Risk of cardiovascular disease after Hodgkin lymphoma, testicular cancer and breast cancer
We showed that the occurrence of treatment-related cardiovascular disease (CVD) is a serious problem in long-term survivors of breast cancer, testicular cancer and Hodgkin lymphoma (HL). It has long been known that radiation treatments used for breast cancer and HL treatment in the 1960s and early 1970s increase the risk of CVD. However, we showed that more recent RT regimens used 1980-2000 also increase the risk of CVD (both myocardial infarction, valvular heart disease (VHD) and congestive heart failure). Cisplatin-containing CT increases CVD risk in testicular cancer survivors.
Our study on CVD risk in 2,524 5-year survivors of HL showed that, after 35 years of follow-up, HL survivors still had a 4- to 6-fold increased SIR of coronary heart disease (CHD) or heart failure (HF) compared to the general population (Van Nimwegen et al. JAMA Int Med 2015; 175(6): 1007-17). Mediastinal RT increased the risks of CHD, VHD and HF, and anthracycline-containing CT increased the risks of VHD and HF as first events, compared with patients not treated with mediastinal RT or anthracyclines (relative risks were 3- to-7-fold increased). Joint effects of mediastinal RT, anthracyclines and smoking appeared to be additive.
We conducted three case-control studies nested in the HL cohort, to assess the shape of the radiation dose-response curves for different CVDs (Van Nimwegen et al, J Clin Oncol 2016, Van Nimwegen et al, Blood 2017). We also quantified separate and joint effects of radiation dose to the heart and cardiac substructures, anthracycline dose and established cardiovascular risk factors on CVD risk. Interestingly, high levels of physical activity were associated with 50% decreased risk of CHD.
The radiation dose-response curves established in these three case-control studies enable prediction of CVD risk for patients treated with contemporary radiotherapy techniques, which expose organs at risk to lower radiation doses.
We set up the HARBOR study within our cohort of breast cancer patients, to study markers for early cardiotoxicity among 570 women, who were 5-12 years after treatment at ages 40-50 years (Jacobse et al, Eur J Heart Failure, 2019). Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were assessed by echocardiography. Anthracycline-treated patients, compared to the no-anthracycline group, more often had low LVEF (10% versus 4%) and impaired GLS (34% versus 27%). GLS and LVEF declined in a linear fashion with increasing cumulative anthracycline dose and GLS was worse for patients with left breast irradiation. We concluded that early cardiotoxicity is present in a substantial proportion of young breast cancer survivors treated with anthracyclines.