The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE)

Summary

Background

Survivors of childhood cancer develop early and severe chronic health conditions (CHCs). A quantitative landscape of morbidity of survivors, however, has not been described. We aimed to describe the cumulative burden of curative cancer therapy in a clinically assessed ageing population of long-term survivors of childhood cancer.

Methods

The St Jude Lifetime Cohort Study (SJLIFE) retrospectively collected data on CHCs in all patients treated for childhood cancer at the St Jude Children's Research Hospital who survived 10 years or longer from initial diagnosis and were 18 years or older as of June 30, 2015. Age-matched and sex-frequency-matched community controls were used for comparison. 21 treatment exposure variables were included in the analysis, with data abstracted from medical records. 168 CHCs for all participants were graded for severity using a modified Common Terminology Criteria of Adverse Events. Multiple imputation with predictive mean matching was used for missing occurrences and grades of CHCs in the survivors who were not clinically evaluable. Mean cumulative count was used for descriptive cumulative burden analysis and marked-point-process regression was used for inferential cumulative burden analysis.

Findings

Of 5522 patients treated for childhood cancer at St Jude Children's Research Hospital who had complete records, survived 10 years or longer, and were 18 years or older at time of study, 3010 (54·5%) were alive, had enrolled, and had had prospective clinical assessment. 2512 (45·5%) of the 5522 patients were not clinically evaluable. The cumulative incidence of CHCs at age 50 years was 99·9% (95% CI 99·9–99·9) for grade 1–5 CHCs and 96·0% (95% CI 95·3–96·8%) for grade 3–5 CHCs. By age 50 years, a survivor had experienced, on average, 17·1 (95% CI 16·2–18·1) CHCs of any grade, of which 4·7 (4·6–4·9) were CHCs of grade 3–5. The cumulative burden in matched community controls of grade 1–5 CHCs was 9·2 (95% CI 7·9–10·6; p<0·0001 vs total study population) and of grade 3–5 CHCs was 2·3 (1·9–2·7, p<0·0001 vs total study population). Second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden. Notable heterogeneity in the distribution of CHC burden in survivors with differing primary cancer diagnoses was observed. The cumulative burden of grade 1–5 CHCs at age 50 years was highest in survivors of CNS malignancies (24·2 [95% CI 20·9–27·5]) and lowest in survivors of germ cell tumours (14·0 [11·5–16·6]). Multivariable analyses showed that older age at diagnosis, treatment era, and higher doses of brain and chest radiation are significantly associated with a greater cumulative burden and severity of CHCs.

Interpretation

The burden of CHCs in survivors of childhood cancer is substantial and highly variable. Our assessment of total cumulative burden in survivors of paediatric cancer, with detailed characterisation of long-term CHCs, provide data to better inform future clinical guidelines, research investigations, and health services planning for this vulnerable, medically complex population.

Funding

The US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities.

Introduction

With 10-year survival for paediatric cancer now more than 80%, and late mortality decreasing in long-term survivors, the population of survivors of paediatric cancer is ever increasing.1, 2, 3, 4 Incidence and prevalence data, mostly generated by cohort studies, have documented that survivors have a lifelong increased risk of morbidity associated with their curative therapies.5, 6, 7, 8, 9, 10 However, the true price of cure is reflected by the cumulative burden of disease, or total disease morbidity, after taking into account the occurrences and severities of multiple medical conditions and recurrent events.

Comprehensive characterisation of the excess cumulative burden of morbidity associated with childhood cancer survivorship is a missing but necessary piece of evidence for addressing clinical and health policy interventions in this population. Previous research has focused on reporting relative risk, cumulative incidence (ie, time to first occurrence), or prevalence of chronic health conditions (CHCs). Furthermore, other cohort studies have often used patient-reported morbidities without medical validation, not had a control population, or not obtained detailed treatment exposure data. By addressing each of these limitations and using new analytical methods, the St Jude Lifetime Cohort Study (SJLIFE) provides an opportunity to describe and visualise, for the first time, the overall and excess cumulative burdens of curative cancer therapy in a clinically assessed ageing population of long-term survivors.

Research in context

Evidence before this study

Because of their curative treatment-related exposures, survivors of childhood cancer are at increased risk for a broad range of chronic health conditions. We searched PubMed from database inception to Oct 13, 2016, using the terms “childhood cancer survivor” and “childhood or adolescent” and “burden or chronic health conditions or morbidity or long-term outcome” for English language publications describing the burden of chronic health conditions in the population of survivors of childhood cancer. Previous efforts to describe disease burden in childhood cancer survivors have all used traditional statistics such as relative risk and cumulative incidence, largely relied on either patient-reported data without concurrent medical validation of chronic health conditions, did not have a control cohort, or were missing the detailed radiation and chemotherapy exposure data we have abstracted in our cohort.

Added value of the study

To our knowledge, this is the first study to provide a comprehensive medical account of the disease burden landscape for a clinically assessed cohort of childhood cancer survivors, with comparison of survivor morbidity to a community control population. Earlier studies have examined few aspects of this narrative, generally within selected subsets of the survivor population and relying upon self-reported outcomes. None have explored, in a clinically assessed cohort, how a large and diverse series of chronic health conditions in all major organ systems relate to one another to form unique patterns of illness between survivor subgroups that, when combined, result in a cumulative burden of disease that is substantially larger than and distinct from that observed in the general population.

Implications of all the available evidence

By the addition of a new statistical method, which provides greater resolution of disease burden than ever before, and addressing long-standing cohort limitations in survivorship research, we present and visualise a detailed condition-by-condition assessment of morbidity in the growing high-risk population of childhood cancer survivors. Previous work has shown, in less comprehensively assessed and characterised populations than that used in our study, that survivors of childhood cancer have more chronic health conditions than do the general population. Our data go much further and provide a comprehensive landscape of morbidity while presenting context on the interrelationships between the various components of disease burden. In clinical and research settings, general health practitioners and clinical investigators can use the information we provide to address risks as part of patient care, assess trade-offs between exposures and different chronic health conditions to aid the design of future clinical trials, and inform the development of follow-up guidelines. Furthermore, from a policy perspective, our data offer the most extensive documentation to date that survivors of childhood cancer are not a monolithic population but are instead heterogeneous subgroups with complex medical needs and a substantially higher overall disease burden. Although adjunctive survivorship care clinics and close adherence to survivorship guidelines in primary health-care settings are the current global standard, the numerous morbidity profiles that we describe suggest that survivors might benefit from specialised health-care delivery, similar to that being advocated for other high-risk populations.