Letters To The Editor

Dear Editor,

A recent article in this journal evaluating the significance of progression-free survival as a major end point in neuro-oncology clinical trials (Progression-free survival: An important end point in evaluating therapy for recurrent high-grade gliomas [Neuro-Oncology 2008;10: 162–170]) stated that, due to the lack of validated instruments for the assessment of symptomatic end points, time to symptom deterioration would probably not be a useful end point.¹ To readers less familiar with this literature, that statement may obscure the fact that, especially for neurocognitive function, validated instruments exist and are currently used, that the feasibility and tolerability of neurocognitive assessment in brain tumor patients has been well demonstrated, and that neurocognitive outcomes are increasingly being incorporated into clinical trials of new antineoplastic agents.² Cognitive dysfunction predicts survival better than clinical prognostic factors alone in patients with primary brain tumors, leptomeningeal disease, and parenchymal brain metastases.^3–6 There is also evidence that neurocognitive decline may precede progression on neuroimaging, suggesting that neurocognitive surveillance may be more sensitive to tumor progression than MRI.^6–8 These alternative end points can be considered in the drug approval process. For one agent, the U.S. Food and Drug Administration (FDA) indicated that “radiological response alone is not acceptable for approval. However, improvement in neurocognitive function or delay in neurocognitive progression are acceptable endpoints” (minutes of end-of-phase II meeting, 10/21/98). The conclusion of a workshop sponsored by the FDA, American Association for Cancer Research, and American Society of Clinical Oncology evaluating end points for registrational trials of new agents to treat primary brain cancer stated that “the limitations of imaging-based assessment can in part be ameliorated by incorporation of additional clinically observed, neurocognitive, and patient reported outcomes into a composite progression endpoint.”⁹

Management of this disease remains difficult, and long-term survival, if achieved, is often accompanied by significant disability. Thus, freedom from symptomatic progression in itself represents a benefit. This issue was highlighted by the report of the Brain Tumor Progress Review Group,¹⁰ which stated that there was an immediate need to measure quality of life and other surrogate benefit markers to better assess therapeutic response in all brain tumor clinical trials. Longer life and better life should be integrated; longer life is only truly beneficial if it is better life.

Sincerely,