key: cord-1036031-ezt5tqmh
authors: Cook, Maclean M.; Schaub, Stephanie K.; Goff, Peter H.; Fu, Alex; Park, Song Y.; Hippe, Daniel S.; Liao, Jay J.; Apisarnthanarax, Smith; Bhatia, Shailender; Tseng, Yolanda D.; Nghiem, Paul T.; Parvathaneni, Upendra
title: Post operative single fraction radiation therapy in Merkel cell carcinoma of the head and neck
date: 2020-07-21
journal: Adv Radiat Oncol
DOI: 10.1016/j.adro.2020.07.003
sha: 5f8373caecd0b39ccccbc468b8489bbbc689f32d
doc_id: 1036031
cord_uid: ezt5tqmh

PURPOSE: Conventionally fractionated, post-operative radiotherapy (cPORT; 50 Gy in 25 fractions) is considered for patients with Merkel cell carcinoma (MCC) to improve locoregional control. However, cPORT is associated with acute toxicity, especially in the head and neck (H&N) region, and requires daily treatments over several weeks. We previously reported high rates of durable local control with minimal toxicity using 8 Gy single-fraction radiation therapy (SFRT) in the metastatic setting. We report early results on a cohort of patients with localized H&N MCC, who received post operative SFRT if a cPORT regimen was not feasible. METHODS: Twelve patients with localized MCC of the H&N (clinical/pathologic stages: I-II) and no prior RT to the region were identified from an IRB-approved prospective registry who underwent surgical resection followed by post operative SFRT. Time-to-event was calculated starting from the date of resection prior to SFRT. The cumulative incidence of in-field locoregional recurrences and out-of-field recurrences was estimated with death as a competing risk. RESULTS: Twelve H&N MCC patients were identified with clinical/pathologic stages I-II H&N MCC. Median age at diagnosis was 81 years (58-96); 25% had immunosuppression. At a median follow-up of 19 months (range: 8-34), there were no in-field locoregional recurrences. A single out-of-field regional recurrence was observed, which was successfully salvaged. There were no MCC specific-deaths. No radiation-associated toxicities greater than grade 1 (CTCAE v5) were observed. CONCLUSIONS: Preliminary data suggest that SFRT could offer a potential alternative to cPORT to treat the primary site for localized H&N MCC, particularly in elderly or frail patients, with promising in-field local control and minimal toxicity. Further data with validation in larger cohorts is needed to confirm the sustained safety and efficacy of post operative SFRT.

Merkel cell carcinoma (MCC) is often treated with excision followed by conventional fractionated radiotherapy for localized disease. Single fraction radiation therapy (SFRT) has been shown to be effective for treating patients with metastatic MCC. This study presents early results for patients with MCC of the head and neck treated with 8 Gy SFRT to the post operative bed following surgery.

Purpose: Conventionally fractionated, post-operative radiotherapy (cPORT; 50 Gy in 25 fractions) is considered for patients with Merkel cell carcinoma (MCC) to improve locoregional control. However, cPORT is associated with acute toxicity, especially in the head and neck (H&N) region, and requires daily treatments over several weeks. We previously reported high rates of durable local control with minimal toxicity using 8 Gy single-fraction radiation therapy (SFRT) in the metastatic setting. We report early results on a cohort of patients with localized H&N MCC, who received post operative SFRT if a cPORT regimen was not feasible.

Methods: Twelve patients with localized MCC of the H&N (clinical/pathologic stages: I-II) and no prior RT to the region were identified from an IRB-approved prospective registry who underwent surgical resection followed by post operative SFRT. Time-to-event was calculated starting from the date of resection prior to SFRT. The cumulative incidence of in-field locoregional recurrences and out-of-field recurrences was estimated with death as a competing risk.

Twelve H&N MCC patients were identified with clinical/pathologic stages I-II H&N MCC. Median age at diagnosis was 81 years (58-96); 25% had immunosuppression. At a median follow-up of 19 months (range: 8-34), there were no in-field locoregional recurrences. A single out-of-field regional recurrence was observed, which was successfully salvaged. There were no MCC specific-deaths. No radiation-associated toxicities greater than grade 1 (CTCAE v5) were observed.

Conclusions: Preliminary data suggest that SFRT could offer a potential alternative to cPORT to treat the primary site for localized H&N MCC, particularly in elderly or frail patients, with promising in-field local control and minimal toxicity. Further data with validation in larger cohorts is needed to confirm the sustained safety and efficacy of post operative SFRT.

Introduction:

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy with an estimated 2,488 cases per year in the United States with an exponential increase in incidence. 1 MCC patients have a high (appx >30%) risk for locoregional recurrences and distant metastases after resection. [2] [3] [4] [5] [6] For patients who have localized disease with clinically negative draining lymph nodes (AJCC 8 th edition stage I-IIIA) initial treatment typically consists of wide excision of the primary tumor and sentinel lymph node biopsy (SLNB). 7 Surgery is then often followed by adjuvant conventionally fractionated post-operative radiation therapy (cPORT) (50 Gy in 25 fractions). [2] [3] [4] [5] [6] 8 For patients with MCC of the head and neck (H&N), cPORT provides a locoregional control benefit over observation alone, even amongst the most favorable low-risk cases. 3, 4 However, acute toxicity in the sensitive regions of the H&N can be substantial (e.g. skin erythema and desquamation, painful mucositis, xerostomia, altered taste, anorexia, weight loss). In addition, patients often face logistical challenges in attending a protracted course of radiotherapy (RT) for 5 weeks. Logistical considerations are of particular relevance with the increased risk of infection, complications and death that may occur over a protracted radiation course during the COVID-19 epidemic. [9] [10] [11] Previously, a study found durable local control for gross disease with 8 Gy SFRT among patients with metastatic MCC with minimal toxicity, 12 reflecting the radiosensitivity of MCC. Here, we present the preliminary results of utilizing SFRT treatment in a post operative curative setting for H&N patients.

Twelve patients were identified from an IRB-approved prospective registry of 1459 MCC patients based on the following inclusion criteria: (1) localized MCC of the H&N with clinically negative lymph nodes treated in the initial or recurrent setting (AJCC 8 th edition stage I-II), (2) surgical resection with or without SLNB, (3) no residual gross disease, (4) received post-operative 8 Gy SFRT, (5) >90 days of follow-up after SFRT, and (5) no prior RT to the H&N region. Patients provided consent for SFRT after an informed discussion. The patients who opted for this regimen were typically elderly with multiple comorbidities and/or with significant logistical difficulties, who were otherwise willing to forgo RT despite having an indication for cPORT. No tumor related selection criteria were applied. RT was delivered using electrons (6-8 MeV prescribed to 90% isodose line with a bolus) or photons to the entire surgical bed plus 3 to 5 cm margins as illustrated in Figure 1 . Patients had RT to the primary site alone in 11 of 12 patients, and one patient received elective nodal irradiation using an en-block technique (Patient #9). The patient who received elective nodal RT was immunosuppressed and had a large primary (stage IIB) in close proximity to the first echelon draining lymph nodes.

Negative margins were defined as no tumor at the inked edge. In-field recurrences were defined by an event that occurred within the 50% isodose line. Local recurrences were defined by an event that occurred within 2-cm of the primary tumor's surgical bed. Regional recurrences were defined by an event that occurred beyond 2-cm of the primary tumor's surgical bed and within the in-transit pathways and/or lymph nodal regions of the head and neck that drain the primary site. Common Terminology Criteria for Adverse Events (CTCAE) v5 was employed to grade acute toxicity < 90 days and late toxicity ≥ 90 days after SFRT. Time to event was calculated from the date of resection prior to SFRT.

The cumulative incidence of in-field and out-of-field locoregional recurrence was estimated with death considered a competing risk. Patients who did not experience an event during follow up were right-censored at the time of last follow up. Confidence intervals (CIs) for the rate of recurrence at different timepoints were calculated using conventional standard error formulas except when the estimate rate was 0%. In those cases, CIs were calculated using the Clopper-Pearson exact method. All statistical calculations were conducted with the statistical computing language R (version 3.6.1; R Foundation for Statistical Computing, Vienna, Austria).

Surveillance consisted of follow-up visits with physical exam including complete skin and lymph nodes every 3-6 months for 3 years, then every 6-12 months thereafter. 7 Patient cohort had a median age of 81 years (range 58-96) with 25% (n=3/12) being immunosuppressed, and 8% (n=1/12) positive microscopic margins (R1 resection).

Ten patients (#1-10) were treated in the de novo setting. Two patients (#11-12) were treated in the recurrent setting after they experienced a local recurrence at the primary site alone. They had prior wide local excision and SLNB or neck dissection followed by observation in the initial setting. No patients had a history of prior radiation therapy to the H&N region or received systemic therapy. The documented rationale for patients pursuing SFRT after an informed consent included: logistics for all patients (#1-12) with 16% living within 30 miles of our academic institution; potential for decreased acute side effects (patients #7-9); and, significant medical comorbidities (patient #9).

At a median follow-up time of 19 months (range: 8-34), there were no local recurrences. Eleven of twelve patients received radiation to the post operative bed alone, and one of these patients (#5) experienced a recurrence in the regional draining lymph nodes that were not treated with PORT. Patient #5 was also immunosuppressed, but had clinical stage I disease with negative surgical margins and a failed SLNB (Figure 1) . The patient was successfully salvaged with a neck dissection and post-operative conventional fractionated radiation therapy. Thus, there was one out-of-field recurrence and no in-field recurrences. The overall out-of-field locoregional recurrence rate at 1 year was 8.3% (95% CI: 1.3-54.4%) and 0% (95% CI: 0.0-26.5%) in-field (Figure 2) .

No patient developed distant metastatic disease. There was one patient death during the follow-up period due to significant cardiac co-morbidities, which were present prior to the MCC diagnosis. No patient experienced any radiation-related toxicity greater than grade 1 (CTCAE v5).

We present a preliminary experience of treating localized MCC in the H&N region with a single Other series have reported on the efficacy of RT for the treatment of MCC of the H&N region. 13, 14 Lok et al reported a 10% crude rate of locoregional failures (4% local and 6% regional) at a median follow-up of 51-months among 48 H&N MCC patients (clinical stages I-III and recurrent) treated with cPORT. 13 Bishop et al demonstrated 5-year local and locoregional control outcomes (96% and 92%, respectively) for 102 patients with MCC of the H&N region (clinical stages I-III and recurrent) treated with definitive radiation therapy (61%) or cPORT (39%) to the post operative bed and ipsilateral neck. 14 Our study albeit with a small sample size, had patients with the highest percentage of immunosuppression of 25% (n=3/12) compared to other H&N series reported rates of 0 to 10%. 3, 4, 13, 14 The only regional recurrence noted in this study was in an immunosuppressed patient, who developed an out-of-field recurrence in the regional lymph nodes. This patient also had a failed sentinel lymph node biopsy. However, there was no radiological evidence of regional nodal disease at the time of SFRT. This is consistent with the observation noted in the literature that immunosuppression is a negative prognostic factor associated with an increased probability of recurrence and death from MCC. 15, 16 There were no observed acute or late toxicities > grade 1 (CTCAE v5) within this cohort after SFRT. A previous study demonstrating the durability of SFRT for gross metastatic MCC in all anatomic sites similarly demonstrated no acute or late toxicities when treating tumors in the H&N region with a median follow-up of 9 months. 12 In regard to acute toxicity after cPORT, Lok et al reported 10% and 2% rate of RTOG grade 3 dermatitis and mucositis, respectively. 13 For late toxicity after cPORT, Bishop et al reported a 5% RTOG Grade ≥3 or greater event rate (4 ocular, 1 mandible). 14 In addition to the minimal toxicity, another attractive feature of this 8 Gy SFRT approach is that it would not significantly interfere with salvaging a potential in-field failure given the low dose of radiation therapy. This study is limited by its retrospective design, a small sample size and relatively short followup period of 19 months, although with MCC most locoregional recurrences occur within 1-year. Patient selection was not based on any specific tumor related factors. All patients expressed logistical considerations as the primary reason for preferring SFRT to cPORT. This data applies to treatment of the primary site in patients with localized H&N MCC. The safety and efficacy of SFRT for higher stage MCC patients with clinical or pathologic node positive disease (AJCC 8 th Ed. Stage III) remains unknown. It is possible that the biology of the primary site and regional nodes may differ. Moreover, there was only one patient in this study who received elective nodal RT. Caution should be applied with using this approach for elective nodal RT for an aggressive primary in the setting of a failed or no SLNB.

This study suggests that favorable in-field locoregional control may be achieved, including in a patient who had microscopically positive margins. In addition, consistent with MCC typically being very radiosensitive, SFRT using a lower biologically equivalent dose (BED α/ß = 10 ) of 14.4 Gy compared to 50 Gy with cPORT was able to achieve promising in-field local control. Despite the lower BED of SFRT, the similar local control may be explained by emerging data demonstrating that higher dose-per-fraction may potentiate a greater immune mediated effect compared to conventionally fractionated RT. [17] [18] [19] This is relevant given MCC is a highly immunogenic malignancy. 20 Ongoing work will refine the ideal patient population for post operative SFRT. To the best of our knowledge, this is the first study to demonstrate promising outcomes with a single fraction post operative radiation therapy in localized MCC of the head and neck region. This approach can also address a need to shorten the course of radiotherapy while maintaining excellent oncologic outcomes during the COVID-19 pandemic. [9] [10] [11] Conclusion:

This study provides preliminary data for prospective evaluation to determine the long-term durability and toxicity of post operative SFRT for MCC of the head and neck region. Further work is needed to identify which MCC patients may benefit from abbreviated versus protracted post-operative radiation therapy. Figure 1 : Patient #5 is an 81-year-old immunosuppressed man with a history of clinical stage I Merkel cell carcinoma of the right cheek status post wide local excision with negative margins and a technically failed sentinel lymph node biopsy, who elected to undergo adjuvant 8 Gy single-fraction radiation therapy (SFRT) to his primary surgical tumor bed site with electrons (A-B). Four months after SFRT, he exhibited out-of-field regional failure in the lymph nodes in the parotid (C), level 2A (D) and level 5 (E). He was successfully salvaged with surgical resection followed by adjuvant conventional fractionated proton radiation therapy. He never failed within his initial SFRT field. 

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Abbreviations: p, pathologic; c, clinical; y, years; EQ SQ, equivalent square of radiotherapy field (cm); WLE, wide local excision; SLNB, sentinel lymph node biopsy; N/A †, denotes not available due to radiation treatment at an outside institution; WLE ‡ , denotes surgical procedure performed in the recurrent setting after WLE and ipsilateral SLNB or neck dissection followed by observation in the initial setting; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia.