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Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1532-1538 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.8194 Survival and Late Mortality in Long-Term Survivors of Pediatric CNS Tumors
From the Departments of Oncology, Biostatistics, Radiological Sciences, Epidemiology and Cancer Control, St Jude Children's Research Hospital; University of Tennessee College of Medicine, Memphis, TN; and the Department of Public Health Sciences; School of Public Health, University of Alberta, Edmonton, Alberta, Canada Address reprint requests to E. Brannon Morris, MD, Division of Cancer Survivorship, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105; e-mail: brannon.morris{at}stjude.org
Purpose: To describe the pattern of survival and late mortality among contemporary long-term survivors of pediatric CNS tumor.
Patients and Methods: The study population comprised 643 pediatric patients with primary CNS tumor treated at St Jude Children's Research Hospital (Memphis, TN) from 1985 to 2000 who survived Results: Overall survival estimates for patients who survived at least 5 years postdiagnosis was 91.3% ± 2% and 86% ± 3% at 10 and 15 years postdiagnosis, respectively. A significant difference in the survival rates according to original tumor type (P = .001) was seen. Sixty-six (10%) of 643 patients experienced late mortality: 38 patients (58%) died of progressive disease while 14 patients (21%) died of second malignant tumor. Twelve patients (18%), predominantly with diencephalic tumor location, died of a specific medical cause: cardiovascular disease (n = 2), cerebrovascular accident (n = 1), metabolic collapse and/or sepsis (n = 7), respiratory failure (n = 1), or shunt malfunction (n = 1). Conclusion: Late mortality occurs in a substantial number of long-term survivors of pediatric CNS tumors and is most influenced by the initial tumor histopathology. Progressive disease remains the most common cause of death within the first decade of diagnosis. Teenage patients requiring treatment for panhypopituitarism may be especially vulnerable and deserve significant medical surveillance.
The number of children diagnosed and ultimately surviving a primary CNS tumor in the United States has steadily increased during the past 40 years. Unfortunately, survivors of pediatric CNS tumor are often burdened with significant medical1-6 and neuropsychological conditions,7,8 which negatively impact their health status.9,10 In fact, when compared with either the general population or other pediatric cancer survivor groups, risk of death is highest in CNS tumor survivors.11 An examination into the cause of death among such patients may help to identify future patients who require closer surveillance and/or specific interventions to help reduce their risk of death. Previous reports of late mortality in pediatric CNS tumor survivors have cited treatment-related toxicity, recurrence or progression of original CNS tumor, development of a second malignancy, or greater vulnerability for accidental trauma as the principal causes of death.11-15 Although consistent with each other, the available data is often derived from patients treated in an era dominated by whole-brain megavoltage irradiation. Furthermore, previous investigators did not well delineate between the various histologies that comprise pediatric CNS tumors, nor did they take into account primary tumor location. Because these factors may contribute to late mortality, we undertook this study to estimate overall survival and determine causes of death in a more contemporary cohort of long-term pediatric CNS tumor survivors and further analyze cause of death with respect to specific tumor and clinical characteristics.
Patients Our study sample comprised patients who had received any component of their therapy for a primary CNS tumor at St Jude Children's Research Hospital (SJCRH; Memphis, TN) between 1985 and 2000 and who had survived at least 5 years from their original diagnosis. Six hundred forty-three patients were identified from the SJCRH brain tumor database. Patients with primary CNS lymphoma and tumors arising from the meninges (eg, meningioma, hemangiopericytoma) were excluded from the analysis. All patients were  21 years of age at time of diagnosis. Survival status and last follow-up dates are current as of July 2006.
Tumor Classification and Location On the basis of magnetic resonance imaging, we classified tumor location as optic nerve (no involvement of optic chiasm), cerebrum (includes hemispheres and basal ganglia), diencephalon (includes optic chiasm/tract, hypothalamus, and thalamus), pineal, posterior fossa (includes brainstem and cerebellum), and spinal cord. With the exception of optic nerve tumors, if the tumor overlapped more than one of the above regions, the site with predominant involvement was considered the primary site. Based on initial or subsequent treatment exposure, patients were classified as having received surgery, chemotherapy, and/or irradiation.
Cause of Death
Statistical Methods Mortality rates and standardized mortality ratios (SMRs) were used to quantify risk of death in this cohort. The mortality rate was calculated as the number of deaths before the end of follow-up divided by the number of person-years at risk for death. Person-years at risk were computed, beginning on the date of diagnosis, and included time to either the date of death or date of censoring for those still alive at the date of follow-up. To compute the SMR, an expected number of deaths was calculated by using age-, sex-, calendar year-specific US mortality rates, reported by the National Center for Health Statistics, as the standard rates. All-cause SMRs were computed for all deaths.
Cohort Characteristics All patients were treated at SJCRH between 1985 and 2000 and their mean age at diagnosis was 7.5 years (range, 0.1 to 21.0 years). Fifteen patients were diagnosed with a CNS tumor before 1985 and received treatment for recurrent disease. The mean follow-up time since diagnosis was 10.8 years (range, 5.0 to 20.8 years). Clinical follow-up of survivors occurred in 66% of patients within 12 months, in 74% of patients within 24 months, and 84% of patients within 36 months. Table 1 provides overall cohort demographic and clinical features of the cohort. Sex difference was minimal, but white race predominated. Excluding patients who were observed without treatment or whose treatment consisted of surgery only (248 patients), 245 patients (62%) of the cohort received therapy according to either an institutional or multi-institutional protocol.
Cohort Survival Estimates When compared with a US population that is matched for age, sex, and calendar period, our cohort demonstrated inferior outcomes. The reported survival estimates for the US population (10 years, 99.5%, and 15 years, 99%) was higher than the overall survival estimates observed in our cohort (10 years, 91%; 95% CI, 88.5 to 93.5%; and 15 years, 85%; 95% CI, 81.3% to 89.6%). Survival with respect to underlying histology is graphically represented in Figure 1.
Cohort Mortality Estimates The overall estimated probability for death in  5-year pediatric CNS cancer survivors (measured from time of diagnosis) at 10 years was 8.7% ± 1.5% and 14.0% ± 3.1% at 15 years (SE). Mortality estimates categorized by tumor histology, location of tumor, and age at diagnosis are summarized in Table 2. We observed no significant difference in mortality on the basis of tumor location or by age at diagnosis. However, a statistically significant difference (P < .001) in mortality was noted with respect to initial tumor histology.
Late Mortality Late mortality occurred most commonly in the adolescent period (median, 16.4 years; range, 5.9 to 30.0 years) and in the 5- to 9-year period after a diagnosis of primary CNS tumor (median, 7.8 years; range, 5.1 to 20.0 years). As presented in Table 3, death (overall) occurred in this population almost 30 times more than expected (SMR, 28.2; 95% CI, 21.8 to 35.9). SMRs were elevated in all age groups but highest in those patients who were diagnosed with CNS tumor 3 years of age (62.2; 95% CI, 36.8 to 98.3).
Cause of Death Medical records documenting cause of death were available for all deceased patients. Overall, 34 patients died of PD, 14 patients of SMT, 12 patients with MC, four patients with MT, and two patients with EC. The 10-year cumulative incidence estimates of different causes of death and various factors are provided in Table 4. The cumulative incidence of death due to progression differed significantly by tumor histology (P < .0001). The other comparisons that were significant are: cumulative incidence of death due to second malignancy by tumor histology (P = .007), cumulative incidence of death due to medical condition by tumor histology (P < .0001), and death due to medical condition by tumor location (P = .014).
Four patients died as a result of the transformation of a low-grade tumor (three LGG; one ganglioglioma) into a high-grade tumor (glioblastoma multiforme). Transformation of the initial tumor was histologically confirmed in all patients, and it occurred at an average of 9 years (range, 5 to 11.6 years) from initial diagnosis. These patients were included in a recent institutional review of malignant transformation in pediatric CNS cancer.22 A second malignant tumor was directly implicated as cause of death in 14 patients. A high-grade CNS neoplasm was diagnosed in 10 patients, three patients developed myelodysplastic syndrome, and one patient died as a result of metastatic ovarian cancer. All patients but one had a history of prior irradiation. The patient who did not receive irradiation developed a secondary myelodysplastic syndrome. In this cohort of 5-year survivors, the average interval between first and second cancer diagnosis was 9.8 years (range, 4.9 to 18.5 years). The average interval between second tumor diagnosis and death was 10.5 months (range, 0.5 to 23 months). Twelve patients (18%) died from a secondary medical condition. Pertinent clinical and diagnostic information regarding these patients is provided in Table 5. The majority of patients had a primary tumor located within the diencephalon, multiple endocrinopathies, and subsequently died from multiorgan failure—including metabolic collapse, cardiopulmonary compromise, or sepsis. Overall, in our cohort, death due to a medical complication occurred almost 25 times more often than would be expected for a similarly matched population (SMR, 24.9; 95% CI,12.8 to 43.5).
In our cohort of 5-year survivors of pediatric CNS tumor, the overall 10- and 15-year survival estimates were approximately 90% and 85%, respectively. Unfortunately, these optimistic estimates cannot be generalized to all pediatric CNS tumor survivors alike. Our results suggest that continued long-term survival is primarily dictated by the underlying tumor histology (Fig 1). Not surprisingly, long-term survivors of LGG had the highest survival rate (10 year, 97%; 15 year, 91%), while patients with HGG had the poorest survival (10 year, 67% ± 11%; 15 year, 61% ± 14%). Worse survival estimates in more than 5-year survivors of HGG and ependymoma were reported over a decade ago,23 and our results underscore a continued need for long-term surveillance in these two tumor types. Embryonal tumors are the most common CNS tumor in childhood, and 5-year survival rates have steadily improved over recent years. In this series of patients, the chance of surviving an embryonal tumor an additional 5 to 10 years after reaching the 5-year postsurvival milestone appears to be approximately 90%. No deaths among the embryonal group occurred between postdiagnosis years 9 to 15. In accordance with other recent reports of patients who survived an embryonal tumors longer than 5 years,23,24 risk of death (most often due to disease progression) is heavily weighted in years immediately after diagnosis and significantly less within the decade after the attainment of 5-year survival. Unfortunately, given the degree of morbidity often recognized in this population, premature death is expected as these patients continue to age. The overall incidence of late mortality in our cohort was 10%. Because our incidence value is less than those previously reported11-15 (15% to 26%; mean, 18%), improved long-term cancer control and reduced treatment toxicity in an era dominated by multimodal therapy may be supposed. However, because mortality is an asymptotic term that approaches 100% over time, we believe a more meaningful description of late mortality in cancer survivors is provided by a cumulative incidence analysis. To the best of our knowledge, the cumulative incidence of late mortality (both overall and factor dependent) in pediatric primary CNS tumor survivors has not been previously reported. Similar to previous studies,12,23,25 the predominant cause of death in our cohort was PD or recurrence of primary tumor. Although PD most often occurred in 5 to 9 years after diagnosis, seven patients died (three ependymoma; four LGG) from PD more than 10 years after diagnosis (10.5 to 20 years). After reaching the 5-year survival milestone, risk of death from PD in the subsequent 5 years is notable in patients with ependymoma and HGG. No patients with craniopharyngioma, germ cell tumor, or choroid plexus carcinoma in this cohort died from PD. Together, PD, MT, and SMT were responsible for almost 80% of the deaths in our cohort. In a cohort of 912 irradiated patients between 1958 and 1991, Jenkin et al23 reported an incidence of PD plus SMT of 93%. Hawkins et al12 reported an incidence of cancer-related mortality of 83% in 1,257 patients diagnosed with CNS tumor before 1971. Because our ability to identify patients at risk for cancer-related late mortality remains limited, further research that focuses on genetic and molecular factors attributable to late PD, MT, and SMT is of interest. Death from either a medical condition or trauma comprised the remaining 20% of our cohort. Patients with primary tumor of craniopharyngioma or germ cell tumor had a significantly elevated risk for death from a medical condition relative to other tumor types. Of the various causes, death from hormone dysfunction predominated. Hawkins et al12 identified this vulnerable population more than 15 years ago and presumed these deaths were potentially avoidable given available life-saving treatment. In our series, all seven of the patients who died of sepsis/metabolic collapse had a known history of panhypopituitarism and were prescribed chronic hormone replacement therapy. Unfortunately, full compliance of hormone therapy in CNS tumor survivors may be limited by a number of factors: neurocognitive impairment, relatively asymptomatic condition, reliance on a caregiver, and complexity of treatment.26 In addition, similar to other chronic illnesses of childhood, adherence to chronic hormone replacement therapy may be complicated by the unique biopsychosocial processes implicit in the period of adolescence.27 In this regard, the average age of 14.1 years in these seven patients at death is pertinent to note. Certain limitations should be considered when interpretating these findings. Despite adequate documentation of terminal status, this study was retrospective in nature. Our cohort is relatively large, but assessment of patient status is current only to the date of the last clinical encounter. Given that 25% of the cohort had no clinical follow-up within 24 months of the analysis, the rate of mortality was potentially underestimated. However, it is unlikely many deaths occurred without our knowledge; St Jude Children's Research Hospital's Cancer Registry and Alumnus Program Office is quite active, and vital status of survivors are periodically monitored through National Death Index searches. Because SJCRH serves as a national referral center, the cohort may be over-represented with patients requiring significant therapy for recalcitrant disease. However, the majority of these patients are referred for phase I therapy, do not survive more than 5 years, and would not have been eligible for this review. It is also possible that lack of access to community providers familiar with health complications experienced by brain tumor survivors may have influenced our results. If access to appropriate medical care is limited, particularly for those living greater distances from SJCRH, higher mortality rates due to treatment toxicity might be expected. In this regard, it is pertinent to note that four of seven patients who died of sepsis/metabolic collapse were local residents. Finally, because the CNS tumor program at SJCRH was not initiated until 1985, only a small number of 20-year survivors are available for analysis. Consequently, interpretation of results is limited to 15-year survival. The incidence of late mortality in long-term pediatric CNS tumor survivors may be decreasing. However, these patients' risk of mortality continues to be substantially higher than that of a matched population. As previously reported, the primary cause of death is progressive or recurrent tumor occurring within the first decade of diagnosis. Further analysis identified initial tumor histopathology as the most significant factor to influence survival and late mortality. Patients previously diagnosed with ependymoma or HGG have significantly worse survival estimates and are more likely to die of progressive disease. Patients with germ cell tumor and craniopharyngioma are more likely to die from a medical complication. Although primary tumor location did not predict survival or late mortality, patients with diencephalic tumors should be carefully monitored. Death related to hormone dysfunction may be preventable, and interventions to improve adherence to hormone replacement therapy should be considered. Particular attention should be given to independent adolescent patients. Death from ventricular shunt malfunction may also be preventable. Signs and symptoms of increased intracranial pressure should be reviewed with patients periodically.
The authors indicated no potential conflicts of interest.
Conception and design: E. Brannon Morris, Amar Gajjar, Melissa M. Hudson Provision of study materials or patients: E. Brannon Morris, Amar Gajjar, Larry E. Kun, Thomas E. Merchant, Maryam Fouladi, Alberto Broniscer, Melissa M. Hudson Collection and assembly of data: E. Brannon Morris, Amar Gajjar, James O. Okuma, Dana Wallace, Melissa M. Hudson Data analysis and interpretation: E. Brannon Morris, Amar Gajjar, James O. Okuma, Yutaka Yasui, Dana Wallace, Larry E. Kun, Thomas E. Merchant, Maryam Fouladi, Alberto Broniscer, Leslie L. Robison, Melissa M. Hudson Manuscript writing: E. Brannon Morris, Amar Gajjar, Larry E. Kun, Alberto Broniscer, Melissa M. Hudson, Thomas E. Merchant Final approval of manuscript: Melissa M. Hudson
We thank James Boyett, PhD, for his critical review of the manuscript. We also thank Annemarie McClellan, Tad McKeon, and Jana Freeman for their expertise and assistance with the SJCRH brain tumor database.
Supported by the Cancer Center Support Grant No. P30 CA 21765 from the National Institutes of Health, by the Noyes Foundation, Musicians Against Childhood Cancer, and by the American Lebanese Syrian Associated Charities. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
