Evolving treatment options for melanoma brain metastases

doi:10.1016/S1470-2045(15)00141-2

The Lancet Oncology

Volume 16, Issue 13, October 2015, Pages e486-e497

https://doi.org/10.1016/S1470-2045(15)00141-2 Get rights and content

Summary

Melanoma is a leading cause of lost productivity due to premature cancer mortality. Melanoma frequently spreads to the brain and is associated with rapid deterioration in quality and quantity of life. Until now, treatment options have been restricted to surgery and radiotherapy, although neither modality has been well studied in clinical trials. However, the new immune checkpoint inhibitors and molecularly targeted agents that have been introduced for treatment of metastatic melanoma are active against brain metastases and offer new opportunities to improve disease outcomes. New challenges arise, including how to integrate or sequence multiple treatment modalities, and current practice varies widely. In this Review, we summarise evidence for the treatment of melanoma brain metastases, and discuss the rationale and evidence for combination modalities, highlighting areas for future research.

Introduction

Melanoma is the third most common cause of brain metastasis after lung and breast cancers.¹ The biological predisposition for melanoma to spread to the brain is not fully understood, but the brain is frequently a site of metastasis at the end stages of the disease. Although around 7% of patients with melanoma present with brain involvement at diagnosis, up to 60% of all patients with melanoma will develop brain metastases during the course of their illness, including 25% with a solitary brain lesion.1, 2, 3

Surgery, radiotherapy, and radiosurgery have traditionally been used in the management of melanoma brain metastases either as single-modality treatments or in combination. The median overall survival of patients with untreated brain metastases is less than 3 months, but might be longer if aggressive loco-regional treatment is possible.⁴ Immunomodulators and targeted agents against mutations in the BRAF gene have become established treatment for patients with metastatic melanoma, offering a survival benefit.⁵ Here, we review the present understanding and evolving multimodal management of melanoma brain metastases, and the challenges of how best to integrate new systemic therapies.

Section snippets

Risk factors for melanoma brain metastases

A review of 702 patients with melanoma brain metastases¹ identified male sex, head and neck or truncal primary, mucosal melanoma, nodular or acral lentiginous histologies, and visceral or nodal metastases as risk factors for melanoma brain metastases, although the evidence is not entirely consistent. For example, a study of similar size (686 patients)³ did not find that truncal primaries increase the risk of brain metastases; however, in agreement with other studies,6, 7 the investigators noted

Imaging and response assessment

The radiological appearance of melanoma brain metastases varies substantially. CT scanning generally shows extensive oedema with a slightly hyperdense irregular lesion (or lesions), which enhances heterogeneously after contrast administration.¹¹ Melanomas are generally highly vascular and intracerebral haemorrhage is common, which might be evident on CT imaging. The typical so-called melanotic pattern of brain metastasis is hyperintense on T1-weighted images and hypointense on T2-weighted

Treatment of melanoma brain metastases: limitations of the evidence base

The quality of the efficacy data for surgery, radiosurgery, radiotherapy, and systemic treatment in the management of melanoma brain metastases is variable. Most interventional studies assessing surgery or radiotherapy, or a combination of both, to treat brain metastases have recruited patients with disease originating from various primary sites, with very few studies confined to patients with melanoma. Therefore, interpretation of the available data to inform clinical practice is difficult. In

Surgery

In patients with a solitary brain metastasis, surgery can result in rapid improvement in neurological symptoms. The best supportive evidence for surgery as the standard of care is retrospective. In the study of 686 patients with melanoma brain metastases,³ median overall survival for patients selected for surgery (8·7 months) or surgery plus radiotherapy (8·9 months) was significantly longer than that for patients given radiotherapy alone (3·4 months) or supportive care (2·1 months; p<0.001).

Whole-brain radiotherapy

WBRT versus surgery plus WBRT

Three randomised trials have compared WBRT with the combination of surgery followed by WBRT in patients diagnosed with a single brain metastasis. However, in all of these studies, the number of patients with melanoma brain metastases was small, and the reported outcomes were for the whole cohort of patients. In a study of 48 patients (three with melanoma brain metastases),²⁷ the combined-modality treatment was associated with a longer median overall survival (40 weeks vs 15 weeks; p<0·01), a

Melanoma-specific graded prognostic assessment

Sperduto and colleagues³⁷ studied 481 patients with newly diagnosed melanoma brain metastases, who were given WBRT (n=86), surgery plus WBRT (n=29), surgery plus WBRT and SRS (n=26), SRS alone (n=221), WBRT plus SRS (n=89), or surgery plus SRS (n=30). The investigators identified KPS and the number of brain metastases as significant prognostic factors for overall survival and derived scoring criteria for a melanoma-specific graded prognostic assessment. Using these criteria, patients with a KPS

Summary of local treatment

The choice of local treatment depends on the number of brain metastases, KPS, and the extent of extracranial disease (figure 2). On the basis of the studies reviewed here, the median overall survival is roughly 2–3 months for untreated melanoma brain metastases, 2–5 months with WBRT, 8–11 months with surgery or SRS, and 13–14 months with combined-modality local treatment.

Evidence available at present has the major drawback of inherent selection bias. Therefore, definitive recommendations for

Cytotoxic chemotherapy

Many studies have assessed the role of cytotoxic chemotherapy in melanoma brain metastases, but none have reported significant activity. Dacarbazine has historically been the standard cytotoxic chemotherapy for this disease, but it does not cross the blood–brain barrier. Temozolomide, a derivative of dacarbazine, can penetrate the CNS, but randomised trials did not show superiority over dacarbazine for either systemic or brain metastases. Addition of temozolomide to radiotherapy or SRS has no

Combining systemic therapies with radiotherapy

Experiments in mice have shown that radiotherapy might have an immunomodulatory effect on CTLA-4 blockade by ipilimumab, especially when hypofractionated radiotherapy is used.⁶⁶ In a retrospective series of 77 patients with melanoma brain metastases, of whom 35 received combined modality treatment, the addition of ipilimumab to SRS improved median overall survival from 4·9 months to 21·3 months (p=0·03) and 2-year overall survival from 19·7% to 47·2% compared with SRS alone (table 4).⁶⁷ In a

Brain metastases from melanoma of unknown primary site

Around 3% of patients present with melanoma of unknown primary site. Since most studies on this type of melanoma include brain metastases along with non-nodal clinical presentation, the true incidence of brain-only metastases is not known. The management of brain metastases from melanoma of unknown primary site is similar to that from a known primary site and depends on the KPS and the number, size, and location of metastases (figure 2).⁷⁸

Primary leptomeningeal melanotic tumours

Primary leptomeningeal melanotic tumours occur as melanocytoma (low-grade and intermediate-grade tumours) and melanoma (high-grade tumours). Melanocytomas usually occur in the spinal region and melanomas in the subtentorial region. Typical radiological appearance is that of a solitary so-called melanotic brain metastasis, and metastasis from a cutaneous melanoma must be ruled out. Complete surgical excision is the treatment of choice. In patients with incomplete resection, adjuvant radiotherapy

Conclusions

Development of brain metastases and treatment resistance are key obstacles in improving the survival of patients with advanced melanoma. In selected patients with limited brain involvement, the possibility of long-term control by use of surgery or SRS should be considered. The role of WBRT after local intervention in oligometastatic melanoma brain metastases has yet to be defined. However, surgery or SRS is likely to be an option only in at best a third of patients with melanoma brain

Search strategy and selection criteria

References in this Review were identified through searches of PubMed with the search terms “melanoma”, “brain metastasis”, “surgery”, “radiotherapy”, “radiosurgery”, “targeted therapy”, “immunomodulation”, and “BRAF” from Jan 1, 1990, to June 15, 2015. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this Review.

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Resection of a Recurrent Metastatic Leptomeningeal Melanoma: Case Report and Literature Review
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Malignant melanoma is considered the most aggressive among all cutaneous cancer. Malignant melanoma commonly causes cerebral metastasis. The survival rate of melanoma with cerebral metastases is considerably poor. Surgical resection, radiotherapy, and chemotherapy are often used to increase overall survival. In this case report we present a fifty-four-year-old female with recurrent leptomeningeal metastatic malignant melanoma after gross total resection, with an additional literature review of the management. We describe how gross tumor resection results in an immediate clinical improvement in symptomatology in this patient who has previously undergone tumor resection.
NF1-mutated melanomas reveal distinct clinical characteristics depending on tumour origin and respond favourably to immune checkpoint inhibitors
2021, European Journal of Cancer
Citation Excerpt :
Cutaneous melanoma is a highly malignant tumour with a potential for distant metastasis [1,2].
NF1-mutated tumours represent a small subset (10–15%) of melanomas, not sufficiently analysed in large clinical cohorts. This study investigated the largest multicentre collection of NF1-mutated melanomas to date.
This study analysed a multicentre tumour tissue sample cohort from 266 patients with NF1-mutated melanoma. Targeted next-generation sequencing of the TERT promoter and 29 relevant melanoma genes was performed. Survival was compared with NF1 wild-type cohorts from the Tissue Registry in Melanoma project (n = 432).
Most NF1-mutated melanoma arose in the head-and-neck region of patients >60 years. NF1 alterations were frequently inactivating, primarily non-sense, less frequently truncating mutations. Non-inactivating NF1 mutations more frequently co-occurred with activating BRAF and RAS mutations. NF1-mutated tumours had higher numbers of gene mutations and UV signature C>T and CC>TT transitions than BRAF, RAS and triple wild-type melanomas. NF1-mutated acral and mucosal melanomas harboured a different mutation signature and were frequent in women (69% and 83%, respectively), differing from non-acral cutaneous NF1-mutated melanomas (men 73%, women 27%). Overall survival in stage IV disease was comparable for patients with NF1-mutated or wild-type melanoma. However, in patients receiving first-line immune checkpoint inhibitor treatment, better median overall survival (mOS) was observed for NF1-mutated than wild-type tumours (mOS = not reached vs mOS = 25.82, p = 0.0154, n = 80 and 432, respectively).
Cutaneous, acral and mucosal NF1-mutated melanomas vary in clinical and genetic characteristics and demonstrate a favourable outcome on immune checkpoint inhibition therapy.
Real-life data for first-line combination immune-checkpoint inhibition and targeted therapy in patients with melanoma brain metastases
2021, European Journal of Cancer
Citation Excerpt :
Melanoma is one of the most frequent cancers to metastasize to the brain [1]. Approximately 50% of patients with stage IV melanoma will eventually develop brain metastases (MBM), and this proportion increases up to 75% in autopsy reports [2,3]. Before the advent of effective systemic therapy, patients with MBM have historically had a poor prognosis and median overall survival (mOS) in unselected patients with active MBM ranged between 4 and 6 months [4–7].
Melanoma brain metastases (MBM) have a poor prognosis. Systemic treatments that have improved outcomes in advanced melanoma have been shown to have an intracranial (IC) effect. We studied the efficacy and outcomes of combined immune checkpoint inhibitor ipilimumab/nivolumab (Combi-ICI) or targeted therapy (Combi-TT) as first-line treatment in MBM.
MBM patients treated with Combi-ICI or Combi-TT within 3 months after MBM diagnosis. Endpoints were progression-free survival (PFS) and overall survival (OS).
53 patients received Combi-ICI, 32% had symptomatic MBM and 33.9% elevated LDH. 71.7% required local treatment. The disease control rate was 60.3%. IC response rate (RR) was 43.8% at 3-months with durable responses at 6- (46.5%) and 12-months (53.1%). Extracranial (EC) RR was 44.7% at 3-months and 50% at 12-months. Median PFS was 9.6 months (95% CI 3.6-NR) and median overall survival (mOS) 44.8 months (95% CI; 26.2-NR).
63 patients received Combi-TT, 55.6% of patients had symptomatic MBM, 57.2% of patients had elevated LDH and 68.3% of patients required local treatment. The disease control rate was 60.4%. ICRR was 50% at 3-months, but dropped at 6-months (20.9%). ECRR was 69.2% at 3-months and 17.6% at 12-months. Median PFS was 5.8 months (95% CI 4.2–7.6) and mOS 14.2 months (95% CI 8.99–26.8).
In BRAFV600 patients, 26.7% of patients received Combi-ICI and 73.3% Combi-TT with OS (p = 0.0053) and mPFS (p = 0.03) in favour to Combi-ICI.
Combi-ICI showed prolonged mOS with sustainable IC and EC responses. Despite the initially increased efficacy, Combi-TT responses at 12 months were low. Combi-ICI appeared superior to Combi-TT for OS and PFS in BRAFV600 patients. Other clinical factors are determinants for first-line treatment choice.
Ferroptosis-apoptosis combined anti-melanoma immunotherapy with a NIR-responsive upconverting mSiO<inf>2</inf> photodynamic platform
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Photodynamic therapy (PDT) is an appealing treatment for oncologic skin diseases owing to its high spatiotemporally selectivity and non-invasive features. However, its application in melanoma has been restricted by limited penetration depth of ultraviolet (UV)-visible (vis) light, melanin-optical filtration and weak immunogenicity. To circumvent the incomplete tumor damage and insufficient anti-tumor immunity, we prepared a mesoporous coated upconverting nanoparticles (NaYF₄:Yb,Er@NaYF₄@mSiO₂@lipsome)-based platform by co-loading chlorin e6 (Ce6) and buthionine sulfoximine (BSO). This platform converts near-infrared (NIR) light to UV-vis light which enables the destruction of deeply seated nidus, amplification of ferroptotic and apoptotic cell death, as well as an increase in the anti-tumor immunity. Under NIR laser irradiation, NaYF₄:Yb,Er@NaYF₄@mSiO₂@lipsome nanoparticles embedded with Ce6 were designed to ease burden in tumor sites via elevating levels of hydroxyl radicals and the induction of apoptosis. Meanwhile, glutathione depletion was induced through BSO co-administration and direct thiol oxidation, followed by the inactivation of lipid peroxide repair enzyme and initiation of ferroptosis. This combinational strategy resulted in an amplification in intratumoral oxidative stress, which was accompanied with the strong cytotoxicity in vitro and in vivo. The aggravated anti-tumor performance then brought about the exposure of damage-associated molecular patterns, followed by promoted maturation of dendritic cells and effector function of tumor-infiltrating lymphocytes. Taken together, this ferroptosis-apoptosis combined photodynamic strategy provides insights in designing nanomedicines for immunotherapy in melanoma.
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ReviewEvolving treatment options for melanoma brain metastases

Summary

Introduction

Section snippets

Risk factors for melanoma brain metastases

Imaging and response assessment

Treatment of melanoma brain metastases: limitations of the evidence base

Surgery

Whole-brain radiotherapy

WBRT versus surgery plus WBRT

Melanoma-specific graded prognostic assessment

Summary of local treatment

Cytotoxic chemotherapy

Combining systemic therapies with radiotherapy

Brain metastases from melanoma of unknown primary site

Primary leptomeningeal melanotic tumours

Conclusions

Search strategy and selection criteria

Eur J Radiol

Lancet Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Lancet Oncol

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Lancet

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Lancet Oncol

Ann Oncol

Lancet Oncol

Eur J Cancer

Lancet

Lancet Oncol

Eur J Surg Oncol

Surg Neurol

Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma

J Neurosurg

Disease presentation and outcome in young patients (<40 years) with brain metastases from malignant melanoma

Anticancer Res

Determinants of outcome in melanoma patients with cerebral metastases

J Clin Oncol

Melanoma brain metastasis: overview of current management and emerging targeted therapies

Expert Rev Neurother

Management of melanoma

Br Med Bull

Predictive factors for the development of brain metastases in patients with malignant melanoma: a study by the Anatolian Society of Medical Oncology

J Cancer Res Clin Oncol

Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival

Cancer

Predictive factors for the development of brain metastasis in advanced unresectable metastatic melanoma

Am J Clin Oncol

NRAS mutation status is an independent prognostic factor in metastatic melanoma

Cancer

Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma

Br J Cancer

Treatment of melanoma metastases in the brain

Semin Surg Oncol

A variety of appearances of malignant melanoma in the head: a review

Radiographics

A prognostic index that predicts outcome following palliative whole brain radiotherapy for patients with metastatic malignant melanoma

Br J Cancer

Whole-brain radiotherapy in patients with brain metastases from melanoma

CNS Oncol

Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases

Cochrane Database Syst Rev

Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial

J Clin Oncol

Whole brain radiotherapy after local treatment of brain metastases in melanoma patients—a randomised phase III trial

BMC Cancer

Whole brain helical tomotherapy with integrated boost for brain metastases in patients with malignant melanoma—a randomized trial

Radiat Oncol

Analysis of radiosurgical results in patients with brain metastases according to the number of brain lesions: is stereotactic radiosurgery effective for multiple brain metastases?

J Neurosurg

A randomized trial of surgery in the treatment of single metastases to the brain

N Engl J Med

Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery?

Ann Neurol

Review
Evolving treatment options for melanoma brain metastases