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Letters to the Editor |
Department of Neuro-Oncology (C.A.M.), The University of Texas M. D. Anderson Cancer Center, Houston, TX; Department of Neurological Surgery (K.R.L., M.D.P.), University of California San Francisco, San Francisco, CA; USA
Address correspondence to Christina A. Meyers, Ph.D., Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030 (cameyers{at}mdanderson.org).
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,
Received for publication May 13, 2008. Accepted for publication June 3, 2008.
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References |
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 Top References |
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Lamborn KR, Yung WKA, Chang SM, et al. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro-Oncology. 2008;10(2): 162-170.
Meyers C, Brown P. Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. J Clin Oncol. 2006;24: 1305-1309.
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.
Sherman AM, Jaeckle K, Meyers CA. Pretreatment cognitive performance predicts survival in patients with leptomeningeal disease. Cancer. 2002;15: 1311-1316.
Meyers CA, Hess KR, Yung WKA, Levin VA. Cognitive function as a predictor of survival in patients with recurrent malignant glioma. J Clin Oncol. 2000;18: 646-650.
Taphoorn MJ, Klein M. Cognitive deficits in adult patients with brain tumours. Lancet Neurol. 2004;3: 159-168.[CrossRef][Web of Science][Medline]
Meyers CA, Hess KR. Multifaceted end points in brain tumor clinical trials: cognitive deterioration precedes MRI progression. Neuro-Oncology. 2003;5: 89-95.[Abstract]
Brown PD, Jensen AW, Felten SJ, et al. Detrimental effects of tumor progression on cognitive function of patients with high-grade glioma. J Clin Oncol. 2006 24(34): 5427-5433.
U.S. Food and Drug Administration. Primary Brain Tumor Endpoints: AACR/FDA Public Workshop on Clinical Trial End Points in Primary Brain Tumors, January 20, 2006. http://www.fda.gov/cder/drug/cancer_endpoints.
National Cancer Institute, National Institute of Neurological Disorders and Stroke. Report of the Brain Tumor Progress Review Group, November 2000. http://osp.nci.nih.gov/Prg_assess/PRG/BTPRG.
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