Research in context
Evidence before this study
5-year survival after childhood cancer has improved dramatically over the past 50 years, and survivors have the potential for decades of life after cancer. However, it is well known that cancer and cancer treatment contribute to an increased risk of late morbidity and mortality among long-term survivors. Although previous reports have shown improvements in the relative risk of late mortality among 5-year survivors of childhood cancer treated in the 1990s compared with earlier decades, there has been little change in the absolute number of excess deaths attributable to childhood cancer (from diagnosis through survivorship) over the past 30 years in the USA. This is in part due to a growing and ageing population of long-term survivors leading to an increase in excess deaths occurring more than 10 years from diagnosis. However, specific causes of late mortality across survival times and the contribution of modifiable risk factors to these late deaths have not been well described. We searched PubMed from database inception to Jan 1, 2022, using the search terms “childhood cancer OR pediatric cancer”, “survivor OR five-year survivor”, and “mortality OR death”, with no language restrictions, to identify studies that investigated late mortality among 5-year survivors of childhood cancer. Although a large number of studies across international cohorts have described late mortality (death beyond 5-years from diagnosis), most have used six causes of death (primary cancer, subsequent cancer, cardiac, respiratory, external and accidental, and other) or organ system specific causes (eg, malignancy, cardiac, endocrine, and gastrointestinal) and have not included therapy exposures or modifiable risk factors.
Added value of this study
To our knowledge, this study is the first to report on specific causes of late mortality among 5-year survivors of childhood cancer beyond broad, systems-based categories such as cardiac, respiratory, or infectious causes. Since the most recent report from the Childhood Cancer Survivor Study (CCSS) in 2016, there has been an additional 10 years of mortality data with nearly 2000 additional deaths reported, most due to health-related causes (which includes deaths related to late-effects of cancer therapy but excludes deaths due to the primary cancer or external and accidental causes). With this added follow-up, we were able to report on over 70 discrete causes of death using a modification of 113 established causes of death according to the International Classification of Disease 9th and 10th revisions codes from the Centers for Disease Control and National Vital Statistics Report and compare them to the general US population including measures of relative and absolute excess risk. This study adds to the existing literature by further detailing specific causes of death (eg, valvular heart disease, ischaemic heart disease, heart failure, and hypertensive heart disease all are cardiac deaths but have differing magnitudes of excess risk and patterns of change over survival time). This detailed classification also allowed us to show, for the first time, that many specific causes of death experienced in late survivorship are the same as the major causes of death in the general population; however, survivors are dying at a younger age and higher rate. Further, the CCSS includes detailed treatment data and self-report of potentially modifiable lifestyle and traditional cardiovascular risk factors—information that is not routinely available in other large survivor cohorts. Therefore we could identify associations between healthy lifestyle, absence of cardiovascular risk factors, and reduced risk for health-related late mortality among survivors, independent of previous cancer treatment. Collectively, these findings better characterise excess late mortality and the effect of modifiable lifestyle and cardiovascular risk factors, and identify opportunities for future research into interventions to mitigate risk for these common causes of death among survivors who have uniquely high risks associated with their previous cancer treatment.
Implications of all the available evidence
Despite improvements in 5-year survival from childhood cancer and reduced late mortality among individuals treated in the 1990s compared with earlier decades, the excess risk of death among survivors continues to increase in late survivorship. Although deaths within the first 10 years from diagnosis are primarily due to recurrence or progression of the primary cancer, those occurring beyond 10 years from diagnosis are most often related to early onset of many of the leading causes of death commonly observed in the middle-aged (35–64 years) and older adult (≥65 years) populations including age-related cancers, heart disease, cerebrovascular disease, and specific infectious causes of death. As a result, by 40 years from diagnosis, survivors of childhood cancer in the CCSS had 138 excess deaths per 10 000 person-years of follow-up compared with the general population of the USA. Further, even decades after treatment, many therapy exposures remain associated with a dose dependent increase in risk of death among survivors, and further motivate efforts to reduce exposure to these agents while maintaining 5-year survival. Finally, the absence of potentially modifiable lifestyle and cardiovascular risk factors were found to be associated with a reduced risk of late mortality and could be a target for future interventions.