Elsevier

The Lancet Oncology

Volume 21, Issue 3, March 2020, Pages 421-435
The Lancet Oncology

Articles
Late mortality and chronic health conditions in long-term survivors of early-adolescent and young adult cancers: a retrospective cohort analysis from the Childhood Cancer Survivor Study

https://doi.org/10.1016/S1470-2045(19)30800-9Get rights and content

Summary

Background

Treatment outcomes among survivors of cancer diagnosed during adolescence and early young adulthood have not been characterised independently of survivors of cancers diagnosed during childhood. We aimed to describe chronic health conditions and all-cause and cause-specific mortality among survivors of early-adolescent and young adult cancer.

Methods

The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort study with longitudinal follow-up of 5-year survivors diagnosed with cancer before the age of 21 years at 27 academic institutions in the USA and Canada between 1970 and 1999. We evaluated outcomes among survivors of early-adolescent and young adult cancer (aged 15–20 years at diagnosis) and survivors diagnosed at age younger than 15 years (matched on primary cancer diagnosis, including leukaemia, lymphoma, CNS tumours, neuroblastoma, Wilms tumour, soft-tissue sarcomas, and bone cancer) by comparing both groups to siblings of the same age. Mortality was ascertained with the National Death Index. Chronic health conditions were classified with the Common Terminology Criteria for Adverse Events. Standardised mortality ratios (SMRs) were estimated with age-specific, sex-specific, and calendar year-specific US rates. Cox proportional hazard models estimated hazard ratios (HRs) for chronic health conditions and 95% CIs.

Findings

Among 5804 early-adolescent and young adult survivors (median age 42 years, IQR 34–50) the SMR compared to the general population for all-cause mortality was 5·9 (95% CI 5·5–6·2) and among 5804 childhood cancer survivors (median age 34 years; 27–42), it was 6·2 (5·8–6·6). Early-adolescent and young adult survivors had lower SMRs for death from health-related causes (ie, conditions that exclude recurrence or progression of the primary cancer and external causes, but include the late effects of cancer therapy) than did childhood cancer survivors (SMR 4·8 [95% CI 4·4–5·1] vs 6·8 [6·2–7·4]), which was primarily evident more than 20 years after cancer diagnosis. Early-adolescent and young adult cancer survivors and childhood cancer survivors were both at greater risk of developing severe and disabling, life-threatening, or fatal (grade 3–5) health conditions than siblings of the same age (HR 4·2 [95% CI 3·7–4·8] for early adolescent and young adult cancer survivors and 5·6 [4·9–6·3] for childhood cancer survivors), and at increased risk of developing grade 3–5 cardiac (4·3 [3·5–5·4] and 5·6 [4·5–7·1]), endocrine (3·9 [2·9–5·1] and 6·4 [5·1–8·0]), and musculoskeletal conditions (6·5 [3·9–11·1] and 8·0 [4·6–14·0]) when compared with siblings of the same age, although all these risks were lower for early-adolescent and young adult survivors than for childhood cancer survivors.

Interpretation

Early-adolescent and young adult cancer survivors had higher risks of mortality and severe and life threatening chronic health conditions than the general population. However, early-adolescent and young adult cancer survivors had lower non-recurrent, health-related SMRs and relative risks of developing grade 3–5 chronic health conditions than childhood cancer survivors, by comparison with siblings of the same age, which were most notable more than 20 years after their original cancer. These results highlight the need for long-term screening of both childhood and early-adolescent and young adult cancer survivors.

Funding

National Cancer Institute and American Lebanese-Syrian Associated Charities.

Introduction

Nearly 70 000 adolescents and young adults aged 15–39 years are diagnosed with cancer annually in the USA.1 Almost 80% of these adolescents and young adults will survive more than 5 years after their cancer diagnosis.2 As such, survivors of adolescent and young adult cancer represent a population with a substantial number of potential life-years saved who remain at risk of developing long-term morbidity or dying prematurely because of their previous cancer treatments.

In 2006, the Adolescent and Young Adult Oncology Progress Review Group (PRG), supported by the National Cancer Institute (NCI) and the LIVESTRONG Foundation, identified research priorities to improve outcomes for adolescent and young adult cancer survivors.3 One priority called for research to understand the long-term health outcomes associated with adolescent and young adult cancer and its treatment—an essential step towards providing appropriate risk-based care. Yet, a decade after the PRG report, a paucity of data exists about long-term morbidity and late mortality in this population. Although studies have examined the morbidity and premature mortality of survivors of both paediatric and adult cancers,4, 5, 6, 7 few have focused on those treated for their cancer as adolescents and early young adults (aged 15–20 years). Thus, the aim of the current analysis was to describe chronic health conditions and all-cause and cause-specific late mortality among survivors of cancer diagnosed during adolescence and early young adulthood within the Childhood Cancer Survivor Study (CCSS), compared with survivors diagnosed as children with the same primary cancers and compared with non-cancer populations.

Research in context

Evidence before this study

Long-term outcomes in survivors of cancer diagnosed during adolescence or young adulthood are not well understood. We searched PubMed from database inception to May 18, 2019, using the terms “adolescent and young adult or AYA cancer survivors” and “health conditions or morbidity” and “death or mortality” for English language publications describing the health consequences of cancer treatment in this population. Many studies have described the important psychosocial consequences of being treated for cancer as an adolescent or young adult, including decrements in health-related quality of life. Several studies have examined the morbidity and mortality of adolescents and young adults based on large cancer registries (eg, registries in Denmark and in England and Wales); however, detailed treatment exposure data or severity of illness were not considered in these studies.

Added value of the study

To our knowledge, this retrospective cohort study is the first to provide a comprehensive assessment of long-term health outcomes in early-adolescent and young adult cancer survivors. We used detailed outcome and treatment data to summarise the long-term outcomes of early-adolescent and young adult survivors in comparison with survivors of childhood cancer (aged <15 years at diagnosis), a cohort of siblings, and the general population. In general, the patterns of chronic health conditions in early-adolescent and young adult survivors reflect those of childhood cancer survivors, although we identified differences in risk for non-recurrent, health-related causes of death and chronic cardiac, endocrine, and musculoskeletal conditions between survivors of childhood cancer and early-adolescent and young adult cancer (despite similar treatment exposures).

Implications of all the available evidence

Our previous understanding of the long-term consequences of cancer treatment on adolescents and young adults was largely extrapolated from data describing survivors of childhood cancer. This analysis confirms the substantial burden of long-term health complications in the youngest subset of adolescents and young adults, can be used to inform current therapies for this population, and underscores the need for targeted interventions to ensure life-long, risk-based follow-up care for this population.

Section snippets

Study design and participants

The CCSS is a retrospective cohort with longitudinal follow-up of 24 363 5-year survivors diagnosed with cancer aged younger than 21 years at 27 academic institutions in the USA and Canada between 1970 and 1999 (appendix p 26). Details of the CCSS have been reported previously.8 Briefly, eligible survivors were identified and initially recruited through their original cancer treatment institutions. Survivors who died after their 5-year anniversary of cancer diagnosis were eligible and a proxy

Results

5979 survivors were diagnosed with cancer as early-adolescents and young adults in the CCSS (table 1). The mortality analysis excluded 175 Canadian participants or those not in the NDI (appendix p 7), resulting in 5804 survivors of early-adolescent and young adult cancer followed up for a median of 20·6 years (IQR 12·5–27·8), and 5804 childhood cancer survivors followed up for a median of 21·1 years (13·5–28·4), up to death or the date of the NDI search. The chronic health condition analysis

Discussion

To our knowledge, this retrospective cohort study is the first to comprehensively characterise long-term health outcomes in a large cohort of cancer survivors diagnosed and treated in adolescence and early adulthood (≥15 to <21 years of age) and to describe their outcomes relative to survivors of similar cancers diagnosed in childhood (<15 years of age) as well as the general population. Our cohort of more than 4000 survivors of early-adolescent and young adult cancer was at greater risk of

References (31)

  • W Stock et al.

    What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies

    Blood

    (2008)
  • N Howlader et al.

    SEER Cancer Statistics Review, 1975–2012

    (April, 2015)
  • A Bleyer

    Latest estimates of survival rates of the 24 most common cancers in adolescent and young adult Americans

    J Adolesc Young Adult Oncol

    (2011)
  • Closing the gap: research and care imperatives for adolescents and young adults with cancer. Report of the Adolescent and Young Adult Oncology Progress Review Group

    (2006)
  • KC Oeffinger et al.

    Chronic health conditions in adult survivors of childhood cancer

    N Engl J Med

    (2006)
  • GT Armstrong et al.

    Reduction in late mortality among 5-year survivors of childhood cancer

    N Engl J Med

    (2016)
  • MM Fidler et al.

    Long term cause specific mortality among 34 489 five year survivors of childhood cancer in Great Britain: population based cohort study

    BMJ

    (2016)
  • K Rugbjerg et al.

    Long-term risk of hospitalization for somatic diseases in survivors of adolescent or young adult cancer

    JAMA Oncol

    (2016)
  • LL Robison et al.

    The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research

    J Clin Oncol

    (2009)
  • DM Green et al.

    The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study

    Pediatr Blood Cancer

    (2014)
  • EA Feijen et al.

    Equivalence ratio for daunorubicin to doxorubicin in relation to late heart failure in survivors of childhood cancer

    J Clin Oncol

    (2015)
  • M Stovall et al.

    Dose reconstruction for therapeutic and diagnostic radiation exposures: use in epidemiological studies

    Radiat Res

    (2006)
  • GT Armstrong et al.

    Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study

    J Clin Oncol

    (2014)
  • R Geskus

    Cause-specific cumulative incidence estimation and the fine and gray model under both left truncation and right censoring

    Biometrics

    (2011)
  • National Center for Health Statistics Compressed Mortality File on CDC Wonder Online Database; CMF 1999–2013, Series 20, No 2s, 2014; CMF 1968–1988, Series 20, No. 2A, 2000; CMF 1989–1998, Series 20, No. 2E

  • Cited by (156)

    View all citing articles on Scopus
    View full text