International Journal of Radiation Oncology * Biology * Physics
Volume 73, Issue 4 , Pages 1069-1076 , 15 March 2009

Motexafin Gadolinium Combined With Prompt Whole Brain Radiotherapy Prolongs Time to Neurologic Progression in Non–Small-Cell Lung Cancer Patients With Brain Metastases: Results of a Phase III Trial

  • Minesh P. Mehta, M.D.

      Affiliations

    • Department of Human Oncology, University of Wisconsin, Madison, WI
    • Corresponding Author InformationReprint requests to: Minesh P. Mehta, M.D., Department of Human Oncology, Radiation Oncology, University of Wisconsin–Madison, K4/B100, 600 Highland Ave., Madison, WI 53792. Tel: (608) 263-8500; Fax: (608) 263-9167
    • ,
  • William R. Shapiro, M.D.

      Affiliations

    • Barrow Neurological Institute, Phoenix, AZ
    • ,
  • See C. Phan, M.D.

      Affiliations

    • Clinical Development, Pharmacyclics, Sunnyvale, CA
    • ,
  • Radj Gervais, M.D.

      Affiliations

    • Centre François Baclesse, Caen, France
    • ,
  • Christian Carrie, M.D.

      Affiliations

    • Centre Léon-Bérard, Lyon, France
    • ,
  • Pierre Chabot, M.D.

      Affiliations

    • Hôpital Maisonneuve-Rosemont, Montreal, QB, Canada
    • ,
  • Roy A. Patchell, M.D.

      Affiliations

    • University of Kentucky, Lexington, KY
    • ,
  • Michael J. Glantz, M.D.

      Affiliations

    • University of Massachusetts, Hinsdale, MA
    • ,
  • Lawrence Recht, M.D.

      Affiliations

    • Stanford University, Palo Alto, CA
    • ,
  • Corey Langer, M.D.

      Affiliations

    • Fox Chase Cancer Center, Philadelphia, PA
    • ,
  • Ranjan K. Sur, M.D., Ph.D.

      Affiliations

    • Juravinski Cancer Centre at Hamilton Regional Cancer Centre, Hamilton, ON, Canada
    • ,
  • Wilson H. Roa, M.D.

      Affiliations

    • Cross Cancer Institute, Edmonton, AB, Canada
    • ,
  • Marc A. Mahe, M.D.

      Affiliations

    • Centre René Gauducheau, Nantes-St. Herblain, France
    • ,
  • Andre Fortin, M.D.

      Affiliations

    • Hotel-Dieu de Québec, Québec, QB, Canada
    • ,
  • Carsten Nieder, M.D.

      Affiliations

    • Klinikum rechts der Isar der Technischen Universität Műnchen, Munich, Germany
    • ,
  • Christina A. Meyers, Ph.D.

      Affiliations

    • University of Texas M. D. Anderson Cancer Center, Houston, TX
    • ,
  • Jennifer A. Smith, Ph.D.

      Affiliations

    • Clinical Development, Pharmacyclics, Sunnyvale, CA
    • ,
  • Richard A. Miller, M.D.

      Affiliations

    • Clinical Development, Pharmacyclics, Sunnyvale, CA
    • ,
  • Markus F. Renschler, M.D.

      Affiliations

    • Clinical Development, Pharmacyclics, Sunnyvale, CA

Received 25 March 2008 ,Revised 19 May 2008 ,Accepted 20 May 2008.

References 

  1. Langer CJ, Mehta MP. Current management of brain metastases, with a focus on systemic options. J Clin Oncol. 2005;23:1–13
  2. Posner JB. Neurologic complications of cancer. Philadelphia: FA Davis; 1995;p. 4–5
  3. Mehta MP, Shapiro WR, Glantz MJ, et al. Lead-in phase to randomized trial of motexafin gadolinium and whole-brain radiation for patients with brain metastases: Centralized assessment of magnetic resonance imaging, neurocognitive, and neurologic end points. J Clin Oncol. 2002;20:3445–3453
  4. Mehta MP, Rodrigus P, Terhaard C, et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol. 2003;21:2529–2536
  5. Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: Results of a randomized phase III trial. J Clin Oncol. 2004;22:157–165
  6. Shapiro WR, Smith JA, Patchell RA, et al. Validation of blinded Events Review Committee (ERC)-determined time to neurologic progression (TTNP) demonstrates correlation with survival, radiologic progression, and functional independence endpoints. [Abstract] J Clin Oncol. 2005;23:122s
  7. Lecane P, Karaman MW, Sirisawad M, et al. Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005;65:1–13
  8. Magda D, Lecane P, Miller RA, et al. Motexafin gadolinium disrupts zinc metabolism in human cancer cell lines. Cancer Res. 2005;65:3837–3845
  9. Hashemy SI, Ungerstedt JS, Avval FZ, et al. Motexafin gadolinium, a tumor-selective drug targeting thioredoxin reductase and ribonucleotide reductase and ribonucleotide reducatase. J Biol Chem. 2006;281:10691–10697
  10. Kakolyris S, Giatromanolaki A, Koukourakis M, et al. Thioredoxin expression is associated with lymph node status and prognosis in early operable non-small cell lung cancer. Clin Cancer Res. 2001;7:3087–3091
  11. Rosenthal DI, Nurenberg P, Becerra CR, et al. A phase I single-dose trial of gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer detectable by magnetic resonance imaging. Clin Cancer Res. 1999;5:739–745
  12. Viala J, Vanel D, Meingan P, et al. Phases IB and II multidose trial of gadolinium texaphyrin, a radiation sensitizer detectable at MR imaging: Preliminary results in brain metastases. Radiology. 1999;212:755–759
  13. Carde P, Timmerman R, Mehta MP, et al. Multicenter phase Ib/II trial of the radiation enhancer motexafin gadolinium in patients with brain metastases. J Clin Oncol. 2001;19:2074–2083
  14. Xu S, Zakian K, Thaler H, et al. Effects of motexafin gadolinium on tumor metabolism and radiation sensitivity. Int J Radiat Oncol Biol Phys. 2001;49:1381–1390
  15. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Bull World Health Org. 2001;79:373–374
  16. Wei LJ, Lachin JM. Properties of the urn randomization in clinical trials [published erratum appears in Control Clin Trials 1989;10; following 126]. Control Clin Trials. 1988;9:345–364
  17. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481
  18. Halfdanarson TR, Hogan WJ, Moynihan TJ. Oncologic emergencies: Diagnosis and treatment. Mayo Clin Proc. 2006;81:835–848
  19. Robinet G, Thomas P, Breton JL, et al. Result of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Francais de Pneumo-Cancerologie (GFPC) Protocol 95-1. Ann Oncol. 2001;12:59–67

 Supported by Pharmacyclics, Inc., Sunnyvale, CA.

 Conflict of interest: the study was sponsored by Pharmacyclics, Inc.; the following authors are (or were during the study period) employees and shareholders of Pharmacyclics, Inc.: See-Chun Phan, M.D., Jennifer Smith, Ph.D., Richard Miller, M.D., and Markus Renschler, M.D.

PII: S0360-3016(08)02953-2

doi: 10.1016/j.ijrobp.2008.05.068

International Journal of Radiation Oncology * Biology * Physics
Volume 73, Issue 4 , Pages 1069-1076 , 15 March 2009

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