Radiation therapy in the management of melanoma

INTRODUCTION — Radiation therapy (RT) can be a useful treatment option for patients with melanoma in some settings. RT has been utilized as adjuvant therapy after complete excision of a primary melanoma or after therapeutic lymphadenectomy to reduce the rate of local or nodal recurrence for certain types of melanoma.

Based upon important developments in targeted therapy and immunotherapy, systemic therapy is the preferred option in most clinical settings of stage IV disease (table 1A and table 1B), with RT use reserved for palliation, such as for painful bony metastasis, spinal cord compression, brain metastasis, or soft tissue metastasis causing pain, bleeding, or obstruction. Increasingly, RT is used as consolidation therapy for residual disease in patients not achieving a major response to systemic treatment. Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) can be particularly effective in ablating oligometastatic disease. Multidisciplinary consultation involving a surgeon, medical oncologist, and radiation oncologist with expertise in melanoma is required to assure optimal patient care.

The role of RT in the management of patients with melanoma is reviewed here. Discussions of the integration of RT in the treatment of melanoma brain metastases and the role of specialized RT techniques in the treatment of uveal melanoma are presented separately, as is the role of systemic therapy in the management of advanced melanoma.

●(See "Management of brain metastases in melanoma".)

●(See "Initial management of uveal and conjunctival melanomas", section on 'Radiation therapy'.)

●(See "Overview of the management of advanced cutaneous melanoma".)

DOSE AND SCHEDULE — The notion that melanoma is intrinsically radioresistant initially arose from cell culture studies [1-4] that showed a broad shoulder in the cell survival curves, implying better response to a higher dose per fraction and an unusually high repair capacity [5]. Some early clinical observations using large fractions of radiation per fraction supported these laboratory findings. However, other studies did not observe a difference between various large-fraction schedules, and some single-institution series reported similar outcomes with conventional fractionation schedules [6-8].

These conflicting observations led to a multicenter randomized phase III trial, which failed to show better outcomes with large fraction sizes. The Radiation Therapy Oncology Group (RTOG) trial randomly assigned 137 patients with metastatic melanoma at any site other than the abdomen or brain to four fractions of 8 Gy administered at weekly intervals or 20 fractions of 2.5 Gy administered daily five days per week [9]. There was no difference in the clinical response rate (24 and 23 percent, respectively, for complete response and 36 versus 34 percent for partial response); the durations of tumor control and survival were not reported. There were three grade 4 toxicities and three grade 3 toxicities in the four fractions of 8 Gy arm compared with only four grade 3 toxicities in the 20 fractions of 2.5 Gy arm. Toxicity data from this trial are difficult to interpret due to the short follow-up, limited number of events, and nonstandard treatment schedules used in both arms of this study.

With advances in RT delivery, a high dose per fraction over a shorter period can be delivered using stereotactic body radiation therapy (SBRT). This has a potential synergetic effect when combined with checkpoint inhibitor immunotherapy. (See 'Combined RT and systemic treatments' below.)

CUTANEOUS PRIMARY LESIONS — Wide resection is the definitive treatment of localized cutaneous melanoma. In rare cases (eg, inoperability because of medical comorbidities or proximity to vital structures such as the eye), definitive RT may be considered to the primary site. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

Lentigo maligna — Lentigo maligna, historically known as Hutchinson melanotic freckle, is a subtype of melanoma in situ characterized by atypical intraepidermal melanocytes. It has a slow growth rate and low potential to develop into invasive disease. In most instances, surgical resection remains the preferred approach. For patients with lentigo maligna where complete surgical excision is not feasible (eg, large lesion in the head and neck region), definitive RT is an appropriate alternative to surgery. (See "Lentigo maligna: Clinical manifestations, diagnosis, and management", section on 'Management'.)

The typical dose is 50 to 56 Gy in 2 Gy fractions with superficial energy radiation treating to a depth of 5 mm. A hypofractionated schedule can also be used depending on the size and location of the disease and the comorbidity of the patients.

In a large series, 593 patients with lentigo maligna and early lentigo maligna melanoma were treated with superficial energy RT [10]. The study assessed outcomes for primary treatment with RT, partial surgical removal followed by RT alone, and wide excision followed by postoperative RT, with reported complete clearance rates of 83, 90, and 97 percent, respectively.

Invasive melanoma — For most patients with localized primary melanomas, we do not offer primary (ie, definitive) RT to the tumor site as initial therapy. When these tumors are treated using wide local excision with adequate surgical margins, recurrence at the primary tumor site is uncommon, with local recurrence rates of less than 5 percent [11]. Additionally, observational data have not demonstrated a benefit for definitive RT over surgery in this population [12]. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

Adjuvant RT may improve local control in carefully selected patients at high risk for local recurrence at the primary site postoperatively, such as those with primary cutaneous melanoma of the head and neck with positive surgical margins not amenable to reresection without significant morbidity or reconstructive surgery [13-15]. In these particular patients, we recommend surgery followed by adjuvant RT to the primary site, rather than surgery alone. Adjuvant RT after re-excision is also appropriate for patients with locally recurrent melanoma of any subtype. As an example, RT has been effectively used in patients with head and neck primary tumors, including those with either positive or close margins where further excision was not considered feasible, with five-year locoregional control rates at the primary tumor site of up to 82 percent [15].

The approach to adjuvant RT in those with desmoplastic or neurotropic melanomas is discussed below. (See 'Desmoplastic melanoma' below.)

Adjuvant RT is not routinely suggested for patients with adverse pathologic features, such as thick tumors (Breslow thickness >4 mm), angiolymphatic and/or perineural invasion, or satellitosis, as advances in other treatment options for melanoma have improved outcomes in these patients [11,13,16]. Patients with thick tumors that are fully resected with negative margins are typically observed or can be offered clinical trials evaluating the use of adjuvant systemic therapy (eg, immunotherapy). Additionally, per the American Joint Committee on Cancer (AJCC) eighth edition staging system, patients with microsatellite metastases without nodal involvement have stage III disease and are thus typically treated with adjuvant immunotherapy. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

The approach to adjuvant RT directed at locoregional nodal disease in patients with melanoma (either with or without lymph node dissection) is discussed below. (See 'Regional lymph nodes' below.)

Desmoplastic melanoma — Desmoplastic melanoma is a rare subtype that accounts for approximately 1 to 4 percent of all melanomas. It is frequently associated with perineural spread (neurotropism), a risk factor for local recurrence. Adjuvant RT has been incorporated into the treatment of desmoplastic melanoma, since treatment with wide local excision alone has resulted in local recurrence rates up to 48 percent [11]. (See "Pathologic characteristics of melanoma", section on 'Desmoplastic melanoma'.)

For patients with desmoplastic melanoma and a high risk of local recurrence, we suggest surgery followed by adjuvant RT to the primary site, rather than surgery alone. Risk factors that are indications for RT include a head and neck primary site, extensive neurotropism, and positive or close surgical resection margins where re-resection is not feasible. In addition, adjuvant RT may also be appropriate for those with locally recurrent, surgically resectable disease.

Observational studies suggest that the addition of adjuvant RT to the primary tumor site is associated with improved local control and overall survival (OS) [17,18]. In particular, adjuvant RT has clinical benefit in patients with a significant neurotropic component to the tumor [18,19], as well as those with an incomplete primary resection [20]. However, patients with desmoplastic melanoma also respond well to immunotherapy [21], so the role of adjuvant RT is evolving, and further randomized trials in this setting are needed.

Data for the use of adjuvant RT are as follows:

●In a single-arm phase II trial, 20 patients with surgically resected desmoplastic melanoma were treated with adjuvant RT (30 Gy in five fractions to the postoperative bed) [22]. The two-year local recurrence rate was 10 percent, and five-year OS was 77 percent. Adjuvant RT was well tolerated, with no grade ≥3 adverse events.

●An initial OS benefit for adjuvant RT was illustrated in a retrospective, observational cohort study from the National Cancer Database (NCDB) [23]. This study included 2390 patients with early stage desmoplastic melanoma without nodal involvement treated with complete wide local excision either with (308 patients) or without adjuvant RT (2082 patients) to the primary tumor bed. In the propensity score matched analysis, adjuvant RT was associated with improved OS (five-year OS 72 versus 67 percent, hazard ratio [HR] 0.72, 95% CI 0.53-0.98).

By contrast, in a later separate analysis from the NCDB of 3527 patients (including 186 patients who also received immunotherapy), adjuvant radiation therapy was not associated with an OS benefit [21]. On multivariable analysis, older age, T stage ≥2, N stage ≥1, and no receipt of immunotherapy were associated with worse OS.

●A benefit in patients with neurotropic melanoma and close surgical margins was illustrated in another series from the Melanoma Institute Australia [18]. This study compared the outcomes of 671 neurotropic melanomas (72 percent of which were desmoplastic melanomas) with those of a control cohort of 718 non-neurotropic melanomas. Eighty-two patients received adjuvant RT to the primary site. At a median follow-up of approximately four years, adjuvant RT reduced the risk of local recurrence in patients with neurotropic melanoma with close pathological margins less than 8 mm (HR 0.48, 95% CI 0.27-0.87). RT was also associated with a reduction in the overall risk of recurrence (HR 0.51, 95% CI 0.29-0.87), particularly at the primary site (HR 0.30, 95% CI 0.13-0.69) and regional nodal sites (HR 0.41, 95% CI 0.17-0.98), but not at distant sites (HR 0.60, 95% CI 0.29-1.24).

●Further benefit for patients with melanoma of the head and neck was illustrated in a separate series of 277 patients with desmoplastic melanoma, 113 of whom received adjuvant RT [20]. RT was an independent predictor of local control (HR 0.15, 95% CI 0.06-0.39). RT was associated with lower recurrence rates for those with positive resection margins (14 versus 54 percent). For those with negative margins, adjuvant RT was also associated with improved local control (95 versus 76 percent), particularly in those with a head and neck primary site.

Additionally, data suggest high rates of efficacy with immunotherapy using programmed cell death protein 1 (PD-1) inhibitors in desmoplastic melanoma [24]. Therefore, initial treatment with immunotherapy may be offered to patients with locally advanced primary desmoplastic melanoma; local treatment with surgery or RT may be reserved for those with residual disease. Such patients should be managed in a multidisciplinary setting, and clinical trial participation is encouraged. (See "Overview of the management of advanced cutaneous melanoma", section on 'Desmoplastic melanoma' and "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Neoadjuvant pembrolizumab'.)

MUCOSAL MELANOMA — Mucosal melanomas constitute approximately 1 percent of all melanomas [25]. Mucosal melanomas are most common in the head and neck, followed by those in anorectal and genitourinary (including vulvovaginal) sites. Surgery is the first choice of therapy for mucosal melanomas. If resection cannot be accomplished, RT may be used to achieve local control in addition to adjuvant therapy [26]. (See "Locoregional mucosal melanoma: Epidemiology, clinical diagnosis, and treatment".)

For unresectable or locally advanced disease, primary RT has been used to treat sinonasal melanomas. The Northern Japan Radiation Therapy Oncology Group reported a series of 31 patients treated with definitive RT to a median dose of 50 Gy for unresectable primary mucosal melanoma in the head and neck region. The complete and partial response rates were 29 and 58 percent. Another series of 28 patients showed an actuarial local control rate of 49 percent at three years using a schedule of 50 to 55 Gy in 15 to 16 fractions [27]. With the advances in systemic therapy, there may be a role for upfront systemic therapy or concurrent systemic therapy with RT. These cases should be discussed in a multidisciplinary team meeting and enrolled in a clinical trial if available.

In the postoperative setting, adjuvant RT decreases the likelihood of local recurrence after complete resection but does not impact survival, in part because of the high rate of systemic relapse in these patients [28-31].

●As an example, mucosal head and neck melanomas are associated with a high rate of local disease recurrence, even if the primary lesion is small and the regional nodes are not involved [29,32]. In a large retrospective series of patients with head and neck mucosal melanomas from the Groupe d'Etude des Tumeurs de la Tête et du Cou (GETTEC), adjuvant RT improved local control [33]. The role of RT in the management of mucosal melanoma is discussed separately. (See "Locoregional mucosal melanoma: Epidemiology, clinical diagnosis, and treatment", section on 'Management of locoregional disease'.)

●The role of adjuvant RT in vulvovaginal melanoma was addressed in a retrospective Surveillance, Epidemiology, and End Results (SEER) database review of 201 patients in which 40 percent had received adjuvant RT. Overall survival (OS) was not significantly different when compared with those who received surgery alone, but the treatment groups were not comparable [34].

●Based upon a 45-year literature review of anorectal mucosal melanomas, adjuvant RT was found to be beneficial in patients with muscle invasive and regional nodal disease, with definitive RT providing palliation in unresectable advanced disease [35].

UVEAL MELANOMA — RT techniques and results for the treatment of uveal melanoma are discussed separately. (See "Initial management of uveal and conjunctival melanomas", section on 'Radiation therapy'.)

REGIONAL LYMPH NODES — Adjuvant RT has been utilized in the regional nodal basin after therapeutic nodal dissection for macroscopic disease (stage III disease (table 1A-B)). It is rarely indicated as the definitive management of melanoma metastatic to regional lymph nodes, as surgical excision provides superior local control as well as important prognostic information. RT can also often be used to treat the regional lymph node basin in stage IV disease for palliation.

Adjuvant RT after lymph node dissection — For patients at high risk of regional recurrence after lymph node dissection, adjuvant RT following surgery significantly decreases the rate of nodal field relapse but does not improve relapse-free survival or overall survival (OS) [36,37]. This should also be balanced against the possible side effects of RT, especially in the groin region. Given the efficacy of systemic therapies for melanoma in the neoadjuvant and adjuvant settings, the use of adjuvant RT for patients at high risk for both local and distant metastases requires careful multidisciplinary evaluation and discussion with patients.

Adjuvant RT is an option for patients treated with lymph node dissection who are ineligible for adjuvant systemic therapy or those with high-risk tumors where regional control is an issue (eg, poor pathological response to neoadjuvant systemic therapy, nodal recurrence despite previous systemic immunotherapy or targeted therapy; heavy tumor burden in the cervical region) [38]. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

In a phase III trial of 250 patients conducted primarily in Australia and New Zealand, patients with high-risk stage III melanoma were randomly assigned to RT (48 Gy in 20 fractions) or observation after therapeutic nodal dissection [36,37]. Patients were considered at high risk if there was extranodal spread of melanoma, multiple nodes involved (any parotid involvement, ≥2 nodes in the neck or axilla, ≥3 nodes in the groin), or large nodes with disease (≥3 cm in the neck, ≥4 cm in the axilla or groin). At a median follow-up of six years, there were significantly fewer relapses in the adjuvant RT group (21 versus 36 percent, hazard ratio [HR] 0.52, 95% CI 0.31-0.88). However, there was no significant difference in either relapse-free survival (HR 0.89, 95% CI 0.65-1.22) or OS (HR 1.27, 95% CI 0.89-1.79). In multivariable analysis, treatment arm (HR 0.49, 95% CI 0.28-0.85) and extranodal extension (HR 1.69, 95% CI 1.21-2.36) were independent predictors of nodal field relapse. This trial also examined toxicity and quality of life as secondary endpoints. Twenty percent of the RT patients had a grade 3 toxic effect, mainly affecting skin and subcutaneous tissues. Grade 4 toxicity after RT was uncommon (two patients). Over five years, there were no significant differences in upper limb volume between the two groups. In the lower limbs, there was a significant increase in volume after adjuvant RT compared with observation (mean volume ratio 15.0 versus 7.7 percent, 95% CI 1.5-13.1). In terms of quality of life, there were no significant differences between the two groups at the 3-, 6-, 12-, 24-, and 60-month time points except for in physical wellbeing at three months and the Response to Stress Questionnaire total score at 3, 6, and 12 months, all favoring the observation group.

Based upon these results, patients should be evaluated for adjuvant RT for improvement in nodal field control after therapeutic nodal dissection if they have a poor pathologic response to neoadjuvant therapy or are ineligible for adjuvant systemic therapy and have one of the following:

●Multiple positive nodes (any parotid disease, ≥2 nodes in the neck or axilla, ≥3 nodes in the groin)

●Extranodal spread [39]

●Large involved nodes (≥3 cm in the neck, ≥4 cm in the axilla or groin)

●Positive margins

●Recurrent disease despite previous surgery and adjuvant systematic therapy

Adjuvant RT without lymph node dissection for head and neck melanoma — The current standard of care in the treatment of melanoma of the skin of the head and neck includes wide excision of the primary site. The roles of sentinel lymph node biopsy and complete nodal dissection are evolving. When sentinel biopsy is not feasible for either medical or technical reasons, the regional basins can be carefully followed with clinical examination and serial ultrasonography. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites", section on 'Head and neck' and "Evaluation and management of regional nodes in primary cutaneous melanoma".)

Lymph node basin RT has been advocated as an alternative to complete nodal dissection in older adults or those with a contraindication to extensive surgery, particularly in patients with metastatic melanoma to cervical nodes from head and neck primary sites. As an example, 36 patients underwent cervical nodal basin irradiation (30 Gy at 6 Gy per fraction twice per week) after excisional biopsy of the macroscopic involved node(s) [40]. The five-year rate of complications was reported as less than 10 percent, and the five-year nodal field control rate was greater than 90 percent. In another observational study of 28 older adults treated for melanoma of the head and neck or an unknown primary site with simple excision of the palpable node and adjuvant RT, the five-year regional control and OS rates were 69 and 50 percent, respectively [41].

Elective RT to the clinically node-negative regional basin after wide excision of primary cutaneous melanoma of the head and neck greater than 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 [42]. Patients with desmoplastic melanoma and those who had undergone surgery for suspicion of lymph node metastasis were excluded. The 10-year locoregional control rate was 86 percent. However, based upon the lack of high-level evidence, elective prophylactic nodal RT is not recommended. (See 'Regional lymph nodes' above.)

PALLIATIVE RT — RT can provide symptomatic palliation for cerebral metastases, bone pain, spinal cord compression, and symptomatic soft tissue metastases.

Cutaneous and lymph node metastases — Metastatic spread to the skin and lymph nodes occurs in approximately 50 percent of patients with stage IV melanoma and is associated with a better median survival than visceral or skeletal metastases [43]. They can be problematic, causing pain, bleeding, or compression of surrounding normal structures. In the absence of extensive distant metastases, surgical excision is the primary approach for in-transit metastases when feasible; regional chemotherapy (isolated limb perfusion or isolated limb infusion), systemic therapy (checkpoint inhibitors, BRAF targeted therapy), intralesional therapy (talimogene laherparepvec), and RT are alternatives when surgery is not possible. (See "Cutaneous melanoma: In-transit metastases".)

RT can provide symptomatic benefit and prolonged local disease control. In a randomized study that compared the effectiveness of two different RT schedules in the treatment of soft tissue and nodal metastasis, the overall response rate was 59 percent and the complete response rate was 24 percent [9]. 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 choice of fraction size and total dose.

Skeletal metastases — RT is effective in relieving pain from skeletal metastasis, with complete pain relief in 23 percent and an overall response rate of 60 percent.

A systematic review of 27 randomized trials including a variety of malignancies showed that a single fraction of 8 Gy was as effective as multiple fractions in relieving bone pain [44]. However, patients who received a single fraction of RT were 2.6 times more likely to require retreatment with RT than those treated with multiple fractions of RT. Therefore, as a result, RT regimens commonly used for non-melanoma metastases (8 Gy in one fraction to 30 Gy in 10 to 12 fractions) are reasonable. For skeletal metastases associated with a large soft tissue component, a high total dose should be considered, taking into account the patient performance status and burden of disease. (See "Radiation therapy for the management of painful bone metastases".)

Visceral metastases — Visceral metastases often respond to RT [43,45]. At least one report suggests that large doses per fraction may be beneficial for patients with metastases to the lung, liver, abdominal and pelvic structures, and mediastinum [45]. The likelihood of response was much higher in patients who received fractional doses above 4 Gy compared with lower doses (82 versus 44 percent). The choice of large fractions in patients with visceral metastases must be individualized to the clinical situation and the structures to be irradiated. The use of a large dose per fraction to treat these anatomic sites may be particularly appropriate in the setting of tumor-related hemorrhage.

Brain metastases — Brain metastases are a frequent complication in patients with advanced melanoma and are an important cause of both morbidity and mortality. The approach to patients with melanoma brain metastases is rapidly evolving. Advances in neurosurgical techniques and RT, especially stereotactic radiosurgery (SRS), and systemic therapy with intracranial activities (eg, immunotherapy, targeted therapy) have led to major improvement in the ability to control brain metastases.

The prolonged survival and durable remissions in some patients with metastatic melanoma raise important issues concerning complications of therapy, which need to be considered in planning a therapeutic approach. Because of this, a multidisciplinary approach that considers all available treatment modalities is essential for the management of the patient with brain metastases. (See "Management of brain metastases in melanoma", section on 'Approach to management' and "Management of brain metastases in melanoma", section on 'Stereotactic radiosurgery'.)

STEREOTACTIC RADIOSURGERY AND STEREOTACTIC BODY RT — Stereotactic radiosurgery (SRS) delivers a very high dose of radiation to a stereotactically defined target in a single treatment session while sparing the adjacent normal tissue. Stereotactic body radiation therapy (SBRT) can deliver hypofractionated (high dose per fraction) treatment with high degrees of precision in 2 to 10 treatment sessions over one to three weeks with minimum exposure to the surrounding normal tissues. Rigorous and reproducible patient immobilization is required, and organ/target motions induced by respiration must be minimized. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

Extracranial oligometastases — SBRT is an established approach for patients with extracranial oligometastatic disease in a variety of tumor types. The SABR-COMET trial that included patients with one to five extracranial metastases of a variety of tumor types (breast, lung, colorectal, and prostate) showed an improvement in the five-year overall survival (OS) with the addition of SBRT to standard of care therapy (42 versus 18 percent) [46]. For patients with metastatic melanoma, SBRT may also have a role in the treatment of residual oligometastatic disease or isolated sites of disease progression after systemic therapy if the presence of residual melanoma is confirmed with a biopsy, imaging, or circulating tumor DNA. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

The precision of stereotactic techniques allows the spinal cord to be spared while delivering a large radiation dose to involved vertebrae or paraspinal tumors, and these approaches may provide important symptom palliation. Several institutions have published their experiences with SBRT 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 percent), was treated with a dose of 12.5 to 25 Gy in a single fraction [47]. Significant pain palliation was reported in 86 percent of the patients, and tumor control was achieved in 90 percent of the patients; melanoma bone metastases responded as well as other histologies. Another study analyzed 36 patients with melanoma spinal metastases treated with single-fraction SRS and reported that 96 percent of patients reported improvement of axial and radicular pain and none experienced radiation-induced toxicity [48]. For those who previously received conventional external beam RT to the vertebrae, SBRT may also play a role in salvage retreatment. (See "Radiation therapy for the management of painful bone metastases", section on 'Stereotactic radiation therapy'.)

SBRT has also been extensively applied in the treatment of lung lesions, including both primary tumors and metastases. Studies in patients with metastatic disease have included patients with a variety of histologies, including melanoma; these reports indicate a high degree of local control, making this a potentially valuable option for patients with oligometastatic disease. In a randomized phase II trial (SABR-COMET), SBRT improved OS in patients with mixed primary tumor histologies and one to five oligometastases of varying extracranial sites (including lung, liver, bone, and adrenal gland) compared with standard palliative treatments [46]. Further details of this trial are discussed separately. (See "Stereotactic body radiation therapy for lung tumors", section on 'Lung metastases'.)

Given the improved effectiveness of systemic treatments for patients with advanced melanoma, the role of palliative RT to oligo- or symptomatic metastatic disease requires reassessment. Decisions about RT should be made in the context of multidisciplinary management discussions and most likely should be reserved for patients who have isolated disease progression or unresectable biopsy-proven oligometastatic disease following systemic therapy.

COMBINED RT AND SYSTEMIC TREATMENTS

RT plus BRAF inhibitor — Forty to 60 percent of cutaneous melanomas harbor activating BRAF mutations, which are important for cell proliferation and resistance to apoptosis. This has led to the development of therapies targeted against the mitogen-activated protein kinase (MAPK) pathway that have significantly prolonged survival in this patient subset. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)

There are few reports on the combination of radiation therapy (RT) and selective inhibitors of the mutant BRAF kinase. One group examined in vitro the radiosensitivity effect of vemurafenib in RAF positive melanoma cell lines. They treated radioresistant melanoma cell lines with vemurafenib and found them to be significantly radiosensitized, probably due to G1 phase cell cycle arrest. By contrast, none of the BRAF wild-type cell lines could be radiosensitized by vemurafenib [49]. Further studies are needed in melanoma patients being treated with a combination of targeted therapy and RT.

Radiation sensitization and recall, in some cases severe and involving cutaneous and visceral organs, have been reported in patients treated with RT prior to, during, or subsequent to treatment with vemurafenib or dabrafenib alone [50,51]. However, radiation sensitization with combined BRAF and MEK inhibitors has not been reported.

RT and immune checkpoint inhibitors — Immune checkpoint inhibitors (ICI) that target programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) induce antitumor immune responses, resulting in a significant improvement in survival.

Radiation causes local inflammatory effects, and there might be an improved response to therapy if ICI is administered in conjunction with RT. There are good preclinical data to support a synergetic effect of combining RT with ICI in terms of enhanced response rates within the irradiated site as well as outside the RT field (abscopal effect) [52,53].

●The rate of abscopal effect was defined retrospectively in 47 patients treated with RT and ipilimumab. Prior to RT, the out of RT field index lesion response rate to ipilimumab was 11 percent, and this increased to 25 percent after RT to the non-index lesion. In multivariable analysis, fractionated RT was a significant predictor of response [54].

●In a prospective study of 22 patients in which RT was given within five days after starting ipilimumab, there were six patients with objective responses, including three complete responses and three partial responses [55]. Treatment was well tolerated, without unexpected toxicities.

●Similarly, blockade of PD-1 with nivolumab or pembrolizumab appears to enhance immune-mediated responses. Treatment responses have been reported with the combination of PD-1 inhibitors and radiation in advanced melanoma with response rates of up to 64 percent [56-58].

As examples, an initial report on combining PD-1 inhibitors with RT showed a nonirradiated lesional response rate of 46 percent [57]. The response rate of the irradiated lesion was 44 percent for those who had sequential RT and anti-PD-1 therapy and was 64 percent for those who had concurrent RT and anti-PD-1 therapy. Subsequently, in a phase II trial of 20 patients with advanced melanoma treated with concurrent nivolumab and stereotactic body RT (24 Gy in three fractions), overall responses were seen in nine patients (45 percent) [58]. Serial analysis of eight patients with detectable mutant BRAF and NRAS-circulating tumor DNA prior to treatment suggested that a subset of tumors with low programmed death ligand-1 (PD-L1) scores only started to respond after the addition of SBRT.

The extent to which RT contributes to these distant responses is uncertain given the efficacy of ICI in the absence of RT. A randomized study evaluating the addition of sub-ablative stereotactic RT to ICI in 96 patients with multiple tumor types (24 with melanoma) failed to demonstrate an improvement in progression-free survival or overall survival [59]. However, interpretation of this study is limited by its small size, inclusion of many distinct tumor types, and RT was delivered to all sites of disease in only 18 percent of the patients. Additional clinical trials are underway combining ICI and RT. Until these trial results are reported, treatment decisions should be individualized and made in the context of a multidisciplinary consultation.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)" and "Patient education: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●General principles

•The efficacy of systemic therapy for patients with advanced melanoma has forced a reassessment of the risk-benefit ratio of radiation therapy (RT) in multiple settings. As a result, wherever possible, decisions about RT for patients with melanoma should be made in the context of a multidisciplinary consultation involving specialists with expertise in the management of melanoma. (See 'Introduction' above.)

•Early clinical experience suggested that melanoma was a radioresistant tumor. However, subsequent preclinical and clinical studies indicate that melanoma may be sensitive to RT, particularly when greater than standard doses of radiation are administered in each fraction. (See 'Dose and schedule' above.)

●Is there a role for definitive RT to the primary site? – For most patients with localized primary melanoma, we do not offer primary (ie, definitive) RT to the tumor site as initial therapy, as surgical resection alone results in low rates of local recurrence. (See 'Cutaneous primary lesions' above.)

●Indications for adjuvant RT to the primary site – We offer adjuvant RT to the following populations:

•For patients with primary cutaneous melanoma of the head and neck region with positive surgical margins not amenable to re-resection, we recommend surgery followed by adjuvant RT to the primary site, rather than surgery alone (Grade 1B). (See 'Invasive melanoma' above.)

•In addition, for patients with fully resected desmoplastic melanoma with risk factors for local recurrence (ie, head and neck primary, extensive neurotropism, close margins), we suggest surgery followed by adjuvant RT, rather than surgery alone (Grade 2C). (See 'Desmoplastic melanoma' above.)

•Adjuvant RT is also appropriate for patients with locally recurrent melanoma of any subtype after re-excision.

●Mucosal melanoma – Surgery is the first choice of therapy for mucosal melanomas. However, if resection is not possible, RT may be used to achieve local control. (See 'Mucosal melanoma' above.)

●What is the role of adjuvant RT to the regional lymph nodes? – Adjuvant RT can decrease the incidence of regional lymph node recurrence in patients with high-risk regional node involvement, but does not improve relapse-free survival or OS. Given the efficacy of systemic therapies for melanoma in the adjuvant setting, the use of adjuvant RT for patients at high risk for both local and distant metastases requires careful multidisciplinary evaluation and discussion with patients. (See 'Regional lymph nodes' above.)

●Palliative RT – RT can provide useful palliation for patients with metastatic disease. Whether larger dose fractions improve palliation in these settings is unclear. (See 'Palliative RT' above.)

●SRS and SBRT – Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) may be beneficial in patients with a single or limited number of brain and/or extracranial metastases. (See 'Stereotactic radiosurgery and stereotactic body RT' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Anand Mahadevan, MD, who contributed to an earlier version of this topic review.