Source: Cancer Network, October 2015

The initial treatment for primary and locoregional melanoma is surgery. Systemic therapy, and more recently immune therapy, has been the mainstay in the adjuvant and particularly the metastatic setting. Aside from palliation, there is a limited role for definitive radiation therapy for melanoma. However, in the adjuvant setting, postoperative radiation can improve locoregional disease control, albeit with potential toxicity and limited survival benefit. Stereotactic radiosurgery plays a vital role in the treatment of limited brain and extracranial metastasis.

Introduction

Melanoma has historically been considered a radioresistant tumor. Emerging data have challenged this viewpoint, and radiation therapy (RT) is now considered an effective treatment option in some settings, although its use has dwindled in recent years with the advent of new therapies for the competing risk of systemic disease. More important, RT can provide effective palliation for the 40% to 50% of patients with unresectable locally recurrent or metastatic disease that produces bone pain, epidural spinal cord compression, and central nervous system dysfunction. Stereotactic radiosurgery (SRS) and stereotactic body RT (SBRT) can be effective in ablating limited metastasis.

The potential roles of RT in the treatment of patients with melanoma will be reviewed here.

Radiobiology of Melanoma

The notion that melanoma is intrinsically radioresistant arose from initial cell culture studies that showed a broad shoulder in cell survival curves,[1,2] which implied a better response to a higher dose per fraction and unusual repair capacity.[3] In the 1980s, clinical observations based on the treatment of recurrent and metastatic lesions with varying dose schedules corroborated these laboratory findings.[4,5] Initial clinical retrospective data from a large series of patients supported a higher likelihood of benefit for large fraction sizes as an independent variable. However, other earlier studies that used the high dose per fraction showed no difference between 3 fractions of 9 Gy and 5 fractions of 8 Gy.[4]

Others have questioned this relative radioresistance.[6-8] Other single-institution series reported similar outcomes with conventionally fractionated radiation.[9] These data led to the inception of a multicenter randomized phase III trial, which failed to show better outcomes with large fraction sizes.

The Radiation Therapy Oncology Group (RTOG) 83-05 trial randomly assigned 137 patients with metastatic melanoma involving any site other than the brain or abdomen to 4 fractions of 8 Gy administered at weekly intervals or 20 fractions of 2.5 Gy each, administered daily 5 days per week.[10] There was no difference in the clinical response rate according to fraction size: 24% and 23%, respectively, for complete response, and 36% and 34%, respectively, for partial response. The duration of tumor control and survival were not reported. Three grade 4 toxicities and three grade 3 toxicities were noted in the 4 × 8 Gy arm compared with only four grade 3 toxicities in the 20 × 2.5 Gy arm. Because follow-up was short and both arms received nonstandard treatment schemes, toxicity data from this trial are difficult to interpret.

Some of the disparity and controversy over the dose fractionation in melanoma may result from inadequate knowledge of the relationship between total dose, dose per fraction, duration of therapy, and site of treatment.[5]

Clinical Role of RT in Melanoma

Wide resection remains the primary initial treatment of cutaneous melanoma. In rare cases, such as inoperability because of medical comorbidities or other reasons, definitive radiation to the primary site may be considered. Conventional RT has been used as definitive therapy for melanoma in the skin, mucosa, and uvea. Adjuvant radiation is used at the primary site and in the regional nodal basin after surgery when the risk of local failure is high. RT is also effective for palliation. SRS has been efficacious in brain metastasis from melanoma. With improving systemic therapy, patients with limited metastases are increasingly being treated with ablative SBRT in addition to surgery or other ablative modalities.

Primary RT for Melanoma

Cutaneous lesions

Among cutaneous melanomas, superficial lentigo maligna (confined to the epidermis) and lentigo maligna melanoma (invasive into the dermis) have a slow growth rate and low metastatic potential. These lesions have been treated successfully with RT.

In one series, local control was achieved in 92% of 46 evaluable patients at a median follow-up of 24 months (range, 6 months to 8 years), using orthovoltage radiation with doses between 35 Gy in 1 week and 50 Gy in 3 to 4 weeks.[11] The choice of fractionation schedule depended on field size. The median time to complete regression was 8 months (range, 1–24 months). Four local recurrences were salvaged with further treatment, and regional and distant metastases developed in only one patient.

In a second series, 64 patients were treated with 100 Gy of orthovoltage RT in 10 fractions (10 Gy per fraction, 5 days per week for 2 weeks).[12] The median follow-up was 15 months (range, 1–96 months). All patients with lentigo maligna melanoma underwent excision of the nodular component of their disease before the start of RT. Among those with lentigo maligna melanoma, there were two local recurrences, at 13 and 44 months, both of which were salvaged surgically. Metastatic disease without a local recurrence developed in one patient.

Data about the effectiveness of RT for more deeply invasive nodular melanomas are limited. In a series of 95 cases, high radiation doses (100 to 110 Gy) were delivered in 6-Gy fractions using superficial 60 kVp x-rays.[13] The 5-year survival rate was 68%, a value similar to that seen with wide local excision, but these observations have not been confirmed in a randomized trial.

Mucosal melanoma

Mucosal melanomas represent about 4% of all melanomas.[14,15] The head, neck, and anorectal and vulvovaginal areas are common sites; less frequent sites are the urethra, gallbladder, esophagus, and small intestine.

Surgery is the first choice of therapy for mucosal melanomas of the head and neck. However, if resection cannot be accomplished, RT may be used to achieve local control.[16] The largest series in this setting included 28 patients with nasal cavity and paranasal sinus tumors.[17] The actuarial local control rate using a treatment schedule of 50 to 55 Gy in 15 to 16 fractions was 49% at 3 years.

Newer techniques, such as intensity-modulated RT[18] and carbon ion therapy,[19,20] may offer advantages, but there are only limited results with the use of these techniques in patients with mucosal melanoma.

Uveal melanoma

RT techniques and results for the treatment of uveal melanoma are a separate topic.[21] Traditionally, uveal melanoma was treated by enucleation of the globe but is now increasingly managed by an eye-preserving option, which saves vision without compromising the life of the patient. More than 90% of eyes now preserved receive some form of RT—most often episcleral brachytherapy and, less frequently, charged-particle irradiation, stereotactic radiotherapy, or radiosurgery.

While RT for uveal melanoma can cause significant side effects and complications, the vast majority of patients can keep their eyes, with some remaining function. This is of significant benefit to quality of life for many patients. The side effects of RT are intimately related to the size of the irradiated tumor; hence, early detection and identification of tumors that need to be treated are critical to improving the functional outcome.