Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970–99: a report from the Childhood Cancer Survivor Study cohort

Summary

Background

Treatments for childhood cancer have evolved over the past 50 years, with the goal of maximising the proportion of patients who achieve long-term survival, while minimising the adverse effects of therapy. We aimed to assess incidence patterns of serious chronic health conditions in long-term survivors of childhood cancer across three decades of diagnosis and treatment.

Methods

We used data from the Childhood Cancer Survivor Study, a retrospective cohort with longitudinal follow-up of 5-year survivors of common childhood cancers (leukaemia, tumours of the CNS, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumour, neuroblastoma, soft tissue sarcoma, or bone tumours) who were diagnosed before the age of 21 years and from 1970 to 1999 in North America. We examined the cumulative incidence of severe to fatal chronic health conditions occurring up to 20 years post-diagnosis among survivors, compared by diagnosis decade. We used multivariable regression models to estimate hazard ratios per diagnosis decade, and we added treatment variables to assess whether treatment changes attenuated associations between diagnosis decade and chronic disease risk.

Findings

Among 23 601 survivors with a median follow-up of 21 years (IQR 15–25), the 20-year cumulative incidence of at least one grade 3–5 chronic condition decreased significantly from 33·2% (95% CI 32·0–34·3) in those diagnosed 1970–79 to 29·3% (28·4–30·2; p<0·0001) in 1980–89, and 27·5% (26·4–28·6; p=0·012 vs 1980–89) in 1990–99. By comparison, the 20-year cumulative incidence of at least one grade 3–5 condition in 5051 siblings was 4·6% (95% CI 3·9–5·2). The 15-year cumulative incidence of at least one grade 3–5 condition was lower for survivors diagnosed 1990–99 compared with those diagnosed 1970–79 for Hodgkin lymphoma (17·7% [95% CI 15·0–20·5] vs 26·4% [23·8–29·1]; p<0·0001), non-Hodgkin lymphoma (16·9% [14·0–19·7] vs 23·8% [19·9–27·7]; p=0.0053), astrocytoma (30·5% [27·8–33·2] vs 47·3% [42·9–51·7]; p<0·0001), Wilms tumour (11·9% [9·5–14·3] vs 17·6% [14·3–20·8]; p=0·034), soft tissue sarcoma (28·3% [23·5–33·1] vs 36·5% [31·5–41·4]; p=0·021), and osteosarcoma (65·6% [60·6–70·6] vs 87·5% [84·1–91·0]; p<0·0001). By contrast, the 15-year cumulative incidence of at least one grade 3–5 condition was higher (1990–99 vs 1970–79) for medulloblastoma or primitive neuroectodermal tumour (58·9% [54·4–63·3] vs 42·9% [34·9–50·9]; p=0·00060), and neuroblastoma (25·0% [21·8–28·2] vs 18·0% [14·5–21·6]; p=0·0045). Results were consistent with changes in treatment as a significant mediator of the association between diagnosis decade and risk of grade 3–5 chronic conditions for astrocytoma (HR per decade without treatment in the model = 0·77, 95% CI 0·64–0·92; HR with treatment in the model=0·89, 95% CI 0·72–1·11; p_mediation=0·0085) and Hodgkin lymphoma (HR without treatment=0·75, 95% CI 0·65–0·85; HR with treatment=0·91, 95% CI 0·73–1·12; p_mediation=0·024). Temporal decreases in 15-year cumulative incidence comparing survivors diagnosed 1970–79 to survivors diagnosed 1990–99 were noted for endocrinopathies (5·9% [5·3–6·4] vs 2·8% [2·5–3·2]; p<0·0001), subsequent malignant neoplasms (2·7% [2·3–3·1] vs 1·9% [1·6–2·2]; p=0·0033), musculoskeletal conditions (5·8% [5·2–6·4] vs 3·3% [2·9–3·6]; p<0·0001), and gastrointestinal conditions (2·3% [2·0–2·7] vs 1·5% [1·3–1·8]; p=0·00037), while hearing loss increased (3·0% [2·6–3·5] vs 5·7% [5·2–6·1]; p<0·0001).

Interpretation

Our results suggest that more recently treated survivors of childhood cancer had improvements in health outcomes, consistent with efforts over the same time period to modify childhood cancer treatment regimens to maximise overall survival, while reducing risk of long-term adverse events. Continuing advances in cancer therapy offer promise of further reducing the risk of long-term adverse events in childhood cancer survivors. However, achieving long-term survival for childhood cancer continues to come at a cost for many survivors, emphasising the importance of long-term follow-up care for this population.

Funding

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

Introduction

In the USA, there are more than 420 000 survivors of childhood cancer and this number is estimated to exceed half a million by 2020.¹ More than 80% of children diagnosed with a malignancy now achieve 5-year survival, but these individuals have substantial risks of morbidity and mortality later in life because of the late effects of cancer and its treatments.1, 2, 3, 4 A previous study in the Childhood Cancer Survivor Study (CCSS) reported that 54% of long-term childhood cancer survivors, diagnosed between 1970 and 1986, developed at least one severe, disabling, life-threatening, or fatal chronic health condition by the age of 50 years, representing a 5-times increased risk compared with siblings.⁵ In a retrospective cohort study from a single institution, Hudson and colleagues⁶ reported that 81% of survivors who underwent systematic clinical assessment were identified with at least one severe, disabling, or life-threatening chronic health condition by the age of 45 years.

Associations between specific cancer therapies and increased risk of late effects in survivors have led to modifications in treatment regimens with the goal of maintaining or improving the proportion of patients who achieve long-term survival, while reducing the risk and severity of late adverse events. For some cancers, elimination of radiotherapy or or combinations of conformal fields and reduced radiotherapy doses were able to minimise exposure to healthy tissues, while maintaining therapeutic activity.7, 8, 9, 10 Furthermore, risk-adapted therapy has allowed reduced treatment exposures for children with a lower risk of relapse or recurrence of their primary cancer.7, 8 These changes contributed to reductions in late mortality from late adverse events in survivors treated more recently across the three decades between 1970 and 1999.11, 12, 13 By contrast, over the same time period, more recently treated survivors reported reduced health status, emphasising the need to further examine temporal changes in chronic health conditions in this population.¹⁴ Optimum survivorship should include both extended lifespan and improvements in overall health; therefore, the goal of our analysis was to examine associations between treatment era and the incidence of severe, disabling, life-threatening, or fatal chronic health conditions, using the expanded CCSS cohort of childhood cancer patients who were diagnosed from 1970 to 1999 and survived at least 5-years after diagnosis.