Melanoma brain metastasis: the impact of stereotactic radiosurgery, BRAF mutational status, and targeted and/or immune-based therapies on treatment outcome

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OBJECTIVE

The goal of this study was to investigate the impact of stereotactic radiosurgery (SRS), BRAF status, and targeted and immune-based therapies on the recurrence patterns and factors associated with overall survival (OS) among patients with melanoma brain metastasis (MBM).

METHODS

A total of 366 patients were treated for 1336 MBMs; a lesion-based analysis was performed on 793 SRS lesions. The BRAF status was available for 78 patients: 35 had BRAFmut and 43 had BRAF wild-type (BRAF-WT) lesions. The Kaplan-Meier method evaluated unadjusted OS; cumulative incidence analysis determined the incidences of local failure (LF), distant failure, and radiation necrosis (RN), with death as a competing risk.

RESULTS

The 12-month OS was 24% (95% CI 20%–29%). On multivariate analysis, younger age, lack of extracranial metastases, better Karnofsky Performance Status score, and fewer MBMs, as well as treatment with BRAF inhibitors (BRAFi), anti–PD-1/CTLA-4 therapy, or cytokine therapy were significantly associated with OS. For patients who underwent SRS, the 12-month LF rate was lower among those with BRAFmut lesions (6%, 95% CI 2%–11%) compared with those with BRAF-WT lesions (22%, 95% CI 13%–32%; p < 0.01). The 12-month LF rates among lesions treated with BRAFi and PD-1/CTLA-4 agents were 1% (95% CI 1%–4%) and 7% (95% CI 1%–13%), respectively. On multivariate analysis, BRAF inhibition within 30 days of SRS was protective against LF (HR 0.08, 95% CI 0.01–0.55; p = 0.01). The 12-month rates of RN were low among lesions treated with BRAFi (0%, 95% CI 0%–0%), PD-1/CTLA-4 inhibitors (2%, 95% CI 1%–5%), and cytokine therapies (6%, 95% CI 1%–13%).

CONCLUSIONS

Prognostic schema should incorporate BRAFi or immunotherapy status and use of targeted therapies. Treatment with a BRAF inhibitor within 4 weeks of SRS improves local control without an increased risk of RN.

ABBREVIATIONS BRAFi = BRAF inhibitors; DF = distant failure; GPA = graded prognostic assessment; KPS = Karnofsky Performance Status; LF = local failure; MBM = melanoma brain metastasis; OS = overall survival; RN = radiation necrosis; SRS = stereotactic radiosurgery; WBRT = whole-brain radiation therapy; WT = wild type.

Article Information

Correspondence Manmeet S. Ahluwalia, Department of Hematology/Oncology, Taussig Cancer Institute, Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Main Campus, Mail Code S73, 9500 Euclid Ave., Cleveland, OH 44195. email: ahluwam@ccf.org.

INCLUDE WHEN CITING Published online August 11, 2017; DOI: 10.3171/2017.1.JNS162797.

Disclosures Dr. Suh received consulting payment from Varian Medical Systems; had travel and lodging paid for by Elekta; and received speaking fees from Philips. Dr. Ahluwalia received a consulting payment and grant from Elekta; grant support from Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Spectrum Pharmaceuticals, Tracon Pharmaceuticals, and Novocure; and is a consultant for Merck, Genentech/Roche, Incyte, Caris Lifesciences, Monteris Medical, MRI Interventions Inc., Bristol-Myers Squibb, Astrazeneca, and Abbvie. He received support of non–study-related clinical or research efforts that he oversaw from Novartis, Novocure, and Bristol-Myers Squibb. Dr. Kotecha is on the medical advisory board of Varian Medical Systems.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Graphs showing estimates of (A) cumulative incidence of intracranial progression; (B) cumulative incidence of distant intracranial progression; and OS from the time of diagnosis of brain metastasis for patients with melanoma, stratified by (C) BRAF mutational status and (D) use of BRAFi. Values on the x axis denote the number of months postdiagnosis. inhib. = inhibitor; unt. = untested.

  • View in gallery

    Graphs showing cumulative incidences of LF for MBM undergoing SRS, stratified by (A) BRAF mutational status, (B) treatment with BRAFi, and (C) treatment with PD-1/CTLA-4 inhibitors.

  • View in gallery

    Graphs showing cumulative incidences of RN for MBM treated with SRS, stratified by (A) BRAF status and (B) treatment with BRAFi and PD-1/CTLA-4 inhibitors.

References

  • 1

    Ahmed KAFreilich JMSloot SFigura NGibney GTWeber JS: LINAC-based stereotactic radiosurgery to the brain with concurrent vemurafenib for melanoma metastases. J Neurooncol 122:1211262015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Anker CJGrossmann KFAtkins MBSuneja GTarhini AAKirkwood JM: 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 95:6326462016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Brown PDAsher ALBallman KVFarace ECerhan JHAnderson SK: NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. J Clin Oncol 33 Suppl:LBA42015 (Abstract)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Chang ELSelek UHassenbusch SJ IIIMaor MHAllen PKMahajan A: Outcome variation among “radioresistant” brain metastases treated with stereotactic radiosurgery. Neurosurgery 56:9369452005

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Chao STAhluwalia MSBarnett GHStevens GHMurphy ESStockham AL: Challenges with the diagnosis and treatment of cerebral radiation necrosis. Int J Radiat Oncol Biol Phys 87:4494572013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Dummer RGoldinger SMTurtschi CPEggmann NBMichielin OMitchell L: Vemurafenib in patients with BRAFV600 mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer 50:6116212014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Gaudy-Marqueste CCarron RDelsanti CLoundou AMonestier SArchier E: On demand Gamma-Knife strategy can be safely combined with BRAF inhibitors for the treatment of melanoma brain metastases. Ann Oncol 25:208620912014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Gummadi TZhang BYValpione SKim CKottschade LAMittapalli RK: Impact of BRAF mutation and BRAF inhibition on melanoma brain metastases. Melanoma Res 25:75792015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Hara WTran PLi GSu ZPuataweepong PAdler JR Jr: Cyberknife for brain metastases of malignant melanoma and renal cell carcinoma. Neurosurgery 64 (2 Suppl):A26A322009

    • Search Google Scholar
    • Export Citation
  • 10

    Harding JJBarker CACarvajal RDWolchok JDChapman PBLacouture ME: Cutis verticis gyrata in association with vemurafenib and whole-brain radiotherapy. J Clin Oncol 32:e54e562014

    • Search Google Scholar
    • Export Citation
  • 11

    Kotecha RDamico NMiller JASuh JHMurphy ESReddy CA: Three or more courses of stereotactic radiosurgery for patients with multiply recurrent brain metastases. Neurosurgery [epub ahead of print] 2016

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Liew DNKano HKondziolka DMathieu DNiranjan AFlickinger JC: Outcome predictors of Gamma Knife surgery for melanoma brain metastases. Clinical article. J Neurosurg 114:7697792011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Long GVStroyakovskiy DGogas HLevchenko Ede Braud FLarkin J: Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371:187718882014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Long GVTrefzer UDavies MAKefford RFAscierto PAChapman PB: 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 13:108710952012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Lwu SGoetz PMonsalves EAryaee MEbinu JLaperriere N: Stereotactic radiosurgery for the treatment of melanoma and renal cell carcinoma brain metastases. Oncol Rep 29:4074122013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Ly DBagshaw HPAnker CJTward JDGrossmann KFJensen RL: Local control after stereotactic radiosurgery for brain metastases in patients with melanoma with and without BRAF mutation and treatment. J Neurosurg 123:3954012015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Margolin KErnstoff MSHamid OLawrence DMcDermott DPuzanov I: Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 13:4594652012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Miller JABennett EEXiao RKotecha RChao STVogelbaum MA: Association between radiation necrosis and tumor biology after stereotactic radiosurgery for brain metastasis. Int J Radiat Oncol Biol Phys 96:106010692016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Mingione VOliveira MPrasad DSteiner MSteiner L: Gamma surgery for melanoma metastases in the brain. J Neurosurg 96:5445512002

  • 20

    Mohammadi AMSchroeder JLAngelov LChao STMurphy ESYu JS: Impact of the radiosurgery prescription dose on the local control of small (2 cm or smaller) brain metastases. J Neurosurg 126:7357432017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Qian JMYu JBKluger HMChiang VL: Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer 122:305130582016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Ramanujam SSchadendorf DLong GV: Systemic therapies for melanoma brain metastases: which drug for whom and when? Chin Clin Oncol 4:252015

  • 23

    Sahgal AAoyama HKocher MNeupane BCollette STago M: 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 91:7107172015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Sambade MJPeters ECThomas NEKaufmann WKKimple RJShields JM: Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032. Radiother Oncol 98:3943992011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Sawrie SMGuthrie BLSpencer SANordal RAMeredith RFMarkert JM: Predictors of distant brain recurrence for patients with newly diagnosed brain metastases treated with stereotactic radiosurgery alone. Int J Radiat Oncol Biol Phys 70:1811862008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Schulze BMeissner MWolter MRodel CWeiss C: Unusual acute and delayed skin reactions during and after whole-brain radiotherapy in combination with the BRAF inhibitor vemurafenib. Two case reports. Strahlenther Onkol 190:2292322014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Shaw EScott CSouhami LDinapoli RKline RLoeffler J: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 47:2912982000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Sloan AENock CJEinstein DB: Diagnosis and treatment of melanoma brain metastasis: a literature review. Cancer Contr 16:2482552009

  • 29

    Sperduto PWKased NRoberge DXu ZShanley RLuo X: 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 30:4194252012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Villanueva JVultur ALee JTSomasundaram RFukunaga-Kalabis MCipolla AK: Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18:6836952010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Wolf AZia SVerma RPavlick AWilson MGolfinos JG: Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases. J Neurooncol 127:6076152016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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