Late Cardiovascular Toxicity Following Chemotherapy for Germ Cell Tumors

Abstract

The introduction of cisplatin-based chemotherapy has transformed germ cell tumors (GCTs), the most common malignancy to affect young adult men, into a highly curable cancer, even in the setting of advanced disease. However, over the past decade, the success of these chemotherapy regimens in curing GCTs has been temporized by an increasing recognition of their important late toxicities, such as cardiovascular disease. The relative risk of coronary artery disease in this population is particularly elevated within the first 10 years of follow-up, when patients are still in their 30s and 40s, which are age groups often considered too young to experience cardiovascular events. Two hypotheses have been proposed to explain the association between chemotherapy and cardiovascular disease in this population. The direct hypothesis asserts that chemotherapy causes diffuse endothelial damage, including in the coronary arteries, gradually leading to cardiovascular disease. In contrast, the indirect hypothesis proposes that chemotherapy leads to an increased incidence of cardiovascular disease risk factors, such as hypertension, hyperlipidemia, and the metabolic syndrome, which in turn enhance the risk of cardiovascular disease. This article summarizes the data on the association between chemotherapy (predominantly cisplatin-based) and the development of cardiovascular disease among GCT survivors, and reviews the evidence supporting both mechanistic hypotheses. In addition, recommendations are provided for the management of GCT survivors who received cisplatin-based chemotherapy and are therefore at risk for cardiovascular toxicity.

Cardio-Oncology

“…With close to 90% cure rates in testicular cancer patients treated with platinum-based agents, cardiovascular disease has emerged as one of the significant consequences by guest on http://circres.ahajournals.org/ Downloaded from facing survivors. 65 Platinum-based antineoplastic agents cause crosslinking of DNA. 66,67 They act on the adjacent N-7 position of guanine, forming 1, 2 intrastrand crosslink, impeding cellular processes, such as replication and transcription.…”

“…65 The major cardiovascular issues that have been studied include hypertension, dyslipidemia, early atherosclerosis, coronary artery disease, Raynaud's phenomenon, and thromboembolic events 68 ( Figure 1). Survivors of testicular cancer have an increased risk of developing both an unfavorable cardiac risk factors (obesity, hypertension, hyperlipidemia, diabetes mellitus) and cardiovascular disease.…”

Long-term Morbidity of Testicular Cancer Treatment

“…26 TCS comprise an ideal population for survivorship studies, given their young age at diagnosis, long-term survival, and use of largely homogenous therapies. 97 Future research priorities with regard to late effects of TC and its treatment were recently summarized during an international consensus conference (Box 1).…”

“…31 Patients with TC should be advised to adhere to these guidelines for primary prevention of CVD and should also establish care with medical providers who will monitor and modify their CVD risk factors according to currently accepted guidelines. 26 …”

Reply to S. Alanee et al

“…As reviewed by Feldman et al, 4 direct vascular injury and endothelial dysfunction likely play important roles in the pathophysiology of cardiovascular effects of cisplatin-based chemotherapy. Survivors of TC display increased levels of biomarkers for endothelial dysfunction and inflammation after cisplatin-based chemotherapy, including von Willebrand factor, fibrinogen, tissue-type plasminogen activator, and high-sensitivity C-reactive protein.…”