Cardioprotection During Chemotherapy
Emily Moore, ND, LAc, FABNO
Heather Paulson, ND
Marcia Prenguber, ND, FABNO
Cardiovascular disease and cancer are the two most common disease conditions in the developing world. Many women have cardiac disease prior to a cancer diagnosis. When cardiac conditions are present at baseline, patients may be treated less aggressively for their cancer. One study revealed that 43% of breast cancer patients had cardiac disease at diagnosis, and those patients received less intensive chemotherapy when compared to patients with healthy hearts.1 Certain cardiotoxic chemotherapeutic agents may induce heart disease in healthy women, while compromising the heart further in women with pre-existing conditions. Recognition of a woman’s cardiovascular risk factors and pre-existing disease when she enters treatment for breast cancer is essential. With continuously improving treatments for breast cancer, there is a shifting paradigm in oncology to view cancer as a chronic disease, warranting even more
effective strategies for off-setting the long term toxicities of treatment.
It is also important to note that approximately 1 in 500 adults are childhood cancer survivors. Cardiotoxic chemotherapeutics are commonly used in pediatric oncology, and pose secondary risk factors for ill health as adults. As a preventative measure, adults previously treated with cardiotoxic agents should be evaluated for cardiac function and given tools to reduce the likelihood of cardiac disease. The natural therapies shown to improve cardiac function with cardiotoxic chemotherapeutics are further discussed in this article.
Cardiotoxic Chemotherapeutics
Anthracyclines are well-known cardiotoxic agents. These medications include doxorubicin, daunorubicin, epirubicin, and idarubicin. Anthracyclines are a class of drugs derived from Streptomyces bacteria and inhibit cancer growth by: 1) inhibiting DNA/RNA synthesis, 2) blocking DNA transcription and replication, and 3) ironmediated free radical synthesis. Anthracycline cardiotoxicity may be caused by interfering with the sarcoplasmic reticulum of cardiac muscle cells, free radical buildup in the heart cells, or by intracellular buildup of metabolic byproducts of the medication. EKG changes or arrhythmias may be seen, but often the cardiac damage is not seen for years after treatment for cancer, presenting as cardiomyopathy or congestive heart failure. The degree of cardiotoxicity is determined by lifetime exposure to the medications, as well as long-term survivorship.2
Trastuzumab is a monoclonal antibody that works by interfering with the HER2/ neu receptor on breast cancer cells. HER proteins are involved in cell growth and differentiation of some breast cancer cells. When the protein is over-expressed, trastuzumab is typically administered every 3 weeks for one full year. Trastuzumab is associated with cardiotoxicity in the form of congestive heart failure (CHF), and patients with pre-existing heart conditions may not be able to tolerate this drug.3 The risk of cardiac damage is increased when combined with doxorubicin, as often is the case in HER2/neu-positive breast cancers.4
Other chemotherapeutic agents, including fluorouracil, cyclophosphamide, and the vinca alkaloids, have been implicated in cases of ischemic cardiac toxicity.5,6 Newer anti-VEGF (vascular endothelial growth factor) agents, such as bevacizumab, have a less understood component of cardiotoxicity as well. By interfering with small blood vessel function to reduce blood flow to tumors, it is hypothesized that systemic effects may be problematic.7
Identifying and Treating Cardiovascular Toxicity
Cardiac function before, during, and after chemotherapy is most often measured by a change in left ventricular ejection fraction (LVEF). Cardiac biomarkers (troponin or brain natriuretic peptide) may also be a reliable predictor of myocyte damage.8
Dexrazoxane is a derivative of EDTA that chelates iron. It is used as a cardioprotectant to reduce the risk of anthracycline cardiotoxicity by about two thirds, without affecting response to chemotherapy or overall survival.9 The proposed mechanism of action is that iron chelation blocks free radical formation in the myocardial cells.
Other cardiovascular medications may include: ACE inhibitors, beta blockers, diuretics, digoxin, or vasodilators. There is research on the role of erythropoetin (EPO) in reducing the cardiotoxic effects of both doxorubicin and trastuzumab.10
Naturopathic Approach Exercise
Encouraging regular cardiovascular exercise for women undergoing chemotherapy for breast cancer is an excellent way to manage treatment-related fatigue.11 Based on animal studies, exercise prior to and during administration of doxorubicin or trastuzumab is emerging as a hopeful cardioprotective intervention.12 The animal models show that exercise increases cardiac antioxidant capacity by increasing cardiac levels and activity of superoxide dismutase, catalase, and glutathione peroxidase.
Coenzyme Q10
Coenzyme Q10 deficiency has been observed in patients with congestive heart failure, angina, coronary artery disease, cardiomyopathy, and hypertension. Coenzyme Q10 is involved in the synthesis of ATP and the clinical benefits are mainly due to its ability to improve energy production, its antioxidant activity, and its membrane-stabilizing properties.13
In vitro research has demonstrated that doxorubicin inhibits coenzyme Q10- dependent enzymatic activities in cardiac cells, and that exogenous supplementation could reverse the effect.14 Supplementation with coenzyme Q10 does not interfere with the effectiveness of anthracyclines, and preventative use of supplemental coenzyme Q10 may actually allow patients to receive higher doses with less cardiotoxicity.15
L-carnitine
In patients undergoing treatment for advanced cancer, oral L-carnitine supplementation has significantly reduced fatigue and increased lean body mass.16 It has been proposed that with higher cumulative exposure to doxorubicin, serum levels of L-carnitine drop.17 Supplemental L-carnitine has been shown to reverse cardiomyopathy in patients with serum carnitine deficiency,18 and prevent doxorubicin-induced apoptosis of cardiac myocytes in mice.19 Therefore, L-carnitine may be an effective adjuvant therapy to prevent chemotherapy-induced cardiotoxicity.
Ginkgo biloba
Extracts of Ginkgo biloba have several beneficial effects on cardiovascular health, including reduction of free radical damage to myocardial cells, reduction of platelet aggregation, and stimulation of nitric oxide release.20 One clinical trial randomized women with stage IV breast cancer to receive a doxorubicincontaining chemotherapy regimen alone or the same regimen with the addition of an extract of Ginkgo biloba. Although there was no significant difference in ejection fraction between groups, there were fewer ECG changes and more favorable cardiac enzyme profiles in the Ginkgo group.21
Grape Seed Proanthocyanidins
Grape seed extract shows a strong synergistic effect with doxorubicin in human breast cancer cell death, independent of estrogen receptor status.22 One rat study found that grape seed proanthocyanidins not only enhanced the anti-cancer effect of doxorubicin, but also increased NK cell activity and lymphocyte proliferation, while completely eliminating myocardial oxidative stress.23
Angelica sinensis
Angelica sinensis is traditionally used for gynecological conditions, high blood pressure, cardiovascular conditions, inflammation, and nerve pain. A mouse study looked at the pre-treatment with Angelica sinensis to prevent cardiac toxicity from doxorubicin. The study showed a significant reduction in mortality, normalized AST, and improved cardiac function when pre-treated with a 15 g/kg oral dose of Angelica sinensis.24
Lycium barbarum
Lycium barbarum is traditionally used for anemia, cough, and poor vision. A study randomized mice to receive one of the following treatments: 1) Water extract of Lycium equivalent to 25 mg/kg by mouth daily followed by IV doxorubicin, 2) Water extract of Lycium equivalent to 25 mg/kg by mouth daily followed by IV saline, or 3) Doxorubicin alone. Pretreatment of Lycium combined with doxorubicin normalized SDT and serum CK, improved arrhythmia, and improved conduction changes.25
Panax
Both Panax ginseng and Panax notoginseng have been studied for reducing the cardiac toxicity caused by doxorubicin. For Panax notoginseng, mice were randomized to receive one of the following treatments: saline, doxorubicin alone, Panax notoginseng saponins (PNS) alone (100 mg/kg orally), doxorubicin with PNS pretreatment, or doxorubicin pretreated with amifostine. Mice pretreated with PNS had significantly lower levels of LDH, CK, CK-MB, myocardial superoxide dismutase, glutathione peroxidase, and catalase activity. There was also improved ventricular function in mice pretreated with PNS. An in vitro study demonstrated no decrease in doxorubicin cytotoxicity when combined with PNS.26
Panax ginseng was studied for reducing heart failure in rats treated with doxorubicin. The rats were divided into four groups: no treatment, doxorubicin alone, ginseng alone, and doxorubicin with ginseng. Rats given ginseng, before and concurrent with doxorubicin, had a significant decrease in myocardial effects, lowered mortality, decreased amount of ascites, increased in myocardial glutathione peroxidase and superoxide dismutase activities, with a concomitant decrease in lipid peroxidation.27
Summary
As cardiovascular disease incidence continues to rise and more curative treatments for breast cancer and pediatric cancers are available, naturopathic physicians must take an active and aggressive approach towards cardio-protection prior to and following the initiation of chemotherapy. While human research studies point towards coenzyme Q10 and L-carnitine for protection, lifestyle modification can also be employed. Activities such as exercise and a largely vegetarian diet reduce cardiovascular risk factors, improve cardiovascular function, and reduce overall risk of recurrence for women diagnosed with breast cancer.28 The information from animal studies encourages us to watch for human clinical trials elucidating the cardio-protective role of several commonly used herbs. The naturopathic physician’s role in protecting patients from the damaging effects of chemotherapy continues to evolve and grow.
Emily Moore, ND, LAc, FABNO contributes to the CAM aspect of patient care using natural therapies to promote wellness, increase efficacy and reduce side effects of conventional cancer treatments. Dr. Moore joined the team at Goshen Center for Cancer Care in October 2005 as a naturopathic resident. She graduated from Bastyr University in Seattle with a doctorate degree in naturopathic medicine and a masters degree in acupuncture. She completed her residency in oncology under the supervision of Marcia Prenguber, ND, director of Integrative Care at Goshen Health System.
Heather Paulson, ND graduated from the University of California – Santa Barbara with a BS in aquatic biology. Dr. Paulson pursued her doctorate in naturopathic medicine at SCNM. Currently, Dr. Paulson is completing a two-year residency focusing on naturopathic oncology at the Center for Cancer Care in Goshen, Ind. This integrative medical facility is part of Goshen General Hospital and includes a team of integrative practitioners including radiation, medical and surgical oncologists; naturopathic physicians; dietitians; and psychoneuroimmunologists. Goshen Center for Cancer Care was recently recognized with the national HOPE Award for integration of care by Hematology & Oncology News & Issues magazine.
Marcia Prenguber, ND, FABNO is a board-certified naturopathic oncologist and director of integrative care at Goshen Center for Cancer Care. A leader in her field, Dr. Prenguber is one of a limited number of naturopathic physicians to accomplish the designation of a distinguished Fellow of the American Board of Naturopathic Oncology (FABNO), which recognizes the highest level of expertise in this holistic treatment approach. With previous experience as a teacher and administrator, Dr. Prenguber received her naturopathic physician doctorate from NCNM, an MS in education administration from California State University in Fullerton, and an MS in education from Johns Hopkins University in Baltimore.
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