The Role of Radiation T h e r a p y in Me l a n o m a Jacqueline Oxenberg,

DO

a

, John M. Kane III,

MD

b,

*

KEYWORDS  Melanoma  Radiation therapy  Locoregional recurrence  Nodal metastases  Lymphedema KEY POINTS  Adjuvant radiation therapy can reduce local recurrence for certain high-risk primary melanomas, including lentigo maligna, desmoplastic/neurotropic features, and mucosal melanomas (head and neck and anorectal).  There are retrospective and limited prospective data to support adjuvant radiation following lymphadenectomy for nodal metastatic disease at high risk for regional recurrence.  Radiation therapy is associated with increased potential toxicity, such as lower extremity lymphedema, and may negatively interact with concurrent adjuvant interferon therapy.

INTRODUCTION

Radiation therapy (RT) is a locoregional treatment that can be very effective at reducing the risk of recurrence for many cancers. Given that radiation is not tumor specific, there can also be significant toxicity to adjacent anatomic structures. Historically, melanoma was thought to be radiation “resistant.” This assumption led to either its exclusion as an adjuvant therapy or very hypofractionated dosing regimens. More recent data would suggest that melanoma is radiation sensitive, including to standard fractionation treatment plans. This review examines high-risk situations for locoregional recurrence following melanoma surgical therapy, the available literature supporting the role of both adjuvant and definitive RT, and treatment-related complications. The use of RT for situations whereby melanoma is not typically treated surgically (uveal melanoma, brain metastases, palliation, and so forth) are not addressed.

a Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA; b Melanoma-Sarcoma Service, Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA * Corresponding author. E-mail address: [email protected]

Surg Clin N Am 94 (2014) 1031–1047 http://dx.doi.org/10.1016/j.suc.2014.07.006 surgical.theclinics.com 0039-6109/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

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RADIATION FOR LOCAL CONTROL Lentigo Maligna

Although it is only melanoma in situ, complete surgical excision of a lentigo maligna (LM) can be difficult secondary to the large size, poorly visualized margins, and cosmetically important locations such as the face. In addition, 16% to 50% of cases can have an associated invasive melanoma component (lentigo maligna melanoma [LMM]).1–3 Local recurrence rates following conventional surgical resection can be as high as 20%.4 However, even negative margin staged excisions or Mohs micrographic surgery with a low risk for local recurrence often produces a very morbid cutaneous defect. In light of these issues, RT has been used as definitive therapy for LM. A small series by Harwood5 reported on conventional fractionated RT for 17 patients with LM and 23 with LMM. The clinical response following RT took up to 24 months. Although the follow-up was variable, only 2 of the LM patients recurred, both of whom were salvaged by either surgery or additional radiation. Local control was obtained in 91% of the LMM patients. The 2 recurrences were both salvaged by surgical excision. Grenz rays, or “soft” x-rays, are produced at low kilovoltages, being completely absorbed within the first 2 mm of the skin. Schmid-Wendtner and colleagues6 examined 42 patients with LM and 22 with LMM treated with fractionated radiation (100 Gy). In contrast to the Harwood study, the nodular melanoma portion of the LMM lesion was excised before radiation. At a median follow-up of 15 months, local control was 100% in the LM group and 91% in the LMM patients (all recurrences were salvaged with surgery). Another study of Grenz rays/soft x-rays for definitive therapy involved patients with LM alone (n 5 93), LMM (n 5 54), or both components (n 5 3).7 The patients were older (mean age 70 years) and 90% of tumors were on the face. For patients with 2 years or more of follow-up, the local recurrence rate was only 5%. Eighty percent of recurrences were at the edge of the radiation field; all were salvaged with surgery or additional radiation. Only 2 patients developed nodal disease, both of whom died of distant metastases. The largest series of Grenz rays/soft x-rays for LM is 593 patients: definitive therapy in 350, partial excision/radiation in 71, and adjuvant therapy after surgery in 172.8 The total radiation dose was 100 to 160 Gy (given as twice-weekly fractions over 3 weeks). Only 3.6% of patients with residual LM did not have a complete response, and the overall recurrence rate was only 9.8%. In most of the aforementioned studies, it was considered that the cosmetic outcome was very good, with only occasional radiation-field skin hypopigmentation or hyperpigmentation. High-Risk Cutaneous Melanoma

Several primary tumor features, such as thickness, ulceration, anatomic location, and satellitosis, predict an increased risk for local recurrence. Reported local recurrence rates for melanomas greater than 4 mm are 12% to 13.2%.9,10 Even melanomas 3 to 4 mm thick may recur up to 11.7%.11 In 2 randomized, prospective trials of wide excision margins, ulceration was associated with a rate of local recurrence of 6.6% to 16.2%.11,12 Local recurrence rates based on high-risk primary tumor site include 9.4% for head and neck, 11.1% for hands, and 11.6% for feet.10,12 Many of these high-risk features are additive; the recurrence rate for ulcerated melanomas of the distal extremity or head and neck was the highest, at 16.2%.12 Typically associated with thicker tumors, primary melanomas with histopathologic microsatellites have been shown to recur locally up to 14%.13 In 1983, Johanson and colleagues14 reported on a very hypofractionated RT regimen (800 rad fractions  3) for high-risk melanoma. There were 3 cohorts: 22

Role of Radiation Therapy in Melanoma

patients with microscopic residual tumor after surgery (3 primary tumor and 19 nodal), 9 patients with gross residual tumor after surgery (3 primary tumor and 6 nodal), and 23 patients with recurrent gross disease no longer amenable to surgical resection (including 15 with skin/subcutaneous tumor). Median follow-up was not specified, and 59% patients also received dacarbazine before the first and third doses of radiation. Only 1 of the 3 patients with primary tumor and positive margins recurred (14 months after radiation). At last follow-up, all 3 patients were alive and diseasefree. Fifty-five percent of the patients with gross residual tumor had a complete response after radiation and there were no in-field recurrences. Finally, 39% of patients with unresectable gross disease also had a complete response, which was durable in 78%. There were also 5 postradiation partial responses and 3 patients with stable disease. In a series by Stevens and colleagues15 of postoperative RT for locally advanced melanoma, 32 patients received adjuvant radiation to the primary tumor site; 11 for a high-risk primary tumor and 21 after a previous recurrence. High-risk features included close or positive resection margins, satellitosis, or neurotropic/perineural features. Eighty-eight percent of tumors were on the head and neck. Hypofractionated regimens were used to a total dose of 30 to 36 Gy. Although not specifically calculated for each patient subset, the in-field recurrence rate for the entire study was only 11.5%. The 5-year overall survival for the high-risk primary tumors was 49%. Desmoplastic and Neurotropic Melanoma

Representing only 1% to 4% of all melanoma cases, desmoplastic melanoma (DM) is most common in the head and neck region (37%–68%) and has an increased propensity for local recurrence.16–20 Approximately 30% to 40% will also be neurotropic, with perineural invasion and extension along adjacent nerves.21 Although one study showed no difference in local control between DM and case-matched controls, others have shown high local recurrence rates of 14% to 48% (including 27%–45% for the neurotropic variant).16–19,22–24 Several studies have also shown that margin status and head and neck location are associated with an increased risk for local recurrence.19,21,22,24,25 Most of the published studies on adjuvant RT for DM are anecdotal in nature, but there are a few larger series. Vongtama and colleagues20 identified 44 DM patients from their tumor registry, 21 with recurrent disease. Twenty-nine patients were treated with surgery alone, 1 received preoperative RT, and 14 underwent postoperative RT. Though not clearly stated, it appears that all of the patients who received radiation had recurrent tumor. Following initial surgery, the local recurrence rate was 48% with a median of 2 recurrences. The rate of subsequent local recurrence in 7 patients with a prior history of recurrence who did not receive RT was 57%. By contrast, there were no local recurrences in the patient group who received RT for a previous recurrence. There was no grade 3/4 toxicity (including the eye, ear, or bone). Foote and colleagues26 noted a 91% 3-year local relapse-free survival in 24 DM patients who underwent surgery followed by adjuvant RT, including 71% with margins of less than 1 cm. The investigators stated that these findings were leading to the development of a randomized prospective trial. Finally, in a study by Chen and colleagues,21 there was no significant difference in the local recurrence rate for 27 neurotropic DM patients who received 28 to 64 Gy of adjuvant RT in a comparison with 101 surgeryalone patients (7.4% vs 5.9%). However, the RT patients had significantly thicker tumors, a deeper Clark level, and narrower excision margins (60% 1 mm), placing them at a greater risk for local recurrence.

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Head and Neck Mucosal Melanoma

Head and neck mucosal melanoma (nasal cavity and paranasal sinuses) is rare, accounting for only 1% of all melanoma. Negative margin wide excision is the potentially curative treatment, but is technically challenging because of the complex anatomic location and close proximity to critical structures. Local recurrences are common, ranging from 26% to 85%, and the mean time to local recurrence is 5 to 20 months.27–30 Even with this locally aggressive biology, 5-year overall survival is still reasonable at 20% to 46%.28–33 Consequently, RT has been studied as both postsurgical adjuvant therapy and definitive treatment. There is significant variation in the postoperative adjuvant RT regimens used for head and neck mucosal melanoma from hypofractionation (6–8 Gy fractions  3–5), total doses of 30 to 70 Gy, intensity-modulated RT (IMRT), and occasionally even combined photon/proton therapy.29,30,34,35 Reported local control rates for postoperative RT following surgical resection have ranged from 29% to 83%.29,34–37 Within the group of patients receiving adjuvant RT, Moreno and colleagues30 found that cumulative doses of 54 Gy or greater resulted in better local control (P 5 .02). Several retrospective studies have directly compared surgery alone with the addition of adjuvant RT. Owens and colleagues36 reported a nonsignificant trend toward a lower rate of locoregional recurrence with adjuvant RT versus surgery alone (17% vs 45%; P 5 .13). Despite more locally advanced tumors in the 39 patients receiving postoperative RT, Temam and colleagues37 found that local control was 62% as opposed to only 26% for the 30 patients in the surgery-alone group (P 5 .02). On Cox multivariate analysis, postoperative RT was a significant predictor of better local control (relative risk 0.4; P 5 .05). The largest retrospective review of adjuvant RT for head and neck mucosal melanoma is the GETTEC study of 160 patients from multiple institutions over 28 years.33 Eighty-two patients who underwent surgery alone were compared with 78 patients who received postoperative RT. Although there was no difference in 5-year overall survival between the 2 groups (46% vs 27.5%, respectively; P 5 .31), the 5-year cumulative locoregional recurrence rate was significantly lower in the radiation group (29.9% vs 55.6%; P4 positive nodes OR ECE

Epitrochlear

>3 cm size OR >4 positive nodes OR ECE

Inguinal

>3 cm size AND ECE >3 cm size AND >4 positive nodes >4 positive nodes AND ECE

Abbreviation: ECE, extracapsular extension. From Agrawal S, Kane JM 3rd, Guadagnolo BA, et al. The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node metastatic melanoma. Cancer 2009;115(24):5836–44; with permission.

Table 2 Selected published studies of regional control for adjuvant radiation therapy following lymph node dissection for nodal metastatic melanoma Number of Patients Authors,Ref. Year

Type

Nodal Basin

Ballo et al,58 2003

Retro

C

Ballo et al,64 2002

Retro

A

Ballo et al,59 2004

Retro

I

Burmeister et al,51 2006

Pro

C, A, I

RT

No RT

Regional Control Rate RT Dose (Gy)

Median F/U (mo)

RT (%)

No RT (%)

P Value

160

30

78

94

[10 y]

89

30

63

87

[5 y]

40

30

22.5

74

[3 y]

234

48

58.4

91

[5 y]

Adjuvant Radiation

Adjuvant Radiation vs LND Alone Retro

C

129

587

33

34.7

89.9

93.9

[6 y]

.20

Strojan et al,49 2010

Retro

C

43

40

60

25

78

56

[2 y]

.015

23

[2 y]

.395

Pinkham et al,50 2013

Retro

A

121

156

48

Gojkovic-Horvat et al,65 2012

Retro

I

37

64

50.6

Bibault et al,60 2011

Retro

C, A, I

60

26

50

73

Agrawal et al,52 2009

Retro

C, A, I

60

Creagan et al,53 1978

Pro

Burmeister et al,54 2012

Pro

C, A, I

509

106

30

27

29

50

109

108

48

40

86

87

86

91

C 85 A 90 I 80

50 70 72

89.8

59.4

88.9

96.6

81

69

.4

[5 y]

The role of radiation therapy in melanoma.

Although melanoma was historically thought to be radiation resistant, there are limited data to support the use of adjuvant radiation therapy for cert...
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