REVIEW ARTICLE

Integrative Therapies and Cardiovascular Disease in the Breast Cancer Population: A Review, Part 1 Khara Lucius, ND, FABNO; Kristen Trukova, MS, RD, CSO, CNSC, LDN

Abstract The cardiovascular toxicities of breast cancer treatment are important health problems, with potential public health consequences. Integrative therapies may represent important tools for prevention in this population. This article reviews the cardiotoxicity of conventional breast cancer therapy, including chemotherapy, radiation, and hormonal therapy. Data are presented on the benefits of substances such as

Khara Lucius, ND, FABNO, is a naturopathic doctor in the Department of Naturopathic Medicine; and Kristen Trukova, MS, RD, CSO, CNSC, LDN, is a registered dietitian in the Nutrition Department. Both are located at the Cancer Treatment Centers of America, Midwestern Regional Medical Center, in Zion, Illinois. Corresponding author: Khara Lucius, ND, FABNO E-mail address: [email protected]

T

he most common cancer in women aside from skin cancer, breast cancer remains a concern in the United States, with an estimated 232 000 new cases diagnosed in 2013.1 With earlier detection and improved treatment, survivorship is also on the rise. The American Cancer Society currently estimates that there are 2.8 million breast cancer survivors in the United States, and the 5-year relative survival in women with invasive ductal carcinoma has improved from approximately 75% in the 1970s to the current overall survival rate of 90%.2 As indicated by data from the Surveillance, Epidemiology, and End Results (SEER) program, between 2004 and 2010, patients with localized, non-nodal disease now experience a 5-year survival rate of 98.5%, and patients with regional disease (spread to regional lymph nodes) experience a 5-year survival rate of 84.6%.3 22

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curcumin, melatonin, Ginkgo biloba, resveratrol, coenzyme Q10, and L-carnitine. Although clinical studies on many of these substances are limited both in size and number, preclinical studies are available for several, and this article summarizes the potential mechanisms of action. Areas for future research are also identified.

The treatments that have contributed to increased survivorship carry risks. The cardiotoxicity of several breast cancer therapies is well established and may be a growing concern for patients who now survive decades after completing treatment. Cardiovascular disease (CVD), rather than cancer, remains the leading cause of mortality among Americans, accounting for 24.2% of deaths in 2010.4 Patnaik et al5 found CVD actually surpassed breast cancer recurrence as the cause of mortality in older breast cancer survivors. With both comorbidities and long-term effects of treatment contributing to risk, effective interventions to support cardiovascular health in this population are of special interest. Part 1 of this review discusses the current literature on the cardiac toxicity of standard breast cancer treatment and the natural agents that may play a role in preventing cardiac effects of treatment for breast cancer. Part 2 will address the lifestyle interventions that may represent some of the most powerful tools for cardioprotection and prevention in this population. Cardiotoxicity of Treatment Chemotherapy Among the chemotherapies most commonly used in breast cancer, the anthracyclines remain those best known to contribute to cardiotoxicity. Doxorubicin cardiotoxicity is attributable to free radical formation by drug metabolites. Both acute cardiotoxicity (including acute arrhythmias occurring immediately with first administration) and late cardiotoxicity (manifesting as dilated chronic Lucius—Integrative Therapies, CVD, and Breast Cancer

cardiomyopathy) are possible. Cases of late doxorubicin toxicity ranging from 7 to 15 years after completion of chemotherapy have been reported in the literature.6,7 Cardiomyopathy may manifest as biventricular congestive heart failure (CHF) or as left ventricular dysfunction. In addition, cardiomyopathy is both schedule and dose related, with reported incidences ranging from 1% with doses up to 300 mg/m2, and 4% with doses of 450 mg/m2 of doxorubicin,8 to 26% at cumulative dose of 550 mg/m2.9 Typical modern doses of doxorubicin as part of combination treatment regimens in early stage breast cancer patients (as part of neoadjuvant or adjuvant treatment with doxorubicin and cyclophosphamide) would be 60 mg/m2, with cumulative doses generally ranging from 240 to 360 mg/m2 in clinical practice. Aside from cumulative dose, increased age,10 history of a preexisting cardiovascular condition (such as diabetes or hypertension),11 and history of mediastinal radiation12 may represent additional risk factors. Additional chemotherapeutic agents that may contribute to cardiotoxicity include cyclophosphamide (which causes an acute cardiomyopathy)13 and docetaxel.14 Many chemotherapeutics, such as 5-fluorouracil (the second mostcommon cause of chemotherapy-related cardiotoxicity following anthracyclines15) and capecitabine,16 paclitaxel,17 ixabepilone,18 and eribulin mesylate19 may also be associated with cardiac toxicity, although these would likely be less relevant in the setting of early-stage breast cancer.

Other trials of adjuvant trastuzumab have indicated lower incidences of cardiotoxicity. In a North American trial requiring an EF of at least 50% for participation, Rastogi et al23 found 15.6% of participants had to discontinue trastuzumab due to cardiac dysfunction, and 3.9% of patients experienced CHF. In the Herceptin Adjuvant (HERA) trial, a European trial requiring an EF of at least 55% for participation, only 4.3% of patients had to discontinue trastuzumab due to cardiac dysfunction, and the rate of CHF was less than 1%.24 Variation in rates of cardiotoxicity in these trials may be attributable to variations in study protocols and varying participation requirements, such as more stringent requirements for EF. Following the development of trastuzumab, several other HER2-targeting agents have been introduced: (1) lapatinib, a dual tyrosine kinase inhibitor of both HER2 and the epidermal growth factor receptor (EGFR)— data support a low risk of cardiotoxicity, approximately 1% to 2%25; (2) ado-trastuzumab emtansine, a conjugate of trastuzumab with emtansine, a derivate of the antimitotic agent maytansine—preliminary evidence suggests adotrastuzumab emtansine does not carry the same risk of cardiotoxicity as trastuzumab does26; and (3) pertuzumab, a HER2 extracellular subdomain 2 binder. Again, data support reduced cardiotoxicity compared with trastuzumab, with 4.5% to 14.5% of patients in phase 2 and 3 trials affected by cardiac dysfunction.27

Targeted Therapies Trastuzumab is a human epidermal growth factor receptor 2 (HER2)–targeting monoclonal antibody. Approximately 20% of patients with breast cancer have tumors that overexpress HER2, making trastuzumab an important component of treatment in both the early stage and metastatic settings. Unlike the cardiotoxicity associated with anthracyclines, the cardiac effects of trastuzumab are not dose dependent. The mechanisms of trastuzumab-related cardiotoxicity have not been fully elucidated. Inhibition of the neuregulin-1 survival-signaling pathway, together with activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activated via angiotensin 2, have been postulated to increase production of reactive oxygen species (ROS).20 HER2 has also been found to be instrumental in the growth and survival pathways of cardiomyocytes; thus, trastuzumab, through HER2 inhibition, may inhibit myocardial repair.21 Regardless of the mechanism, the cardiotoxicity of HER2-targeting therapy remains an important concern, and sequential monitoring of ejection fraction (EF) is recommended. In one retrospective series, 44% of patients with early stage breast cancer who received trastuzumab experienced cardiotoxicity (manifested by more than a 15-point reduction in EF, or an EF below 50%), with 2% of patients experiencing heart failure.22

Radiation Radiation to the breast may involve exposure of the heart to ionizing radiation as well. In a study by Darby et al,28 the risk of ischemic heart disease increased proportionally with the mean dose to the heart, and risk persisted for at least 20 years after radiation. As would be expected, radiation to the left breast carried a higher risk. In Darby et al’s study, the mean dose to the heart for patients with left breast cancer was 6.6 Gy and with right breast cancer was 2.9 Gy. The risk of major coronary events increased by 7.4% with each Gy of radiation dose to the heart. The proportional increase was greater in women with pre-existing cardiac risk factors, such as smoking, obesity, diabetes, chronic obstructive pulmonary disease (COPD), or chronic analgesic use.

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Hormonal Therapies Hormonal therapies used to treat breast cancer include tamoxifen and aromatase inhibitors (AIs). Compared with users of tamoxifen, those on AIs have a greater risk of cardiovascular events, whereas those on tamoxifen have a greater risk of thromboembolic events.29 A large meta-analysis including 34 070 postmenopausal women has confirmed this pattern.30 A prospective cohort study involving more than 13 000 postmenopausal women without known CVD at the time of breast cancer diagnosis has helped further define this risk. In this study, Integrative Medicine • Vol. 14, No. 4 • August 2015

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participants on adjuvant AIs only, or on sequential tamoxifen followed by AIs, had a 26% to 28% greater risk of nonischemic CVD events than those women who were on tamoxifen only.31 As the use of AIs and the length of treatment with AIs have increased, those findings have become increasingly important. Integrative Interventions To determine what natural substances have been studied for a cardioprotective effect with anthracyclines, PubMed was searched for abstracts with the words doxorubicin and cardiotoxicity or adriamycin and cardiotoxicity. Results were surveyed for studies that used integrative interventions. Only those substances with 3 or more abstracts were included in the current review. Human data are presented here when available (for coenzyme Q10 and L-carnitine), but only animal data were available for other substances. Coenzyme Q10 The respiratory chain cofactor coenzyme Q10 has been studied in a limited number of clinical trials in patients on anthracyclines. Okuma et al32 examined 80 cancer patients receiving doxorubicin. The control group received doxorubicin only, whereas the treatment group received doxorubicin with coenzyme Q10. In the control group, QTc duration was prolonged significantly, and QRS voltage was also significantly decreased. In the treatment group, QTc duration was not significantly prolonged, and QRS voltage was not decreased. Based on these findings, coenzyme Q10 may help prevent electrocardiographic (ECG) changes in patients on doxorubicin. Tsubaki et al33 also examined the impact of coenzyme Q10 for patients receiving anthracyclines. A total of 79 cancer patients (the majority of whom had lymphoma) on either doxorubicin or daunorubicin were placed into a control group or a treatment group. In the control group, the participants received chemotherapy only; in the treatment group, participants received coenzyme Q10 administered intravenously (IV) at 1 mg/kg/d the day prior to chemotherapy, on the day of chemotherapy, and for a further 2 days after treatment. ECG aggravation (defined as depression of ST, changes in T waves with R/10 greater than T, flat, inversion) was found in 20 of 40 patients given coenzyme Q10 (50.0%) and in 18 of 25 (72.0%) in the control group (P < .10). Finally, Iarussi et al34 examined the impact of coenzyme Q10 administration in children with acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL) receiving anthracyclines in a randomized trial. Echocardiogram was performed at baseline, at the point of cumulative anthracycline dose of 180 mg/m2, and at the completion of therapy. Patients in the treatment group received 100 mg of coenzyme Q10 twice daily by mouth for the duration of treatment. In the coenzyme Q10–treated group, the left ventricular fractional 24

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shortening (%LVFS) decreased from baseline (40.36 ± 4.6) to the endpoint by 11.25% (P < .05) in the coenzyme Q10 treated group and by 16.19% (P < .002) in the control group. In addition, interventricular septum wall thickening decreased only in the control group, from 46 ± 10.1 at baseline, to 27.00 ± 18.54 at completion of chemotherapy (P < .01). Septum wall motion abnormalities were detected in only 2 patients, both in the control group. The data from this study indicated a protective effect of coenzyme Q10 on cardiac function during anthracycline chemotherapy.34 L-Carnitine L-Carnitine

is an endogenous amino acid that the body synthesizes from lysine and methionine. It plays a key role in energy production in the cell and is involved in β-oxidation of long-chain fatty acids in the mitochondria. To cross into the mitochondria, long-chain fatty acyl-CoA molecules must use enzymatic transporters that are L-carnitine dependent. Once in the mitochondria, these fatty acids undergo β-oxidation to adenosine triphosphate (ATP). In addition to its role in mitochondrial function, carnitine is a free radical scavenger and antioxidant. Waldner et al35 randomized 40 patients with NHL to receive either 3 g of L-carnitine before each cycle of anthracycline chemotherapy and 1 g of L-carnitine per day during the following 21 days, or a placebo. This study measured mRNA levels in white blood cells as an indicator of cardiomyocyte toxicity. This technique was based on findings from a rat study indicating a correlation between gene expression profiles in white blood cells and in the heart following anthracycline-related cardiomyopathy, suggesting white blood cells may represent a surrogate marker for cardiac tissue.36 L-Carnitine treated patients showed a rise in plasma carnitine (P < .001), and the mRNA content of carnitine palmitoyltransferase was increased in the treatment group (P = .1). Following supplementation, a significant correlation was found between the mRNA level of CPT1A and the carnitine transporter OCTN2 (P = .04). The authors concluded that the blockade of L-carnitine induced by doxorubicin could be attenuated by L-carnitine supplementation.35 Yaris et al37 have examined the relationship between serum carnitine level and cardiac dysfunction during doxorubicin treatment in children. This study was a prospective evaluation of 15 patients. Baseline measurement of carnitine level and evaluation of cardiac function were performed prior to treatment for the 15 patients, as well as for 20 healthy controls for comparison. In patients receiving doxorubicin, the measurements were repeated after cumulative anthracycline doses of 180 and 300 mg/m2. The authors observed a nonstatistically significant trend toward decreasing serum carnitine levels and increasing cardiac dysfunction with increasing cumulative doses of doxorubicin in the patients.37 Lucius—Integrative Therapies, CVD, and Breast Cancer

Melatonin The pineal hormone melatonin (MLT) is synthesized from the amino acid tryptophan and is secreted into both the bloodstream and cerebrospinal fluid. MLT relays signals to distant organs, chiefly the brain, although MLT receptors are widely distributed both centrally and peripherally, including in cardiac tissue.38 MLT is well studied in patients with multiple tumor types, including breast cancer, and has been found to reduce myelosuppression, neuropathy, and fatigue in patients receiving chemotherapy, while also improving 1-year

survival rate and tumor remission.39 Clinical studies on the use of MLT for cardioprotection in the oncology setting have not been performed. A number of rodent studies have examined the cardioprotective effects of MLT during anthracycline treatment (Table 1). The studies overall have indicated a protection of cardiac tissue via an antioxidant effect, inhibition of lipid peroxidation, increased levels of superoxide dismutase (SOD) or glutathione (GSH), and preservation of cardiocyte structure.40-43,66-71

Table 1. Preclinical Data on MLT Researchers

Chemo Agent

MLT Dose

Outcomes

Bilginoğlu et al41 (2014)

Adriamycin 18 mg/kg IP

10 mg/kg IP

Prevented elevation of cardiac injury markers.

Zhang et al66 (2013)

Adriamycin 2.5 mg/mL

10 mg/kg

Reduced concentration of lipid peroxidase and increased concentration of glutathione peroxidase in myocardial tissue.

Aydemir et al40 (2010)

Adriamycin 15 mg/kg

5 mg/kg

Increased SOD.

Guven et al67 (2007)

Epirubicin 10 mg/kg

200 mg/kg/d IP

Oz et al68 (2006)

Adriamycin 45 mg/kg

10 mg/kg

Improved GSH and MDA levels; protected cardiac cell structure.

Kim et al42 (2005)

Adriamycin 25 mg/kg

10 mg/kg SC

Mortality rate for controls was 86%; mortality rate for MLT group was 20%. Enhanced antitumor activity of adriamycin.

Sahna et al43 (2003)

Doxorubicin 20 mg/kg

4 mg/kg IP

Decreased levels of MDA, a lipid-peroxidation product.

Koçak et al69 (2003)

Adriamycin 15 mg/kg

5 mg/kg IP

Inhibited lipid peroxidation; myocardial damage.

Liu et al70 (2002)

Doxorubicin 25 mg/kg

10 mg/L water orally (PO)

Dziegiel et al71 (2002)

Daunorubicin 3 mg or doxorubicin 10 mg/kg

10 mg/kg

Increased GSH; decreased nitrozative stress.

reduced

Mortality rate for controls was 60%; mortality rate for MLT group was 0%. Reduced cardiac cell lesions.

Abbreviations: MLT, melatonin; IP, intraperitoneal; SOD, superoxide dismutase; GSH, glutathione; MDA, malondialdehyde; SC, subcutaneously; PO, per os.

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Resveratrol Resveratrol is a dietary polyphenol compound found in plants, fruits, and vegetables, as well as in wine, especially red wine. Resveratrol possesses antiinflammatory and antioxidant properties and may also function as a chemopreventive.44 Although human studies using resveratrol as a cardioprotectant in the oncology setting have not been performed, a number of preclinical studies have been conducted (Table 2). In rodents receiving anthracycline therapy, resveratrol has been found to decrease nitric oxide (NO) formation, decrease lipid peroxidation, and reduce cardiac dysfunction.45-48,72-73 Curcumin The polyphenol curcumin is derived from Curcuma longa, or turmeric, and is a potent anti-inflammatory and antioxidant. Many of the activities of curcumin are attributable to its action as an inhibitor of nuclear factor κΒ (NF-κΒ).49 Studies in humans indicate that curcumin reduces left ventricular afterload in combination with exercise50 and decreases the incidence of acute myocardial infarction after coronary artery bypass grafting.51

Bayet-Robert et al52 have studied curcumin for use together with docetaxel in patients with metastatic breast cancer. In that study, a total of 14 patients enrolled and received the combination of chemotherapy and curcumin, and no patient experienced progressive disease with the combination. Docetaxel was administered at 100 mg/m2 IV once every 3 weeks for a total of 6 cycles, with curcumin administered for 7 consecutive days starting 4 days prior to chemotherapy administration and continuing for 2 days after. The study was a dose escalation trial, with participants receiving 500 mg of curcumin daily, up to 8000 mg/d. The main dose-limiting toxicities in the trial were neutropenia and diarrhea. The safety profile for the combination of docetaxel and curcumin was determined to be similar to that of docetaxel monotherapy. Cardiovascular parameters were not evaluated as part of the study, but the trial established the feasibility and safety of the combination in breast cancer patients. A small number of animal studies have examined the cardioprotective effects of curcumin together with anthracycline chemotherapy (Table 3). In each study, curcumin was found to prevent elevation of creatine kinase (CK), also known as creatine phosphokinase (CPK), and to enhance antioxidant status.53,54

Table 2. Preclinical Data on Resveratrol Researchers Osman et al46 (2013)

Chemo Agent Resveratrol Dose Doxorubicin 10 mg/kg 15 mg/kg Doxorubicin 20 mg/kg Dudka et al45 (2012) 1-2 mg/kg Doxorubicin 15 mg/kg Zhang et al47 (2011) 8 mg/kg 10 mg/kg Olukman et al48 (2009) Doxorubicin 20 mg/kg 10 mg/kg Tatlidede et al72 (2009) Doxorubicin 20 mg/kg Adriamycin 30-120 mg/kg Wang et al73 (2007) 10 mg/kg

Outcomes Increased mean survival time; increased intracellular level of doxorubicin. Decreased lipid peroxidation; attenuated histopathological changes. Decreased LDH; reduced myocyte apoptosis, increased SIRT1. Prevented excess NO formation. Decreased cardiac dysfunction; decreased lactate dehydrogenase level. Decreased NO; increased antioxidant activity.

Abbreviations: LDH, lactate dehydrogenase; SIRT1, sirtuin 1; NO, nitric oxide. Table 3. Preclinical Data on Curcumin Researchers Chemo Agent Curcumin Dose Doxorubicin 200 mg/kg Swamy et al53 (2012) 15 mg/kg Doxorubicin 200 mg/kg Mohamad et al54 (2009) 15 mg/kg 200 mg/kg, 7 d Venkatesan55 (1998) Adriamycin 30 mg/kg prior and 2 d post

Outcomes Prevented rise in LDH and CPK; preserved GSH and SOD levels. Decreased mortality; prevented rise in CK-MB and LDH; increased GSH and antioxidant enzyme activity. Prevented rise in serum CK and LDH; decreased lipid peroxidation; increased endogenous antioxidants.

Abbreviations: LDH, lactate dehydrogenase; CPK, creatine phosphokinase; GSH, glutathione; SOD, superoxide dismutase; CK-MB, creatine kinase MB fraction; CK, creatine kinase. 26

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Table 4. Preclinical Data on Ginkgo biloba Researchers

Chemo Agent

Gingko Dose

Boghdady59 (2013)

Doxorubicin 20 mg/kg

100 mg/kg

El-Boghdady60 (2013)

Adriamycin 20 mg/kg

100 mg/kg PO

Liu et al61 (2008)

Doxorubicin 3 mg/kg IP

5 mg/kg IP

Reduced apoptotic indexes in cardiac tissue.

Naidu et al58 (2002)

Doxorubicin 4 mg/kg

100 mg/kg PO

Increased total antioxidant levels; reduced mortality rate; reduced myocardial lipid peroxidation.

Doxorubicin 30 to 45 mg/kg

100 mg/kg IP

Significantly decreased CK-MB and MDA.

Timioğlu et al62 (1999)

Outcomes Reduced markers of cardiac oxidative damage. Decreased cardiac MDA; increased GSH.

Abbreviations: MDA, malondialdehyde; GSH, glutathione; CK-MB, creatine kinase MB fraction. Ginkgo biloba Ginkgo biloba (G biloba) is a unique species of tree with a long history of medicinal use. The leaves are rich in flavone glycosides, such as kaempferol and quercetin, as well as terpene lactones. G biloba has been found to improve coronary artery blood flow in healthy elderly adults56 as well as in patients with coronary artery disease.57 Animal studies combining anthracycline chemotherapy with G biloba supplementation have indicated that G biloba exerts an antioxidant function and preserves cardiac markers during treatment (Table 4).58-62 A single human trial has been performed evaluating G biloba for cardioprotection in breast cancer patients receiving doxorubicin.63 A total of 60 stage IV breast cancer patients were divided into 2 groups, a control group receiving doxorubicin and a treatment group receiving doxorubicin and EGb761, a standardized extract of G biloba. The incidence of abnormal ECG was 6.7% in the treatment group and 30.0% in the control group (P < .05). Ultrasound indicated significant differences between the groups in left ventricular diastolic and systolic diameters and fractional shortening (FS), although no significant difference in EF was found between the groups. Additional human studies evaluating the safety and pharmacokinetics of G biloba and doxorubicin in combination have not been performed. Doxorubicin is a major substrate of both CYP2D6 and CYP3A4 and is also a P-glycoprotein substrate. Although preclinical analysis has indicated that G biloba has little effect on CYP2D6 and mild-to-moderate inhibition of CYP3A4,64 a study of healthy volunteers indicated that G biloba at a dose of 120 mg twice daily was unlikely to significantly affect coadministered medications that are metabolized by the CYP2D6 or CYP3A4 pathway.65 Lucius—Integrative Therapies, CVD, and Breast Cancer

Discussion To summarize these interventions, 3 human studies have assessed coenzyme Q10, 1 in oncology patients, 1 in patients with lymphoma, and 1 in patients with pediatric acute lymphocytic leukemia and NHL. Two human studies assessed L-carnitine, 1 in patients with NHL and 1 related to pediatric oncology. None of the trials for coenzyme Q10 or L-carnitine were specific to breast cancer patients. For MLT, resveratrol, and curcumin, only preclinical models are available, with MLT having the highest number of studies. For G biloba, only 1 trial was specific to breast cancer patients, and the remaining studies on this botanical were animal trials. All of these trials were specific to chemotherapy, and no studies were available for integrative cardioprotective measures for radiation. Larger, more rigorous trials specific to breast cancer patients receiving cardiotoxic therapies would be helpful in each of these areas. These trials would represent promising areas of future research that could benefit patients and clinicians alike, allowing the provision of evidence-based recommendations in this population. Although these interventions may have strong safety profiles individually, it is important to evaluate the side effect profile for each in conjunction with chemotherapy to determine both safety and efficacy of coadministration. Although the evidence is limited, the interventions described earlier may provide options for maintenance of cardiac health during breast cancer treatment. However, the impact of lifestyle modifications cannot be understated. Part 2 will focus on the triad of healthy weight, plantbased diet, and physical activity that together promote a reduced risk of cardiovascular events. Integrative Medicine • Vol. 14, No. 4 • August 2015

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Conclusions Contemporary studies on coenzyme Q10 and L-carnitine in breast cancer populations receiving cardiotoxic treatment could represent valuable tools for clinicians working with these patients. In addition, clinical studies of agents such as MLT, curcumin, resveratrol, and G biloba represent promising future research opportunities. Although preclinical studies are available for these substances, human research is required to confirm the potential benefits. Acknowledgements

The authors thank Carolyn Lammersfeld, MS, RD, CSO, LD, CNSC; and Christina Shannon, ND, FABNO, for their support of the initial presentation of this work at the 17th World Congress for Clinical Nutrition.

Author Disclosure Statement

No grant(s) or other types of financial support were used in this study. The authors declare no conflicts of interest.

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