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Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma

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Abstract

Neurofibromatosis type 2 (NF2) is a tumor suppressor gene syndrome characterized by multiple schwannomas, especially vestibular schwannomas (VS), and meningiomas. Anticancer drug trials are now being explored, but there are no standardized endpoints in NF2. We review the challenges of NF2 clinical trials and suggest possible response criteria for use in initial phase II studies. We suggest two main response criteria in such trials. Objective radiographic response is defined as a durable 20% or greater reduction in VS volume based on post-contrast T1-weighted MRI images collected with 3 mm or finer cuts through the internal auditory canal. Hearing response is defined as a statistically significant improvement in word recognition scores using 50-word recorded lists in audiology. A possible composite endpoint incorporating both radiographic response and hearing response is outlined. We emphasize pitfalls in response assessment and suggest guidelines to minimize misinterpretations of response. We also identify research goals in NF2 to facilitate future trial conduct, such as identifying the expectations for time to tumor progression and time to measurable hearing loss in untreated NF2-related VS, and the relation of both endpoints to patient prognostic factors (such as age, baseline tumor volume, and measures of disease severity). These data would facilitate future use of endpoints based on stability of tumor size and hearing, which might be more appropriate for testing certain drugs. We encourage adoption of standardized endpoints early in the development of phase II trials for this population to facilitate comparison of results across trials of different agents.

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Authors and Affiliations

  1. Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA, USA

    Scott R. Plotkin

  2. Audiology Department, Massachusetts Eye and Ear Infirmary, Boston, MA, USA

    Chris Halpin

  3. Department of Neurology, Johns Hopkins Medical Institute, Baltimore, MD, USA

    Jaishri O. Blakeley

  4. Department of Otolaryngology, House Ear Institute, Los Angeles, CA, USA

    William H. Slattery III

  5. Department of Otolaryngology, Ohio State University, Columbus, OH, USA

    D. Bradley Welling

  6. Department of Neurological Surgery, University of California, San Francisco, CA, USA

    Susan M. Chang

  7. Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA

    Jay S. Loeffler

  8. Department of Radiology, Massachusetts General Hospital, Boston, MA, USA

    Gordon J. Harris & A. Gregory Sorensen

  9. Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA

    Michael J. McKenna

  10. Neurosurgical Service, Pappas Center for Neuro-Oncology, Yawkey 9E, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA

    Fred G. Barker II

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Correspondence to Fred G. Barker II.

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Plotkin, S.R., Halpin, C., Blakeley, J.O. et al. Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma. J Neurooncol 93, 61–77 (2009). https://doi.org/10.1007/s11060-009-9867-7

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