skull base chondrosarcomas treated with maximal safe resection and post‐operative proton therapy. Extrapolating from these findings, we report our institutional experience treating symptomatic or growing laryngeal chondrosarcomas using proton beam therapy.

laser resection and debulking. Given the excellent long-term prognosis, with 10-year survival rates of 95%, 1,2,7,8 larynx preservation is imperative to conserving vocal function and optimizing quality of life.
Accordingly, most studies focus on surgical considerations and outcomes. Radiotherapy is inconsistently employed for recurrent disease following resection or positive margins, but it's effectiveness for these indications is controversial. 1,2,[7][8][9] Improved image guidance and treatment planning innovations culminated in more precise radiotherapy delivery. These technological improvements are further advanced using proton therapy, facilitating more conformal treatment than photon beam therapy, promoting high integral dose delivery to the targeted lesion while minimizing side effects, and preserving post-surgical laryngeal function. 10 While there is a dearth of data evaluating modern radiation therapy techniques in LCs, the skull base chondrosarcoma literature suggests maximally safe surgical resection followed by post-postoperative proton therapy provides excellent local control and functional outcomes with acceptable toxicity. [11][12][13] Extrapolating from these experiences, the intention of this study is to provide a modern institutional experience treating LCs utilizing proton therapy.

| MATERIALS AND METHODS
This study was an institutional review board approved retrospective review  of patients with primary LCs who were treated with proton therapy at our proton facility (Procure, Somerset, New Jersey).
All studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Electronic medical records and all available dosimetric data for eligible patients were reviewed.

| Radiation therapy
All patients underwent CT simulation in the supine position with 3-point or 5-point head and neck masks. Positron emission tomography/CT and magnetic resonance (MR) simulation were co-registered to the CT simulation to facilitate target volume delineation. Gross tumor volume (GTV) was defined as any gross primary detected clinically or radiographically following resection. A clinical target volume (CTV) was created from an isometric 1 cm GTV expansion to account for subclinical disease. A planning target volume (PTV_50) was generated by adding 3-5 mm margin to the CTV to account for interfraction and intrafraction motion errors. The PTV was used as a volume for plan evaluation of dose coverage. Patients received 50 Cobalt-Gray Equivalents (CGE) to PTV_50, with a sequential boost to the GTV with a 3-5 mm PTV expansion (PTV_70) to 70 CGE. Elective nodal volumes were not targeted given the historically low rates of nodal involvement, as well as low rates of nodal dissection performed on LCs. 1,3,4,[7][8][9]14 All patients received conventional fractionation defined as 2 CGE per fraction, once daily, 5 days a week.

| Proton techniques
All patients were treated with proton therapy using the Proteus 235 system (Ion Beam Applications, Louvain-la-Neuve, Belgium).
Patients were treated with either uniform scanning beam (US) using the match field technique or pencil beam scanning (PBS), depending on machine availability. Those treated with US technique had custom-made apertures and compensators to shape the lateral and distal edges of the target, respectively. The PBS was delivered in 2 ways; single-field uniform dose, with each beam angle delivering a uniform dose to cover the entire volume, or multifield optimization, utilizing the beams to collectively encompass the volume. Monte Carlo algorithm was used as a PBS calculation model. Setup variations of 3 mm and range uncertainties of 63.5% were accounted for in the planning optimization. A RBE value of 1.1 was used in planning and evaluation. Daily orthogonal x-ray imaging on a 6 degree-of-freedom couch was performed for setup verification.
CT scans were performed weekly as QA (quality assurance) to evaluate anatomic changes. If significant changes were noted, a QA plan was calculated using the weekly QA CT to ensure accurate dose measurement to the target and organs at risk. Any unacceptable dose coverage required adaptive radiotherapy planning.

| Follow-up
Patients were evaluated weekly during radiation therapy by a radiation oncologist, and if applicable, by a multidisciplinary team including head and neck surgeons, nurses, and advanced practice providers. Patients were followed clinically and radiographically at approximate intervals of 1-3 months after treatment completion, every 3 months up to 2 years, and every 6-12 months thereafter. In general, MRI of the head and neck was performed 3 months after the end of radiotherapy then every 6-12 months or as clinically indicated.

| Response
Patients were monitored with serial MRI scans and flexible laryngoscopies during their routine follow-up visits. They were also monitored for worsening or new symptoms related to their laryngeal chondrosarcoma, including hoarseness, voice strength, and swallowing. Stable disease following radiotherapy was defined as no progression of disease on imaging and no progressive or new symptoms attributable to their tumor.
Progression-free survival and overall survival (OS) were determined from date of treatment completion to date of last follow-up.

| Patient selection and characteristics
We queried our institutional records for all patients with primary LCs treated with proton beam radiotherapy. This cohort entailed four Caucasian males with a mean age of 53 (Table 1). All patients were evaluated by an otolaryngologist and a radiation oncologist with subsequent discussion of their case and treatment options at our multidisciplinary head and neck case conference. Two patients underwent subtotal resection followed by post-operative radiotherapy, while two patients received definitive radiotherapy ( Table 2). All patients were treated with proton therapy to 70 CGE (Table 3).

| Case 3
A 52-year-old man presented with hoarseness of 1.5 year's duration.
Initial evaluations were unremarkable until a right-sided subglottic mass was identified at his last otolaryngology visit. A CT scan showed 2.7 cm lesion involving less than half of the cricoid cartilage underneath the arytenoid cartilage on the right side. He underwent biopsy which was complicated by life-threatening hemorrhage, and was taken back to the operating room for cautery. He continued to have intermittent bleeding for 2 weeks. Pathology was consisted with a low-grade chondrosarcoma. He subsequently established care with our institution. Following multidisciplinary discussion of treatment options, he opted for definitive radiation to minimize treatment-related morbidity.
He developed mild odynophagia and mild dermatitis during radiotherapy which resolved within 6 months of completing treatment. He is currently 5 years post-treatment with stable disease on imaging, no long-term side effects, and preservation of his post-treatment vocal quality and strength.

| Case 4
A 68-year-old man initially presented to an outside institution with hoarseness and was initially diagnosed with gastroesophageal reflux disease. His course was uneventful until his hoarseness acutely wors-    Their review found only eight evaluable cases: four had total laryngectomy, two had partial laryngectomy, one had debulking and one only underwent a biopsy. In these cases, radiotherapy was used for residual tumor, local relapse, and unspecified reasons. 15 They discussed the difficulty assessing response to radiotherapy, as durable local control can be obtained even if there is no change in tumor extent, 15 which has also been considered in other reports, [16][17][18] and may contribute to the notion that these are radioresistant tumors. Thompson  The aforementioned studies promote conservative approaches entailing larynx-preserving, maximal safe resection to preserve quality of life in patients with symptomatic or growing LCs.
Given the relatively slow growth of these tumors, frequent followup would allow adequate time to perform a repeat surgery for recurrent disease. The added benefit of radiotherapy is difficult to determine outside of a study designed to assessed local control, and preservation of quality of life and vocal function given the excellent survival rates cited above in parallel with few cases receiving adjuvant radiotherapy. An alternative is a hybrid approach extrapolating from the skull base chondrosarcoma literature entailing maximally safe resection followed by adjuvant radiotherapy. [11][12][13] Accordingly, in our case series we defined stable disease as no growth of the tumor following treatment and no new or progressing symptoms attributable to the tumor, rather than inducing further regression. Given the average patient age at presentation, OS rates following resection, and slow growth at of these tumors, this strategy can achieve excellent long-term local control and preserva-

CONFLICT OF INTEREST
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

PRIOR PRESENTATION
This work has not been presented at any meetings.

DATA AVAILABILITY STATEMENT
Availability of data and material: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.