Page 1 of 5 DIAGNOSIS RISK STATUS TREATMENT WORKUP

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1 Note: Consider Clinical Trials as treatment options f eligible patients. Signs and symptoms suggestive of leptomeningeal metastases Leptomeningeal Metastases WORKUP Physical exam with comprehensive neurologic evaluation 1 Brain and spine MRI Cerebrospinal fluid (CSF) exam 2 f the following: Cell count with differential, with pathologist review as applicable Glucose Protein Cytopathology (10-12 ml) Flow cytometry f lymphoma hematologic malignancies If indicated, consider: Gram stain and culture Cryptococcal antigen Calcoflu white smear Viral PCR (HSV, CMV, EBV) Fungal and viral cultures Lifestyle risk assessment 3 DIAGNOSIS CSF positive f tum cells Positive radiologic findings with supptive neurologic findings Suggestive CSF 4 findings with supptive neurologic findings in a patient with a known malignancy RISK STATUS Po Risk 5 : Low Karnofsky perfmance status (KPS) 6 Multiple, serious, maj neurologic deficits Extensive systemic disease with few treatment options Encephalopathy Good Risk: High Karnofsky perfmance status (KPS) 7 No maj neurologic deficits Minimal systemic disease Reasonable treatment options available f systemic disease (if applicable) Involved field radiation therapy 8 to bulky disease and/ symptomatic sites Consider clinical trials f eligible patients Consider systemic therapy with targeted therapies checkpoint inhibits f special patient populations (ALK inhibits f NSCLC; BRAF inhibits ipilimumab f melanoma) TREATMENT Page 1 of 5 Consider: Fractionated external beam radiation therapy to symptomatic sites and/ Best supptive care Consider placing intraventricular catheter (Ommaya Resevoir) and/ Consider ventriculoperitoneal shunt with on/off valve f intrathecal chemotherapy if symptoms and/ radiological findings suggestive of hydrocephalus Conduct CSF scan, see Page 2 1 Mental status, cranial nerves, mot, sensy and cerebellar exam 2 Use caution f lumbar punctures in patients who are anticoagulated, thrombocytopenic, who have a bulky intra-cranial mass 3 See Physical Activity, Nutrition, and Tobacco Cessation Algithms; ongoing reassessment of lifestyle risks should be a part of routine clinical practice 4 CSF suggestive of leptomeningeal metastasis in the absence of positive cytology includes high WBC and/ low glucose and/ high protein. If CSF is not positive f tum cells, up to 3 lumbar punctures may be of clinical value. 5 Po risk patients with exceptionally chemosensitive tums (e.g,, small cell lung cancer, lymphoma) may be treated 6 Refer Karnofsky Perfmance Status Scale (Appendix A) Sce of 50 lower is considered a po risk fact 7 Refer Karnofsky Perfmance Status Scale (Appendix A) Sce of 60 higher is considered a good risk fact 8 Usually whole brain radiation therapy (WBRT) and/ partial spine field recommended

2 Page 2 of 5 Note: Consider Clinical Trials as treatment options f eligible patients. PRIMARY TREATMENT POST-INDUCTION THERAPY Conduct CSF scan Nmal Flow abnmalities Induction intra-csf chemotherapy 1 f 4-8 weeks, if systemic disease stable Consider high-dose methotrexate (if breast lymphoma) Consider radiation (if breast lymphoma 2 ) Fractionated external beam radiation to sites of involvement 3 Nmal Reassess CSF from site where positive CSF cytology was iginally obtained; if CSF cytology was iginally negative reassess by obtaining CSF from a different site Repeat CSF scan 1 Induction intra-csf chemotherapy can start after radiation 2 Depending upon the extent of the disease, consider appropriate radiation therapy 3 Usually WBRT and/ partial spine field recommended 4 Consider switching intra-csf medications and treat f 4 weeks befe re-testing CSF CSF cytology negative CSF cytology positive Evidence of clinical radiologic progression of leptomeningeal metastases? Flow abnmalities No Yes Consider increasing the interval of treatments between intra-csf chemotherapy Consider increasing the interval of treatments between intra-csf chemotherapy Consider switching intra-csf medications and treat f 4 weeks befe re-testing CSF Consider switching intra-csf medication Repeat CSF cytology Consider radiation therapy to previously un-irradiated symptomatic sites: Fractionated external beam radiation Stereotactic radiosurgery and/ Best supptive care Maintenance intrathecal chemotherapy and monit CSF cytology every month f 1 year then reassess Negative cytology Cytology continually positive and/ evidence of clinical radiologic progression of leptomeningeal metastases 4 Radiation to symptomatic sites Systemic chemotherapy and/ Best supptive care

3 Page 3 of 5 APPENDIX A: Karnofsky Perfmance Status Scale Definitions Able to carry on nmal activity and to wk; no special care needed Nmal; no complaints; no evidence of disease Able to carry on nmal activity; min signs symptoms of disease Nmal activity with efft; some signs of disease Unable to wk; able to live at home and care f most personal needs; varying amount of assistance needed Cares f self; unable to carry on nmal activity to do active wk Requires occasional assistance, but is able to care f most of his personal needs Requires considerable assistance and frequent medical care 40 Disabled; requires special care and assistance Unable to care f self; requires equivalent of institutional hospital care; disease may be progressing rapidly Severely disabled; hospital admission is indicated although death not imminent Very sick; hospital admission necessary; active supptive treatment necessary Mibund; fatal processes progressing rapidly 0 Dead

4 Page 4 of 5 SUGGESTED READINGS Chamberlain, M. C. (2010, July). Leptomeningeal metastasis. In Seminars in Neurology (Vol. 30, No. 03, pp ). Chamberlain, M., Soffietti, R., Raizer, J., Rudà, R., Brandsma, D., Boogerd, W.,... & van den Bent, M. (2014). Leptomeningeal metastasis: a Response Assessment in Neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials. Neuro-oncology, 16(9), Glantz, M. J., Cole, B. F., Recht, L., Akerley, W., Mills, P., Saris, S.,... & Egin, M. J. (1998). High-dose intravenous methotrexate f patients with non-leukemic leptomeningeal cancer: is intrathecal chemotherapy necessary?. Journal of Clinical Oncology, 16(4), Glantz, M. J., Hall, W. A., Cole, B. F., Chozick, B. S., Shannon, C. M., Wahlberg, L.,... & Choy, H. (1995). Diagnosis, management, and survival of patients with leptomeningeal cancer based on cerebrospinal fluid status. Cancer, 75(12), Glantz, M. J., LaFollette, S., Jaeckle, K. A., Shapiro, W., Swinnen, L., Rozental, J. R.,... & Lyter, D. (1999). Randomized trial of a slow-release versus a standard fmulation of cytarabine f the intrathecal treatment of lymphomatous meningitis. Journal of Clinical Oncology, 17(10), Groves, M. (2010). New Strategies in the management of leptomenigeal metastases. Archives of Neurology; 67(3): National Comprehensive Cancer Netwk. Central Nervous System Cancers (Version ). https://www.nccn.g/professionals/physician_gls/pdf/cns.pdf. Accessed July 11, Van Hn, A., & Chamberlain, M. C. (2012). Neoplastic meningitis. The Journal of Supptive Oncology, 10(2),

5 Page 5 of 5 DEVELOPMENT CREDITS This practice consensus algithm is based on majity expert opinion of the Leptomeningeal Metastases Wk Group at the University of Texas MD Anderson Cancer Center. It was developed using a multidisciplinary approach that included input from the following: Andrew J. Bishop, MD Eva Lu Lee, MSN, RN, ANP-BC Cheryl Martin, MS, RN, FNP-C Barbara O Brien, MD Ŧ Marta Penas-Prado, MD Ganesh Rao, MD Ŧ Komal Shah, MD Ŧ Julie G. Walker, PhD, APRN, FNP-C Jeffrey Wefel, PhD Anita M. Williams, BS Sonal Yang, PharmD Ŧ Ce Development Team Clinical Effectiveness Development Team

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