COMBINED RISK OF SECOND MALIGNANT NEOPLASMS AND CARDIOVASCULAR DISEASE IN LONG‐TERM HODGKIN LYMPHOMA SURVIVORS

Abstract

Background: Hodgkin lymphoma (HL) survivors are at increased risk of late treatment-related complications, including second malignant neoplasms (SMNs) and cardiovascular diseases (CVDs). Research to date has focused on separate risk estimates for these outcomes. We aimed to examine the combined risk of SMN and CVD, providing more insight into the total burden of morbidity from these severe late effects. Methods: Our cohort comprised 2,908 5-year HL survivors, treated before age 51 in 1965-2000. CVD endpoints, including coronary heart disease, cardiomyopathy/congestive heart failure, and valvular heart disease (≥grade 2 according to the CTCAE, vs. 4.0), were assessed through general practitioners. Data on SMNs were obtained from linkage with the Netherlands Cancer Registry. Cumulative incidences of SMN and/or CVD were calculated with death from other causes as competing risk. Treatment-specific risks of developing SMN and/or CVD were quantified using Cox regression. The mean cumulative count (MCC) was calculated as the average number of events per individual in our cohort over a given follow-up period, as an alternative measure of burden from SMN and CVD events. Results: Median age at HL treatment was 27.3 years. The majority of patients received either radiotherapy (RT) only (27.1%) or RT in combination with chemotherapy (CT; 65.9%). Among patients treated with RT, 24.5% received mantle field irradiation only, 16.2% incomplete mantle field only and 32.7% received (sub)total nodal irradiation. RT was applied using parallel opposed fields. Forty percent of all patients received anthracycline containing CT. After a median follow-up of 22 years, we identified 888 SMNs and 1,045 CVDs. 1247 patients developed ≥1 event; of those 240 developed both SMN and CVD. After a follow-up of 40 years, at a median attained age of 60 years, the cumulative incidence of SMN or CVD was 67.8% (95%CI: 65.1-70.4) and the cumulative incidence for developing both SMN and CVD was 17.2% (95%CI: 15.0-19.6). Overall, an average of 1.2 events per patient (MCC) over a follow-up period of 40 years was observed. Compared to no or limited RT, both incomplete mantle field and mantle field RT were associated with increased risks of SMN or CVD (HR: 1.9, 95% CI: 1.4-2.5 and HR: 2.6, 95% CI: 2.1-3.4, respectively). Anthracycline-chemotherapy (HR: 1.3, 95%CI: 1.1-1.5) independently increased the risk of SMN or CVD. The 25-year cumulative incidence of SMN or CVD was 28.2% (95% CI, 17.1-40.3) in patients treated with anthracyclines and no or limited RT fields, 37.6% (95% CI, 26.8-48.4) after anthracyclines in combination with incomplete mantle field RT, and 51.4% (95% CI, 42.2-59.8) after mantle field RT without anthracyclines. Conclusions: HL survivors treated between 1965 and 2000 experience a high disease burden from SMN and CVD during follow-up. Supradiaphragmatic RT increased the risk of developing either SMN or CVD more strongly than anthracyclines. Keywords: Hodgkin lymphoma (HL).