Definitive radiotherapy for Merkel cell carcinoma confers clinically meaningful in-field locoregional control: A review and analysis of the literature

REVIEW

Definitive radiotherapy for Merkel cell carcinoma confers clinically meaningful in-field locoregional control: A review and analysis of the literature Dakshika A. Gunaratne, BMed, MS, MPH,a Julie R. Howle, MBBS, MS, FRACS,b,c,d and Michael J. Veness, MBBS, MD(UNSW), MD(USyd), MMed, FRANZCRc,d,e Sydney, Australia Background: Merkel cell carcinoma (MCC) is an uncommon radiosensitive, neuroendocrine malignancy. Treatment often involves surgery; however, older, sicker patients may not be candidates for an operation. Institutions have published data favoring the role of definitive radiotherapy for macroscopic locoregional disease. Objective: Our objective was to report the outcome of patients treated with definitive radiotherapy. Methods: We performed a systematic review of Medline, PubMed, and Embase databases for reported cases or series of definitive radiotherapy for macroscopic locoregional MCC. Results: The mean radiation dose did not significantly differ between primary and regional sites (48.7 6 13.2 vs 49.4 6 10.1 Gy, P = .74). The rate of recurrence was calculated on the basis of the site of disease (11.7%) and per patient (14.3%). Recurrence was significantly more likely to occur at regional than at primary irradiated sites (16.3% vs 7.6%, P = .02). There was no association between radiotherapy dose and incidence of recurrence or nonrecurrence; primary (42.7 6 23 vs 49.3 6 11.8 Gy, P = .197) and regional (48.6 6 10 vs 49.5 6 10.3 Gy, P = .77). Limitations: A limitation of this report is that most publications were retrospective; heterogeneity was present in the size of MCC and in radiotherapy details. Conclusions: Definitive radiotherapy for locoregional macroscopic MCC was found to confer clinically meaningful local and regional in-field control. ( J Am Acad Dermatol http://dx.doi.org/10.1016/ j.jaad.2017.02.015.) Key words: definitive treatment; Merkel cell carcinoma; neuroendocrine; radiotherapy; recurrence.

M

erkel cell carcinoma (MCC) is an aggressive, cutaneous neuroendocrine malignancy often reported in elderly white men, with an annual incidence of 1 to 2 per 100,000 population in Australia; the rate is lower in

From the Department of Otolaryngology, Head and Neck Surgery, Westmead Hospital, Sydney, Australiaa; Department of Surgery, Westmead Hospital, Sydney, Australiab; Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, Australiac; University of Sydney, Australiad; and the Department of Radiation Oncology, Westmead Hospital, Sydney, Australia.e Funding sources: None. Conflicts of interest: None declared. Accepted for publication February 7, 2017. Reprints not available from the authors.

Abbreviations used: Gy: MCC: NCCN:

Gray Merkel cell carcinoma National Comprehensive Cancer Network

Correspondence to: Professor Michael J. Veness, MBBS, MD(UNSW), MD(USyd), MMed, FRANZCR, Department of Radiation Oncology, Crown Princess Mary Cancer Care Centre, Westmead Hospital, PO Box 533, Westmead, NSW 2145, Australia. E-mail: michael. [email protected]. Published online May 8, 2017. 0190-9622/$36.00 Ó 2017 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2017.02.015

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other countries but increasing in incidence globally.1 is universally accepted, we chose to include all 3 so A diagnosis of MCC can portend a poor prognosis as to identify as many eligible studies as possible. characterized by locoregional and distant relapse.2-4 The last search was performed in June 2016 without However, the unique radiosensitivity of MCC has led language or time limitations. The reference lists of to an established role of radiotherapy for adjuvant the relevant studies were also reviewed to identify treatment of locoregional disease and palliation from additional citations. Care was taken to avoid duplidistant metastases.5,6 In the former setting, adjuvant cation of patient data from repeated publications of wide-field radiotherapy has series from a single institubeen demonstrated, in some tion or database, with only CAPSULE SUMMARY studies, to improve locorethe most recent reports gional control rates by up to considered. Radiotherapy has an established role in 30% and improve survival by Definitive radiotherapy the treatment of Merkel cell carcinoma, 20% to 30%, compared with was defined as radiotherapy especially after surgery, in decreasing surgery alone.2-4,7,8 delivered to macroscopic locoregional recurrence by up to 30% In a subset of patients with disease: treatment of a non(absolute terms). Definitive radiotherapy MCC, surgery with or without excised primary lesion, adjumay be recommended for inoperable adjuvant radiotherapy may vant treatment to a grossly patients, with many cured. not be the optimal approach. residual primary lesion, or MCC demonstrates a prediThis analysis found definitive treatment of clinically lection for the head and radiotherapy to confer clinically apparent regional lymphadeneck,1 and, in this subsite, meaningful locoregional in-field control nopathy. Treatment of initial difficulty can arise in obtainrates of at 75% to 85%. or recurrent MCC at the priing adequate surgical margins mary tumor site, in-transit In patients considered medically or without functional and cosbetween the primary site technically inoperable, definitive metic sequelae.9 In addition, and regional lymphatic baradiotherapy provides a means of MCC is prevalent in the sin, and/or in the regional potential cure, with a reported 5-year elderly, in whom risks associlymph nodes were included. overall survival rate of 40% to 60%. ated with general anesthesia, Inclusion criteria were as folsurgery, and hospitalization lows: biopsy-confirmed are increased. It is in this macroscopic (or gross residsubset, often considered nonoperable candidates, ual) primary, in-transit, or regional (nodal) MCC; that definitive radiotherapy may have a curative curative intent of treatment of cancer with definitive role, with 5-year overall survival in up to 40% to radiotherapy; description of the radiotherapy field 60% of patients with macroscopic primary and/or (primary and/or regional); and follow-up informanodal metastases.2 tion pertaining specifically to the absence or presOur institution has published extensively on ence of in-field recurrence. definitive radiotherapy for the treatment of macroWe attempted to include only those studies in scopic MCC,2,10,11 with our most recent update which the aim of treatment was to offer patients the reporting an in-field control rate of 85% and a 5chance of a cure as opposed to merely palliating year overall survival of 40%.11 Noting that previous symptoms. We believe that it is unlikely that authors publications were limited to small institutional series, offered moderate- to high-dose radiotherapy in the we sought to review the world literature to confirm palliative setting or that they redefined the intent of the efficacy of this approach, especially considering treatment in the event of relapse. As such, we are the heterogeneity between studies in many aspects confident that our search has included most eligible of radiotherapy, such as techniques used and doses studies. delivered. Series with presentation of individual patient data or grouped results were accepted, with the proviso that disease burden met the aforementioned incluMETHODS sion criteria and the radiation field and outcome of A literature search was conducted of the Medline in-field cancer control was described or deducible. (1946 to present), Embase (1974 to present), and Edge-of-field recurrence was considered as in-field PubMed databases, using the algorithm ‘‘Merkel recurrence for the purpose of this review. Full-length AND (radiotherapy OR radiation) AND (definitive manuscripts of publications for inclusion were obOR monotherapy OR radical).’’ The terms ‘‘definitained, and the following features noted, if provided: tive,’’ ‘‘monotherapy,’’ and ‘‘radical’’ have been used age, gender, site and size of primary tumor, margins interchangeably by authors, and, because no 1 term d

d

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Fig 1. Search strategy flowchart. MCC, Merkel cell carcinoma; RT, radiotherapy.

of primary tumor at time of treatment (positive or negative), disease extent at diagnosis (primary or regional), radiotherapy setting (initial or recurrence), radiotherapy treatment site (primary, in-transit, regional), in-field recurrence, time to in-field recurrence, other out-of-field recurrences, duration of follow-up, and status at last follow-up. Data were reviewed in aggregate to create a cumulative review. Statistical analysis Descriptive statistics were used to report the patient, tumor, and radiotherapy characteristics of the cumulative cohort and are described as means with standard deviations. Statistical associations between radiotherapy dose and recurrence were examined with odds ratios and two-tailed Fisher’s exact tests conducted to determine any significance. Unpaired Student t tests were conducted to assess the significance of difference between the mean radiotherapy dose delivered between sites and

follow-up periods between patients with and without in-field recurrence. A value of P \ .05 was considered statistically significant. Missing or unknown data were excluded from analysis. IBM SPSS Statistics for Windows, Version 20.0 (Armonk, NY), was used for analysis.

RESULTS A thorough literature search retrieved 94 publications, of which 57 were excluded as duplicate results. Title and abstract review led to exclusion of a further 26 articles. The remaining 11 publications were retrieved and appraised in full, along with an additional 27 articles identified through bibliography review. After full text review, 23 studies encompassing 264 patients fulfilled our inclusion criteria (Supplemental Table I; available at http://www. jaad.org).2,11-32 The search strategy is outlined in Figure 1. Of note, previous publications from the Clinique de Dermatologie,22 Princess Alexandra

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Hospital, Brisbane,33 and our own institution2,10 were carefully examined, and duplicate patients were excluded from the cumulative review. Patient, disease, treatment, and outcome findings are summarized in Table I. In total, 332 sites of MCC were irradiated: primary (51.5%), regional (48.2%), and in-transit (0.3%). Recurrence occurred in 39 sites: primary (n = 13) and regional (n = 26), for a cumulative postradiotherapy in-field recurrence rate of 11.7%. Recurrence was significantly more likely to occur at regional irradiated sites (16.3%) than at primary sites (7.6%) (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.66-4.77; P = .02). Calculation of in-field recurrence was limited by a lack of documentation regarding whether or not primary and regional sites were irradiated concurrently within 1 field, or separately as 2, particularly for nonehead and neck subsites. Mean radiotherapy dose was documented for 100 patients and 148 sites of disease. From this subset, which included 7 primary and 14 regional postradiotherapy recurrences, there was no significant difference between radiotherapy dose delivered to primary (n = 75) and regional (n = 73) subsites (48.7 6 13.2 vs 49.4 6 10.1 Gy, P = .74). In addition, there was no association between radiotherapy dose and incidence of recurrence or nonrecurrence: primary (42.6 6 23 vs 49.3 6 11.8 Gy, P = .2) and regional (48.6 6 10 vs 49.5 6 10.3 Gy, P = .77). Mean time to postradiotherapy recurrence was reported for 24 sites at 6.3 6 6.8 months.2,11,12,14,15,17,21,34 There was no significant difference in the duration between irradiation and recurrence in primary and regional sites (5 6 1.4 vs 6.9 6 8.1 months, P = .55). Duration of follow-up was recorded for 103 patients, and the difference in follow-up for patients with (n = 22) and without (n = 81) recurrences did differ significantly (14.3 6 11.2 vs 26 6 23.3 months, P = .03). Twenty-one studies comprising 228 patients provided information regarding other relapse: regional (out of field) (n = 21) and distant (n = 59).2,11-21,23-26,29-32,34 Mean time to distant relapse was 11.3 6 14.6 months. Distant relapse was significantly more likely to occur after recurrence at primary (OR, 6.8; 95% CI, 1.24-36.94; P = .03) and regional (OR, 3.9; 95% CI, 1.36-11.41; P = .01) sites. Locoregional recurrence was significantly associated with MCC diseaseespecific death (OR, 9; 95% CI, 1.12-72.52; P = .04; n = 131). Status at final followup was no evidence of disease (34.9%), alive with disease (5.8%), died of disease (32%), and died of other causes (27.3%). Treatment-related toxicity was inconsistently and rarely documented.

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DISCUSSION Consensus management of locoregional MCC is yet to be reached because of the rarity of the diagnosis and lack of randomized data. Current recommendations from the National Comprehensive Cancer Network (NCCN) advocate first-line wide local excision of the primary tumor with 1- to 2-cm margins to investing fascia of muscle, or pericranium (when clinically feasible).35 Radiation monotherapy is suggested for select cases if complete surgical excision is unattainable, if significant morbidity is likely to result from wide local excision (Figs 2 and 3), or if surgery is refused by the patient.35 Management principles thereafter remain undefined, with inadequate evidence to support or refute the role of adjuvant radiotherapy to the primary site, the role of prophylactic radiotherapy to the clinically and pathologically N0 nodal basin, and the role of definitive or adjuvant radiotherapy for the clinically or pathologically N-positive nodal basin.35 At present, the role of radiation (mono)therapy for macroscopic disease is best described in patients who are unsuitable for general anaesthesia and/or or who have primary or in-transit disease localities that may result in significant cosmetic disfigurement and functional impairment if wide-margin surgical excision is attempted. This is particularly the case for MCC located in the head and neck. In our experience, delivered radiotherapy is almost always ipsilateral (not comprehensive), and, even in elderly, poor-performance patients, well tolerated. In addition, if surgery does proceed, postoperative complications may delay commencement of adjuvant treatment, and Tsang et al36 noted that a median wait of 24 days for radiotherapy was associated with a high risk of progression. Our analysis revealed 48.2% of irradiated sites to have addressed macroscopic regional disease, with a 16.3% recurrence rate. Given that few patients avoid adjuvant radiotherapy, the perceived benefits, cost, and toxicity of combined treatment over definitive radiotherapy must be carefully considered. In a prospective analysis of 43 patients, Fang et al34 demonstrated no difference in overall survival when patients with regional microscopic or macroscopic disease were treated with completion lymphadenectomy with/without radiotherapy or with radiotherapy alone. In addition, for patients with clinically positive regional MCC, no significant difference was noted in 2-year recurrence-free survival between those undergoing completion lymphadenectomy with/without radiotherapy and those undergoing definitive radiotherapy (78% vs 73%, P = .8).34

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Table I. Cumulative analysis summary of Merkel cell carcinoma patient, disease, radiotherapy, and outcome parameters Parameter

Age Gender Site of primary MCC

Size of MCC (primary, in-transit, or node) Extent of MCC

Margin of primary MCC excision

RT setting RT site

RT dose In-field recurrence rate Follow-up Outcome

n and/or %

Studies (patients)

76.4 6 11.3 years Male (50.6%) Head and neck (58.7%) Upper limb (10.9%) Lower limb (14.1%) Thorax/abdomen (4.3%) Unknown (12%) 32.5 6 27.3 mm Local/primary (42%) Regional (57.2%) In-transit (0.8%) Macroscopically (grossly) positive (64.1%) Negative (19%) Unknown/not reported (16.9%) Initial MCC (81.8%) Recurrent MCC (18.2%) Primary (51.5%) Regional (48.2%) In-transit (0.3%) 49.1 6 11.7 Gy 11.7% (per site) to 14.3% (per RT field) 23.7 6 21.9 months NED (34.9%) AWD (5.8%) DOD (32%) DOC (27.3%)

13 (124)2,11-16,18,19,21,24,30,31 14 (160)2,11-16,18,19,21,25,29-31 15 (184)2,11-16,18,19,21,24,25,29-31

10 (103)2,11,12,15,18,21,24,25,30,31 23 (264)2,11-32

23 (264)2,11-32

23 (264)2,11-32 23 (264)2,11-32

11 23 15 18

(100)2,11,12,14,16-19,21,30,31 (264)2,11-32 (103)2,11,12,14-19,21,23,30,31,34 (172)2,11-15,17-21,23-25,29-31,34

AWD, Alive with disease; DOC, died of other cause; DOD, died of disease; Gy, Gray; MCC, Merkel cell carcinoma; NED, no evidence of disease; RT, radiotherapy.

There is a lack of consensus about the optimal dose/fractionation schedule in this very radiosensitive malignancy. Current NCCN guidelines stipulate doses of 60 to 66 Gy for definitive treatment of grossly positive primary tumor resection margins and clinically evident lymphadenopathy.35 Our analysis documented a mean dose of 49.1 6 11.7 Gy for all irradiated sites of macroscopic disease; however, because of a small sample size, we could not demonstrate a statistically significant difference in dose of radiotherapy to primary (49.3 6 11.8 vs 42.6 6 23 Gy, P = .2) and regional (49.5 6 10.3 Gy vs 48.6 6 10, P = .77) sites where recurrence did and did not occur. Noting the marked radiosensitivity of MCC, it is possible that other factors beyond just the dose of radiotherapy, such as the radiotherapy technique and modality, may also contribute to the development of recurrence. The higher rate of regional compared with primary recurrence (16.3 vs 7.6%; P = .02) may also possibly reflect a larger volume of disease being treated combined with the increased technical difficulty of delivering regional versus primary treatment. Fractionation scheduling

was not uniformly reported; however, most authors documented 2- to 2.5-Gy fractions.2,5,11,14,19,29,31 The impact and efficacy of larger fractions of radiotherapy (3-6 Gy) given to lower total doses (2040 Gy) is yet to be elucidated but requires further investigation. At least 1 study has documented 45% complete response with the use of an 8-Gy singe fraction (including large tumors up to 16 cm) and almost 80% in-field lesion control.37 We believe our review to be the largest analysis of MCC definitive radiotherapy alone evaluated to date. It is strengthened by statistical analysis specifically performed on the basis of the subsite of disease and by patient and not on locoregional recurrence or recurrence-free survival estimates. Furthermore, care was taken to avoid duplication of patients. Nonetheless, the present study has several limitations pertaining to the nature and subject matter of the data extracted, mitigating the robustness of our results. Our literature search strategy identified articles with a distinct focus on radiation monotherapy. Thus, discrete cases of patients receiving radiation monotherapy within

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Fig 2. In preparation for radiotherapy, a 5-cm-wide field margin (as marked) was applied to encompass the primary site and the surrounding in-transit tissue. Treatment was commenced within 2 weeks of presentation.

Fig 3. The patient was prescribed 40 Gy in 10 weekday fractions with the use of orthovoltage energy photons (200kVp). At 3 weeks after completion of radiotherapy, the patient had complete regression of Merkel cell carcinoma with resolving moist desquamation delineating the primary lesion. Within 5 weeks after radiotherapy, complete healing and tumor regression was achieved.

larger series may have been missed. Most included publications were retrospective in nature, and, although disease extent was analyzed, significant heterogeneity was present in the size of primary and regional MCC disease treated and the volume, type, and method by which radiation was administered and duration of follow-up. In addition, a minority of patients (n = 30) from 6 studies received concomitant chemotherapy, but available data were not sufficient to determine the impact of systemic treatment, if any, on distant recurrence.19,20,28,29,32,34 Because of the aggregate nature in which data were reported in certain studies, patients who received chemotherapy could not reliably be excluded from the analysis. As the result of limitations in documentation, rate of in-field recurrence could not be precisely calculated because of assumptions being required regarding use of single or multiple radiation fields when patients with primary and nodal

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disease were concurrently irradiated. Nonetheless, we are confident that at most, this analysis ascertains an in-field recurrence rate of 14.3%. However, this result must be placed in the context of final outcome at follow-up documented in only 18 studies (n = 172) with duration of follow-up reported in only 15 (n = 103). There are very few contraindications to recommending radiotherapy, if indicated, even in poorperformance patients. Previous radiotherapy is considered a contraindication to further highdose irradiation, and patients with severe scleroderma (or similar) or radiotherapy sensitivity syndromes (notably ataxia-telangiectasia and Fanconi anemia)38 must be considered carefully. However, these scenarios are uncommon, and, as long as patients are cooperative and can lie still and relatively flat for a short period of time, treatment can usually be delivered. Acute cutaneous reactions are self-limiting and tolerable, and even patients with MCC of the head and neck tolerate treatment well as a result of limited mucosal irradiation, noting the ipsilateral delivery of radiotherapy. On the basis of the available evidence, clinicians should consider radiotherapy as an efficacious and potentially curable option in their patients, especially in those of poor performance status and when the risks of surgery are deemed unacceptable or the patient refuses surgery. Further investigation is required into the optimal dose/fractionation schedule. REFERENCES 1. Youlden DR, Soyer P, Youl PH, Fritschi L, Baade PD. Incidence and survial for Merkel cell carcinoma in Queensland, Australia. JAMA Dermatol. 2014;150(8):864-872. 2. Veness M, Foote M, Gebski V, Poulsen M. The role of radiotherapy alone in patients with merkel cell carcinoma: reporting the Australian experience of 43 patients. Int J Radiat Oncol Biol Phys. 2010;78(3):703-709. 3. Veness MJ. Merkel cell carcinoma (primary cutaneous neuroendocrine carcinoma): an overview on management. Australas J Dermatol. 2006;47(3):160-165. 4. Veness MJ, Palme CE, Morgan GJ. Merkel cell carcinoma: a review of management. Curr Opin Otolaryngol Head Neck Surg. 2008;16(2):170-174. 5. Sundaresan P, Hruby G, Hamilton A, et al. Definitive radiotherapy or chemoradiotherapy in the treatment of Merkel cell carcinoma. Clin Oncol. 2012;24(9):e131-e136. 6. Hruby G, Scolyer RA, Thompson JF. The important role of radiation treatment in the management of Merkel cell carcinoma. Br J Dermatol. 2013;169(5):975-982. 7. Strom T, Naghavi AO, Messina JL, et al. Improved local and regional control with radiotherapy for Merkel cell carcinoma of the head and neck. Head Neck. 2017;39:48-55. 8. Veness MJ, Morgan GJ, Gebski V. Adjuvant locoregional radiotherapy as best practice in patients with Merkel cell carcinoma of the head and neck. Head Neck. 2005;27(3): 208-216.

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9. Warner RE, Quinn MJ, Hruby G, et al. Management of merkel cell carcinoma: the roles of lymphoscintigraphy, sentinel lymph node biopsy and adjuvant radiotherapy. Ann Surg Oncol. 2008;15(9):2509-2518. 10. Koh CS, Veness MJ. Role of definitive radiotherapy in treating patients with inoperable Merkel cell carcinoma: the Westmead Hospital experience and a review of the literature. Australas J Dermatol. 2009;50(4):249-256. 11. Veness M, Howle J. Radiotherapy alone in patients with Merkel cell carcinoma: the Westmead Hospital experience of 41 patients. Australas J Dermatol. 2015;56(1): 19-24. 12. Elliott E. Trabecular cell carcinoma: report of a case. Ann Plast Surg. 1981;7(2):163-164. 13. Zakzouk MS, Ramsay AD, Buchanan G. Merkel cell tumour of the skin. J Laryngol Otol. 1986;100(5):561-572. 14. Pacella J, Ashby M, Ainslie J, Minty C. The role of radiotherapy in the management of primary cutaneous neuroendocrine tumors (Merkel cell or trabecular carcinoma): experience at the Peter MacCallum Cancer Institute (Melbourne, Australia). Int J Radiat Oncol Biol Phys. 1988; 14(6):1077-1084. 15. Pilotti S, Rilke F, Bartoli C, Grisotti A. Clinicopathologic correlations of cutaneous neuroendocrine Merkel cell carcinoma. J Clin Oncol. 1988;6(12):1863-1873. 16. Ashby MA, Jones DH, Tasker AD, Blackshaw AJ. Primary cutaneous neuroendocrine (Merkel cell or trabecular carcinoma) tumour of the skin: a radioresponsive tumour. Clin Radiol. 1989;40(1):85-87. 17. Morrison WH, Peters LJ, Silva EG, et al. The essential role of radiation therapy in securing locoregional control of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys. 1990;19(3): 583-591. 18. Hasle H. Merkel cell carcinoma: the role of primary treatment with radiotherapy. Clin Oncol. 1991;3(2):114-116. 19. Boyle F, Pendlebury S, Bell D. Further insights into the natural history and management of primary cutaneous neuroendocrine (Merkel cell) carcinoma. Int J Radiat Oncol Biol Phys. 1995; 31(2):315-323. 20. Meeuwissen JA, Bourne RG, Kearsley JH. The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys. 1995;31(2): 325-331. 21. Suntharalingam M, Rudoltz MS, Mendenhall WM, et al. Radiotherapy for Merkel cell carcinoma of the skin of the head and neck. Head Neck. 1995;17(2):96-101. 22. Mortier L, Mirabel X, Fournier C, et al. Radiotherapy alone for primary Merkel cell carcinoma. Arch Dermatol. 2003;139(12): 1587-1590.

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23. McAfee WJ, Morris CG, Mendenhall CM, et al. Merkel cell carcinoma: treatment and outcomes. Cancer. 2005;104(8): 1761-1764. 24. Pape E, Rezvoy N, Penel N, et al. Radiotherapy alone for Merkel cell carcinoma: a comparative and retrospective study of 25 patients. J Am Acad Dermatol. 2011;65(5):983-990. 25. Deneve JL, Messina JL, Marzban SS, et al. Merkel cell carcinoma of unknown primary origin. Ann Surg Oncol. 2012; 19(7):2360-2366. 26. Kukko H, Bohling T, Koljonen V, et al. Merkel cell carcinoma: a population-based epidemiological study in Finland with a clinical series of 181 cases. Eur J Cancer. 2012;48(5):737-742. 27. Lok B, Khan S, Mutter R, et al. Selective radiotherapy for the treatment of head and neck Merkel cell carcinoma. Cancer. 2012;118(16):3937-3944. 28. Santamaria-Barria JA, Boland GM, Yeap BY, et al. Merkel cell carcinoma: 30-year experience from a single institution. Ann Surg Oncol. 2013;20(4):1365-1373. 29. Harrington C, Kwan W. Outcomes of Merkel cell carcinoma treated with radiotherapy without radical surgical excision. Ann Surg Oncol. 2014;21(11):3401-3405. 30. Chatzinasiou F, Papadavid E, Korkolopoulou P, et al. An unusual case of diffuse Merkel cell carcinoma successfully treated with low dose radiotherapy. Dermatol Ther. 2015;28(5):282-286. 31. Kitamura N, Tomita R, Yamamoto M, et al. Complete remission of Merkel cell carcinoma on the upper lip treated with radiation monotherapy and a literature review of Japanese cases. World J Surg Oncol. 2015;13:152. 32. 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. 33. Foote M, Harvey J, Porceddu S, et al. Effect of radiotherapy dose and volume on relapse in Merkel cell cancer of the skin. Int J Radiat Oncol Biol Phys. 2010;77(3):677-684. 34. Fang LC, Lemos B, Douglas J, et al. Radiation monotherapy as regional treatment for lymph node-positive Merkel cell carcinoma. Cancer. 2010;116(7):1783-1790. 35. Network NCC. NCCN Clinical Practice Guidelines in Oncology. Merkel Cell Carcinoma (Version 1.2016). 2016 (accessed April 2016). 36. Tsang G, O’Brien P, Robertson R, et al. All delays before radiotherapy risk progression of Merkel cell carcinoma. Australas Radiol. 2004;48(3):371-375. 37. Iyer JG, Parvathaneni U, Gooley T, et al. Single-fraction radiation therapy in patients with metastatic Merkel cell carcinoma. Cancer Med. 2015;4(8):1161-1170. 38. Pollard JM, Gatti RA. Clinical radiation sensitivity with DNA repair disorders: an overview. Int J Radiat Oncol Biol Phys. 2009; 74(5):1323-1331.

RT setting Author (year)

Elliot (1981)12 Zakzouk et al (1986)13 Pacella et al (1988)14 Pilotti et al (1988)15 Ashby et al (1989)16 Morrison et al (1990)17 Hasle (1991)18 Boyle et al (1995)19 Meeuwissen et al (1995)20 Suntharalingham et al (1995)21 McAfee et al (2005)22 Veness et al (2010)2 Fang et al (2010)23 Pape et al (2011)24 Deneve et al (2012)25 Kukko et al (2012)26 Lok et al (2012)27 Santamaria-Barria et al (2013)28 Harrington et al (2014)29 Chatzinasiou et al (2015)30 Kitamura et al (2015)31 Bishop et al (2015)32 Veness et al (2015)11

Mean RT dose (Gy)

In-field recurrence

Mean age

Initial

Recurrence

Primary

Regional

Primary

Regional

Primary

Regional

In-field control (%)

Mean follow-up (months)

1 1 12 7 2 10 1 4 8 3 8 25 9 25 3 6 10 7 57 1 1 22 41

55 56 74.5 68.9 88.5 d 78 70 d 72.3 d 74.1 d 80 82y d d d 75y 81 75 d 78.6

d d 3 5 2 10 1 3 8 4 8 15 9 25 3 6 3 7 57 1 1 22 24

1 1 10 2 d d d 1 d d d 10 d d d d 7 d d d d d 17

1 d 13 3 2 8 1 1 2 3 8 19 d 25 d 6 5 5 42 1 1 d 25

1 1 5 4 d 3 d 3 8 1* d 24 9 d 3 d 5 2 33 d d 22 37

38.5 d 40.2 d 42 64.1 40 45 d 53.5 d 52.1 d d d d d d d 20 65 d 47.6

55 d 48.2 d d 61.7 d 46 d 62* d 51.1 d d d d d d d d d 66y 47.4

1 d 1 0 0 2 0 0 0 2 1 1 d 0 d 0 0 0 4 0 0 d 1

1 0 0 1 d 0 d 0 4 0 d 8 2 d 1 d 0 0 4 d d 0 5

0 100 94.4 85.7 100 81.8 100 100 60 50 87.5 79.1 77.8 100 66.7 100 100 100 89.3 100 100 100 90.3

5 d 13.2 57.3 24 5z 31 22 21z 25.7 36.5 21.8 9.5 d d d d d d 5 12 d 24.5

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Gy, Gray; RT, radiotherapy. *In-transit. y Median. z Results from 1 patient in study only.

RT site

Patient no.

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Supplemental Table I. Summary of reported cases, definitive radiotherapy for Merkel cell carcinoma