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Change in Neurocognitive Functioning After Treatment With Cranial Radiation in Childhood

From the Departments of Psychology, Pediatrics, and Surgery, and Divisions of Hematology/Oncology and Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada

Address reprint requests to Donald Mabbott, PhD, Paediatric Brain Tumor Program, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada; e-mail: donald.mabbott{at}sickkids.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To evaluate the pattern of stability and change over time across multiple domains of neurocognitive function in radiated survivors of posterior fossa (PF) tumors.

PATIENTS AND METHODS: Thirty-four children (25 males) treated for malignant PF tumors were observed with serial clinical neuropsychologic assessments. Thirty patients were treated for medulloblastoma and four patients were treated for ependymoma. Twelve patients were treated with reduced-dose and 21 patients were treated with standard-dose cranial radiation. All patients received an additional boost to the PF. One patient was treated with PF radiation only. Standardized neuropsychologic tests were administered at different times after diagnosis for each child. The rate of change in scores was determined using a mixed model regression.

RESULTS: Results showed a 2- to 4-point decline per year in intelligence scores. For our relatively young sample, intellectual function declined quickly in the first few years after treatment, and then more gradually. Significant declines in visual-motor integration, visual memory, verbal fluency, and executive functioning were also documented. No decline was evident for verbal memory and receptive vocabulary.

CONCLUSION: Cranial radiation is associated with a decline in multiple neurocognitive domains, with a few notable exceptions. Our results must be interpreted in the context of common limitations of clinical research, including patient variability, changes in test versions, small sample size, and clinical referral bias.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Tumors of the CNS are the most common form of solid tumors in childhood, accounting for 20% of all pediatric malignancies [1,2]. Half of all pediatric brain tumors are located within the posterior fossa (PF) [1,3], and with the exception of cerebellar astrocytoma, most of these tumors require treatment with radiation therapy for effective control. Medulloblastomas account for 50% of PF tumors: these are malignant tumors that require surgery, cranial-spinal radiation (to a dose of 23 to 36 Gy), and an additional boost to the PF (to a total PF dose of 54 Gy), with or without adjuvant chemotherapy. With recent advances in medical treatment, particularly the use of both radiotherapy and chemotherapy, 5-year survival rates for children treated for standard-risk medulloblastoma approach 80% [3,4]. Ependymomas comprise approximately 10% of PF tumors in childhood [3]. Depending on the tumor grade, the age of the patient, and the extent of resection, ependymomas are typically treated with surgery, and either cranial or focal radiation. Although survival rates for completely excised ependymomas are good (66% to 77%), few are completely resected, and for incompletely resected tumors, survival rates are considerably lower [3].

Unfortunately, survival is achieved at considerable cost. Therapeutic cranial-spinal radiation has adverse late effects on many systems, including the endocrine, skeletal, and central nervous systems. In particular, cranial radiation has been associated with long-term neurocognitive deficits [5-13]. Variables associated with increased risk of neurocognitive impairment, beyond treatment with cranial radiation, include younger age at diagnosis, and in some studies, perioperative factors [12,14,15].

Because of the demonstrated deleterious effects of cranial radiation on later cognitive function, newer protocols investigate the efficacy of lower doses or reduced fields of radiation for the treatment of medulloblastoma [4]. In group comparison studies, children treated with lower doses of cranial radiation (23.4 Gy) demonstrate less impairment in intelligence than children treated with higher doses [7,12]. Nevertheless, reduced-dose cranial radiation is still associated with a decline in neurocognitive functioning [16].

More recently, intellectual outcome has been examined longitudinally using growth curve analyses and a progressive decline has been observed [5,16-18]. The use of growth curve modeling is a significant improvement on previous prospective methodologies because the rate of change in neurocognitive function over time can be estimated. Although it is now clear that intelligence quotient (IQ) scores decline after cranial radiation, few studies have observed children for more than 5 years [17]. Because of improvement in long-term survival, it is important to investigate the course and pattern of IQ decline over a longer period of time.

With a few exceptions, most longitudinal studies have been limited to evaluation of intellectual functioning [5]. Using cross-sectional retrospective designs, deficits in other neurocognitive domains have been documented in children with brain tumors and children with leukemia treated with cranial radiation. Specifically, poor performance has been reported on tests of visual-perceptual ability, memory and learning, attention, and information processing speed [5,10,12,19-25]. However, few attempts have been made to examine the progressive decline or stability in these domains prospectively.

The effect of cranial radiation on neurocognitive function is unique in that deficits are relatively slow to emerge and are manifest progressively over time. Most other pediatric brain insults (eg, traumatic brain injury, stroke) cause immediate deficits and involve some degree of recovery over time. The goal of this study is to examine patterns of neurocognitive change over time after treatment with cranial radiation. First, we evaluate the rate of decline in intelligence over a long survival period. Recently, it has been demonstrated that the function of the decline is also relevant in understanding changes in intelligence [26,27]. Hence, we also examine the function of decline in our sample. Intelligence tests have been useful in monitoring the global neurotoxic effects of disease and treatment. The aim of current treatment protocols is to improve neurocognitive outcome and reduce toxicity, while maintaining treatment efficacy. Measures that are more specific than intelligence tests may contribute to our evaluation of whether these goals are being met. Therefore, our second goal is to examine the impact of cranial radiation on specific neurocognitive domains. Our intent is to determine the pattern of stability and change across multiple domains of neurocognitive function over a prolonged survival period in children treated with cranial radiation for malignant PF brain tumors.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Patients
Thirty-four children (25 males) treated for malignant PF tumors within the last 20 years at the Hospital for Sick Children (Toronto, Canada) were observed with serial clinical neuropsychologic assessments. Thirty patients were treated for medulloblastoma and four patients were treated for ependymoma. Gross total resection was achieved in 50% of patients. One patient was treated for meningitis. Thirty-three patients were treated with cranial radiation: 12 patients were treated with reduced-dose (ie, 23.4 to 30.2 Gy), and 21 patients were treated with standard-dose (ie, 34 to 36 Gy) radiation to the whole brain. All of these patients received an additional boost to the PF, so that the total PF radiation dose ranged from 45 to 55.8 Gy. One patient was treated with PF radiation only, although the field was large and included the posterior half of the brain to a dose of 54 cGy. Eleven patients had a ventriculo-peritoneal shunt inserted to treat associated hydrocephalus. Twenty-four patients received adjuvant chemotherapy. Two patients were seen for neuropsychologic assessment after treatment for tumor progression or recurrence. One of these patients experienced disease recurrence as an infant before any treatment with cranial radiation: her first neuropsychologic evaluation was conducted a number of years after cranial radiation for recurrence. The other patient, who was originally treated with cranial radiation, was seen for her final neuropsychologic evaluation within weeks of her recurrence, which was treated with chemotherapy only. Hence, all patients were seen for neuropsychologic assessment after a single course of cranial radiation.

The mean age at diagnosis for the entire sample was 6.08 years (standard deviation [SD] = 2.73). The patients in this series were accrued by clinical referral and only those patients who were seen for multiple neuropsychologic evaluations were included. We compared the 27 patients (70% males) with medulloblastoma in this series who were diagnosed after 1985 with the overall population of patients diagnosed with medulloblastoma at the Hospital for Sick Children (Toronto, Canada) since 1985 (n = 180; 66% males). (Information before 1985 is unavailable; thus, the three patients in the current sample who were diagnosed before this year are not included in this comparison. Furthermore, the three patients treated for ependymoma are not included because many of these tumors are treated without radiotherapy; hence, comparisons with this population are not relevant.) The mean age at diagnosis was essentially the same for the current subsample relative to the overall population (6.46 years, SD = 2.68 v 6.51 years, SD = 3.93), as was the percentage of children treated with adjuvant chemotherapy (78% v 74%) and the percentage of patients in whom gross total resection was achieved (52% v 50%). (Information regarding extent of excision was available for only 164 of the patients seen since 1985.) Finally, the majority of patients in the overall sample were treated with standard-dose radiation (74%), which is somewhat higher than the present subsample (63%). (Information regarding radiation dose was available for only 114 of the patients seen since 1985.)

Materials and Procedures
A battery of standardized neuropsychologic tests was administered at different times after diagnosis for each child. Measures of intellectual functioning, receptive vocabulary, visual-motor function, memory, executive function, and fine motor ability were most consistently administered, and hence are reported here (Table 1). Because not all participants were administered all the tests at each assessment point (because of age or time constraints), the number of patients assessed with each measure varies across time. Thirteen patients had two assessments, 16 patients had three assessments, two patients had four assessments, and three patients had five assessments. Seventeen patients were seen for baseline assessment within 6 months of diagnosis and the remainder had their first assessment at various times beyond 6 months after diagnosis (Table 2). Median time from diagnosis to the first assessment was 0.79 years (range, 0 to 9.33 years). Median time from diagnosis to the last assessment was 4.71 years (range, 1.33 to 15.25 years). This study was approved by the Hospital for Sick Children's Research Ethics Board before the data were extracted from the clinical records.

To determine change or stability over time, growth curve analyses were conducted for all measures. Specifically, the rate of change in scores over time from diagnosis was determined using a mixed model regression, which is consistent with the recent literature [5,16-18,26,27]. Because patients were evaluated at various times after diagnosis, the mixed model approach was used: unbalanced and missing data are common methodologic problems with clinical populations. Mixed model techniques were implemented using PROC MIXED (SAS Institute, Cary, NC). To correct for multiple analyses, results were considered significant at the P < .01 level only.

	RESULTS

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Two linear models were generated to evaluate changes in neurocognitive function after treatment with cranial radiation therapy. First, the estimated rate of change for all 34 patients was determined. The predicted values for longest times from radiation treatment are less stable because of the smaller number of data points contributing to the model at these times [5,16]. Hence, caution must be used in interpreting the estimated values at the end of the time period. To evaluate change from baseline, a second model was generated which included only those children who were seen for baseline assessment within 6 months of diagnosis (n = 17; median follow-up time, 3.33 years from diagnosis; maximum follow-up time, 6.00 years). The baseline sample was slightly older at diagnosis than the overall sample (mean age at diagnosis, 7.20 and 6.08 years, respectively). This second model is important for evaluating changes that occur soon after radiation therapy. Because those patients seen for baseline assessment were given an abbreviated battery consisting of measures of intelligence, receptive vocabulary, visual-motor integration, and verbal and visual memory, only changes in these measures were evaluated in this model. For all models, intercepts represent the estimated baseline functioning and slopes characterize change in functioning over time. Intercepts and estimated slopes are found in Tables 3, 4, and 5 for the complete sample and Table 6 for the sample observed from baseline. Finally, a model that included the quadratic term was generated for the entire sample for full-scale IQ (FIQ), verbal IQ (VIQ), and performance IQ (PIQ). The quadratic term was not evaluated for other measures or the baseline sample because there were too few patients with the three or more data points required to produce a relatively stable estimate of curvilinearity.

In fact, when the observed scores of all patients are plotted as a function of time and examined qualitatively, there is a steeper decline shortly after treatment with a gradual leveling off in observed scores over time (Fig 1; FIQ is used as an example, but the pattern is similar for VIQ and PIQ), suggesting an overall nonlinear function in intellectual decline. To evaluate whether this pattern was significant, the quadratic term was then included for the 21 patients who had three or more assessments: both the linear and quadratic terms were significant for FIQ, VIQ, PIQ (P < .01; Fig 2). A significant quadratic term reflects curvature in the slope of the function, representing change over time. Thus, for global IQ measures, the rate of decline from year to year decreased as time from diagnosis increased, which cannot be accounted for by the simple linear model that assumes a constant rate of change over time. These findings are consistent with the view that there is an attenuation of the decline in intellectual functioning over time.

View larger version (15K): [in this window] [in a new window]   Fig 1. Observed decline in full-scale IQ (FIQ) over time for 32 patients in the sample. Each line is the slope across assessments for individual patients.

View larger version (13K): [in this window] [in a new window]   Fig 2. Estimated decline in full-scale, verbal, and performance IQ (FIQ, VIQ, and PIQ, respectively) over time on the basis of a model including the linear and quadratic terms.

Visual-Motor Functioning and Receptive Language
There was a significant decline in slope for visual-motor functioning in the entire sample (Table 4) and for the baseline sample (Table 6). For receptive vocabulary, no significant decline was observed for either the entire sample (Table 4) or the sample observed from baseline (Table 6).

Memory
There was a significant decline in slope for visual memory for the entire sample but not for the sample observed from baseline, and no decline was seen in slopes for verbal memory (Tables 4 and 6). Furthermore, no decline was evident for multiple measures of verbal learning (short-term memory span, level of learning, immediate recall, and delayed recall) for the entire sample: these data were not available for the baseline sample (Table 4). The stability in verbal memory over time is notable.

Executive Function
Only the model that included all patients was used to evaluate changes in performance on measures of problem solving and verbal fluency (Table 5) because of the small sample of patients observed from baseline with these measures. Significant negative slopes were observed for the Children's Category Test, Verbal Fluency Test, and the Trail Making Test. For measures of problem solving and verbal fluency, the decline was approximately 1 SD every 5 years. The decline in the Trail Making Test was approximately 1 SD every 3 years.

Fine Motor Functioning
Measures of fine motor ability were evaluated in the model that included the complete sample only (Table 5). A significant positive slope was evident for finger tapping for the dominant hand and nondominant hand. In this regard, we note particularly low intercepts, suggesting the adverse impact of the tumor and acute effects of treatment on fine motor speed. No significant changes were observed for motor dexterity over time (grooved pegboard).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
First, the results from this study are consistent with previous findings of intellectual decline in children treated with cranial radiation [16-18,26]. Considering the differences in mean age at diagnosis, radiation dose, and assessment methodologies between our sample and the previous studies, these similarities are striking. For example, the decline in full-scale IQ was similar for our sample compared with a group of older patients (mean age at diagnosis, 7.57 years) observed over a similar time period by Palmer et al [17]: -2.04/yr over a median follow-up of 5.08 years versus -2.55/yr over a mean follow-up of 5.24 years. Furthermore, declines in VIQ, PIQ, and FIQ for patients observed from baseline were similar to those observed by Ris et al [16] for a group of patients treated with reduced-dose cranial spinal radiation observed from baseline: -3.08, -4.47, and -4.08, respectively, over a median of 2.25 years in the current study versus -4.2, -4.0, and -4.3, respectively, over a median of 2.50 years in the study by Ris et al [16]. Because the findings from all of these studies are based on estimated models with relatively small patient numbers and unbalanced and missing data, replication of findings is essential. The consistency between our study and previous results, however, is evidence that intellectual decline after treatment with cranial radiation is a robust finding.

Second, our findings are relevant in delineating the time course and function of the decline in intellectual functioning. Previous studies have suggested that there is a steeper slope from baseline in FIQ for models with shorter relative to longer follow-up periods (ie, -4.3 over 2.5 years in Ris et al [16] v -2.55 over 5.24 years for Palmer et al [17]). A similar pattern emerges from our findings. First, the decline in slope for the model including patients observed from baseline only is steeper than the model including all children, which is based on a longer time from diagnosis. Second, when the observed scores of all patients were plotted as a function of time, there was a steep decline shortly after treatment and then a gradual leveling off in scores (Fig 1). Finally, using a model that included the quadratic term, we found that the rate of decline from year to year decreased as time from diagnosis increased. These findings are consistent with those recently reported by Palmer et al [26]. They found that a quadratic model demonstrated an immediate loss of performance in short-form FIQ in a group of younger patients treated with cranial-spinal radiation that had a mean age similar to that of the patients in our series (5.83 v 6.08 years). Palmer et al found that in older children (mean age, 11.05 years) there was a delay before decline in performance [26].

Taken together, these findings are consistent with the view that for younger children, there is an early decline in intellectual functioning after treatment, and then an attenuation of that decline. If this is true, it will be important to study the rate and pattern of decline within that first 5-year period in greater detail because the current assumption is that radiation effects are not manifest immediately, but slowly emerge in the 2 to 3 years after treatment ends. Additional investigation into the time point at which the decline in intelligence plateaus also is essential [26]. Understanding the expected time course of decline is directly relevant for the timing of effective rehabilitation strategies for these children.

Third, a novel contribution of our study was the serial evaluation of a broad range of neurocognitive functions over a relatively long period of time. Because of this, we were able to examine the patterns of stability and change in neurocognitive function, beyond a decline in intellectual functioning. We documented a significant decline in visual-motor integration, visual memory, verbal fluency, and executive functioning. A notable finding was that no decline was evident for measures of verbal memory or for receptive vocabulary. Hence, a measure of receptive vocabulary, such as Peabody Picture Vocabulary Test, may represent a useful surrogate for estimating premorbid cognitive potential, in so much as such a measure is related to IQ. Measures of fine motor speed and dexterity improved or remained unchanged during the follow-up period. Acute impairments in fine motor skills can occur in children with PF tumors treated with surgery. On the basis of these data, however, fine motor skills are not sensitive to the long-term effects of radiation. When results from all of the measures that we used are considered, it is notable that IQ measures appeared to be the most sensitive to decline in functioning after radiation therapy.

Our results must be interpreted in the context of common limitations of clinical research. First, because the data were accrued clinically over a large time span, some tests were revised and therefore different versions were used across assessments for some individuals. Second, the mediating effects of age at diagnosis and dose of radiation therapy on changes in neurocognitive function were not reported because of limitations in addressing group differences as a result of small sample sizes. Third, our sample size was insufficient to address the influence of other medical and demographic variables including hydrocephalus, chemotherapy, other neurologic conditions, variability in time to first assessment, sex, and socioeconomic status. Multisite studies are required to obtain sufficient numbers of patients to address these issues. Finally, the issue of referral bias must be considered. These clinically obtained data may not reflect the pattern of change and stability that might be observed in a sample of all children observed prospectively from diagnosis. On the basis if the similarity of our referred sample to the overall population seen since 1985, and the similarities in findings compared with previous studies in which patients were observed prospectively, this does not appear to be the case [16-18,26].

Our results are consistent with a decline in multiple neurocognitive domains, with a few notable exceptions. Understanding the factors that contribute to the general decline in functioning but relative stability in specific domains is important for characterizing the mechanism by which cranial radiation leads to cognitive impairment.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted May 29, 2003; accepted December 1, 2003.

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