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Originally published as JCO Early Release 10.1200/JCO.2003.07.080 on August 11 2003 © 2003 American Society for Clinical Oncology
The Use of the Mini-Mental State Examination to Assess Cognitive Functioning in Cancer Trials: No Ifs, Ands, Buts, or SensitivityUniversity of Texas M.D. Anderson Cancer Center, Houston, TX THE IMPORTANCE of addressing the cognitive effects of radiation therapy in patients with low-grade brain tumors is imperative because there is considerable controversy surrounding whether such treatment should be delivered initially or delayed until progression is detected, as a result of concern for potential neurotoxic side effects. The debate centers on the issue of administering early therapy to postpone relapse and to possibly preserve cognitive function as opposed to deferring treatment and potentially sparing cognitive deterioration caused by radiation.1,2 These issues can only be examined in the context of clinical trials that use multifaceted end points that include cognitive function.3 Assessing patient functional outcome in addition to time to progression and survival also coincides with the research priorities set forth by the Brain Tumor Progress Review Group, cosponsored by the National Cancer Institute and the National Institute of Neurological Disorders and Stroke.4
In a recent issue of the Journal of Clinical Oncology, Brown et al5 reported the findings of a large, collaborative, longitudinal trial with long-term follow-up of the cognitive function of patients with low-grade glioma. They reported that few patients developed cognitive decline after treatment, many patients with abnormal pretreatment scores improved over time, and most patients remained stable. Unfortunately, they used the Mini-Mental State Examination (MMSE), a screening tool that sadly is widely used in this setting, despite the fact that it is unable to make these types of determinations. The MMSE is a screen for dementia, and it is true that there is little chance of incorrectly diagnosing cognitive impairment when a person performs in the markedly abnormal range. However, performance in the supposedly normal range (score In this study, improvement over time on the MMSE may simply have been due to practice effects rather than due to any change in neurologic status; some patients were administered the MMSE up to 13 times. Moreover, the sensitivity of the MMSE in a brain tumor population is dismal. We administered the MMSE in conjunction with a comprehensive neuropsychological evaluation to a consecutive series of 67 brain tumor patients to assess the diagnostic accuracy of the MMSE. Using each patient’s performance on the comprehensive evaluation to determine whether they were impaired (ie, performance on two or more tests at the seventh percentile or below), we found that 52 patients were classified as impaired on the basis of the neuropsychological battery, whereas only 26 of those 52 patients were considered abnormal on the basis of the MMSE (using the same criteria as Brown et al5 to determine abnormality; ie, MMSE at the 25th percentile or below). This yields an unacceptably poor sensitivity of only 0.50 (95% CI, 0.36 to 0.64), essentially a coin toss for classification purposes.
One study assessing the neurotoxicity of a mitotic inhibitor used the MMSE and a brief test of memory function.6 Figure 1
Conversely, treatment can conceivably delay the time to expected cognitive decline in brain tumor patients. This was found in a large phase III randomized trial of motexafin gadolinium (MGd), which was used as a radiation sensitizer in patients with brain metastases.7 The addition of MGd to whole-brain radiation seemed to improve memory and executive function, and to prolong time to neurocognitive progression in patients with brain metastases from lung cancer. This study incorporated a brief cognitive test battery that took an average of 23 minutes to administer.8 A screening tool such as the MMSE would not have been able to detect such changes, which are of great significance to the patients and also to pharmaceutical companies that want to demonstrate benefit of a drug to attain US Food and Drug Administration approval. Thus, the risks versus benefits of various treatments on cognitive function, especially those that do not significantly alter survival or time to progression, cannot be determined with the MMSE. Formal, objective, and standardized neurocognitive testing is a sensitive measure of brain functioning. Furthermore, it has been demonstrated that the combination of clinical prognostic variables and brain function assessments seem to predict survival better than the prognostic variables alone in primary brain tumor patients,9 and in patients with leptomeningeal or parenchymal brain metastases.7,10 Again, a screening tool such as the MMSE has not been demonstrated to predict survival in cancer populations. The MMSE also does not measure cognitive functions that are likely to be affected by radiation therapy. It contains items that briefly assess aphasia, apraxia, orientation, and attention. However, the cognitive functions affected by radiation are related to frontal-subcortical white matter dysfunction and include impairments of learning and memory, processing speed, executive function, and fine motor control.11 It cannot be expected that these impairments will be detected by the MMSE. As described above, there has been ample demonstration that brief neurocognitive test batteries are feasible and well tolerated by patients in large clinical trials, and that they yield important and unique information regarding treatment effects. There has been some reluctance to use more sensitive cognitive test batteries because of concerns about increased cost. However, the ability to detect meaningful cognitive deterioration and improvement in clinical trials—to assist ultimately in medical decision making and to inform accurately the drug approval process—is crucial. The use of a screening tool that lacks adequate sensitivity and that may provide misleading information is not a wise use of money and resources.12 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the past 2 years: Christina A. Meyers, Schering-Plough. Performed contract work within the past 2 years: Christina A. Meyers, Pharmacyclis.
REFERENCES
1. Lunsford LD, Kondziolka D: Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients. Neurology 57:2150–2151, 2001
2. Peterson K, DeAngelis L: Weighing the benefits and risks of radiation therapy for low-grade glioma. Neurology 56:1255–1256, 2001 3. Meyers CA, Hess KR: Multifaceted end points in brain tumor clinical trials: Cognitive deterioration precedes MRI progression. Neurooncology 5:89–95, 2003[Abstract] 4. 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
5. Brown PD, Buckner JC, O’Fallon JR, et al: The effects of radiotherapy on cognitive function in patients with low-grade glioma as measured by the Folstein Mini-Mental State Examination. J Clin Oncol 21:2519–2524, 2003 6. Meyers CA, Kudelka AP, Conrad CA, et al: Neurotoxicity of CI-980, a novel mitotic inhibitor. Clin Cancer Res 3:419–422, 1997[Abstract] 7. Meyers CA, Mehta MP, Rodrigus P, et al: Motexafin gadolinium (MGD) delays neurocognitive progression in patients with brain metastases from lung cancer: Results of a randomized phase III trial. Neurooncology 4:372, 2002
8. 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 MRI, neurocognitive, and neurologic endpoints. J Clin Oncol 20:3445–3453, 2002
9. Meyers CA, Hess KR, Yung WKA, et al: Cognitive function as a predictor of survival in patients with recurrent malignant glioma. J Clin Oncol 18:646–650, 2000 10. Sherman AM, Jaeckle K, Meyers CA: Pre-treatment cognitive performance predicts survival in patients with leptomeningeal disease. Cancer 95:1311–1366, 2002[CrossRef][Medline] 11. Meyers CA, Geara F, Wong P, et al: Neurocognitive effects of therapeutic irradiation for base of skull tumors. Int J Radiat Oncol Biol Phys 46:51–55, 2000[CrossRef][Medline] 12. Meyers CA: Neuropsychological assessment and treatment of patients with malignant brain tumors. In Prigatano GP, Pliskin N (eds): Clinical Neuropsychology and Cost Outcome Research: A Beginning. New York, NY, Psychology Press, 2003
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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27 of 30 possible points) does not mean that the individual is free of significant cognitive problems, nor does stability of the MMSE score over time mean that the person has not experienced significant changes, either for better or for worse. 
