Abstract IA23: The overall health burden on aging survivors of childhood cancer
Authors: Armstrong Gregory T. 
Published: May 2016

Abstract
In just half a century, we have witnessed a remarkable improvement in survival of childhood cancer. In the 1960s less than 30-40% of children diagnosed with a malignancy would achieve five-year survival. Now, over 80% of children diagnosed with cancer will become five-year survivors of their disease. As a result, in 2013 it was estimated that there were over 420,000 survivors of childhood cancer in the United States, and that by the year 2020 we would cross the threshold of over one half million survivors. And, perhaps even more remarkable, it can now be stated that one in every 750 persons in the United States is a survivor of childhood cancer.
There have been numerous milestones along the road to curability of childhood cancer, including improvements in surgical technique and in the delivery of radiotherapy, the use of combination chemotherapy and advances in supportive care, all of which have all contributed to improved five-year survival. Moreover, because of these advances, for certain malignancies such as Hodgkin lymphoma, Wilms tumor and standard risk Acute lymphoblastic leukemia five-year survival is approaching or has exceeded 90%.
However, those who survive to the five-year time point remain at risk for late mortality, or death beyond the five-year time point of survival. Previous work from the Childhood Cancer Survivor Study (CCSS) identified that by 30 years from diagnosis, 18% of 5-year survivors will be deceased; and this at a time when these survivors are still in the 30s and 40s, relatively young by anyone's standard. Increasingly with age, this late mortality is due to late-effects of childhood cancer, such as deaths from subsequent malignant neoplasms and death due to cardiotoxicity. These deaths are more common among survivors than in the general population. Based on Standardized Mortality Ratios, survivors have a 15-fold greater risk for death due to subsequent malignant neoplasms compared to death from cancer in the general population and a 7-fold increased risk for cardiac death.
Large survivor cohorts have provided great insight, not only into late mortality but the underlying burden of chronic health conditions that precede late mortality. The CCSS is a multi-institutional, multi-disciplinary collaborative research resource comprised of a large cohort of survivors of childhood cancer and a comparison sibling cohort. Through establishing a well-characterized cohort of five-year survivors, the CCSS resource permits investigators to conduct high quality and high impact research to understand how the diagnosis of cancer and associated therapeutic exposures impact long-term morbidity, mortality and health-related quality of life. With the recent successful expansion of the cohort to include &gt;34,000 survivors diagnosed and treated over three decades (1970-1999), the CCSS is positioned to extend its impact as a resource for identification of late effects from both historical and contemporary therapeutic exposures. Moreover, with the ongoing genomic characterization of survivors using samples from the CCSS's extensive biorepository, the cohort is an unparalleled resource for molecular and genetic investigation of treatment-induced late effects.
The results of the CCSS have advanced knowledge of late effects among survivors of childhood cancer. CCSS investigators have demonstrated that 60-90% of adults treated for cancer during childhood develop one or more chronic health conditions. They have also shown that by age 50 years, the cumulative incidence of self-reported severe, disabling, life-threatening, or fatal health condition was 53.6% among survivors compared with 19.8% among sibling control group. Among childhood cancer survivors who reach age 35 years of age without a previous severe, disabling, life-threatening, or fatal health condition, 25.9% will experience a new severe, disabling, life-threatening or fatal condition within 10 years as compared to 6% of healthy siblings. In addition to the findings related to an increased risk of morbidity and mortality from subsequent neoplasms and cardiac disease, CCSS has shown that long-term survivors are at risk of developing a variety of adverse outcomes which include organ dysfunction (e.g., pulmonary, gonadal), impaired growth and development, impaired cognitive function, difficulties obtaining employment and insurance, and compromises in the quality of life.
Recently, the CCSS provided evidence that survivors treated in more recent eras have a significant reduction in late mortality attributable to two things: fewer deaths from recurrence or progression of primary cancer but more importantly, fewer deaths from treatment related causes such as subsequent malignancies and cardiopulmonary death. In conclusion, the now decades-long strategy of designing pediatric cancer treatment regimens with a focus on adult health and avoidance of late effects appears to have been successful. Taken along with promotion of early detection of late effects and improved treatment of late effects, this approach has now translated to extend the lifespan of many survivors of childhood cancer.
Future directions include the need to: (1) assess the true impact of screening and early detection of late effects on morbidity and mortality and evaluate interventions that improve screening rates as well as alter health behaviors, (2) expand individual risk prediction for poor outcomes, (3) further understand genetic susceptibility for late effects, and (4) target studies for both primary and secondary prevention of late effects, so that we not only extend the lifespan of survivors, but their health span as well.
Citation Format: Gregory T. Armstrong. The overall health burden on aging survivors of childhood cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA23.