Management of melanoma central nervous system metastases

Piotr Rutkowski; Dorota Kiprian; Tomasz Świtaj; Radosław Michalik; Mateusz Spałek; Katarzyna Kozak; Tomasz Mandat; Bożena Cybulska-Stopa; Monika Dudzisz-Śledź

doi:10.5603/OCP.2023.0042

Oncology in Clinical Practice
Vol 20, No 3 (2024) #96483 Management of melanoma central nervous system metastases

Vol 20, No 3 (2024)

Guidelines / Expert consensus

Published online: 2023-10-17

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EXPERTS’ OPINION

Translation: dr n. med. Dariusz Stencel

Oncol Clin Pract 2024, Vol. 20,

No. 3, 161–174, DOI: 10.5603/OCP.2023.0042,

ISSN 2450–1654, e-ISSN 2450–6478

Management of melanoma central nervous system metastases

Piotr Rutkowski1Dorota Kiprian1Tomasz Świtaj1Radosław Michalik1Mateusz Spałek1Katarzyna Kozak1Tomasz Mandat1Bożena Cybulska-Stopa23Monika Dudzisz-Śledź1

1The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland

2Department of Clinical Oncology, Lower Silesian Oncology Center, Pulmonology and Hematology, Wroclaw, Poland

3Department of Hematology and Oncology, Faculty of Medicine, Wroclaw University of Science and Technology, Poland

Received: 12.07.2023 Accepted: 12.07.2023 Early publication date: 17.10.2023

Address for correspondence:

Monika Dudzisz-Śledź, MD PhD,

Department of Soft Tissue/Bone Sarcoma and Melanoma,

Maria Sklodowska-Curie National Research Institute of Oncology,

ul. Roentgena 5, 02–781 Warsaw, Poland,

e-mail: monika.dudzisz-sledz@nio.gov.pl

Introduction

Melanoma is the third most frequent malignancy (after breast and lung cancers) that causes metastases in the central nervous system (CNS). It is one of the 20 most common human cancers, and its incidence is steadily increasing by about 3–7% per year. It is estimated that in about 50–60% of patients with advanced melanoma, the disease will disseminate in the CNS (of whom about 75% of patients will develop multiple metastases often asymptomatic at baseline). Central nervous system metastases are found in 7% of melanoma patients at diagnosis and about 75% on autopsy. The primary tumor cannot be found in 3% of patients diagnosed with melanoma metastasis in the CNS. Of note is that only 8–46% of melanoma patients are diagnosed with CNS metastases. In 94% of them, brain metastases are the direct cause of death. In the latest 8th edition of the American Joint Committee on Cancer (AJCC) staging system, the presence of CNS metastases was distinguished as a separate, last category in stage IV (M1d) [1]. The risk of metastases in the CNS increases with the disease stage [2]. Central nervous system metastases occur in 37% of patients with stage IV melanoma [3]. Currently, there are no known factors identified that predict the risk of CNS metastases in melanoma patients. Nevertheless, it is known that certain factors are associated with a higher risk of metastases in the CNS (primary lesion within the head and neck, elevated lactate dehydrogenase (LDH) activity, ulceration in the primary lesion, mutations in the BRAF, NRAS, and PTEN genes) [4]. The detection of lesions in the CNS is associated with poor prognosis. Central nervous system metastases lead to death in 20–50% of patients, and symptomatic lesions are the immediate cause of death in about 90% of patients. According to historical data, median overall survival (OS) after CNS metastasis diagnosis was 5 to 7 months. However, in symptomatic patients undergoing whole brain radiotherapy (WBRT), which is now rarely used, median OS was 2–5 months, and in patients undergoing surgery or stereotactic radiotherapy — twice as long [5].

This summary study aims to present multidisciplinary guidelines on diagnostic and therapeutic management of melanoma patients with CNS metastases, which is currently the greatest challenge in the care of patients with advanced melanoma.

New treatment methods introduced into daily clinical practice have resulted in a significant change in therapeutic management compared to those used 5 years ago. Central nervous system metastases are increasingly diagnosed at the asymptomatic stage using routine magnetic resonance imaging (MRI) and/or computed tomography (CT) of the brain as part of the follow-up or qualification of patients for systemic treatment. Advanced techniques of stereotactic radiotherapy have become the main therapeutic option used in local treatment. In the last 10 years, 11 new drugs for patients with advanced melanoma have been registered in Europe [vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, encorafenib, ipilimumab, nivolumab, pembrolizumab and relatlimab in combination with nivolumab and talimogene laherparepvec (T-VEC)]. In Poland, 6 of the new therapies are currently available under drug programs (vemurafenib with cobimetinib, dabrafenib with trametinib, encorafenib with binimetinib, ipilimumab with nivolumab, pembrolizumab, and nivolumab). Based on data from clinical trials median OS in the entire group of patients with BRAF mutant metastatic melanoma treated with pembrolizumab/nivolumab and a combination of BRAF (BRAFi) and MEK (MEKi) inhibitors is now approximately 2 years (approximately 4 times longer than 5 years ago). So far, the best results have been achieved with dual immunotherapy (anti-CTLA-4 and anti-PD-1). The combination of anti-PD-L1 therapy with BRAFi and MEKi (e.g. atezolizumab plus vemurafenib and cobimetinib) also allows for obtaining some benefits. Perhaps using other methods of combined treatment, for example, anti-PD-1/anti-PD-L1 with anti-LAG3 and/or TIM3 will allow further improvement. In each case of confirmed CNS metastases, it is mandatory to examine the status of the BRAF gene in the fixed material (if it has not been previously assessed) [6, 7]. According to the current National Comprehensive Cancer Network (NCCN) and European Society of Clinical Oncology (ESMO) guidelines, in patients with BRAF-mutated melanoma and metastases in the CNS (especially asymptomatic and less than 3 cm in size), dual immunotherapy is recommended if no contraindicated. However, depending on the clinical setting, the use of BRAFi and MEKi in the first line of treatment should be considered.

Even in the treatment of multiple metastatic lesions, the use of modern radiotherapy techniques has become much more common, replacing WBRT in many clinical situations. Stereotactic radiotherapy involves delivering a biologically high dose of radiation to a precisely defined small volume with a significant decrease in the dispersed dose in healthy tissues outside the target volume. Treatment can be done with a single fractional dose [stereotactic radiosurgery (SRS)] or 3–5 fractions (fractionated stereotactic radiosurgery, fSRS).

Therapeutic decisions should be individualized, taking into consideration treatment goals (short-term versus long-term benefits) and based on clinical picture (LDH level, other organs involvement, tumor mass, patient performance status, course of the disease, comorbidities and their treatment, and patient preferences) [8]. The basic and applicable rule in the case of melanoma metastases in the CNS should be optimizing the management by multidisciplinary teams whose members are experienced in the diagnosis and treatment of patients with melanoma. The team should include at least a neurosurgeon, a radiation oncologist, and a clinical oncologist [9].

Diagnostics

Signs and symptoms of CNS metastases may be mild and difficult to recognize. They depend, among other things, on the number, size, and location of metastases. Metastases most often occur in the telencephalon; in about 15% of cases they occur in the cerebrum and about 5% in the brainstem. The most common symptoms include headache (sometimes accompanied by nausea and/or vomiting), seizures, speech, comprehension, and vision disorders, numbness, and movement disorders. The presence of clinical symptoms of CNS metastases is associated with poorer treatment outcomes. Patients with stages I and II melanoma have a lower risk of developing metastases in the CNS compared to patients with stages III and IV [10]. In younger patients, the risk of late metastases in the CNS is higher in thicker melanomas [11]. Based on the data from a retrospective analysis of the large multicenter S0008 study, the risk of CNS metastases at stage IIIB and IIIC was 15%, and metastases were mainly diagnosed within the first 3 years after surgery [12]. The time from treatment of the primary lesion may be relatively long and may even be 3–4 years (median) [13].

Therefore, in patients with stage III and IV melanoma, the detection of CNS metastases based on follow-up imaging tests in the absence of clinical symptoms is of great importance. The prognosis in asymptomatic patients and the efficacy of treatment are definitely better compared to patients with symptoms resulting from CNS metastases. The risk of developing CNS metastses in patients with stage IV melanoma is very high and reaches almost 40%. Performing an MRI of the CNS during the disease staging after the diagnosis of stage IV melanoma is the standard of care. In stage III, the risk of developing metastases in the CNS is also high and ranges from 18.5 to 23.5% [14, 15]. In asymptomatic patients with melanoma stage IIIC and higher, CT or MRI of the CNS should be considered [7]. The results of the analysis of 202 patients done by Derks et al. indicate that routine MRI in patients after radical resection of stage III melanoma before starting adjuvant treatment is not recommended [3, 16]. Performing periodic MRI examinations for up to 3 years after treatment cessation is indicated to detect asymptomatic CNS metastases (especially in high-risk patients — i.e. stage IIIC or higher, in whom no CNS metastases have been detected so far). Patients with successful treatment of CNS metastases in the past require regular follow-up with MRI. In patients with signs and/or symptoms (including even mild symptoms) indicating the possibility of CNS lesions, an MRI examination is recommended [17]. MRI is the most sensitive imaging for detecting CNS metastases and has an advantage over contrast-enhanced CT. It should be emphasized that melanoma CNS metastases are usually multifocal and hemorrhagic [18].

Therapeutic management

Therapeutic management depends on the clinical setting and includes systemic, local (radiotherapy and/or surgery), and/or symptomatic treatment. In addition to clinical symptoms, there are numerous disease- and patient-related parameters playing an important role in the treatment of melanoma patients with CNS metastases (number, size, and location of metastases, presence and control of lesions outside the CNS, previous treatment for melanoma and the outcome, BRAF gene mutation status, general condition, and age, comorbidities and their treatment). In symptomatic treatment, anti-edematous drugs (mainly glucocorticosteroids) are used. In the case of seizure, antiepileptic treatment should be initiated, but interactions with other drugs used by the patient (including glucocorticoids) should be taken into consideration.

Tables 1 [19] and 2 [20] present prognostic scales in patients with CNS metastases; Recursive Partitioning Analysis — Radiation Therapy Oncology Group (RPA-RTOG) scale applies to all cancers, and Diagnosis Specific — Graded Prognostic Assessment (DS-GPA) scale applies only to patients with melanoma. However, it should be remembered that the aforementioned scales were developed before the introduction of new methods of systemic treatment of patients with metastatic melanomas. The median OS in all melanoma patients was 6.74 months (range: 3.38 to 13.32 months, number of patients n = 481) (Fig. 1).

Table 1. Recursive Partitioning Analysis (RPA) prognostic scale (n = 1200) [19]

	Class I	Class II	Class III
KPS [points]	≥ 70	≥ 70	< 70
Primary tumor	Cured	Active	Active
Age	< 65 years	> 65 years	Any
Non-CNS lesions	No	Present	Present
Prevalence	15%	65%	20%
Median survival [months]	7.1	4.2	2.3

CNS — central nervous system; KPS — Karnofsky performance status

Table 2. Prognostic assessment of survival in melanoma patients with brain metastases: Diagnosis Specific — Graded Prognostic Assessment (DS-GPA) scale [20]

KPS [points]	< 70	70–80	90–100
Number of CNS metastases	> 3	2–3	1
Points		1	2
Based on the sum of points assigned according to KPS and the number of metastases
DS-GPA	0–1.0	1.5–2.0	2.5–3.0	3.5–4.0
Median survival [months]	3.4	4.7	8.8	13.2

CNS — central nervous system; KPS — Karnofsky performance status

Figure 1. Kaplan-Meier survival curves for individual groups in the Graded Prognostic Assessment (GPA) scale [20]; CNS — central nervous system

The management algorithm in melanoma patients with CNS metastases is presented in Figure 2.

Figure 2. Algorithm of management in melanoma patients with metastases in the central nervous system (CNS); SRS/fSRS — radiosurgery, fractionated radiosurgery (stereotactic radiotherapy); WBRT — whole brain radiotherapy; 1Local treatment is understood as standalone or combined use of surgical methods and techniques of stereotactic radiotherapy, available options include metastasectomy plus adjuvant SRS/fSRS, hybrid treatment (metastasectomy plus adjuvant SRS/fSRS to postoperative bed plus radical SRS/fSRS of other metastases) or only SRS/fSRS. Hybrid treatment may bring particular benefits in the case of multiple metastases available for SRS/fSRS, among which some lesions give neurological symptoms or are associated with expected lower efficacy of SRS/fSRS (large, bleeding lesions, with a fluid component) and are available for surgical treatment; 2Available options include immunotherapy (combination of nivolumab with ipilimumab as a combination effective in the CNS) or BRAF inhibitors with MEK inhibitors in patients with a confirmed BRAF mutation. The preferred treatment option is dual immunotherapy, regardless of BRAF mutation status. In the presence of high-volume disease and clinical symptoms, treatment with BRAF inhibitors with MEK inhibitors in patients with a known BRAF mutation should be considered as an alternative. Single-agent immunotherapy does not provide adequate CNS response rates; 3This management requires close observation of the CNS with the use of contrast-enhanced magnetic resonance imaging (MRI) and comparative assessment. Baseline MRI should be performed at treatment initiation, then in a month, and then every 2–3 months; 4Anti-oedematous and/or anti-epileptic treatment, if necessary; 5In the case of leptomeningeal metastases or if SRS/fSRS/metastasectomy is not possible

Local treatment of melanoma patients with CNS metastases

The expected survival in untreated melanoma patients with symptomatic CNS metastases is 2–3 months, and only 13% of patients have OS longer than a year (prognosis is more favorable in patients below 65 years of age and performance status > 70 according to the Karnofsky scale). Resection or radiotherapy of all metastatic lesions influences the prognosis. In the situation of leaving one of several lesions, the prognosis is identical as in untreated patients [20]. In the case of multiple asymptomatic and non-life-threatening metastases in the CNS, the priority is to start systemic combined treatment with proven value in the CNS (especially — nivolumab and ipilimumab) with the possibility of postponing local treatment until the first assessment of systemic therapy efficacy (especially when WBRT is the only possible procedure due to the multiplicity of metastatic lesions or unavailability of techniques for simultaneous radiotherapy of multiple metastases). In the case of a limited number of metastases available for local treatment techniques, the preferred method of management is a combination of radiotherapy with immunotherapy or molecularly targeted treatment during the first 2–3 months from systemic treatment initiation, instead of radiotherapy as part of salvage treatment [8].

There are still no unequivocal predictors of the occurrence of melanoma metastases in the CNS. However, certain factors are known to be associated with increased risk, including:

primary lesion within the head and neck;
increased LDH level;
ulceration in the primary lesion;
mutations in the BRAF, NRAS, and PTEN genes [4].

In total 24–58% of patients with CNS metastases have BRAF mutation, and 23% of patients have NRAS mutation.

Surgical treatment

Eligibility criteria for surgical treatment of melanoma patients with CNS metastases (EBM, 2010, level 1) include:

newly diagnosed single lesions (up to 4 in total);
size over 3 cm;
location of lesions surgically accessible;
symptomatic lesions:
lesions causing neurological deficit and/or symptoms of increased intracranial pressure due to their volume and/or associated hemorrhagic focus and/or secondary to fluid tract obstruction leading to hydrocephalus (lesions located in the posterior cranial fossa);
Karnofsky performance status (KPS) > 70, age < 65 years;
progression after previous radiosurgery, fractionated radiosurgery (stereotactic radiotherapy) (SRS/fSRS).

The goals of surgical treatment include:

histological verification;
radical removal of all lesions, which affects OS (no justification for biopsy); in multiple tumors, it is possible to use hybrid therapy, involving resection of large and surgically accessible lesions in combination with SRS/fSRS for smaller lesions located in deep brain structures;
improvement or stabilization of neurological status (occurrence of new neurological deficits shortens OS by 4 months);
enabling further oncological treatment;
resection of symptomatic lesions of radiation necrosis after SRS/fSRS.

Radiotherapy

Stereotactic radiotherapy

Radiosurgery, fractionated radiosurgery (stereotactic radiotherapy) can be performed with use of dedicated equipment (GammaKnife, CyberKnife, Edge) or conventional linear accelerators equipped with a high-definition multi-leaf collimator (HD- -MLC). The total dose and fractionation depend on the location and size of metastatic lesions. In order to achieve local control, it is recommended to provide biologically effective dose higher than 100 Gy. The efficacy of SRS/fSRS in the treatment of small CNS melanoma metastases has been confirmed in many studies and is similar to surgical resection. Appropriate qualification of patients for treatment, which should be conducted by multidisciplinary teams, is very important.

Inclusion criteria for SRS/fSRS are:

performance status 0–2 according to the World Health Organization (WHO) scale;
single metastasis < 3 cm in diameter;
a number of metastases > 1, when the total volume of the healthy brain irradiated with a dose of 12 Gy does not exceed 10 cm3 (for single-fraction SRS);
no progression outside the CNS or when potentially effective systemic treatment is available;
indications for radiotherapy of postoperative bed [8, 21, 22];
indications for possible repeated local irradiation when progression is confirmed;
life expectancy > 6 months.

Radiosurgery, fractionated radiosurgery (stereotactic radiotherapy) was originally reserved for patients with fewer than 3 metastases; however, indications for this method have been recently extended [7]. According to them, the number of metastases is less important, and SRS is limited by the total volume of all lesions and brain volume, which receives a total dose of 12 Gy [23, 24]. It has been demonstrated that the volume of healthy brain tissue receiving a single dose of 12 Gy, which is greater than 10 cm3, is associated with high risk of radiation necrosis. In this case, a reduction in the therapeutic dose or fSRS should be considered [25]. With proper qualification, the local efficacy of SRS/fSRS (no progression in the irradiated volume) is achieved in 90–95% of melanoma patients [26, 27]. A radiologically significant tumor response is observed in half of patients [26]. Local efficacy is closely related to the location of metastatic lesions and their size.

According to the ESMO recommendations, SRS/fSRS is the preferred method of adjuvant treatment after resection of melanoma metastases in the CNS [8].

Whole brain radiotherapy (WBRT)

Melanoma is considered to be radioresistant and sensitive only to higher doses per fraction. The fractionation regimens used for WBRT (5 × 4 Gy or 10 × 3 Gy) do not provide an adequate biological dose for long-term CNS disease control. Whole brain radiotherapy is associated with neurological toxicity. The deterioration in patient quality of life is mainly caused by the impairment of cognitive functions [28, 29]. Modern high-conformal radiotherapy techniques enable single isocenter SRS/fSRS for multiple brain metastases (hypothetically without a limited number of lesions if the criteria organs at risk are met, which also limits the use of WBRT) [30, 31].

In addition, the results of a phase III study published in 2019 indicate that WBRT should not be used as adjuvant treatment after resection of 1–3 melanoma metastases in the CNS [32].

Whole brain irradiation should only be reserved for the following patients:

not eligible for surgery and SRS/fSRS;
with rapid progression of metastases and inability or lack of efficacy of systemic treatment with proven value in the CNS;
with leptomeningeal metastases (LMs)

in good general condition.

Patients in poor general condition (WHO performance status 4) and with short life expectancy should be disqualified from any form of radiotherapy. The treatment of choice is best supportive care (BSC) (effective anti-edematous and anti-convulsant treatment as well as alleviating symptoms that often accompany progression in the CNS).

Systemic treatment

Systemic treatment is the backbone therapy in patients with metastatic melanoma (including the CNS). Similar to molecularly targeted agents (BRAFi and MEKi), the use of immunotherapy (including anti-CTLA4, anti-PD1, and anti-PD-L1 drugs) significantly improves the prognosis of melanoma patients with CNS metastases. Currently, in the treatment of advanced disease, anti-PD-1 therapy combined with anti-LAG3 (nivolumab with relatlimab) is also used, although data on the use of this combination in patients with brain metastases are limited. Additionally, long-term remissions in immunotherapy responders are increasingly frequently observed, and drugs introduced into systemic therapy — both immunotherapy and molecularly targeted therapy — allowed for a significant extension of median OS [33]. The choice of appropriate systemic therapy should be determined by previously used treatment, presence of the V600 BRAF mutation, patient’s condition, and clinical setting. In most patients, this therapy should be supplemented with local treatment. In the case of few and minor metastases in the CNS, only systemic treatment remains an option.

Molecularly targeted therapy

The efficacy of molecularly targeted drugs (BRAFi and MEKi) in patients with skin melanoma with CNS metastases has been shown in several prospective clinical trials. The first clinical trials conducted exclusively in this group of patients evaluated the efficacy of BRAFi in monotherapy. The largest study — involving 172 patients with asymptomatic CNS metastases — assessed the efficacy of dabrafenib (phase II BREAK-MB study). Patients included in this study were assigned into 2 groups depending on previous local treatment of CNS metastases (patients without prior local treatment vs. patients with progression after previous local treatment). The intracranial response rate was 39.2% and 30.8%, respectively. Median OS in both groups was over 8 months [2]. In a similar phase II clinical trial of vemurafenib in 146 patients with CNS metastatic skin melanoma, the intracranial response rate was 18%, regardless of previous local treatment. Median OS was approximately 9 months [34]. In the assessment of the response by an independent review committee (IRC), the intracranial response rates in both studies were very similar (approximately 18%). Both studies showed a high disease control rate (approximately 70–80%). In most patients, a reduction in CNS metastatic lesions was observed, but only in some patients, it met partial response criteria.

Symptomatic metastases in the CNS are associated with particularly poor prognosis (median OS — 3–4 months), and this is challenging. A clinical trial involving only patients with symptomatic metastases evaluated the use of vemurafenib in monotherapy [35]. This small study involved 24 patients who were ineligible for neurosurgical treatment after prior treatment of CNS metastases and required glucocorticoids for symptom control. The intracranial response rate was 16% and median OS was 5.3 months. During the treatment, pain relief, an improvement in patient performance status, and a decrease in the need for glucocorticoids were observed. Unfortunately, the treatment effect was short-term, and the disease progressed rapidly.

Combination of BRAFi with MEKi improved the results of targeted treatment. The phase II COMBI-MB study using dabrafenib with trametinib was the first prospective clinical trial evaluating the activity of this treatment in patients with CNS metastases [36]. The study included 125 patients with performance status 0–2 with or without prior local treatment for CNS metastases. Intracranial response rates were 56–59% regardless of previous local treatment and the presence of symptomatic metastases. Duration of response (DoR) was the longest in patients with asymptomatic CNS metastases. However, the median duration of response was much shorter than that observed in phase III clinical trials without the participation of patients with CNS metastases (approximately 6 months versus 12–14 months) [37–39]. However, there were no significant differences in treatment tolerance, with fever and gastrointestinal disorders being the most common. The efficacy of BRAFi/MEKi has also been confirmed in clinical practice, including in patients pretreated with these drugs. In a retrospective analysis of 24 patients with CNS metastatic BRAF mutant melanoma treated with encorafenib and binimetinib, the CNS objective response rate (ORR) was 33%, and the disease control rate (DCR) was 63%. In patients previously treated with BRAFi/MEKi, the ORR and DCR were 24% and 57%, respectively [40].

The results of these studies confirm the activity of the BRAFi/MEKi combination in patients with CNS metastases. The response to treatment is rapid, with most patients achieving tumor reduction. This effect significantly contributes to OS improvement in the group of patients with poor prognosis and quality of life, particularly in patients with symptomatic CNS metastases. Unfortunately, the above data also indicate a short-term therapeutic effect of this targeted therapy. Resistance develops faster than in patients without CNS metastases. Therefore, attempts to combine BRAFi/MEKi with other kinase inhibitors or immunotherapy to improve treatment outcomes are ongoing. The results of studies using BRAFi/MEKi in melanoma patients with CNS metastases are presented in Table 3 [2, 34–36, 41, 42].

Table 3. Studies evaluating the efficacy of molecularly targeted therapy in the treatment of melanoma patients with metastases in the central nervous system (CNS)

Study

Patient characteristics

Number of patients

Median PFS [months]

Median OS [months]

Phase II study [34]

(NCT01378975)

Vemurafenib

CNS metastases previously untreated

CNS metastases after prior treatment

3.7

4.0

8.9

9.6

Pilot study [35]

(NCT01253564)

Vemurafenib

Previously treated, symptomatic CNS metastases

3.9

5.3

Phase II study

BREAK-MB [2]

(NCT01266967)

Dabrafenib

CNS metastases without prior treatment of CNS metastases

Progression after previous local treatment

~4a

~8a

Phase II study

COMBI-MB [36]

(NCT02039947)

Dabrafenib + trametinib

Asymptomatic CNS metastases without previous local treatment

ECOG PS 0–1

Asymptomatic CNS metastases

Prior local treatment

ECOG PS 0–1

Asymptomatic with/without prior local treatment

ECOG PS 0–1

Symptomatic with/without prior local treatment

ECOG PS 0–2

5.6

7.2

4.2

5.5

10.8

24.3

10.1

11.5

GEM1802/EBRAIN-MEL [41, 42]

(NCT03898908)

Encorafenib and binimetinib in combination with radiotherapy

Asymptomatic CNS metastases

Symptomatic CNS metastases

7.1

9.3

18.4

amedian applies to patients with the BRAF V600E mutation; ECOG — Eastern Cooperative Oncology Group; NA — data not available

Radiotherapy in combination with targeted treatment

High BRAFi/MEKi initial activity in melanoma patients with CNS metastases slightly changed the approach to using radiotherapy. Increasing use of SRS enables a high local control rate. Therefore, radiotherapy is often used only during BRAFi/MEKi treatment. Data on combining BRAFi drugs with concomitant radiotherapy are contradictory. On the one hand, there are potential benefits in terms of sensitization of melanoma cells to radiotherapy after BRAFi administration, which was described in in vitro studies [43]. On the other hand, the radiosensitizing effect of BRAFi can lead to increased side effects, which has been confirmed by several dozen case reports of significant skin toxicity with simultaneous use of irradiation (including WBRT) and BRAFi. It is worth mentioning, however, that these data refer only to older-generation BRAFi, currently replaced with newer molecules. New reports indicate that there is no need to interrupt treatment with newer-generation inhibitors. The data from the analysis of a small group of patients (GEM1802/EBRAINMEL study with encorafenib and binimetinib) indicate the possibility of improving treatment outcomes with new BRAFi/MEKs combined with radiotherapy [41, 42, 44, 45]. However, these findings were not reflected in the recommendations (as of 2023). There is no unequivocal evidence of an increased risk of neurotoxicity, hemorrhage, or radiation-related brain necrosis in the case of a combination of targeted treatment with radiotherapy [46–48]. In the case of conventional radiotherapy, the most common side effect is skin toxicity (more severe with vemurafenib) [49]. Currently, it is recommended to discontinue BRAFi/MEKi at least 3 days before the start of WBRT and to restart the drugs 3 days after completion of radiotherapy at the earliest. Withdrawal of molecularly targeted therapy is not justified when using SRS/fSRS [8].

Immunotherapy

Immunotherapy is the basic treatment option in melanoma patients with CNS metastases without V600 BRAF mutation. In patients with a mutation in the BRAF gene, the use of immunotherapy or BRAFi/MEKi treatment depends on the clinical situation.

In the open-label phase II study of ipilimumab (NCT00623766), the highest response rates were observed in asymptomatic patients not receiving glucocorticoids. Based on criteria for the immune-related response (IRR), median PFS in patients with CNS lesions was 1.9 months in the asymptomatic group vs. 1.2 months in the group requiring symptomatic treatment with glucocorticoids, and median OS was 7.0 vs. 3.7 months, respectively [50]. In the CheckMate 204 study (NCT02320058) with nivolumab and ipilimumab in glucocorticosteroids-naïve patients with at least one CNS lesion, the composite primary endpoint was the intracranial clinical benefit rate (CBR), consisting of objective responses and disease stabilization lasting more than 6 months. The CNS control rate was 55%, and the complete response rate reached 21%. Non-CNS responses were similar to those seen in the CNS, with a 6-month PFS rate of 67%. The results of the study confirm that, similar to the treatment of extracranial lesions, in patients with CNS metastases, it is possible to obtain a similar response to treatment for CNS lesions [51].

In 2019, updated results of the CheckMate 204 study in cohort A (patients with asymptomatic metastases in the CNS, e.g. without neurological symptoms and not taking glucocorticoids) and cohort B (patients with neurological symptoms regardless of glucocorticoid use) were presented. Patients in both groups received nivolumab at a dose of 1 mg/kg body weight (bw) and ipilimumab at a dose of 3 mg/kg bw every 3 weeks (4 administrations), and then only nivolumab at a dose of 3 mg/kg bw every 2 weeks until disease progression or treatment toxicity. In cohort A, after a follow-up of 20.6 months, the CBR was 58.4%, and in cohort B, after a follow-up of 5.2 months, it was 22.2%. Grade 3 and 4 treatment-related adverse events were observed in 54% of patients in cohort A and 56% of patients in cohort B. Grade 3 and 4 treatment-related neurologic adverse events occurred in 7% and 17% of patients, respectively [52, 53]. Similarly, the Australian ABC study (NCT02374242), which compared nivolumab versus nivolumab with ipilimumab in 79 melanoma patients with CNS metastases, demonstrated the efficacy of immunotherapy (including the advantage of doublet therapy in melanoma patients with asymptomatic CNS metastases). In the ABC study, patients were assigned to 3 cohorts: A (asymptomatic patients not treated locally due to CNS metastases receiving ipilimumab with nivolumab; n = 36), B (asymptomatic patients not treated locally due to CNS metastases and receiving nivolumab; n = 27) and C (patients after failure of local treatment of CNS metastases, or symptomatic patients with CNS metastases, and patients with LM and receiving nivolumab; n = 16). Complete responses to treatment were observed in 17% of patients in cohort A and 12% of patients in cohort B (cohort C — no response) [54, 55].

In the CheckMate 204 study and ABC study, grade 3 and 4 treatment-related adverse events occurred in 52% and 54% of patients receiving doublet therapy, respectively.

In asymptomatic patients, the presented clinical trials demonstrated the efficacy and good tolerance of immunotherapy. With ipilimumab, the response rate was as high as 16%, and with nivolumab and pembrolizumab it was approximately 20%. In studies on the combination of anti-PD-1 and anti-CTLA-4 agents in the group of asymptomatic patients, further significant improvement in treatment results was obtained. In patients with symptomatic metastases, the intracranial clinical response rate was also significant and amounted to 16.7%. With the availability of anti-PD-1 and anti-CTLA-4 combination therapy (nivolumab with ipilimumab — regardless of BRAF gene mutation status) and anti-BRAF and anti-MEK therapy in patients with mutation in the BRAF gene and good performance status, it is the treatment of choice, especially in the case of asymptomatic metastases in the brain, with the option of postponing local treatment until disease progression in patients receiving combined therapy.

Overall, the safety profile of immunotherapy in the aforementioned studies was consistent with that for patients without brain metastases. Moreover, intracranial and extracranial responses were largely consistent, which was confirmed by the results of a meta-analysis published by Rulli et al. in 2019 [56].

The choice of systemic therapy after diagnosis of CNS metastases remains an important issue.

The authors of an analysis published in 2023 retrospectively assessed the results of treatment in patients after first-line therapy due to generalized melanoma without CNS metastases (n = 1704), with and without the BRAF mutation. In patients with BRAF mutation-positive melanoma undergoing first-line anti-PD1 and anti-CTLA4 immunotherapy, brain metastases occurred less frequently and later as compared to BRAFi and MEKi therapy. In addition, the use of doublet immunotherapy was associated with longer OS. Interestingly, no differences in terms of OS were found between dual immunotherapy and anti-PD-1 monotherapy in melanoma patients without the BRAF mutations [57].

Derks et al. [58] published 2023 an analysis of melanoma patients with CNS metastases treated in daily clinical practice in Rotterdam from 2005 to 2021, comparing the period before and after the introduction of new treatment methods (cut-off point 2015). In total, 430 patients were analyzed, and OS was assessed before and after 2015 when checkpoint inhibitors and molecularly targeted therapy began to be used much more frequently. The analysis included 152 melanoma patients with CNS metastases before 2015 and 278 treated after 2015. Median OS in patients treated after 2015 was significantly longer compared to patients treated before 2015 (6.9 vs. 4.4 months, hazard ratio 0.67, p < 0.001). Median OS was shorter in patients who received systemic treatment before the diagnosis of CNS metastases. The use of immunotherapy immediately after the diagnosis of CNS metastases was associated with an increase in median OS from 4.2 months to 21.5 months (p < 0.001). BRAF and MEK inhibitors can cause a rapid response to treatment and have been frequently administered (> 70%) in patients with symptomatic metastases and poor performance status [58].

Studies have also been conducted to evaluate sequential and combination therapy with BRAF and MEK inhibitors and immunotherapy in melanoma patients with CNS metastases. The combined use of atezolizumab plus vemurafenib and cobimetinib resulted in an intracranial response rate of 42% and median OS of 13.7 months. In some situations, the above regimen may be an option in subsequent treatment lines, but currently, the combination of BRAF and MEK inhibitors with immunotherapy is not a standard of care.

The results of studies using immunotherapy in melanoma patients with CNS metastases are summarized in Table 4 [50, 52–54, 59–61] while the results of studies evaluating the efficacy of molecularly targeted therapy combined with immunotherapy are presented in Table 5 [62–65].

Table 4. Studies evaluating the efficacy of immunotherapy in the treatment of melanoma patients with metastases in the central nervous system (CNS)

Treatment	Patients	Patient characteristics	IC DCR	IC ORR	IC DOR [months]	mPFS [months]	mOS [months]
Ipilimumab CA184-042 [50]	51 (A) 21 (B)	Asymptomatic Symptomatic	24% 10%	16% 5%	–	1.4 1.2	7.0 3.7
Ipilimumab + fotemustine: NIBIT-M1 [59]	20	Asymptomatic	50%	40%	30.3	4.5	12.7
Pembrolizumab: (NCT02085070) [60, 61]	23	Untreated or progressive brain metastases	–	26%	–	2	17
Nivolumab: ABC; CA209-170 [54] (NCT02374242)	27 (B) 16 (C)	Asymptomatic, no local treatment (B) previously treated or symptomatic (C)	20% 19%	20% 6%	NR NR	2.5 2.3	18.5 5.1
Nivolumab + ipilimumab: ABC; CA209-170	36 (A)	Asymptomatic, no local treatment (A)	57%	46%	NR	NR	NR
Nivolumab + ipilimumab: CheckMate 204 [52, 53] (NCT02320058)	75	Asymptomatic, previously treated, ≤ 3 metastases	60%	55%	NR	NR	–

IC DCR — intracranial diseases controls rate; IC DOR — intracranial duration of response; IC ORR — intracranial objective response rate; NR — not reached; OS — overall survival; PFS — progression-free survival

Table 5. Studies evaluating the efficacy of molecularly targeted therapy combined with immunotherapy in melanoma patients with the BRAF mutation and metastases in the central nervous system (CNS)

Study	Study phase	Treatment	Number of patients	IC ORR % (CR + PR)	mPFS [month]	mOS [month]
TRIDENT [62] Patients with anti-PD1 resistance (n = 17) or previous or current brain metastases, including active metastases, asymptomatic metastases, or mild symptoms/requiring corticosteroids (n = 10)	II	Nivolumab + + dabrafenib + + trametinib	10	4/7 patients (57%)	8.0	NR
IMSpire 150 [63, 64] Exploratory analysis	III	Vemurafenib + + cobimetinib + + atezolizumab versus vemurafenib + + cobimetinib	244 versus 247	Cumulative incidence of brain metastasis as the first site of progression: after 12 months: 16% vs. 19% after 24 months: 24% vs. 26% after 36 months: 25% vs. 28% after 48 months: 28% vs. 29% Stratified HR = 0.91; 95% CI 0.64–1.29
TRICOTEL [65] (Cohort 1: BRAF V600 positive melanoma patients with brain metastases; n = 15; Cohort 2: BRAF V600 negative melanoma patients with brain metastases)	II	Atezolizumab + + vemurafenib + + cobimetinib	65	42 IRC-assessed (51 investigator- -assessed)	5.3 IRC-assessed (5.8 investigator- -assessed)	13.7

CI — confidence interval; CR — complete response; HR — hazard ratio; IC ORR — intracranial objective response rate; ICR — independent review committee; NR — not reached; OS — overall survival; PFS — progression-free survival; PR — partial response

Combining radiotherapy with immunotherapy

There are more and more reports related to the beneficial effect of combining radiotherapy with immunotherapy. The studies published so far have shown a significant increase in the percentage of abscopal effect phenomenon (response of untreated lesions to local treatment of another lesion) after adding radiotherapy to immunotherapy [66, 67]. The effect is explained by local stimulation of the immune system and intensification of antigenic effect, where dendritic cells probably play an important role. Currently, many clinical trials are conducted in which radiotherapy and immunotherapy are combined. There are no contraindications to combining radiotherapy with immunotherapy, and this decision should be made at a multidisciplinary meeting individually for each patient [8]. Attention should be paid to the prophylactic anti-edematous treatment administered during radiotherapy in the form of high doses of glucocorticosteroids, which may reduce immunotherapy efficacy. According to the current recommendations, indications for the use of glucocorticosteroids as part of anti-edematous treatment during SRS/fSRS are significantly limited.

The combination of immunotherapy or molecularly targeted therapy with SRS/fSRS seems to be generally well tolerated, as demonstrated by studies and analyses conducted so far. In 2016, the results of a retrospective analysis conducted in a subgroup of patients participating in two prospective studies with nivolumab due to unresectable or metastatic disease were published [68]. Twenty-six patients treated for melanoma and undergoing SRS/fSRS due to CNS metastases were analyzed, including patients with CNS metastases diagnosed and treated with SRS within 6 months of nivolumab treatment (before, after, or during immunotherapy). A total of 73 lesions in the CNS were identified in this group of patients. The primary endpoint was treatment tolerance, while the secondary endpoints included control of CNS disease, lesions outside the CNS, and OS. Most metastatic patients were treated with SRS, and only 12 CNS lesions underwent fSRS. Grade 2 headache was observed in one patient, which resolved after using glucocorticoids. No other treatment-related neurological complications were observed. In 8 CNS lesions (11%), treatment failure was observed in the form of an increase in lesion volume of at least 20%. Local control rates at 6 and 12 months were 91% and 85%, respectively. Median OS was 12.0 months from initiation of nivolumab treatment and 11.8 months from SRS/ fSRS.

In 2017, a systematic review was published to assess the tolerance of the combination of immunotherapy or targeted therapy with SRS/fSRS. The review included 6 retrospective studies and 2 case reports on patients treated with SRS/fSRS and ipilimumab. Based on this analysis, it can be concluded that the combination of ipilimumab and SRS/fSRS for intracranial lesions is a safe treatment option [69].

New methods of systemic treatment in melanoma patients with CNS metastases

Due to often short-term or insufficient response to immunotherapy or molecularly targeted therapy in melanoma patients with CNS metastases, attempts are currently being made to combine BRAF/MEK inhibitors with other kinase inhibitors or immunotherapy to improve the outcomes. An example is the TRIDeNT study with the use of nivolumab in combination with dabrafenib and/or trametinib, involving melanoma patients with CNS and leptomeningeal metastases (NCT02910700) [62]. Another interesting trial is the NCT05704933 study with the perioperative use of nivolumab in combination with ipilimumab or relatlimab in patients with resectable melanoma metastases in the CNS [70]. Strategies based on systemic therapy combined with radiotherapy are also being evaluated. An example is the phase II BEPCOME-MB study, in which binimetinib with encorafenib and pembrolizumab are used together with SRS/fSRS in patients with BRAF mutation-positive melanoma and CNS metastases (NCT04074096) [71].

Monitoring of patients after local treatment due to CNS metastases and management in case of progression

The melanoma brain metastases occurrence is associated with an increased risk of new brain metastases. This justifies the regular brain MRI in all patients treated due to melanoma with CNS dissemination [7]. In approximately 50% of patients, new metastatic lesions or progression of previously treated metastases (recurrence in the postoperative bed, progression after SRS/fSRS/WBRT) will be detected [72]. The first MRI is recommended within a month after neurosurgery or SRS, and every 2–3 months afterwards. The results of imaging tests should be interpreted with caution, especially in patients receiving immunotherapy due to the risk of pseudoprogression and/or posttreatment lesions that may be difficult to distinguish from real disease progression. Despite the introduction of modern neuroimaging techniques, it is difficult to determine the nature of the detected changes (progression of an active neoplastic process or radiation necrosis). In doubtful situations, resection should be the treatment of choice, because — apart from oncological indications — removal of necrotic tissues reduces brain edema. In order to differentiate between radiation necrosis and disease recurrence, magnetic resonance spectroscopy (MRS) may be considered [73]. It is helpful to use structured assessment methods, such as the RANO (Response Assessment in Neuro-Oncology) criteria [74].

In the case of CNS progression, it is usually possible to use one of the local salvage treatments (resection, SRS/fSRS, WBRT) after discussing the patient’s case at a multidisciplinary meeting [75–78]. There are possible two different scenarios. If progression is found outside the irradiated volume, it is usually possible to use SRS/fSRS or WBRT. In the case of progression within the irradiated volume, emergency surgical treatment remains the method of choice, with maintaining the previously described qualification criteria for neurosurgical treatment.

Leptomeningeal metastases

The prognosis of patients with leptomeningeal metastases is poor and survival usually does not exceed a few weeks. Data on the efficacy of modern systemic therapies in patients with meningeal involvement are limited, and evidence-based standards of management are missing. The results of recently published retrospective analyzes indicate that molecularly targeted therapy and immunotherapy may improve the prognosis in these patients [79, 80]. A phase I clinical trial (NCT03025256) is currently conducted with the use of systemic and intrathecal nivolumab in patients with leptomeningeal disease.

Data on systemic use of interleukin-2 (IL-2) are encouraging — 1-, 2-, and 5-year survival rates in the group of 43 patients were 36%, 26%, and 13%, respectively. However, due to increased toxicity, the use of IL-2 is not a standard procedure [81].

Radiotherapy in the form of WBRT involving the meninges up to level C2 is a palliative treatment and should be used only in a selected group of patients (good general condition, active systemic treatment).

Summary

The basic and applicable rule in the management of melanoma metastases in the CNS should be a multidisciplinary approach involving, at least, a neurosurgeon, radiation oncologist and clinical oncologist experienced in the treatment of melanoma patients with CNS metastases. There are no clear risk factors for melanoma brain metastases. The detection of CNS metastases is associated with poor prognosis; they are the cause of death in 20–50% of patients, and symptomatic tumors are the immediate cause of death in about 90% of patients. Historical data indicated a median OS of 5–7 months after the diagnosis of CNS metastasis. Currently, more and more CNS metastases are diagnosed at the asymptomatic stage using routine brain imaging during the follow-up or qualification for systemic treatment. Treatment of melanoma with CNS metastases includes, depending on the clinical situation, local and/or systemic therapy and symptomatic treatment. In local treatment, advanced techniques of stereotactic radiotherapy are the most valuable. During the last 10 years, 11 new drugs have been registered in Europe for the treatment of patients with advanced melanoma. Due to the introduction of modern systemic therapies, median OS is now about 2 years, based on data from clinical trials. Anti-PD1 and anti-CTLA-4 dual therapy (nivolumab with ipilimumab), when available, can be the choice in patients with CNS metastasis up to 3 cm in diameter and with good performance status. BRAF inhibitors and MEKi can be the upfront treatment in patients with BRAF mutation and asymptomatic metastases.

Article Information and Declarations

Acknowledgments

None.

Conflict of interest

P.R.: honoraria for lectures and participation in advisory boards from Novartis, BMS, MSD, Pierre Fabre, Merck, Sanofi, Amgen, Philogen, Astra Zeneca, and Blueprint Medicines, which did not affect the content of the guidelines.

K.K.: honoraria from BMS, MSD, Novartis, and Pierre Fabre.

M.D.-S.: honoraria from Pierre Fabre, Merck KGaA, MSD, Sanofi Aventis, Novartis, MedisonPharma, BMS, Incyte, and Nutricia.

Other authors report no conflict of interest.

Data availability statement

Literature review available on request.

Funding

None.

Supplementary material

None.

References

Gershenwald JE, Scolyer RA. Melanoma Staging: American Joint Committee on Cancer (AJCC) 8th Edition and Beyond. Ann Surg Oncol. 2018; 25(8): 2105–2110, doi: 10.1245/s10434-018-6513-7, indexed in Pubmed: 29850954.
Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012; 13(11): 1087–1095, doi: 10.1016/S1470-2045(12)70431-X, indexed in Pubmed: 23051966.
Derks SH, de Joode K, Mulder EE, et al. The meaning of screening: detection of brain metastasis in the adjuvant setting for stage III melanoma. ESMO Open. 2022; 7(6): 100600, doi: 10.1016/j.esmoop.2022.100600, indexed in Pubmed: 36265261.
Ramakrishna N, Margolin KA. Multidisciplinary approach to brain metastasis from melanoma; local therapies for central nervous system metastases. Am Soc Clin Oncol Educ Book. 2013: 399–403, doi: 10.14694/EdBook_AM.2013.33.399, indexed in Pubmed: 23714560.
Davies MA, Liu P, McIntyre S, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer. 2011; 117(8): 1687–1696, doi: 10.1002/cncr.25634, indexed in Pubmed: 20960525.
Rutkowski EP, Wysocki PJ. Cutaneous melanomas. Oncology in Clinical Practice. 2019; 15(1): 1–19, doi: 10.5603/OCP.2018.0055.
Coit DG, Thompson JA, Albertini MR, et al. Cutaneous Melanoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019; 17(4): 367–402, doi: 10.6004/jnccn.2019.0018, indexed in Pubmed: 30959471.
Keilholz U, Ascierto PA, Dummer R, et al. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020; 31(11): 1435–1448, doi: 10.1016/j.annonc.2020.07.004.
Tawbi HA, Boutros C, Kok D, et al. New Era in the Management of Melanoma Brain Metastases. Am Soc Clin Oncol Educ Book. 2018; 38: 741–750, doi: 10.1200/EDBK_200819, indexed in Pubmed: 30231345.
Zakrzewski J, Geraghty LN, Rose AE, et al. Clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post-brain metastases survival. Cancer. 2011; 117(8): 1711–1720, doi: 10.1002/cncr.25643, indexed in Pubmed: 21472718.
Osella-Abate S, Ribero S, Sanlorenzo M, et al. Risk factors related to late metastases in 1,372 melanoma patients disease free more than 10 years. Int J Cancer. 2015; 136(10): 2453–2457, doi: 10.1002/ijc.29281, indexed in Pubmed: 25331444.
Samlowski WE, Moon J, Witter M, et al. High frequency of brain metastases after adjuvant therapy for high-risk melanoma. Cancer Med. 2017; 6(11): 2576–2585, doi: 10.1002/cam4.1223, indexed in Pubmed: 28994212.
Salvati M, Cervoni L, Caruso R, et al. Solitary cerebral metastasis from melanoma: value of the ‚en bloc’ resection. Clin Neurol Neurosurg. 1996; 98(1): 12–14, doi: 10.1016/0303-8467(95)00077-1, indexed in Pubmed: 8681471.
Sandhu MR, Chiang VL, Tran T, et al. Incidence and characteristics of metastatic intracranial lesions in stage III and IV melanoma: a single institute retrospective analysis. J Neurooncol. 2021; 154(2): 197–203, doi: 10.1007/s11060-021-03813-8, indexed in Pubmed: 34351544.
Barnholtz-Sloan JS, Sloan AE, Davis FG, et al. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol. 2004; 22(14): 2865–2872, doi: 10.1200/JCO.2004.12.149, indexed in Pubmed: 15254054.
Le Rhun E, Guckenberger M, Smits M, et al. EANO Executive Board and ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. Ann Oncol. 2021; 32(11): 1332–1347, doi: 10.1016/j.annonc.2021.07.016, indexed in Pubmed: 34364998.
Fink KR, Fink JR. Imaging of brain metastases. Surg Neurol Int. 2013; 4(Suppl 4): S209–S219, doi: 10.4103/2152-7806.111298, indexed in Pubmed: 23717792.
Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep. 2012; 14(1): 48–54, doi: 10.1007/s11912-011-0203-y, indexed in Pubmed: 22012633.
Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997; 37(4): 745–751, doi: 10.1016/s0360-3016(96)00619-0, indexed in Pubmed: 9128946.
Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012; 30(4): 419–425, doi: 10.1200/JCO.2011.38.0527, indexed in Pubmed: 22203767.
Ling DC, Vargo JA, Wegner RE, et al. Postoperative stereotactic radiosurgery to the resection cavity for large brain metastases: clinical outcomes, predictors of intracranial failure, and implications for optimal patient selection. Neurosurgery. 2015; 76(2): 150–6; discussion 156, doi: 10.1227/NEU.0000000000000584, indexed in Pubmed: 25549189.
Choi CYH, Chang SD, Gibbs IC, et al. Stereotactic radiosurgery of the postoperative resection cavity for brain metastases: prospective evaluation of target margin on tumor control. Int J Radiat Oncol Biol Phys. 2012; 84(2): 336–342, doi: 10.1016/j.ijrobp.2011.12.009, indexed in Pubmed: 22652105.
Hunter GK, Suh JH, Reuther AM, et al. Treatment of five or more brain metastases with stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2012; 83(5): 1394–1398, doi: 10.1016/j.ijrobp.2011.10.026, indexed in Pubmed: 22209150.
Skeie BS, Skeie GO, Enger PØ, et al. Gamma knife surgery in brain melanomas: absence of extracranial metastases and tumor volume strongest indicators of prolonged survival. World Neurosurg. 2011; 75(5-6): 684–91; discussion 598, doi: 10.1016/j.wneu.2010.12.054, indexed in Pubmed: 21704936.
Minniti G, Scaringi C, Paolini S, et al. Single-Fraction Versus Multifraction (3 × 9 Gy) Stereotactic Radiosurgery for Large (>2 cm) Brain Metastases: A Comparative Analysis of Local Control and Risk of Radiation-Induced Brain Necrosis. Int J Radiat Oncol Biol Phys. 2016; 95(4): 1142–1148, doi: 10.1016/j.ijrobp.2016.03.013, indexed in Pubmed: 27209508.
Mori Y, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for cerebral metastatic melanoma: factors affecting local disease control and survival. Int J Radiat Oncol Biol Phys. 1998; 42(3): 581–589, doi: 10.1016/s0360-3016(98)00272-7, indexed in Pubmed: 9806518.
Yu C, Chen JCT, Apuzzo MLJ, et al. Metastatic melanoma to the brain: prognostic factors after gamma knife radiosurgery. Int J Radiat Oncol Biol Phys. 2002; 52(5): 1277–1287, doi: 10.1016/s0360-3016(01)02772-9, indexed in Pubmed: 11955740.
Li J, Bentzen SM, Li J, et al. Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis. Int J Radiat Oncol Biol Phys. 2008; 71(1): 64–70, doi: 10.1016/j.ijrobp.2007.09.059, indexed in Pubmed: 18406884.
Welzel G, Fleckenstein K, Schaefer J, et al. Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys. 2008; 72(5): 1311–1318, doi: 10.1016/j.ijrobp.2008.03.009, indexed in Pubmed: 18448270.
Krc RF, Ryckman J, Thomas E, et al. Dosimetric Comparison of Hyper Arc Single-Isocenter Multi-Target and Gamma Knife Based Stereotactic Radiosurgery for a Patient with 53 Brain Metastases. Cureus Journal of Medical Science. 2022; 14.
Kraft J, van Timmeren JE, Mayinger M, et al. Distance to isocenter is not associated with an increased risk for local failure in LINAC-based single-isocenter SRS or SRT for multiple brain metastases. Radiother Oncol. 2021; 159: 168–175, doi: 10.1016/j.radonc.2021.03.022, indexed in Pubmed: 33798610.
Hong AM, Fogarty GB, Dolven-Jacobsen K, et al. Adjuvant Whole-Brain Radiation Therapy Compared With Observation After Local Treatment of Melanoma Brain Metastases: A Multicenter, Randomized Phase III Trial. J Clin Oncol. 2019; 37(33): 3132–3141, doi: 10.1200/JCO.19.01414, indexed in Pubmed: 31553661.
Sloot S, Chen YA, Zhao X, et al. Improved survival of patients with melanoma brain metastases in the era of targeted BRAF and immune checkpoint therapies. Cancer. 2018; 124(2): 297–305, doi: 10.1002/cncr.30946, indexed in Pubmed: 29023643.
McArthur GA, Maio M, Arance A, et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol. 2017; 28(3): 634–641, doi: 10.1093/annonc/mdw641, indexed in Pubmed: 27993793.
Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. 2014; 50(3): 611–621, doi: 10.1016/j.ejca.2013.11.002, indexed in Pubmed: 24295639.
Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAF-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017; 18(7): 863–873, doi: 10.1016/S1470-2045(17)30429-1, indexed in Pubmed: 28592387.
Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015; 386(9992): 444–451, doi: 10.1016/S0140-6736(15)60898-4, indexed in Pubmed: 26037941.
Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017; 28(7): 1631–1639, doi: 10.1093/annonc/mdx176, indexed in Pubmed: 28475671.
Robert C, Karaszewska B, Schachter J, et al. Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib (T) in patients (pts) with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma. Ann Oncol. 2016; 27: vi575, doi: 10.1093/annonc/mdw435.37.
Holbrook K, Lutzky J, Davies MA, et al. Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series. Cancer. 2020; 126(3): 523–530, doi: 10.1002/cncr.32547, indexed in Pubmed: 31658370.
Marquez-Rodas I, Arance A, Guerrero MAB, et al. 1038MO Intracranial activity of encorafenib and binimetinib followed by radiotherapy in patients with BRAF mutated melanoma and brain metastasis: Preliminary results of the GEM1802/EBRAIN-MEL phase II clinical trial. Ann Onco. 2021; 32: S870, doi: 10.1016/j.annonc.2021.08.1423.
Marquez-Rodas I, Fernandez AMA, Guerrero MAB, et al. 826P Encorafenib and binimetinib followed by radiotherapy for patients with symptomatic BRAF mutated melanoma brain metastases: GEM1802/E-BRAIN clinical trial. Ann Oncol. 2022; 33: S926, doi: 10.1016/j.annonc.2022.07.952.
Ugurel S, Thirumaran RK, Bloethner S, et al. B-RAF and N-RAS mutations are preserved during short time in vitro propagation and differentially impact prognosis. PLoS One. 2007; 2(2): e236, doi: 10.1371/journal.pone.0000236, indexed in Pubmed: 17311103.
Rossi E, Schinzari G, Cellini F, et al. Dabrafenib-Trametinib and Radiotherapy for Oligoprogressive Mutant Advanced Melanoma. Biomedicines. 2023; 11(2), doi: 10.3390/biomedicines11020394, indexed in Pubmed: 36830931.
Wang TW, Smith JL, Carlino M, et al. Evaluating the Safety and Tolerability of the Combination of Dabrafenib, Trametinib and Palliative Radiotherapy in Patients with Metastatic BRAF V600E/K Mutation-positive Cutaneous Melanoma. International Journal of Radiation Oncology*Biology*Physics. 2020; 108(3): S133–S134, doi: 10.1016/j.ijrobp.2020.07.866.
Anker CJ, Grossmann KF, Atkins MB, et al. Avoiding Severe Toxicity From Combined BRAF Inhibitor and Radiation Treatment: Consensus Guidelines from the Eastern Cooperative Oncology Group (ECOG). Int J Radiat Oncol Biol Phys. 2016; 95(2): 632–646, doi: 10.1016/j.ijrobp.2016.01.038, indexed in Pubmed: 27131079.
Rompoti N, Schilling B, Livingstone E, et al. Combination of BRAF Inhibitors and Brain Radiotherapy in Patients With Metastatic Melanoma Shows Minimal Acute Toxicity. J Clin Oncol. 2013; 31(30): 3844–3845, doi: 10.1200/JCO.2013.50.8473, indexed in Pubmed: 24062392.
Ly D, Bagshaw HP, Anker CJ, et al. Local control after stereotactic radiosurgery for brain metastases in patients with melanoma with and without BRAF mutation and treatment. J Neurosurg. 2015; 123(2): 395– –401, doi: 10.3171/2014.9.JNS141425, indexed in Pubmed: 25768829.
Hecht M, Zimmer L, Loquai C, et al. Radiosensitization by BRAF inhibitor therapy-mechanism and frequency of toxicity in melanoma patients. Ann Oncol. 2015; 26(6): 1238–1244, doi: 10.1093/annonc/mdv139, indexed in Pubmed: 25762352.
Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012; 13(5): 459–465, doi: 10.1016/S1470-2045(12)70090-6, indexed in Pubmed: 22456429.
Long GV, Atkinson V, Lo S, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 2018; 19(5): 672–681, doi: 10.1016/S1470-2045(18)30139-6, indexed in Pubmed: 29602646.
Tawbi HH, Forsyth P, Algazi A, et al. Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204. J Clin Oncol. 2017; 35(15_suppl): 9507–9507, doi: 10.1200/jco.2017.35.15_suppl.9507.
Tawbi HA, Forsyth PA, Hodi FS, et al. Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204). Neuro Oncol. 2021; 23(11): 1961–1973, doi: 10.1093/neuonc/noab094, indexed in Pubmed: 33880555.
Long G, Atkinson V, Lo S, et al. Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets). J Clin Oncol. 2021; 39(15_suppl): 9508–9508, doi: 10.1200/jco.2021.39.15_suppl.9508.
Long GV, Atkinson VG, Lo S, et al. Long-term outcomes from the randomized phase II study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets): Anti-PD1 brain collaboration (ABC). Ann Oncol. 2019; 30: v534, doi: 10.1093/annonc/mdz255.001.
Rulli E, Legramandi L, Salvati L, et al. The impact of targeted therapies and immunotherapy in melanoma brain metastases: A systematic review and meta-analysis. Cancer. 2019; 125(21): 3776–3789, doi: 10.1002/cncr.32375, indexed in Pubmed: 31287564.
Franklin C, Mohr P, Bluhm L, et al. Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG. J Immunother Cancer. 2023; 11(4), doi: 10.1136/jitc-2022-005828, indexed in Pubmed: 37028819.
Derks SH, Jongen JLM, van der Meer EL, et al. Impact of Novel Treatments in Patients with Melanoma Brain Metastasis: Real-World Data. Cancers (Basel). 2023; 15(5), doi: 10.3390/cancers15051461, indexed in Pubmed: 36900253.
Di Giacomo AM, Ascierto PA, Queirolo P, et al. Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study. Ann Oncol. 2015; 26(4): 798–803, doi: 10.1093/annonc/mdu577, indexed in Pubmed: 25538176.
Goldberg SB, Schalper KA, Gettinger SN, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016; 17(7): 976–983, doi: 10.1016/S1470-2045(16)30053-5, indexed in Pubmed: 27267608.
Kluger HM, Chiang V, Mahajan A, et al. Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. J Clin Oncol. 2019; 37(1): 52–60, doi: 10.1200/JCO.18.00204, indexed in Pubmed: 30407895.
Burton E, Amaria R, Glitza I, et al. Phase II Study of TRIplet combination Nivolumab (N) with Dabrafenib (D) and Trametinib (T) (TRIDeNT) in patients (pts) with PD-1 naïve or refractory BRAF-mutated metastatic melanoma (MM) with or without active brain metastases. J Clin Oncol. 2021; 39(15_suppl): 9520–9520, doi: 10.1200/jco.2021.39.15_suppl.9520.
Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020; 395(10240): 1835–1844, doi: 10.1016/S0140-6736(20)30934-X, indexed in Pubmed: 32534646.
Ascierto PA, Stroyakovskiy D, Gogas H, et al. Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAF mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study. Lancet Oncol. 2023; 24(1): 33–44, doi: 10.1016/S1470-2045(22)00687-8, indexed in Pubmed: 36460017.
Dummer R, Queirolo P, Abajo Guijarro AM, et al. Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2022; 23(9): 1145–1155, doi: 10.1016/S1470-2045(22)00452-1, indexed in Pubmed: 35940183.
Park SS, Dong H, Liu X, et al. PD-1 Restrains Radiotherapy-Induced Abscopal Effect. Cancer Immunol Res. 2015; 3(6): 610–619, doi: 10.1158/2326-6066.CIR-14-0138, indexed in Pubmed: 25701325.
Spałek M, Czarnecka A. The role of radiotherapy in melanoma. Oncol Clin Pract. 2020; 15(6): 310–319, doi: 10.5603/ocp.2019.0031.
Ahmed KA, Abuodeh YA, Echevarria MI, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy. Ann Oncol. 2016; 27(12): 2288– –2294, doi: 10.1093/annonc/mdw417, indexed in Pubmed: 27637745.
Kroeze SGC, Fritz C, Hoyer M, et al. Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: A systematic review. Cancer Treat Rev. 2017; 53: 25–37, doi: 10.1016/j.ctrv.2016.11.013, indexed in Pubmed: 28056412.
Pilot Study of Nivolumab w/Ipilimumab or Relatlimab in Surgically Resectable Melanoma Brain Metastases. https:/clinicaltrials.gov/ct2/show/NCT05704933 (9.07.2023).
Binimetinib Encorafenib Pembrolizumab +/- Stereotactic Radiosurgery in BRAFV600 Melanoma With Brain Metastasis. https:/clinicaltrials.gov/ct2/show/NCT04074096 (9.07.2023).
Samlowski WE, Watson GA, Wang M, et al. Multimodality treatment of melanoma brain metastases incorporating stereotactic radiosurgery (SRS). Cancer. 2007; 109(9): 1855–1862, doi: 10.1002/cncr.22605, indexed in Pubmed: 17351953.
Chuang MT, Liu YS, Tsai YS, et al. Differentiating Radiation-Induced Necrosis from Recurrent Brain Tumor Using MR Perfusion and Spectroscopy: A Meta-Analysis. PLoS One. 2016; 11(1): e0141438, doi: 10.1371/journal.pone.0141438, indexed in Pubmed: 26741961.
Lin NU, Lee EQ, Aoyama H, et al. Response Assessment in Neuro-Oncology (RANO) group. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 2015; 16(6): e270–e278, doi: 10.1016/S1470-2045(15)70057-4, indexed in Pubmed: 26065612.
Noël G, Proudhom MA, Valery CA, et al. Radiosurgery for re-irradiation of brain metastasis: results in 54 patients. Radiother Oncol. 2001; 60(1): 61–67, doi: 10.1016/s0167-8140(01)00359-0, indexed in Pubmed: 11410305.
Spałek MJ, Mandat T. Salvage Treatment for Progressive Brain Metastases in Breast Cancer. Cancers (Basel). 2022; 14(4), doi: 10.3390/cancers14041096, indexed in Pubmed: 35205844.
Chao ST, Barnett GH, Vogelbaum MA, et al. Salvage stereotactic radiosurgery effectively treats recurrences from whole-brain radiation therapy. Cancer. 2008; 113(8): 2198–2204, doi: 10.1002/cncr.23821, indexed in Pubmed: 18780319.
Ammirati M, Cobbs CS, Linskey ME, et al. The role of retreatment in the management of recurrent/progressive brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2010; 96(1): 85–96, doi: 10.1007/s11060-009-0055-6, indexed in Pubmed: 19957016.
Geukes Foppen MH, Brandsma D, Blank CU, et al. Targeted treatment and immunotherapy in leptomeningeal metastases from melanoma. Ann Oncol. 2016; 27(6): 1138–1142, doi: 10.1093/annonc/mdw134, indexed in Pubmed: 26961150.
Smalley KSM, Fedorenko IV, Kenchappa RS, et al. Managing leptomeningeal melanoma metastases in the era of immune and targeted therapy. Int J Cancer. 2016; 139(6): 1195–1201, doi: 10.1002/ijc.30147, indexed in Pubmed: 27084046.
Glitza IC, Rohlfs M, Guha-Thakurta N, et al. Retrospective review of metastatic melanoma patients with leptomeningeal disease treated with intrathecal interleukin-2. ESMO Open. 2018; 3(1): e000283, doi: 10.1136/esmoopen-2017-000283, indexed in Pubmed: 29387478.