Leptomeningeal Carcinomatosis: Risks, Detection, and Treatment. Goldie Kurtz, MD, FRCPC Department of Radiation Oncology University of Pennsylvania

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1 Leptomeningeal Carcinomatosis: Risks, Detection, and Treatment Goldie Kurtz, MD, FRCPC Department of Radiation Oncology University of Pennsylvania May 13, 2016

2 Disclosures None to declare 2

3 Outline Epidemiology of brain metastases Mechanisms of leptomeningeal spread Investigations Treatment options Moving forward: opportunities to maximize benefit and personalize therapy 3

4 A Growing Need 1954: 2015: Because no national cancer registry documents brain metastases, the exact incidence is unknown, but it has been estimated that 98,000 to 170,000 new cases are diagnosed in the United States each year. National Cancer Institute 1954 US Population : 163 million 2015 US Population : 320 million 4

5 Epidemiology Occurs in 4-15% of patients with solid tumors Autopsy studies suggest that this incidence may be higher Most commonly occurs in breast, lung, and melanoma patients 5

6 Risks Increased risk with prolonged disease course Higher propensity to develop leptomeningeal spread with history of brain metastases originating in the posterior fossa, and posterior fossa resection of metastases if piecemeal (vs en bloc resection) Risk following surgery may be histology dependent 6

7 CNS as the sanctuary site More than 99% of the brain s capillaries are covered by a continuous endothelium: the blood brain barrier Compared with systemic endothelium, composed of very tight gap junctions: zonulae occludentes Lipid soluble, small molecules, can cross The following classes of systemic agents penetrate poorly: Platinum salts: Carboplatin, Cisplatin Anthracyclines: Doxorubicin, Daunorubicin, Epirubicin Topoisomerases: Irinotecan, Etoposide Vinca alkyloids: Vincristine, Vinblastine, Vinorelbine Anti-metabolites: Cytarabine 7

8 Mechanisms of Spread Direct spread from dural based lesions Hematogenous spread via leptomeningeal veins and potentially the choroid plexus Venous spread of tumor cells originating from areas of marrow involvement Perineural spread along cranial or spinal nerves 8

9 Symptoms and Signs Headache, nausea or vomiting Posterior fossa signs Cranial nerve palsies Sensory and motor deficits 9

10 Investigations History and physical exam MRI Brain MRI Spine Lumbar puncture 10

11 MRI Brain 11

12 MRI Spine 12

13 Treatment Options Literature consists mainly of retrospective reviews with nonuniform treatment interventions Radiation: Whole brain Craniospinal Chemotherapy: Intrathecal Best supportive care 13

14 Chemotherapy Most common agents include methotrexate, and liposomal cytarabine Among the largest series of patients with leptomeningeal disease, a prospective series of 137 patients suggested intrathecal methotrexate did not improve survival, however, a retrospective series of 103 patients did show mixed benefits Confers an increased risk for encephalopathy and myelopathy 14

15 Radiotherapy Across multiple studies, has been demonstrated to cause regression of symptoms, improve quality of life, and improve survival Whole brain confers risk of neurocognitive deficits Craniospinal treatment carries significant risk of myelosuppression, and with treatment delivered using photon therapy (most widespread approach), acute GI Toxicity (mucositis, esophagitis, enteritis) is expected Craniospinal treatment delivered with proton therapy can significantly decrease dose beyond vertebral bodies, sparing the GI tract 15

16 CSI: Photons 16

17 CSI: Protons 17

18 Prognosis Without treatment: measured in weeks With treatment: measured in months Median survival: 2-3 months; longest reported is 33.3 months Prognostic scoring: no formal grading system at present 18

19 Opportunites to improve management Epidemiology of LMD collecting brain metastases and LMD incidence in registries Prognostic scoring to assist with patient selection for treatment Improving therapies: CSI delivered with protons Improving therapies: Targeted agents - histology matters: consider disease-specific scoring and treatment strategies 19

20 Example 1: NSCLC Up to 25% of patients have EGFR mutation positive NSCLC; 1/3 of these patients develop brain metastases Evidence that suggests intracranial metastases do not develop TKI-resistance similarly to systemic lesions Standard Erlotinib at 150 mg daily does not penetrate into the CNS well Can we augment this? 20

21 Proton Radiotherapy for LMD Prospective study of CSI for leptomeningeal disease Use of proton therapy to limit toxicity in this population Compare proton and photon plans created for each patient Collection of toxicity, quality of life, and outcomes Collect CTCs 21

22 One final thought 22

23 Surveillance and Secondary Prevention Lung NCCN Guidelines: No role for surveillance MRI Brain Breast NCCN Guidelines: Screening MRI only if recurrent or Stage IV disease Melanoma NCCN Guidelines: if sentinel LN+ consider MRI; if clinically LN+, recommend MRI 23

24 Roadmap Epidemiology: Global and disease specific Site specific prognostic scoring and outcomes Combination with systemic agents; where possible, molecular profiles of brain metastases lesions Ongoing surveillance in high risk disease: lung, locally advanced/metas tatic breast; consider CTCs Post-treatment support: awareness of side effects, access to high grade imaging; neurocognitive support: medication, therapy 24

25 References Chao JH, Phillips R, Nickson JJ. Roentgen-ray therapy of cerebral metastases. Cancer 1954; 7(4): Leptomeningeal metastasis from solid tumors: a diagnostic and therapeutic challenge. Passarin MG, Sava T, Furlanetto J et al. Neurol Sci 2015; 36 (1): Glass JP, Melamed M, Chernik NL, Posner JB (1979) Malignant cells in cerebrospinal fluid (CSF): the meaning of a positive CSF cytology. Neurology 29: Suki D, Abouassi H, Patel AJ et al. Comparative risk of leptomeningeal disease after resection or stereotactic radiosurgery for solid tumor metastasis to the posterior fossa. J Neurosurg 2008 Feb;108(2): Atalar B, Modlin LA, Choi CY et al. Risk of leptomeningeal disease in patients treated with stereotactic radiosurgery targeting the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys Nov 15;87(4):713-8 Bokstein F, Lossos A, and Siegal T. Leptomeningeal Metastases from Solid Tumors: A Comparison of Two Prospective Series Treated with and without Intra-Cerebrospinal Fluid Chemotherapy. Cancer 1998;82: Taillibert S, Laigle-Donadey F, Chodkiewicz C, et al. Leptomeningeal metastases from solid malignancy: a review. J Neruooncol 2005;75: Rhun EL, Taillibert S, Zairi F, et al. A retrospective case series of 103 consecutive patients with leptomeningeal metastasis and breast cancer. J Neurooncol 2013;113: Lee SJ, Lee JI, Nam DH, et al. Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol 2013;8: Azevedo CR, Cruz MR, Chinen LT, et al. Meningeal carcinomatosis in breast cancer: prognostic factors and outcome. J Neruooncol 2011;104: Gani C, Muller AC, Eckert F, et al. Outcome after whole brain radiotherapy alone in intracranial leptomeningeal carcinomatosis from solid tumors. Strahlenther Onkol 2012;188: Rhun EL, Taillibert S, Zairi F, et al. Prolonged Survival of Patients with Breast Cancer-related Leptomeningeal Metastases. Anticancer Research 2013;33:

26 Acknowledgements Department of Radiation Oncology, CNS Division: Michelle Alonso-Basanta, Robert Lustig, Jay Dorsey Department of Neurosurgery James Janopaul-Naylor 26

27 Thank you 27

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