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Treatment of Leptomeningeal Spread of NSCLC: A Continuing Challenge

  • Lung Cancer (HA Wakelee, Section Editor)
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Opinion statement

Leptomeningeal metastasis is a serious and frequently fatal complication of non-small cell lung cancer. Curative treatment remains elusive, but careful use of radiation, systemic chemotherapy, intrathecal chemotherapy, and symptoms management can greatly improve quality of life and survival. For most patients, we recommend a combination of skull-based radiation with focal radiation to any symptomatic spinal segments followed by systemic chemotherapy. For patients with EGFR mutations, erlotinib may be used as first-line therapy in a daily or high-dose regimen. Pemetrexed has promise for use in patients with brain and leptomeningeal metastases. Patients with multiple comorbidities or low performance status may tolerate intrathecal therapy better than systemic chemotherapy. The most commonly used intrathecal chemotherapies are methotrexate and liposomal cytarabine, although newer agents, such as topotecan and mafosfamide, may be more effective. Elevated intracranial pressure, which causes headaches, vertigo, nausea, and vomiting, should be treated with dexamethasone and acetazolamide. In select patients, cerebrospinal fluid shunting may be considered. The use of antidepressants, central nervous system stimulants, benzodiazepines, antiemetics, and pain medications can increase quality of life in patients with leptomeningeal metastases.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Cancer Facts and Figures 2012. Available at http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf. Accessed 29 May 2012.

  2. Eichler AF, Wang DL, Joshi VA, et al. EGFR mutation status and survival after diagnosis of brain metastasis in non-small cell lung cancer. J Clin Oncol. 2012;5(Suppl(May 20)):7542.

    Google Scholar 

  3. Chen AM, Jahan TM, Jablons DM, et al. Risk of cerebral metastases and neurological death after pathological complete response to neoadjuvant therapy for locally advanced nonsmall-cell lung cancer: clinical implications for the subsequent management of the brain. Cancer. 2007;109(8):1668–75.

    Article  PubMed  Google Scholar 

  4. Oechsle K, Lange-Brock V, Kruell A, et al. Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: a retrospective analysis. J Cancer Res Clin Oncol. 2010;136(11):1729–35.

    Article  PubMed  Google Scholar 

  5. Kesari S, Batchelor TT. Leptomeningeal metastases. Neurol Clin. 2003;21(1):25–66.

    Article  PubMed  Google Scholar 

  6. Pauls S, Fischer AC, Brambs HJ, et al. Use of magnetic resonance imaging to detect neoplastic meningitis: limited use in leukemia and lymphoma but convincing results in solid tumors. Eur J Radiol. 2012;81(5):974–8.

    Article  PubMed  Google Scholar 

  7. Strik H, Proemmel P, Pilgram-Pastor S, Buhk JH. Neoplastic Meningitis- is MRI as sensitive as CSF cytology? J Clin Oncol. 2009;25(15 supplement).

  8. Glantz MJ, Cole BF, Glantz LK, et al. Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results. Cancer. 1998;82(4):733–9.

    Article  PubMed  CAS  Google Scholar 

  9. Patel AS, Allen JE, Dicker DT, et al. Identification and enumeration of circulating tumor cells in the cerebrospinal fluid of breast cancer patients with central nervous system metastases. Oncotarget. 2011;2(10):752–60.

    PubMed  Google Scholar 

  10. Gore EM, Bae K, Wong SJ, et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of radiation therapy oncology group study RTOG 0214. J Clin Oncol. 2011;29(3):272–8.

    Article  PubMed  Google Scholar 

  11. Patel N, Lester JF, Coles B, Macbeth FR. Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small cell lung cancer. Cochrane Database Syst Rev. 2009;18(2):CD005221. doi:10.1002/14651858.CD005221.

  12. Pottgen C, Eberhardt W, Grannass A, et al. Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. J Clin Oncol. 2007;25(31):4987–92.

    Article  PubMed  Google Scholar 

  13. Morris PG, Reiner AS, Szenberg OR, et al. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol. 2012;7(2):382–5.

    Article  PubMed  Google Scholar 

  14. Balis FM, Savitch JL, Bleyer WA, Reaman GH, Poplack DG. Remission induction of meningeal leukemia with high-dose intravenous methotrexate. J Clin Oncol. 1985;3(4):485–9.

    PubMed  CAS  Google Scholar 

  15. Lopez JA, Nassif E, Vannicola P, et al. Central nervous system pharmacokinetics of high-dose cytosine arabinoside. J Neurooncol. 1985;3(2):119–24.

    Article  PubMed  CAS  Google Scholar 

  16. Glantz MJ, Cole BF, Recht L, et al. High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol. 1998;16(4):1561–7.

    PubMed  CAS  Google Scholar 

  17. Park JH, Kim YJ, Lee JO, et al. Clinical outcomes of leptomeningeal metastasis in patients with non-small cell lung cancer in the modern chemotherapy era. Lung Cancer. 2012;76(3):387–92.

    Article  PubMed  Google Scholar 

  18. Clarke JL, Pao W, Wu N, et al. High-dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol. 2010;99(2):283–6.

    Article  PubMed  Google Scholar 

  19. Grommes C, Oxnard GR, Kris MG, et al. "Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neurooncol. 2011;13(12):1364–9.

    Google Scholar 

  20. Masuda T, Hattori N, Hamada A, et al. Erlotinib efficacy and cerebrospinal fluid concentration in patients with lung adenocarcinoma developing leptomeningeal metastases during gefitinib therapy. Cancer Chemother Pharmacol. 2011;67(6):1465–9.

    Article  PubMed  CAS  Google Scholar 

  21. Agarwal S, Sane R, Gallardo JL, et al. Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux. J Pharmacol Exp Ther. 2010;334(1):147–55.

    Article  PubMed  CAS  Google Scholar 

  22. Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29(15):e443–445.

    Article  PubMed  Google Scholar 

  23. Weickhardt AJ, Burke JM, Gan G, et al. Continuation of EGFR/ALK inhibition after local therapy of oligoprogressive disease in EGFR mutant (Mt) and ALK + non-small cell lung cancer (NSCLC). J Clin Oncol. 2012;30(suppl; abstr 7526).

  24. Stapleton SL, Reid JM, Thompson PA, et al. Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates. Cancer Chemother Pharmacol. 2007;59(4):461–6.

    Article  PubMed  CAS  Google Scholar 

  25. Barlesi F, Gervais R, Lena H, et al. Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07–01). Ann Oncol. 2011;22(11):2466–70.

    Article  PubMed  CAS  Google Scholar 

  26. Bearz A, Garassino I, Tiseo M, et al. Activity of Pemetrexed on brain metastases from Non-Small Cell Lung Cancer. Lung Cancer. 2010;68(2):264–8.

    Article  PubMed  Google Scholar 

  27. Glantz MJ, Hall WA, Cole BF, et al. Diagnosis, management, and survival of patients with leptomeningeal cancer based on cerebrospinal fluid-flow status. Cancer. 1995;75(12):2919–31.

    Article  PubMed  CAS  Google Scholar 

  28. Bleyer WA. Clinical studies in the central nervous system pharmacology of methotrexate. Clinical Pharmacology of Anti-neoplastic Drugs. Amsterdam: Elsevier/North-Holland Biomedical; 1978. p. 115–31.

    Google Scholar 

  29. Shapiro WR, Young DF, Mehta BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med. 1975;293(4):161–6.

    Article  PubMed  CAS  Google Scholar 

  30. Bleyer WA, Poplack DG, Simon RM. "Concentration x time" methotrexate via a subcutaneous reservoir: a less toxic regimen for intraventricular chemotherapy of central nervous system neoplasms. Blood. 1978;51(5):835–42.

    PubMed  CAS  Google Scholar 

  31. Ettinger LJ, Chervinsky DS, Freeman AI, et al. Pharmacokinetics of methotrexate following intravenous and intraventricular administration in acute lymphocytic leukemia and non-Hodgkin's lymphoma. Cancer. 1982;50(9):1676–82.

    Article  PubMed  CAS  Google Scholar 

  32. Moser AM, Adamson PC, Gillespie AJ, et al. Intraventricular concentration times time (C x T) methotrexate and cytarabine for patients with recurrent meningeal leukemia and lymphoma. Cancer. 1999;85(2):511–6.

    Article  PubMed  CAS  Google Scholar 

  33. Groves MD, Glantz MJ, Chamberlain MC, et al. A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol. 2008;10(2):208–15.

    Article  PubMed  CAS  Google Scholar 

  34. Glantz MJ, Jaeckle KA, Chamberlain MC, et al. A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res. 1999;5(11):3394–402.

    PubMed  CAS  Google Scholar 

  35. Glantz MJ, Van Horn A, Fisher R, et al. Route of intracerebrospinal fluid chemotherapy administration and efficacy of therapy in neoplastic meningitis. Cancer. 2010;116(8):1947–52.

    Article  PubMed  Google Scholar 

  36. Matsumoto Y, Horiike S, Fujimoto Y, et al. Effectiveness and limitation of gamma knife radiosurgery for relapsed central nervous system lymphoma: a retrospective analysis in one institution. Int J Hematol. 2007;85(4):333–7.

    Article  PubMed  Google Scholar 

  37. Yap TA, Vidal L, Adam J, et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol. 2010;28(25):3965–72.

    Article  PubMed  CAS  Google Scholar 

  38. Janjigian YY, Groen HJ, Horn L, Smit EF, et al. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. Am Soc Clin Oncol Meet. 2011;29(suppl; abstr 7525):7525.

    Google Scholar 

  39. Sun JM, Nam MH, Chung JY, et al. Safety and pharmacokinetics of intrathecal administration of pemetrexed in rats. Cancer Chemother Pharmacol. 2011;68(2):531–8.

    Article  PubMed  CAS  Google Scholar 

  40. Giglio P, Tremont-Lukats IW, Groves MD. Response of neoplastic meningitis from solid tumors to oral capecitabine. J Neurooncol. 2003;65(2):167–72.

    Article  PubMed  Google Scholar 

  41. Paydas S, Bicakci K, Yavuz S. Dramatic response with capecitabine after cranial radiation to the brain parenchymal and leptomeningeal metastases from lung cancer. Eur J Intern Med. 2009;20(1):96–9.

    Article  PubMed  CAS  Google Scholar 

  42. Blaney SM, Balis FM, Berg S, et al. Intrathecal mafosfamide: a preclinical pharmacology and phase I trial. J Clin Oncol. 2005;23(7):1555–63.

    Article  PubMed  CAS  Google Scholar 

  43. Reijneveld JC, Brandsma D, Boogerd W, et al. CSF levels of angiogenesis-related proteins in patients with leptomeningeal metastases. Neurology. 2005;65(7):1120–2.

    Article  PubMed  CAS  Google Scholar 

  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. Int J Radiat Oncol Biol Phys. 2011;79(5):1487–95.

    Article  PubMed  CAS  Google Scholar 

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Disclosures

S. Nagpal: none; J. Riess: none; H. Wakelee: Has ongoing clinic trial research with Eli Lilly and Genentech/Roche.

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Correspondence to Seema Nagpal MD.

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Nagpal, S., Riess, J. & Wakelee, H. Treatment of Leptomeningeal Spread of NSCLC: A Continuing Challenge. Curr. Treat. Options in Oncol. 13, 491–504 (2012). https://doi.org/10.1007/s11864-012-0206-4

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