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Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 7152-7160 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.214 Intellectual and Functional Outcome of Children 3 Years Old or Younger Who Have CNS MalignanciesFrom the Departments of Hematology-Oncology, Biostatistics and Epidemiology, Behavioral Medicine, and Radiological Sciences, Neurology, St Jude Children's Research Hospital, Memphis, TN Address reprint requests to Maryam Fouladi, MD, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: maryam.fouladi{at}stjude.org
PURPOSE: To evaluate the impact of tumor location, clinical parameters, and therapy on neurocognitive, neuroendocrine, and functional outcomes in children  3 years old with intracranial CNS malignancies who survived at least 2 years after diagnosis. PATIENTS AND METHODS: Records were retrospectively reviewed for 194 children diagnosed from 1985 to 1999 at St Jude Children's Research Hospital (Memphis, TN).
RESULTS: The median age at diagnosis was 1.8 years (range, 0.1 to 3.5 years). Median follow-up was 7.64 years (2.0 to 19.4 years). Tumors were infratentorial (102), diencephalic (53), and hemispheric (39); 47% required ventriculoperitoneal shunts, 36% developed seizure disorders, and 20% developed severe ototoxicity. Therapy included no radiation therapy (RT) in 57 (30%), local RT in 87 (45%), and craniospinal irradiation (CSI) in 49 (25%). Overall survival at 10 years was 78 ± 4%. In a longitudinal analysis of 126 patients with at least one neurocognitive evaluation (NE), the mean rate of intelligence quotient (IQ) change for patients who received CSI (–1.34 points per year) and local RT (–0.51 points per year) was significantly different from the no RT group (0.91 points per year; P = .005 and P = .036, respectively). Patients with hemispheric tumors had a significantly greater IQ decline (–1.52 points per year) than those with midline tumors (0.59 points per year; P = .038). Among those with NE CONCLUSION: In young children with CNS tumors, CSI and hemispheric location are associated with significant declines in IQ scores.
Approximately 20% of pediatric CNS tumors occur in children younger than 3 years old. Although treatment for resectable low-grade gliomas includes surgery followed by observation, most young children with CNS tumors require more aggressive treatment, including chemotherapy and/or radiotherapy (RT). Studies have demonstrated the adverse neurocognitive sequelae associated with RT in older children with brain tumors, reporting significant declines in intelligence quotient (IQ) over time among patients treated with cranial irradiation.1-13 Limitations of these reports have included small patient numbers and considerable variability in follow-up and treatment. Unfortunately, there are no comprehensive reports of neurocognitive, functional, and neuroendocrine outcome in children younger than 3 years treated for CNS malignancies. Such data would prove invaluable in defining future treatment strategies, including the role of early RT, in this poor-prognosis patient population.
We examine the impact of tumor location, clinical parameters, and therapy on neurocognitive, neuroendocrine, and functional outcome in children
Patients Between January 1985 and December 1999, 224 patients with intracranial CNS tumors who were diagnosed at 3 years old and survived for at least 2 years after diagnosis were evaluated and treated at St Jude Children's Research Hospital. Thirty patients with ependymoma who were treated with up-front focal conformal radiation therapy on an institutional protocol, representing a significant change in treatment strategy, have been reported separately.14 The 194 remaining patients are the subject of this report. Patients were enrolled on protocols approved by the institutional review board. Informed consent was obtained from parents or guardians at protocol enrollment. Seventy-six had a gross total resection at diagnosis (no surgical or imaging evidence of residual disease), nine had nearly total resection (< 10% residual tumor by surgical report and postoperative imaging), 53 had subtotal resection (< 50% residual tumor by surgical report and postoperative imaging), 37 had biopsy, and 19 had no tumor surgery (17 with optic pathway gliomas and two with brainstem gliomas). A chart review documented clinical features, including location of initial tumor (infratentorial, midline [diencephalic], or hemispheric), type of therapy (including type of radiation therapy [RT]: local, craniospinal [CSI], or none), presence or absence of ventriculoperitoneal (VP) shunt, grade 3 or 4 hearing loss, seizure disorder, endocrinopathy, neurocognitive outcome, and other measures of functional outcome (ie, type of schooling, employment, vision, dexterity, ambulation, speech) as well as overall and progression-free survival.
Therapy
Disease Surveillance and Follow-Up During platinum-containing therapy, audiology assessments were routinely conducted using auditory brainstem responses or audiograms before and after RT, and annually thereafter. The ototoxicity reported is the worst grade recorded for each patient. Opthalmologic testing was conducted in all patients with hypothalamic optic pathway tumors and coincided with their neuroimaging assessments. Others were followed by an ophthalmologist if patients or clinicians suspected specific visual problems. Data from the last examination are reported.
Neuropsychological Evaluation To estimate premorbid developmental trajectories, we computed an approximation of IQ based on a demographic algorithm (parental education, race) validated on the normative sample of the Wechsler Intelligence Scale for Children-III as well as children experiencing traumatic brain injury,23 where ethnicity is coded as two variables (white = 1 or non-white = 0, and black = 1 or non-black = 0) and parental education for both parents is also coded (0 to 8 years = 1, 9 to 11 years = 2, 12 years or GED = 3, 13 to 15 years = 4, 16 + years = 5) in the formula: premorbid IQ = 5.44 (mean parental education) + 2.80 (white/non-white) – 9.01 (black/non-black) + 81.68.
Statistical Considerations
Progression-free survival (PFS) was measured from the date of diagnosis to the date of first progression (or death, whichever was first) or last contact. Overall survival (OS) was measured from the date of diagnosis to death or last contact. Distributions of PFS and OS were estimated using Kaplan-Meier methods. The current cohort included a selected group of patients who lived Mean rate of change in IQ scores was assessed using a random coefficients model in which the IQ score is a linear function of the time since diagnosis, and both the intercept and the slope are considered random effects. The model fit was obtained using the MIXED procedure in SAS (SAS/STAT User’s Guide, Version 6, 1990; SAS Institute, Cary, NC). The longitudinal effects of RT, tumor location, shunt, seizure disorder, neurofibromatosis type 1 (NF1), and ototoxicity on the IQ scores were investigated independently. Factors significant at the P < .05 level were investigated in a multivariate model. Because status of RT, shunt, seizure disorder, and ototoxicity variables vary over time, they were included in the models as time-dependent variables.24,25 Patients who had only one neurocognitive assessment were kept in the analysis to improve the baseline estimate and reduce variation. Removing these patients did not significantly affect the slope estimates.
Characteristics of the Study Population The distribution of clinical characteristics of the 194 patients diagnosed with an intracranial CNS tumor at 3 years old and surviving at least 2 years are summarized in Table 1. Histologic confirmation was available in 175 patients. Locations included infratentorial (102), diencephalic (53), and hemispheric (39). Ninety-one patients (47%) required VP shunts at a median of 0.03 years from diagnosis, 70 (36%) had a seizure disorder diagnosed at a median of 0.49 years, and 22 (11.3%) had NF1.
Treatment and Outcome The OS for the whole group at 10 years was 78 ± 4%, with a PFS of 34 ± 5% (median follow-up, 7.64 years; range, 2.0 to 19.4 years; Fig 1A). OS in patients with high-grade gliomas, ependymomas, and medulloblastoma/primitive neuroectodermal tumor are summarized in Figure 1B.
Chemotherapy Patients were enrolled on a number of different protocols. Most patients with malignant embryonal tumors of infancy received a combination of cyclophosphamide, vincristine, etoposide, and platinum-containing regimens as their front-line therapy. Those with midline low-grade tumors generally received platinum-containing regimen with or without vincristine. Overall, 145 patients received chemotherapy at some point during therapy. Thirty-seven patients underwent neither chemotherapy nor RT at any time.
Radiation Therapy The median age at RT for the entire cohort was 3.1 years (range, 0.7 to 11.2 years). The median age at initial diagnosis was 1.79 years. Among those who received CSI (median age, 3.1 years; range, 1.1 to 14.6 years), 34 patients received cranial doses greater than 30 Gy (range, 30 to 48.4 Gy), 11 patients received 23.4 Gy, and four patients received 18 Gy. CSI was followed by local RT to the primary site with a median dose of 51.9 Gy. Among the 42 patients who received at most local conformal RT (median age, 3.3 years; range, 1.0 to 10.8 years), the median dose of RT was 54.0 Gy (range, 45.0 to 59.4 Gy); of the 41 patients who received at most parallel opposed field local RT (median age, 3.1 years; range, 0.7 to 9.7 years), the median dose was 50.4 Gy (range, 40 to 70.2 Gy).
Follow-Up Information Table 2 summarizes the number of patients with neurocognitive and audiology assessments at selected time points from diagnosis, demonstrating that the majority were obtained in the first 5 years after diagnosis.
Functional Outcome Functional outcome, including endocrinopathies, ototoxicity, visual acuity, education type, marital status, living arrangements, hearing, vision, speech, ambulation, and dexterity are summarized in Table 3. Neurocognitive outcomes are summarized in Tables 4 and 5. Overall, 52% developed at least one endocrinopathy, 21% grade 3 or 4 ototoxicity (69% had infratentorial tumors, 13% had diencephalic tumors), and 18% were legally blind (visual acuity 20/200 in at least one eye).
Twenty-four percent attended regular school and 36% were in special education (Table 3). The former group was significantly less likely to have received CSI (8.5%) than the latter (40%; P = .0007).
Only 13 patients were
Endocrinopathies
Effects of RT on Neurocognitive Outcome Longitudinal IQ analysis. Of the 194 patients, 101 had sufficient data to estimate premorbid IQ. The obtained estimate was 100.86 (standard deviation, 7.0), suggesting that the mean IQ is projected to have been in the normal range for age. Of the 194 patients, 126 (65%) had at least one IQ assessment and are included in the longitudinal analysis, examining the effect of tumor location, RT, VP shunt, seizure, hearing loss, and NF1 on IQ over time. The mean IQ at the time of first assessment (median, 1.1 years) was 82 (range, 46 to 130). The median number of IQ assessments was four (range, one to seven). Among those with an IQ assessment within 6 months of diagnosis (n = 44), the mean initial IQ was 84 (range, 50 to 120). Table 5 summarizes the clinical characteristics of the patients included in the longitudinal IQ analysis.
The subgroup of 126 patients with at least one IQ assessment was compared with the cohort of 194 patients using the exact
Overall, there was a mean IQ decline of –0.29 points per year in all patients. The IQ increase of 0.91 points per year in patients who received no RT was significantly different from the IQ decline in patients who underwent CSI (–1.34 points per year; P = .005; Fig 2A) or local RT (–0.51 points per year; P = .036), respectively. Although patients who received CSI (–1.34 points per year) seemed to have a worse neurocognitive outcome than those who received local RT (–0.51 points per year), the difference was not statistically significance (P = .26). Recipients of more than 33 Gy CSI experienced a greater IQ decline (–1.7 points per year) than those receiving
The IQ decline of patients who received CSI as planned consolidative therapy (–0.31 points per year) was not statistically different from those who received CSI at the time of progression (–1.26 points per year; P = .39). Among patients with infratentorial tumors, those receiving CSI had a significant decline in IQ (–1.34 points per year) compared with those who received local RT (0.35 points per year; P = .032) and those who received no RT (1.28 points per year; P = .009). Although patients undergoing local RT or no RT tended to have a slight gain in IQ points per year, the rate of change did not differ significantly (P = .34) between these two groups. There was no statistically significant difference in the rate of IQ decline for those who received conformal RT compared with parallel opposed fields RT (P = .71). However, the latter results should be interpreted with caution because of the small sample size.
To assess the effect of age at RT on neurocognitive outcome, we reanalyzed the data to determine rates of IQ decline in patients who underwent CSI at less than 3 years or at
Effects of Other Patient Variables on Neurocognitive Outcome
Effects of Tumor Location and RT on Neurocognitive Outcome
This study demonstrates that, in young children with intracranial CNS tumors, treatment with CSI and hemispheric location are associated with significant declines in IQ scores. Patients undergoing CSI are more likely to develop endocrinopathies (P < .0001) and require special education (P = .0007). Among patients with infratentorial tumors, patients undergoing local RT (whether conformal or parallel opposed fields) had a slight gain in IQ that did not differ significantly from the gain in the no-RT group (P = .34).
Functional Outcome The relative effect of therapy on the development of endocrinopathies in children with CNS malignancies has been reported previously, with various reports confirming or questioning the role of RT in the development of endocrinopathies.10,27-31 In the present study, patients who received RT had a significantly greater likelihood of developing endocrinopathy than those who did not (P < .0001); 90% of those who received CSI had an endocrinopathy compared with 68% and 26% of those who received local RT and no RT, respectively. The current report offers a comprehensive review of social attainment in this group of patients. The 36% of patients who required special education were significantly more likely to have received CSI than those in regular school. Only one of the 13 surviving patients older than 18 years was working independently, and none was married. Likewise, Kiltie et al11 reported that of 16 medulloblastoma patients alive 10 years after treatment, 15 required special education, only one was working independently, and none was married. Hoppe-Hirsch et al8 reported that, 10 years after therapy, 71% of patients with ependymoma (median age at presentation, 5.8 years) attended regular school compared with 20% of medulloblastoma patients (median age at presentation, 5.8 years). Zebrack et al32 recently reviewed the psychological outcomes in 1,101 long-term survivors of childhood CNS tumors younger than 18 years at diagnosis and reported that 74% were currently employed, 63% had graduated from high school, and 74% remained single; they concluded that diminished social functioning contributed to increased psychological distress.
Factors Affecting Neurocognitive Outcome For infratentorial tumors, there was no significant IQ decline for those treated only with local irradiation, whether parallel opposed fields or conformal RT. The latter finding is in keeping with a report from this institution in which patients with ependymoma receiving conformal RT demonstrated no statistically significant change in IQ 24 months after completion of therapy.14 VP shunting did not have a significant impact on the rate of IQ decline, although patients with VP shunts tended to have lower initial IQs than those without. The relative effects of the tumor, surgery, and perioperative factors compared with treatment effects have always been difficult to delineate.9,33-35 In the current cohort, patients who had neurocognitive assessments done within 6 months of diagnosis demonstrated a lower baseline IQ than expected, confirming that the presence of tumor, surgery, and perioperative factors do have an effect on neurocognitive outcome regardless of subsequent treatment. Although this study provides the most comprehensive overview of functional, social, and neurocognitive outcomes in a large cohort of infants with a long follow-up period, it has several limitations. Neurocognitive data were available in only 65% of the cohort. Our analysis demonstrated the relative similarity of the cohorts with and without neurocognitive follow-up. However, patients who were followed or had surgery only were less likely to undergo neurocognitive testing (54.9%) than those who received chemotherapy or RT (68.5%), probably because of the lower risk for neurocognitive sequelae. Similarly, there may have been a bias not to test patients who were more severely affected. Of those with neurocognitive data, a subset was included in an estimation of premorbid functioning using a prediction formula previously published.23 This constitutes an initial attempt to use such an inferential model. However, the model was developed for estimating full-scale IQ scores comparable with subsequent scores derived from the Wechsler Intelligence Scale for Children–Third Edition, recommended for children aged 6 through 16 years 11 months.18 In addition, the coding for ethnic classifications used to determine the model are restrictive (black/non-black, white/non-white) and may not be suitable for highly diverse populations. Extrapolating outside the data on which the model was developed may not be appropriate. Among patients with endocrinopathy, the endocrinopathies were coded as present or absent without regard to time of onset, thus making any conclusions regarding the relationship between endocrinopathy and type of therapy difficult to assess. Finally, the diversity of histology and tumor location in this cohort has implications for choice of therapy and, hence, long-term outcome in this particularly vulnerable group. It is imperative that future studies include prospective and comprehensive neurocognitive and functional assessments to accurately evaluate the impact of novel therapeutic approaches on long-term functional outcome.
The authors indicated no potential conflicts of interest.
We thank Dr James Boyett for his input regarding the statistical analysis and Patsy Burnside for typing the manuscript.
Supported by Center of Research Excellence support Grant No. CA21765 and by American Lebanese Syrian Associated Charities. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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3. Ris MD, Packer R, Goldwein J, et al: Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: A Children's Cancer Group study. J Clin Oncol 19:3470-3476, 2001 4. Mulhern RK, Reddick WE, Palmer SL, et al: Neurocognitive deficits in medulloblastoma survivors and white matter loss. Ann Neurol 46:834-841, 1999[CrossRef][Medline] 5. Mulhern RK, Kepner JL, Thomas PR, et al: Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: A Pediatric Oncology Group study. J Clin Oncol 16:1723-1728, 1998[Abstract] 6. Dennis M, Spiegler BJ, Hetherington CR, et al: Neuropsychological sequelae of the treatment of children with medulloblastoma. J Neurooncol 29:91-101, 1996[CrossRef][Medline] 7. Grill J, Renaux VK, Bulteau C, et al: Long-term intellectual outcome in children with posterior fossa tumors according to radiation doses and volumes. Int J Radiat Oncol Biol Phys 45:137-145, 1999[CrossRef][Medline] 8. Hoppe-Hirsch E, Brunet L, Laroussinie F, et al: Intellectual outcome in children with malignant tumors of the posterior fossa: Influence of the field of irradiation and quality of surgery. Childs Nerv Syst 11:340-345, 1995[CrossRef][Medline]
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10. Walter AW, Mulhern RK, Gajjar A, et al: Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children's Research Hospital. J Clin Oncol 17:3720-3728, 1999 11. Kiltie AE, Lashford LS, Gattamaneni HR: Survival and late effects in medulloblastoma patients treated with craniospinal irradiation under three years old. Med Pediatr Oncol 28:348-354, 1997[CrossRef][Medline]
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33. Ater JL, Moore BD III, Francis DJ, et al: Correlation of medical and neurosurgical events with neuropsychological status in children at diagnosis of astrocytoma: Utilization of a neurological severity score. J Child Neurol 11:462-469, 1996 34. Chin HW, Maruyama Y: Age at treatment and long-term performance results in medulloblastoma. Cancer 53:1952-1958, 1984[CrossRef][Medline] 35. Mulhern RK, Horowitz ME, Kovnar EH, et al: Neurodevelopmental status of infants and young children treated for brain tumors with preirradiation chemotherapy. J Clin Oncol 7:1660-1666, 1989[Abstract] Submitted September 17, 2004; accepted June 14, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5 years after diagnosis, 71.4% of CSI recipients compared with 23% of local RT recipients had IQ less than 70 (P = .021). Patients undergoing CSI were more likely to develop endocrinopathies (P < .0001) and to require special education (P = .0007). 
2 tests were used to assess associations with RT type. 
