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Erlotinib in combination with pemetrexed/cisplatin for leptomeningeal metastases and cerebrospinal fluid drug concentrations in lung adenocarcinoma patients after gefitinib faliure

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Abstract

Limited treatment options are available for lung cancer with brain metastases. Recent reports indicated that erlotinib and pemetrexed had synergistic effects in lung adenocarcinoma. Thus, we speculated that erlotinib plus pemetrexed/cisplatin may be more effective for the treatment of refractory central nervous system metastases in patients after gefitinib failure. Six lung adenocarcinoma patients with leptomeningeal metastasis (LM) who showed initial good response to gefitinib and subsequent gefitinib resistance were enrolled in this retrospective study. Five of the six patients had an epidermal growth factor receptor (EGFR) mutation in the primary tumor tissues or plasma. One patient showed complete remission, two patients showed a partial response, and two patients had stable disease. Performance and symptoms improved in the six patients. The survival time after the combination therapy was from 8 to 15 months (median, 9 months). There was no significant difference in cerebrospinal fluid (CSF) penetration rates of erlotinib between the erlotinib-only and the combination groups (P = 0.44). Erlotinib combined with pemetrexed/cisplatin may be effective in the treatment of LM in EGFR mutation patients after gefitinib failure. Small but measurable penetration of erlotinib and pemetrexed into the CSF was observed.

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References

  1. Hazard LJ, Jensen RL, Shrieve DC (2005) Role of stereotactic radiosurgery in the treatment of brain metastases. Am J Clin Oncol 28(4):403–410

    Article  PubMed  Google Scholar 

  2. Kawabe T, Phi JH, Yamamoto M, Kim DG, Barfod BE, Urakawa Y (2012) Treatment of brain metastasis from lung cancer. Prog Neurol Surg 25:148–155

    Article  PubMed  Google Scholar 

  3. Song Z, Yu X, He C, Zhang B, Zhang Y (2013) Re-administration after the failure of gefitinib or erlotinib in patients with advanced non-small cell lung cancer. J Thorac Dis 5(4):400–405

  4. Porta R, Sánchez-Torres JM, Paz-Ares L, Massutí B, Reguart N, Mayo C, Lianes P, Queralt C, Guillem V, Salinas P, Catot S, Isla D, Pradas A, Gúrpide A, de Castro J, Polo E, Puig T, Tarón M, Colomer R, Rosell R (2011) Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J 37(3):624–631

    Article  CAS  PubMed  Google Scholar 

  5. Bailon O, Chouahnia K, Augier A, Bouillet T, Billot S, Coman I, Ursu R, Belin C, Zelek L, Des Guetz G, Levy C, Carpentier AF (2012) Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma. Neuro Oncol 14(4):491–495

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Spicer J, Harper P (2005) Targeted therapies for non-small cell lung cancer. Int J Clin Pract 59(9):1055–1062

    Article  CAS  PubMed  Google Scholar 

  7. Ranson M, Reck M, Anthoney A, Hanauske AR, Dean E, Melezinek I, Klingelschmitt G, Kletzl H, Blatter J, Twelves C (2010) Erlotinib in combination with pemetrexed for patients with advanced non-small-cell lung cancer (NSCLC): a phase I dose-finding study. Ann Oncol 21(11):2233–2239

    Article  CAS  PubMed  Google Scholar 

  8. Minami S, Kijima T, Takahashi R, Kida H, Nakatani T, Hamaguchi M, Takeuchi Y, Nagatomo I, Yamamoto S, Tachibana I, Komuta K, Kawase I (2012) Combination chemotherapy with intermittent erlotinib and pemetrexed for pretreated patients with advanced non-small cell lung cancer: a phase I dose-finding study. BMC Cancer 12:296

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. 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(2):228–247

    Article  CAS  PubMed  Google Scholar 

  10. Wu YL, Zhou C, Cheng Y, Lu S, Chen GY, Huang C, Huang YS, Yan HH, Ren S, Liu Y, Yang JJ (2013) Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803). Ann Oncol 24(4):993–999

    Article  PubMed  Google Scholar 

  11. Yi HG, Kim HJ, Kim YJ, Han SW, Oh DY, Lee SH, Kim DW, Im SA, Kim TY, Kim CS, Heo DS, Bang YJ (2009) Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non-small cell lung cancer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI. Lung Cancer 65(1):80–84

    Article  PubMed  Google Scholar 

  12. 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(11):1415–1419

    Article  PubMed  Google Scholar 

  13. 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(12):1364–1369

    Article  PubMed Central  PubMed  Google Scholar 

  14. Togashi Y, Masago K, Masuda S, Mizuno T, Fukudo M, Ikemi Y, Sakamori Y, Nagai H, Kim YH, Katsura T, Mishima M (2012) Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 70(3):399–405

    Article  CAS  PubMed  Google Scholar 

  15. 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(2):283–286

    Article  PubMed Central  PubMed  Google Scholar 

  16. Saito H, Murakami S, Kondo T, Oshita F, Noda K, Yamada K (2012) Effectiveness of erlotinib in advanced non-small cell lung cancer in cases of gefitinib resistance after treatment of more than 6 months. Onkologie 35(1–2):18–22

    Article  CAS  PubMed  Google Scholar 

  17. Hata A, Katakami N, Yoshioka H, Fujita S, Kunimasa K, Nanjo S, Otsuka K, Kaji R, Tomii K, Iwasaku M, Nishiyama A, Hayashi H, Morita S, Ishida T (2011) Erlotinib after gefitinib failure in relapsed non-small cell lung cancer: clinical benefit with optimal patient selection. Lung Cancer 74(2):268–273

    Article  PubMed  Google Scholar 

  18. Li T, Ling YH, Goldman ID, Perez-Soler R (2007) Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells. Clin Cancer Res 13(11):3413–3422

    Article  CAS  PubMed  Google Scholar 

  19. 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 

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Funding

This research was supported by Guangdong Science and Technology Program.

Conflict of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Respiratory Oncology, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, 510120, Guangzhou, China

    Haihong Yang, Yalei Zhang, Qiuhua Deng, Meiling Zhao, Xin Xu & Jianxing He

  2. Department of Pharmacy, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

    Xinyun Yang

  3. Department of Oncology and Hematology, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

    Xin Liu

Authors
  1. Haihong Yang
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  2. Xinyun Yang
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  3. Yalei Zhang
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  4. Xin Liu
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  5. Qiuhua Deng
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  6. Meiling Zhao
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  7. Xin Xu
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  8. Jianxing He
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Correspondence to Jianxing He.

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Haihong Yang and Xinyun Yang contributed equally.

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Yang, H., Yang, X., Zhang, Y. et al. Erlotinib in combination with pemetrexed/cisplatin for leptomeningeal metastases and cerebrospinal fluid drug concentrations in lung adenocarcinoma patients after gefitinib faliure. Targ Oncol 10, 135–140 (2015). https://doi.org/10.1007/s11523-014-0326-9

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  • DOI: https://doi.org/10.1007/s11523-014-0326-9

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