Cancer Chemotherapy and Pharmacology

, Volume 70, Issue 3, pp 399–405 | Cite as

Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer

  • Yosuke Togashi
  • Katsuhiro Masago
  • Satohiro Masuda
  • Tomoyuki Mizuno
  • Masahide Fukudo
  • Yasuaki Ikemi
  • Yuichi Sakamori
  • Hiroki Nagai
  • Young Hak Kim
  • Toshiya Katsura
  • Michiaki Mishima
Original Article

Abstract

Purpose

Several cases have been reported in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) resistant to gefitinib were improved by erlotinib. However, there has been no study in which cerebrospinal fluid (CSF) concentrations of gefitinib and erlotinib are directly compared. Thus, we aimed to compare them.

Methods

We examined 15 Japanese patients with NSCLC and CNS metastases with epidermal growth factor receptor gene mutations who received CSF examinations during epidermal growth factor receptor-tyrosine kinase inhibitors treatment (250 mg daily gefitinib or 150 mg daily erlotinib). Plasma and CSF concentrations were determined using high-performance liquid chromatography with tandem mass spectrometry.

Results

The concentration and penetration rate of gefitinib (mean ± standard deviation) in the CSF were 3.7 ± 1.9 ng/mL (8.2 ± 4.3 nM) and 1.13 ± 0.36 %, respectively. The concentration and penetration rate of erlotinib in the CSF were 28.7 ± 16.8 ng/mL (66.9 ± 39.0 nM) and 2.77 ± 0.45 %, respectively. The CSF concentration and penetration rate of erlotinib were significantly higher than those of gefitinib (P = 0.0008 and <0.0001, respectively). The CNS response rates of patients with erlotinib treatment were preferentially (but not significantly) higher than those with gefitinib treatment. (1/3 vs. 4/7, respectively). Leptomeningeal metastases in one patient, which were refractory to gefitinib, dramatically responded to erlotinib.

Conclusions

This study suggested that higher CSF concentration could be achieved with erlotinib and that erlotinib could be more effective for the treatment for CNS metastases, especially leptomeningeal metastases, than gefitinib.

Keywords

Non-small cell lung cancer Epidermal growth factor receptor gene mutation Gefitinib Erlotinib Cerebrospinal fluid Leptomeningeal metastases 

References

  1. 1.
    Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500PubMedCrossRefGoogle Scholar
  2. 2.
    Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139PubMedCrossRefGoogle Scholar
  3. 3.
    Omuro AM, Kris MG, Miller VA, Franceschi E, Shah N, Milton DT, Abrey LE (2005) High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer 103:2344–2348PubMedCrossRefGoogle Scholar
  4. 4.
    Lee YJ, Choi HJ, Kim SK, Chang J, Moon JW, Park IK, Kim JH, Cho BC (2010) Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall-cell lung cancer. Cancer 116:1336–1343PubMedCrossRefGoogle Scholar
  5. 5.
    Jackman DM, Holmes AJ, Lindeman N, Wen PY, Kesari S, Borras AM, Bailey C, de Jong F, Janne PA, Johnson BE (2006) Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol 24:4517–4520PubMedCrossRefGoogle Scholar
  6. 6.
    Dhruva N, Socinski MA (2009) Carcinomatous meningitis in non-small-cell lung cancer: response to high-dose erlotinib. J Clin Oncol 27:31–32CrossRefGoogle Scholar
  7. 7.
    Clarke JL, Pao W, Wu N, Miller VA, Lassman AB (2010) 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 99:283–286PubMedCrossRefGoogle Scholar
  8. 8.
    Hata A, Kaji R, Fujita S, Katakami N (2011) High-dose erlotinib for refractory brain metastases in a patient with relapsed non-small cell lung cancer. J Thorac Oncol 6:653–654PubMedCrossRefGoogle Scholar
  9. 9.
    Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, Clarke JL, Lassman AB (2011) “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 13:1364–1369PubMedCrossRefGoogle Scholar
  10. 10.
    Katayama T, Shimizu J, Suda K, Onozato R, Fukui T, Ito S, Hatooka S, Sueda T, Hida T, Yatabe Y, Mitsudomi T (2009) Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J Thorac Oncol 4:1415–1419PubMedCrossRefGoogle Scholar
  11. 11.
    Fukuhara T, Saijo Y, Sakakibara T, Inoue A, Morikawa N, Kanamori M, Nakashima I, Nukiwa T (2008) Successful treatment of carcinomatous meningitis with gefitinib in a patient with lung adenocarcinoma harboring a mutated EGF receptor gene. Tohoku J Exp Med 214:359–363PubMedCrossRefGoogle Scholar
  12. 12.
    Togashi Y, Masago K, Fukudo M, Terada T, Fujita S, Irisa K, Sakamori Y, Kim YH, Mio T, Inui K, Mishima M (2010) Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer. J Thorac Oncol 5:950–955PubMedCrossRefGoogle Scholar
  13. 13.
    Masuda T, Hattori N, Hamada A, Iwamoto H, Ohshimo S, Kanehara M, Ishikawa N, Fujitaka K, Haruta Y, Murai H, Kohno N (2011) Erlotinib efficacy and cerebrospinal fluid concentration in patients with lung adenocarcinoma developing leptomeningeal metastases during gefitinib therapy. Cancer Chemother Pharmacol 67:1465–1469PubMedCrossRefGoogle Scholar
  14. 14.
    Togashi Y, Masago K, Fukudo M, Tsuchido Y, Okuda C, Kim YH, Ikemi Y, Sakamori Y, Mio T, Katsura T, Mishima M (2011) Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation. Cancer Chemother Pharmacol 68:1089–1092PubMedCrossRefGoogle Scholar
  15. 15.
    Jones HK, Stafford LE, Swaisland HC, Payne R (2002) A sensitive assay for ZD1839 (Iressa) in human plasma by liquid–liquid extraction and high performance liquid chromatography with mass spectrometric detection: validation and use in Phase I clinical trials. J Pharm Biomed Anal 29:221–228PubMedCrossRefGoogle Scholar
  16. 16.
    Zhao M, Hartke C, Jimeno A, Li J, He P, Zabelina Y, Hidalgo M, Baker SD (2005) Specific method for determination of gefitinib in human plasma, mouse plasma and tissues using high performance liquid chromatography coupled to tandem mass spectrometry. J Chromatogr, B: Anal Technol Biomed Life Sci 819:73–80CrossRefGoogle Scholar
  17. 17.
    Zhao M, He P, Rudek MA, Hidalgo M, Baker SD (2003) Specific method for determination of OSI-774 and its metabolite OSI-420 in human plasma by using liquid chromatography-tandem mass spectrometry. J Chromatogr, B: Anal Technol Biomed Life Sci 793:413–420CrossRefGoogle Scholar
  18. 18.
    Masters AR, Sweeney CJ, Jones DR (2007) The quantification of erlotinib (OSI-774) and OSI-420 in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr, B: Anal Technol Biomed Life Sci 848:379–383CrossRefGoogle Scholar
  19. 19.
    Nagai Y, Miyazawa H, Huqun, Tanaka T, Udagawa K, Kato M, Fukuyama S, Yokote A, Kobayashi K, Kanazawa M, Hagiwara K (2005) Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp. Cancer Res 65:7276–7282Google Scholar
  20. 20.
    Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T (2004) Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 64:8919–8923PubMedCrossRefGoogle Scholar
  21. 21.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247PubMedCrossRefGoogle Scholar
  22. 22.
    Langer CJ, Mehta MP (2005) Current management of brain metastases, with a focus on systemic options. J Clin Oncol 23:6207–6219PubMedCrossRefGoogle Scholar
  23. 23.
    Paz-Ares L, Soulières D, Melezínek I, Moecks J, Keil L, Mok T, Rosell R, Klughammer B (2010) Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations: pooled analysis. J Cell Mol Med 14:51–69PubMedCrossRefGoogle Scholar
  24. 24.
    Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329–336PubMedCrossRefGoogle Scholar
  25. 25.
    Nakagawa K, Tamura T, Negoro S, Kudoh S, Yamamoto N, Takeda K, Swaisland H, Nakatani I, Hirose M, Dong RP, Fukuoka M (2003) Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid malignant tumors. Ann Oncol 14:922–930PubMedCrossRefGoogle Scholar
  26. 26.
    Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R (2003) FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 8:303–306PubMedCrossRefGoogle Scholar
  27. 27.
    Yamamoto N, Horiike A, Fujisaka Y, Murakami H, Shimoyama T, Yamada Y, Tamura T (2008) Phase I dose-finding and pharmacokinetic study of the oral epidermal growth factor receptor tyrosine kinase inhibitor Ro50–8231 (erlotinib) in Japanese patients with solid tumors. Cancer Chemother Pharmacol 61:489–496PubMedCrossRefGoogle Scholar
  28. 28.
    Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R (2005) FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist 10:461–466PubMedCrossRefGoogle Scholar
  29. 29.
    Gerstner ER, Fine RL (2007) Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol 25:2306–2312PubMedCrossRefGoogle Scholar
  30. 30.
    Elmeliegy MA, Carcaboso AM, Tagen M, Bai F, Stewart CF (2011) Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation. Clin Cancer Res 17:89–99PubMedCrossRefGoogle Scholar
  31. 31.
    Mukohara T, Engelman JA, Hanna NH, Yeap BY, Kobayashi S, Lindeman N, Halmos B, Pearlberg J, Tsuchihashi Z, Cantley LC, Tenen DG, Johnson BE, Janne PA (2005) Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst 97:1185–1194PubMedCrossRefGoogle Scholar
  32. 32.
    Zhang RD, Price JE, Fujimaki T, Bucana CD, Fidler IJ (1992) Differential permeability of the blood-brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice. Am J Pathol 141:1115–1124PubMedGoogle Scholar
  33. 33.
    Stewart DJ (1994) A critique of the role of the blood-brain barrier in the chemotherapy of human brain tumors. J Neurooncol 20:121–139PubMedCrossRefGoogle Scholar
  34. 34.
    Davey P (2002) Brain metastases: treatment options to improve outcomes. CNS Drugs 16:325–338PubMedCrossRefGoogle Scholar
  35. 35.
    Weber B, Winterdahl M, Memon A, Sorensen BS, Keiding S, Sorensen L, Nexo E, Meldgaard P (2011) Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor. J Thorac Oncol 6:1287–1289PubMedCrossRefGoogle Scholar
  36. 36.
    Gleissner B, Chamberlain MC (2006) Neoplastic meningitis. Lancet Neurol 5:443–452PubMedCrossRefGoogle Scholar
  37. 37.
    Lombardi G, Zustovich F, Farina P, Della Puppa A, Manara R, Cecchin D, Brunello A, Cappetta A, Zagonel V (2011) Neoplastic meningitis from solid tumors: new diagnostic and therapeutic approaches. Oncologist 16:1175–1188PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Yosuke Togashi
    • 1
  • Katsuhiro Masago
    • 1
  • Satohiro Masuda
    • 2
  • Tomoyuki Mizuno
    • 2
  • Masahide Fukudo
    • 2
  • Yasuaki Ikemi
    • 2
  • Yuichi Sakamori
    • 1
  • Hiroki Nagai
    • 1
  • Young Hak Kim
    • 1
  • Toshiya Katsura
    • 2
  • Michiaki Mishima
    • 1
  1. 1.Department of Respiratory Medicine, Graduate School of MedicineKyoto UniversityKyotoJapan
  2. 2.Department of Pharmacy, Graduate School of MedicineKyoto University HospitalKyotoJapan

Personalised recommendations