Risk of valvular heart disease after treatment for Hodgkin lymphoma

Abstract

Background: Hodgkin lymphoma (HL) survivors are at increased risk of developing valvular heart disease (VHD). We evaluated the determinants of the risk and the radiation dose-response.

Methods: A case-control study was nested in a cohort of 1852 five-year HL survivors diagnosed at ages 15 to 41 years and treated between 1965 and 1995. Case patients had VHD of at least moderate severity as their first cardiovascular diagnosis following HL treatment. Control patients were matched to case patients for age, gender, and HL diagnosis date. Treatment and follow-up data were abstracted from medical records. Radiation doses to heart valves were estimated by reconstruction of individual treatments on representative computed tomography datasets. All statistical tests were two-sided.

Results: Eighty-nine case patients with VHD were identified (66 severe or life-threatening) and 200 control patients. Aortic (n = 63) and mitral valves (n = 42) were most frequently affected. Risks increased more than linearly with radiation dose. For doses to the affected valve(s) of less than or equal to 30, 31-35, 36-40, and more than 40 Gy, VHD rates increased by factors of 1.4, 3.1, 5.4, and 11.8, respectively (P trend < .001). Approximate 30-year cumulative risks were 3.0%, 6.4%, 9.3%, and 12.4% for the same dose categories. VHD rate increased with splenectomy by a factor of 2.3 (P = .02).

Conclusions: Radiation dose to the heart valves can increase the risk of clinically significant VHD, especially at doses above 30 Gy. However, for patients with mediastinal involvement treated today with 20 or 30 Gy, the 30-year risk will be increased by only about 1.4%. These findings may be useful for patients and doctors both before treatment and during follow-up.

Figure 1.

An example of an original simulation film used during the 1960s to 1990s to plan radiotherapy for Hodgkin lymphoma, with field borders marked in black (left). The same field has been reconstructed within a modern radiotherapy treatment planning system on a substitute CT dataset with the field overlaid on a digitally reconstructed radiograph, with the field borders marked in yellow (right). The heart (pink) and the heart valves (blue) are outlined to demonstrate their position. A = aortic valve; M = mitral valve; P = pulmonary valve; T = tricuspid valve.

Figure 2.

Cumulative risk of valvular heart disease as (VHD) a first cardiac diagnosis among five-year survivors of Hodgkin lymphoma (HL) by years since initial HL diagnosis. Cumulative risk was calculated treating patients as censored when they developed another heart disease and death as a competing risk.

Figure 3.

Rate ratios (RRs) for valvular heart disease (VHD) by estimated radiation dose (EQD2, Gy) to the affected heart valve compared with no radiation exposure. RRs calculated conditional on matched sets. Matching variables were gender, age at Hodgkin lymphoma (HL) diagnosis and date of HL diagnosis (Supplementary Table 1, available online). Circles are estimates for dose categories: 0 Gy, up to 30 Gy, 31–35 Gy, 36–40 Gy, and >40 Gy and are plotted at the median doses in each category, ie, 0.0, 22.9, 34.0, 38.8, and 42.2 Gy. Vertical lines are 95% confidence intervals. Curved line is the best fitting dose-response relationship (RR = 1+exp[-5.02]dose*exp[0.075*dose]), allowing for curvature (two-sided P _nonlinearity = .03, likelihood ratio test). See Supplementary Figure 2 (available online) for additional details.

Figure 4.

Cumulative risks of valvular heart disease (VHD) as their first cardiac diagnosis among five-year survivors of Hodgkin lymphoma (HL) by years since initial HL diagnosis for categories of radiation dose (EQD2) to the affected heart valve. Cumulative risks were calculated treating patients as censored when they developed another heart disease and death as a competing risk.