Skip to main content

Advertisement

Log in

Imatinib mesylate in thymic epithelial malignancies

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Thymic epithelial tumors (TETs) are rare tumors of the mediastinum, with an estimated incidence of about 3 cases per 100,000 inhabitants. Although anthracycline- and platinum-based chemotherapy is an active treatment for TETs, novel systemic therapeutic options are especially needed for metastatic disease, which is virtually incurable. On the basis of the radiographic response obtained with imatinib (Novartis Pharma, Basel, Switzerland) in a patient with thymic carcinoma harboring the V560del c-KIT mutation, a phase II trial was initiated at the Department of Molecular and Clinical Oncology and Endocrinology of University “Federico II of Naples” with the purpose to test imatinib in TETs.

Methods

Imatinib was daily delivered at the dose of 400 mg to patients affected by TETs, who had progressed after at least one chemotherapy regimen. Positivity of c-KIT on immunohistochemistry was not mandatory for study entry. Radiographic responses were measured by CT scans performed every 3 months, according to the RECIST criteria. Toxicity was graded according to the Common Toxicity Criteria of the National Cancer Institute, version 3.0.

Results

Fifteen patients with advanced TETs were enrolled from March 2008 to May 2010. Three patients presented with thymic carcinomas. Two of these three patients presented c-kit expression on immunohistochemistry. No patient harbored a known c-kit activating mutation. Imatinib was very well tolerated, with no toxicity-related death. Diarrhea and migraine were the most frequent events, occurring both in 20% of patients, but were manageable and mild. No radiographic responses were recorded. Median progression-free survival was 3 months (interquartile range, 2.5–4). Median overall survival was not reached. The study was terminated before it reached its target accrual of 42 patients, because of the lack of responses and low accrual rate.

Conclusions

This trial indicates the lack of effectiveness of imatinib in unselected patients with thymic epithelial tumors. Nevertheless, imatinib may represent a valuable option in selected patients with TETs, such as those harboring the V560del c-KIT mutation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. De Jong WK, Blaauwgeers JL, Schaapveld M, Timens W, Klinkenberg TJ, Groen HJ (2008) Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer 44:123–130

    Article  PubMed  Google Scholar 

  2. Travis WD, Brambilla E, Müller-Hemerlink HK (2004) Tumours of the lung, pleura, thymus and heart. In: Pathology & Genetics series, World Health Organization Classification of Tumours, IARC Press, Lyon

  3. Masaoka A, Monden Y, Nakahara K, Tanioka T (1981) Follow-up study of thymomas with special reference to their clinical stages. Cancer 48:2485–2492

    Article  PubMed  CAS  Google Scholar 

  4. Falkson CB, Bezjak A, Darling G et al (2009) The management of thymoma: a systematic review and practice guideline. J Thorac Oncol 4:911–919

    Article  PubMed  Google Scholar 

  5. Palmieri G, Merola G, Federico P et al (2010) Preliminary results of phase II study of capecitabine and gemcitabine (CAP-GEM) in patients with metastatic pretreated thymic epithelial tumors (TETs). Ann Oncol 21:1168–1172

    Article  PubMed  CAS  Google Scholar 

  6. Blay JY (2010) A decade of tyrosine kinase inhibitor therapy: historical and current perspectives on targeted therapy for GIST. Cancer Treat Rev. [Epub ahead of print]

  7. Hornick JL, Fletcher CD (2007) The role of KIT in the management of patients with gastrointestinal stromal tumors. Hum Pathol 38:679–687

    Article  PubMed  CAS  Google Scholar 

  8. Petrini I, Zucali PA, Lee HS (2010) Expression and mutational status of c-kit in thymic epithelial tumors. J Thorac Oncol 5(9):1447–1453

    Article  PubMed  Google Scholar 

  9. Nakagawa K, Matsuno Y, Kunitoh H et al (2005) Immunohistochemical KIT (CD117) expression in thymic epithelial tumors. Chest 128:140–144

    Article  PubMed  CAS  Google Scholar 

  10. Ströbel P, Hartmann M, Jakob A et al (2004) Thymic carcinoma with overexpression of mutated KIT and the response to imatinib. N Engl J Med 350(25):2625–2626

    Article  PubMed  Google Scholar 

  11. Heinrich MC, Corless CL, Demetri GD et al (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349

    Article  PubMed  CAS  Google Scholar 

  12. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, National cancer institute of the United States, National cancer institute of Canada. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  13. Verweij J, Casali PG, Zalcberg J et al (2004) Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364:1127–1134

    Article  PubMed  CAS  Google Scholar 

  14. Young H, Baum R, Cremerius U et al (1999) Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer 35:1773–1782

    Article  PubMed  CAS  Google Scholar 

  15. A’Hern RP (2001) Sample size tables for exact single-stage phase II designs. Stat Med 20(6):859–866

    Article  PubMed  Google Scholar 

  16. Huizinga JD, Thuneberg L, Klüppel M, Malysz J, Mikkelsen HB, Bernstein A (1995) W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 373:347–349

    Article  PubMed  CAS  Google Scholar 

  17. Paral J, Slaninka I, Kalabova H, Hadzi-Nikolov D (2010) Gastrointestinal stromal tumors: review on morphology, molecular pathology, diagnostics, prognosis and treatment options. Acta Gastroenterol Belg 73(3):349–359

    PubMed  CAS  Google Scholar 

  18. Krug LM, Crapanzano JP, Azzoli CG et al (2005) Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial. Cancer 103(10):2128–2131

    Article  PubMed  CAS  Google Scholar 

  19. Hotte SJ, Winquist EW, Lamont E et al (2005) Imatinib mesylate in patients with adenoid cystic cancers of the salivary glands expressing c-kit: a Princess Margaret Hospital phase II consortium study. J Clin Oncol 23(3):585–590

    Article  PubMed  CAS  Google Scholar 

  20. Huh WK, Sill MW, Darcy KM et al (2010) Efficacy and safety of imatinib mesylate (Gleevec) and immunohistochemical expression of c-Kit and PDGFR-beta in a gynecologic oncology group phase Il Trial in women with recurrent or persistent carcinosarcomas of the uterus. Gynecol Oncol 117(2):248–254

    Article  PubMed  CAS  Google Scholar 

  21. Girard N (2010) Thymic tumors: relevant molecular data in the clinic. J Thorac Oncol 10(4):291–295

    Article  Google Scholar 

  22. Giaccone G, Rajan A, Ruijter R et al (2009) Imatinib mesylate in patients with WHO B3 thymomas and thymic carcinomas. J Thorac Oncol 4(10):1270–1273

    Article  PubMed  Google Scholar 

  23. Dişel U, Oztuzcu S, Beşen AA et al (2011) Promising efficacy of sorafenib in a relapsed thymic carcinoma with C-KIT exon 11 deletion mutation. Lung Cancer 71:109–112

    Article  PubMed  Google Scholar 

  24. Ströbel P, Bargou R, Wolff A et al (2010) Sunitinib in metastatic thymic carcinomas: laboratory findings and initial clinical experience. Br J Cancer 103:196–200

    Article  PubMed  Google Scholar 

  25. Girard N, Shen R, Guo T et al (2009) Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas. Clin Cancer Res 15:6790–6799

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

CB wrote the article, which was revised by GP and MM. All authors made substantial contribution to the work. Contribution by MM was partially supported by grants from the Italian National Health Institutes (US-Italian NHI program for Rare Diseases, 2006).

Conflict of interest

The authors declare no potential conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Giovannella Palmieri.

Additional information

This study was supported by “Agenzia Italiana del Farmaco” (AIFA code, FARM6HJ7CA).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Palmieri, G., Marino, M., Buonerba, C. et al. Imatinib mesylate in thymic epithelial malignancies. Cancer Chemother Pharmacol 69, 309–315 (2012). https://doi.org/10.1007/s00280-011-1690-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-011-1690-0

Keywords

Navigation