In this study of 5-year neuroblastoma survivors, we observed that the cumulative 20-year incidence of a chronic health condition is 41.1%, with an 8.3-fold increased risk when compared with their siblings. The most prevalent outcomes involved the neurological, sensory, endocrine, and musculoskeletal systems, with 20-year cumulative incidences of 29.8%, 8.6%, 8.3%, and 7.8%, respectively. Survivors treated with multimodality therapy were at increased risk of developing a chronic health condition compared with those treated with surgery alone. Six percent of patients died more than 5 years after their diagnosis, with the most common causes of death being disease recurrence and second malignant neoplasms.
The published literature on late outcomes for neuroblastoma survivors, which is based on case series and small cohorts of neuroblastoma survivors, reports treatment-related outcomes including musculoskeletal and neurological problems (7
), severe sensorineural hearing loss (14
), endocrine deficits (8
), and increased risk of second malignant neoplasms (17
). The current study of more than 900 neuroblastoma survivors who were followed up to 30 years from diagnosis, to our knowledge, represents the largest comprehensive investigation of long-term outcomes in this specific population. Our data confirm the results of many of the previous smaller studies and provide additional information regarding the incidence or prevalence and risk factors for specific outcomes. We demonstrate that the risks of mortality and of developing a chronic health condition are statistically significantly higher for neuroblastoma survivors than would be expected in the general population or observed among siblings. In expanding on our previous report about chronic health conditions 30 years after a diagnosis of neuroblastoma (4
), we now demonstrate that risks were particularly high for development of a second malignant neoplasm and musculoskeletal or neurological complications. It is also noteworthy that neuroblastoma survivors who were diagnosed and treated more recently (1981–1986) had the highest cumulative rate of chronic health conditions. The latter finding may reflect the introduction of more intensive therapies for patients who were judged by risk stratification to have a poor prognosis and the treatment of low- or intermediate-risk patients with relapsed disease. Increased therapeutic exposure in this population could result from greater dose intensity, stem cell transplantation, and regimens using multimodality approaches (2
The 25-year cumulative risk of late mortality in this study was 6%. Main causes for late mortality were disease recurrence, second malignant neoplasms, and cardiac complications. These findings are similar to those reported for survivors of all types of childhood cancer (30
). Also, the increased risk of late mortality for patients who were older than 5 years at diagnosis is consistent with the findings of previous studies of childhood cancer survivors (30
Similar to observations among all survivors of childhood cancer combined (32
), the cumulative incidence of second malignant neoplasm among neuroblastoma survivors was 3.5% at 25 years and increased to 7.0% at 30 years, with risk being statistically significantly associated with exposure to radiation therapy. As in previous smaller series, thyroid cancer, breast cancer, and acute myeloid leukemia were among the most common second malignant neoplasms observed in neuroblastoma survivors (13
). The occurrence of five patients with renal cell carcinoma in our cohort is particularly noteworthy. The occurrence of renal cell carcinoma after neuroblastoma has been described previously (34
). Although some cases of renal cell carcinoma have occurred following exposure to chemotherapy, particularly with cyclophosphamide, the fact that others have occurred in neuroblastoma patients who were not exposed to any chemotherapy suggests the possibility of an underlying genetic predisposition (35
). Recently, Altinok et al. (36
) described an Xp11.2/TFE3
translocation in a neuroblastoma patient who developed renal cell carcinoma after exposure to chemotherapy. The same translocation has been described in patients with renal cell carcinoma after chemotherapy in individuals with diagnoses other than neuroblastoma, suggesting that cytotoxic chemotherapy may predispose to the development of this specific form of renal cell carcinoma (35
Musculoskeletal and neurological late effects have been reported in small series of low- or intermediate-risk neuroblastoma survivors (7
). The most common of these is the development of scoliosis that is associated with moderate to high doses of radiation therapy (1500–5000 cGy, frequently administered in an asymmetric spinal field). Neurological complications, including mild to severe paresis, paraplegia, and neurogenic bladder, have also been described. These conditions, which occurred at 3- to 20-fold higher rates in neuroblastoma survivors than siblings, could be disease related (eg, intraspinal tumors) and/or could be complications of surgery. In addition, the data indicated that age at diagnosis was a statistically significant risk factor for the development of a neurological complication, with infants who were diagnosed at less than 1 year of age being at greatest risk. This increased risk may be a reflection of the difficulties inherent in operating on small infants, in cases of epidural neuroblastoma.
We also found that the risk of blindness was increased in neuroblastoma survivors compared with siblings. Cranial radiation therapy was associated with increased risk of blindness. Blindness was most likely to be due to disease that involved either the base of the skull or the orbits and that was treated with radiation therapy.
Not unexpectedly, we found neuroblastoma survivors to be at a statistically significantly increased risk of hearing loss. Exposure to cisplatin was the major risk factor for hearing loss. Hearing loss at a young age has a substantial impact on speech acquisition and academic achievement and may contribute to an increased need for special education services (37
). Nonetheless, neuroblastoma survivors reported educational attainment similar to siblings. However, the neuroblastoma survivors differed substantially from the sibling cohort in psychosocial outcomes, including having never been employed, having lower individual and household income, and being less likely to have ever married. These outcomes are suggestive of a diminished level of social integration among neuroblastoma survivors. Few studies have specifically investigated the quality of life of neuroblastoma survivors (16
). A recent Children's Oncology Group study (16
) found that the 137 neuroblastoma survivors did not score substantially different from population norms on validated quality-of-life measures but those with hearing loss had substantially increased risk of academic problems and indicators of psychosocial distress. Barrera et al. (38
) also reported neuroblastoma survivors to be at risk for decreased emotional well-being and adverse social outcomes.
Several issues need to be considered when interpreting our findings. First, the medical conditions are self-reported without external verification, with the exception of mortality and second malignant neoplasms, and self-reporting has the potential to result in misclassification of outcome status and imprecision in risk estimates. Second, it was necessary to restrict the current report to selected outcomes because it is not possible to adequately present results on the full range of potential late effects. Many additional possible outcomes (eg, chronic pain, hepatitis C, posttraumatic stress, etc) will be the subject of future CCSS publications and will present findings stratified on initial diagnosis.
Third, the CCSS cohort is hospital based as opposed to population based, and a proportion of eligible subjects did not participate in the baseline survey and thus are not included in analyses of risk factors for chronic health conditions. These features must be considered within the context of the generalizability of the results and the potential validity of the rates obtained. Although the similarity of demographic- and treatment-specific characteristics of participants and nonparticipants is reassuring, it is still possible that nonparticipants systematically differ with respect to prevalence of chronic health conditions, thus resulting in biased estimates. Nonetheless, previously published results from the CCSS relative to late mortality and morbidity are similar to those in smaller population-based studies from Europe (40
). With this in mind, it is still important to note that the population of neuroblastoma survivors in the current project represents one of the largest series reported to date.
Fourth, neuroblastoma staging was not collected for participants in the CCSS cohort. Although lack of staging data might appear to be a limitation, it actually had minimal consequences because there has been a marked shift in risk- and stage-based tailoring of therapy, which makes it more relevant to considering late effects among survivors relative to the actual treatment exposure of the patients rather than to their stage of disease.
In summary, young adult neuroblastoma survivors who were treated in the 1970s and 1980s are at risk for many adverse outcomes, including second malignant neoplasms, chronic health conditions, and unfavorable psychosocial outcomes. It will be important to continue to follow this relatively young adult cohort of survivors to determine whether the pattern of adverse outcomes will change as they age. For children who are currently undergoing intensive treatment for neuroblastoma, the results of the current study are quite relevant and underscore the need for close surveillance and lifelong follow-up to ameliorate potential medical and psychosocial late effects. Future research should build on these data and investigate risk factors for long-term complications of neuroblastoma treatment and second malignant neoplasms, including genetic studies for the risk of renal cell carcinoma.