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© 1999 American Society for Clinical Oncology Survival and Neurodevelopmental Outcome of Young Children With Medulloblastoma at St Jude Children's Research HospitalFrom the Departments of Hematology-Oncology, Behavioral Medicine, Radiation Oncology, and Biostatistics, St Jude Children's Research Hospital; and Departments of Pediatrics, Radiation Oncology, and Pediatric Neurosurgery, University of Tennessee College of Medicine, Memphis, TN. Address reprint requests to Andrew W. Walter, MS, MD, Pediatric Hematology/Oncology, A.I. duPont Hospital for Children, 1600 Rockland Rd, PO Box 269, Wilmington, DE 19899; email awwalter{at}nemours .org.
PURPOSE: Young children treated for medulloblastoma are at especially high risk for morbidity and mortality from their disease and therapy. This study sought to assess the relationship, if any, between patient outcome and M stage. Neuropsychologic and endocrine outcomes were also assessed. PATIENTS AND METHODS: Twenty-nine consecutively diagnosed infants and young children were treated for medulloblastoma at St Jude Children's Research Hospital between November 1984 and December 1995. All patients were treated with the intent of using postoperative chemotherapy to delay planned irradiation. RESULTS: The median age at diagnosis was 2.6 years. Six patients completed planned chemotherapy without progressive disease and underwent irradiation at completion of chemotherapy. Twenty-three children experienced disease progression during chemotherapy and underwent irradiation at the time of progression. The 5-year overall survival rate for the entire cohort was 51% ± 10%. The 5-year progression-free survival rate was 21% ± 8%. M stage did not impact survival. All patients lost cognitive function during and after therapy at a rate of -3.9 intelligence quotient points per year (P = .0028). Sensory functions declined significantly after therapy (P = .007). All long-term survivors required hormone replacement therapy and had growth abnormalities. CONCLUSION: The majority of infants treated for medulloblastoma experienced disease progression during initial chemotherapy. However, more than half of these patients can be cured with salvage radiation therapy, regardless of M stage. The presence of metastatic disease did not increase the risk of dying from medulloblastoma. All patients treated in this fashion have significant neuropsychologic deficits. Our experience demonstrates that medulloblastoma in infancy is a curable disease, albeit at a significant cost.
THE TREATMENT OF medulloblastoma in infants and very young children differs from that in children older than 3 to 5 years of age. This is related to apparent differences in the biologic behavior and clinical course of disease and because of the significantly higher risks of radiation-related brain injury among very young children.1-4 For example, medulloblastoma in very young children may be more often associated with disseminated disease at diagnosis.3,5-10 Given similar therapy, younger patients have had inferior outcomes compared with older children with medulloblastoma.9-13 Despite this poorer prognosis, oncologists have been reluctant to use potentially curative doses of craniospinal irradiation in the very young because of late toxicity concerns.5,14,15 More recently, chemotherapy has been used for the purpose of delaying subsequent, systematic use of planned radiation therapy in this population.12,16,17 The rationale for delaying neuraxis irradiation in young children results from the desire to decrease late radiation-associated toxicity, especially neurocognitive losses, by allowing the patient's CNS to become more mature and resistant to radiation damage.3 Contemporary studies have attempted to address this problem by eliminating irradiation completely for children with localized medulloblastoma (M0) who remained disease free at the completion of planned chemotherapy.3,5,18 The use of potentially curative radiation therapy in very young children is a difficult trade off. Although radiation therapy clearly improves overall survival, the late toxicity is significant and sometimes devastating. The dilemma of trying to choose between using potentially curative, multimodality therapy as opposed to concerns about long-term quality of life can be a painful choice for families and health care providers alike. This article reviews the St Jude Children's Research Hospital experience with the treatment of such patients. Our experience demonstrates the efficacy and cost of using maximal effort to attempt a cure in this young population. Our objectives were to analyze patient outcome as a function of M stage and to assess neurodevelopmental status among surviving children.
Patients Twenty-nine consecutively diagnosed children with histologically confirmed medulloblastoma diagnosed before their fourth birthday and treated at this institution between November 1, 1984, and December 31, 1995, are the subjects of this review. No patients who otherwise fit these study criteria were excluded from this list. The Chang stage and the degree of resection were determined based on the surgeon's report, preoperative and postoperative neuroimaging studies, and CSF cytology.13 Computed tomography (n = 9) or magnetic resonance imaging (n = 20) scans of the brain were obtained in all patients preoperatively and within 48 hours postoperatively for the purpose of staging. Magnetic resonance imaging scan of the spine or computed tomography/metrizamide myelography scan was obtained in all patients at the time of diagnosis. Samples of spinal fluid obtained by lumbar puncture were used to determine the absence or presence of metastatic disease in the CSF at the time of diagnosis. Tumor resection was classified as gross total resection (no evidence of tumor at the primary site after surgery), subtotal resection (50% to 90% of tumor removed), or biopsy (< 50% of tumor removed).
Therapy
Neurodevelopmental Assessments All children treated for brain tumors were routinely referred for neuropsychologic testing at the time of their admission to the institution. Standardized testing with the Bayley Scales of Infant Development was used for infants (age, < 30 months), the McCarthy Scales of Children's Abilities was used for preschool-aged children (age, 30 months to 6 years), and the Wechsler Scales (Wechsler Intelligence Scale for Children, Revised or Edition 3) were used for children older than 6 years.19-22 Each of these instruments is individually administered and results in an age-corrected index of mental development (intelligence quotient [IQ]; mean, 100; SD, 15). Serial changes in scores can then be interpreted relative to what is expected from similarly aged children in the general population. These prospective assessments of mental development were supplemented by retrospective chart reviews of physical examinations at identified time intervals: before chemotherapy, before irradiation, and 6, 12, and 24 months after irradiation. Further testing was planned at least yearly for a minimum of 5 years after diagnosis during routine follow-up evaluation. Patients were routinely retested at the time of disease progression, before starting radiation therapy. The baseline IQ score was identified as the highest score attained during the period between diagnosis and up to 6 months after initiation of radiation therapy, thus allowing for recovery from acute and subacute perioperative deficits.23 Results of physical examinations were categorized using the Health Utilities Index 2 system developed at McMaster University for sensation and mobility.24 The Health Utilities Index 2 assigns levels from 1 (normal) to 4 (deaf, blind, mute) for sensation and levels from 1 (normal) to 5 (unable to control or use arms and legs) for mobility assessments.
Disease Surveillance
Growth and Endocrine Surveillance
Statistical Methods The IQ trend was assessed using a random effects model in which the IQ score is a linear function of the time since radiation therapy.28 We assumed that each patient had his/her own baseline and slope of change. The intercept and the slope of the time are random effects in the model. If the average slope is negative, the IQ scores are decreasing over time in the patients as a group. Graphically, a fitted line that has the average intercept and the average slope represents the trend of IQ in the time since craniospinal irradiation. The sensation and mobility measurements were assessed using logistical regression for ordinal categoric data.29 In the model, the logit of probability that the sensation or mobility score is greater than a given score is a linear function of the time since diagnosis. If the slope of the function is positive, the scores are increasing, indicating that function is deteriorating over time.
Twenty-nine patients with medulloblastoma met the study criteria. The median age at diagnosis was 2.6 years (range, 0.7 to 4 years). There were seven girls (24%) and 22 boys (76%). Thirteen (45%) had M0 stage disease (defined as no disease outside of the posterior fossa) and 16 (55%) had M+ disease (defined as disease outside the primary tumor site: CSF only [M1], supratentorial [M2], or spinal cord [M3]). Five patients had stage M1 disease, two had stage M2, and nine had M3. There were no patients with extraneural disease.
Surgery
Chemotherapy
Radiation Therapy
Survival and Progression-Free Survival
M Stage
Pattern of Failure for Patients With M0 Disease
The median age at irradiation for the 11 patients with M0 disease with early progression was 2.9 years (range, 1.3 to 5.3 years). The median irradiation doses delivered were 35.2 Gy (range, 2.2 to 35.2 Gy conventional fractionation and 44 to 55 Gy hyperfractionation) to the cranium, 51.6 Gy (range, 4.1 to 53.6 Gy conventional fractionation and 60.6 to 66 Gy hyperfractionation) to the posterior fossa, and 35.2 Gy (range, 2.2 to 35.2 Gy conventional fractionation and 39.6 to 48.4 hyperfractionation) to the spine. The remaining two patients experienced no disease progression and underwent elective irradiation (craniospinal, 24 Gy; posterior fossa, 51 Gy) at 15 and 24 months, respectively. Both were alive and well at 6 and 9 years after diagnosis, respectively.
Pattern of Failure for Patients With M0 Disease The median age at irradiation for these 12 patients with M+ disease with early progression was 3.3 years (range, 2.1 to 5.1 years). The median irradiation doses delivered were 40.45 Gy (range, 35.2 to 40.2 Gy conventional fractionation and 40.7 to 55 Gy hyperfractionation) to the cranium, 56.5 Gy (range, 49.6 to 54.6 Gy conventional fractionation and 59.8 to 66.5 Gy hyperfractionation) to the posterior fossa, and 40.45 Gy (range, 35.2 to 40.2 Gy conventional fractionation and 40.7 to 48.4 Gy hyperfractionation) to the spine. The remaining four patients did not experience disease progression during chemotherapy or later and were alive and well 4 to 12 years after diagnosis. All four underwent irradiation 11 to 13 months after diagnosis. Patients who had metastatic disease either at diagnosis or at the time of irradiation received higher doses of radiation (Table 2) both to the posterior fossa and craniospinal axis, compared with those with localized disease (P < .05).
Surgical Resection
Age
Neurodevelopmental Outcome
Cognitive outcomes as a function of staging and age were also examined at a single time point 2 years after completion of therapy. Six patients with M0 disease had adequate IQ testing with a median score of 76 (range, 62 to 97), compared with 10 patients with M+ disease with a median score of 61 (range, 50 to 85). These values were not significantly different. An age analysis showed that there was no correlation between age at irradiation and subsequent IQ scores. Finally, the two assessable patients who were treated with lower-dose craniospinal irradiation (24 Gy) had 5-year IQ scores of 55 and 62, not appreciably higher than the other patients. We examined whether patients who progressed during chemotherapy with subsequent "early" irradiation fared any worse than those who underwent irradiation only after completing chemotherapy. The numbers are too small to make any meaningful comparisons (a total of six patients), but there does not seem to be any difference between these two groups. Patients were assessed for functional levels of sensory and motor abilities at six intervals before, during, and after therapy. Approximately 68% had normal sensation scores, defined as a composite of vision, hearing, and speech skills, at the initiation of chemotherapy. Sensation abilities improved slightly after diagnosis but then steadily declined at each subsequent time point (P = .007). This persistent loss had not yet reached a plateau at the time of most recent follow-up evaluation (median, 6.4 years; range, 1.3 to 10.6 years). In contrast, mobility skills were more impaired at the initiation of chemotherapy, with only 37% functioning normally. Patients did not regain mobility skills after diagnosis; no statistically significant recovery was noted throughout the follow-up period (P = .7). Further analyses were conducted to determine if changes in IQ score could be accounted for by changes in the sensation and mobility scores; none of these was statistically significant.
Growth and Endocrine Outcome Children who were long-term survivors (> 5 years) with no evidence of disease after completion of therapy were divided into a prepubertal group and a postpubertal group at their most recent follow-up visit based on Tanner staging. A trend emerged while examining the growth data from these two groups: if the patients' weight percentiles are examined as a function of their height percentiles, it seems that patients who are long-term survivors and prepubertal tend to be short and underweight. Long-term survivors who are postpubertal tend to be short and overweight (Table 3). This has not been described before in a population of long-term survivors after intensive therapy for medulloblastoma in infancy.
This is the largest series, with the longest follow-up, of infants and young children with medulloblastoma who were treated with a modern therapeutic approach. Long-term follow-up is critical in the study of infant medulloblastoma to account for potential late recurrences and to assess adequately functional outcome. The overall survival rate of 51% at 5 years in the current report is among the highest reported in this age group (Table 4). A relatively positive outcome is documented despite the fact that more than half of the patients had metastatic disease at presentation, an incidence that seems to be greater than that reported in other series. However, it is of interest that M stage did not impact on survival. The overall survival and progression-free survival for these young children with medulloblastoma were not significantly different in patients with localized disease compared with those with disseminated disease. This counterintuitive finding differs from prior series in this age group and older children as well.4,9,30
The youngest children with medulloblastoma might have an even worse prognosis than others.9,31 We specifically examined children diagnosed with medulloblastoma before 36 months of age and compared them with patients diagnosed at
We could not establish a relationship between surgical resection and outcome in our series, although the largest series to assess malignant infant brain tumors found that the extent of surgical resection was strongly linked to outcome.12 Other publications demonstrate either no correlation between extent of resection and outcome5 or a benefit only for children Our experience highlights the important role that radiation therapy can play as salvage treatment in young children with recurrent medulloblastoma. The young children in this series were treated with postoperative chemotherapy until all planned chemotherapy had been given or until disease progression occurred. As a result, although most patients were able to defer craniospinal irradiation for several months after diagnosis, virtually all patients (almost 80%) had disease progression during chemotherapy. Despite this high rate of disease progression, radiation therapy was effective as salvage therapy, resulting in an overall survival rate of 51% at 7.8 years even in this high-risk population. This is in contrast to the experience of other investigators who report a poor salvage rate (< 10%) in young patients with medulloblastoma and progressive disease.31 Attempts at salvage without the use of radiation therapy have been ineffective.5 The therapeutic approach followed during the era described in this series was to attempt to delay the initiation of craniospinal irradiation for a minimum of 1 year and, if possible, 2 years with chemotherapy, thereby limiting age-related radiation effects on cognitive function. Despite this intent, IQ scores significantly decreased from near normal at diagnosis to a median of 68 among survivors, falling in the mentally deficient range for age. This decrease in IQ score continued for years after the completion of therapy, on the order of approximately -4 IQ points per year. No plateau had been reached at a median of almost 5 years of follow-up evaluation. This intellectual deterioration can most likely be attributed to the use of cranial irradiation in this young population; the presence of recurrent disease in almost 80% of these patients and the subsequent use of higher doses of cranial irradiation likely exacerbated this loss. The cognitive and functional status of patients after intensive, multimodality therapy for medulloblastoma is variable. Most often, cognitive deficits are attributed to cranial irradiation, especially at a young age, and to perioperative deficits.32-34 In a recent series from the Hospital for Sick Children, Dennis et al35 reported a mean IQ score of 68 among children surviving medulloblastoma who were younger than 4 years at the time of irradiation as compared with a value of 82 for similarly treated children 4 to 6 years of age. Alternative approaches to treatment reported recently may hold greater promise for preserving intellectual function among young children with medulloblastoma. Goldwein et al36 at Children's Hospital of Philadelphia reduced the craniospinal irradiation dose to 18 Gy in selected patients who are then treated with intensive postirradiation chemotherapy, and they reported largely normal intellectual development among survivors. Ater et al3 at the M.D. Anderson Cancer Center only planned craniospinal irradiation for children who experienced treatment failure with methotrexate, vincristine, prednisone, and procarbazine chemotherapy. Among the survivors who completed chemotherapy without recurrence, the decrease in IQ score was not significant. In a randomized study of craniospinal irradiation dose for medulloblastoma published by the Pediatric Oncology Group, a reduction from 36 Gy to 23.4 Gy resulted in significant conservation of intellectual abilities even among patients as young as 4 years at the time of treatment.23 Sensation scores were abnormal in approximately one third of young children postoperatively, even before beginning therapy, presumably as a result of direct or indirect (eg, elevated intracranial pressure, surgical injury) tumor-related effects. The sensation scores steadily and persistently deteriorated after the completion of therapy and had not yet reached a plateau at more than 6 years of follow-up evaluation. The majority of this worsening deficit can be ascribed to continued hearing loss, a well-described toxicity of medulloblastoma therapy that includes cisplatinum and radiation therapy.37,38 In contrast, mobility scores, although abnormal in two thirds of patients before irradiation, improved after therapy but not to a statistically significant degree. All patients were on hormone replacement therapy at their most recent follow-up evaluation. Endocrinopathies are common after radiation therapy for medulloblastoma and other brain tumors.39-41 Overall, our results confirm the significant negative effects of conventional-dose craniospinal irradiation among very young children treated for medulloblastoma.42 Current studies at St Jude Children's Research Hospital and planned Intergroup studies in the United States will modify therapy to overcome some of the shortcomings of the first generation of infant therapies. Based on published data4,43 the combination of intensive, brief chemotherapy and early local irradiation may be explored in an attempt to avoid disease progression on chemotherapy and the subsequent use of higher craniospinal irradiation doses. These interventions, and the addition of intensified intrathecal chemotherapy regimens, may allow us to maintain good overall survival rates while significantly reducing the devastating late effects of therapy described herein. In summary, we demonstrate an overall 5-year survival rate of 51% ± 10% in infants and young children with medulloblastoma, despite the presence of metastatic disease in more than half of these young patients. M stage was not predictive of outcome. All the patients in this series were treated with postoperative chemotherapy and subsequent consolidative or salvage craniospinal irradiation, and all had significant neuropsychologic injury.
Supported in part by grants no. P30 CA-21765, PO1 CA-20180, and PO1 CA-23099 from the National Cancer Institute, Bethesda, MD, and by the American Lebanese Syrian Associated Charities, Memphis, TN.
Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.
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Geyer JR, Zeltzer PM, Boyett JM, et al: Survival of infants with primitive neuroectodermal tumors or malignant ependymomas of the CNS treated with eight drugs in 1 day: A report from the Childrens Cancer Group. J Clin Oncol12:1607-1615, 1994 6. Gentet JC, Bouffet E, Doz F, et al: Preirradiation chemotherapy including "eight drugs in 1 day" regimen and high-dose methotrexate in childhood medulloblastoma: Results of the M7 French Cooperative Study. J Neurosurg82:608-614, 1995[Medline] 7. Mosijczuk AD, Nigro MA, Thomas PR, et al: Preirradiation chemotherapy in advanced medulloblastoma: A Pediatric Oncology Group pilot study. Cancer72:2755-2762, 1993[Medline] 8. Packer RJ, Sutton LN, Goldwein JW, et al: Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma. J Neurosurg74:443-440, 1991 9. Evans AE, Jenkin RDT, Sposto R, et al: The treatment of medulloblastoma: Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg72:572-582, 1990[Medline] 10. Hughes WN, Shillito J, Sallan SE, et al: Medulloblastoma at the Joint Center for Radiation Therapy between 1968 and 1984. Cancer61:1992-1998, 1988[Medline] 11. Albright AL, Wisoff JH, Zeltzer PM, et al: Effects of medulloblastoma resections on outcome in children: A report from the Children's Cancer Group. Neurosurgery38:265-271, 1996[Medline]
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Mason WP, Grovas A, Halpern S, et al: Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors. J Clin Oncol16:210-221, 1998 44. Stiller CA, Bunch KJ: Brain and spinal tumours in children aged under two years: Incidence and survival in Britain, 1971-85. Br J Cancer 18:S50-S53, 1992 (suppl) Submitted December 28, 1998; accepted July 22, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
1 year and/or to decrease the craniospinal irradiation dose used. An outline of the chemotherapy used in each protocol is presented in 
36 months at diagnosis compared with those aged 36 to 48 months (P = .8). 
