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Table 1.  Pertinent Studies Evaluating Whole-Brain Radiation Therapy (WBRT) and Stereotactic Radiosurgery (SRS) in the Treatment of Multiple Brain Metastases
Pertinent Studies Evaluating Whole-Brain Radiation Therapy (WBRT) and Stereotactic Radiosurgery (SRS) in the Treatment of Multiple Brain Metastases
Table 2.  Pertinent Studies Evaluating Chemotherapy in the Treatment of Multiple Brain Metastases
Pertinent Studies Evaluating Chemotherapy in the Treatment of Multiple Brain Metastases
Table 3.  Pertinent Studies Evaluating Ipilimumab in the Treatment of Multiple Brain Metastases
Pertinent Studies Evaluating Ipilimumab in the Treatment of Multiple Brain Metastases
1.
Mehta  MP, Tsao  MN, Whelan  TJ,  et al.  The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases.  Int J Radiat Oncol Biol Phys. 2005;63(1):37-46.PubMedGoogle ScholarCrossref
2.
Patchell  RA.  The management of brain metastases.  Cancer Treat Rev. 2003;29(6):533-540.PubMedGoogle ScholarCrossref
3.
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4.
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5.
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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.PubMedGoogle ScholarCrossref
7.
Andrews  DW, Scott  CB, Sperduto  PW,  et al.  Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial.  Lancet. 2004;363(9422):1665-1672.PubMedGoogle ScholarCrossref
8.
Aoyama  H, Shirato  H, Tago  M,  et al.  Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial.  JAMA. 2006;295(21):2483-2491.PubMedGoogle ScholarCrossref
9.
Chang  EL, Wefel  JS, Hess  KR,  et al.  Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.  Lancet Oncol. 2009;10(11):1037-1044.PubMedGoogle ScholarCrossref
10.
Kocher  M, Soffietti  R, Abacioglu  U,  et al.  Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study.  J Clin Oncol. 2011;29(2):134-141.PubMedGoogle ScholarCrossref
11.
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12.
Kondziolka  D, Patel  A, Lunsford  LD, Kassam  A, Flickinger  JC.  Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases.  Int J Radiat Oncol Biol Phys. 1999;45(2):427-434.PubMedGoogle ScholarCrossref
13.
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14.
Flaherty  KT, Infante  JR, Daud  A,  et al.  Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.  N Engl J Med. 2012;367(18):1694-1703.PubMedGoogle ScholarCrossref
15.
Flaherty  KT, Robert  C, Hersey  P,  et al; METRIC Study Group.  Improved survival with MEK inhibition in BRAF-mutated melanoma.  N Engl J Med. 2012;367(2):107-114.PubMedGoogle ScholarCrossref
16.
Hauschild  A, Grob  JJ, Demidov  LV,  et al.  Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.  Lancet. 2012;380(9839):358-365.PubMedGoogle ScholarCrossref
17.
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18.
Robert  C, Karaszewska  B, Schachter  J,  et al.  Improved overall survival in melanoma with combined dabrafenib and trametinib.  N Engl J Med. 2015;372(1):30-39.PubMedGoogle ScholarCrossref
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20.
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30.
Li  J, Bentzen  SM, Li  J, Renschler  M, Mehta  MP.  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.PubMedGoogle ScholarCrossref
31.
Sanghavi  SN, Miranpuri  SS, Chappell  R,  et al.  Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method.  Int J Radiat Oncol Biol Phys. 2001;51(2):426-434.PubMedGoogle ScholarCrossref
32.
Manon  R, O’Neill  A, Knisely  J,  et al; Eastern Cooperative Oncology Group.  Phase II trial of radiosurgery for one to three newly diagnosed brain metastases from renal cell carcinoma, melanoma, and sarcoma: an Eastern Cooperative Oncology Group study (E 6397).  J Clin Oncol. 2005;23(34):8870-8876.PubMedGoogle ScholarCrossref
33.
Sneed  PK, Suh  JH, Goetsch  SJ,  et al.  A multi-institutional review of radiosurgery alone vs radiosurgery with whole brain radiotherapy as the initial management of brain metastases.  Int J Radiat Oncol Biol Phys. 2002;53(3):519-526.PubMedGoogle ScholarCrossref
34.
Soffietti  R, Cornu  P, Delattre  JY,  et al.  EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force.  Eur J Neurol. 2006;13(7):674-681.PubMedGoogle ScholarCrossref
35.
Tsao  MN, Lloyd  NS, Wong  RK, Rakovitch  E, Chow  E, Laperriere  N; Supportive Care Guidelines Group of Cancer Care Ontario’s Program in Evidence-based Care.  Radiotherapeutic management of brain metastases: a systematic review and meta-analysis.  Cancer Treat Rev. 2005;31(4):256-273.PubMedGoogle ScholarCrossref
36.
Sahgal  A, Aoyama  H, Kocher  M,  et al.  Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis.  Int J Radiat Oncol Biol Phys. 2015;91(4):710-717.PubMedGoogle ScholarCrossref
37.
Yamamoto  M, Serizawa  T, Shuto  T,  et al.  Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study.  Lancet Oncol. 2014;15(4):387-395.PubMedGoogle ScholarCrossref
38.
Yamamoto  M, Kawabe  T, Sato  Y,  et al.  Stereotactic radiosurgery for patients with multiple brain metastases: a case-matched study comparing treatment results for patients with 2-9 versus 10 or more tumors.  J Neurosurg. 2014;121(suppl):16-25.PubMedGoogle Scholar
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40.
Fogarty  GB, Hong  A, Jacobsen  KD,  et al.  Accrual to a randomised trial of adjuvant whole brain radiotherapy for treatment of melanoma brain metastases is feasible.  BMC Res Notes. 2014;7:412.PubMedGoogle ScholarCrossref
41.
Kickingereder  P, Dorn  F, Blau  T,  et al.  Differentiation of local tumor recurrence from radiation-induced changes after stereotactic radiosurgery for treatment of brain metastasis: case report and review of the literature.  Radiat Oncol. 2013;8:52.PubMedGoogle ScholarCrossref
42.
Serizawa  T, Saeki  N, Higuchi  Y,  et al.  Diagnostic value of thallium-201 chloride single-photon emission computerized tomography in differentiating tumor recurrence from radiation injury after gamma knife surgery for metastatic brain tumors.  J Neurosurg. 2005;102(suppl):266-271.PubMedGoogle ScholarCrossref
43.
Chao  ST, Ahluwalia  MS, Barnett  GH,  et al.  Challenges with the diagnosis and treatment of cerebral radiation necrosis.  Int J Radiat Oncol Biol Phys. 2013;87(3):449-457.PubMedGoogle ScholarCrossref
44.
Levin  VA, Bidaut  L, Hou  P,  et al.  Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system [published correction appears in Int J Radiat Oncol Biol Phys. 2012 1;84(1):6].  Int J Radiat Oncol Biol Phys. 2011;79(5):1487-1495.PubMedGoogle ScholarCrossref
45.
Rao  MS, Hargreaves  EL, Khan  AJ, Haffty  BG, Danish  SF.  Magnetic resonance-guided laser ablation improves local control for postradiosurgery recurrence and/or radiation necrosis.  Neurosurgery. 2014;74(6):658-667.PubMedGoogle ScholarCrossref
46.
Berk  L, Berkey  B, Rich  T,  et al.  Randomized phase II trial of high-dose melatonin and radiation therapy for RPA class 2 patients with brain metastases (RTOG 0119).  Int J Radiat Oncol Biol Phys. 2007;68(3):852-857.PubMedGoogle ScholarCrossref
47.
Knisely  JP, Berkey  B, Chakravarti  A,  et al.  A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118).  Int J Radiat Oncol Biol Phys. 2008;71(1):79-86.PubMedGoogle ScholarCrossref
48.
Mornex  F, Thomas  L, Mohr  P,  et al.  A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma.  Melanoma Res. 2003;13(1):97-103.PubMedGoogle ScholarCrossref
49.
Phillips  TL, Scott  CB, Leibel  SA, Rotman  M, Weigensberg  IJ.  Results of a randomized comparison of radiotherapy and bromodeoxyuridine with radiotherapy alone for brain metastases: report of RTOG trial 89-05.  Int J Radiat Oncol Biol Phys. 1995;33(2):339-348.PubMedGoogle ScholarCrossref
50.
Suh  JH, Stea  B, Nabid  A,  et al.  Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases.  J Clin Oncol. 2006;24(1):106-114.PubMedGoogle ScholarCrossref
51.
Shaw  E, Scott  C, Suh  J,  et al.  RSR13 plus cranial radiation therapy in patients with brain metastases: comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database.  J Clin Oncol. 2003;21(12):2364-2371.PubMedGoogle ScholarCrossref
52.
Agarwala  SS, Kirkwood  JM, Gore  M,  et al.  Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study.  J Clin Oncol. 2004;22(11):2101-2107.PubMedGoogle ScholarCrossref
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Hwu  WJ, Lis  E, Menell  JH,  et al.  Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study.  Cancer. 2005;103(12):2590-2597.PubMedGoogle ScholarCrossref
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Hofmann  M, Kiecker  F, Wurm  R,  et al.  Temozolomide with or without radiotherapy in melanoma with unresectable brain metastases.  J Neurooncol. 2006;76(1):59-64.PubMedGoogle ScholarCrossref
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Larkin  JM, Hughes  SA, Beirne  DA,  et al.  A phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma.  Br J Cancer. 2007;96(1):44-48.PubMedGoogle ScholarCrossref
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Schadendorf  D, Hauschild  A, Ugurel  S,  et al.  Dose-intensified bi-weekly temozolomide in patients with asymptomatic brain metastases from malignant melanoma: a phase II DeCOG/ADO study.  Ann Oncol. 2006;17(10):1592-1597.PubMedGoogle ScholarCrossref
57.
Margolin  K, Atkins  B, Thompson  A,  et al.  Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group.  J Cancer Res Clin Oncol. 2002;128(4):214-218.PubMedGoogle ScholarCrossref
58.
Atkins  MB, Sosman  JA, Agarwala  S,  et al.  Temozolomide, thalidomide, and whole brain radiation therapy for patients with brain metastasis from metastatic melanoma: a phase II Cytokine Working Group study.  Cancer. 2008;113(8):2139-2145.PubMedGoogle ScholarCrossref
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Vestermark  LW, Larsen  S, Lindeløv  B, Bastholt  L.  A phase II study of thalidomide in patients with brain metastases from malignant melanoma.  Acta Oncol. 2008;47(8):1526-1530.PubMedGoogle ScholarCrossref
60.
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61.
Ahmed  KA, Freilich  JM, Sloot  S,  et al.  LINAC-based stereotactic radiosurgery to the brain with concurrent vemurafenib for melanoma metastases.  J Neurooncol. 2015;122(1):121-126.PubMedGoogle ScholarCrossref
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Peuvrel  L, Saint-Jean  M, Quéreux  G,  et al.  Incidence and characteristics of melanoma brain metastases developing during treatment with vemurafenib.  J Neurooncol. 2014;120(1):147-154.PubMedGoogle ScholarCrossref
63.
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.PubMedGoogle ScholarCrossref
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Review
August 2015

Clinical Management of Multiple Melanoma Brain Metastases: A Systematic Review

Author Affiliations
  • 1Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick
  • 2Division of Medical Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick
  • 3Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick
JAMA Oncol. 2015;1(5):668-676. doi:10.1001/jamaoncol.2015.1206
Abstract

Importance  The treatment of multiple brain metastases (MBM) from melanoma is controversial and includes surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiation therapy (WBRT). Several new classes of agents have revolutionized the treatment of metastatic melanoma, allowing some subsets of patients to have long-term survival. Given this, management of MBM from melanoma is continually evolving.

Objective  To review the current evidence regarding the treatment of MBM from melanoma.

Evidence Review  The PubMed database was searched using combinations of search terms and synonyms for melanoma, brain metastases, radiation, chemotherapy, immunotherapy, and targeted therapy published between January 1, 1995, and January 1, 2015. Articles were selected for inclusion on the basis of targeted keyword searches, manual review of bibliographies, and whether the article was a clinical trial, large observational study, or retrospective study focusing on melanoma brain metastases. Of 2243 articles initially identified, 110 were selected for full review. Of these, the most pertinent 73 articles were included.

Findings  Patients with newly diagnosed MBM can be treated with various modalities, either alone or in combination. Level 1 evidence supports the use of SRS alone, WBRT, and SRS with WBRT. Although the addition of WBRT to SRS improves the overall brain relapse rate, WBRT has no significant impact on overall survival and has detrimental neurocognitive outcomes. Cytotoxic chemotherapy has largely been ineffective; targeted therapies and immunotherapies have been reported to have high response rates and deserve further attention in larger clinical trials. Further studies are needed to fully evaluate the efficacy of these novel regimens in combination with radiation therapy.

Conclusions and Relevance  At this time, the standard management for patients with MBM from melanoma includes SRS, WBRT, or a combination of both. Emerging data exist to support the notion that SRS in combination with targeted therapies or immune therapy may obviate the need for WBRT; prospective studies are required to fully evaluate the efficacy of these novel regimens in combination with radiation therapy.

Introduction

There are 170 000 to 200 000 new cases of brain metastases diagnosed each year, and 20% to 40% of patients with cancer will develop brain metastases.1,2Quiz Ref ID Brain metastases are especially important in the context of malignant melanoma because 44% of patients with metastatic melanoma will develop symptomatic brain metastases, and intracranial disease accounts for 20% to 54% of deaths in patients with melanoma.3-5 Prognosis is poor, and expected survival ranges from 3 to 13 months despite radiation therapy (RT).6 Whereas the clinical management of single metastases with craniotomy and/or stereotactic RT is well established, the treatment of patients with multiple brain metastases (MBM) is not well defined. Patients with newly diagnosed MBM can be treated with various modalities, either alone or in combination. Level 1 evidence supports the use of stereotactic radiosurgery (SRS) alone, whole-brain radiation therapy (WBRT) alone, and SRS with WBRT.7-12 The rationale for WBRT is that patients with undetectable metastases after SRS may later develop additional brain lesions if left untreated.

Since 2011, the US Food and Drug Administration (FDA) has approved 7 new drugs for the systemic therapy of metastatic melanoma. Targeting mutations in the BRAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway has demonstrated significant improvements in progression-free and overall survival in randomized clinical trials (RCTs).13-18 In addition, advances in tumor immunotherapy largely focused on cytokines and T-cell checkpoint inhibitors have shown durable therapeutic responses and emerging confirmation of overall survival benefits in RCTs.19-21 These novel therapies have prolonged survival in a disease that previously had a dismal outcome. As patients are living longer as a result of more effective systemic therapy, surveillance and management of intracranial disease is of increasing importance. Emerging data support the activity of some targeted and immunotherapy agents in MBM, which suggests that control of MBM may be possible with aggressive multimodality management. Reports of an abscopal effect when RT is used in combination with immunotherapy also suggest that combination approaches may be especially interesting therapeutic strategies, and MBM represents a clinical scenario that is highly appropriate for testing these combinations.22

Herein, we describe the contemporary peer-reviewed literature with high-quality data related to the clinical management of multiple melanoma brain metastases. On the basis of the review of the data, emerging recommendations for patient management are discussed and future areas of interest for clinical investigation are proposed. Given the advances in systemic therapy of melanoma, it is critical that oncologists treating these patients be aware of new treatment paradigms to optimize the outcomes for all patients with metastatic melanoma.

Box Section Ref ID

At a Glance

  • Twenty-five to fifty percent of patients with metastatic melanoma will develop multiple brain metastases.

  • Randomized clinical trials of combinations of stereotactic radiosurgery (SRS) and whole-brain radiation therapy (WBRT) in patients with brain metastasis revealed no survival advantage among SRS alone, WBRT alone, or SRS plus WBRT.

  • The role of chemotherapy and radiation sensitizers in MBM is limited and comparable to supportive care only.

  • The role of targeted therapies or immune therapy in the treatment of melanoma brain metastasis has not yet been defined.

Methods

A literature search of PubMed was conducted by one of us (S.G.) using combinations of search terms and synonyms for melanoma, brain metastases, radiation, chemotherapy, immunotherapy, and targeted therapy in articles published between January 1, 1995, and January 1, 2015. Studies in languages other than English or involving animals and children were excluded. Articles were identified (n = 2243) from which titles and abstracts were examined to eliminate studies without evidence-based data, such as case reports, dosimetry studies, reviews, and studies of other cancers. All remaining articles were screened carefully; clinical trials, large observational studies, and studies focusing on melanoma brain metastases received priority in the selection process. Bibliographies of these studies were searched for other relevant studies. Initially, 110 articles were identified; duplicate studies or studies that did not meet these criteria on full review were then excluded (n = 37). Of these, the most pertinent 73 articles were selected for inclusion.

The results were reviewed by a multidisciplinary team composed of medical, surgical, and radiation oncologists. Critical issues were identified and key findings from the current literature are summarized in this report.

Results
Prognostic Factors in Patients With MBM

In an attempt to identify prognostic factors in patients with brain metastases, the Radiation Therapy Oncology Group (RTOG) conducted a recursive partitioning analysis that stratified patients with brain metastases from any histologic subtype into 3 groups using age, Karnofsky performance status (KPS) greater than 70, and status of systemic metastases. The most favorable group had a median survival of 7.1 months, and the least favorable group had a median survival of 2.3 months.23Quiz Ref ID Sperduto et al6 developed a Graded Prognostic Assessment providing a disease-specific classification of outcomes in patients with brain metastases. In this classification, the only factors that affected outcomes in patients with melanoma brain metastases were KPS and number of metastases. In 86 patients with melanoma brain metastases receiving WBRT alone, the median survival was 3 months. In contrast, SRS was associated with a median survival of 7 months whereas surgery was correlated with a median survival of 11 to 12 months.6 Although these data were not based on RCTs and may be subject to selection bias, they do provide some insight into important prognostic variables in predicting outcome. In addition, it is notable that the melanoma Graded Prognostic Assessment was not influenced by the presence of extracranial disease or age, implying that aggressive management of intracranial disease is reasonable even in older patients with active systemic disease.

Role of Surgery in Patients With MBM

Advances in neurosurgical technique such as awake craniotomy, functional monitoring, and intraoperative magnetic resonance imaging (MRI) have revolutionized modern neurosurgery in an effort to improve gross total resection and reduce surgical morbidity. In patients with MBM, surgical resection is necessary for those patients who need a histologic diagnosis, whose neurological symptoms do not resolve with supportive care, or who have a dominant lesion deemed too large to be treated with SRS. Outside this context, the role of surgical intervention in patients with MBM remains controversial given factors involved in operative decision making such as the performance status and comorbidities of the patient, the size and accessibility of the lesion, and the proximity of the lesion to eloquent areas. To our knowledge, there have been no randomized studies of surgery in patients with MBM and as such, RT has been standard treatment in the management of MBM. One RCT currently open to enrollment is randomizing patients with 1 to 4 brain metastases to SRS or WBRT after resection of at least 1 of the lesions (NCT01372774).

Role of WBRT Alone in Patients With MBM

Traditionally, the treatment of MBM has included WBRT and corticosteroids.11,24 Meta-analyses of WBRT clinical reports have demonstrated that median survival is not altered with varying dosage, fractionation scheme, or overall treatment time.25,26 The most commonly used regimens are 35 Gy (to convert to rad, multiply by 100) delivered in 2.5-Gy fractions during 14 treatment days or 30 Gy in 3-Gy fractions during 10 treatment days. Quiz Ref IDThe potential neurocognitive toxic effects related to WBRT include deterioration of verbal fluency, fine motor skills, immediate recall, and delayed recall. Sun et al27 provided evidence that radiotherapy itself causes neurocognitive decline, independent of tumor burden as scored by the Hopkins Verbal Learning Test (HVLT) for immediate and delayed recall as early as 3 months in patients with lung cancer without evidence of brain metastases who were treated with prophylactic cranial irradiation.

Methods to reduce the potential for neurocognitive decline have been a focus of contemporary WBRT trials.28-30 The RTOG 0933 study was a single-arm, phase 2 study investigating hippocampal-sparing WBRT in patients with brain metastases.29 Irradiation of the subgranular zone of the hippocampal dentate gyrus, which contains neural stem cells, is thought to suppress the formation of new memories and impair recall.29 With a primary end point of the HVLT–Revised Delayed Recall at 4 months, patients receiving hippocampal-sparing WBRT experienced a mean relative decline of 7.0%, which was significantly less than the 30% decline observed in historical controls (P < .001). Another large RCT, RTOG 0614, investigated the addition of memantine, an N-methyl-D-aspartate receptor antagonist, to WBRT.28 Although the primary end point of HVLT–Revised Delayed Recall was not statistically significant, many of the secondary end points showed that memantine therapy delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed compared with placebo.

Role of Adding SRS to WBRT in Patients With MBM

Quiz Ref IDThere have been 2 RCTs that have shown that the addition of SRS to WBRT in patients with 1 to 2 or 3 to 4 lesions reduced the risk of central nervous system (CNS) relapse but did not portend a survival advantage compared with patients receiving WBRT alone (Table 1).7,12 The largest study, RTOG 9508, randomized 333 patients with 1 to 3 brain metastases to WBRT with or without SRS, including 14 patients with melanoma.7 In the entire cohort, they found a 43% reduction in local failure with the addition of SRS to WBRT; this failed to translate into an overall survival benefit. These findings were confirmed in a meta-analysis of these studies.26 Interestingly, patients receiving WBRT+SRS noted an improvement in KPS and decreased steroid use. It is important to note that neither study reported neurocognitive outcomes after WBRT or WBRT+SRS.

Role of Adding WBRT to SRS in Patients With MBM

Although WBRT has been considered standard of care with MBM, neurologic toxicity and limited sustained local efficacy have called into question its use as initial therapy for MBM. Stereotactic radiosurgery has several advantages over WBRT, and changes in treatment guidelines have mirrored its increasing use.34,35 Stereotactic radiosurgery is an especially attractive modality in the context of melanoma because systemic therapy is not delayed or disrupted for single-session SRS. Because of limited tumor control after WBRT, intracranial melanoma metastases were traditionally considered resistant to fractionated therapy. However, this limitation is not applicable to treatment with SRS. Local tumor control rates range from 70% to 80% after SRS, suggesting that SRS has the potential to overcome several limitations of fractionated RT.8-10

There have been 2 RCTs that have shown that in patients with single or a limited number (3-4) of lesions SRS plus WBRT reduced the risk of CNS relapse without an improvement in overall survival.8,10 A third RCT by Chang et al9 found an overall survival benefit to SRS alone compared with SRS plus WBRT, a secondary end point; the primary end point of this study was HVLT–Revised Total Recall. A meta-analysis of these 3 trials confirmed the reduced risk of CNS relapse, both local and distant, in addition to the lack of a survival advantage in patients receiving SRS plus WBRT compared with SRS alone.26 A second meta-analysis using patient-level data noted a survival improvement in patients younger than 50 years who received SRS alone.36 These data indicate that CNS relapses after SRS alone can be salvaged with either WBRT or SRS effectively without a detriment in survival.

Furthermore, the RCT by Chang et al9 revealed that the omission of WBRT improved neurocognitive function, and the other 2 RCTs8,10 found significantly improved health-related quality-of-life measures and functional independence when omitting WBRT. These results suggest that cognitive function in patients with brain metastases declines faster because of adverse effects of WBRT rather than disease progression; however, this topic remains controversial. Given this, advocates of SRS believe strongly that WBRT should be omitted given the associated neurocognitive toxic effects seen in patients, particularly in those younger than 50 years old.36 It should also be noted that patients with melanoma only made up 5% to 10% of the enrolled patients in all 3 RCTs of SRS with or without WBRT. Thus, we extrapolate the local control, survival, and neurocognitive data when applying it in the context of MBM from melanoma.

There are no RCTs investigating the role of SRS or WBRT in patients with 4 or more metastatic lesions in the brain. A recently published large prospective observational cohort of 1194 patients with MBM from various tumor types reported that the overall survival of patients with 2 to 4 brain metastases was noninferior to patients with 5 to 10 metastases (median survival, 10.8 months for each group).37 These results suggest that SRS alone may be a viable treatment option even in patients with up to 10 metastases. Another study by the same group sought to determine whether outcomes from SRS alone for patients with 10 or more tumors differed from those for patients with 2 to 9 lesions (n = 1814) and found that the median survival time, neurological death–free survival times, neurological deterioration, and SRS-related complications were not statistically different between the 2 cohorts.38 Neither study was focused solely on melanoma metastases, making histology-specific conclusions problematic. Nevertheless, improvements in technology have made tumor localization and measurement more accurate; this, coupled with the improved technical skills of neurosurgeons and radiation oncologists engaged in SRS, may be improving tumor control.

Melanoma has long been considered a radioresistant tumor, and more recent preclinical data suggest that melanoma cell lines show high levels of DNA damage repair at conventional fraction sizes and increased cell death with larger doses per fraction.39 Many oncologists advocate for the omission of WBRT given the relative radio-insensitivity to standard fraction sizes. To date, there have been no reported RCTs of WBRT compared with SRS for patients with MBM from melanoma, although one study is currently enrolling patients.40 There are, however, many RCTs of patients with brain metastases from mixed histologic subtypes that help provide insight into the role of RT for MBM.

Management of In-field Recurrence After Radiation Therapy

There are instances in which an MBM will recur inside the field of treatment following maximum radiation exposure. In patients whose systemic disease is under relatively good control, the treatment of the in-field recurrence becomes the priority. A long-standing dilemma is the need to differentiate the recurrent brain metastasis from progressive radiation necrosis. Patients may present with similar radiographic imaging features and progressive symptoms; even advanced imaging modalities often fail to differentiate the 2 entities.41,42 Surgical resection is typically indicated for those situations in which the diagnosis is unclear or for those patients whose disease is refractory to corticosteroid therapy.43 Bevacizumab, a VEGF inhibitor, has also been shown to reverse the effects of radiation necrosis.44 The use of MRI-guided laser therapy has reemerged as a potentially useful tool for in-field recurrences for which surgery is not possible, particularly because of advances in real-time magnetic resonance thermometry. Rao et al45 demonstrated a greater than 90% control rate in lesions that exhibited progressive growth on 2 MRI scans; in all cases, a differentiation between a recurrent brain metastasis and radiation necrosis was not made. If a treatment modality exists that treats both recurrent brain metastasis and progressive radiation necrosis effectively, then the differentiation between the two may not be critical for clinical management.

Cytotoxic Chemotherapy in MBM

The role of chemotherapy and radiation sensitizers in the management of patients with MBM is limited. Presumably, the failure of cytotoxic therapy is due to the low activity of the drugs and the limited penetration of the drugs across the blood-brain barrier (BBB). The BBB is a protective layer of tightly joined endothelial cells reinforced by the astrocyte foot processes called the glia limitans. There have been several RCTs in patients with MBM from mixed tumor types investigating various cytotoxic and radiosensitizing agents in combination with WBRT with negative results46-50 (Table 2). Use of available cytotoxic treatments that can cross the BBB, such as temozolomide and fotemustine, has not resulted in significant improvements in either intracranial disease control or overall survival in patients with melanoma MBM (Table 2).48,52-59 For example, temozolomide alone or in combination with WBRT resulted in a progression-free survival of only 1 to 2 months, which is comparable to the expected prognosis with supportive care only.

BRAF-Targeted Therapy

BRAF kinase is an intracellular enzyme that leads to increased signaling of the MAPK pathway. BRAF mutations occur in 50% of melanoma cases, providing a useful target for treatment in these patients. Vemurafenib is an oral inhibitor of mutated BRAF kinase that specifically targets mutations resulting from substitution of glutamic acid for valine at codon 600, known as BRAF V600E. Vemurafenib therapy was associated with improvements in overall survival for patients with MBM in an RCT.13 In a small pilot study for brain metastases, vemurafenib therapy resulted in a partial response rate of 16%, and the median survival was only 5.3 months.60 In another study of patients who received SRS and concurrent vemurafenib, 58% of patients developed new brain metastases outside the irradiated volume.61 Furthermore, in patients without known brain metastases who are treated with vemurafenib, the brain is a common (20%-25%) site of treatment failure.62 Taken together, these data suggest that vemurafenib alone is not adequate for treatment of brain metastases.

Dabrafenib is another inhibitor of the mutated BRAF kinase, and a large phase 2 study of 172 patients demonstrated its efficacy in patients with melanoma metastatic to the brain, which is the largest prospective trial in patients with melanoma brain metastases to date.63 In patients with previously untreated brain metastases who carried BRAF V600E mutations, 39% (95% CI, 28%-51%) achieved an overall intracranial response and the median overall survival was 7.7 months. Dabrafenib has also demonstrated enhanced clinical activity when combined with trametinib, a selective MEK inhibitor.14 Currently, NCT02039947 is under way to test the combination of a BRAF and MEK inhibitor specifically in patients with BRAF mutation–positive melanoma brain metastases.

Immunotherapy

Unlike cytotoxic or targeted agents, which must cross the BBB to be effective, it is not necessary for immunotherapy agents to gain direct access to the brain parenchyma to have therapeutic effect. Insights from recent experiences in autoimmune disease support this hypothesis.64,65 Interleukin 2 (IL-2) and checkpoint inhibitors induce activation of T cells in the extracranial compartment, and the activated T cells can then enter the brain, a process that is mediated by P-selectin and α4 integrin.65

Interleukin 2

Interleukin 2 is a cytokine produced primarily by CD4+ T cells that is necessary for T-cell and natural killer cell growth and differentiation. High-dose IL-2 has been used therapeutically in metastatic melanoma and is associated with a consistent objective response rate of approximately 16%, and many of the responses are durable for decades.66 Administration of IL-2 requires hospitalization in specialized centers with experience in IL-2 management because of substantial toxic effects, including capillary leak syndrome.67 Capillary leak syndrome results in generalized edema, which is a safety concern in patients with brain metastases because of the possibility of increased intracranial pressure. There are no RCTs or prospective studies investigating the role of IL-2 therapy in patients with MBM. There are limited retrospective data regarding the administration of high-dose IL-2 in melanoma patients with brain metastases.67,68 In general practice, IL-2 is typically considered after control of MBM through RT has been achieved and only when intracerebral edema is minimal and patients do not require corticosteroid administration.

Ipilimumab

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is expressed on T cells, and it normally impedes the activation of T cells by antigen-presenting cells, acting as a checkpoint in the immune response. Ipilimumab is a humanized monoclonal antibody that blocks CTLA-4; therefore, inhibition of CTLA-4 signaling leads to continued T-cell activation and proliferation. Ipilimumab therapy has demonstrated an improvement in overall survival in an RCT and was approved by the FDA for the treatment of advanced and metastatic melanoma in 2011.20 As a monoclonal antibody, Quiz Ref IDipilimumab does not appreciably cross the BBB. However, T cells that have been activated in the periphery are able to migrate into the CNS,65 which may also occur in patients treated with ipilimumab.

There are no RCTs investigating the role of ipilimumab therapy in patients with melanoma MBM. Two prospective phase 2 studies found that ipilimumab has activity among patients with brain metastatic melanoma (Table 3).19,69 The first study evaluated the use of ipilimumab and fotemustine in combination and found that the complete CNS response rate among patients with previously untreated brain metastases was 38%.19 The second study evaluating the efficacy of ipilimumab enrolled 72 patients, including 51 patients who were neurologically asymptomatic.69 In this group, the CNS response rate was 16% and the median overall survival was 7.0 months. These data suggest that ipilimumab may have clinically relevant disease activity in the CNS, and additional studies are needed to clarify its role in these patients.

Anti–Programmed Cell Death-1 Antibodies

Similar to CTLA-4, the programmed cell death-1 (PD-1) is a T cell checkpoint receptor expressed on recently activated T cells, B cells, and myeloid cells and mediates inhibition of immune cell effector functions on binding to its natural ligands PD-L1 and PD-L2. Tumors coopt the PD-1 pathway by expressing the ligands PD-L1 or PD-L2, enabling them to evade immunosurveillance by inhibition of PD-1–expressing T cells within the tumor microenvironment. On the basis of preliminary data showing a 24% systemic objective response rate in an advanced patient population, pembrolizumab, a humanized monoclonal antibody against PD-1, achieved accelerated, conditional approval by the FDA for the treatment of metastatic melanoma in patients who have been previously treated with ipilimumab (and if the tumor is BRAF mutated, a BRAF inhibitor).21 Nivolumab, also known as BMS-936558, is the second fully humanized IgG4 monoclonal antibody against PD-1 to be conditionally approved by the FDA for second- or third-line treatment of metastatic melanoma. Although there are no completed studies of PD-1–blocking antibodies performed specifically in a brain metastases population, there are multiple studies under way (NCT02320058, NCT02374242).

Immunotherapy in Combination With SRS

Radiotherapy has the potential for synergizing with immunotherapy by increasing the permeability of the BBB, stimulating cytokine release, and increasing antigen presentation.73 Combination treatment with SRS and immunotherapy is supported by multiple clinical studies.22,74 Three retrospective single-institution studies suggest that ipilimumab in combination with RT may be more effective than RT alone in patients with brain metastases (Table 3).70-72 In all 3 studies, approximately 35% of patients received ipilimumab prior to RT whereas 65% received the drug after RT. Notably, responses to ipilimumab therapy in the brain, as in extracranial disease, have been reported to be durable beyond 4 years.75 The term abscopal effect (from the Latin “ab” and Greek “scopus”) denotes a phenomenon of tumor regression at sites that are remote from an irradiated target.22 The abscopal effect is uncommon, but it has been described with RT to the body and the brain.

In summary, concurrent treatment with ipilimumab and SRS seems to be safe and may increase efficacy of SRS; this practice is supported by consensus in the National Comprehensive Cancer Network guidelines.76 At present, mature studies are needed to determine whether immunotherapies in conjunction with SRS have the potential to supplant WBRT to control microscopic intracranial disease. At least 3 ongoing studies will combine SRS with ipilimumab for treatment of brain metastases in patients with advanced melanoma (NCT01950195, NCT01703507, and NCT02097732).

Conclusions

At this time, the standard management for patients with MBM from melanoma includes SRS, WBRT, or a combination of both. Stereotactic radiosurgery is taking hold as the preferred treatment for metastases in the brain because it avoids the neurologic decline experienced with WBRT. Cytotoxic chemotherapy regimens have largely been ineffective without evidence for survival benefit. Emerging data exist to support the notion that SRS in combination with immune checkpoint inhibitors may be an effective treatment, and prospective studies are required to fully evaluate the efficacy of these novel combination regimens and whether they can supplant the use of WBRT. The improvements in survival for patients with melanoma seem to be affecting those with MBM, and patients should be evaluated by a multidisciplinary team to individualize the therapeutic approach and maximize clinical benefit. Further clinical investigation will help provide definitive evidence-based data for optimizing the treatment of patients with melanoma with MBM.

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Article Information

Accepted for Publication: March 30, 2015.

Corresponding Author: Sharad Goyal, MD, Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08903 (goyalsh@rutgers.edu).

Published Online: May 21, 2015. doi:10.1001/jamaoncol.2015.1206.

Author Contributions: Drs Goyal and Silk had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Goyal, Tian, Kaufman.

Acquisition, analysis, or interpretation of data: Goyal, Silk, Mehnert, Danish, Ranjan, Kaufman.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Goyal, Silk, Danish, Kaufman.

Administrative, technical, or material support: Goyal, Kaufman.

Study supervision: Goyal, Kaufman.

Conflict of Interest Disclosures: Dr Kaufman serves as a consultant for Alkermes, Amgen, EMD Serono, Prometheus, and Sanofi, has received research funding from Bristol-Myers Squibb, and serves on the speaker’s bureau for Merck. No other disclosures are reported.

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