Risk of heart failure in survivors of Hodgkin lymphoma: effects of cardiac exposure to radiation and anthracyclines

Abstract

Hodgkin lymphoma (HL) survivors treated with radiotherapy and/or chemotherapy are known to have increased risks of heart failure (HF), but a radiation dose-response relationship has not previously been derived. A case-control study, nested in a cohort of 2617 five-year survivors of HL diagnosed before age 51 years during 1965 to 1995, was conducted. Cases (n = 91) had moderate or severe HF as their first cardiovascular diagnosis. Controls (n = 278) were matched to cases on age, sex, and HL diagnosis date. Treatment and follow-up information were abstracted from medical records. Mean heart doses and mean left ventricular doses (MLVD) were estimated by reconstruction of individual treatments on representative computed tomography datasets. Average MLVD was 16.7 Gy for cases and 13.8 Gy for controls (P_difference = .003). HF rate increased with MLVD: relative to 0 Gy, HF rates following MVLD of 1-15, 16-20, 21-25, and ≥26 Gy were 1.27, 1.65, 3.84, and 4.39, respectively (P_trend < .001). Anthracycline-containing chemotherapy increased HF rate by a factor of 2.83 (95% CI: 1.43-5.59), and there was no significant interaction with MLVD (P_interaction = .09). Twenty-five-year cumulative risks of HF following MLVDs of 0-15 Gy, 16-20 Gy, and ≥21 Gy were 4.4%, 6.2%, and 13.3%, respectively, in patients treated without anthracycline-containing chemotherapy, and 11.2%, 15.9%, and 32.9%, respectively, in patients treated with anthracyclines. We have derived quantitative estimates of HF risk in patients treated for HL following radiotherapy with or without anthracycline-containing chemotherapy. Our results enable estimation of HF risk for patients before treatment, during radiotherapy planning, and during follow-up.

Figure 1.

Relationship between HF rate and cardiac dose. RRs for HF by MHD (A) and by MLVD (B) in Gy compared with no radiation exposure. RRs are calculated conditionally on matched sets after adjustment for anthracycline-based chemotherapy (yes/no). Squares indicate anthracycline-adjusted estimates for the following dose categories: MHD: 0 Gy, 1-20 Gy, 20-25 Gy, 26-30 Gy, ≥31 Gy; MLVD: 0 Gy, 1-15 Gy, 16-20 Gy, 21-25 Gy, ≥26 Gy, and are plotted at the median dose in each category (0 Gy, 16 Gy, 23 Gy, 28 Gy, and 33 Gy for MHD; 0 Gy, 13 Gy, 19 Gy, 23 Gy, and 30 Gy for MLVD). Vertical lines are 95% CIs. For MHD, there was a statistically significant linear dose-response relationship (P = .006) and allowing for curvature improved the fit significantly (P ≤ .001). For MLVD, there was a statistically significant linear dose-response relationship (P = .004), and allowing for curvature did not significantly improve the fit (P = .09). Further details are given in supplemental Table 2.

Figure 2.

Approximate cumulative risks of HF by MLVD and whether treatment with anthracyclines was given. Modeled cumulative risk of HF as first cardiac event among 5-year survivors of HL by time since initial HL treatment of categories of MLVD (Gy). Lines indicate estimated cumulative incidences for dose categories (0-15 Gy, 16-20 Gy, and ≥21 Gy) with and without anthracycline exposure. Cumulative risks were calculated with other heart disease or death as a competing risk. Further details are given in supplemental Text 3.