As a young(er), semi-athletic female working in oncology, I often find myself especially unsettled when a fellow young female, newly diagnosed with breast cancer, ends up with high-risk disease and the treatment of choice includes doxorubicin (Adriamycin), a known potentially cardiotoxic drug.
I was encouraged to recently come across an article by Curigliano, et al., addressing this issue of cardiotoxicity in various anticancer therapies.1 This article goes into great detail about the incidence and presentation of cardiotoxicity, along with ways to detect and possibly manage these effects. I'd like to highlight for you some of the fascinating "take-aways" and strongly encourage you to read this article in its entirety.
The cardiotoxic effects of anticancer therapies such as anthracyclines (i.e., doxorubicin) and traztuzumab (Herceptin) have long been established. The direct cardiotoxicity effects of trastuzumab is actually quite limited in the absence of prior anthracycline administration, but a combination regimen can lead to both acute or chronic left ventricular dysfunction.
As advancements in oncology continue to be made, more and more people are surviving their disease, placing them at increased risk for cardiac complications later in life.
So how do we monitor cardiac function? Can myocardial damage be prevented or reversed?
Detection of cardiac dysfunction is typically done through a 2-D echocardiogram or a multigated acquisition (MUGA) scan to evaluate the left ventricular ejection fraction (LVEF). However, a decrease in LVEF does not occur until a significant amount of myocardial damage has taken place, therefore making it difficult to detect changes early and intervene.
Cardiac biomarkers may be a helpful tool for detection of changes to the myocardium. Troponins are regulatory proteins within the myocardium that are released into the circulation when damage to the myocyte has occurred.
A study of 703 (mostly breast cancer) patients whose troponin-1 (Tn1) levels were monitored both throughout chemotherapy and after, found that those with an increasing Tn1 level had associated decreasing LVEF and increased risk of cardiac-related events.1
Cardioprotective drugs are being heavily studied in light of the known risks from anticancer therapies:
- Angiotensin converting enzyme inhibitors (ACE-I): Four hundred seventy-three patients treated with high-dose anthracyclines were evaluated. Of those, 114 showed an early increase in troponin levels and were randomized to receive enalapril (Vasotec) versus placebo. Enalapril was started one month after the end of chemotherapy and continued for one year. Those on enalapril had no change in their LVEF whereas a progressive decrease in LVEF was noted in the placebo arm.
- Beta Blockers (BB): Carvedilol (Coreg) has shown promise for cardioprotection during doxorubicin therapy. A study of 90 patients with hematologic cancers treated with anthracyclines were randomized, with the treatment group receiving enalapril plus carvedilol, with no change in LVEF shown after 6 months; however, a significant LVEF decrease was seen in the control group.
- Statins: Sixty-seven women with breast cancer given anthracycline-based therapy also received statins during treatment, compared with 134 controls. Those women given statins had a lower incidence of heart failure.
- Aldosterone antagonists: Eighty-three patients were randomized to placebo versus spironolactone (Aldactone) therapy while receiving anthracycline-based therapy. Spironolactone prevented a decrease in LVEF, stopped increase of TnI, and maintained diastolic dysfunction.
Currently, several major studies are underway to determine what drugs might offer the most benefit to patients receiving cardiotoxic therapies. These include the MANTICORE-101 trial (perindopril [Aceon] versus bisoprolol [Zebeta] in HER2-positive breast cancer patients receiving trastuzumab); PRADA trial (candesartan [Atacand], metoprolol, or combination to prevent LVD in patients on epirubicin-containing regimens); and the NCT02177175 trial through Memorial Sloan Kettering Cancer Center (carvedilol for prevention of anthracycline/trastuzumab cardiotoxicity).
Personally, I am excited to see these studies taking place as they are timely and overdue. I find myself wondering what specific doses are being used for the various cardioprotective drugs and wonder what possible adverse effects might come from them (i.e., slowed heart rate from BBs; hypotension with aldosterone antagonists). In addition, several drugs have emerged in more recent years, to either treat cancer or treat side effects of therapy, which pose a cardiac risk as well.
Tyrosine kinase inhibitors (TKIs), such as sorafenib (Nexavar) and sunitinib (Sutent), may cause hypertension. Agents used in some hematologic cancers like leukemia (dasatinib [Sprycel], nilotinib [Tasigna]) and multiple myeloma (lenalidomide [Revlimid], carfilzomib [Kyprolis]) pose increased risk of thrombosis. The 5-HT3 inhibitors used for antiemetic support (ondansetron, granisetron) have the potential for QT prolongation, especially when combined with antidepressants, which not surprisingly many cancer patients utilize. Further studies into possible cardioprotection in these realms are warranted as well.
What, if any, interventions are you seeing in clinical practice to help prevent or treat cardiotoxicity?
- Curigliano G, Cardinale D, Dent S, et al. Cardiotoxicity of anticancer treatments: Epidemiology, detection, and management. CA Cancer J Clin. 2016 Jul;66(4):309-25.