Testicular cancer treatment is associated with cardiovascular morbidity and mortality, but can clinicians identify the survivors at highest risk? A study in the Journal of Clinical Oncology begins to answer that question.
Jourik Gietema, MD, PhD, and Sjoukje Lubberts, MD, both of the University of Groningen in the Netherlands, and colleagues analyzed data from a cohort of 4,748 younger patients (ages 12-50) treated for testicular cancer from 1976 through 2007. Patients completed questionnaires about cardiovascular risk factors, and a subset underwent clinical evaluation. At a median 16 years of follow-up, 272 patients developed cardiovascular disease (CVD).
One notable finding was the high prevalence of cardiovascular risk factors among testicular cancer survivors: 86% had dyslipidemia, 50% had hypertension, and 35% had metabolic syndrome, irrespective of the treatment they received.
The study also found that cisplatin combination chemotherapy was associated with nearly double the cardiovascular risk compared with use of orchiectomy only (HR 1.9, 95% CI 1.1-3.1). Significantly higher cardiovascular risk was also associated with Raynaud’s phenomenon, as well as known risk factors including obesity, smoking, and a family history of CVD.
“Previous major studies looked mostly at treatment associations with CVD risk and did not assess in depth the characteristics of testicular cancer survivors who developed CVD,” the researchers wrote. “Our study is the first to investigate a possible association between early adverse treatment effects such as Raynaud’s phenomena and subsequent CVD development.”
In the following interview, Gietema and Lubberts provided joint answers about the clinical implications of the findings as well as next steps for future research.
What is your advice to clinicians based on this study?
First, testicular cancer survivors should be aware of an increased risk for developing cardiovascular disease after their treatment. Secondly, from diagnosis — as a cancer diagnosis turns out to be a teachable moment — through follow-up, patients should receive advice to optimize their lifestyle.
In an ideal world, we should arrange coaching to help them, as losing weight, being physically active, and quitting smoking is not as easy as it sounds. Patients should participate in prevention programs including cardiovascular risk management. We as oncologists should work together with other health professionals in a joint effort to lower cardiovascular risk after testicular cancer treatment.
Can you explain in more detail how your study differed from previous research on this topic?
Unique about our study is that we zoomed in on a large group of patients who developed cardiovascular disease after their cancer treatment: How were they treated? Which cardiovascular risk factors were present at diagnosis? Next, all living patients who developed cardiovascular disease completed a questionnaire to gather further information on cardiovascular risk factors, lifestyle, and development of other adverse treatment effects. These patients were compared with a random sample of the cohort, to investigate which factors were more prevalent in the patients with cardiovascular disease and therefore are associated with cardiovascular disease development.
Most previous studies were of epidemiological origin, and they did not include such a large group of testicular cancer patients who developed cardiovascular disease and completed informative questionnaires.
What is known or suspected about the ways testicular cancer treatment may cause vascular damage?
Previous research has shown that testicular cancer treatment with platinum-based chemotherapy leads to endothelial dysfunction, both in vitro and in vivo. Years after treatment, platinum levels are still detectable in the circulation, contributing to chronic endothelial activation/damage. Endothelial dysfunction is influenced by cardiovascular risk factors.
Previous reports from other groups as well as our current study confirm that testicular cancer treatment is associated with an unfavorable cardiovascular risk profile, including dyslipidemia, hypertension, insulin resistance, and overweight — all components of the metabolic syndrome.
Furthermore, development of Raynaud’s phenomena, a subclinical marker of small vessel dysfunction, was also associated with an increased risk of cardiovascular disease, pointing at the endothelium playing a role in pathophysiology.
Genetic susceptibility is also of importance, as a positive family history is a risk factor, but the exact role still has to be elucidated. Whether development of hypogonadism after orchiectomy and gonadal toxic therapy plays a role in pathophysiology remains a question we could not answer in the current study.
You also investigated the impact of CVD on quality of life in testicular cancer survivors. What did you find?
Patients who developed cardiovascular disease reported a lower quality of life on several domains than patients without cardiovascular disease, especially a lower physical function accompanied by role limitations because of physical health. They also reported less energy and vitality and had a lower general health score than testicular cancer survivors without cardiovascular disease.
This underlines the importance of preventing cardiovascular disease, as in unselected testicular cancer survivors, health-related quality of life seems similar compared with the general population.
Finally, you suggested a future study to determine whether a combination panel could predict which patients are at increased cardiovascular risk. Can you tell us about this?
Ultimately, we would like to point out the patients with testicular cancer with an increased risk for cardiovascular disease. We now know that patients who were treated with platinum-based chemotherapy, were obese or were smoking at diagnosis, developed dyslipidemia during follow-up, had a positive family history of CVD, or developed Raynaud’s phenomenon are at increased risk.
Next to these risk factors, maybe an “endothelial dysfunction-profile,” including presence of Raynaud’s phenomenon, long-term platinum exposure, albuminuria and fibrinolytic markers, and genetic susceptibility factors could identify high-risk patients.
We should investigate whether we should treat these high-risk patients with platelet aggregation inhibitors or statin-based, lipid-lowering therapy, or maybe only stringent treatment of modifiable cardiovascular risk factors.
Cardiovascular morbidity endangers the remaining lifespan of patients with successfully treated testicular cancer, so we must act and take next steps into preventing cardiovascular disease and other treatment-related disease in these young men.
Read the study here.
The study was supported by the Dutch Cancer Society.
Gietema reported institutional research funding from Roche/Genentech, AbbVie, and Siemens; Lubberts reported no potential conflicts of interest.