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Management of brain metastases in melanoma

Management of brain metastases in melanoma
Authors:
Wolfram E Samlowski, MD
Julian K Wu, MD
Section Editors:
Michael B Atkins, MD
Russell S Berman, MD
Deputy Editors:
Sonali Shah, MD
April F Eichler, MD, MPH
Literature review current through: Jun 2022. | This topic last updated: Nov 24, 2021.

INTRODUCTION — Brain metastases are a frequent complication in patients with melanoma. In the past, brain metastases almost invariably contributed to neurologic morbidity and death. However, the prognosis for many patients has been substantially improved by major advances in neuroimaging, improved options for the neurosurgical and radiotherapeutic management of brain metastases, improved management of metastatic disease at systemic sites, and demonstrated activity of systemic treatments against brain and other sites of central nervous system (CNS) metastases (eg, leptomeningeal, spinal cord).

The management of patients with melanoma and brain metastases will be reviewed here. General aspects of the clinical manifestations, diagnosis, and management of cancer-related brain metastases are discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases" and "Overview of the treatment of brain metastases".)

EPIDEMIOLOGY AND CLINICAL PRESENTATION — Melanoma accounts for approximately 10 percent of all patients who develop brain metastases. In the United States, only lung and breast cancers are more frequent primary sites associated with brain metastases [1]. Approximately one-third of patients with newly diagnosed metastatic melanoma are estimated to also present with brain metastases [2].

In the eighth edition of the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system for melanoma, brain metastases are separated from other sites of metastasis and form a separate M category, M1d (table 1).

Patients with melanoma limited to the skin and without lymph node involvement (stage I, II (table 2)) have a low incidence of brain metastases [3], although younger patients with thick primaries may have an increased risk of late central nervous system (CNS) failure [4]. In patients who presented with advanced regional melanoma (stage IIIB and C), a retrospective analysis of data from the large multi-institutional S0008 adjuvant trial observed a 15 percent incidence of subsequent brain metastases, which occurred predominantly in the first three years after surgery [5]. The incidence of brain metastases in stage III melanoma patients was subsequently confirmed in a larger dataset [6]. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

The risk of brain metastases in advanced melanoma increases with disease duration. In patients with metastatic disease but without brain involvement, a phase III trial comparing dacarbazine and temozolomide found that 20 to 30 percent of patients had brain metastases detected by one year and 30 to 40 percent by three years [7]. The frequency of brain metastases during melanoma treatment may be decreasing, likely due to treatment with checkpoint inhibitor immunotherapy and targeted therapies [8]; however, CNS involvement still represents an important clinical challenge.

Eighty percent of melanoma brain metastases are supratentorial, while 15 percent are infratentorial or leptomeningeal, and 5 percent are located in the brainstem [9]. Hippocampal metastases are quite rare (<0.1 percent) [10]. Common symptoms include headache, neurologic deficits, and/or seizures. In addition, brain metastases have a high propensity for spontaneous hemorrhage. Patients who present with larger, symptomatic metastases are at higher risk for deteriorating performance status and worse prognosis [11]. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases", section on 'Clinical manifestations'.)

Symptomatic patients often do not recover to completely normal neurologic function following treatment. This observation provides a rationale for the early detection and treatment of asymptomatic melanoma brain metastases. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases", section on 'Diagnosis' and "Imaging studies in melanoma", section on 'Brain' and "Staging work-up and surveillance of cutaneous melanoma", section on 'Symptomatic disease or suspected metastases'.)

RISK FACTORS — Factors that are associated with an increased risk of systemic metastases also correlate with the subsequent development of brain metastasis. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

Factors that have been specifically linked to the development of brain metastases include [3,12-15]:

Male sex [13]

Age >60 [13]

Melanomas arising on mucosal surfaces or the skin of the trunk, head, neck, or scalp [13,16]

Deeply invasive or ulcerated primary lesions [13]

Unknown primary melanomas [5]

Acral, lentiginous, or nodular histology

Involvement of >3 regional lymph nodes, either at diagnosis or relapse [14]

Visceral metastasis at the time of diagnosis, especially if disseminated to more than one organ (eg, M1b, M1c disease (table 3 and table 1)) [13]

Elevated serum lactate dehydrogenase (LDH) [13]

Mutations in BRAF and NRAS [17-19]

Expression of C-C chemokine receptor 4 (CCR4) on melanoma cells [20]

Activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway [21]

PROGNOSIS — In historical series, melanoma patients who developed brain metastases had a very poor prognosis [12,22-24]. In analyses of over 1400 patients diagnosed in the 1980s and 1990s, the median survival was three to four months, the one-year survival rate was 9 to 19 percent, and only rare patients had prolonged survival.

However, the contemporary use of stereotactic radiosurgery (SRS) and systemic therapy (eg, checkpoint inhibitor immunotherapy or targeted therapy with BRAF plus MEK inhibitors) to control both brain metastases and other metastatic sites has resulted in a meaningful improvement in prognosis [25-27]. As an example, in a series of 179 consecutive cases of patients treated with SRS for brain metastases followed by either immunotherapy or targeted therapy, the median overall survival (OS) was 11 months, and the one- and two-year OS rates were 50 and 27 percent, respectively [25]. A population-based study of over 1100 patients with melanoma brain metastases treated with radiation found an improvement in OS for patients who received immunotherapy compared with those who did not (11.1 versus 6.2 months), which remained significant after propensity score matching [28]. Other studies suggest that intracranial progression rates after initial therapy may be decreasing in the era of immunotherapy and targeted therapy [29-31].

Favorable prognostic signs include the delayed onset of a single brain metastasis without other visceral metastatic disease and a normal serum lactate dehydrogenase (LDH) [32], or a patient with an unknown primary tumor presenting as a solitary melanoma brain metastasis [12]. By contrast, multiple brain lesions, extensive visceral metastases, high serum LDH, and a primary lesion of the head and neck region have historically carried an unfavorable prognosis [12,13,33-35].

A variety of tools were developed for prognostic purposes in individual patients. These included recursive partitioning analysis (table 4), a diagnosis-specific graded prognostic assessment tool for patients with melanoma brain metastases (table 5), the Basic Score for Brain Metastases (BSBM) tool (table 6), and the score index for radiosurgery in brain metastases (table 7) [36-39]. The graded prognostic assessment tool for melanoma incorporates molecular markers (eg, BRAF mutation status) [40].

The preceding prognostic prediction tools have all been criticized, as they do not incorporate choice of therapy. As a result, a volume-timing-systemic therapy (VTS) prognostic score has also been proposed, which incorporates the influence of cumulative brain metastasis volume, timing of metastases, and choice of systemic treatment (immunotherapy or targeted therapy) (table 8) [41]; however, this assessment tool needs to be further validated in prospective studies.

APPROACH TO MANAGEMENT

Multidisciplinary approach — Both extracranial and central nervous system (CNS) melanoma metastases can profoundly affect quality of life and shorten longevity in the absence of effective treatment. The general approach to melanoma brain metastases is summarized in the algorithm (algorithm 1).

Advances in locoregional CNS therapy such as neurosurgical techniques, conformal radiation therapy (RT), and stereotactic radiosurgery (SRS) have led to a major improvement in the ability to control brain metastases, and systemic therapy (immunotherapy, BRAF plus MEK inhibitor therapy) has dramatically prolonged overall survival (OS) in patients with disseminated cutaneous melanoma at extracranial sites. Although the CNS has been considered a sanctuary site that does not respond to systemic therapy, newer data suggest that this is not the case, and systemic therapy is becoming an important component of the treatment of brain metastases in many patients. (See 'Neurosurgery' below and 'Stereotactic radiosurgery' below and 'Systemic therapy' below and "Overview of the management of advanced cutaneous melanoma".)

The prolonged survival and durable remissions in some patients with metastatic cutaneous 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 proper treatment of the patient with brain metastases.

Important factors that need to be considered in planning a comprehensive treatment approach for patients with melanoma brain metastases include:

Clinical characteristics of brain metastases (eg, number, size, location, and extent of CNS symptoms)

Extent of extracranial systemic disease

Patient performance status and comorbidities

BRAF mutation status

Prior exposure to therapy with intracranial efficacy (eg, immunotherapy, BRAF/MEK inhibitors, SRS)

Diagnostic uncertainty — The approach to new and recurrent brain metastases presented below assumes that the most likely diagnosis is metastatic melanoma, or that the diagnosis has been confirmed pathologically. However, not all new tumors or mass lesions in patients with melanoma are metastases, and alternative diagnoses should be considered in all patients before treating empirically, particularly for single masses and in the absence of systemic metastatic disease. Surgery is often indicated in such situations before proceeding with additional therapy, even for relatively small or asymptomatic tumors, in order to ensure an accurate diagnosis. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases", section on 'Diagnosis' and "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Differential diagnosis'.)

New untreated brain metastases, systemic therapy-naïve — Significant intracranial and extracranial response rates are observed with both BRAF plus MEK inhibitors (in patients with BRAF-mutant disease) and immunotherapy. They are acceptable treatment options for select patients eligible for systemic therapy with small (<1 cm), asymptomatic or minimally symptomatic, previously untreated brain metastases, along with extracranial metastatic disease burden (algorithm 1). This is a common clinical scenario, as a high proportion of patients with metastatic melanoma and brain metastases also have active systemic disease, which may pose the most important threat to quality and duration of life.

For patients with intracranial disease who are not eligible for (or choose to forego) systemic therapy with intracranial efficacy, locoregional CNS therapy with surgical resection and/or SRS may be offered. (See 'Neurosurgery' below and 'Stereotactic radiosurgery' below.)

Small, minimally symptomatic or asymptomatic brain metastases — Based on evolving data, patients with small (<1 cm), minimally symptomatic or asymptomatic brain metastases are increasingly considered to be candidates for immediate systemic therapy with deferred locoregional therapy (ie, SRS or surgery). When this approach is used, patients require very careful monitoring for early detection of CNS disease progression. Patients who have not previously received immunotherapy are optimal candidates for this approach, and selection of therapy is influenced by the extent of extracranial disease and BRAF mutation status (algorithm 1).

For patients with tumors that do not contain a BRAF mutation, who have active extracranial disease, and who are able to tolerate the potential toxicities of immunotherapy, the combination of nivolumab and ipilimumab (table 9) is preferred over other systemic regimens because intracranial response rates and durability are highest with this combination therapy. For rare patients with isolated intracranial metastases, treatment selection should be individualized, and either definitive locoregional CNS therapy (ie, SRS or surgery) or immunotherapy would be reasonable options. (See 'Nivolumab plus ipilimumab' below.)

For patients with a BRAF-mutant tumor, both immunotherapy (nivolumab plus ipilimumab) and targeted therapy (BRAF plus MEK inhibition) are active intracranially [42]. Targeted therapy produces rapid but short durations of intracranial response, whereas intracranial responses with immunotherapy are sometimes slower, but more durable. Immunotherapy may be preferred in such patients without symptomatic extracranial disease posing an immediate threat to well-being.

However, combined BRAF plus MEK inhibitor therapy may be offered to patients with symptomatic extracranial disease who are unable to tolerate the possible toxicities of immunotherapy. Such agents can be initiated quickly to obtain more rapid and reliable responses, with very careful monitoring for early detection of CNS progression. (See 'BRAF and MEK inhibitors' below.)

Surgery and/or SRS remain important salvage options for patients who progress intracranially during or after systemic therapy. (See 'Neurosurgery' below and 'Stereotactic radiosurgery' below.)

Large or symptomatic brain metastases — For patients with a symptomatic brain metastasis or with multiple large brain metastases, local control is a high priority, since progression of brain metastases can lead to rapid functional deterioration, impaired quality of life, or death. These patients often require a course of glucocorticoids to manage CNS symptoms in conjunction with definitive locoregional CNS therapy. (See 'Symptom control' below.)

Although there are evolving data on the role of systemic therapy in patients with large or symptomatic brain metastases as well as the optimal timing to integrate systemic therapy with neurosurgery or SRS, early locoregional CNS therapy remains a priority in most of these patients. Therefore, closely coordinated multidisciplinary management is necessary to avoid lengthy delays in initiating subsequent systemic therapy. (See 'Symptomatic brain metastases' below.)

Surgical resection is the preferred approach for solitary large (>3 cm) tumors, metastases in the posterior fossa that cause significant effacement of the fourth ventricle or cerebral aqueduct, and lesions surrounded by significant edema. Compared with SRS, resection of such tumors is typically associated with more rapid symptomatic improvement and resolution of peritumoral edema. Prompt control of edema and discontinuation of glucocorticoids are particularly important for patients who will initiate immunotherapy postoperatively, to maximize efficacy. Debulking of large tumors may also lower the risk of immunotherapy-related pseudoprogression and edema. (See 'Neurosurgery' below.)

Postoperative SRS (single-fraction or hypofractionated) or fractionated RT to the resection bed has been used as an adjunct to neurosurgery to minimize the risk of local recurrence. However, in the current era of BRAF plus MEK inhibitor therapy and immunotherapy, the role of postoperative RT to the resection bed for patients with melanoma metastases is controversial. (See 'Management following surgery' below.)

For patients who are not candidates for surgical resection, RT alone, usually in the form of single-fraction or hypofractionated SRS, has become an effective alternative to surgical resection. For patients with a large number of metastases, whole brain radiation therapy (WBRT) was originally used in this setting. However, given the poor historical survival and neurocognitive outcomes after WBRT, more-targeted radiation approaches are being used more extensively. Carefully selected patients with multiple lesions may be successfully managed with single-fraction or hypofractionated SRS courses along with systemic therapy, which can aid in the control of at least small-volume disease [43-45]. (See 'Role of WBRT after SRS' below.)

The approach to selecting systemic therapy in patients with persistently symptomatic brain metastases who are unable to taper off glucocorticoids despite definitive locoregional CNS therapy is discussed below. (See 'Symptomatic brain metastases' below.)

New brain metastases, current or prior systemic therapy — Some patients with new melanoma brain metastases may have been previously exposed to systemic therapy. For example, patients may receive adjuvant systemic therapy (eg, immunotherapy or BRAF plus MEK inhibitors) after resection of cutaneous melanoma, but subsequently develop recurrent systemic metastatic disease along with newly diagnosed brain metastases. (See "Overview of the management of advanced cutaneous melanoma".)

For those patients who develop brain metastases as a site of progression during or after immunotherapy, options for systemic therapy are more limited, and control of CNS disease is often best achieved with surgery and/or SRS. One exception may be patients with BRAF-mutant tumors who have not previously received such targeted therapy; in such cases, immediate initiation of BRAF plus MEK inhibitor therapy with deferred definitive locoregional CNS therapy may be an option for select patients, such as those with small, asymptomatic brain metastases and active systemic disease. (See 'BRAF and MEK inhibitors' below.)

For patients with prior exposure to single-agent programmed cell death receptor 1 (PD-1) inhibitors, some experts offer combination immunotherapy with nivolumab plus ipilimumab (table 9) [46,47].

Similarly, patients who develop progressive brain metastases during or after BRAF plus MEK inhibitor therapy may be offered surgery and/or SRS. However, such patients also may be eligible for either combination (preferred) or single-agent immunotherapy, if such agents are also being used to treat systemic extracranial disease. (See 'Immunotherapy' below.)

In the remaining patients, the choice and sequence of definitive CNS therapy depends primarily on the number, size, and location of brain metastases, as well as the extent of CNS symptoms and overall performance status.

Surgery may be important in the uncommon patient whose only manifestation of metastatic disease is a lesion in the brain. Surgical resection of an isolated metastasis may also be an important component of initial management for larger asymptomatic lesions where there is concern about early progression of the brain metastasis or need for high doses of glucocorticoids to control edema. SRS may be an alternative to neurosurgical resection, particularly in cases where the lesion is not surgically accessible or where the patient's overall condition precludes surgery; however, this approach frequently limits the ability to taper symptomatic patients off glucocorticoids due to residual edema around the radiation site. (See 'Neurosurgery' below and 'Stereotactic radiosurgery' below.)

For patients with multiple brain metastases with limited intracranial tumor burden, good performance status, and relatively favorable life expectancy, systemic immunotherapy with or without SRS is the preferred treatment [43-45,48,49]. The use of SRS was thought to decrease the risk of late neurocognitive deficits compared with WBRT [50]. However, radiation necrosis may be an increasing issue even with SRS, particularly in combination with systemic therapy, due to the longer survival associated with the improved systemic disease control being achieved with immunotherapy and BRAF plus MEK inhibitor therapy [51-56]. (See 'Stereotactic radiosurgery' below.)

Surveillance and recurrent disease — Imaging surveillance with brain magnetic resonance imaging (MRI; or contrast-enhanced computed tomography [CT] if MRI is not possible) is critical for all patients with brain metastases.

For patients treated with systemic therapy with intracranial efficacy, and deferred initial locoregional CNS therapy, we repeat imaging after four to six weeks and then every six weeks to three months as long as disease is stable or responding to systemic therapy.

For patients with brain metastases treated with surgical resection or SRS, we reimage at one month and then repeat imaging every two to three months. For tumors previously treated with SRS, care must be taken to distinguish tumor recurrence from pseudoprogression/radiation necrosis. Follow-up scans always need to be compared with prior radiation treatment fields for accurate assessment. (See "Delayed complications of cranial irradiation", section on 'Brain tissue necrosis'.)

Historically, approximately 50 percent of patients developed additional brain metastases or progression at the treated site within six months to one year [57]. Recurrences or new lesions may be amenable to treatment with locoregional CNS therapy such as salvage SRS, surgery, or WBRT, depending upon the overall condition of the patient and the extent and location of the brain lesions [58-61]. Patients with progressive brain metastases after locoregional CNS therapy may be candidates for systemic therapy with intracranial efficacy (eg, immunotherapy and/or BRAF plus MEK inhibitors), if they have not previously received such therapy. Details on the intracranial efficacy of these systemic treatments are discussed below. (See 'Systemic therapy' below.)

Leptomeningeal disease — The prognosis is particularly poor for melanoma patients with leptomeningeal disease. Both RT and intrathecal chemotherapy are occasionally used to palliate symptoms, but benefits are limited, since neither are felt to offer durable control [62]. Immunotherapy and targeted therapy in BRAF-mutant tumors may be considered in this setting, although data are extremely limited [63]. For patients with increased intracranial pressure or hydrocephalus related to immunotherapy, we offer insertion of a ventriculoperitoneal (VP) shunt to control intracranial pressure and allow time for immunotherapy response. Further details on the management of patients with leptomeningeal disease are discussed separately. (See "Treatment of leptomeningeal disease from solid tumors".)

Symptom control — Systemic glucocorticoids are often needed to treat symptomatic brain edema surrounding metastases until definitive treatment is underway. Glucocorticoids should be considered a temporizing measure and always be used at the lowest dose necessary to control symptoms [64,65].

For patients with moderate to severe symptoms and large amounts of edema, a typical regimen is dexamethasone 10 mg intravenous or oral loading dose, then 16 mg daily in two to four divided doses [66]. For patients with milder symptoms, lower doses of dexamethasone (4 to 8 mg divided once or twice daily) are often sufficient and less toxic. Most patients who are asymptomatic do not require glucocorticoids. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors".)

When the patient is no longer in immediate danger of neurologic compromise, attempts should be made to provide the minimum effective dose of glucocorticoids to prevent acute and long-term glucocorticoid sequelae. In patients who are being treated with immunotherapy, there is concern that the use of glucocorticoids limits efficacy [67,68]. Although there are no well-established data or thresholds for glucocorticoid dose in this context, we attempt to taper dexamethasone to a dose of 2 mg twice daily or less before initiation of systemic immunotherapy. For patients with refractory edema due to radiation necrosis, bevacizumab has been used selectively to ameliorate symptoms and facilitate glucocorticoid taper. (See "Delayed complications of cranial irradiation", section on 'Treatment'.)

Unless the patient has had a seizure, there is no evidence to support prophylactic use of antiepileptic medications, due to the risk of side effects and interactions with other anticancer agents [69,70]. (See "Seizures in patients with primary and metastatic brain tumors", section on 'Patients without seizures'.)

While any initial symptoms are being controlled, information on the number and locations of metastatic lesions is integrated with information about the overall condition of the patient (performance status, comorbidity, extent of other metastatic disease) to plan the optimal management approach to the CNS lesions.

Duration of therapy after complete response — For patients who have a complete response to immunotherapy and successfully treated brain metastases, the optimal duration of systemic therapy is not yet known. The benefits of prolonged treatment must be balanced against the risk of potential immune-related adverse events. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

The decision to discontinue immunotherapy is based mainly on treatment response to systemic disease, as most available data on duration of immunotherapy and off-treatment survival come from patients with extracranial disease only [71-77]. Additionally, CNS progression that is discordant from systemic response to immunotherapy can often be controlled with SRS. Duration of immunotherapy and subsequent off-treatment survival among patients with extracranial involvement of metastatic melanoma are discussed separately. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'All patients' and "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Imaging studies'.)

For patients with complete clinical responses of systemic disease and treatment-responsive brain metastases following immunotherapy, we use the following approach to discontinuation of immunotherapy:

Patients should have received at least six months of immunotherapy, with two sequential scans (usually every three months) demonstrating a systemic complete remission.

Brain lesions should be either improving or stable over the same interval on serial brain imaging without development of new metastases. CNS response assessment may be challenging due to persistence of residual posttreatment changes on MRI, the possibility of radiologic pseudoprogression due to brain necrosis at the site of treated brain metastases, and the invasive nature of biopsying intracranial lesions suspicious for disease progression. (See 'Surveillance and recurrent disease' above.)

Further data are needed on whether this approach is also appropriate for patients with partial response to systemic disease and treatment-responsive brain metastases following immunotherapy.

NEUROSURGERY — Advances in surgical techniques (eg, magnetic resonance imaging [MRI] localization of lesions, stereotactic computer-assisted navigation, intraoperative functional mapping to avoid damage to eloquent regions of the brain) have contributed to improved neurosurgical results [78-82].

Patient selection — The best candidates for surgical resection of brain metastases have a very good performance status (Karnofsky Performance Status [KPS] 90 to 100 percent (table 10)), minimal comorbidity, and one or a very limited number of superficial metastases in noneloquent areas of the brain, where surgery will not lead to unacceptable loss of function [83]. Surgery can sometimes be performed in eloquent locations using advanced neurosurgical techniques, including preoperative functional MRI testing, intraoperative computer-assisted navigation, and monitoring with cortical stimulation during awake craniotomy. (See "Overview of the treatment of brain metastases", section on 'Large tumor or diagnostic uncertainty'.)

Surgery can also be considered to relieve symptoms from larger (>3 cm) lesions that are unlikely to respond to radiation therapy (RT), are producing symptomatic edema, or are threatening to herniate. Older data from small, randomized trials in patients with diverse primary tumors and observational data from patients with melanoma suggest that surgery is more effective than whole brain radiation therapy (WBRT) in such patients [22]. (See "Overview of the treatment of brain metastases", section on 'Efficacy of surgery'.)

Management following surgery — Following complete surgical resection of a melanoma brain metastasis, stereotactic radiosurgery (SRS; single-fraction or hypofractionated) or conventionally fractionated involved-field RT to the resection cavity can be offered to lower the risk of local recurrence from microscopic residual disease. However, gains in local control with SRS are weighed against the risk of pseudoprogression/radiation necrosis, and treatment decisions are increasingly individualized. Decisions also take into account plans for systemic therapy postoperatively.

A postoperative MRI with and without contrast should be obtained to determine the extent of resection and identify any macroscopic residual disease. For patients with an incomplete resection, postoperative RT is indicated to treat the residual tumor and the margins of the cavity. For patients who have undergone complete resection, our contributors differ in their use of postoperative RT to the cavity. Some offer RT routinely to maximize the chance of durable local control, regardless of extracranial disease status and systemic therapy options. Others may forego postoperative RT when systemic therapy is planned, with the rationale that systemic therapy may lower recurrence risk and RT can be used later as a salvage therapy. There is agreement that postoperative WBRT should be avoided, based on the same considerations as discussed below in the context of SRS. (See 'Role of WBRT after SRS' below.)

The evidence base for the use of postoperative RT after complete resection of a brain metastasis is drawn primarily from studies in patients with a mix of primary histologies, including lung cancer, melanoma (often approximately 20 to 25 percent of the total), and other studies largely conducted in the era before effective systemic therapy options for patients with melanoma and resultant long-term survival. In such patients, randomized trials have shown that postoperative SRS to the surgical cavity decreases the risk of neurocognitive decline compared with postoperative WBRT [84] and improves local control at the resection cavity compared with observation [85]. All three strategies (ie, WBRT, SRS, and observation) have been associated with similar overall survival (OS). These data are reviewed separately. (See "Overview of the treatment of brain metastases", section on 'Postoperative radiation'.)

No randomized trials have been conducted purely in patients with metastatic melanoma. Based on the subset of patients with melanoma in randomized trials and observational series, SRS to the tumor bed after resection of a metastasis results in local control rates of approximately 70 percent at one year [84-87]. The expected local control rate without postoperative RT is approximately 40 to 60 percent by one year [85,88]. Postoperative combination immunotherapy may also control intracranial disease in patients who are immunotherapy naïve at the time of resection [89].

In the era of reduced use of postoperative WBRT, patients who undergo resection of a brain metastasis may have an increased risk of pachymeningeal and/or leptomeningeal disease recurrence (outside the postoperative RT field) compared with those who have not had surgery [90,91]. Further data are needed to understand whether postoperative systemic therapy mitigates this risk. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors", section on 'Epidemiology'.)

STEREOTACTIC RADIOSURGERY — Stereotactic radiosurgery (SRS) has the ability to treat deep-seated lesions or lesions near eloquent brain structures that are not amenable to surgical resection. SRS employs multiple convergent radiation beams to deliver a high radiation dose to a radiographically discrete treatment volume. SRS allows higher doses of radiation to be delivered to a target lesion with decreased normal tissue injury, due to the rapid drop-off in the radiation dose at the margins of the treatment field. (See "Stereotactic cranial radiosurgery" and "Overview of the treatment of brain metastases", section on 'Efficacy of SRS alone'.)

SRS is often given as a single high dose of radiation (ie, single-fraction SRS), but it may also be given over two to five medium-dose fractions (ie, hypofractionated SRS) for targets that are larger sized or near critical normal tissues, such as the brainstem or the optic apparatus.

Efficacy — Multiple studies suggest that surgery and SRS are similarly effective for the control of small brain metastases in melanoma patients. SRS was initially limited to patients with one to three brain metastases [43-45]. Subsequent studies have shown that some patients with more than five brain metastases can be successfully treated with SRS; however, systemic disease control has an important impact on outcome [92].

Patient selection plays a key role in successful radiosurgery. In general, the optimal patient will have five or fewer lesions, with none greater than 3 cm. In properly selected patients, freedom from progression at the treated site can be achieved in approximately 90 to 95 percent of melanoma lesions [34,93,94], with disappearance or a reduction in size occurring in approximately 55 percent [34,95].

Local control is primarily influenced by the dose and lesion size [96]. An increasing number of lesions predict a higher likelihood of relapse at new sites in the brain. However, the total volume of tumor treated in the brain appears to be more prognostic of outcome, including overall survival (OS), than the number of lesions [97,98].

The results with single-fraction SRS are illustrated by the outcomes in a series of 54 melanoma patients with a total of 103 brain metastases treated in an era before the application of effective systemic therapy [99]. The majority of these patients (71 percent) had active extracranial disease at the time of SRS. The median number of brain metastases was one (range one to six); local control at 6 and 12 months was 87 and 68 percent, respectively, and the 6- and 12-month OS rates were 50 and 25 percent, respectively.

Despite the decreased volume of brain irradiated compared with whole brain radiation therapy (WBRT), late severe cognitive impairment or radiation necrosis can be a significant problem, particularly when used with systemic therapy [51-53]. It is likely that the longer-term survival conferred by more-effective systemic therapy will be associated with higher risks of late radionecrosis [56]. Consideration of surgical resection of limited numbers of brain metastases is a reasonable alternative.

How should SRS and immunotherapy be sequenced? — The timing of immunotherapy in relation to stereotactic radiosurgery (SRS) is evolving and an active area of investigation [100,101]. The most common approach is the sequential use of SRS followed by immunotherapy in order to treat potentially symptomatic or bleeding lesions. This approach also allows patients to avoid or taper off glucocorticoids prior to initiating immunotherapy, as concurrent use of glucocorticoids is associated with reduced efficacy of immunotherapy [102].

However, some UpToDate experts have successfully used concurrent SRS and immunotherapy (ie, either both treatments are initiated simultaneously, or immunotherapy is initiated first and continued during SRS). Observational studies suggest this combination can achieve high levels of intracranial response and durable control of brain metastases with acceptable toxicity [101,103-107]. Further randomized trials directly comparing sequential versus concurrent SRS and immunotherapy are necessary to establish the optimal approach. Clinicians who offer concurrent SRS and immunotherapy should discuss the risks and benefits with their patients, as there is a modestly increased risk of radionecrosis and CNS edema (10 to 20 percent) [56,108].

Some studies suggest that, for patients where concurrent SRS and immunotherapy are planned, immunotherapy can be started promptly and safely continued during SRS. As an example, a retrospective observational DeCOG study of 380 patients with melanoma brain metastases (both symptomatic and asymptomatic) showed modestly improved OS and an acceptable toxicity profile for the combination of nivolumab plus ipilimumab and local therapy (ie, SRS or surgery) compared with delayed local therapy [109].

Other patients with asymptomatic brain metastases may be candidates for immediate systemic immunotherapy with deferred definitive locoregional CNS therapy (such as SRS) and close monitoring. (See 'Asymptomatic brain metastases' below.)

Radiation sensitization with BRAF inhibitors — Radiation sensitization and recall, in some cases severe and involving cutaneous and visceral organs, have been reported in patients treated with radiation prior to, during, or subsequent to treatment with the BRAF inhibitors vemurafenib and dabrafenib [110-113]. Holding treatment with a BRAF with or without a MEK inhibitor for one to three days before and one day after SRS appears to minimize the risk of significant toxicity. The same approach is used for both intracranial and extracranial systemic metastases. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)

Role of WBRT after SRS — For patients whose brain metastases have been treated with SRS, we suggest observation with surveillance rather than adjuvant whole brain radiation therapy (WBRT). Studies evaluating WBRT after primary SRS have had mixed results regarding local control but have consistently shown increased neurocognitive impairment and no OS benefit from adjuvant WBRT. Preservation of neurocognitive function by avoiding WBRT is increasingly important as more patients with brain metastases are living longer with systemic agents such as immunotherapy and combination BRAF plus MEK inhibitors. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

In melanoma patients with limited brain metastases treated with SRS, adjunctive WBRT adds no additional survival benefit [50,114-118]. Data regarding local control are mixed. Among randomized studies evaluating adjunctive WBRT, some have shown improved local intracranial disease control, while others have not [50,115,116,118]. As an example, one phase III trial of 215 patients receiving local treatment for one to three melanoma brain metastases, adjuvant WBRT did not improve distant intracranial control, survival, or preservation of performance status [118].

Importantly, studies have consistently demonstrated that adjunctive WBRT results in increased neurocognitive deterioration. Long-term survivors who attain intracranial disease control with WBRT experience neurocognitive sequelae and decline in quality of life [118-121]. If WBRT is felt to be indicated, radiologic techniques for hippocampal sparing with addition of memantine should be offered to decrease neurocognitive sequelae of WBRT [122]. Intracranial disease can be controlled with SRS alone in approximately 50 percent of patients with one to five brain metastases [57]. Such patients can avoid WBRT. Alternative strategies to mitigate cognitive risks, including use of memantine, are reviewed separately. (See "Delayed complications of cranial irradiation", section on 'Prevention'.)

SYSTEMIC THERAPY — Immunotherapy and targeted therapies (ie, BRAF/MEK inhibitors) have provided significant advances in the treatment of melanoma with previously untreated brain metastases. Evolving clinical evidence suggests considerable intracranial activity with these systemic agents. For select treatment-naïve patients with asymptomatic brain metastases, there is growing interest in using these agents to simultaneously treat intra- and extracranial disease burden, rather than a traditional sequential approach using locoregional therapies to the brain (ie, surgery and/or radiation therapy [RT]) followed by systemic therapy. (See 'New untreated brain metastases, systemic therapy-naïve' above.)

This section discusses the activity of systemic therapy in previously untreated brain metastases due to melanoma. The optimal approach to patients with brain metastases using multidisciplinary treatment options is discussed above. The optimal use of systemic therapy and its integration with other modalities continues to evolve. (See 'Small, minimally symptomatic or asymptomatic brain metastases' above and 'Large or symptomatic brain metastases' above and "Overview of the management of advanced cutaneous melanoma", section on 'Immunotherapy'.)

Immunotherapy — Immunotherapy significantly prolongs survival in patients with disseminated extracranial systemic melanoma. Immunotherapy options that have also demonstrated clinically useful activity against melanoma brain metastases include combination immunotherapy (nivolumab plus ipilimumab (table 9)), single-agent immunotherapy (ipilimumab, pembrolizumab (table 11), nivolumab (table 12)), and rarely high-dose interleukin 2 (IL-2). (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Nivolumab plus ipilimumab (preferred)'.)

The use of immunotherapy to treat patients with melanoma brain metastases has been associated with improved survival [42,123]. A diagnosis of brain metastases should not discourage the use of active systemic immunotherapy, as data suggest similar overall survival (OS) in patients with metastatic melanoma treated with single-agent PD-1 inhibitors, regardless of the presence or absence of brain metastases [108]. The use of immunotherapy is more controversial in patients with larger, symptomatic brain metastases. (See 'Large or symptomatic brain metastases' above.)

Based on evolving data, select patients are candidates for immediate systemic immunotherapy with deferred definitive locoregional central nervous system (CNS) therapy (ie, stereotactic radiosurgery [SRS] or surgery) and close monitoring. If immunotherapy is chosen over locoregional CNS therapy, the combination of nivolumab plus ipilimumab is preferred over other regimens. (See 'Small, minimally symptomatic or asymptomatic brain metastases' above.)

Details on combining immunotherapy and SRS are discussed above. (See 'How should SRS and immunotherapy be sequenced?' above.)

Nivolumab plus ipilimumab — The combination of the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab plus the programmed cell death receptor 1 (PD-1) inhibitor nivolumab (table 9) has intracranial response rates of over 50 percent in patients with asymptomatic brain metastases, and may result in improved survival and durable long-term responses [42,124-126].

Combination immunotherapy also demonstrates higher toxicity rates than single-agent immunotherapy; however, combination immunotherapy toxicity rates among patients with intracranial disease are similar to those reported in patients with extracranial systemic disease only. (See 'Single-agent immunotherapy' below.)

Asymptomatic brain metastases — Nivolumab plus ipilimumab (table 9) is a preferred treatment option for select patients with a small, asymptomatic, solitary or limited number of brain metastases along with extracranial metastatic disease burden. Data supporting its use in this population come from the following phase II and III studies in which ipilimumab was given at a dose of 3 mg/kg every three weeks for four doses in combination with nivolumab 1 mg/kg [124,125,127,128]. After completing combination therapy, patients received maintenance nivolumab 3 mg/kg every two weeks.

In an open-label single-arm phase II trial (CheckMate-204), 101 patients with asymptomatic brain metastases were treated with nivolumab plus ipilimumab as above [124,125,127,128]. After a median follow-up of approximately 34 months, this combination demonstrated [128]:

Intracranial objective response rate (ORR) of 54 percent (33 and 21 percent with complete and partial responses, respectively) with most responses occurring early in treatment (median 1.4 months). Among those with objective responses, a majority (85 percent) had ongoing treatment responses.

Three-year intracranial progression-free survival (PFS) of 54 percent.

Three-year OS of 72 percent.

Grade ≥3 treatment-related adverse events were seen in 56 percent. One patient died from immune-related myocarditis.

In another phase II trial (ABC trial), 60 asymptomatic patients with no prior therapy for their brain metastases were randomly assigned to the combination of nivolumab plus ipilimumab versus nivolumab alone (table 12) [125]. In preliminary results, at median follow-up of 53 months, compared with single-agent nivolumab, combination immunotherapy demonstrated a higher intracranial ORR (59 versus 21 percent), with complete and partial intracranial response rates of 30 percent each [129]. Patients treated with combination immunotherapy versus single-agent nivolumab demonstrated five-year PFS of 52 and 14 percent; five-year OS was 55 and 40 percent, respectively. Grade ≥3 toxicities were higher in the combination arm (54 versus 20 percent), with no new long-term toxicities reported. Rates of systemic disease control were similar to the intracranial ORRs observed between the two treatments.

In another randomized phase III trial (NIBIT-M2) of 80 patients with treatment-naïve asymptomatic brain metastases, combination nivolumab plus ipilimumab (table 9) improved OS (median 29 versus 8 months) and had a better safety profile compared with ipilimumab plus fotemustine [130].

Symptomatic brain metastases — There are limited data regarding the efficacy of immunotherapy as a sole initial treatment in patients with symptomatic brain metastases. These patients often require a course of glucocorticoids and/or locoregional CNS therapy (ie, surgical resection and/or SRS) to manage CNS symptoms prior to initiation of systemic therapy [89,131]. Glucocorticoids must be discontinued prior to starting immunotherapy to maximize both intra- and extracranial activity. Patients with BRAF V600-positive disease who are unable to discontinue glucocorticoids may be offered treatment with combination BRAF plus MEK inhibition. Patients should receive multidisciplinary evaluation with medical oncology, radiation oncology, and neurosurgery to optimize treatment benefits. Enrollment in clinical trials is encouraged, where available. Other treatment modalities for patients with symptomatic brain metastases from melanoma are discussed separately. (See 'Large or symptomatic brain metastases' above and 'BRAF and MEK inhibitors' below.)

In an expanded cohort of 18 patients with symptomatic brain metastases enrolled on the CheckMate-204 trial of nivolumab plus ipilimumab followed by maintenance nivolumab (table 9) reported an intracranial ORR of approximately 17 percent (all complete responses) [127,128]. After a median follow-up of 7.5 months, three-year OS was 37 percent. Grade ≥3 adverse events were reported in 67 percent of patients.

Single-agent immunotherapy — In patients with untreated brain metastases, the anti-CTLA-4 inhibitor ipilimumab and the anti-PD-1 inhibitors nivolumab (table 12) and pembrolizumab (table 11) have less intracranial activity as single agents than combination immunotherapy with nivolumab plus ipilimumab (table 9). (See 'Nivolumab plus ipilimumab' above and "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)

Ipilimumab Historically, ipilimumab was one of the first active systemic immunotherapy agents approved for metastatic melanoma, during an era when locoregional CNS therapy was the only available treatment for brain metastases. Therefore, most data on the intracranial efficacy of ipilimumab are obtained from studies of patients with previous brain radiation [98,132,133].

In one cohort study, ipilimumab demonstrated similar survival among patients with and without CNS involvement [98]. This finding supported inclusion of patients with brain metastases in the approved indications for ipilimumab.

Ipilimumab has an intracranial response rate of approximately 24 percent, with long-term durable intracranial responses noted [67,98,134,135]. Ipilimumab was also associated with improved survival outcomes in retrospective cohort studies of patients with brain metastases previously treated with SRS [132,133].

Pembrolizumab Pembrolizumab (table 11) demonstrated intracranial response rates up to 26 percent in patients with untreated brain metastases [136,137]. Pembrolizumab also sustained intracranial and extracranial responses at two-year follow-up.

Nivolumab – In a phase II trial (ABC), nivolumab (table 12) demonstrated intracranial response rates of 20 percent in untreated brain metastases [125], similar to single-agent pembrolizumab, and 6 percent in those with symptomatic and/or previously treated brain metastases [129].

Adoptive cell therapy — Adoptive cell therapy, using autologous antitumor lymphocytes plus IL-2 following a lymphocyte-depleting preparative regimen, has antitumor activity in carefully selected patients with metastatic melanoma. An analysis of the experience at the National Cancer Institute found that 7 of 17 evaluable patients (44 percent) with brain metastases had a complete response in the brain, although some also were treated with surgical resection [138]. (See "Interleukin 2 and experimental immunotherapy approaches for advanced melanoma", section on 'Alternative interleukin 2 regimens'.)

BRAF and MEK inhibitors — For patients who harbor BRAF-mutant bulky extracranial metastases, targeted therapy with BRAF plus MEK inhibitors can often provide a rapid radiographic and clinical response. Intracranial responses are generally of shorter duration than extracranial responses. By contrast, single-agent BRAF inhibitors are no longer used for the treatment of metastatic melanoma given the availability of more effective, less toxic treatment options [139-141]. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Choice of BRAF plus MEK inhibitor therapy'.)

For those receiving combined BRAF plus MEK inhibitor as initial therapy for brain metastases, our preferred combination of agents is dabrafenib plus trametinib, which offered clinical intracranial responses in more than half of patients in one nonrandomized phase II trial [142]. Other BRAF/MEK inhibitor combinations (eg, encorafenib plus binimetinib or vemurafenib plus cobimetinib) may be offered as alternatives, as limited observational studies report similar intracranial activity to dabrafenib plus trametinib [143,144]. Further randomized studies are necessary to directly compare activity between these combinations of agents in this setting.

In an open-label phase II trial, 125 patients with BRAF V600E-positive melanoma brain metastases were treated with dabrafenib plus trametinib [142]. In the subset of 76 patients with asymptomatic brain metastases without prior CNS treatment, intracranial response rate was 58 percent and median PFS was 5.6 months. Similar intracranial response rates were observed in asymptomatic patients who had received prior local CNS treatment (56 percent), in asymptomatic patients with other BRAF V600 mutations (44 percent), and in those with symptomatic brain metastases (59 percent).

Of note, the median intracranial PFS for dabrafenib plus trametinib reported in this study is approximately half of the median extracranial PFS observed in other studies [145]. These findings may reflect differences in the pharmacokinetics or site-specific activity for tumors in the CNS compared with extracranial disease. The efficacy of dabrafenib plus trametinib for extracranial systemic disease is discussed separately.

Some data suggest that continuing BRAF plus MEK inhibitors during SRS for treatment of small numbers of brain metastases may result in high rates of local tumor control with acceptable toxicity [146,147]. However, caution should also be employed in combining concurrent BRAF inhibitor therapy and RT (especially to large treatment fields) due to apparent radiosensitization of normal tissues and an increased risk of adverse effects. (See 'Radiation sensitization with BRAF inhibitors' above.)

Is there a role for combined immunotherapy and targeted therapy for melanoma brain metastases? — The combination of immunotherapy with BRAF and MEK inhibitors (ie, targeted therapy) has efficacy in patients with metastatic melanoma and extracranial disease. However, the role of such combination therapy in patients with brain metastases remains to be established. Based on our clinical experience, it is likely that the treatment of CNS disease will remain challenging, even with this combination therapy. Further data on the efficacy of combination immunotherapy plus targeted therapy in patients with BRAF-mutant metastatic melanoma are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Is there a role for combined immunotherapy and targeted therapy?'.)

Chemotherapy — Cytotoxic chemotherapy does not have a significant role in the management of patients with melanoma brain metastases, either alone or in conjunction with RT. Studies evaluating the addition of chemotherapy (eg, temozolomide or fotemustine) to whole brain radiation therapy (WBRT) failed to demonstrate clinically significant activity or survival benefit [148,149].

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 5th to 6th 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 10th to 12th 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

Brain metastases are a frequent complication in patients with advanced regional and metastatic melanoma and are an important cause of both morbidity and mortality. The treatment of patients with melanoma brain metastases is rapidly evolving and should be distinguished from the current approach for patients with nonmelanoma brain metastases. (See "Overview of the treatment of brain metastases".)

Historically, locoregional treatments with surgical resection and/or radiation therapy (RT) were the only options to control brain metastases. However, newer systemic treatments such as immunotherapy and BRAF plus MEK inhibitors have intracranial efficacy and provide an alternative for patients with metastatic melanoma. As such, management of brain metastases benefits from a multidisciplinary management plan (algorithm 1). (See 'Approach to management' above.)

For systemic therapy-naïve patients with small (<1 cm), minimally symptomatic or asymptomatic untreated brain metastases and extracranial disease burden, a closely monitored trial of systemic therapy with intracranial efficacy and deferral of locoregional central nervous system (CNS) therapy is an acceptable treatment approach. Selection of a specific regimen takes into account the nature and extent of extracranial disease, the presence or absence of a BRAF mutation, and patient performance status and comorbidities. (See 'New untreated brain metastases, systemic therapy-naïve' above and 'Small, minimally symptomatic or asymptomatic brain metastases' above.)

For patients who are eligible for systemic therapy and able to tolerate the potential toxicities of immunotherapy, we suggest the combination of nivolumab plus ipilimumab (table 9), rather than single-agent immunotherapy (Grade 2B). Combination immunotherapy has demonstrated higher intracranial response rates, many of which have had long-term durability. (See 'Nivolumab plus ipilimumab' above.)

For patients with a BRAF V600 mutation who require rapid extracranial disease response and/or are unable to discontinue glucocorticoids, or are otherwise not candidates for immunotherapy, an alternative systemic option is BRAF plus MEK inhibitor therapy with dabrafenib plus trametinib. (See 'BRAF and MEK inhibitors' above.)

For patients who are not eligible for systemic therapy due to prior therapies received or the large and symptomatic nature of the brain metastases, and those who progress on an initial trial of systemic therapy, locoregional CNS-directed therapy depends largely on the number and location of lesions.

For patients with a single large (>3 cm) metastasis in an accessible location, we suggest surgical resection rather than radiation (Grade 2B). Lesions with diagnostic uncertainty, symptomatic edema, or posterior fossa location are especially important to resect, when possible. For patients who cannot undergo surgery, focal RT options for large tumors include hypofractionated stereotactic radiosurgery (SRS) and fractionated RT. (See 'Neurosurgery' above and 'Stereotactic radiosurgery' above.)

For patients who undergo incomplete resection, focal RT (SRS or fractionated) is typically indicated postoperatively to treat the residual tumor and cavity. For those who undergo complete surgical resection, some contributors routinely treat with RT to the resection cavity to maximize the chance of durable local control. Other contributors may forego postoperative RT when systemic therapy is planned. Close monitoring for disease recurrence with periodic neuroimaging is appropriate regardless of treatment approach. (See 'Management following surgery' above.)

For patients with multiple small brain metastases, all of which are amenable to SRS, we recommend SRS alone rather than SRS plus whole brain radiation therapy (WBRT) or WBRT alone (Grade 1B). The addition to WBRT after primary SRS may improve local control but has no overall survival (OS) benefit and increases neurocognitive impairment. (See 'Role of WBRT after SRS' above.)

The timing of immunotherapy in relation to SRS is an evolving, active area of investigation. For patients receiving both SRS and immunotherapy, the most common approach is SRS followed sequentially by immunotherapy. However, some UpToDate experts have successfully used concurrent SRS and immunotherapy, which can achieve high levels of intracranial response and durable control of brain metastases with acceptable toxicity. (See 'How should SRS and immunotherapy be sequenced?' above.)

For larger metastases that are not amenable to single-fraction SRS, options may include hypofractionated SRS, fractionated focal RT, and surgical resection. Such treatment should be combined with systemic therapy to control extracranial disease. (See 'Stereotactic radiosurgery' above and 'Neurosurgery' above and 'New brain metastases, current or prior systemic therapy' above.)

For patients with a short life expectancy, in whom systemic therapy options are no longer likely to offer substantial benefit, and a large intracranial tumor burden, WBRT may be offered. In many cases, discussion of hospice is appropriate, especially when prognosis and quality of life are dismal. (See "Overview of the treatment of brain metastases", section on 'High tumor burden or multiple large tumors' and "Approach to symptom assessment in palliative care" and "Overview of managing common non-pain symptoms in palliative care".)

Patients with brain metastases remain at risk of CNS progression even after definitive treatment. As such, all patients should have imaging surveillance every two to three months with brain magnetic resonance imaging (MRI), or contrast-enhanced computed tomography (CT) if MRI is not possible. (See 'Surveillance and recurrent disease' above.)

Immunotherapy may be discontinued after at least six months of therapy if evaluation of extracranial disease burden shows a complete clinical response confirmed on two sequential imaging evaluations approximately three months apart, and brain lesions are either improving or stable over the same interval on serial neuroimaging without development of new metastases. (See 'Duration of therapy after complete response' above and 'Surveillance and recurrent disease' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Marc Friedberg, MD, PhD, Eric Wong, MD, and Kevin Oh, MD, who contributed to an earlier version of this topic review.

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Topic 7611 Version 65.0

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