We have comprehensively assessed long-term outcomes of 5-year survivors of CNS tumors who were diagnosed and treated from 1970 to 1986. This extended follow-up evaluation of the CCSS cohort quantifies the occurrence and impact of late effects secondary to childhood CNS malignancies and their treatment on the lives of adult survivors. Unfortunately, survivors of CNS malignancies are at increased risk for mortality, subsequent cancer, and other outcomes resulting from their disease and treatment throughout their lifetime (36
). Survival beyond 5 years of cancer diagnosis is often the benchmark for defining cancer survivorship. However, according to our analysis, even after surviving to the 5-year time point, more than 25% of CNS survivors will die within 30 years of their diagnosis. This mortality rate is 13 times higher than that for the age- and sex-matched US population. Late mortality is highest for 5-year survivors of ependymoma or embryonal tumors (approximately 33% of these patients die within 20 years). Survivors of medulloblastoma or primitive neuroectodermal tumors have a risk of death that is 17-fold that of the general population.
The annual death rate from second neoplasms did not surpass the annual death rate attributable to recurrence or progression of primary disease until approximately 30 years from diagnosis. This is much later than for other pediatric cancers, largely because low-grade gliomas in children may remain indolent for many years before ultimate progression and mortality (3
). However, a similar pattern of late mortality was seen for medulloblastoma or primitive neuroectodermal tumors such that recurrence or progression of the original diagnosis was the primary cause of death until 20 years from diagnosis, and for ependymoma, recurrence or progression was the leading cause of death until 30 years after diagnosis. This pattern of late recurrence suggests a need for continued surveillance of disease well beyond the first 5 years from diagnosis.
Survivors of CNS tumors are at a statistically significantly increased risk of developing subsequent neoplasms, the most common site being the CNS. Previous investigations have reported cumulative incidence estimates of subsequent neoplasms for brain tumor survivors from single institutions (4% at 15 years) (6
), cooperative groups (11% at 8 years) (8
), and those covered in tumor registry–based studies (2.6% at 20 years; 7.3% at 30 years) (9
), but these studies were limited by small sample size, inability to capture all second neoplasms, or insufficient treatment information.
Medical complications in survivors of pediatric CNS malignancies in the first 5 years subsequent to diagnosis are common due to neurosurgical procedures, therapeutic modalities, and the tumor itself (43
). Unfortunately, even after 5 years, these survivors remain at high risk for developing new medical conditions. Many of the centers where childhood cancer patients are treated are pediatric-based institutions that are not able to provide continuing medical care for survivors of CNS neoplasms as they become adults. With increasing time from the original cancer diagnosis, the proportion of adult survivors of childhood cancer who receive long-term, risk-based follow-up in a cancer center or a clinic specific for long-term follow-up of cancer patients decreases substantially (44
). Thus, disseminating information about risks to the general practitioners who follow-up the majority of survivors and developing guidelines for long-term care is important (46
Previous investigations have established that CNS tumor survivors differ from those with other primary cancers in having more adverse outcomes in terms of education, employment, and health status and quality of life (47
). However, most previous studies of the long-term effects of CNS neoplasms analyzed fewer than 100 CNS tumor survivors and followed them up for only the first 10 years of diagnosis, thus failing to capture outcomes in adulthood. We have previously reported statistically significant health impairment and poor sociodemographic outcomes in this population (55
). In this study, we have identified important associations between frontal and temporal lobe radiation and outcomes in employment and marriage. Because the frontal and temporal lobes mediate executive function and memory, these findings have biologically significant implications and underline the need to limit the extent of radiation fields during radiation delivery.
Some limitations of this research should be considered when assessing the validity and generalizability of these findings. First, medical conditions and sociodemographic and health status outcomes were self-reported. Subsequent neoplasms may be underreported despite a thorough validation process (5
). Second, not all eligible survivors participated, and this could introduce participation bias, although previous assessment showed few differences between participants and nonparticipants (21
). Third, in diagnosing the eligible cohort for this period, World Health Organization classifications of brain tumors were followed, according to which many glial tumors were classified “Astrocytoma, NOS,” (not otherwise specified) precluding a more specific classification. Given the extremely poor overall survival of patients with high-grade gliomas in this study period, most 5-year survivors of glial tumors likely had low-grade lesions. Finally, primary therapeutic modalities have changed substantially since the period (1970–1986) when the patients in this study were initially treated: There has been a reduction in radiotherapy doses for lower risk patients, increased use of chemotherapy, including high-dose chemotherapy, and adoption of improved surgical and radiotherapy delivery techniques. Thus, the results of this analysis may not be generalizable to tomorrow's long-term survivors.
In conclusion, adult survivors of childhood CNS tumors are at high risk for late mortality and for developing second neoplasms and new chronic medical conditions related to their disease and treatment. Continued follow-up will help determine temporal patterns in incidence and late effects as this cohort ages. We are expanding the CCSS cohort to include 5-year survivors diagnosed from 1987 to 1999. Modern therapeutic regimens that increasingly use chemotherapy to reduce RT dose or use limited RT fields will likely improve long-term outcomes and minimize the risk of adverse late effects. Meanwhile, the dissemination of these results to care providers will enable informed medical care and help develop screening recommendations for patients.