Oncologic Outcomes for Head and Neck Skin Malignancies Treated with Protons

Purpose Radiation therapy (RT) is the standard treatment for patients with inoperable skin malignancies of the head and neck region (H&N), and as adjuvant treatment post surgery in patients at high risk for local or regional recurrence. This study reports clinical outcomes of intensity-modulated proton therapy (IMPT) for these malignancies. Materials and Methods We retrospectively reviewed cases involving 47 patients with H&N malignancies of the skin (squamous cell, basal cell, melanoma, Merkel cell, angiosarcoma, other) who underwent IMPT for curative intent between July 2016 and July 2019. Overall survival was estimated via Kaplan-Meier analysis, and oncologic outcomes were reported as cumulative incidence with death as a competing risk. Results The 2-year estimated local recurrence rate, regional recurrence rate, local regional recurrence rate, distant metastasis rate, and overall survival were 11.1% (95% confidence interval [CI], 4.1%-30.3%), 4.4% (95% CI, 1.1%-17.4%), 15.5% (95% CI, 7%-34.3%), 23.4% (95% CI, 5.8%-95.5%), and 87.2% (95% CI, 75.7%-100%), respectively. No patient was reported to have a grade 3 or higher adverse event during the last week of treatment or at the 3-month follow-up visit. Conclusion IMPT is safe and effective in the treatment of skin malignancies of the H&N.

However, radiation therapy (RT) is used in some situations, such as patients with disease in the head and neck region for whom surgery may result in cosmetic and/or functional deficits, patients with unresectable disease, or patients with multiple medical comorbidities. Radiation therapy also plays a role as an adjuvant treatment following surgery in patients with close or positive margins, satellite tumors, deep invasion, high-grade http://theijpt.org malignancies, bone or cartilage invasion, perineural invasion, lymph node metastases, extranodal extension, or recurrent disease.
For scalp lesions, the dose distribution of electrons and orthovoltage RT is not conformal along the curved surfaces of the scalp. Large targets will require matched fields with these techniques, which are likely to introduce severe inhomogeneity. IMRT can conform dose to curved surfaces, resulting in increased homogenous tumor coverage as compared with other RT techniques [6][7][8][9][10]. However, the penetrating nature of megavoltage RT used by IMRT can lead to increased doses to the underlying brain [7][8][9] and eyes [7,8] as compared with other RT techniques.
Ipsilateral neck RT in patients with skin lesions is indicated for treating primary lesions in the neck and for treating regional nodes, which requires exclusion of organs of the upper aerodigestive tract from the treatment volume. IMRT provides good dose conformity to the target volume. However, the integral dose to normal organs in the central or contralateral regions of the neck results in toxicity [11][12][13][14].
For larger lesions involving the face, IMRT is preferred because it can confine dose within the tumor target volume and restrict dose to the eyes, oral cavity, pharyngeal mucosa, and salivary glands. IMRT is also a recommended RT technique for tumors with cranial nerve invasion because nerve pathways to the skull, cavernous sinus, and brainstem are close to critical sensitive structures [15,16]. However, IMRT has the limitation of entrance and exit dose in adjacent normal organs [17]. In some patients who have gross disease close to critical normal organs, it is extremely difficult to increase dose to a therapeutic level while keeping an acceptable dose constraint to the adjacent critical normal organs.
IMPT can produce conformal dose distributions around the tumor target volume like IMRT, but the distal dose is truncated, sparing adjacent structures from collateral dose. Therefore, it is expected in some situations that toxicities can be minimized by using IMPT for skin carcinomas and sarcomas in the head and neck region, compared with other RT modalities.
Previous studies of proton RT for treating patients with head and neck cancer, which included a small number of patients with skin malignancies, showed at least similar or better dose distributions in the tumor target volume [11,[18][19][20][21][22] with less dose to adjacent normal structures [11,[19][20][21][22][23][24][25][26][27][28][29] when compared to patients who were treated with IMRT. However, we are in need of data to confirm whether the dosimetric advantages from IMPT can result in clinical advantages.
To date, there are limited studies documenting the clinical outcome of patients with skin malignancies in the head and neck region treated with IMPT. The aim of this study is to provide oncologic outcomes of patients with skin carcinomas and sarcomas in the head and neck region treated with IMPT. A subsequent article will report patient-reported outcomes related to organ-at-risk dose-volume histogram statistics.

Study Design and Patient Population
This study is a retrospective study of skin carcinomas and sarcomas of the head and neck region treated with curative-intent IMPT between July 2016 and July 2019. The study was approved by the Institutional Review Board. Patients were excluded from analysis if they had previous RT to the same area, they did not give consent for their medical records to be used for research, they did not receive a complete course of IMPT, or they were treated with a mixture of photons and protons. Fortyseven patients were included. Demographic data, disease and treatment details, and patient status were extracted from the electronic health records.

Radiation therapy
All patients underwent computed tomography (CT) simulation with a customized head and neck rest, thermoplastic mask, and intraoral device for immobilization. Bolus helmets were used for proton energy degradation and optimizing beam spot size for superficial tumors that were close to critical organs, such as ocular structures. The relative biological equivalent of 1.1 was used for proton dose calculation. Commonly prescribed dose regimens are shown in Table 1.
For regions at intermediate or low risk of tumor extension, such as elective lymph nodes, a lower dose was prescribed. Stereotactic radiosurgery was used as a boost technique for intracranial gross tumor extension in 3 patients. Treatment volumes were determined and contoured by the treating radiation oncologist depending on the risk of microscopic tumor extension. If there were risks for cranial nerve involvement the nerves at risk were contoured retrogradely to the brain stem. Robust optimization was used with 3-to 5-mm translational setup uncertainties and 3% to 5% range uncertainties. The treatment planning system was Varian Medical System's Eclipse (Varian Medical Systems, Palo Alto, California).
IMPT planning used proton convolution superposition or an in-house Monte Carlo-based algorithm called Spock. Imageguided RT was performed daily by using 2D-3D kV imaging with 6-degrees-of-freedom couch adjustments with an option for in-room CT on rails volumetric verification. Weekly CT verification scans were performed on the in-room CT on rails with the patient in the treatment position, and replanning was performed when the target volume that received at least 95% of the prescribed dose (V95%) was , 95% or when a high-priority organ-at-risk dose deviation was . 5% or when a low-priority organ-at-risk dose deviation was . 10%.

Systemic therapy and surgery
All patients underwent multidisciplinary evaluation. Patients who were appropriate surgical candidates were treated with surgery. Most patients who received surgery at outside hospitals had their pathology specimens reviewed at Mayo Clinic and a surgeon was consulted if there was a concern for margin status. The aim of surgery for skin malignancies was to remove the tumor with negative margins and still maintain acceptable cosmesis, function, and quality of life. Systemic treatment was determined by the consulting medical oncologist. For 9 patients with squamous cell carcinoma, 5 were treated with concurrent cisplatin, 2 were treated with concurrent cemiplimab, 1 was treated with induction and concurrent cemiplimab, and 1 was treated with induction carboplatin, paclitaxel, and cetuximab and concurrent cisplatin. For 3 patients with melanoma, 1 was treated with adjuvant nivolumab following IMPT and 2 were treated with concurrent and adjuvant nivolumab.

Adverse Events
Provider-reported adverse events related to IMPT were recorded prospectively during the last week of treatment and at the 3month, 6-month, and 12-month follow-up visit by using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (National Cancer Institute, Bethesda, Maryland).

Statistical Methods
The events of interest were local recurrence, regional nodal recurrence, local regional recurrence, distant metastasis, and overall survival.
Patient characteristics, pathology, and dosimetry data are reported as median (interquartile range [IQR]) or percentage (N) as appropriate. Local recurrence, regional nodal recurrence, local regional recurrence, distant metastasis, and overall survival were calculated as the time from the last day of IMPT treatment to the date of the event or death. Recurrence and metastasis rates were estimated by using a competing risks model, and overall survival was estimated by using the Kaplan-Meier method. Effects of predictors were estimated by using Cox proportional hazards regression. Statistical significance was defined as P , .05. Statistical analyses were conducted with SAS version 9.4 (SAS Institute, Cary, North Carolina).

Patient and Tumor Characteristics
Forty-seven patients were treated with IMPT.

Univariable Analysis
Univariable analysis revealed that treatment with surgery and postoperative adjuvant IMPT was associated with lower risk for local recurrence and local regional recurrence than IMPT alone. None of the other factors evaluated were found to be associated with local recurrence, regional nodal recurrence, local regional recurrence, distant metastasis, or death as shown in Table 5. A multivariable analysis was not performed owing to the small number of events.

Adverse Events
No patient was reported to have a grade 3 or higher adverse event during the last week of treatment or at the 3-month followup visit, including ocular toxicity, radiation dermatitis, dry mouth, dysgeusia, mucosal infection, oral pain, pharyngolaryngeal pain, salivary duct inflammation, brain necrosis, or osteoradionecrosis.
For grade 2 adverse events reported during the last week of treatment, 9 patients were reported to have radiation dermatitis, 3 dysgeusia, 3 oral pain, 2 pharyngolaryngeal pain, 2 dry mouth, 2 salivary duct inflammation, 2 ocular toxicity, and 1 mucosal infection. At the 3-month follow-up visit, 2 patients were reported to have grade 2 dry mouth, 1 skin ulceration with infection, and 1 dysgeusia.

Discussion
This retrospective early report of skin malignancies of the head and neck region treated with IMPT suggests that IMPT is safe and effective in providing local and regional control of disease, particularly in the adjuvant setting for advanced disease. There is limited research investigating proton therapy for skin malignancies of the head and neck region. One small retrospective trial from Japan studied the results of proton therapy in 6 patients with skin carcinomas. Good tumor response (at least 90% tumor regression in all patients) was observed [31]. Romesser et al [19] conducted a retrospective study in 41 patients with major salivary gland cancer or skin squamous cell carcinoma treated with ipsilateral neck proton or photon RT. Comparing passive scattering proton RT to IMRT, they reported no difference in tumor dose coverage or 1-year local regional tumor control.
There are several limitations in this retrospective study. The length of follow-up is relatively short. Longer follow-up will be required to document long-term oncologic outcomes and late adverse events. However, these early results are promising. Tumor and nodal classification could not be assessed in approximately 50% of patients. The reason for the missing initial staging information was the lack of this information in the medical record, which could not be determined by any means for patients referred from outside our institution. Another limitation is the variety of malignancies including squamous cell carcinoma, basal cell carcinoma, melanoma, Merkel cell carcinoma, angiosarcoma, and other malignancies, which may have  differing disease control and survival outcomes. This is why we performed a separate analysis for the largest squamous cell carcinoma subgroup.

Conclusion
IMPT is safe and effective in providing local and regional disease control for patients with skin malignancies of the head and neck region.

ADDITIONAL INFORMATION AND DECLARATIONS
Conflicts of Interest: The authors have no relevant conflicts of interest to disclose. Funding: The authors have no funding to disclose. Ethical Approval: All patient data have been collected under institutional review board (IRB)-approved protocol.

Figure.
Competing risks curves for local recurrence, regional nodal recurrence, local regional recurrence, distant metastasis, and death.