While improvements in the treatment of Hodgkin lymphoma (HL) have led to higher survival rates, recent research has revealed that patients face a long-term elevated risk of cardiovascular disease for decades after their radiotherapy or chemotherapy regimens. The results of a new, retrospective, case-control study has assessed the dose-response relationship for cardiac radiation and risk of coronary heart disease (CHD) after radiotherapy in HL survivors (Journal of Clinical Oncology 2015 DOI: 10.1200/JCO.2015.63.4444).
The total cohort included 2,617 subjects who had survived for at least five years after HL diagnosis and were treated in the Netherlands between 1965 and 1995. Out of these patients, 325 developed CHD—either symptomatic myocardial infarction or angina pectoris requiring intervention as their first clinically significant heart disease. Each CHD case had four individually matched, CHD-free survivors for a total of 1,204 patients making up the control arm.
In terms of estimated dose-response relationship, the risk of CHD appeared to increase linearly with higher mean heart dose—specifically, the analysis found an excess relative risk of 7.4 percent per Gray. Chemotherapy was not associated with CHD risk. The study is the first to report a linear dose-response relationship for mean heart dose and development of CHD in survivors of HL. The results can be used by clinicians to predict CHD risk for future patients and help plan follow-up care for survivors, the study authors said.
“For patients treated in the past, these results can be helpful in estimating the risk of coronary heart disease for survivorship care,” said first author Frederika van Nimwegen, MSc, a PhD student in the Department of Epidemiology at The Netherlands Cancer Institute. “For patients treated nowadays, it's a bit harder to estimate this risk as the late effects of currently given treatment are not known yet, but since the results show a linear dose-response relationship, you can also use it to estimate the risk for patients treated today who have been given lower doses of radiation—about eight to 15 Gray.”
This study is a follow-up to an earlier investigation by van Nimwegen and her colleagues published in JAMA Internal Medicine earlier this year, where they found a persistently higher risk of cardiovascular disease in HL survivors with longer follow-up, even up to 40 years after initial treatment (OT 7/10/15 issue).The effect was particularly prominent for patients treated at a younger age, although those treated as adults were still at greater risk than healthy control subjects. In particular, mediastinal radiotherapy was linked to CHD, heart failure, and valvular heart disease.
Radiotherapy to the heart area—particularly for children who may be more radiosensitive—can cause significant tissue damage. Radiation can damage the coronary arteries and the microvasculature of the heart, causing them to stiffen and calcify, potentially leading to increased atherosclerosis and coronary heart disease, according to van Nimwegen.
“In the previous study, we found there was an increased risk of radiation therapy for cardiovascular disease in Hodgkin lymphoma, but we wanted to look more in depth at the association,” said van Nimwegen. “It has been found in childhood cancer and breast cancer survivors that there is a dose-response relationship, and we wanted to see what the relationship was for Hodgkin lymphoma survivors and what the shape of the relationship is.”
For the current study, van Nimwegen and her colleagues used the same cohort of Dutch HL survivors derived from hospital-based cancer registries of four large university hospitals and one cancer center. Cases with CHD were matched with four controls from the cohort based on sex, age at HL diagnosis, and date of HL diagnosis. Data on treatment and medical history, medication use, smoking, cardiovascular risk factors, and lifestyle information were gathered from medical records, radiation charts, and questionnaires.
The median age of HL diagnosis was 32.2 years, while the average time interval between HL and development of CHD was 19 years. The vast majority of CHD cases (91%) had received mediastinal radiotherapy during HL treatment compared to 79 percent of the controls, and it was associated with a 2.63-fold increased likelihood of CHD. The data was best described by a linear radiation dose-response relationship; for instance, there was a 1.74-fold increased risk at a mean heart dose of 10 Gray and a 2.48-fold increased risk at 20 Gray.
Mean Heart Dose
To estimate mean heart dose, the researchers employed a previously published method that uses the percentage of cardiac volume within the radiation field. They used any available HL simulation radiographs, which provide the treatment fields, as well as the location, size, and shape of each patient's heart. For each patient, the contours of the heart were outlined to obtain the percentage of cardiac volume within the radiation field. Then, a correction factor was applied to transform a 2D surface to a 3D volume.
In terms of cardiovascular risk factors, patients with hypertension, obesity, recent smoking activity, and a first-degree family history of CHD had a higher likelihood of developing CHD. In an adjusted analysis, a high level of physical activity (more than three hours per week of walking, cycling, or sports) compared to inactivity (less than one hour per week) at the time of follow-up was associated with a lowered risk of CHD.
“Studies like this are painting a clear picture for us clinicians to be able to identify the risk factors that we need to pay attention to, and when someone walks in our door with a history of cancer and has had these exposures, we can gauge how concerned we should be,” said Linda Overholser, MD, MPH, Assistant Professor of Medicine at the University of Colorado Hospital. “There seems to be a tremendous amount of momentum for looking at cardiovascular risk in cancer survivors now, and I think it's exciting.”
When asked for her opinion on the study, Overholser remarked that this follow-up investigation is well-done and impressive. As a primary care physician, she is seeing more in her field's literature about how to best treat cancer survivors while taking past radiotherapy and chemotherapy into account as risk factors. In her opinion, primary care practices need to be aware and proactive about treating this subset of patients—and studies like this one help to guide proper care.
“Even 20 years ago, we weren't seeing so many survivors, but as much as the childhood and adult cancer survivor population is growing now, they still make up a pretty small percentage of overall patients,” she said. “I may have one or two patients on my entire panel who have had this type of history, but the picture of increased morbidity and mortality is so striking that this is really a component we need to recognize.”
In the Works
Van Nimwegen and her colleagues are working on a similar case-control study involving the radiation dose-response relationship with respect to heart failure in the same population. Later on, they hope to investigate the role of single nucleotide polymorphisms that might be related to cardiotoxicity to help future patients decide whether chemotherapy would be a better option than radiotherapy, while taking into account the increased future risk of cardiovascular disease.