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Pharmacokinetics and efficacy of pemetrexed in patients with brain or leptomeningeal metastases

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Brain metastases (BM) and leptomeningeal metastases (LM) are devastating neurologic complications. Pemetrexed is a multi-targeted anti-folate agent approved for treatment of nonsquamous non-small cell lung cancer but has anti-tumor activity in other solid tumors. We performed two trials using pemetrexed in patients with BM and LM to assess CSF penetration and anti-tumor activity. Patients were treated with intravenous pemetrexed at doses of 500 (n = 3), 750 (n = 3), 900 (n = 12) or 1,050 mg/m2 (n = 3) every 3 weeks. Neuro-imaging was done every 6 weeks. Matched CSF and plasma samples were obtained serially from three patients with Ommaya reservoirs; the remaining patients had a single paired collection. Twenty-one patients (15 women and six men) with median age of 50 years and median KPS of 90 were treated. Primary tumors included breast (13), lung (4), colorectal (1), endometrial (1), esophageal (1) and pinealoblastoma (1). Nine patients had prior whole brain RT and median number of prior chemotherapies was two including prior methotrexate in four patients. Median pemetrexed doses administered was three (range 1–14). Responses included one partial response, ten stable disease and ten progressive disease. Median time to progression and survival was 2.7 and 7.3 months; PFS six was 22 %. No major toxicities were seen. Pemetrexed distributed from the plasma to the CSF within 1–4 h with the resulting CSF concentrations < 5 % of plasma. Pemetrexed was tolerated in solid tumor patients with CNS metastases. Limited anti-tumor activity was seen, which might have been due to low CSF concentrations, although some patients displayed prolonged benefit.

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References

  1. Eichler AF, Chung E, Kodack DP, Loeffler JS, Fukumura D, Jain RK (2011) The biology of brain metastases-translation to new therapies. Nat Rev Clin oncol 8(6):344–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chamberlain MC (2009) Leptomeningeal metastasis. Curr Opin Neurol 22(6):665–674

    Article  CAS  PubMed  Google Scholar 

  3. Yamanaka R (2009) Medical management of brain metastases from lung cancer (Review). Oncol Rep 22(6):1269–1276

    Article  CAS  PubMed  Google Scholar 

  4. Cheng X, Hung MC (2007) Breast cancer brain metastases. Cancer Metastasis Rev 26(3–4):635–643

    Article  PubMed  Google Scholar 

  5. Gaspar LE, Mehta MP, Patchell RA, Burri SH, Robinson PD, Morris RE, Ammirati M, Andrews DW, Asher AL, Cobbs CS, Kondziolka D, Linskey ME, Loeffler JS, McDermott M, Mikkelsen T, Olson JJ, Paleologos NA, Ryken TC, Kalkanis SN (2010) The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 96(1):17–32

    Article  PubMed  Google Scholar 

  6. Linskey ME, Andrews DW, Asher AL, Burri SH, Kondziolka D, Robinson PD, Ammirati M, Cobbs CS, Gaspar LE, Loeffler JS, McDermott M, Mehta MP, Mikkelsen T, Olson JJ, Paleologos NA, Patchell RA, Ryken TC, Kalkanis SN (2010) The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 96(1):45–68

    Article  PubMed  Google Scholar 

  7. Ammirati M, Cobbs CS, Linskey ME, Paleologos NA, Ryken TC, Burri SH, Asher AL, Loeffler JS, Robinson PD, Andrews DW, Gaspar LE, Kondziolka D, McDermott M, Mehta MP, Mikkelsen T, Olson JJ, Patchell RA, Kalkanis SN (2010) The role of retreatment in the management of recurrent/progressive brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 96(1):85–96

    Article  PubMed  Google Scholar 

  8. Lassman AB, Abrey LE, Shah GD, Panageas KS, Begemann M, Malkin MG, Raizer JJ (2006) Systemic high-dose intravenous methotrexate for central nervous system metastases. J Neurooncol 78(3):255–260

    Article  CAS  PubMed  Google Scholar 

  9. Glantz MJ, Cole BF, Recht L, Akerley W, Mills P, Saris S, Hochberg F, Calabresi P, Egorin MJ (1998) High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J clin 16(4):1561–1567

    Article  CAS  Google Scholar 

  10. Abrey LE, Christodoulou C (2001) Temozolomide for treating brain metastases. Semin Oncol 28(4 Suppl 13):34–42

    Article  CAS  PubMed  Google Scholar 

  11. Christodoulou C, Bafaloukos D, Kosmidis P, Samantas E, Bamias A, Papakostas P, Karabelis A, Bacoyiannis C, Skarlos DV (2001) Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases. Ann oncol 12(2):249–254

    Article  CAS  PubMed  Google Scholar 

  12. Abrey LE, Olson JD, Raizer JJ, Mack M, Rodavitch A, Boutros DY, Malkin MG (2001) A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. J Neurooncol 53(3):259–265

    Article  CAS  PubMed  Google Scholar 

  13. Lin NU, Eierman W, Greil R, Campone M, Kaufman B, Steplewski K, Lane SR, Zembryki D, Rubin SD, Winer EP (2011) Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J Neurooncol 105(3):613–620

    Article  CAS  PubMed  Google Scholar 

  14. Oberhoff C, Kieback DG, Wurstlein R, Deertz H, Sehouli J, van Soest C, Hilfrich J, Mesrogli M, von Minckwitz G, Staab HJ, Schindler AE (2001) Topotecan chemotherapy in patients with breast cancer and brain metastases: results of a pilot study. Onkologie 24(3):256–260

    CAS  PubMed  Google Scholar 

  15. Lorusso V, Galetta D, Giotta F, Rinaldi A, Romito S, Brunetti C, Silvestris N, Colucci G (2006) Topotecan in the treatment of brain metastases. A phase II study of GOIM (Gruppo Oncologico dell’Italia Meridionale). Anticancer Res 26(3B):2259–2263

    CAS  PubMed  Google Scholar 

  16. Tsimberidou AM, Letourneau K, Wen S, Wheler J, Hong D, Naing A, Iskander NG, Uehara C, Kurzrock R (2011) Phase I clinical trial outcomes in 93 patients with brain metastases: the MD anderson cancer center experience. Clin Cancer Res 17(12):4110–4118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Groves MD, Glantz MJ, Chamberlain MC, Baumgartner KE, Conrad CA, Hsu S, Wefel JS, Gilbert MR, Ictech S, Hunter KU, Forman AD, Puduvalli VK, Colman H, Hess KR, Yung WK (2008) A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro-oncology 10(2):208–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jaeckle KA, Phuphanich S, Bent MJ, Aiken R, Batchelor T, Campbell T, Fulton D, Gilbert M, Heros D, Rogers L, O’Day SJ, Akerley W, Allen J, Baidas S, Gertler SZ, Greenberg HS, LaFollette S, Lesser G, Mason W, Recht L, Wong E, Chamberlain MC, Cohn A, Glantz MJ, Gutheil JC, Maria B, Moots P, New P, Russell C, Shapiro W, Swinnen L, Howell SB (2001) Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine. Br J Cancer 84(2):157–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Glantz MJ, Jaeckle KA, Chamberlain MC, Phuphanich S, Recht L, Swinnen LJ, Maria B, LaFollette S, Schumann GB, Cole BF, Howell SB (1999) A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 5(11):3394–3402

    CAS  PubMed  Google Scholar 

  20. Livingston RB (1986) Current chemotherapy of small cell lung cancer. Chest 89(4 Suppl):258S–263S

    Article  CAS  PubMed  Google Scholar 

  21. Samonis G, Bafaloukos D, Margioris AN, Katsarma G, Toloudis P, Bacoyannis C, Karvounis N, Georgoulias V, Kosmidis P (1997) First-line chemotherapy of advanced breast cancer with a combination of mitoxantrone, methotrexate, and vincristine (MIMO). Oncology 54(5):371–375

    Article  CAS  PubMed  Google Scholar 

  22. Clatot F, Philippin-Lauridant G, Ouvrier MJ, Nakry T, Laberge-Le-Couteulx S, Guillemet C, Veyret C, Blot E (2009) Clinical improvement and survival in breast cancer leptomeningeal metastasis correlate with the cytologic response to intrathecal chemotherapy. J Neurooncol 95(3):421–426

    Article  CAS  PubMed  Google Scholar 

  23. Kimelberg HK, Biddlecome SM, Bourke RS (1977) Distribution and degradation of [3H]methotrexate after intravenous and cerebral intraventricular injection in primates. Cancer Res 37(1):157–165

    CAS  PubMed  Google Scholar 

  24. Kwong YL, Yeung DY, Chan JC (2009) Intrathecal chemotherapy for hematologic malignancies: drugs and toxicities. Ann Hematol 88(3):193–201

    Article  CAS  PubMed  Google Scholar 

  25. Reni M, Ferreri AJ, Guha-Thakurta N, Blay JY, Dell’Oro S, Biron P, Hochberg FH (2001) Clinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-dose methotrexate. Int J Radiat Oncol Biol Phys 51(2):419–425

    Article  CAS  PubMed  Google Scholar 

  26. Villela LR, Stanford BL, Shah SR (2006) Pemetrexed, a novel antifolate therapeutic alternative for cancer chemotherapy. Pharmacotherapy 26(5):641–654

    Article  CAS  PubMed  Google Scholar 

  27. Curtin NJ, Hughes AN (2001) Pemetrexed disodium, a novel antifolate with multiple targets. Lancet Oncol 2(5):298–306

    Article  CAS  PubMed  Google Scholar 

  28. Schneeweiss A, Marme F, Ruiz A, Manikhas AG, Bottini A, Wolf M, Sinn HP, Mansouri K, Kennedy L, Bauknecht T (2011) A randomized phase II trial of doxorubicin plus pemetrexed followed by docetaxel versus doxorubicin plus cyclophosphamide followed by docetaxel as neoadjuvant treatment of early breast cancer. Ann Oncol 22(3):609–617

    Article  CAS  PubMed  Google Scholar 

  29. Garin A, Manikhas A, Biakhov M, Chezhin M, Ivanchenko T, Krejcy K, Karaseva V, Tjulandin S (2008) A phase II study of pemetrexed and carboplatin in patients with locally advanced or metastatic breast cancer. Breast Cancer Res Treat 110(2):309–315

    Article  CAS  PubMed  Google Scholar 

  30. Robert NJ, Conkling PR, O’Rourke MA, Kuefler PR, McIntyre KJ, Zhan F, Asmar L, Wang Y, Shonukan OO, O’Shaughnessy JA (2011) Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer. Breast Cancer Res Treat 126(1):101–108

    Article  CAS  PubMed  Google Scholar 

  31. Martin M, Blasinska-Morawiec M, Salas JF, Falcon S, Rolski J, Ferrari BL, Gulyas S, Liu Y, Benhadji KA (2009) A multicenter, single-arm phase II study of pemetrexed plus doxorubicin administered every 21 days in patients with advanced breast cancer. Clinical breast cancer 9(3):155–160

    Article  CAS  PubMed  Google Scholar 

  32. Miles DW, Smith IE, Coleman RE, Calvert AH, Lind MJ (2001) A phase II study of pemetrexed disodium (LY231514) in patients with locally recurrent or metastatic breast cancer. Eur J Cancer 37(11):1366–1371

    Article  CAS  PubMed  Google Scholar 

  33. Cohen MH, Cortazar P, Justice R, Pazdur R (2010) Approval summary: pemetrexed maintenance therapy of advanced/metastatic nonsquamous, non-small cell lung cancer (NSCLC). Oncologist 15(12):1352–1358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bearz A, Garassino I, Tiseo M, Caffo O, Soto-Parra H, Boccalon M, Talamini R, Santoro A, Bartolotti M, Murgia V, Berretta M, Tirelli U (2010) Activity of pemetrexed on brain metastases from non-small cell lung cancer. Lung Cancer 68(2):264–268

    Article  PubMed  Google Scholar 

  35. Omlin A, D’Addario G, Gillessen S, Cerny T, von Hessling A, Fruh M (2009) Activity of pemetrexed against brain metastases in a patient with adenocarcinoma of the lung. Lung Cancer 65(3):383–384

    Article  CAS  PubMed  Google Scholar 

  36. Stapleton SL, Reid JM, Thompson PA, Ames MM, McGovern RM, McGuffey L, Nuchtern J, Dauser R, Blaney SM (2007) Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates. Cancer Chemother Pharmacol 59(4):461–466

    Article  CAS  PubMed  Google Scholar 

  37. Raizer JJ, Rademaker A, Evens AM, Rice L, Schwartz M, Chandler JP, Getch CC, Tellez C, Grimm SA (2012) Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. Cancer 118(15):3743–3748

    Article  CAS  PubMed  Google Scholar 

  38. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8(7):1277–1280

    Article  CAS  PubMed  Google Scholar 

  39. Latz JE, Chaudhary A, Ghosh A, Johnson RD (2006) Population pharmacokinetic analysis of ten phase II clinical trials of pemetrexed in cancer patients. Cancer Chemother Pharmacol 57(4):401–411

    Article  PubMed  Google Scholar 

  40. Vezmar S, Becker A, Bode U, Jaehde U (2003) Biochemical and clinical aspects of methotrexate neurotoxicity. Chemotherapy 49(1–2):92–104

    Article  CAS  PubMed  Google Scholar 

  41. Sweeney CJ, Takimoto CH, Latz JE, Baker SD, Murry DJ, Krull JH, Fife K, Battiato L, Cleverly A, Chaudhary AK, Chaudhuri T, Sandler A, Mita AC, Rowinsky EK (2006) Two drug interaction studies evaluating the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or Ibuprofen in patients with advanced cancer. Clin Cancer Res 12(2):536–542

    Article  CAS  PubMed  Google Scholar 

  42. Dickgreber NJ, Sorensen JB, Paz-Ares LG, Schytte TK, Latz JE, Schneck KB, Yuan Z, Sanchez-Torres JM (2010) Pemetrexed safety and pharmacokinetics in patients with third-space fluid. Clin Cancer Res 16(10):2872–2880

    Article  CAS  PubMed  Google Scholar 

  43. Niyikiza C, Baker SD, Seitz DE, Walling JM, Nelson K, Rusthoven JJ, Stabler SP, Paoletti P, Calvert AH, Allen RH (2002) Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 1(7):545–552

    CAS  PubMed  Google Scholar 

  44. Chattopadhyay S, Tamari R, Min SH, Zhao R, Tsai E, Goldman ID (2007) Commentary: a case for minimizing folate supplementation in clinical regimens with pemetrexed based on the marked sensitivity of the drug to folate availability. Oncologist 12(7):808–815

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Study was supported by Lilly Oncology (research support for JJR).

Conflict of interest

None for Priya Kumthekar, Sean A. Grimm, Michael J. Avram, Virginia Kaklamani, Irene Helenowski, Alfred Rademaker, Mary Cianfrocca, William Gradishar, Jyoti Patel, Mary Mulcahy, Katie McCarthy; Jeffrey J. Raizer has research funding from Lilly Oncology.

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Authors and Affiliations

  1. Departments of Neurology, Northwestern University, Chicago, IL, 60611, USA

    Priya Kumthekar, Katie McCarthy & Jeffrey J. Raizer

  2. Departments of Anesthesiology, Northwestern University, Chicago, IL, 60611, USA

    Michael J. Avram

  3. Internal Medicine-Hematology/Oncology Division, Northwestern University, Chicago, IL, 60611, USA

    Virginia Kaklamani, William Gradishar, Jyoti Patel & Mary Mulcahy

  4. Division of Preventive Medicine, Northwestern University, Chicago, IL, 60611, USA

    Irene Helenowski & Alfred Rademaker

  5. Department of Neurology, University of Minnesota, Minneapolis, MN, 55455, USA

    Sean A. Grimm

  6. Banner MD Anderson Cancer Center, Gilbert, AZ, 85234, USA

    Mary Cianfrocca

  7. Feinberg School of Medicine, Northwestern University, 710 North Lake Shore Drive, Abbott Hall, Room 1123, Chicago, IL, 60611, USA

    Jeffrey J. Raizer

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  1. Priya Kumthekar
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Correspondence to Jeffrey J. Raizer.

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Kumthekar, P., Grimm, S.A., Avram, M.J. et al. Pharmacokinetics and efficacy of pemetrexed in patients with brain or leptomeningeal metastases. J Neurooncol 112, 247–255 (2013). https://doi.org/10.1007/s11060-013-1055-0

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