This report delineates the type and prevalence of specific health conditions systematically ascertained across multiple organ systems among a large, histologically heterogeneous population of adults formerly treated for childhood cancer. In contrast to published studies, the SJLIFE study prospectively applied consistent risk-based screening to quantify the burden of chronic disease among long-term childhood cancer survivors. These results provide precise estimates of the prevalence of treatment-related morbidities among long-term childhood cancer survivors and an enumeration of the chronic health conditions known to be associated with early mortality in the general population. Unique from previous publications, the present study also quantifies the substantial proportion of previously undiagnosed disease among cohort members, underscoring the need for ongoing follow-up and assessment.
Prior studies investigating long-term outcomes of adults treated for cancer during childhood have largely relied on survivor self-report of outcomes or registry data.2-5
U.S. research programs reporting outcomes based on medical assessments have featured relatively small cohorts, including those with pediatric-aged survivors.12-14
A previous study retrospectively evaluated the prevalence of adverse outcomes that were identified through late effects clinic evaluations undertaken from 1996 to 2004 among 1362 five-year survivors of childhood cancer (median age 24.4 years) in the Netherlands.1
Medical assessments were performed according to standardized follow-up protocols; however, specific screening methodologies and total numbers screened for each condition were not described. Their findings confirmed the burden of morbidity present in a young adult cohort (88% were younger than 35 years). At an average follow-up of 17 years, 75% of survivors experienced at least one adverse event; 40% had at least one severe, life-threatening or disabling event. Our results extend these findings in an older survivor population by documenting yield from risk-based screening according to standardized guidelines and by demonstrating the age-specific burden of particular chronic health conditions followed for a mean of 26.3 years from diagnosis. Moreover, the focus on exposure-driven, risk-based screening increases the relevance of our findings, considering the fact that despite the substantial evolution of therapeutic approach for various pediatric malignancies over the last 50 years, most of the specific treatment modalities prompting screening remain in use.15,16
Analyses evaluating outcomes related to the evolution of “packaging” these modalities over time and its influence on the prevalence of organ-specific outcomes for clinical diagnostic groups will be the subject of future investigations.
For some organ systems evaluated, the results of risk-based assessment revealed a substantial number of previously undiagnosed problems that are typically observed in older populations.17-21
This had a marked effect on the estimates of age-specific organ dysfunction. Comparing the prevalences of our outcomes to those reported in previously published studies is difficult as the latter often represent clinically manifest conditions,2-5
those derived from inconsistent screening practices administered over a long period of time,1
or those applied to convenience cohorts.13,14
Recent studies implementing systematic screening in younger survivor cohorts have similarly identified a high prevalence of abnormalities after selected systems were evaluated, e.g., pulmonary.13
In our cohort, the prevalence of newly discovered neurocognitive and neurosensory deficits, heart valve disorders and pulmonary dysfunction were particularly striking. Considering the median age of this cohort was only 32 years, these data are concerning and may indicate a pattern of accelerated or premature aging. Evaluation of the contribution of predisposing host and treatment factors to this phenomenon will be the focus of future research.
The primary aim of our study was to establish the prevalence of late health effects following systematic screening after predisposing cancer treatment-related exposures, with a particular emphasis on preclinical disease manifestations. For analytical purposes we dichotomized screening outcomes, which included a spectrum of conditions of varying severity, as present or absent. Ninety-eight percent of our cohort had one or more chronic health condition with 67.6% having a severe or life-threatening/disabling condition by CTCAEv4.0 (Grade 3-4). While some findings may not immediately influence on the health status of survivors, their presence may reflect early disease outcomes that may be remediated or at least monitored prospectively to assess the relationship to future decline in function. For example, adult survivors of childhood leukemia who received 24 Gy cranial irradiation demonstrated reduced cognitive status and memory on formal neuropsychological testing.22
The abnormalities detected did not affect functional status measures like employment, but are consistent with early onset mild cognitive dementia, underscoring the need for longitudinal evaluation as this group ages.
Exposure-specific, risk-based screening resulted in identification and referral for treatment of some conditions that are amenable to remediation. These included low stage occult breast cancers identified by breast imaging in women treated with chest radiation, and cardiomyopathy identified by echocardiography among those exposed to anthracyclines and chest radiation. In contrast, the yield from screening for other outcomes, e.g., myelodysplasia and kidney dysfunction, was negligible. Low yield from laboratory assessments of hematological and biochemical parameters has been reported in a younger survivor cohort followed just over 10 years.13
Confirmation of these findings in this older and larger cohort provides reassurance that these conditions do not increase in prevalence with aging. Collectively, the data from risk-based screening also provide clinically relevant information about the magnitude of risk and preclinical manifestations of common late effects to guide refinement of health screening recommendations.
Assessment of all survivors with a core laboratory battery permitted evaluation of associations of specific cancer treatment and chronic health conditions. As expected, endocrine and reproductive disorders were largely associated with previous treatment with radiation and alkylating agents. The association of cancer treatment with conditions highly prevalent in the general population, such as obesity and diabetes, was lower. For example, an increased risk of metabolic syndrome or its components has been observed among cancer survivors treated with HPA irradiation.23
However, within the SJLIFE cohort, the AF of obesity, diabetes mellitus, dyslipidemia and hypertension ranged from 9%-42% among survivors. The current report describes the occurrence of health outcomes within childhood cancer survivors following the initial cross-sectional clinical assessment. In depth analyses are underway to identify predictors of and risk profiles for specific outcomes, which take into consideration the inter-relationships between genetics, demographic and lifestyle factors, treatment exposures, and co-morbidities. The ongoing prospective follow-up of these patients will also provide additional insights into the longitudinal changes in health outcomes within an aging survivor population.
These findings should be considered in the context of study limitations. Results could be influenced by selection bias considering the 60% participation rate for onsite comprehensive evaluations. However, the lack of substantial differences between the studied and the source population of SJLIFE in the relative frequencies of demographic, disease, or neighborhood characteristics reduces concerns about selective non-participation.7
It is possible that differences in attained age and time from diagnosis between participants and non-participants could bias results if the older non-participants who had a greater elapsed time from treatment had more chronic health conditions. Because of enrollment priorities based on treatment exposures in this dynamic cohort, the study population does not precisely reflect the distribution of histologies that would be expected in a long-term childhood cancer survivorship cohort. For example, the proportion of those with leukemia is somewhat higher, and those with brain cancer lower, than would be anticipated in a large random sample of survivors. Those relative proportions will tend to balance as recruitment and enrollment in this ongoing study continue over time. In addition, the yield of screening is likely underestimated in the SJLIFE cohort as many had been previously screened as participants in the pediatric long-term follow-up clinic at St. Jude. Moreover, the absence of controls in our study precluded assessment of the actual clinical effect of screening. Failure to undertake uniform evaluations among all cohort participants also precluded the discovery of novel treatment-related outcomes. Finally, when interpreting the cumulative prevalence within our population it is important to keep in mind that the rates are based upon the experience of patients who were alive at the time of recruitment for clinical evaluation. Thus, these prevalence rates underestimate actual incidence if one assumes that the population of patients who met eligibility criteria, but died prior to recruitment to the SJLIFE cohort, experienced a high rate of morbidity prior to death. This assumption seems reasonable because reports of late mortality among childhood cancer survivors have indicated that death from second cancers, cardiac events, and pulmonary events are the most frequent causes.24
In summary, this study provides global and age-specific estimates of clinically ascertained morbidity in multiple organ systems in a large systematically evaluated cohort of long-term childhood cancer survivors. The percentage of survivors with one or more chronic health conditions prevalent in a young adult population was extraordinarily high. These data underscore the need for clinically-focused monitoring, both for conditions that have significant morbidity if not detected and treated early, such as second malignancies and heart disease, and also for those that if remediated can improve quality of life, such as hearing loss and vision deficits.