A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results

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✓ As survival rates have risen for children with malignant primary brain tumors, so has the concern that many survivors have significant permanent cognitive deficits. Cranial irradiation (CRT) has been implicated as the major cause for cognitive dysfunction. To clarify the etiology, incidence, and severity of intellectual compromise in children with brain tumors after CRT, a prospective study was undertaken comparing the neuropsychological outcome in 18 consecutive children with malignant brain tumors treated with CRT to outcome in 14 children harboring brain tumors in similar sites in the nervous system who had not received CRT. Children with cortical or subcortical brain tumors were not eligible for study. Neuropsychological testing was performed after surgery prior to radiotherapy, after radiotherapy, and at 1- and 2-year intervals thereafter. Children who had received CRT had a mean full-scale intelligence quotient (FSIQ) of 105 at diagnosis which fell to 91 by Year 2. Similar declines were noted in their performance intelligence quotient (IQ) and verbal IQ. After CRT, patients demonstrated a statistically significant decline from baseline in FSIQ (p < 0.02) and verbal IQ (p < 0.04). Children who had not received CRT did not demonstrate a fall in any cognitive parameter over time. The decline between baseline testing and testing performed at Year 2 in patients who had CRT was inversely correlated with age (p < 0.02), as younger children demonstrated the greatest loss of intelligence. Children less than 7 years of age at diagnosis had a mean decline in FSIQ of 25 points 2 years posttreatment. No other clinical parameter correlated with the overall IQ or decline in IQ. After CRT, children demonstrated a wide range of dysfunction including deficits in fine motor, visual-motor, and visual-spatial skills and memory difficulties. After CRT, children with brain tumors also demonstrated a fall in a wide range of achievement scores and an increased need, over time, for special help in school. The 2-year results of this study suggest that children with brain tumors treated with CRT are cognitively impaired and that these deficits worsen over time. The younger the child is at the time of treatment, the greater is the likelihood and severity of damage. These children, although not retarded, have a multitude of neurocognitive deficits which detrimentally affects school performance. New treatment strategies are needed for children with malignant brain tumors.

Abstract

✓ As survival rates have risen for children with malignant primary brain tumors, so has the concern that many survivors have significant permanent cognitive deficits. Cranial irradiation (CRT) has been implicated as the major cause for cognitive dysfunction. To clarify the etiology, incidence, and severity of intellectual compromise in children with brain tumors after CRT, a prospective study was undertaken comparing the neuropsychological outcome in 18 consecutive children with malignant brain tumors treated with CRT to outcome in 14 children harboring brain tumors in similar sites in the nervous system who had not received CRT. Children with cortical or subcortical brain tumors were not eligible for study. Neuropsychological testing was performed after surgery prior to radiotherapy, after radiotherapy, and at 1- and 2-year intervals thereafter. Children who had received CRT had a mean full-scale intelligence quotient (FSIQ) of 105 at diagnosis which fell to 91 by Year 2. Similar declines were noted in their performance intelligence quotient (IQ) and verbal IQ. After CRT, patients demonstrated a statistically significant decline from baseline in FSIQ (p < 0.02) and verbal IQ (p < 0.04). Children who had not received CRT did not demonstrate a fall in any cognitive parameter over time. The decline between baseline testing and testing performed at Year 2 in patients who had CRT was inversely correlated with age (p < 0.02), as younger children demonstrated the greatest loss of intelligence. Children less than 7 years of age at diagnosis had a mean decline in FSIQ of 25 points 2 years posttreatment. No other clinical parameter correlated with the overall IQ or decline in IQ. After CRT, children demonstrated a wide range of dysfunction including deficits in fine motor, visual-motor, and visual-spatial skills and memory difficulties. After CRT, children with brain tumors also demonstrated a fall in a wide range of achievement scores and an increased need, over time, for special help in school. The 2-year results of this study suggest that children with brain tumors treated with CRT are cognitively impaired and that these deficits worsen over time. The younger the child is at the time of treatment, the greater is the likelihood and severity of damage. These children, although not retarded, have a multitude of neurocognitive deficits which detrimentally affects school performance. New treatment strategies are needed for children with malignant brain tumors.

Over one-half of children with primitive neuroectodermal tumors (PNET's)/medulloblastoma of the posterior fossa and many children with other malignant central nervous system (CNS) tumors can be expected to be alive and free of progressive disease 5 years after diagnosis, many apparently cured of their primary illness.24 Several factors are responsible for this improvement in survival times; presymptomatic craniospinal radiation therapy, utilized to eradicate disease which has involved the leptomeninges prior to diagnosis, has been of prime importance.20,24,25 As survival rates have risen, so has the concern that many survivors have significant permanent cognitive deficits which are primarily due to the treatment employed to eradicate their disease.11,21,24,26 Whole-brain radiotherapy has been considered the most likely, if not the sole, reason for cognitive dysfunction.11,21,24,26 The severity of deficits suffered has been variable, with mental retardation reported in 10% to 80% of children with brain tumors after cranial radiation therapy (CRT).7,8,11,21,24,26 Even in those reports suggesting a lower frequency of mental retardation, milder but clinically significant cognitive dysfunction has been documented in the majority of patients.23

The importance of factors other than the amount of radiation received (such as postoperative complications, the direct effects of the tumor, or the effects of associated hydrocephalus on mentation) has not been assessed by most studies and almost all reports of cognitive dysfunction in patients surviving brain tumors have been retrospective in nature.23,24 Despite this, based on the information available, attempts have been made to reduce the amount of radiation given.31 The reduction or deletion of such radiotherapy potentially places patients at higher risk for disease relapse and death. Clarification is needed concerning the incidence and severity of intellectual compromise in children with brain tumors receiving whole-brain radiotherapy, how much of this intellectual compromise is directly related to the radiotherapy, and what other factors may be responsible for cognitive deficits. To address these issues, a prospective neuropsychological study was begun in our institution in 1983 to evaluate all children who were treated with whole-brain radiotherapy for malignant brain tumors that did not directly involve the cerebral cortex. Cognitive function in these children was compared to function in children harboring tumors in similar sites in the CNS who had not received radiotherapy.

Clinical Material and Methods
Patient Selection

Between January, 1983, and January, 1986, all newly diagnosed patients between the ages of 18 months and 18 years who had malignant primary CNS tumors diagnosed and who were treated with whole-brain radiotherapy at Children's Hospital of Philadelphia were eligible for this study. Patients were excluded from study if the tumors at the time of diagnosis involved the cerebral cortex, subcortical white matter, or deep gray masses. Patients included those with posterior fossa PNET's/medulloblastoma, posterior fossa anaplastic gliomas, malignant pineal tumors (pineoblastomas (pineal PNET's) and germinomas), and suprasellar malignant tumors (germinomas). Children under 18 months of age with malignant tumors were excluded from the study, as they were entered into a separate treatment protocol utilizing chemotherapy without radiotherapy. A “control group” of all children with cerebellar astrocytomas, who were treated with surgery and received no further radiotherapy or chemotherapy, underwent identical evaluation. Patients must have remained in continuous progression-free remission for a minimum of 2 years after diagnosis to be included in this analysis (Table 1).

TABLE 1

Characteristics of groups studied*

ParameterGroup AGroup B
no. of cases18 14 
type of treatmentsurgery + RT ± CHT surgery 
median age7.7 yrs 7.7 yrs 
age (range)20 mos – 18 yrs 18 mos – 16.8 yrs 
sex (M/F)14/4 5/9 
no. with full test battery14 9 
no. with IQ test alone4 5 

Groups distinguished by type of treatment. RT = radiotherapy; CHT = chemotherapy; IQ = intelligence quotient.

Initially, a third group of patients, children with posterior fossa tumors treated with local radiotherapy were eligible for this study. Since so few patients in this group survived for 2 years free of progressive disease (almost all of these patients had brain-stem gliomas) they were excluded from this analysis.

Children Receiving Whole-Brain Radiotherapy

Over this time period, 21 children with malignant brain tumors were eligible for study. Two patients with PNET's/medulloblastoma developed progressive disease within 2 years of diagnosis and were excluded from the study. One other child refused follow-up testing 2 years after diagnosis. The remaining 18 patients were included in Group A and underwent serial studies (Table 1). Fifteen had posterior fossa PNET's/medulloblastoma, two had pineal tumors (one PNET and one germinoma), and one had a suprasellar germinoma. There were four girls and 14 boys, with a median age of 7.7 years at the time of diagnosis (range 20 months to 18 years).

Treatment was relatively uniform for these children with malignant tumors. Patients between the ages of 18 months and 36 months of age at the time of diagnosis received 2400 cGy of whole-brain radiotherapy plus a boost of 2400 to 2600 cGy to the primary tumor site (total tumor dose 4800 to 5000 cGy). Patients above 36 months of age at the time of diagnosis received 3600 cGy of whole-brain radiotherapy plus a boost of 1800 to 2000 cGy to the tumor site (total tumor dose 5400 to 5600 cGy).

All patients underwent tumor staging postoperatively, including postoperative computerized tomography (CT) with dye, myelography, and cerebrospinal fluid cytology. Based on these results and previously published criteria, 12 of the 15 children with PNET's/medulloblastoma and the one child with pineoblastoma received postradiation chemotherapy consisting of eight 6-week cycles of cis-platinum (90 mg/sq m intravenously once every 6 weeks), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU, 100 mg/sq m by mouth once weekly every 6 weeks), and vincristine (1.5 mg/sq m intravenously for 3 weeks every 6 weeks).22,24 Patients with germinomas did not receive chemotherapy.

Patients Treated with Surgery Alone

Over this time period, 18 patients were admitted with cerebellar astrocytomas. All patients are alive and free of disease since surgery; however, four patients have refused serial cognitive assessment (Table 1). The remaining 14 were included in Group B (the control group). There were nine girls and five boys, with a median age of 7.7 years at diagnosis (range 18 months to 16.8 years).

Neuropsychological Assessment

The neuropsychological tests performed varied with age. The test battery for children under 5 years of age at diagnosis consisted of the Bayley Mental Scale of Infant Development3 for children between 18 and 24 months of age and Stanford-Binet Intelligence Scale, Form L–M,30 for children between 24 and 60 months of age. For children older than 5 years of age at the time of diagnosis, the neuropsychological battery measured global intelligence, but also assessed other skills, including fine motor, visuospatial, verbal fluency, language, memory and auditory attention abilities (Table 2)4,6,10,12–15,18,27,29,32–34

TABLE 2

Neurocognitive test battery by age group

Age (mos)Tests*
18–24Bayley
25–60Stanford-Binet, L–M
>60WISC-R (WAIS-R, 16 yrs)
fine motor abilities
 finger tapping
 grooved pegboard
visuospacial abilities
 Beery
 colored progressive matrices
verbal fluency
 P, C naming
 token
verbal memory/auditory attention
 Rey
 selective reminding
 sentence repetition

WISC-R = Wechsler Intelligence Scale for Children-Revised. WAIS-R = Wechsler Adult Intelligence Scale-Revised.

All children were evaluated individually and results are compared to appropriate age norms. For the purposes of this analysis, results of fine motor, visuomotor integration, visuoperceptual function, memory, and language abilities were evaluated as normal (⩽ 0.9 standard deviation (SD) below mean); mildly impaired (1 to 1.9 SD below mean); moderately impaired (2.0 to 2.9 SD below mean); and severely impaired (⩾ 3.0 SD below mean). Reading, spelling, and arithmetic skills in school-age children were assessed by the Wide-Range Achievement Test.

Children who received whole-brain radiotherapy were evaluated after surgery prior to radiotherapy, 2 to 4 months following completion of radiotherapy, and at 1-year intervals thereafter. Children who did not receive radiotherapy were tested 3 to 5 months after surgery and at 1-year intervals thereafter.

Means of Analysis

For both groups, information was collected concerning age at diagnosis, sex, duration of symptoms prior to diagnosis, the presence of hydrocephalus at diagnosis, the need for permanent ventriculoperitoneal shunting, and the development of postoperative complications such as bacterial infections, hemorrhage, or prolonged obtundation. For children receiving radiation therapy, additional information was obtained including the extent of disease at the time of diagnosis, the amount of local and whole-brain radiotherapy received, and whether chemotherapy was given.

Differences between groups in the distribution of the clinical and demographic variables and neurocognitive performance were assessed by the Wilcoxon rank sum or chi-square tests. The Wilcoxon signed-rank test for pairs was used to evaluate whether measures of intelligence changed with time.28 Differences between groups in intelligence quotient (IQ) change over time were tested by the Wilcoxon rank sum statistic.28 Within each group, the effects of demographic and clinical factors except for age on baseline cognitive function and on changes in cognitive function after treatment were evaluated by Wilcoxon rank sum or Kruskal-Wallis tests.5 The effect of age on change in IQ was studied by linear regression.

Many children were too ill or irritable to be adequately assessed after surgery prior to radiotherapy, but pre-CRT testing could be performed in 11 of the 18 evaluable patients. The remainder were only tested 2 to 4 months after completion of radiotherapy. For those children who were tested both prior to and within 4 months of completion of radiotherapy, the highest score achieved was considered the baseline result.

Results
Children Receiving Whole-Brain Radiotherapy

Sixteen children in Group A underwent assessment before or just after CRT and again 1 year and/or 2 years later. One child was retested only at 1 year (2-year testing was refused) and one was retested only at 2 years (1-year testing was refused). Fourteen were evaluated with the full test battery, and four who were under 5 years of age at the time of analysis had global intelligence testing alone. Three children, who were eligible by age for the full test battery, were too uncooperative early in the course of their illness to complete any except intelligence testing. The mean full-scale IQ (FSIQ) for children in Group A was 105 at baseline, 97 at Year 1, and 91 at Year 2 (Table 3). Smaller declines were observed in performance IQ (PIQ) and verbal IQ (VIQ). Compared with baseline testing, children demonstrated a statistically significant decline in FSIQ at Year 1 (decrease of 6.6 points, p = 0.04) and at Year 2 (decrease of 13.8 points, p = 0.02), and in VIQ at Year 2 (decrease of 6.8 points, p = 0.04); a marginally significant decline was identified in PIQ at Year 2 (decrease of 9.0 points, p = 0.06). Two years following treatment, two children had FSIQ's below 70 and seven had FSIQ's greater than 100.

TABLE 3

Mean results of intelligence quotient (IQ) testing*

Group & TestBaselineYear 1Year 2
Group A
 full-scale IQ1059791
 verbal IQ109106102
 performance IQ1029797
Group B
 full-scale IQ105109106
 verbal IQ109115108
 performance IQ9811109

For a description of groups, see text.

The decline between baseline testing and testing performance at 2 years in FSIQ (p > 0.002), VIQ (p > 0.001), and PIQ inversely correlated with age (Fig. 1): younger children demonstrated the greatest loss in intelligence. The relationship between a younger age at diagnosis and the decline in PIQ did not reach statistical significance. Two years following completion of CRT, children who were 7 years of age or less at diagnosis had a median FSIQ of 82 (range 50 to 98) as compared to 103 (range 92 to 133) for older children. Children 7 years of age or less at diagnosis had a mean decline of 25 points in FSIQ 2 years posttreatment.

Fig. 1.
Fig. 1.

Scattergram showing the correlation between changes in full-scale intelligence quotient (F.S.I.Q.) results and patients' age.

No other parameter, including the occurrence of postoperative complications or the use of postirradiation chemotherapy, was significantly associated with overall intelligence or change in intelligence over time. Since the radiation dose varied little, it did not significantly correlate with outcome. The three children who received a reduced dose of craniospinal radiation therapy (2400 cGy), who were all less than 3 years of age at the time of diagnosis, had declines of 34, 36, and 37 points in FSIQ between baseline and retesting 2 years later. These patients had FSIQ's of 50, 68, and 87, respectively, 2 years after treatment.

Older children, when tested for selective deficits, showed a wide range of dysfunction, most clearly involving fine motor skills (Table 4). Mild to severe deficits in dominant and, to a slightly lesser degree, in nondominant fine motor hand speed and dexterity were found both at the time of baseline evaluation and at the 2-year follow-up testing in the majority of children (Table 4). This function did not deteriorate over time. Significant visuomotor and visuospatial impairments were infrequent, with only two of 14 subjects having consistent difficulties. Significant memory impairment was evident for only a few children at baseline but at 2 years almost half (42%) performed below the normal range in list learning, while 64% had significant difficulty with immediate auditory recall. In no case was signficant language impairment found, although there is a slight increase at 2 years in the number of children showing mildly reduced verbal fluency.

TABLE 4

Selective impairment in Group A children with malignant tumors*

Function Tested†Baseline2 Years After Irradiation
fine motor function
 speed-dominant6/119/14
 speed-nondominant7/1111/14
 dexterity-dominant5/116/14
 dexterity-nondominant6/1110/14
visuospatial function
 Berry visuomotor2/116/14
 Raven visuospacial1/121/14
memory7/1211/14
language2/117/14

Numbers indicate children showing impairment (see text)/children evaluable; not all children finished the full test battery. Four children who were initially impaired suffered a greater decline in score.

The impact of treatment on school performance was evident in classroom placement. At the time of diagnosis, 11 children in Group A were in school, all in a regular classroom, two repeated their grade and three were in a special-education classroom setting. Two years after completion of radiation therapy, six children were in a regular classroom. One year after completion of radiotherapy, six children remained in a regular classroom and five were receiving special education. The children who remained in a regular classroom setting were older at diagnosis (median 10.5 years of age) compared to those requiring help (7.5 years of age at the time of diagnosis). All seven children who were not yet in school at the time of diagnosis required special-education placement when they began formal education.

Wide-Range Achievement Test scores disclosed that, at the time of baseline examination, patients tended to score more poorly in mathematical function than in reading or spelling. There was a significant decline between baseline testing and retesting at Year 2 in reading (p = 0.03) and spelling (p = 0.03), and a nonsignificant decline in arithmetic (p = 0.01) (Table 4). None of the demographic or clinical parameters, including age, significantly affected the scores or the change in scores.

Children with Benign Tumors

Fourteen Group B children with cerebellar astrocytomas underwent sequential evaluation. Nine children were examined at both Year 1 and Year 2 after diagnosis and five underwent testing at only Year 2. Three patients in this group had FSIQ's ranging between 70 and 80 on initial evaluation. Results of intelligence testing were not significantly associated with any factor. There was no significant decline over time in any measure of intelligence.

Fine motor speed and dexterity was frequently impaired at both baseline and follow-up evaluations, but there was no deterioration over time. Visuomotor abilities were impaired at initial testing in four children and at follow-up testing in five. Visuospatial function was less frequently impaired, as two children at baseline and three children at follow-up evaluation showed mild to moderate impairment. Memory function was relatively well preserved; three patients were impaired at the initial testing time. This did not deteriorate over time, as only two children showed impairment on sequential follow-up testing. Language function was severely impaired in two children at initial testing and in three at follow-up evaluation.

At the time of diagnosis, nine children were already in school, eight in a regular classroom and one in a special-education setting. Two years following surgery, seven children were in a regular classroom, one required tutorial help, and one needed resource-room help. Baseline Wide-Range Achievement Test scores were in the normal range in reading (109), spelling (105), and mathematics (94) for children not receiving CRT and there was no significant decline in academic abilities over time (Table 5). Four of five children who were in school at the time of diagnosis were in a regular classroom setting; the remaining child required a resource-room school placement.

TABLE 5

Results of Wide-Range Achievement Tests

Group & TestBaselineYear 1Year 2
Group A
 reading109102101
 spelling10998102
 arithmetic999192
Group B
 reading109103108
 spelling105101107
 arithmetic949898

Comparison Between Group A and Group B

The patients in Groups A and B did not differ significantly as regards age at diagnosis, sex, preoperative neurological status, or postoperative complications. Full scale IQ, VIQ, and PIQ at diagnosis did not differ between the groups. A significant difference between the two groups was found in the decline in FSIQ (a 14-point decrease in Group A vs. a 1-point gain in Group B, p = 0.05) between baseline testing and repeat testing 2 years later. For PIQ the difference between the two groups approached statistical significance (9-point decrease vs. 11-point gain, p = 0.06). The difference in VIQ decline between the groups was not significant.

Academic performance, in relation to the need for special help in school, was worse in Group A (12 of 18 required special education) as compared to Group B (1 of 14; p = 0.002).

Discussion

The results of this study fit well with clinical impressions that many children with brain tumors who receive CRT are cognitively impaired, and that the younger the child is at the time of treatment, the greater is the likelihood and severity of damage.24 However, information to substantiate these clinical impressions has been sparse and has been primarily extrapolated from studies in children with leukemia who were treated with CRT.9,16,19 Although these primarily retrospective leukemia studies have serious methodological flaws, the majority have shown that after treatment with CRT children with leukemia have a lower FSIQ than patients with leukemia not receiving CRT or than their siblings.21 In a prospective study of 18 survivors of leukemia treated with both CRT and intrathecal methotrexate, Meadows, et al.,17 documented a progressive decline in FSIQ in 11 patients, but this decline only became evident 3 years or more after treatment. Intellectual decline was most marked in children between the ages of 2 and 5 years at the time of diagnosis.

In comparison to the results of the leukemia studies in which most children have received a somewhat lower amount of CRT (1800 to 2400 cGy in the majority of studies) and intrathecal methotrexate, our study disclosed a greater and earlier difference between irradiated and non-irradiated groups in cognitive function as well as in school achievement and placement. The decline in IQ is especially marked (a mean decline in IQ of 25) in children less than 7 years old.

Cognitive studies in children with brain tumors are sparse and primarily retrospective in nature. In 1979, Raimondi and Tomita26 reported that only three of 15 children surviving medulloblastoma who had been treated with whole-brain radiotherapy had FSIQ scores of greater than 80. However, the patients in their study had received higher doses of CRT (between 4000 and 5000 cGy) than is now conventionally given. In a study of six children with medulloblastoma who were treated with 2635 to 4000 rads of CRT, Duffner, et al.,8 found IQ scores of less than 80 in three patients; but these patients had also received intrathecal and intravenous methotrexate. In probably the most compelling study to date, Hirsch, et al.,11 retrospectively found significant intellectual problems in 28 children surviving medulloblastoma who had been treated with 3500 cGy of whole-brain radiotherapy and received 5000 cGy to the posterior fossa. One-third of patients in that study had also received intrathecal methotrexate. Thirty-one percent of the children had IQ's below 70 and 58% had IQ's ranging between 80 and 90. Our prospective study, however, does not confirm this severe degree of intellectual impairment in children following treatment and it is impossible to determine how much impairment the patients in the Hirsch report had sustained prior to receiving whole-brain radiotherapy. With the advent of CT and other noninvasive means to diagnose these patients earlier, it is conceivable that children with brain tumors are now being diagnosed earlier and have suffered less damage at the time of diagnosis. It is also possible that other advances in treatment, including better surgical techniques and postoperative care, are decreasing the incidence of severe brain damage prior to the initiation of treatment.

In a previous publication describing the outcome of 24 long-term survivors with similar tumors seen in our institution prior to 1984,23 we found associations between overall intelligence and preoperative factors including preoperative obtundation or postoperative complications. Only two patients in the present study were obtunded at the time of diagnosis and only two had significant postoperative complications, so this relationship cannot be confirmed.

The relatively small sample size of our study limits our ability to fully characterize the cognitive deficits in patients after whole-brain radiotherapy. It was clear from our results that patients had other significant difficulties. The majority of patients had some impairment of fine motor function and others had problems with language and visuospatial function. Memory was frequently impaired in children with malignant tumors who received whole-brain radiotherapy, and in four of 12 tested children a decline in memory function could be documented over time. It is conceivable that a larger study will show a clearer association between whole-brain radiotherapy and a decline in memory over time.

The results at 2 years in our population did not document a significant decline in IQ over time in older children, especially in those 10 years of age or greater at the time of diagnosis. A longer follow-up duration may demonstrate such a relationship, but it seems unlikely that the amount of intellectual impairment will be as severe as in our younger children. Three-year follow-up studies have been performed in seven children to date. In those who demonstrated a rapid decline in FSIQ between baseline testing and 2 years of age, a further decline in intelligence could not be documented, and children 10 years of age or older at diagnosis have shown stable intellectual ability.

The academic performance of children in this study paralleled the results of formal cognitive testing. Children who did not receive radiotherapy, although having occasional selective learning difficulties, were generally able to enter the classroom and succeed at an age-appropriate level. In contradistinction, following treatment with whole-brain radiotherapy the majority of children had significant learning problems and required specialized help to make progress in school. Once again, a relationship was seen between the ability to succeed in school and age diagnosis, as younger children almost uniformly required individualized help in school.

This study could not address other significant issues concerning the relationship between radiotherapy and intellectual decline. All patients in the radiotherapy group also received a local boost of radiotherapy to the posterior fossa. In the majority of patients some cortical areas, especially the temporal lobes, were included in the boost area. It is impossible to exclude the possibility that the local radiotherapy was in part responsible for cognitive sequelae. Initially, this study was to include a third group of patients: children with posterior fossa tumors who received local radiotherapy alone. Since in our institutional experience, so few patients with tumors requiring such therapy survived free of progressive disease, cognitive function could not be compared. In addition, this type of study cannot determine whether the cognitive changes seen represented an inability to gain in intellectual abilities rather than an actual decline in intelligence. The large fall in measured IQ suggests that for the youngest patients, the latter explanation is more likely. In any event, either type of intellectual impairment is devastating in these young children.

In this review, no evidence was found that chemotherapy increased the incidence of intellectual dysfunction. The agents employed (CCNU, vincristine, and cis-platinum) have not been shown to cause intellectual damage. Methotrexate, a known neurotoxic agent which has been linked with development of cognitive dysfunction in children with leukemia, was not employed in any patient in this series. However, the majority of children receiving radiotherapy did receive chemotherapy and this must be closely evaluated in other studies.

In conclusion, this 2-year follow-up of children with noncortical tumor strongly suggests that whole-brain radiotherapy detrimentally effects cognitive function in children with brain tumors. This is especially true in younger patients, and a reduction of radiotherapy to 2400 cGy did not seem to significantly reduce the severity of cognitive loss in the three patients so treated in our series. Recent work has suggested that the addition of chemotherapy may be of benefit for some patients with posterior fossa PNET's/medulloblastoma.1,22 Similarly, a study by Allen, et al.,2 has suggested that chemotherapy may allow for the reduction of radiotherapy in children with germinomas. It seems most likely that chemotherapy will need to be coupled with an even further reduction in the dose of radiotherapy to significantly reduce the degree of intellectual sequelae in children with malignant CNS tumors without increasing the incidence of disease relapse. In any event, studies attempting to alter the type of therapy for children with malignant tumors should prospectively monitor cognitive function, in view of the frequency and severity of the resultant sequelae.

Acknowledgment

We thank Linda Cella for secretarial assistance.

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    Raimondi AJTomita T: Advantages of “total” resection of medulloblastoma and disadvantages of full head postoperative radiation therapy. Childs Brain 5:50591979Childs Brain 5:

  • 27.

    Raven J: Colored Progressive Matrices. London: Lewis and Cox1978Raven J: Colored Progressive Matrices.

  • 28.

    Snedecor GWCochran WG: Statistical Methodsed 7. Ames, Iowa: The Iowa State University Press1980141143

  • 29.

    Taylor E: Psychological Appraisal of Children with Cerebral Defects. Cambridge: Harvard University Press1961423428Taylor E: Psychological Appraisal of Children with Cerebral Defects.

  • 30.

    Terman LMMerrill MA: Boston: Houghton-Mifilin1973

  • 31.

    Tomita TMcLone DG: Medulloblastoma in childhood: results of radical resection and low-dose neuraxis radiation therapy. J Neurosurg 64:2382421986J Neurosurg 64:

  • 32.

    Wechsler D: Wechsler Adult Intelligence Scale-Revised. New York: The Psychological Corp1981Wechsler D: Wechsler Adult Intelligence Scale-Revised.

  • 33.

    Wechsler D: Wechsler Intelligence Scale for Children. New York: The Psychological Corp1949Wechsler D: Wechsler Intelligence Scale for Children.

  • 34.

    Wechsler D: Wechsler Intelligence Scale for Children-Revised. New York: The Psychological Corp1974Wechsler D: Wechsler Intelligence Scale for Children-Revised.

This work was supported in part by the Foerderer Fund for Excellence: Neuro-Oncology, and the Eagles Fly for Leukemia Fund.

This paper was presented in part at the Annual Meeting of the Child Neurology Society, San Diego, California in October, 1987.

Article Information

Address reprint requests to: Roger J. Packer, M.D., Division of Neurology, Children's Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, Pennsylvania 19104.

© AANS, except where prohibited by US copyright law.

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Figures

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    Scattergram showing the correlation between changes in full-scale intelligence quotient (F.S.I.Q.) results and patients' age.

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Wechsler D: Wechsler Intelligence Scale for Children-Revised. New York: The Psychological Corp1974Wechsler D: Wechsler Intelligence Scale for Children-Revised.

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