Elsevier

The Lancet

Volume 401, Issue 10386, 29 April–5 May 2023, Pages 1447-1457
The Lancet

Articles
Specific causes of excess late mortality and association with modifiable risk factors among survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort

https://doi.org/10.1016/S0140-6736(22)02471-0Get rights and content

Summary

Background

5-year survival after childhood cancer does not fully describe life-years lost due to childhood cancer because there are a large number of deaths occurring beyond 5-years (late mortality) related to cancer and cancer treatment. Specific causes of health-related (non-recurrence, non-external) late mortality and risk reduction through modifiable lifestyle and cardiovascular risk factors are not well described. Through using a well-characterised cohort of 5-year survivors of the most common childhood cancers, we evaluated specific health-related causes of late mortality and excess deaths compared with the general US population and identified targets to reduce future risk.

Methods

In this multi-institutional, hospital-based, retrospective cohort study, late mortality (death ≥5 years from diagnosis) and specific causes of death were evaluated in 34 230 5-year survivors of childhood cancer diagnosed at an age younger than 21 years from 1970 to 1999 at 31 institutions in the USA and Canada; median follow-up from diagnosis was 29 years (range 5–48) in the Childhood Cancer Survivor Study. Demographic, self-reported modifiable lifestyle (ie, smoking, alcohol, physical activity, and BMI) and cardiovascular risk factors (ie, hypertension, diabetes, and dyslipidaemia) associated with health-related mortality (which excludes death from primary cancer and external causes and includes death from late effects of cancer therapy) were evaluated.

Findings

40-year cumulative all-cause mortality was 23·3% (95% CI 22·7–24·0), with 3061 (51·2%) of 5916 deaths from health-related causes. Survivors 40 years or more from diagnosis experienced 131 excess health-related deaths per 10 000 person-years (95% CI 111–163), including those due to the top three causes of health-related death in the general population: cancer (absolute excess risk per 10 000 person-years 54, 95% CI 41–68), heart disease (27, 18–38), and cerebrovascular disease (10, 5–17). Healthy lifestyle and absence of hypertension and diabetes were each associated with a 20–30% reduction in health-related mortality independent of other factors (all p values ≤0·002).

Interpretation

Survivors of childhood cancer are at excess risk of late mortality even 40 years from diagnosis, due to many of the leading causes of death in the US population. Modifiable lifestyle and cardiovascular risk factors associated with reduced risk for late mortality should be part of future interventions.

Funding

US National Cancer Institute and the American Lebanese Syrian Associated Charities.

Introduction

Survivors of childhood cancer have the potential to live for many decades beyond cancer.1 Although 5-year survival now exceeds 85% in the USA,2 long-term survivors have excess morbidity and late mortality (death beyond 5 years from cancer diagnosis) compared with the general population attributable to late effects of treatment.3, 4, 5, 6, 7, 8, 9, 10, 11 To reduce premature mortality, a better understanding of the specific causes of and risk factors for excess late mortality compared with the general population is needed as the first generation of survivors now enter their fifth, sixth, and seventh decades of life.

A previous study using the Childhood Cancer Survivor Study (CCSS) cohort identified improvements in late mortality attributable to reductions in treatment exposures and fewer deaths from recurrence among survivors diagnosed in the 1990s compared with previous decades.6 Although there were substantial reductions in late occurring deaths from the primary cancer, the incremental improvement in health-related late mortality (deaths not caused by the primary cancer or external and accidental causes but including chronic health conditions acquired due to cancer treatment) was only modest. A report using data from the Surveillance, Epidemiology, and End Results (SEER) Program highlighted the importance of evaluating survival among ageing survivors using the metric of excess deaths. Despite a 20% absolute increase in 5-year survival, the total number of annual excess deaths due to childhood cancer between 1985 and 2016 was largely unchanged attributable to a dramatic increase in excess deaths occurring more than 10 years from diagnosis.12 Further, although modifiable lifestyle and cardiovascular risk factors affect risk of death in the general population,13, 14 their association with late mortality risk in survivors is largely unknown. Our previous study documented death in the CCSS cohort through 2007,6 and with an additional 10 years of observation, nearly 2000 new deaths have occurred. Thus, through using a well-characterised cohort of 5-year survivors of the most common childhood cancers diagnosed between 1970 and 1999, we evaluated specific health-related causes of late mortality and excess deaths compared with the general US population and identified targets to reduce future risk.

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.

Section snippets

Study design and participants

This study is a multi-institutional, hospital-based, retrospective cohort with longitudinal follow-up of survivors treated at 31 institutions in the USA and Canada. Eligibility included 5-year or greater survival from cancer (including leukaemia, CNS tumours, lymphoma, Wilms' tumour, neuroblastoma, and soft tissue or bone sarcoma) diagnosed before the age of 21 years and between Jan 1, 1970, and Dec 31, 1999. Canadian survivors (n=1293) were excluded from this analysis because information on

Results

Among 34 230 eligible 5-year survivors (median age at diagnosis 6·0 years; median follow-up from diagnosis 29·1 years, IQR 22·0–36·2 years, range 5·0–48·0 years; table 1), there were 5916 deaths, with 2009 (34·0%) attributable to recurrence or progression of the primary cancer and 3061 (51·2%) attributable to non-recurrence, health-related causes, including subsequent neoplasms (n=1458), cardiac causes (n=504), pulmonary causes (n=238), and other health-related causes (n=861; appendix pp 18–20

Discussion

Despite the 20% increase in 5-year survival in childhood cancer from 61·5% between 1975 and 1977 to 80·3% between 1999 and 2001,2 5-year survival alone does not describe the full influence of cancer and its therapy. Using the CCSS cohort, we present, to our knowledge, the most comprehensive assessment of specific causes of excess late mortality and novel associations with modifiable lifestyle and cardiovascular risk factors and excess risk of death among survivors of childhood cancer. We now

Data sharing

The Childhood Cancer Survivor Study is an National Cancer Institute-funded resource (U24 CA55727) to promote and facilitate research among long-term survivors of cancer diagnosed during childhood and adolescence. Access to the CCSS data will be considered on a case-by-case basis. For all types of access, a research application of intent followed by an analysis concept proposal must be submitted for evaluation by the CCSS Publications Committee. Users interested in potential uses of this

Declaration of interests

We declare no competing interests.

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