Currently, there is a paucity of studies specifically addressing gender disparity in cardiovascular mortality after radiation treatment for Hodgkin's lymphoma. Our study is the first systematic review and meta-analysis evaluating this disparity. Previously, mantle field or mediastinal radiation has been proven in several studies to significantly raise the risk for cardiovascular diseases independently of traditional cardiac risk factors as well (4, 8). Our analysis revealed that for women, such radiation therapy significantly raises CV events and mortality by three-fold and raises all-cause mortality by almost 2 fold.
Interestingly, studies have shown that the risk of CAD and related CV mortality increases when combined with the traditional risk factors and radiation exposure (8, 10). For example, diabetes had been linked to cause further hospitalizations and hypertension and hyperlipidemia were two times as likely to develop ischemic cardiac disease among patients with R-HL (8, 11). Our study further demonstrated that with aging, the incidence of CV events markedly increased for female patients. While all the studies evaluated in this meta-analysis were independently corrected for the traditional cardiac risk factors for CAD, like diabetes, hyperlipidemia, hypertension, and tobacco use. Most of the studies did not clearly comment on the use of specific medical therapies for these conditions.
Additionally, high-dose mediastinal irradiation (cumulative dose of 35–40 Gy), increases cardiovascular disease and mortality in long-term survivors (12–14). Mediastinal radiation treatment incidentally exposes a large quantity of the heart to radiation within the field, leading to increased risk of endothelial damage and promotion of atherosclerosis (15, 16). In our analysis, most patients received over 30 Gy of radiation (Table 1). It should be recognized that in recent years, alterations to procedures and reductions in the radiation field volume have led to a significant reduction in cardiac exposure resulting in less cardiotoxicity than previously identified (3, 17).
The National Comprehensive Cancer Network currently recommends the following cardiovascular screening guidelines for survivors of Hodgkin’s lymphoma to proactively reduce cardiovascular risk: annual blood pressure measurements, lipid panels, and serial serum glucose levels (18–20). The American College of Radiology Appropriateness Criteria Expert Panel on Hodgkin Lymphoma Follow-up has broad recommendations: a stress test and an echocardiogram every five to ten years after treatment as appropriate (1). We suggest development of specific screening guidelines for high risk patient groups treated with mantle field or mediastinal radiation, including female gender, radiation doses over 30 Gy, concomitant use of cardiotoxic chemotherapy, and/or having one or more traditional CV risk factors.
STUDY LIMITATIONS. We acknowledge certain limitations associated with this study. Since this is a study-level analysis, it is not possible to make definitive conclusions about gender risks for patients with radiation-induced CAD. We identified only 10 retrospective and prospective observational cohort studies, accounting for an overall smaller sample size. None of the selected studies matched men and women with Hodgkin’s disease (HD) to radiation therapy dose, age of HD diagnosis, and how CVD was diagnosed. The studies did not specify the dose, frequency, and duration of radiation therapy for their patient populations. These findings may have led to a different course of CAD and subsequently CV mortality. Our study population mostly consisted of Caucasian nations. Most of the selected studies included young patients with a median age of 40 years.