Paediatric, Adolescent, and Young Adult Survivors of Hodgkin’s Disease Face an Elevated Risk of Cardiovascular Disease

Increased risk of severe cardiovascular events in survivors is associated with historic radiotherapy treatment

Paediatric, adolescent and young adult survivors of Hodgkin’s lymphoma are at substantially higher risk of cardiovascular disease compared to matched community controls due to curative treatments, according to an analysis appearing in a recent issue of Lancet Oncology.

In particular, long-term survivors of childhood Hodgkin’s lymphoma who received high doses of radiotherapy have an increased risk of grade 3 to 5 cardiovascular events.

Nickhill Bhakta, and colleagues performed an analysis of data from survivors of Hodgkin’s lymphoma participating in two ongoing studies of the St Jude Children’s research Hospital, the St Jude Lifetime Cohort Study (SJLIFE), and the St Jude Long-term Follow-up Study (SJLTFU). The SJLIFE cohort study was begun on 27 April 2007 to allow longitudinal clinical evaluation of health outcomes of survivors of childhood cancer treated or followed at St Jude Children’s Research Hospital, and SJLTFU is an ongoing administrative system-based study initiated in 2000 to collect outcome and late toxicity data for all patients treated at the hospital for childhood cancer.

The cohort in this analysis included patients treated at St Jude Children’s Research Hospital who reached 18 years of age and were at least 10 years post-diagnosis of pathologically confirmed primary Hodgkin’s lymphoma. The analysis aimed to determine the incidence of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin’s lymphoma, which was currently unknown.

The investigators applied the cumulative burden metric to a comparison of the occurrence of cardiovascular events using confirmed medical data from the survivors of Hodgkin lymphoma in both studies. The comparison of outcomes was made between a sample of SJLIFE cancer survivors and frequency-matched subjects in the community, who served as controls and were aged 18 years or older at the time of assessment. Survivors and controls were stratified into 5-year age blocks within each sex.

Although community controls were selected irrespective of previous medical history, first-degree relatives of patients of the St Jude Children’s Research Hospital, individuals with a history of childhood cancer, and pregnant women were excluded from the community control population.

All survivors in the SJLIFE study and controls were assessed for 22 chronic cardiovascular health conditions. This assessment together with retrospective clinical reviews, were used to assign severity to conditions using a modified Common Terminology Criteria of Adverse Events (CTCAE) version 4.03 grading schema. The mean cumulative count, which treated death as a competing risk, was used to estimate cumulative burden.

Overall, 670 patients who survived 10 years or longer and reached the age of 18 years were treated at St Jude Children’s Research Hospital. Of these, 348 subjects were clinically assessed in the SJLIFE study and the remaining 322 eligible participants did not participate in SJLIFE. The age and sex frequency-matched SJLIFE community control cohort contained 272 subjects. The analysis compared the cumulative incidence of cardiovascular events occurring in the survivor and control cohorts by the age of 50 years.

The cumulative incidence of cardiovascular events in cancer survivors is more than double that of controls in the general population

The mean time from Hodgkin’s lymphoma diagnosis to the first SJLIFE clinical assessment was 23.1 years and the median was 22.2 years (range, 10.9 to 45.4 years).

While the average annual increase of grade 1 to 5 cardiovascular conditions was higher across all age brackets of SJLIFE-eligible survivors between the ages of 30 and 55 years compared to community controls, the grade 1 to 5 cumulative burden in survivors aged 50 years was nearly twice that of the control cohort.

The cumulative burden of grade 1 to 5 cardiovascular conditions experienced by age 50 per 100 survivors was 430.6 (95% confidence interval [CI] 380.7, 480.6) compared to 227.4 (95% 192.7, 267.5) per 100 individuals the control cohort.

Regarding grade 3 to 5 serious cardiovascular events, the cumulative incidence by age 50 per 100 survivors was 100.8 (95% CI 77.3, 124.3) compared to 17.0 (95% CI 8.4, 27.5) per 100 controls.

The investigators found that the cumulative incidence was 45.5% (95% CI 36.6, 54.3) of experiencing at least one grade 3 to 5 cardiovascular condition in cancer survivors compared to 15.7% (95% CI 7.0, 24.4) in community controls. 

The cardiovascular death rate per 10 000 person-years was 6.8 in SJLIFE participants versus 42.3 in non-participants and 42.3 and 21.8 in the overall population of survivors (p = <0.0001).

The leading contributors to the greatly increased number of grade 3 to 5 cardiovascular events observed in survivors consisted of myocardial infarction and structural heart defects.

Radiation dose received in treatment linked to the increased cardiovascular burden of grade 3 to 5 events

The cumulative doses of chemotherapeutic agents were obtained from medical records and the maximum heart field dose of radiotherapy was obtained from the abstracted radiation therapy record for 186 survivors and radiation dosimetry calculations of maximum heart field dose estimations were done for 484 survivors by the Radiation Physics Center at the University of Texas MD Anderson Cancer Center. 

Marked-point-process regression that adjusted for sex, treatment era, and race was done to estimate the association of cumulative anthracycline dose and radiation dose to the heart with the cumulative burden of chronic cardiovascular health conditions, using cubic splines. 

Using these methods, an association was found between high cardiac radiation dose of ≥35 Gy received by survivors during treatment for Hodgkin’s lymphoma and the increased proportion of grade 3 to 5 cardiovascular conditions (p = 0.008). 

However, no association was determined between increased cardiovascular events and an increasing exposure to anthracyclines up to doses of ≥250 mg/m (p = 0.15) received in treatment by the survivors. 

Conclusions

The authors pointed out that this analysis confirmed reports from other studies of high rates of cardiovascular morbidity in adult survivors of Hodgkin’s lymphoma. They commented that the increased risk is best reflected by measurements of the cumulative burden metric.

They noted that survivors aged 50 years will experience more than twice the number of chronic cardiovascular health conditions and nearly five times the number of more severe, grade 3 to 5, cardiovascular conditions compared with community controls including one severe life-threatening or fatal cardiovascular condition, on average.

The authors advised that physicians should develop unique care plans for younger survivors of Hodgkin’s lymphoma due to their higher risk of cardiovascular disease, even in comparison with older adults. They emphasise the importance of clinicians to be aware of these risks when screening and treating survivors, particularly those who received therapy with older protocols when radiation doses of 35 Gy or higher were routinely used.

The study was funded from the US National Cancer Institute, St Baldrick’s Foundation, and the American Lebanese Syrian Associated Charities was disclosed. 

Reference

Bhakta N, Liu Q, Yeo F, et al. Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin’s lymphoma: an analysis from the St Jude Lifetime Cohort Study. Lancet Oncol 2016;17(9):1325-34.