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Effects of Radiotherapy on Cognitive Function in Patients With Low-Grade Glioma Measured by the Folstein Mini-Mental State Examination

Paul D. Brown, Jan C. Buckner, Judith R. O’Fallon, Nancy L. Iturria, Cerise A. Brown, Brian P. O’Neill, Bernd W. Scheithauer, Robert P. Dinapoli, Robert M. Arusell, Walter J. Curran, Ross Abrams, Edward G. Shaw

From the Mayo Clinic, Rochester, MN; Roger Maris Cancer Center, Fargo, ND; Radiation Therapy Oncology Group (RTOG) Operations Office, Philadelphia, PA; and Wake Forest University, School of Medicine, Winston-Salem, NC.

Address reprint requests to Paul D. Brown, MD, Division of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

	ABSTRACT

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Purpose: To assess the neurocognitive effects of cranial radiotherapy on patients with low-grade gliomas, we analyzed cognitive performance data collected in a prospective, intergroup clinical trial.

Methods: Patients included 203 adults with supratentorial low-grade gliomas randomly assigned to a lower dose (50.4 Gy in 28 fractions) or a higher dose (64.8 Gy in 36 fractions) of localized radiotherapy. Folstein Mini-Mental State Examination (MMSE) scores and neurologic function scores (NFS) at baseline and key evaluations were analyzed. Median follow-up was 7.4 years in 101 patients still alive. A change of more than three MMSE points was considered clinically significant.

Results: In patients without tumor progression, significant deterioration from baseline occurred at years 1, 2, and 5 in 8.2%, 4.6%, and 5.3% of patients, respectively. Most patients with an abnormal baseline MMSE score (< 27) experienced significant increases. Baseline variables such as radiation dose, conformal versus conventional radiotherapy, number of radiation fields, age, sex, tumor size, NFS, seizures, and seizure medications did not predict cognitive function changes.

Conclusion: In this population, most low-grade glioma patients maintained a stable neurocognitive status after focal radiotherapy as measured by the MMSE. Patients with an abnormal baseline MMSE were more likely to have an improvement in cognitive abilities than deterioration after receiving radiotherapy. Only a small percentage of patients had cognitive deterioration after radiotherapy. However, more discriminating neurocognitive assessment tools may identify cognitive decline not apparent with the use of the MMSE.

	INTRODUCTION

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THE ROLE of cranial radiotherapy in the management of low-grade gliomas has generated much controversy in the neuro-oncology community.^1–10 This controversy continues even after the reporting of three prospective, randomized phase III clinical trials.^11–13 Part of the controversy stems from concerns about potential morbidity after cranial radiotherapy. The effect of radiotherapy on long-term cognitive performance of patients treated for intracranial neoplasms is an important question. Data from the North Central Cancer Treatment Group (NCCTG) indicate that, over time, radiotherapy and chemotherapy have a limited effect on neurocognition in patients with high-grade gliomas.¹⁴ However, because of the rapid progression of high-grade gliomas, the data from this group cannot address the effect of radiotherapy on long-term cognitive outcome. Patients with low-grade gliomas have an expected progression-free survival that is much longer than that for patients with high-grade gliomas. A study analyzing the cognitive function of patients with low-grade gliomas before and after radiotherapy would provide insight into the long-term effect of radiotherapy on cognitive performance. Therefore, in a prospective manner, we assessed the effect of radiotherapy on the cognitive abilities of 203 patients with low-grade gliomas entered onto an intergroup trial,¹³ using the Folstein Mini-Mental State Examination (MMSE), a well-validated screening test for dementia and cognitive impairment.^15–19

	METHODS

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Patients
We analyzed cognitive performance data collected in a prospective intergroup trial (NCCTG 86–72-51)¹³ in which patients with supratentorial low-grade gliomas were randomly assigned to receive a lower or higher dose of localized radiotherapy. This trial enrolled adult patients (age ≥ 18 years) with completely or incompletely resected World Health Organization (WHO) grade 2 astrocytoma, oligodendroglioma, or mixed oligoastrocytomas (pilocytic astrocytomas and other low-grade glioma variants were excluded). Patient accrual occurred from 1986 to 1994. Central pathologic review was performed at Mayo Clinic (Rochester, MN) by one of the authors (B.W.S.). Informed consent was obtained before patients were enrolled into the trial. The study was approved by the institutional review boards for all sites that participated in the trial.

Treatment
In both treatment arms, radiotherapy fields were localized and included the preoperative tumor volume (as defined by computed tomography in the earlier years of the study and by magnetic resonance imaging in the later years) and a 2-cm margin. Patients in the lower-dose arm received a total dose of 50.4 Gy in 28 fractions. Patients in the higher-dose arm received an additional 14.4 Gy in eight fractions to the preoperative tumor volume (with a 1-cm margin), for a total dose of 64.8 Gy. Per protocol, the patients did not receive chemotherapy, although after progression a patient could receive chemotherapy off protocol.

Patient Evaluations
At study entry (baseline) and after the completion of protocol therapy (every 4 months for 2 years, every 6 months for 3 years, and yearly until year 15), patients had a physical examination that included a neurologic examination, a determination of the neurologic function score (NFS; Table 1), an MMSE,¹⁵ assessment of toxicity, and computed tomography or magnetic resonance imaging. The MMSE is a brief, standardized tool to grade patients’ cognitive function. The MMSE begins with an assessment of orientation to place and time. A maximum of 10 points may be obtained on this section (the number of points provides a subscore). A test of memory has the subject immediately repeat the names of three objects presented orally. After this, the patient subtracts sevens serially from 100. The subject is then asked to recall the three items previously repeated. The final section evaluates aphasia and apraxia by testing naming, repetition, compliance with a three-step command, comprehension of written words, writing, and copying a drawing for a total of nine points in this section. The maximum score that can be obtained for the entire MMSE is 30 points.

Data Analysis
Evaluations performed at baseline and approximately 1, 2, and 5 years after study entry were designated as key evaluations. Patients were included in the analysis of the data gathered at a key evaluation point if they were evaluated within 60 days of the specified time. This 60-day window was increased to 120 days for year 5 because patients were receiving annual follow-up at that point. At each key evaluation, participants were classified as progressors or nonprogressors according to whether they met the criteria for disease progression by the end of the interval. A decrease of more than three points in the MMSE score was considered to represent clinically significant deterioration.¹⁹ Partly on the basis of this definition and because MMSE scores of 26 or less would be in the lower quartile of scores for an age-matched reference group,²⁰ we defined as "normal" patients with an MMSE of 27 to 30 and as "abnormal" patients with an MMSE of 26 or less.

Proportions of the population with a specific characteristic were estimated with binomial point estimators and 95% confidence intervals. For categorical variables, cross-tabulations were generated, and Wilcoxon tests (for ordered variables) and ² tests (for unordered variables) were used to compare their distributions. For continuous variables, Wilcoxon tests were used to compare the distributions between subsets of patients classified by categorical data. Also, for several continuous variables (eg, age, MMSE score), categorical variables were defined to create scientifically appropriate groups (eg, conventional radiotherapy defined as two or fewer radiation fields, conformal radiotherapy defined as three or more fields). Linear correlation between pairs of variables was assessed using Spearman rank correlation coefficients.

	RESULTS

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Patient Characteristics
MMSE data were recorded at baseline for 187 (92%) of the 203 patients. The mean MMSE at baseline was 27.87 (median, 29; range, 2 to 30). Table 2, which summarizes the baseline characteristics for patients with abnormal baseline MMSE scores (0 through 26) and those with normal baseline MMSE scores (27 through 30) shows that the two groups were similar in most respects, although a significantly smaller percentage of patients in the group with abnormal MMSE scores had a normal baseline NFS.

Baseline Variables and Change in MMSE Score
To identify associations between possibly predictive baseline variables and changes in cognitive function after cranial radiotherapy, we classified patients according to their MMSE status (clinically significant increase in score, stable score, clinically significant decrease in score) at each key evaluation and compared the distributions of their baseline variables. Among these three cognitive groups, no significant differences were found at any key evaluations in the distributions of age, sex, tumor size, tumor location, tumor histologic type, NFS, seizures, seizure medication, radiation dose, conventional versus conformal radiotherapy (conventional defined as two or fewer fields, conformal defined as three or more fields), and number of radiation fields. A detailed review of the changes in MMSE score by the randomization arms of radiation dose (Table 4) revealed no clear trend for better or worse neurocognitive outcome in the higher-dose arm of 64.8 Gy.

At year 1, MMSE subscores were available for 88 (91%) of the 97 patients who had both baseline and year 1 examinations. Of these 88, 38 missed at least one point. Patients lost points most frequently on recall and orientation to time. In contrast, the 10 patients with abnormal MMSE scores at year 1 most frequently lost points on recall and serial sevens.

At year 2, MMSE subscores were available for 62 of the 65 patients (95%) who had both baseline and year 2 examinations. Of these 62, 16 missed at least one point. They missed points most frequently on recall and serial sevens. The eight patients with abnormal MMSE scores at year 2 lost points most frequently on language and orientation.

At year 5, MMSE subscores were available for 37 (97%) of the 38 patients who had both baseline and year 5 examinations. Of the 37, seven patients missed at least one point. Points most frequently were lost on recall and language. All three patients with abnormal MMSE scores at year 5 lost points on serial sevens and language.

Missing Values
MMSE scores were not recorded at each key evaluation for many patients in whom there was no tumor progression (Table 3). To identify possible biases introduced because of this, we compared the baseline characteristics of patients who had no tumor progression and no MMSE scores with the characteristics of patients who had no tumor progression but did have MMSE scores. There were no statistically significant differences between the two groups except for a better year 5 NFS in the latter group (data not shown). The lack of significant differences suggests patients without tumor progression but with MMSE scores are representative of all patients without tumor progression.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Whether cranial radiotherapy results in an unacceptably high level of cognitive decline is an important question for patients and their families. We addressed this question using MMSE data recorded for 203 adults with supratentorial low-grade gliomas who were enrolled onto a large, intergroup, randomized clinical trial designed to assess the effectiveness of a lower dose (50.4 Gy in 28 fractions) or a higher dose (64.8 Gy in 36 fractions) of localized radiotherapy. There were no significant differences in time to progression or survival between the treatment arms.¹³

Only a small proportion of patients experienced a clinically significant decrease in their MMSE score from baseline. In contrast, most patients with an abnormal baseline MMSE score experienced a clinically significant increase. Although the confidence interval estimates overlap because of decreasing sample sizes, there was no trend indicating a significant decline in cognitive performance over time at any key evaluation point. By analyzing patients with an abnormal baseline MMSE score separately from those with a normal baseline MMSE score (≥ 27), we found that the vast majority of patients with a normal baseline MMSE score maintained neurocognitive function after brain irradiation. In patients with an abnormal baseline MMSE score, cognitive improvement and cognitive deterioration were equally likely after radiotherapy. Consistent with these findings, in a subset of 19 patients entered during the early years of the intergroup trial, no significant loss of intellectual, new learning, or memory function occurred in the low-dose and high-dose groups for up to 5 years after radiotherapy.²¹

The results of our review of patients with low-grade glioma mirror the results reported by Taylor et al¹⁴ in their review of patients with high-grade glioma treated at the North Central Cancer Treatment Group. In two consecutive prospective randomized treatment trials, 701 patients received radiotherapy and chemotherapy. Baseline MMSE scores and scores at serial evaluations were analyzed to identify any cognitive changes over time. No statistically significant increase in the percentage of patients experiencing a clinically significant decrease in their MMSE score was found. Patients with tumor progression at the 6- or 12-month evaluation point had significantly lower baseline MMSE scores than nonprogressors. The authors concluded that there was no clear trend to cognitive worsening related to therapy. Older age, poorer performance score, and subclinical tumor progression were the most important factors in patients who did demonstrate cognitive decline.

Neurocognitive deficits from radiotherapy can take years to develop. An inherent limitation of the study by Taylor et al¹⁴ is the short survival of patients with high-grade gliomas. Only 8.3% of the study participants were alive without progression 24 months after radiotherapy. Late radiation neurotoxicity may need more time to develop.^22–25 In our current study of patients with low-grade gliomas, the median time to progression and survival are 5.5 and 8.4 years, respectively. More than 30% of patients are alive without progression 10 years after radiotherapy, which is sufficient time for neurocognitive deficits to develop because most late radiation neurotoxicity occurs within 3 years.^22–25

Other retrospective²⁶ and prospective²⁷ studies have performed batteries of neuropsychologic tests and not found significant neurocognitive deficits after focal conventionally fractionated radiotherapy. This is in contrast to the neurocognitive deficits seen in patients treated with whole-brain radiotherapy, especially when large fraction sizes are used.²⁸ The negative impact of whole-brain radiotherapy in patients with low-grade gliomas was confirmed recently by a retrospective study conducted at the University of Helsinki.²⁹ Others have compared the long-term neurocognitive effects of whole-brain radiotherapy and partial-brain irradiation in adult patients with brain tumors and found more neurocognitive deficits in patients treated with whole-brain radiotherapy.³⁰ Gregor et al³¹ performed a battery of neuropsychologic testing on a cohort of adult brain tumor patients in remission more than 4 years after radiotherapy and found a seven-fold greater chance of developing significant neuropsychometric impairment after whole-brain radiotherapy as compared with focal radiotherapy. These studies possibly explain the lack of neurocognitive decline in our series of patients treated on an intergroup study with focal radiotherapy and small fraction sizes.

In our analysis, we found no relationship between radiation dose and decrease in MMSE score. Kiebert et al³² did find some negative impact of higher doses of radiotherapy when they reviewed the European Organization for Research and Treatment of Cancer (EORTC) phase III study comparing the results of high-dose (59.4 Gy in 6.5 weeks) and low-dose (45 Gy in 5 weeks) radiotherapy for patients with low-grade cerebral gliomas. The different measurement tools could account for the dissimilar result between these two studies. The NCCTG-led intergroup trial used the MMSE, whereas the EORTC study used a quality-of-life questionnaire consisting of 47 items assessing physical, psychologic, social, and symptom domains to measure the effects of treatment over time. The EORTC study found statistically significant differences between the treatment groups for fatigue/malaise and insomnia immediately after radiotherapy and for leisure time and emotional functioning at 7 to 15 months after randomization favoring the low-dose arm.

A recently reported trial from Duke University³³ and the previously mentioned study from the Netherlands²⁶ found that patients with left-sided brain tumors had more neurocognitive deficits on extensive testing. In our review, we did not find location of tumor by hemisphere to be predictive of cognitive outcome, possibly because the MMSE is insensitive to subtler neurocognitive deficits.

Tumor progression itself may be an important factor in cognitive decline in patients with brain tumors. Taylor et al¹⁴ suggested that subclinical tumor progression may have a significant effect on cognitive capacity and thus may be a factor in the cognitive decline in some patients. We could not address this issue because of the small number of patients with progression at selected intervals for whom MMSE scores were available.

One of the major difficulties in a study of this type is the insensitivity of the measurement tool. The Folstein MMSE is a well-validated measure of cognitive decline when used to assess dementia.^15–19 High correlation with other, more comprehensive standardized instruments for assessing cognitive function (such as the Wechsler Memory Scale³⁴) and other screening tests (such as the modified Blessed test^35,36) has been reported. However, its validity for patients receiving radiotherapy for brain tumors has not been established. Therefore, although our results suggest that there was no obvious cognitive decline in this patient group, subtle alterations in memory, personality, or intelligence not measurable by such a simple measurement tool may have occurred. Also, tumor site and postsurgical effects may have an undue influence on the predominantly verbal MMSE. Patients with mild aphasia or agnosia may not be adequately assessed by the MMSE.

Only a small percentage of patients with low-grade gliomas were observed to have neurocognitive deterioration after receiving focal radiotherapy. This finding is consistent with the reported literature when whole-brain radiotherapy is not used. However, more discriminating neurocognitive assessment tools may identify cognitive decline not apparent through use of the MMSE.

	ACKNOWLEDGMENTS

 
We thank Debra Kvittem and Jill Burton, Clinical Research Associates, for their expert data management assistance.

	NOTES

 
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grant nos. CA-25224, CA-37404, CA-15083, and CA-35415, and the Linse Bock Foundation, Rochester, MN.

Presented at the Forty-Third Annual Meeting of the American Society for Therapeutic Radiology and Oncology, San Francisco, CA, November 4–8, 2001, and at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001.

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Submitted April 24, 2002; accepted April 8, 2003.

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