Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer
- 2k Downloads
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.
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.
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.
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.
KeywordsNon-small cell lung cancer Epidermal growth factor receptor gene mutation Gefitinib Erlotinib Cerebrospinal fluid Leptomeningeal metastases
This research was partially supported by Funding Program for Next Generation World-Leading Researchers (NEXT Program; LS073).
Conflict of interest
The authors have no conflict of interest.
- 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.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
- 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.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
- 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
- 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.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.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.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.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
- 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
- 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
- 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.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
- 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
- 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
- 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