Radiation Therapy in the Management of Malignant Melanoma


Melanoma has historically been considered a radioresistant tumor. Emerging data have challenged this viewpoint. The potential roles of radiation therapy in the treatment of patients with melanoma will be reviewed here.

Oncology (Williston Park). 29(10):743-751.

Table: Long-Term Complications of Adjuvant Radiation to Lymph Node Regions

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.


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.

Adjuvant RT for Melanoma

Primary cutaneous melanoma

Generally, the rate of local recurrence in invasive cutaneous melanoma is less than 5% after adequately wide excision of the primary site. However, in certain circumstances local recurrence at the primary site is unacceptably high after surgery alone, and adjuvant RT may be considered to improve local control.[16] Occasionally, anatomic constraints may limit the ability to obtain widely negative margins, particularly in the head and neck. RT has been effectively used in the setting of either positive or close margins where further reexcision was not considered feasible.

Key risk factors for local recurrence are thick tumors (Breslow thickness > 4 mm), ulceration, and the presence of satellitosis and/or angiolymphatic invasion.[19] For cutaneous melanoma, adjuvant RT following surgery may also have a role in other patients at increased risk for local recurrence, such as those who have desmoplastic melanoma with narrow resection margins, locally recurrent disease, or extensive neurotropism.[20]


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Roy H. Decker, MD, PhD
Yale University School of Medicine, New Haven, ConnecticutI’ve always hated the term “radioresistant”; it implies a duality of response, when the reality is always more complex. In this review, Dr. Mahadevan and colleagues take us on a 40-year tour of the clinical use of radiation therapy (RT) in patients with melanoma, and paint a thorough and accurate picture of a disease that is both heterogeneously responding and consistently frustrating.What Do We Already Know About RT in Melanoma?We’ve known that melanoma responds atypically to radiation since the 1970s, when it was observed that certain cell lines had a wide “shoulder” on the cell survival curve, implying that they would respond better to larger radiation fractions. This is consistent with the more recent observation that stereotactic body RT and stereotactic radiosurgery (the ultimate examples of hypofractionation) offer better results than more “standard” schedules. But it’s equally clear that despite the use of higher doses, many patients will still experience local recurrences.What Holds Promise for the Future-and WhyWhen interpreting these data, it is important to keep in mind that melanoma is a disease in which the transition from a localized to a metastatic state seems to occur particularly abruptly-the same risk factors that predict local recurrence also predict distant metastasis. Taken together, these two biological characteristics-imperfect local control and a propensity for distant metastasis-suggest where radiation should be applied in patients with melanoma. For definitive treatment of localized disease, the use of radiation should be limited to those who cannot undergo wide excision. The use of adjuvant radiation will improve local or regional control without affecting overall survival, and is, for all intents and purposes, palliative. In my opinion, the most promising role for radiation is in patients with metastases: as simple palliation, to prolong disease-free survival in oligometastatic patients, or potentially to enhance the effects of the targeted biologics and immune checkpoint inhibitors that are currently revolutionizing the treatment of this disease.Financial Disclosure:Dr. Decker receives research support from Merck & Co.

Desmoplastic melanoma. This rare subtype accounts for approximately 1% to 4% of all melanomas. It is characterized by variably pleomorphic, spindle-shaped cells with associated collagen production.[17] Clinically, the lesions often appear to be amelanotic. This subtype is frequently associated with perineural spread, also referred to as neurotropism, and has been associated with increased local failure rates. Although some investigators have shown local failure rates in desmoplastic melanoma to be in the 20% to 50% range after surgery alone, a series of 280 patients from Australia found the rate to be only 10%, with higher recurrence rates in the presence of neurotropism and when surgical margins were less than 1 cm.[22] Some have advocated adjuvant RT to the primary site in all cases of desmoplastic melanoma,[23] particularly those with neurotropic features.[24] In contrast, others have reported local failure rates of less than 5% with surgery alone and advocate close monitoring for disease recurrence.[17] Although prospective data regarding the role of RT in desmoplastic melanoma are lacking, retrospective data suggest improvement in local control with postoperative radiation for tumors that exhibit perineural spread and for lesions thicker than 4 mm. In addition, RT should be considered in desmoplastic melanoma that has not been resected with wide margins and in locally recurrent lesions.[25]

Mucosal melanoma

RT may also have a role as an adjuvant therapy in patients with mucosal melanoma. As an example, mucosal head and neck melanomas are associated with a high rate of local disease recurrence after surgical resection, even if the primary lesion is small and the regional nodes are not involved.[22,26] Adjuvant RT decreases the likelihood of local recurrence after complete resection but does not have an impact on survival, in part because of the high rate of systemic relapse in such patients.[22,25,27,28]

Anorectal melanomas were historically treated with abdominoperineal resection. Given the high locoregional and distant relapse rates, conservative wide excision is currently recommended. Adjuvant RT in the setting of definitive resection appears to improve local control but may not have an impact on survival.[29,30] With vulvovaginal melanomas, there has been a shift toward conservative surgery and away from more aggressive surgical resection.[31]

Regional lymph nodes

RT has been utilized in the regional nodal basin after node dissection or electively in the absence of node dissection. It is often used in the palliative setting.

RT is rarely indicated as definitive management of melanoma metastatic to regional lymph nodes (stage III disease). Surgical excision provides superior local control (in at least 85% of cases), as well as important diagnostic and prognostic information.

Adjuvant radiation after lymph node dissection. Multiple retrospective series have reported apparent improvement in regional control in high-risk resected nodal basins with the use of postoperative RT.[32,33] These studies have consistently shown that high-risk factors for regional failure include multiple positive nodes (> 3 nodes and especially > 10 nodes), 1 or more large nodes (> 3 cm), extracapsular extension of clinically palpable disease, and regionally recurrent disease; combinations of these factors confer the greatest risk. Regional recurrence rates of 50% or more have been reported after axillary node dissection in patients with extracapsular extension and/or the involvement of two or more nodes.[34] The addition of RT after modified or radical neck dissection has resulted in regional control rates upward of 90% in clinically node-positive patients.[35]

Data from an older prospective randomized trial that evaluated the role of radiation after the resection of nodal metastasis were inconclusive.[36] However, multiple limitations surround the interpretation of these data, including the use of low-energy x-rays, planned treatment breaks, a low total dose of radiation, and a daily fraction size of less than 2 Gy.

The current evidence supports the notion that adjuvant regional RT following surgery decreases the rate of local recurrence but may not improve overall survival. The most compelling data come from a phase III trial that was conducted primarily in Australia and New Zealand.[37,38] Following surgical resection, 250 patients with clinically positive lymph nodes (head and neck, axilla, or groin) who were deemed to be at high risk for locoregional recurrence were randomly assigned to RT (48 Gy in 20 fractions) or observation. Patients were considered at high risk if there was extranodal spread of melanoma, involvement of multiple nodes, or bulky nodes; those with only a positive sentinel lymph node biopsy were excluded.

Overall, 109 patients assigned to RT and 108 assigned to observation were evaluable. At a median follow-up of 40 months, the risk of relapse in the regional lymph nodes was significantly reduced with adjuvant RT compared with observation (20 relapses vs 34 relapses; hazard ratio [HR], 0.56 [95% confidence interval, 0.32–0.98]). However, there were no significant differences in relapse-free survival (70 vs 73 events; HR, 0.91) or overall survival (59 vs 47 deaths; HR, 1.37).

A final analysis of the trial was presented at the 2013 American Society of Clinical Oncology Annual Meeting.[38] Those results, at a median follow-up of 6 years, confirmed the reduction in the rate of regional nodal relapse with RT compared with observation (5-year rate of recurrence, 18% vs 33%; HR, 0.52; P = .02). However, there was no improvement in 5-year relapse-free survival (34% vs 28%) or 5-year overall survival (40% vs 45%), and RT was associated with more lymphedema, particularly in the lower extremities. Recent detailed long-term analysis suggests that the complications are significantly more severe after RT to the groin, followed by the axilla, than after RT to the head and neck.[39]

Despite the lack of an effect on overall survival, adjuvant RT may have a role in carefully selected patients. Locoregional relapses may be difficult to manage because they can cause significant bleeding, infection of ulcerated tumors, limb edema, pain, plexopathy, and paralysis, and they are often refractory to therapy. In selected cases, adjuvant RT to the draining lymph node beds may have a role in the prevention of such complications. Features associated with an increased rate of locoregional recurrence that may warrant adjuvant RT include gross extracapsular extension and extensive lymph node involvement,[40] such as > 4 nodes[41,42] or nodes > 3 cm.[41,43-45].

Elective adjuvant nodal radiation without lymph node dissection. Some investigators have advocated the delivery of nodal basin RT instead of complete node dissection, particularly in patients with metastatic melanoma to cervical nodes from head and neck primary sites. In one series, 36 patients underwent cervical nodal basin irradiation after an excisional biopsy established the presence of nodal involvement.[46] The radiation delivered was 30 Gy at 6 Gy per fraction twice per week (a total of five treatments). The 5-year rate of complications was < 10%, and the 5-year regional control rate was > 90%.

Elective radiation to the clinically node-negative regional basin after wide excision of primary cutaneous melanoma of the head and neck of > 1.5 mm in thickness or Clark level IV has been evaluated. Outcomes for 157 patients treated with this approach from 1983 to 1988 were reported in 2004.[47] Patients with desmoplastic melanoma and those who had undergone surgery for suspected lymph node metastasis were excluded. The 10-year locoregional control rate was 86%.

Despite these results, the current standard of care in the treatment of melanoma includes wide excision of the primary site and sentinel lymph node biopsy for appropriately selected patients. The role for completion node dissection when the sentinel nodes are shown to contain malignancy is currently being evaluated. However, circumstances may arise in which sentinel biopsy is not feasible for either medical or technical reasons. In these rare cases, the regional basins can be carefully monitored with clinical examination and serial ultrasonography; regional nodal irradiation is an alternative that can be considered in selected patients.

Complications of regional radiation. The morbidity of RT to the neck is potentially significant; it includes up to a 10% rate of complications at 5 years, including hearing loss, wound breakdown, bone exposure, and ear pain. In cases of bilateral nodal metastases, which occasionally arise from midline head and neck and scalp primary sites, bilateral cervical radiation has been associated with higher complication rates: a 50% rate of complications at 12 months was reported in one series.[48] In axillae treated with postoperative RT, side effects may be seen in up to 30% of patients at 5 years; the most significant adverse effect is lymphedema. The inguinal region is the nodal basin at greatest risk for lymphedema and other complications when node dissection and RT are both used.[39] There is also evidence that patients with body mass indices > 30 kg/m2 are at even higher risk for treatment-related complications (up to 80%) after combined therapy to the groin.[34] The Table shows the incidence of complications of regional radiation in different lymph node regions.

Palliative RT

Cutaneous and lymph node metastases

Metastatic spread to the skin and lymph nodes occurs in approximately 50% of patients with cutaneous melanoma; it is associated with a longer median survival than visceral or skeletal metastases.[49] Overall, complete and partial response rates to RT in such patients range from 59% to 79%.[35,49,50] A large dose per fraction (> 4 Gy) may be more effective for cutaneous melanoma lesions and superficial skin metastases. However, each case must be individualized with respect to the choice of fraction size and total dose.

RT is used infrequently to treat in-transit metastases, and its use is limited to situations in which the disease is too extensive for surgical excision and when isolated limb perfusion is either not possible or unavailable. In such cases, RT may provide palliative benefit and, occasionally, prolonged regional disease control.[5]

Visceral, cerebral, and skeletal metastases

Visceral metastases (stage IV disease) often respond to RT.[50,51] At least one report suggests that large doses per fraction may be beneficial for patients with visceral metastases to the lung, liver, abdominal and pelvic structures, or mediastinum.[51] Response was much more likely in patients who received fractional doses above 4 Gy compared with lower doses (82% vs 44%). The use of large doses per fraction to treat patients with visceral metastases must be tailored to the individual clinical situation and the structures to be irradiated; large doses per fraction may be appropriate in the setting of tumor-related hemorrhage.

In contrast, the degree of palliative benefit for brain and bone metastases appears to be relatively independent of fraction size, and there is no evidence that one fractionation schedule is superior to another.[51-54] As a result, radiation regimens commonly used for nonmelanoma metastases (30 Gy in 10 to 12 fractions) are reasonable, since they minimize the potential for late tissue complications associated with doses per fraction above 4 Gy. Symptomatic response rates in patients with multiple brain metastases treated with RT range from 39% to 76%.

RT provides successful palliation of painful skeletal metastases in 50% to 86% of patients.[51-53] No particular fractionation technique has proved more effective (eg, > 4 vs ≤ 4 Gy). In at least one report, symptom palliation was more successful for lesions on the extremities than for axial lesions (88% vs 60%).[52]


Brain metastasis

SRS delivers a very high dose of radiation to a stereotactically defined target in a single treatment session while sparing the adjacent normal brain tissue. Because brain metastases often displace normal brain tissue rather than infiltrate it, these lesions may be optimally treated with SRS. Both Gamma Knife and linear accelerator–based radiosurgery have been shown to be equally effective, with similar low risks of adverse effects. SRS is generally used for metastases smaller than 3 to 4 cm in diameter. The maximum tolerated doses are 24 Gy for lesions up to 2 cm in maximum diameter, 18 Gy for lesions between 2 and 3 cm, and 15 Gy for lesions larger than 3 cm.

While there have been randomized studies that used SRS in patients with metastases from mixed histologies, retrospective studies that examined outcomes specifically in patients with brain metastasis from melanoma showed that the 12-month local control rate after SRS ranged from 70% to 84%, and that the risk of delayed tumoral hemorrhage was not increased.[55] Patients with 8 or fewer brain metastases, no prior whole-brain RT (WBRT), Karnofsky performance score greater than 70, and controlled extracranial disease had a median survival of 54.3 months,[55] which suggests that SRS is an excellent treatment for patients with limited brain metastases and controlled systemic disease.

Several investigators have reported on their experience with SRS to the surgical bed following resection without WBRT; all of these reports included brain metastases from various histologies. A median dose of 15 to 19 Gy was used to target the resection bed, and the 1-year actuarial local control rate was between 79% and 94%.[56,57] The role of WBRT in addition to SRS has recently been tested in a randomized trial, and the results are awaited.[58]

Extracranial oligometastasis

Targeted RT for oligometastases is an active area of investigation. SBRT delivers hypofractionated (high dose per fraction) treatment with high degrees of accuracy to a variety of sites, including the lung, adrenal gland, liver, and spine. This treatment modality delivers 6 to 10 times the standard daily dose per fraction to the tumor in 3 to 10 treatment sessions over 1 to 3 weeks, with minimum exposure to the surrounding normal tissues. Rigorous and reproducible patient immobilization is required, and organ/target motions induced by respiration should be minimized.

The precision of SRS allows the spinal cord to be spared while a large radiation dose is delivered to involved vertebrae or paraspinal tumors. Several institutions have published their experiences with SRS for spinal lesions in the primary and retreatment settings. A prospective cohort of 393 patients with 500 histologically verified spinal metastases, including 38 melanoma lesions (8%), were treated with a dose of 12.5 to 25 Gy in a single fraction.[59] Significant pain palliation was reported by 86% of patients, and tumor control was achieved in 90% of patients; melanoma bone metastasis responded as well as metastases from other histologies. Another study analyzed 36 patients with melanoma spinal metastases treated with single-fraction SRS; 96% of these patients reported diminished axial and radicular pain, and none had radiation-induced toxicity.[60] For those who previously received conventional external beam RT to the vertebrae, SRS may also play a role in salvage retreatment.

The early success of treating inoperable early-stage non–small-cell lung cancer with SRS has led to the investigation of this technique for the treatment of limited metastatic disease in the lung. In a multicenter phase I/II study in which the dose was escalated from 48 to 60 Gy in 3 fractions in increments of 6 Gy to patients with one to three pulmonary metastases from various histologies, dose-limiting toxicity was not observed and 1-year local control was 100%.[61] Another study reported local control of 87% after 103 lung metastases from various histologies were treated with SRS.[56]

Experience with SRS for liver metastases is also emerging. Recent data from a multi-institutional phase I/II trial of patients with one to three hepatic lesions from various histologies treated to a dose of 60 Gy in 3 fractions showed a 2-year local control rate of 100% for lesions of ≤ 3 cm.[62]

Combination of RT and New Systemic Treatments

RT and vemurafenib

Approximately 40% to 60% of melanomas harbor activating BRAF mutations that are important for cell proliferation and resistance to apoptosis.[63] A recent phase III study revealed that vemurafenib, a selective oral inhibitor of mutant BRAF kinase, led to partial remission in most patients with metastatic BRAF V600E melanoma.[64]

There are limited clinical data on the outcomes of RT used in combination with selective inhibitors of mutant BRAF kinase. One group examined in vitro the radiosensitivity of BRAF-positive melanoma cell lines treated with vemurafenib. They treated selected radioresistant melanoma cell lines with vemurafenib and found them to be significantly radiosensitized, which was potentially attributable to G1-S phase cell-cycle arrest. In contrast, none of the BRAF–wild-type cell lines could be radiosensitized by vemurafenib.[65] Retrospective clinical data support this concept.[66] Further clinical trials are needed to examine the effect of vemurafenib combined with RT in patients with melanoma. One cautionary note: Increased radiation toxicity has been observed with concurrent BRAF inhibition and radiation.[67,68]

RT and immune checkpoint inhibitors

Melanomas that arise in immunocompetent hosts escape immune control by means of immunosuppressive strategies, including activation of immune checkpoints. Ipilimumab, an antibody that targets cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and enhances the antitumor immune response, caused a significant improvement in survival from 6.4 to 10 months in patients with metastatic melanoma.[69] Because RT induces inflammatory effects, it is postulated that the response to ipilimumab may be improved if it is administered with radiation treatment. There are rare reports about ipilimumab treatment combined with RT. Patients have received CTLA-4 antibody after being treated with stereotactic RT, without any adverse effects.[70] More dramatically, abscopal effects of radiation and ipilimumb therapy have been reported,[71,72] which suggest that radiation acts additively with immune therapy by increasing antigenicity. Similarly, blockade of the programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) pathway (via nivolumab or pembrolizumab) appears to enhance immune-mediated responses in the laboratory setting.[73] The clinical significance of and rationale for the combination of immune checkpoint inhibition and radiation have been reviewed.[74-76] Multiple clinical trials are underway to explore this approach.[77] A complete list of clinical trials that are investigating the role of RT in melanoma, particularly in the field of radioimmunotherapy, can be found at https://clinicaltrials.gov.

Irradiation and Hyperthermia

Hyperthermia in the temperature range of 40ºC to 45ºC is cytotoxic, producing a more than 2-log cell kill of human melanoma cells after a 1-hour exposure to 45ºC.[78] However, as with the sensitivity to irradiation, there is major variation among human melanoma cell lines in their sensitivity to heat.[79] Interest in combining heat and irradiation stemmed in part from the perceived radioresistance of melanoma but was primarily motivated by observation of the complementarity of heat-induced and RT-induced injury. The mechanisms underlying resistance to damage by irradiation and heat are different; thus, radioresistant cells may remain sensitive to heat.[80] In a clinical study that compared the dose-response curves for 134 melanoma lesions treated with RT alone or by RT combined with hyperthermia, there was a clinically derived therapeutic enhancement ratio of approximately 2.0.[5]

At least one randomized trial of RT with or without hyperthermia was conducted by the European Society for Hyperthermic Oncology in 70 patients with metastatic or recurrent melanoma.[81] The addition of hyperthermia to RT (3 fractions of 8 to 9 Gy) increased the complete response rate from 35% to 62%, and 2-year local control rates from 28% to 46%. However, only 14% of patients received the prescribed protocol treatment because of “equipment difficulties,” and survival did not differ between the two groups.

While hyperthermia is routinely used in conjunction with RT for palliative treatment of melanoma in some countries,[82,83] it is not widely used in the United States.

Summary and Clinical Recommendations

• Early clinical experience suggested that melanoma was a radioresistant tumor. However, subsequent preclinical and clinical studies indicate that melanoma may be sensitive to RT.

• RT monotherapy rarely has a role in the primary management of melanomas. RT may have a role as adjuvant therapy after surgery for primary melanomas that are associated with a high rate of local recurrence despite apparently adequate excision and in patients with positive margins after surgical excision.

• Surgery is the first choice of therapy for mucosal melanomas. However, if resection is not possible, RT may be used to achieve local control.

• Adjuvant RT can decrease the incidence of regional lymph node recurrence in patients with positive regional nodes in their initial surgical specimen. However, there is no evidence of any improvement in relapse-free or overall survival. The risk/benefit ratio may outweigh local control benefits, particularly in the groin and axilla.

• RT can provide useful palliation for patients with metastatic disease. Whether larger dose fractions improve palliation in this setting is unclear.

• SRS and SBRT may be beneficial in patients with limited brain and visceral metastasis.

• RT in conjunction with targeted therapy (BRAF inhibition) and immune checkpoint inhibition appears promising.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.


1. Fertil B, Malaise EP. Intrinsic radiosensitivity of human cell lines is correlated with radioresponsiveness of human tumors: analysis of 101 published survival curves. Int J Radiat Oncol Biol Phys. 1985;11:1699-707.

2. Doss LL, Memula N. The radioresponsiveness of melanoma. Int J Radiat Oncol Biol Phys. 1982;8:1131-4.

3. Rofstad EK. Radiation biology of malignant melanoma. Acta Radiol Oncol. 1986;25:1-10.

4. Bentzen SM, Overgaard J, Thames HD, et al. Clinical radiobiology of malignant melanoma. Radiother Oncol. 1989;16:169-82.

5. Overgaard J. The role of radiotherapy in recurrent and metastatic malignant melanoma: a clinical radiobiological study. Int J Radiat Oncol Biol Phys. 1986;12:867-72.

6. Williams MV, Drinkwater KJ. Radiotherapy in England in 2007: modelled demand and audited activity. Clin Oncol (R Coll Radiol). 2009;21:575-90.

7. Harwood AR, Cummings BJ. Radiotherapy for malignant melanoma: a re-appraisal. Cancer Treat Rev. 1981;8:271-82.

8. Stevens G, McKay MJ. Dispelling the myths surrounding radiotherapy for treatment of cutaneous melanoma. Lancet Oncol. 2006;7:575-83.

9. Chang DT, Amdur RJ, Morris CG, Mendenhall WM. Adjuvant radiotherapy for cutaneous melanoma: comparing hypofractionation to conventional fractionation. Int J Radiat Oncol Biol Phys. 2006;66:1051-5.

10. Sause WT, Cooper JS, Rush S, et al. Fraction size in external beam radiation therapy in the treatment of melanoma. Int J Radiat Oncol Biol Phys. 1991;20:429-32.

11. Harwood AR. Conventional fractionated radiotherapy for 51 patients with lentigo maligna and lentigo maligna melanoma. Int J Radiat Oncol Biol Phys. 1983;9:1019-21.

12. Schmid-Wendtner MH, Brunner B, Konz B, et al. Fractionated radiotherapy of lentigo maligna and lentigo maligna melanoma in 64 patients. J Am Acad Dermatol. 2000;43:477-82.

13. Hellriegel W. Radiation therapy of primary and metastatic melanoma. Ann N Y Acad Sci. 1963;100:131-41.

14. Postow MA, Hamid O, Carvajal RD. Mucosal melanoma: pathogenesis, clinical behavior, and management. Curr Oncol Rep. 2012;14:441-8.

15. Pfister DG, Ang K-K, Brizel DM, et al. Mucosal melanoma of the head and neck. J Natl Compr Canc Netw. 2012;10:320-38.

16. Balch C, Houghton A, Sober A. Radiotherapy for melanoma. In: Balch C, editor. Cutaneous melanoma. Philadelphia: J.B. Lippincott; 1992. p. 509.

17. Gilligan D, Slevin NJ. Radical radiotherapy for 28 cases of mucosal melanoma in the nasal cavity and sinuses. Br J Radiol. 1991;64:1147-50.

18. Combs SE, Konkel S, Thilmann C, et al. Local high-dose radiotherapy and sparing of normal tissue using intensity-modulated radiotherapy (IMRT) for mucosal melanoma of the nasal cavity and paranasal sinuses. Strahlenther Onkol. 2007;183:63-8.

19. Yanagi T, Mizoe J-E, Hasegawa A, et al. Mucosal malignant melanoma of the head and neck treated by carbon ion radiotherapy. Int J Radiat Oncol Biol Phys. 2009;74:15-20.

20. Inubushi M, Saga T, Koizumi M, et al. Predictive value of 3’-deoxy-3’-[18F]fluorothymidine positron emission tomography/computed tomography for outcome of carbon ion radiotherapy in patients with head and neck mucosal malignant melanoma. Ann Nucl Med. 2013;27:1-10.

21. Seregard S, Pelayes DE, Singh AD. Radiation therapy: uveal tumors. Dev Ophthalmol. 2013;52:36-57.

22. Temam S, Mamelle G, Marandas P, et al. Postoperative radiotherapy for primary mucosal melanoma of the head and neck. Cancer. 2005;103:313-9.

23. Foote MC, Burmeister B, Burmeister E, et al. Desmoplastic melanoma: the role of radiotherapy in improving local control. ANZ J Surg. 2008;78:273-6.

24. Croker J, Burmeister B, Foote M. Neurotropic melanoma: the management of localised disease. J Skin Cancer. 2012;2012:1-6.

25. Trotti A, Peters LJ. Role of radiotherapy in the primary management of mucosal melanoma of the head and neck. Semin Surg Oncol. 1993;9:246-50.

26. Lee SP, Shimizu KT, Tran LM, et al. Mucosal melanoma of the head and neck: the impact of local control on survival. Laryngoscope. 1994;104:121-6.

27. Kingdom TT, Kaplan MJ. Mucosal melanoma of the nasal cavity and paranasal sinuses. Head Neck. 1995;17:184-9.

28. Owens JM, Roberts DB, Myers JN. The role of postoperative adjuvant radiation therapy in the treatment of mucosal melanomas of the head and neck region. Arch Otolaryngol Head Neck Surg. 2003;129:864-8.

29. Kelly P, Zagars GK, Cormier JN, et al. Sphincter-sparing local excision and hypofractionated radiation therapy for anorectal melanoma: a 20-year experience. Cancer. 2011;117:4747-55.

30. Ballo MT. Sphincter-sparing local excision and adjuvant radiation for anal-rectal melanoma. J Clin Oncol. 2002;20:4555-8.

31. Frumovitz M, Etchepareborda M, Sun CC, et al. Primary malignant melanoma of the vagina. Obstet Gynecol. 2010;116:1358-65.

32. 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;115:5836-44.

33. Ballo MT, Ross MI, Cormier JN, et al. Combined-modality therapy for patients with regional nodal metastases from melanoma. Int J Radiat Oncol Biol Phys. 2006;64:106-13.

34. Guadagnolo BA, Zagars GK. Adjuvant radiation therapy for high-risk nodal metastases from cutaneous melanoma. Lancet Oncol. 2009;10:409-16.

35. Corry J, Smith JG, Bishop M, Ainslie J. Nodal radiation therapy for metastatic melanoma. Int J Radiat Oncol Biol Phys. 1999;44:1065-9.

36. Creagan ET, Cupps RE, Ivins JC, et al. Adjuvant radiation therapy for regional nodal metastases from malignant melanoma: a randomized, prospective study. Cancer. 1978;42:2206-10.

37. Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol. 2012;13:589-97.

38. Henderson M. Adjuvant radiotherapy after lymphadenectomy in melanoma patients: final results of an intergroup randomized trial (ANZMTG 0.1.02/TROG 02.01). Presented at the American Society of Clinical Oncology Annual Meeting; May 31, 2013; Chicago.

39. Henderson MA, Burmeister BH, Ainslie J, et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol. 2015;16:1049-60. http://linkinghub.elsevier.com/retrieve/pii/S1470204515001874. Accessed September 14, 2015.

40. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Melanoma version 2.2014. www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed September 14, 2015.

41. Lee RJ, Gibbs JF, Proulx GM, et al. Nodal basin recurrence following lymph node dissection for melanoma: implications for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys. 2000;46:467-74.

42. Miller EJ, Daly JM, Synnestvedt M, et al. Loco-regional nodal relapse in melanoma. Surg Oncol. 1992;1:333-40.

43. Shen P, Wanek LA, Morton DL. Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas? Ann Surg Oncol. 2000;7:554-9.

44. Monsour PD, Sause WT, Avent JM, Noyes RD. Local control following therapeutic nodal dissection for melanoma. J Surg Oncol. 1993;54:18-22.

45. Beadle BM, Guadagnolo BA, Ballo MT, et al. Radiation therapy field extent for adjuvant treatment of axillary metastases from malignant melanoma. Int J Radiat Oncol Biol Phys. 2009;73:1376-82.

46. Ballo MT, Garden AS, Myers JN, et al. Melanoma metastatic to cervical lymph nodes: Can radiotherapy replace formal dissection after local excision of nodal disease? Head Neck. 2005;27:718-21.

47. Bonnen MD, Ballo MT, Myers JN, et al. Elective radiotherapy provides regional control for patients with cutaneous melanoma of the head and neck. Cancer. 2004;100:383-9.

48. Guadagnolo BA, Myers JN, Zagars GK. Role of postoperative irradiation for patients with bilateral cervical nodal metastases from cutaneous melanoma: a critical assessment. Head Neck. 2010;32:708-13.

49. Schmidt-Ullrich RK, Johnson CR. Role of radiotherapy and hyperthermia in the management of malignant melanoma. Semin Surg Oncol. 1996;12:407-15.

50. Seegenschmiedt MH, Keilholz L, Altendorf-Hofmann A, et al. Palliative radiotherapy for recurrent and metastatic malignant melanoma: prognostic factors for tumor response and long-term outcome: a 20-year experience. Int J Radiat Oncol Biol Phys. 1999;44:607-18.

51. Katz HR. The results of different fractionation schemes in the palliative irradiation of metastatic melanoma. Int J Radiat Oncol Biol Phys. 1981;7:907-11.

52. Konefal JB, Emami B, Pilepich MV. Analysis of dose fractionation in the palliation of metastases from malignant melanoma. Cancer. 1988;61:243-6.

53. Dougherty MJ, Kligerman MM. Radiotherapy of melanoma. Cancer Treat Res. 1993;65:355-71.

54. Rate WR, Solin LJ, Turrisi AT. Palliative radiotherapy for metastatic malignant melanoma: brain metastases, bone metastases, and spinal cord compression. Int J Radiat Oncol Biol Phys. 1988;15:859-64.

55. Liew DN, Kano H, Kondziolka D, et al. Outcome predictors of Gamma Knife surgery for melanoma brain metastases. J Neurosurg. 2011;114:769-79.

56. Karlovits BJ, Quigley MR, Karlovits SM, et al. Stereotactic radiosurgery boost to the resection bed for oligometastatic brain disease: challenging the tradition of adjuvant whole-brain radiotherapy. Neurosurg Focus. 2009;27:E7.

57. Soltys SG, Adler JR, Lipani JD, et al. Stereotactic radiosurgery of the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys. 2008;70:187-93.

58. Fogarty GB, Hong A, Dolven-Jacobsen K, et al. First interim analysis of a randomised trial of whole brain radiotherapy in melanoma brain metastases confirms high data quality. BMC Res Notes. 2015;8:192. http://www.biomedcentral.com/1756-0500/8/192. Accessed September 14, 2015.

59. Gerszten PC, Burton SA, Ozhasoglu C, Welch WC. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine. 2007;32:193-9.

60. Gerszten PC, Burton SA, Quinn AE, et al. Radiosurgery for the treatment of spinal melanoma metastases. Stereotact Funct Neurosurg. 2005;83:213-21.

61. Rusthoven KE, Kavanagh BD, Burri SH, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases. J Clin Oncol. 2009;27:1579-84.

62. Rusthoven KE, Kavanagh BD, Cardenes H, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol. 2009;27:1572-8.

63. Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002;62:6997-7000.

64. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-16.

65. Ugurel S, Thirumaran RK, Bloethner S, et al. B-RAF and N-RAS mutations are preserved during short time in vitro propagation and differentially impact prognosis. PLoS One. 2007;2:e236.

66. Gorayski P, Dzienis M, Foote M, et al. Radiotherapy utilization in BRAF mutation-tested metastatic melanoma in the targeted therapy era: RT utilization in melanoma. Asia Pac J Clin Oncol. 2015 Apr 13. [Epub ahead of print]

67. Hecht M, Zimmer L, Loquai C, et al. Radiosensitization by BRAF inhibitor therapy––mechanism and frequency of toxicity in melanoma patients. Ann Oncol. 2015;26:1238-44.

68. Carlos G, Anforth R, Clements A, et al. Cutaneous toxic effects of BRAF inhibitors alone and in combination with MEK inhibitors for metastatic melanoma. JAMA Dermatol. 2015 Jul 22. [Epub ahead of print]

69. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23.

70. Stinauer MA, Kavanagh BD, Schefter TE, et al. Stereotactic body radiation therapy for melanoma and renal cell carcinoma: impact of single fraction equivalent dose on local control. Radiat Oncol. 2011;6:34.

71. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925-31.

72. Stamell EF, Wolchok JD, Gnjatic S, et al. The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys. 2013;85:293-5.

73. Pilones KA, Vanpouille-Box C, Demaria S. Combination of radiotherapy and immune checkpoint inhibitors. Semin Radiat Oncol. 2015;25:28-33.

74. Teng F, Kong L, Meng X, et al. Radiotherapy combined with immune checkpoint blockade immunotherapy: achievements and challenges. Cancer Lett. 2015;365:23-9.

75. Ngiow SF, McArthur GA, Smyth MJ. Radiotherapy complements immune checkpoint blockade. Cancer Cell. 2015;27:437-8.

76. Vatner RE, Cooper BT, Vanpouille-Box C, et al. Combinations of immunotherapy and radiation in cancer therapy. Front Oncol. 2014;4:325. http://journal.frontiersin.org/
article/10.3389/fonc.2014.00325/abstract. Accessed September 14, 2015.

77. Crittenden M, Kohrt H, Levy R, et al. Current clinical trials testing combinations of immunotherapy and radiation. Semin Radiat Oncol. 2015;25:54-64.

78. Roizin-Towle L, Pirro JP. The response of human and rodent cells to hyperthermia. Int J Radiat Oncol Biol Phys. 1991;20:751-6.

79. Bichay TJ, Feeley MM, Raaphorst GP. A comparison of heat sensitivity, radiosensitivity and PLDR in four human melanoma cell lines. Melanoma Res. 1992;2:63-9.

80. Dewey WC, Hopwood LE, Sapareto SA, Gerweck LE. Cellular responses to combinations of hyperthermia and radiation. Radiology. 1977;123:463-74.

81. Overgaard J, Gonzalez Gonzalez D, Hulshof MC, et al. Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic Oncology. 1996. Int J Hyperthermia. 2009;25:323-34.

82. van der Zee J. Heating the patient: a promising approach? Ann Oncol. 2002;13:1173-84.

83. Kroon BB, Bergman W, Coebergh JW, Ruiter DJ. Consensus on the management of malignant melanoma of the skin in the Netherlands. Dutch Melanoma Working Party. Melanoma Res. 1999;9:207-12.

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