Improved local and regional control with ... - Wiley Online Library

ORIGINAL ARTICLE

Improved local and regional control with radiotherapy for Merkel cell carcinoma of the head and neck Tobin Strom, MD,1 Arash O. Naghavi, MD,1 Jane L. Messina, MD,2,3 Sungjune Kim, MD, PhD,1 Javier F. Torres–Roca, MD,1 Jeffery Russell, MD, PhD,4 Vernon K. Sondak, MD,2,5 Tapan A. Padhya, MD,4 Andy M. Trotti, MD,1 Jimmy J. Caudell, MD, PhD,1 Louis B. Harrison, MD1* 1

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, 2Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, 3Departments of Pathology & Cell Biology and Dermatology, University of South Florida Morsani College of Medicine, Tampa, Florida, 4Department of Head and Neck and Endocrine Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, 5Departments of Oncologic Sciences and Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida.

Accepted 16 May 2016 Published online 14 June 2016 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24527

ABSTRACT: Background. We hypothesized that radiotherapy (RT) would improve both local and regional control with Merkel cell carcinoma of the head and neck. Methods. A single-institution institutional review board-approved study was performed including 113 patients with nonmetastatic Merkel cell carcinoma of the head and neck. Postoperative RT was delivered to the primary tumor bed (71.7% cases) 6 draining lymphatics (33.3% RT cases). Results. Postoperative local RT was associated with improved local control (3-year actuarial local control 89.4% vs 68.1%; p 5 .005; Cox hazard ratio [HR] 0.18; 95% confidence interval [CI] 5 0.06–0.55; p 5 .002). Similarly, regional RT was associated with improved regional con-

trol (3-year actuarial regional control 95.0% vs 66.7%; p 5 .008; Cox HR 5 0.09; 95% CI 5 0.01–0.69; p 5 .02). Regional RT played an important role for both clinical node-negative patients (3-year regional control 100% vs 44.7%; p 5 .03) and clinical/pathological node-positive patients (3-year regional control 90.9% vs 55.6%; p 5 .047). Conclusion. Local RT was beneficial for all patients with Merkel cell carcinoma of the head and neck, whereas regional RT was beneficial for clinical node-negative and clinical/pathological node-positive C 2016 Wiley Periodicals, Inc. Head Neck 39: 48–55, 2017 patients. V

INTRODUCTION

shown to influence locoregional control rates when postoperative radiotherapy (RT) is included as a part of the treatment.11 As such, minimally invasive techniques for removal of Merkel cell carcinomas of the head and neck have been reported and are treatment options in the management of Merkel cell carcinoma.9,12–14 Postoperative local RT is often recommended for Merkel cell carcinomas, generally for high-risk cases with close or positive margins, lymphovascular invasion, larger primary tumors, tumor recurrence, or underlying immunosuppression.8–10,15 Given the complex and closely confined neurovascular anatomy of the head and neck, primary tumors located in the head and neck often include high-risk features. The question then arises regarding the safety of omitting postoperative RT for Merkel cell carcinoma of the head and neck. A recent retrospective series of 106 patients with Merkel cell carcinoma of the head and neck treated with definitive or postoperative RT reported a high rate of local control and minimal morbidity with postoperative RT; the group also recommended the use of adjuvant local RT for all primary head and neck cases.16 Merkel cell carcinoma has an extremely high rate of regional lymphatic involvement, ranging from 15% to 35% of cases, and even in low-risk cases, occult nodal positivity has been shown to occur in no less than 15% to

Merkel cell carcinomas are aggressive, small round blue cell tumors of the skin often found on the head and neck. Both UV exposure and infection with the Merkel polyomavirus have been implicated in the development of Merkel cell carcinoma.1,2 Head and neck tumor location accounts for one-third to one-half of reported Merkel cell cases.3–7 The current standard management of Merkel cell carcinoma is excision with wide margins followed by management of the regional lymphatics.8–10 However, because of frequent cosmetic and functional limitations of head and neck surgery, wide circumferential margins are often difficult to obtain. Furthermore, residual disease after excision of the primary tumor has not been clearly

*Corresponding author: L. B. Harrison, Department of Radiation Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. E-mail: [email protected] Contract grant sponsor: Campbell Family Foundation.. Conflict of interest/disclosures: J.L.M. is a consultant for Glaxo Smith Kline and Durect Corporation. V.K.S. is a consultant and on the advisory board for Amgen, BMS, Merck, Navidea, Novartis, and Provectus. J.T.R. is a shareholder and officer at Cvergenix. He has several awarded and pending patents for a radiosensitivity gene signatures not addressed in this article. Jimmy J. Caudell and Louis B. Harrison contributed equally to this work.

48

HEAD & NECK—DOI 10.1002/HED

JANUARY 2017

KEY WORDS: Merkel cell carcinoma, radiotherapy, local control, regional control

IMPROVED

20% of cases.3,4,16,17 As a result, sentinel node biopsy has been recommended for all patients with Merkel cell carcinoma.18,19 Radiotherapy of the draining lymphatics is frequently recommended for patients with pathologic nodal involvement and high-risk features, including multiple nodes or extracapsular extension, and for patients with involved regional lymph nodes who are not surgical candidates. However, it is less clear whether patients with pathologically negative lymph nodes after sentinel node biopsy can safely omit regional RT. One recent study reported a false-negative sentinel lymph node rate of 17.1% among 736 Merkel cell carcinoma cases, confirming a relatively high rate of occult nodal positivity even in pathologically assessed nodal basins.19 We evaluated whether postoperative local RT would improve local control for all cases and whether regional RT would improve regional control with clinical nodenegative, pathological node-negative, and/or node-positive Merkel cell carcinoma of the head and neck.

MATERIALS AND METHODS Patients and histopathologic analysis We performed a retrospective, single-institution review of all patients diagnosed with Merkel cell carcinoma of the head and neck from 1989 through 2012, after obtaining institutional review board approval. Patients who presented with unknown primary tumor status, distant metastasis or locally recurrent disease, who had received prior RT to the area, and those with unavailable radiation treatment details were excluded from this study (n 5 63; 35.8%). In total, 113 patients with nonmetastatic Merkel cell carcinoma of the head and neck were available for analysis. Initial metastatic staging was performed with positron emission tomography in 22 patients (19.5%), with CT in 11 patients (9.7%), with a chest X-ray in 28 patients (24.8%), and is unknown or was not performed in 52 patients (46.0%). Staging was performed using the American Joint Committee on Cancer (AJCC) staging system. Pathologic node-negative patients included those with AJCC nodal classification pN0 and overall stage IA/ IIA/IIC; patients with clinical node-negative disease included those with AJCC nodal classification cN0 and overall stage IB/IIB/IIC; patients with pathologic nodepositive disease included those with AJCC nodal classification pN1 and overall stage IIIA; and patients with clinical node-positive disease included those with AJCC nodal classification cN1 and overall stage IIIB. Demographic, histopathologic, treatment, and outcome data were abstracted from the medical charts.

Primary tumor treatment characteristics Most patients were treated with wide excision (n 5 109; 96.5%) with a minimum margin of 1 to 2 cm. Four patients (3.5%) were treated with excisional biopsy without wide excision. Patients with margins 2 (AJCC T2–4 stage II) Unknown Median depth of invasion, mm (range) Depth of invasion, mm 1 1.01–2.0 2.01–4.0 >4.0 Unknown Lymphovascular invasion No Yes Unknown Nodal stage Pathologic N0 (AJCC stage IA/IIA/IIC) Clinical N0 (AJCC stage IB/IIB/IIC) Pathologic N1 (AJCC N1a stage IIIA) Clinical N1 (AJCC N1b stage IIIB) Median lymph nodes involved, no. (range) Extranodal extension present No Yes Unknown Chemotherapy No Yes

All patients treated, no. (%)

No. of patients treated with local 6 regional RT (%)

No. of patients treated without RT (%)

77 (31–96)

77 (31–96)

79 (63–94)

85 (75.2) 28 (24.8)

59 (72.8) 22 (27.2)

26 (81.3) 6 (18.8)

95 (84.1) 18 (15.9)

68 (84) 13 (16)

27 (84.4) 5 (15.6)

79 (97.5) 2 (2.5)

30 (93.8) 2 (6.3)

p value

.105 .35 .96 .33

109 (96.5) 4 (3.5)

.54 97 (85.8) 14 (12.4) 2 (1.8) 1.0 (0.2–6.0)

68 (84) 11 (13.6) 2 (2.5) 1.2 (0.2–6.0)

29 (90.6) 3 (9.4) 0 (0) 0.8 (0.3–3.3)

52 (46) 11 (9.7) 50 (44.2) 3.5 (0.3–25.0)

40 (49.4) 8 (9.9) 33 (40.7) 3.4 (0.3–25.0)

12 (37.5) 3 (9.4) 17 (53.1) 3.8 (0.4–17.4)

12 (10.6) 13 (11.5) 22 (19.5) 34 (30.1) 32 (28.3)

9 (11.1) 10 (12.3) 16 (19.8) 24 (29.6) 22 (27.2)

3 (9.4) 3 (9.4) 6 (18.8) 10 (31.3) 10 (31.3)

6 (5.3) 15 (13.3) 92 (81.4)

3 (3.7) 13 (16) 65 (80.2)

3 (9.4) 2 (6.3) 27 (84.4)

51 (45.1)

42 (51.9)

9 (28.1)

37 (32.7)

22 (27.2)

15 (46.9)

18 (15.9)

13 (16)

.23 .47

.88 .98

.21

.10

5 (15.6)

7 (6.2)

4 (4.9)

3 (9.4)

1 (1–9)

1 (1–9)

2 (1–7)

.21 .75

15 (60) 7 (28) 3 (12)

11 (64.7) 4 (23.5) 2 (11.8)

4 (50) 3 (37.5) 1 (12.5) .96

100 (90.1) 11 (9.9)

72 (90) 8 (10)

28 (90.3) 3 (9.7)

Abbreviations: RT, radiotherapy; AJCC, American Joint Committee on Cancer.

immunosuppression (84.1%), and underwent marginnegative resection (85.8%). The median pathologic tumor size was 1.0 cm (range, 0.2–6.0 cm) with a median depth of invasion of 3.5 mm (range, 0.3–25.0 mm). A minority of patients had node-positive disease (22.1%) with a median of 1 lymph node involved (range, 1–9 lymph 50


JANUARY 2017

nodes). There were no differences in patient, tumor, or treatment characteristics between patients treated with and without postoperative RT (p > .05). Regarding tumor site-specific details, the cheek was the most commonly involved primary tumor site (34.5%), followed by the forehead (21.2%), scalp (12.4%), nose

IMPROVED

LOCAL AND REGIONAL CONTROL FOR

MERKEL

CELL CARCINOMA

TABLE 2. Variables associated with local control and regional control among all patients with Merkel cell carcinoma of the head and neck. Cox UV analysis Variables

Local control Lymphovascular invasion No Yes RT No RT Local RT Regional control Nodal stage Pathologic N0 Clinical N0 Pathologic N1 Clinical N1 RT No RT Local RT Local 1 regional RT

Cox MV analysis

Kaplan–Meier 3-y

HR (95% CI)

p value

HR (95% CI)

p value

86.3 69.2

2.84 (0.90–8.98)

.07

5.33 (1.54–18.45)

.01

68.1 89.4

0.26 (0.09–0.72)

.01

0.18 (0.06–0.55)

.002

83.5 56.7 87.4 50.0

2.77 (1.13–6.79) 0.78 (0.17–3.68) 3.21 (0.85–12.11)

.06 .03 .76 .09

3.63 (1.41–9.35) 2.04 (0.40–10.45) 6.90 (1.73–27.50)

.02 .008 .39 .006 .04

63.2 68.4 95.0

0.79 (0.35–1.81) 0.09 (0.01–0.73)

.08 .58 .02

1.25 (0.51–3.04) 0.09 (0.01–0.69)

.62 .02

Abbreviations: UV, univariate; MV, multivariate; HR, hazard ratio; CI, confidence interval; RT, radiotherapy; N0, node-negative; N1, node-positive. Variables with nonsignificant values (p > .05) are not shown.

(9.7%), and neck (7.1%). The ear was involved in 7 cases (5.3%), 6 of which underwent auriculectomy and the remaining case was treated with an ear lobectomy. The upper lip, lower lip, and eyelid were involved less frequently in 5 cases (4.4%), 3 cases (2.7%) and 2 cases (1.8%), respectively. The largest median primary tumor sizes were located on the neck (2.0 cm; range, 1.0–3.0 cm), ear (1.7 cm; range, 0.3–3.0 cm), scalp (1.5 cm; range, 0.9–3.6 cm), and cheek (1.0 cm; range, 0.5–6.0 cm). Primary tumors on the forehead, eyelid, cheek, nose, and lips all had median tumor sizes 1.0 cm. Primary tumors located on the neck had the greatest median depth of invasion (7.8 mm; range, 2.8–8.2 mm), followed by the ear (4.8 mm; range, 1.0–20.0 mm), scalp (4.5 mm; range, 0.8–14.0 mm), cheek (4.0 mm; range, 0.5–25.0 mm), and forehead (3.8 mm; range, 0.6–6.0 mm). Merkel cell carcinomas located on the nose and lips all had a median depth of invasion 10% rate of lymph node involvement included the forehead (29.2%), cheek (25.6%), neck (25.0%), scalp (21.4%), upper lip (20.0%), and ear (14.3%). Tumors on the nose, eyelids, and lower lip (9.1%, 0%, 0%, respectively) had low rates of lymph node involvement. Tumors located on the scalp, neck, forehead, and cheek had more tissue excised than other areas of the head and neck with a median of 35.8 cm2, 23.4 cm2, 13.7 cm2, and 10.1 cm2 tissue excised, respectively. Despite having a larger median surface area of tissue removed, primary tumors at these sites also had high rates of positive margins at 28.6%, 25.0%, 8.7%, and 12.8%, respectively. Primary tumors on the nose had a median of 3.4 cm2 removed with a rate of 9.1% positive margins, and primary tumor sites of the eyelids, ears, and lips all had 5.0 cm2 removed with no positive margins. On logistic regression analysis, when primary tumor site, size, depth of invasion, lymphovascular invasion status, surface area of tissue excised, and lymph node status were included,

only lymph node status was significantly associated with margin status. Compared with patients with pathological node-negative disease, patients with clinical nodenegative disease (odds ratio [OR] 5 11.83; 95% confidence interval [CI] 5 1.38–101.03; p 5 .02), pathological node-positive disease (OR 5 9.80; 95% CI 5 0.95– 101.32; p 5 .055), and clinical node-positive disease (OR 5 49.00; 95% CI 5 3.84–624.88; p 5 .003) were all more likely to experience a positive margin after wide excision.

Local control The median follow-up of surviving patients was 27 months (range, 6–181 months). Local RT was associated with improved local control on Kaplan–Meier analysis (Figure 1A; 3-year local control 89.4% vs 68.1%; p 5 .005) and Cox multivariate analysis (Table 2; hazard ratio [HR] 5 0.18; 95% CI 5 0.06–0.55; p 5 .002). Local control was also significantly influenced by the presence of lymphovascular invasion on tumor pathology (HR 5 5.33; 95% CI 5 1.54–18.45; p 5 .008). Of 15 local failures, the median time to local failure was 6.5 months with a range of 2 to 20 months and 14 of 15 local failures (93.3%) occurred within 15 months. On subset analysis, among 14 patients with positive margins, the 3-year actuarial local control rate was 100% with (n 5 11) and 33.3% without (n 5 3) RT (p 5 .003). Among 92 patients with negative margins, the 3-year local control rate was 87.4% with (n 5 66) and 73.0% without (n 5 26) RT (p 5 .07). When assessed by primary tumor size, patients with tumors 2 cm had a 3year local control rate of 90.4% with RT (n 5 37) compared with 80.2% without (n 5 12; p 5 .43), whereas patients with tumors >2 cm had a 3-year local control rate of 75.0% with RT (n 5 8) and 50.0% without (n 5 2; p 5 .05). When assessed by lymphovascular invasion HEAD & NECK—DOI 10.1002/HED

JANUARY 2017

51

STROM ET AL.

FIGURE 1. Kaplan–Meier plots for local control among (A) all patients treated with and without postoperative local radiotherapy (RT). Regional control is demonstrated for (B) all patients and (C) clinical node-negative (cN0) patients treated with and without regional RT. Locoregional control is shown (D) for all patients treated with local and regional RT, local RT alone, or no RT with Merkel cell carcinoma of the head and neck.

status, patients without lymphovascular invasion had a 3year local control rate of 92.4% with RT (n 5 65) compared with 70.8% without (n 5 27; p 5 .003), whereas patients with lymphovascular invasion present had a 3year local control rate of 75.0% with RT (n 5 12) compared with 0% without (n 5 2; p 5 .12). Five cases (33.3%) failed simultaneously in the regional lymph nodes, 1 case (6.7%) failed simultaneously in both the regional and distant lymph nodes, and 2 cases (13.3%) failed simultaneously at a distant site. Of the 8 patients who failed only in the tumor bed, 2 (25%) underwent salvage excision only, 5 (63%) underwent salvage excision and RT, and 1 (13%) had an unknown salvage treatment.

Regional control Patients treated with regional RT had improved regional control compared with patients treated without regional RT on Kaplan–Meier analysis (3-year regional control rates 95.0% vs 66.7%, respectively; p 5 .008). On Cox multivariate analysis, regional RT was associated with improved regional control (Table 2; HR 5 0.09; 95% CI 5 0.01–0.69; p 5 .02). Nodal classification also significantly influenced regional control rates on Cox multivariate analysis (Table 2). Both clinical nodenegative patients (HR 5 3.63; 95% CI 5 1.41–9.35; p 5 .008) and clinical node-positive patients (HR 5 6.90; 52


JANUARY 2017

95% CI 5 1.73–27.50; p 5 .006) experienced higher rates of regional failure compared with pathological nodenegative patients. Regional RT did not significantly improve regional control after lymph node dissection for node-negative patients with a 3-year regional control rate of 100% with regional RT (n 5 5) versus 81.8% without (n 5 42; p 5 .30), although the sample size was small and underpowered to detect this difference. Regional RT played more of an important role among clinical node-negative patients (Figure 1B), with 3-year regional control rates of 100% with prophylactic regional RT (n 5 6) versus 44.7% without (n 5 25; p 5 .03). Regional radiation also played an important role among patients with clinical or pathological node-positive disease with 3-year regional control rates of 90.9% with regional RT (n 5 14) versus 55.6% without (n 5 10; p 5 .047). When broken down further, 5 patients had a positive sentinel node without subsequent lymph node dissection; 4 were treated with definitive RT to the regional nodal basin and did not experience regional failure, whereas the remaining patient treated without RT failed in the regional lymph nodes (3year regional control 100% vs 0%, respectively; p 5 .025). Twenty-five patients failed in the regional lymph nodes with a median time to regional failure of 7.4 months (range, 2–43 months). Twenty-one of 25 (84%) regional failures occurred within 12 months and 24 of 25 (96%)

IMPROVED


MERKEL

CELL CARCINOMA

occurred within 24 months. Seventeen of 25 (68%) regional failures were isolated failures, 4 of 25 (16%) failed both locally and regionally, 3 of 25 (12%) failed regionally and distant, and 1 (4%) failed in all 3 locations. Thirty-three of 35 (94%) locoregional recurrences were first identified clinically by the patient or physician and all were subsequently pathologically proven.

Distant metastasis-free survival The 3-year actuarial distant metastasis-free survival rate was 66.8% among all patients. Patients treated with local 6 regional RT experienced improved distant metastasisfree survival than patients treated without RT (3-year distant metastasis-free survival rates 70.6% vs 57.1%, respectively; p 5 .03). A more refined radiation variable was then created that addressed radiation coverage by disease extent. Patients treated with appropriate radiation coverage for their extent of disease, including patients treated with local RT for pathological node-negative disease and local 1 regional RT for clinical node-negative or clinical and pathological node-positive disease, were combined into a single radiation variable. With this stricter definition of RT, the receipt of RT was associated with a more substantial distant metastasis-free survival benefit on Kaplan–Meier analysis (3-year distant metastasis free survival 80.4% vs 50.4%, respectively; p 5 .002). Radiotherapy with more appropriate coverage for extent of disease was also associated with improved distant metastasis-free survival on Cox multivariate analysis (HR 5 0.42; 95% CI 5 0.20–0.89; p 5 .02). Pathologic and clinical node-positive nodal status (HR 5 3.46; 95% CI 5 1.34–8.93; p 5 .01 and HR 5 3.32; 95% CI 5 1.17– 9.40; p 5 .02, respectively) and the presence of lymphovascular invasion (HR 5 3.27; 95% CI 5 1.44–7.42; p 5 .005) were also associated with distant metastasis-free survival. In total, 12 patients failed distantly with a median time to distant failure of 10.2 months (range, 3–33 months). The most common sites of distant failure included the bones (n 5 3; 25%), liver (n 5 3; 25%), brain (n 5 2; 16.7%), and lungs (n 5 2; 16.7%). Five patients experienced simultaneous locoregional and distant recurrences and all 5 were initially detected clinically and confirmed pathologically. Of the remaining 7 patients with distantonly disease recurrence, 3 patients (43%) presented with clinical symptoms related to their metastatic disease and the remaining 4 patients (57%) had distant disease first identified on follow-up imaging. Five of 7 patients (71%) with distant-only disease had their disease pathologically confirmed, whereas 2 patients (29%), including 1 patient with diffuse liver metastases and 1 patient with multiple brain metastases, did not undergo pathologic confirmation because of a high clinical likelihood of metastatic disease from Merkel cell carcinoma.

Overall survival The receipt of local 6 regional RT among all patients was associated with improved overall survival on both Kaplan–Meier analysis (Figure 2A; 3-year overall survival 77.4% vs 59.6%, respectively; p 5 .004). With a stricter definition of RT (defined above), the receipt of RT was

FIGURE 2. Kaplan–Meier plot for overall survival in patients with Merkel cell carcinoma of the head and neck treated with (A) postoperative local 6 regional radiotherapy (RT) and (B) with a stricter definition of RT, including only patients treated with local RT for pathologic node-negative disease and local 1 regional RT for clinical node-negative or clinical and pathologic node-positive disease.

associated with a more substantial survival benefit on Kaplan–Meier analysis (Figure 2B; 3-year overall survival 85.0% vs 57.0%, respectively; p 5 .001). Radiotherapy with more appropriate fields was associated with improved survival on Cox multivariate analysis (HR 5 0.35; 95% CI 5 0.17–0.73; p 5 .005). Patient age (HR 5 1.04; 95% CI 5 1.004–1.07; p 5 .03), and the presence of lymphovascular invasion (HR 5 3.03; 95% CI 5 1.27–7.20; p 5 .01) were also associated with overall survival.

DISCUSSION We demonstrate improved local control with postoperative RT for Merkel cell carcinoma of the head and neck. Specifically, local RT was associated with a local control benefit on both univariate and multivariate analysis and was beneficial for patients with both negative and positive margins. Similarly, regional radiation, either as prophylactic regional radiation or postoperative regional radiation, was associated with a significant regional control benefit among all patients. On subgroup analysis, both patients treated with prophylactic regional radiation for clinical node-negative disease and those treated with postoperative radiation for lymph node-positive disease experienced improved regional control. HEAD & NECK—DOI 10.1002/HED

JANUARY 2017

53

STROM ET AL.

As with other cutaneous cancers of the head and neck, wide excision of Merkel primaries in many locations of the face is limited by functional and cosmetic constraints. This was seen in the current series in which primary tumors of the nose, ears, eyelids, and upper and lower lips had a relatively small median area of skin removed of 5 cm2. Yet despite the smaller area of skin removed, this was not associated with a higher rate of positive margins. In addition, excision of Merkel cell carcinoma primaries from the lips, ears, and eyelids resulted in a 0% rate of positive margins, whereas a single nasal primary (9.1%) was excised with positive margins. With respect to outcomes, margin status was not significantly associated with local control on multivariate analysis. This suggests that the benefit of adjuvant RT might overcome the recurrence risk of positive margins, and that >2 cm margins might not add benefit when RT is delivered. A previous report by Finnigan et al11 pooled data from 3 prospective trials and included 88 patients with stage I/II Merkel cell carcinoma, 9 with microscopic positive margins, and 26 with macroscopic residual disease, all who were treated with RT. They reported that neither positive margins nor gross macroscopic disease were associated with locoregional failure, consistent with the present findings. A separate study addressed local control outcomes for early stage Merkel cell carcinomas treated with minimal surgery via Mohs micrographic surgery (MMS) with or without RT (n 5 20 and n 5 25, respectively). The group reported 100% local control rate with adjuvant RT compared with 84% without radiation. These results suggest that minimal surgery followed by local RT can result in a high rate of local control. The most recent version of the Appropriate Use Criteria for Mohs Micrographic Surgery14 also supports the use of MMS for all cases of Merkel cell carcinoma of the head and neck, and, as such, we would recommend that patients treated with MMS also receive postoperative local RT to improve their chances of local control in the setting of minimal surgery. The present study does not address MMS as primary treatment for Merkel cell carcinoma, although we did find that more limited excisions were not detrimental with respect to margin status and did not impact local control when RT was delivered. The present study included a large number of patents with clinical node-negative disease (n 5 37; 32.7%), which also implies that there was a high rate of occult nodal positivity. With Merkel cell carcinoma, it is extremely difficult to predict who might have occult nodal metastases based on clinical and pathologic tumor characteristics. Schwartz et al18 assessed the occult nodal metastasis rate among 93 sentinel node biopsies as predicted by primary tumor risk factors, including clinical and histologic tumor size, depth of invasion, mitotic rate, and histologic growth pattern, and reported that even with the lowest risk of primary tumors the occult nodal metastasis rate was 15% to 20% at a minimum. A separate, recent combined analysis including 736 cases of Merkel cell carcinoma treated with sentinel lymph node biopsy by Gunaratne et al19 found 218 cases of clinically occult involved lymph nodes (29.6%). In addition, the group reported that 45 of 518 cases with negative sentinel lymph nodes subsequently developed regional metastasis 54


JANUARY 2017

resulting in a false-negative rate of 17.1%. This high rate of clinically occult lymph nodes is consistent with the present study in which 18 of 69 (26.1%) of sentinel lymph nodes were positive on histopathology. In addition, the present study shows an extremely high rate of regional failures (67.3%) among clinical node-negative patients who were treated without RT, confirming the extremely high risk with observation of the regional lymphatics without treatment. A large analysis of patients with Merkel cell carcinoma previously confirmed that clinical node-negative patients have significantly worse survival than pathological node-negative patients (HR 5 1.80; 95% CI 5 1.4–2.4; p < .0001).20 As such, we would recommend prophylactic RT for all patients with a clinical node-negative neck not evaluated by sentinel node biopsy. A recent report by Bishop et al16 also advocates for routine treatment of clinical node-negative patients with regional radiation. The study included 106 patients with Merkel cell carcinoma of the head and neck, all treated with RT, including regional RT for clinical node-negative patients, and reported a high rate of locoregional control among all patients at 92%. This locoregional control would likely have not been possible without prophylactic treatment of clinical node-negative necks. For patients who have negative sentinel node biopsies, Gunaratne et al19 reported that the addition of regional RT did not affect regional recurrence rates (p 5 .31). We report similar findings and RT did not add a regional control benefit after a negative sentinel node biopsy (p 5 .36), although the number of patients treated with RT was extremely limited (n 5 6). The effect that RT has on patient survival with Merkel cell carcinoma remains controversial. A survival benefit was seen with postoperative RT in a Surveillance, Epidemiology, and End Results database analysis by Mojica et al,17 whereas a subsequent propensity-score based matched-pair analysis of the same patient population showed that patients treated with RT had improved overall survival but not disease-specific survival.21 The present study supports a significant improvement in overall survival with adjuvant RT as seen in the Surveillance, Epidemiology, and End Results database. As such, the overall survival benefit could be a result of patient and clinicopathologic factors not accounted for in the multivariate model, whereas it might also result from the relatively high number of clinical node-negative patients treated without prophylactic regional RT (n 5 25). The survival benefit with radiation might also be a result of improved staging with positron emission tomography, which helps exclude patients with low-volume metastatic disease and better identifies patients who might benefit from locoregional treatment.22,23 To further scrutinize the potential survival benefit of RT, we considered a stricter definition of RT that included only patients who received local RT for pathological node-negative disease and both local 1 regional RT for node-positive disease. With this more conservative definition of RT, we found more of a survival benefit with the delivery of RT (Figure 2B; 3year overall survival 85.2% vs 61.4%, respectively; p 5 .001). These results are intriguing and add support to the survival benefit with RT, but they are not confirmatory.

IMPROVED

This study was limited by its retrospective nature and by the long time frame over which it took place. There were no significant differences in patient characteristics between patients treated with and without RT, although it is possible that there were variables not accounted for that influenced the outcomes. In conclusion, we recommend that patients with Merkel cell carcinoma of the head and neck and pathological node-negative disease be treated with local RT alone, whereas all other patients should be treated with postoperative local and regional RT.

REFERENCES 1. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008;319:1096–1100. 2. Rollison DE, Giuliano AR, Becker JC. New virus associated with Merkel cell carcinoma development. J Natl Compr Canc Netw 2010;8:874–880. 3. Fields RC, Busam KJ, Chou JF, et al. Five hundred patients with Merkel cell carcinoma evaluated at a single institution. Ann Surg 2011;254:465– 473; discussion 473–475. 4. Hui AC, Stillie AL, Seel M, Ainslie J. Merkel cell carcinoma: 27-year experience at the Peter MacCallum Cancer Centre. Int J Radiat Oncol Biol Phys 2011;80:1430–1435. 5. Ghadjar P, Kaanders JH, Poortmans P, et al. The essential role of radiotherapy in the treatment of Merkel cell carcinoma: a study from the Rare Cancer Network. Int J Radiat Oncol Biol Phys 2011;81:e583–e591. 6. Smith FO, Yue B, Marzban SS, et al. Both tumor depth and diameter are predictive of sentinel lymph node status and survival in Merkel cell carcinoma. Cancer 2015;121:3252–3260. 7. Tarantola TI, Vallow LA, Halyard MY, et al. Prognostic factors in Merkel cell carcinoma: analysis of 240 cases. J Am Acad Dermatol 2013;68:425– 432. 8. Tai P. A practical update of surgical management of Merkel cell carcinoma of the skin. ISRN Surg 2013;2013:850797. 9. National Comprehensive Cancer Network: NCCN clinical practice guidelines in oncology: Merkel Cell Carcinoma (version 1.2016). Available at: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2, 2015. 10. Porceddu SV, Veness MJ, Guminski A. Nonmelanoma cutaneous head and neck cancer and Merkel cell carcinoma: current concepts, advances, and controversies. J Clin Oncol 2015;33:3338–3345.


MERKEL

CELL CARCINOMA

11. Finnigan R, Hruby G, Wratten C, et al. The impact of preradiation residual disease volume on time to locoregional failure in cutaneous Merkel cell carcinoma – a TROG substudy. Int J Radiat Oncol Biol Phys 2013;86:91– 95. 12. Boyer JD, Zitelli JA, Brodland DG, D’Angelo G. Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad Dermatol 2002;47: 885–892. 13. O’Connor WJ, Roenigk RK, Brodland DG. Merkel cell carcinoma. Comparison of Mohs micrographic surgery and wide excision in eighty-six patients. Dermatol Surg 1997;23:929–933. 14. Ad Hoc Task F, Connolly SM, Baker DR, et al. AAD/ACMS/ASDSA/ ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery. J Am Acad Dermatol 2012; 67:531–550. 15. Lok B, Khan S, Mutter R, et al. Selective radiotherapy for the treatment of head and neck Merkel cell carcinoma. Cancer 2012;118:3937–3944. 16. Bishop AJ, Garden AS, Gunn GB, et al. Merkel cell carcinoma of the head and neck: favorable outcomes with radiotherapy. Head Neck 2016;38 Suppl 1:E452–E458. 17. Mojica P, Smith D, Ellenhorn JD. Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin. J Clin Oncol 2007;25:1043–1047. 18. Schwartz JL, Griffith KA, Lowe L, et al. Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol 2011;29:1036– 1041. 19. Gunaratne DA, Howle JR, Veness MJ. Sentinel lymph node biopsy in Merkel cell carcinoma: a 15-year institutional experience and statistical analysis of 721 reported cases. Br J Dermatol 2016;174:273–281. 20. Lemos BD, Storer BE, Iyer JG, et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. J Am Acad Dermatol 2010; 63:751–761. 21. Kim JA, Choi AH. Effect of radiation therapy on survival in patients with resected Merkel cell carcinoma: a propensity score surveillance, epidemiology, and end results database analysis. JAMA Dermatol 2013;149:831–838. 22. Siva S, Byrne K, Seel M, et al. 18F-FDG PET provides high-impact and powerful prognostic stratification in the staging of Merkel cell carcinoma: a 15-year institutional experience. J Nucl Med 2013;54:1223–1229. 23. Hawryluk EB, O’Regan KN, Sheehy N, et al. Positron emission tomography/computed tomography imaging in Merkel cell carcinoma: a study of 270 scans in 97 patients at the Dana–Farber/Brigham and Women’s Cancer Center. J Am Acad Dermatol 2013;68:592–599.


JANUARY 2017

55