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Vol. 58, No. 4, 2012
Issue release date: November 2012
Chemotherapy 2012;58:313–320

Pemetrexed for Previously Treated Patients with Non-Small Cell Lung Cancer and Differences in Efficacy according to Thymidylate Synthase Expression

Igawa S. · Ryuge S. · Wada M. · Otani S. · Maki S. · Takakura A. · Katono K. · Sasaki J. · Sato Y. · Masuda N.
aDepartment of Respiratory Medicine, Kitasato University School of Medicine, and bDepartment of Molecular Diagnostics, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan

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The purpose of this study was to evaluate the efficacy of pemetrexed monotherapy in previously treated patients with advanced non-small cell lung cancer (NSCLC) including salvage treatment, and to evaluate whether thymidylate synthase (TS) expression is a predictor for pemetrexed efficacy. Hundred and four previously treated patients with advanced NSCLC who received pemetrexed monotherapy were retrospectively evaluated for clinical efficacy and toxicity. If available, tissue specimens of patients were also analyzed immunohistochemically for TS expression. The patients’ median age was 65 years (range: 43–82). An overall response rate of 9.6% and a median progression-free survival (PFS) time of 3.4 months were achieved. The response rates for the second-line, third-line, fourth-line or further treatments were 9.1, 9.3 and 10.2% (p = 0.33); the median PFS were 3.3, 3.2 and 3.8 months (p = 0.21). The median follow-up duration was 14.9 months; the median overall survival (OS) was 11.9 months. The median PFS and OS were significantly longer in the TS-negative group than in the TS-positive group (5.8 months vs. 1.6 months; p = 0.03, and 14.7 months vs. 8.6 months; p = 0.04, respectively). Pemetrexed monotherapy could be considered as an option in the fourth or later lines of treatment of previously treated patients with advanced NSCLC as well as a second- or third-line treatment, and TS expression may be a potentially predictive factor for pemetrexed efficacy in NSCLC patients.

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  1. Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M: Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 2007;18:317–323.
  2. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–98.
  3. Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2085–2103.
  4. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L: Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 2005;353:132–123.

    External Resources

  5. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589–1597.
  6. Solomon B, Bunn PA: Clinical activity of pemetrexed: a multitargeted antifolate anticancer agent. Future Oncol 2005:1:733–746.
  7. Joerger M, Omlin A, Cerny T, Früh M: The role of pemetrexed in advanced non-small-cell lung cancer: special focus on pharmacology and mechanism of action. Curr Drug Targets 2010;11:37–47.
  8. Huang CL, Yokomise H, Kobayashi S, Fukushima M, Hitomi S, Wada H: Intratumoral expression of thymidylate synthase and dihydropyrimidine dehydrogenase in non-small cell lung cancer patients treated with 5-FU-based chemotherapy. Int J Oncol 2000;17:47–54.
  9. Nakagawa T, Tanaka F, Otake Y, Yanagihara K, Miyahara R, Matsuoka K, Takata T, Yamada T, Fukushima M, Wada H: Prognostic value of thymidylate synthase expression in patients with p-stage I adenocarcinoma of the lung. Lung Cancer 2002;35:165–170.

    External Resources

  10. Takezawa K, Okamoto I, Okamoto W, Takeda M, Sakai K, Tsukioka S, Kuwata K, Yamaguchi H, Nishio K, Nakagawa K: Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer. Br J Cancer 2011;104:1594–1601.
  11. Ceppi P, Volante M, Saviozzi S, Rapa I, Novello S, Cambieri A, Lo Iacono M, Cappia S, Papotti M, Scagliotti GV: Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 2006;107:1589–1596.
  12. Chang MH, Ahn JS, Lee J, Kim KH, Park YH, Han J, Ahn MJ, Park K: The efficacy of pemetrexed as a third- or fourth-line therapy and the significance of thymidylate synthase expression in patients with advanced non-small cell lung cancer. Lung Cancer 2010;69:323–329.

    External Resources

  13. Sun JM, Han J, Ahn JS, Park K, Ahn MJ: Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy. J Thorac Oncol 2011;6:1392–1399.

    External Resources

  14. Chen CY, Chang YL, Shih JY, Lin JW, Chen KY, Yang CH, Yu CJ, Yang PC: Thymidylate synthase and dihydrofolate reductase expression in non-small cell lung carcinoma: the association with treatment efficacy of pemetrexed. Lung Cancer 2011;74:132–138.

    External Resources

  15. Sun JM, Lee KW, Kim JH, Kim YJ, Yoon HI, Lee JH, Lee CT, Lee JS: Efficacy and toxicity of pemetrexed as a third-line treatment for non-small cell lung cancer. Jpn J Clin Oncol 2009;39:27–32.

    External Resources

  16. Zinner RG, Novello S, Peng G, Herbst R, Obasaju C, Scagliotti G: Comparison of patient outcomes according to histology among pemetrexed-treated patients with stage IIIB/IV non-small-cell lung cancer in two phase II trials. Clin Lung Cancer 2010;11:126–131.
  17. Kubota K, Niho S, Enatsu S, Nambu Y, Nishiwaki Y, Saijo N, Fukuoka M: Efficacy Differences of pemetrexed by histology in pretreated patients with stage IIIB/IV non-small cell lung cancer. J Thorac Oncol 2009;4:1530–1536.

    External Resources

  18. Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Pereira JR, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009;24:1432–1440.

    External Resources

  19. Ohe Y, Ichinose Y, Nakagawa K, Tamura T, Kubota K, Yamamoto N, Adachi S, Nambu Y, Fujimoto T, Nishiwaki Y, Saijo N, Fukuoka M: Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. Clin Cancer Res 2008;14:4206–4212.
  20. Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095–2103.
  21. Yu YF, Chen ZW, Zhou Z, Song ZB, Li ZM, Jian H, Zhang YF, Lu S: Cost-effectiveness analysis of docetaxel versus pemetrexed in second-line chemotherapy for stage IIIb or IV non-small cell lung cancer in China. Chemotherapy 2010;56:472–477.
  22. Chung FT, Lee KY, Fang YF, Shieh MH, Lin SM, Yu CT, Lo YL, Lin TY, Kuo CH, Feng PH, Ni YL, Kuo HP: Low-dose weekly docetaxel is as tolerable as pemetrexed in previously treated advanced non-small-cell lung cancer. Chemotherapy 2011;57:147–155.
  23. Krawczyk P, Kowalski DM, Wojas-Krawczyk K, Mlak R, Jaśkiewicz P, Kucharczyk T, Winiarczyk K, Krzakowski M, Milanowski J: The qualification of docetaxel or erlotinib for second-line therapy should be based on clinical and molecular predictive factors. Chemotherapy 2012;58:60–69.
  24. Hotta K, Fujiwara Y, Kiura K, Takigawa N, Tabata M, Ueoka H, Tanimoto M: Relationship between response and survival in more than 50,000 patients with advanced non-small cell lung cancer treated with systemic chemotherapy in 143 phase III trials. J Thorac Oncol 2007;2:402–407.

    External Resources

  25. Massarelli E, Andre F, Liu DD, Lee JJ, Wolf M, Fandi A, Ochs J, Le Chevalier T, Fossella F, Herbst RS: A retrospective analysis of the outcome of patients who have received two prior chemotherapy regimens including platinum and docetaxel for recurrent non-small-cell lung cancer. Lung Cancer 2003;39:55–61.
  26. Nakagawa T, Otake Y, Yanagihara K, Miyahara R, Ishikawa S, Fukushima M, Wada H, Tanaka F: Expression of thymidylate synthase is correlated with proliferative activity in non-small cell lung cancer (NSCLC). Lung Cancer 2004;43:145–149.

    External Resources

  27. Hashimoto H, Ozeki Y, Sato M, Obara K, Matsutani N, Nakagishi Y, Ogata T, Maehara T: Significance of thymidylate synthase gene expression level in patients with adenocarcinoma of the lung. Cancer 2006;106:1595–1601.

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