Through comprehensive, risk-based evaluation and correlation with pertinent host- and disease-related factors, the SJLIFE study is in a unique position to advance knowledge about the impact of aging on childhood cancer-related morbidity and mortality. We aim to define the prevalence and cumulative incidence of selected late treatment complications following predisposing therapeutic exposures. We anticipate that our findings will inform more accurate risk profiles for adverse outcomes in adults surviving childhood cancer and insights into mechanisms of cancer-related morbidity in an aging population. Knowledge gained will be critical for the development of follow-up guidelines and timely interventions to prevent or ameliorate cancer-related sequelae and their adverse effects on quality of life.
The progress achieved in curing childhood malignancies has created unique challenges for health outcomes research in childhood cancer survivors. The required transition of care of aging survivors from pediatric oncology to community medical providers often poses significant barriers to the evaluation of childhood cancer’s impact on health during adulthood. Because many adverse effects of treatment may not become clinically apparent until the survivor attains maturity or begins to age, continued follow-up during adulthood is essential to accurately characterize very late cancer-related sequelae and determine if complications resulting from cancer therapy will be exacerbated by the organ dysfunction associated with aging. Prospective medical assessment of survivors offers the opportunity to accurately characterize long-term survivor health and identify clinical groups at high risk for cancer-related morbidity who may benefit from health promoting interventions. However, most research programs involving medical assessment of health outcomes in adults surviving childhood cancer are limited by substantial participation bias as insurance coverage typically determines the medical assessments undertaken. Only one previous study has undertaken medical assessments in a cohort of comparable magnitude to the SJLIFE cohort.7
Dutch investigators were successful in recruiting 1362 (94.3% of eligible) five-year survivors of childhood cancer treated between 1966 and 1996. Substantial morbidity (both clinical and subclinical) was observed in this group who had attained a median age of 24.4 years and median follow-up of 17 years. This study was facilitated by a robust national health care system and cancer registry. In contrast, the SJLIFE cohort is older (median age 32.3 years) and has longer follow-up (median time, 24.3 years) from diagnosis. Because of the challenges faced by providers supervising follow-up care of childhood cancer survivors in the United States, the SJLIFE study is designed to facilitate prospective and comprehensive risk-based medical assessment of long-term survivors by eliminating key barriers to participation identified by survivors through pre-recruitment surveys. Insurance coverage does not dictate the study evaluations undertaken since all SJLIFE medical assessments are supported entirely by institutional funds. Likewise, travel and lodging are provided for study participants, who are also reimbursed a per diem rate to compensate for miscellaneous costs such as missed days at work or childcare expenses. Providing this type of assistance may alleviate barriers to study participation, such as low socioeconomic status (SES), and explain the excellent participation rates (which are currently > 92%) following study invitation.
Late sequelae of therapy for childhood cancer can be anticipated based on therapeutic exposures, but the magnitude of risk and the manifestations in an individual patient are influenced by numerous factors.2
History pertinent to the host (age at diagnosis, time from therapy, sex, genetic/familial characteristics, premorbid health conditions, tolerance to therapy, socioeconomic status, health habits) and cancer (location, histology/biology, treatment modality) must be considered in the risk assessment for cancer-related morbidity. However, few health outcomes investigations have access to a large and well-characterized clinical cohort of survivors to address the multi-factorial nature of cancer-related morbidity, particularly in regards to the impact of aging on long-term childhood cancer survivor health. This information is essential to guide the development of health screening recommendations and health-preserving interventions for children who present with a new diagnosis of malignancy as well as for those who have already achieved long-term survival. Better understanding of the nature and severity of long-term adverse effects of treatment will also inform the development of newer treatment strategies for childhood cancer.
While cancer-related morbidity is anticipated to adversely impact the natural course of organ senescence during adulthood, factors contributing to the risk of premature organ dysfunction and secondary carcinogenesis require continued investigation as treatment approaches evolve. This is particularly relevant to health risks associated with contemporary risk-adapted treatment regimens that have been modified to reduce therapy intensity for clinically and biologically favorable presentations of pediatric malignancies. Subclinical effects on vital organ function--cardiovascular, pulmonary, hepatic, and renal function--are frequently observed in these cohorts; the impact of these subclinical changes on long-term health in aging survivors has not been established. Characterization of long-term survivor health is also critical to establish if contemporary treatment modalities have been successful in their aims to reduce late cancer-related morbidity. For example, technical advances in therapeutic radiation have largely focused on optimizing protection of normal tissues, but research confirming the effectiveness of these approaches in reducing morbidity in long-term survivors is lacking. Likewise, late health outcomes resulting from more intensive interventions like hematopoietic stem cell transplantation undertaken for children with relapsed and high risk malignancies have not been established. Through a scientifically-rigorous research protocol, the SJLIFE cohort will provide important new information regarding characterization of long-term outcomes in these individuals, which is necessary to determine the true costs of achieving long-term disease-free survival in regards to health status and quality of life. Evaluation of the impact of treatment modifications over time is a priority objective of the SJLIFE study that should be facilitated by recruitment of a large cohort of survivors with diverse pediatric cancer diagnostic types treated over the last 48 years.
Research is also needed to promote the early identification of survivors at risk for cancer-related morbidity using both conventional and novel clinical and laboratory-based methods. Potential novel laboratory investigations utilizing the biologic specimens of the SJLIFE cohort include, but are not limited to, more extensive analyses of: vital organ function, biomarkers of metabolic function, micronutrient levels, cancer-predisposing genetic mutations, cancer susceptibility genes relating to phase I enzymes (that activate or deactivate carcinogens depending on the experimental conditions) and phase II enzymes, (that are more likely to detoxify pharmaceuticals). Correlation of results from these laboratory evaluations with other diagnostic assessments and cancer treatment exposures may enhance understanding of the pathophysiology underlying cancer treatment toxicity. The ability to identify survivors with subclinical changes of treatment-related toxicity then may provide an opportunity for early detection, rehabilitation, and prevention of cancer-related morbidity.
Preliminary SJLIFE investigations will broadly evaluate “at risk” survivors based on treatment exposures to establish prevalence and severity of specific cancer-related toxicities. The prevalence of late treatment complications detected by risk-based screening will provide important information regarding the appropriateness of the COG Guidelines recommendations in at risk survivor populations after specific therapeutic exposures. Notably, the health surveillance measures recommended by the COG Guidelines are derived from the clinical consensus of late effects experts who have identified “at risk” groups based on late effects research. Research is needed to assess the yield from this risk-based screening approach, particularly in very long-term survivors who may have other co-morbid conditions exacerbating cancer-related toxicity. In subsequent investigations, we plan to focus on the specific outcomes associated with therapeutic exposures that have been under-studied in cohorts of adults surviving childhood cancer. Potential topics for investigation may range from global assessment of health status and quality of life, to focused evaluations of a specific tissue or organ system, or of a particular treatment complication in a given diagnostic group, e.g., stroke after Hodgkin lymphoma. In particular, we are interested in advancing knowledge about the cancer-related health complications that may present in adulthood or that may be exacerbated with organ senescence. Early results will inform future investigations that will extend beyond the initial risk-based evaluation outlined by the COG Guidelines. Potential objectives of these investigations include evaluation of novel screening methods for early detection of health conditions predisposed by cancer and intervention trials to remediate or prevent cancer-related complications. In this way, the anticipation is that SJLIFE will serve as a conduit for recruitment of adult survivors to other late health outcomes investigations.
As St. Jude is remarkable in its ability to engage survivors and families in research and maintain long-lasting follow-up of research participants, future SJLIFE investigations will need to consider the generalizability of results derived from the cohort to outcomes reported by pediatric cancer survivors across North America. In this regard, we compared and noted no substantial difference in the diagnostic subtypes and treatment exposures of survivors eligible for the SJLIFE study to those of non-St. Jude survivors eligible for the Childhood Cancer Survivor Study.40
We also compared the racial distribution of eligible survivors in the SJLIFE cohort to that of childhood cancer survivors 10 to 32 years since diagnosis from the Surveillance, Epidemiology and End Results Program (SEER).43
According to the SEER Cancer Statistics Review (1975–2007) the estimated US prevalence of childhood cancer survivors of all races is 158,284, of which, 136,588 (86%) are white and 14,290 (9%) are black. Among participants of SJLIFE, 89% of participants are white and 10% of participants are black. These numbers are remarkably similar to what is seen in SEER suggesting generalizability with regards to race. Considering that the current contact and participation rates are significantly lower among black compared to white survivors, future analyses will need to address the potential impact of differential contact and response rates by race.
Demographic similarities between survivors treated at St. Jude and the US population extend to SES. Previous characterization of SES among ACT patients in 2006 found that 32%, 44% and 24% fell in low, middle and high SES categories, respectively, based on the Hollingshead Four Factor Index of Social Status, whereas 29%, 45%, and 26% of Americans fell in the lower, middle and upper income quintiles among familial households as reported by the US Census Bureau in 2008.44–46
Although SES was not significant in models predicting ACT Clinic attendance, future analyses will examine the impact that SES may have on SJLIFE participation. It is possible that the clinical services routinely provided to St. Jude survivors, compared to survivors treated at other pediatric institutions, foster greater health consciousness that translates into a willingness to collaborate in research. Future investigations will need to consider how medical care, insurance access and adherence to medical follow-up impact outcomes of the SJLIFE cohort compared to those reported by other survivor cohorts.
In summary, the objective of the SJLIFE study is to establish a lifetime cohort of childhood cancer survivors treated at St. Jude Children’s Research Hospital to be used for investigation of the multi-factorial etiology of adverse health outcomes in aging adults surviving pediatric cancer. Our hypothesis is that a multidimensional, comprehensive risk assessment will permit more accurate definition of risk profiles for morbidity in aging childhood cancer survivors, inform the development of long-term follow-up screening guidelines, and facilitate the development of risk-reducing intervention measures. If study recruitment is maintained at the present level, SJLIFE study progress to date suggests its feasibility to recruit aging childhood cancer survivors to research investigations evaluating late health outcomes by medical assessments. While successful recruitment to the cohort is proceeding well, it is equally important to maintain ongoing participation of survivors. A number of mechanisms, beyond the newsletters and website, have been implemented to help retain study subjects. These include having survivors complete a survey after their clinical evaluation to determine satisfaction with all aspects of study participation with modifications in process and procedures based upon responses. In addition, each participant receives a detailed written summary of their visit including the results of evaluations performed and recommendations for follow-up. Those individuals with events detected during their visit also receive follow-up calls and counseling from the study healthcare team to facilitate referral to local healthcare providers. Lastly, in all interactions with study participants, the view is that everyone is part of the research team and contributing knowledge that will help improve the health and well-being of all pediatric cancer patients.