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

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 postcontrast 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.

Natural History of Vestibular Schwannoma Growth and Hearing Decline in Newly Diagnosed Neurofibromatosis Type 2 Patients

“…Following recent recommendations for hearing endpoints in NF2-related VS trials 13 , hearing decline was defined as a statistically significant decrease in word recognition score (p < 0.05) compared to the baseline either due to tumor progression or to surgery. Patients were eligible for progressive hearing decline if their baseline word recognition score was ≥ 6% on a 50-word list (i.e., allowed for a measurable decrease below the lower limit of the critical difference threshold -the "floor effect").…”

“…13 Survival times were calculated from the first study assessment after enrollment until the study closed in 2005. Tumor shrinkage was defined as a decrease in tumor volume of greater than or equal to 20% compared to baseline value on at least 1 measurement.…”

“…Figures for these subsets of patients may be more useful for modeling clinical trial data, as the uncertainty of measuring hearing improvement in VS with WRS > 90% 13 and the increased variability in volumetric measurement of small VS 26 have been used as the rationale for defining a minimum tumor size and maximum hearing level for entry into NF2 clinical trials.…”

Bevacizumab for Progressive Vestibular Schwannoma in Neurofibromatosis Type 2

“…Radiographic progression was defined as either (1) an increase in tumor volume of 20% or more on the most recent MRI study compared to the pretreatment baseline, or (2) surgery for the target vestibular schwannoma. 21 Survival times were calculated from the start of bevacizumab treatment until analysis was closed on 4/1/2011. Tumor size and hearing function in patients on drug holidays due to adverse events, surgical treatment of non-vestibular tumors, or insurance coverage issues were included in the analysis.…”

Recommendations for imaging tumor response in neurofibromatosis clinical trials

“…29 Volumetric analysis of MRIs has been recommended to determine changes in tumor size 30 and has been incorporated into clinical trials targeting NF2-related VS. 17,18,31 Guidelines for response evaluation of benign NF tumors in clinical trials. Image acquisition and analysis.…”