Journal of Clinical Oncology, Vol 19, Issue 15
(August), 2001: 3470-3476
© 2001 American Society for Clinical Oncology
Intellectual Outcome After Reduced-Dose Radiation Therapy Plus Adjuvant Chemotherapy for Medulloblastoma: A Children’s Cancer Group Study
By M. Douglas Ris,
Roger Packer,
Joel Goldwein,
Dana Jones-Wallace,
James M. Boyett
From the Division of Psychology, Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH; Department of Neurology, Children’s National Medical Center, and Departments of Neurology and Pediatrics, George Washington University, Washington, DC; Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA; and Department of Biostatistics and Epidemiology, St Jude Children’s Research Hospital, Memphis, TN.
Address reprint requests to M. Douglas Ris, PhD, Children’s Cancer Group, PO Box 60012, Arcadia, CA 91066-6012; email: risd0{at}chmcc.org
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ABSTRACT
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PURPOSE: To investigate the intellectual outcomes of children with medulloblastomas/primitive neuroectodermal tumors (MB/PNET) treated with reduced-dose craniospinal radiotherapy (RT) plus adjuvant chemotherapy.
PATIENTS AND METHODS: Forty-three children with average-risk posterior fossa MB/PNETs underwent longitudinal intelligence testing. All had been treated with a reduced-dose craniospinal RT regimen (23.4 Gy to the neuraxis, 32.4-Gy boost to the posterior fossa) and adjuvant chemotherapy.
RESULTS: The estimated rate of change from baseline was significant for Full Scale Intelligence Quotient (FSIQ), Verbal IQ (VIQ), and Nonverbal IQ (NVIQ) (P < .001 for all three outcomes). The rate of change was estimated to be -4.3 FSIQ points per year, -4.2 VIQ points per year, and -4.0 NVIQ points per year. Females were more subject to VIQ decline than were males (P = .008), and young children (< 7 years of age) were more negatively affected than were older children, with a significant decline in NVIQ (P = .016). Finally, patients with higher baseline evaluations suffered greater declines in IQ than did those with lower baseline scores.
CONCLUSION: This study represents the largest series of patients with average-risk MB/PNETs treated with a combination of reduced-dose RT and adjuvant chemotherapy whose intellectual development has been followed prospectively. Intellectual loss was substantial but suggestive of some degree of intellectual preservation compared with effects associated with conventional RT doses. However, this conclusion remains provisional, pending further research.
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INTRODUCTION
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SURVIVAL RATES for medulloblastoma/primitive neuroectodermal tumors (MB/PNET) have gradually improved as a result of more effective treatments. Improved staging of the disease has also allowed more accurate stratification of patients into risk groups and is an integral component of management.1 Patients with gross total resections and nondisseminated disease have 5-year survival rates ranging between 60% and 70%.2 Conventional treatment of MB/PNET includes radiation therapy (RT) doses of 36 Gy to the craniospinal axis with a 18- to 20-Gy boost to the posterior fossa. Although this RT regimen results in disease control for a substantial number of patients, evidence of developmental neurotoxicity has mounted over the years.3 For example, Chin and Maruyama4 reported increased learning problems in children with MB/PNET who were younger than 4 years of age at the time of treatment. Silverman et al5 found lowered intelligence quotients (IQs) in children with MB/PNET compared with sibling controls. Packer et al6 reported neurocognitive deficits in more than half of a series of 24 patients with MB/PNET. The decline in intellectual functioning can be quite dramatic, as indicated in a report by Hoppe-Hirsch et al7 in which 42% of their sample were found to have IQs below 80 5 years after treatment. This increased to 75% 10 years after treatment. There is fairly consistent evidence of increased neurocognitive morbidity with higher treatment doses and younger age at the time of treatment.7,8
Recently, treatment protocols have been developed to reduce this morbidity. This can be accomplished by simply decreasing the overall dose of RT to the brain or by combining such reductions in RT dose with adjuvant chemotherapy. Such approaches have shown promise in producing survival and tumor recurrence rates comparable to those of conventional therapy.9,10 However, little is known about whether such approaches achieve the objective of decreased neuropsychologic morbidity. Furthermore, there is some evidence of moderating effects of age and sex11,12 on outcome, and it has yet to be determined whether such effects are found with reduced doses of RT in brain tumor protocols.
A recent report of the neuropsychologic outcome of a series of MB/PNET patients treated with reduced RT compared with standard-dose RT supports the efficacy of such protocols in reducing neurocognitive morbidity.13 These investigators found that, after a median period of 8.2 years after diagnosis, 22 patients had a median prorated (from five subtests) Third Edition of the Wechsler Intelligence Scale for Children (WISC-III) or Wechsler Adult Intelligence Scale-Revised Full Scale IQ of 82.9. Patients who were younger at the time of diagnosis (median age, 8.85 years) and those who received standard RT (36 Gy) scored lower than those who were older at the time of diagnosis and those who received reduced-dose RT (23.4 Gy). The authors concluded that there was a 10- to 15-point advantage in IQ for young children who received the reduced-dose regimen compared with young children who received standard-dose RT.
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PATIENTS AND METHODS
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In October 1989, Children’s Cancer Group study 9892 opened and accrued patients for 5 years, closing in December 1994. Overall, 85 patients entered, with 20 patients subsequently found to be ineligible or to have non–posterior fossa tumors (see Packer et al2 for a complete description of the sample and treatment parameters). The 65 eligible patients with medulloblastoma had a mean age of 6 years at diagnosis (range, 3 to 15 years). This was a single-arm study in which all patients had nondisseminated disease and were treated with reduced-dose craniospinal RT (23.4 Gy) and a 32.4 Gy boost to the posterior fossa. Adjuvant chemotherapy consisted of vincristine, lomustine, and cisplatin. The progression-free survival rate for this sample was 86% ± 4% at 3 years and 79% ± 7% at 5 years, which compares favorably with survival rates after conventional therapy.2
Of the 65 eligible patients, 43 were evaluated on at least two occasions and so were eligible for longitudinal neurocognitive analysis. Baseline testing was conducted between surgery and 12 weeks after RT according to the study protocol. In cases where more than one testing was conducted during this interval, the highest score was designated the baseline. Postsurgical evaluations were found to correlate well with presurgery findings,14 and, because chronic radiation-related intellectual changes are not seen for at least 6 months after RT,15 this method of establishing a benchmark against which to measure late effects seems reasonable and has been used by Mulhern et al.13 Moreover, it allows some discretion in selecting the score that is least likely to be confounded by acute treatment-related influences (eg, illness or postsurgical complications).
Because of age and other considerations, the intelligence tests used varied between the Stanford-Binet Fourth Edition (SB4), the Wechsler Intelligence Scale for Children-Revised (WISC-R), WISC-III, the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R), and in one instance, the McCarthy Scales of Children’s Abilities (McCarthy). Although the SB4 (for children younger than 6 years) and the WISC-R (for children ages 6 years and older) were the instruments stipulated in the study protocol, after this study opened the WISC-III was published and came into widespread use. The other instruments (WPPSI-R and McCarthy) represented unsanctioned deviations from the protocol on the part of participating institutions. However, all of these instruments are well-validated and widely used measures of children’s cognitive abilities and, more importantly, correlate highly with each other.16
Over the course of this prospective, longitudinal study, some subjects graduated from one intelligence test instrument to another. Whereas theoretically this may introduce method variance into the scores, thereby confounding interpretations of change, Silber et al8 used a similar procedure and found that such changes in instrumentation did not account for a significant amount of variance in the outcome.
Composite and IQ scores were converted to a common standard score (mean, 100; SD, 15) for the analyses described below. Full scale intelligence/IQ (FSIQ) will be used to denote WPPSI-R, WISC-R, and WISC-III full scale IQs; SB4 Test Composite; and the McCarthy General Cognitive Index. The term nonverbal intelligence (NVIQ) will be used to denote WPPSI-R, WISC-R, and WISC-III Performance IQs; SB4 Nonverbal/Abstract Reasoning scores; and McCarthy Perceptual-Performance scores. The term verbal intelligence (VIQ) will be used to denote WPPSI-R, WISC-R, and WISC-III Verbal IQs; SB4 Verbal Reasoning scores; and McCarthy Verbal Scale scores.
Statistical Methods
Comparisons of presenting features between those patients included in the analyses and those eligible but not included in analyses were evaluated by Fisher’s exact test for the categorical features of sex, T stage, race, surgery extent, and amount of residual tumor, and by Wilcoxon rank-sums test for age at diagnosis. Random coefficients models were constructed to estimate and compare the rate of change in FSIQ, VIQ, and NVIQ over time. The methods described in Laird and Ware17 and Jennrich and Schluchter18 were used for model construction, estimation, and testing as implemented in PROC MIXED.19 Using this methodology, the predicted curve is defined by the average slope of all of the individual subjects’ curves. As such, these curves do not represent mean scores from each assessment point. Being derived instead from the average slopes (determined by at least two data points) of the curves of each individual patient, this approach mitigates against potential bias introduced by differential attrition. A random coefficients model with both age at diagnosis and sex included was not attempted because of the small number of female patients and patients 7 years or older at diagnosis.
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RESULTS
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Patient characteristics are presented in Table 1. Although subjects undergoing longitudinal neurocognitive testing constituted only a subsample of the Children’s Cancer Group study 9892 sample, we found no differences between the subsample and the overall sample in terms of age at diagnosis, sex, T stage, or amount of residual tumor after surgery.
Change from baseline was significantly different from zero for FSIQ (Fig 1), VIQ, and NVIQ (P < .0001 in each case). The predicted FSIQ of 96.2 at baseline (95% confidence interval [CI], 90 to 102) had dropped to 78.8 (95% CI, 71.4 to 86.3) 4 years after RT, a decline of 17.4 points for FSIQ, 16.8 points for VIQ, and 16 points for NVIQ. Predicted change in IQ points per year was -4.3 (95% CI, -6 to -2.7) for FSIQ, -4.2 (95% CI, -6.0 to -2.4) for VIQ, and -4.0 (95% CI, -5.8 to -2.2) for NVIQ. Table 2 presents the means of the observed IQ scores for each follow-up point as opposed to the modeled or predicted IQ scores that form the bases for the analyses and are depicted in the figures.
It is important to bear in mind that, with each year of follow-up, the number of testings upon which the model is based decreases. Although Table 2 shows the average of the observed IQ scores for all 4 years, the fourth year is not represented in the modeled figures. As can be seen, the number of patients tested at this point is quite small. Inspection of the actual scores from these eight patients indicates that higher scores at prior evaluation points were somewhat over-represented in this group, suggesting a bias. Still, the majority evinced declines in IQ over time consistent with the modeled curves. Although the information in Table 2 suggests a nonlinear relationship between length of follow-up and intellectual functioning, the statistical analyses do not support this, in that quadratic terms were nonsignificant for FSIQ (P = .49), NVIQ (P = .90), and VIQ (P = .31).
Differences in sex were examined using the same longitudinal modeling procedure as above. Although analyses of sex effects are limited by the highly disproportionate number of males in the sample (34 males, nine females), there were no differences between males and females in FSIQ and NVIQ. However, females showed a significantly greater (P = .008) drop in VIQ (8 points per year) than males (3 points per year) (Fig 2).
To examine age effects, the sample was divided into groups of subjects who were younger than 7 years of age at the time of diagnosis (n = 30) and subjects who were 7 years or older at the time of diagnosis (n = 13). Although treating age as a categorical rather than continuous variable has been questioned,3 we chose to group the subjects in this way to promote cross-study comparisons, using the same age of demarcation as another study of treatment effects in children with MB/PNET.20 There was no difference between the groups in decline from baseline for FSIQ and VIQ. However, for NVIQ, the younger group showed a significantly greater (P = .016) decline compared with the older group (-5.2 v -0.8 points) (Fig 3). It is noteworthy that the older group’s baseline was lower with little subsequent change in NVIQ over the follow-up period, while the younger group’s baseline was much higher, followed by a steep decline.
To determine whether baseline IQ places a child at increased or decreased risk for decline, the sample was divided into those patients whose baseline IQs were below 100 (low baseline) and those whose baseline IQs were at or above 100 (high baseline). The high baseline group (VIQ, n = 19; NVIQ, n = 16; FSIQ, n = 12) showed a significantly steeper decline than the low baseline group (VIQ, n = 15; NVIQ, n = 18; FSIQ, n = 20) in VIQ (P < .0054), NVIQ (P < .031), and FSIQ (P < .011) (Fig 4).
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DISCUSSION
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These results show a decline in predicted IQ over the 4-year follow-up interval for a sample of children receiving a reduced-dose RT plus adjuvant chemotherapy regimen for treatment of average-risk MB/PNET. The estimated decline in FSIQ after 4 years was 17.4 points. This decline in intelligence does not clearly differ from that found in other prospective studies of neurocognitive function in children with medulloblastoma, despite the reduced-dose RT used. However, using a regression approach, Silber8 estimated an approximate 4-point per year decline for a similar age cohort treated with 24 Gy, compared with an approximate 8-point per year decline for children treated with 36 Gy. The former is similar to that found in our sample and argues for a possible benefit to the reduced dose RT.
Comparisons across studies are complicated by different methodologies. In particular, in the current study, age groups were defined differently from those of Mulhern et al.13 The conclusions arrived at by Mulhern et al were also based on only four subjects in the younger/reduced RT group, raising a question about the reliability of their finding. Full intelligence test batteries were used in the current study versus the abbreviated scale used by Mulhern et al.13 The use of adjuvant chemotherapy in the current study raises the question as to how this might mediate neurocognitive toxicity at different RT doses. Finally, the absence of a standard RT arm in the current study precludes a direct comparison of the effects of different radiation doses. All of these factors not withstanding, the estimated drop in IQ of approximately 20.8 points for our younger group does not clearly support an advantage to these patients for the reduced-RT regimen, as reported by Mulhern et al.13
Some studies of patients with acute lymphocytic leukemia (ALL) report a sex effect, with female patients showing greater adverse developmental impact of RT.12 A sex effect for only VIQ in the current study is intriguing. This may be a chance finding, given the small number of females in the sample, and it is noteworthy that Silber et al8 failed to find a sex effect. Alternatively, our findings may reflect sex-mediated risk for selective neurocognitive deficits. Although Waber et al12 did not report a specific effect on VIQ in their sample of children with ALL, one difference between this sample of children with MB/PNET and those ALL patients is the older average age of treatment for MB/PNET, which may affect the type of sex effects found if treatments are being delivered at different maturational windows.
An age effect was found for NVIQ only, with the younger group showing a decline of approximately 5 points per year. NVIQ (principally, performance IQ from the WISC) is known to be particularly sensitive to insults to the brain for a number of reasons, including a greater emphasis on speed, fine motor coordination, and novel problem solving in this scale versus the verbal scale.
Patients with higher baseline evaluations experienced greater decline in IQ. This could be explained as regression toward the mean, or it might indicate that children of higher intellect are particularly sensitive to the developmental toxicity of radiation. Alternatively, lower baseline evaluations may indicate greater tumor and surgery-related morbidity accounting for a greater proportion of overall morbidity compared with children not experiencing such acute effects having high levels of functioning initially.
The limitations of this study should be acknowledged. As is the case in any large multi-institutional study involving follow-up over many years, subject attrition was quite high, and interpretations must be tempered by this fact. There are many reasons for the high attrition rate, including geographic moves, decreased motivation after discontinuation of active treatment, and failure of third-party payors to cover the expense of psychologic testing. Although we cannot be sure that our sample represents the population of children with average-risk MB/PNET, we were able to establish that the tested subsample did not differ in critical disease and subject factors from the larger sample. Furthermore, our statistical approach reduced the effects of differential attrition, in that modeled curves were derived from the average slopes of the individual curves, which were based on at least two data points anywhere in the 4-year span of the study. Accordingly, the right ends of the curves do not simply represent the scores of a smaller (and perhaps biased) group of patients.
Admittedly, the intellectual evaluations were quite global, lacking the detail and specificity of extensive neuropsychologic batteries. However, IQ is known to be a highly sensitive index of RT-related effects in children, the tests used have better psychometric properties than most neuropsychologic tests, and more is known about the real-world correlates (ie, ecologic validity) of IQ tests than neuropsychologic tests, thus enhancing the interpretability of these findings. Although differences in instruments both across subjects and within subjects across time add a degree of imprecision to these data, for the reasons given earlier in this report, this is not believed to have been a major confounding factor.
The principal contribution of this study is the prospective characterization of the cognitive development of a sample of patients with MB/PNET treated with an innovative protocol, the purpose of which was to reduce long-term sequelae of radiation without compromising survival. The sample size and the absence of a control group preclude a definitive conclusion in this regard. Whereas the reduction in RT does not seem to place these children at higher risk for relapse or progression,2 the findings indicate that intellectual outcome with this protocol remains suboptimal. Further research will be necessary to confirm and extend these findings. Future studies should include a longer follow-up interval because, at least with conventional doses of RT, some researchers report declines continuing beyond the 4-year end point of this study. Indeed, it may be that the neurocognitive benefits of reduced-dose RT become increasingly apparent with longer term follow-up. Finally, more complete descriptions of academic and adaptive outcomes as well as other neuropsychologic domains (eg, memory) would be important in extending these findings on intellectual outcome.
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APPENDIX
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ACKNOWLEDGMENTS
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Supported by Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. J.M.B. is supported by grant no. CA21765 and by the American-Lebanese-Syrian Association Charities.
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NOTES
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Contributing Children’s Cancer Group investigators, institutions, and grant numbers are given in the Appendix.
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Submitted August 31, 2000;
accepted April 26, 2001.
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TOP
ABSTRACT
INTRODUCTION
, male; 
, female.
7 years.
