Dexrazoxane Protects Breast Cancer Patients With Diabetes From Chemotherapy-Induced Cardiotoxicity

CLINICAL INVESTIGATION

Dexrazoxane Protects Breast Cancer Patients With Diabetes From Chemotherapy-Induced Cardiotoxicity Fangyi Sun, MS, Xiaoyong Qi, MD, Cuizhi Geng, MD and Xingtao Li, BS

Abstract: Background: To evaluate the cardioprotective effect of dexrazoxane (DEX) on chemotherapy in patients with breast cancer with concurrent type 2 diabetes mellitus (DM2). Methods: Eighty female patients with breast cancer with DM2 were randomly assigned to receive chemotherapy only or chemotherapy plus DEX. All patients received 80 mg/m2 epirubicin and 500 mg/m2 cyclophosphamide by intravenous infusion every 3 weeks for a total of 6 cycles. The group assigned to receive chemotherapy alone received placebo 30 minutes before epirubicin administration. The group assigned to receive chemotherapy plus DEX received 800 mg/m2 DEX 30 minutes before epirubicin administration. Cardiac function and hematology before and after 6 cycles of chemotherapy were analyzed. Results: There was no difference in baseline systole or diastole function between the 2 DM2 groups. Patients receiving chemotherapy alone experienced significantly greater reductions in Ea and significantly greater elevations in E/Ea and Tei index in comparison with patients receiving chemotherapy plus DEX. After chemotherapy, superoxide dismutase was significantly reduced, and serum malondialdehyde (MDA) was significantly increased in patients with DM2. Serum superoxide dismutase levels were comparable between the 2 groups before and after chemotherapy, MDA levels were comparable between the 2 groups before chemotherapy, whereas serum MDA was significantly higher after chemotherapy in the chemotherapy alone group in comparison with the group that received DEX. Conculsions: DEX protects against cardiotoxicity induced by chemotherapy in patients with breast cancer with concurrent DM2. Key Indexing Terms: Dexrazoxane; Chemotherapy; Cardiotoxicity; Breast cancer; Diabetes. [Am J Med Sci 2015;349(5):406–412.]

S

ince their introduction in the 1960s, the anthracyclines doxorubicin and epirubicin have been effectively applied in the treatment of breast cancer in adjuvant and palliative regimens1; however, their use is limited by cumulative dose-related progressive myocardial damage that can lead to chronic heart failure, reduced quality of life and even death.2 As an increasing number of women survive breast cancer, the impact of cancer treatment on cardiovascular health is becoming more important. The cardiac abnormalities resulting from anthracycline therapy can be persistent, progressive and irreversible. Because early detection and treatment of cardiotoxicity can reduce its clinical effects, it is particularly important that these adverse effects are appropriately managed.3 Preclinical identification of left ventricular (LV) dysfunction and appropriate clinical intervention can achieve complete recovery of LV function.4,5 From the Department of Internal Medicine, Hebei Medical University, Shijiazhuang, P. R. China (FS, XL), Department of Cardiology, Hebei General Hospital, Shijiazhuang, P. R. China (XQ), Department of surgical medicine, Fourth Hospital of Hebei Medical University, Shijiazhuang, P. R. China (CG), Fourth Hospital of Hebei Medical University, Shijiazhuang, China. Submitted August 28, 2014; accepted in revised form December 9, 2014. The authors have no financial or other conflicts of interest to disclose. Correspondence: Dr. Xiao-Yong Qi, MD, PhD. Department of Internal Medicine, Hebei Medical University, Shijiazhuang 050017, P. R. China and Department of Cardiology, Hebei General Hospital, 348 Heping West Road Shijiazhuang 050051, P. R. China. (E-mail: [email protected]).

406

The risk of anthracycline cardiotoxicity is dose related,6 and although, the mechanism of toxicity is yet to be determined likely involves the generation of reactive oxygen species and induction of cardiac myocyte apoptosis.2 Recent reports have demonstrated that the improvement of screening techniques may facilitate rapid detection of cardiac toxicity, allowing chemotherapeutic doses to be tailored to patient tolerance.7–10 Serial noninvasive surveillance for anthracycline cardiotoxicity has previously centered on the echocardiographic assessment of LV systolic function. However, changes in these indices are symptomatic of significant myocardial dysfunction and cannot predict cardiotoxicity before administration of anthracycline therapy. Tissue Doppler’s imaging (TDI) allows measurement of the ventricular walls and mitral annulus, facilitating precise evaluation of LV diastolic performance.8 Anthracycline can affect LV diastolic function and diastolic filling patterns,11 thus, this technology may enhance evaluation of cardiac function during anthracycline therapy,7 enabling the timely interruption of anthracycline administration. Several parameters of TDI velocity analysis have been used to monitor changes after anthracycline chemotherapy.9,10 Threshold early diastolic peak velocity of mitral annulus (Ea) and the ratio of transmitral early diastolic peak flow velocity (E) and Ea (E/Ea) provide independent and incremental prognostic information in cardiac diseases.12 The systolic peak velocity of mitral annulus (Sa) is a sensitive marker of mildly impaired LV systolic function,13 and lower Sa values are associated with increased mortality.14 The Tei index is a Doppler’s echocardiographic parameter that reflects global LV function, and the TDI-derived Tei index has been demonstrated to correlate with increasing LV diastolic dysfunction,15 echocardiographic parameters of LV diastolic and systolic function and filling pressures. Moreover, it may enable prediction of the risk for anthracycline-induced cardiomyopathy.16 Administration of the cardioprotective agent DEX (Cardioxane, ICRF-187) with anthracycline has been shown to significantly reduce cardiotoxicity in randomized controlled studies.17,18 DEX is thought to exert cardioprotection through chelation of iron,19,20 although additional molecular mechanisms may contribute to cardioprotection,21 DEX can diminish oxidative damage in cardiomyocytes.22,23 As anthracyclines are most frequently prescribed to patients with advanced/metastatic breast cancer, the bulk of the evidence demonstrating cardioprotection with DEX has been obtained in this group.17,18 In this population, DEX facilitates the safe administration of anthracyclines without compromising their efficacy.24 In addition to the total cumulative dose of anthracycline, several patient-related features including previous irradiation therapy and predisposition to heart disease were found to influence the risk of cardiotoxicity.25 Several risk factors, such as age, dose, gender and concomitant radiation therapy, have been well characterized,2,6,25,26 but the relative risks of diabetes and hypertension are not understood. Diabetes mellitus (DM) is an established risk factor for the development of heart failure and has been recognized as a coronary heart disease by the American Heart Association.27 Numerous studies have

The American Journal of the Medical Sciences



Volume 349, Number 5, May 2015

Cardiotoxicity of Chemotherapy in Diabetes

demonstrated an association between DM2 and breast cancer; a meta-analysis of 20 studies (5 case-control studies and 15 cohort studies) indicated an increase of approximately 20% in incidence of breast cancer in patients with diabetes.28 Largescale prospective studies to comprehensively evaluate the cardiovascular disease (CVD) risk burden associated with modern adjuvant therapy are urgently required. This study was designed to investigate the efficacy of DEX in mediating cardioprotection against chemotherapyinduced cardiotoxicity in female patients diagnosed with early-stage breast cancer and DM2. In addition, we evaluated the influence of DEX on serum superoxide dismutase (SOD) and malondialdehyde (MDA) activity.

METHODS Patient Eligibility Between October 2012 and October 2013, 89 female patients diagnosed with early stage breast cancer and DM2, according to current World Health Organization criteria,29 were recruited at the 4th affiliated hospital of Hebei Medical University. Inclusion criteria: histologically confirmed diagnosis of early breast cancer; candidate for treatment with an epirubicin-based adjuvant chemotherapy regimen according to international standardized protocols; completely resected unilateral breast cancer; blood pressure within the normal range (,140/90 mm Hg); echocardiographic left ventricular ejection fraction value $50%; normal hepatic and renal function (bilirubin #1.5 mg/dL, creatinine #2.0 mg/dL); normal sinus rhythm; no concomitant medications, such as angiotensin-converting enzyme inhibitor, B-receptor blocker (B-block), calcium antagonists oxidative stress parameters such as Vc and VE. Exclusion criteria: acute DM2 complications; severe chronic DM2 complications; acute stress reactions, such as external injury, surgery or infection 1 week before blood collection; history of cardiac disease; hypertension; hypo/hyperthyroidism; hemolytic, hepatic and renal diseases; present or history of coronary artery disease, symptoms of congestive heart failure, established structural heart disease such as cardiomyopathy or valvular disease; history of chemotherapy or radiotherapy; ST-segment or T-wave changes specifically for myocardial ischemia, Q waves and incidental left bundle branch block on electrocardiography. Patients provided written informed consent. The study protocol, amendments and patient informed consent were approved by the Ethics Committee of Human Research of the 4th affiliated hospital of Hebei Medical University (2012MEC012), which has been certificated by FERCAP. Study Protocol All patients received 6 cycles of epirubicin-based (epirubicin and cyclophosphamide) adjuvant chemotherapy over 126 days. Patients with DM2 were randomly assigned to receive chemotherapy alone or chemotherapy plus DEX at a 1:1 ratio using a randomization number table, and patients were blinded to the therapy they received. All patients received 80 mg/m2 epirubicin plus 500 mg/m2 cyclophosphamide by intravenous infusion every 3 weeks for a total of 6 cycles. The group assigned to receive chemotherapy plus DEX received 800 mg/m2 DEX by intravenous infusion, 30 minutes before epirubicin administration. The group assigned to receive chemotherapy alone received intravenous infusion of 0.9% NaCl (Shijiazhuang No.4 Pharmaceutical Co., Ltd. Shijiazhuang, Hebei, China), 30 minutes before epirubicin administration. Physical examination included measurement of height, weight and blood pressure. A resting 12-lead electrocardiogram Copyright © 2015 by the Southern Society for Clinical Investigation.

was obtained, and total cumulative dose of epirubicin and laboratory findings were recorded. Standard and TDI transthoracic echocardiographic examination was performed. The blood sampling was performed before chemotherapy for the first time and 12 hours after epirubicin dosing for the second time. Then, the blood sample was immediately processed for the assessment of SOD and MDA. All examinations were all performed at baseline and at the end of chemotherapy treatment. Echocardiography and TDI examinations as well as SOD and MDA assessments were performed by physicians blinded to the patients group. Study Endpoint Primary study endpoint was systolic/diastolic function, assessed by conventional and TDI ECG. Second study endpoint was levels of SOD and MDA in blood. Echocardiographic Examination All echocardiographic evaluations were performed with the patient in the left lateral decubitus position using the IE33 imaging system (Phillips, Andover, MA) equipped with an S5-1 phased-array probe (2 to 5 MHz). Each patient underwent standard conventional echocardiography and TDI examinations at baseline and at the end of chemotherapy. R-wave peak was used as marker of the end of diastole, and the end of T-wave was used as marker of the end of systole. M-mode images of the LV were obtained in the parasternal long-axis view, and the LV end-diastolic and end-systolic diameters were measured just below the mitral valve leaflet tips after alignment of the cursor perpendicular to the LV wall, according to the American Society of Echocardiography guidelines.30 Echocardiography was performed by the same investigator, blinded to clinical data, and echocardiogram recordings were assessed by 2 cardiologists blinded to the patient’s data. The LV end-diastolic and end-systolic volumes were calculated using the biplane modified Simpson’s rule in the 4- and 2-chamber apical views, and the echocardiographic left ventricular ejection fraction was derived from these volumes. The pulsed Doppler’s sample volume was positioned at the mitral leaflet tips. E, A and E/A ratio were measured by transmitral Doppler’s imaging. The TDI program was set to the pulsed-wave Doppler’s mode at a frame rate .80/s. Filters were set to exclude high-frequency signals, and the Nyquist limit was adjusted to a velocity range of 215 to 15 cm/s. All TDI recordings were obtained during normal respiration. The image angle was adjusted to ensure a parallel alignment of the sampling window. Using the apical 4-chamber view, a ,5 mm sample volume was placed at the lateral corner of the mitral annulus and subsequently at the medial (or septal) corner.31 The following parameters were measured at both corners and averaged: Sa, Ea and E/Ea were calculated. The Tei index was calculated from TDI images in which the time interval from the end to the onset of the mitral annular velocity pattern during diastole (am) and the duration of the S wave (bm) were measured,16 at a sweep speed of 75 mm/s. All parameters were measured during 5 cardiac cycles (selected according to image quality) and averaged. Measurement of SOD and MDA Blood samples were obtained from venipuncture of the antecubital vein at 8 AM, after overnight fasting, and centrifuged immediately. Serum was stored at 280°C. The blood sampling was performed before chemotherapy and 12 hours after epirubicin dosing. Serum SOD and MDA were measured by photometer (Beckman Coulter, Fullerton, CA) using a kit from Nanjing Jiancheng Bioengineering Institute (Nanjing, Jiangsu,

407

Sun et al

China) by the physicians blinded to patient’s clinic data. The level of SOD in serum was calculated as a measure of xanthine oxidase activity and MDA level based on the product of thiobarbituric acid reactivity.32

TABLE 1. Patient baseline demographic characteristics DM2, chemotherapy DM2, chemotherapy alone (n 5 40) + DEX (n 5 40)

Statistical Analysis Data were reported as mean 6 SD. Two-tailed paired t test was used to compare group data before and after treatment. Two-sample t test was used between the 2 groups. Wilcoxon test was used when the data do not meet the requirements of normality. The x2 test was used for the count data. P values ,0.05 were considered significant when. Statistical data were processed using the SPSS 9.0 for Windows (SPSS Inc, Chicago, IL) software package.

Age, y Duration, d BMI, kg/m2 Smokers ECOG PS, n (%) 0 Stage, n (%) I II

RESULTS Patients Between October 2012 and October 2013, 170 female patients diagnosed with early-stage breast cancer, and DM2 were screened, and 89 female patients who fulfilled the inclusion criteria were recruited and were randomly assigned to receive chemotherapy only or chemotherapy plus DEX. In the group assigned to receive chemotherapy only, 3 patients were excluded because of severe myelosuppression, 1 patient was excluded because of severe liver damage, and 1 patient was lost to follow-up. In the group assigned to receive chemotherapy plus DEX, 3 patients were excluded because of severe myelosuppression and 1 patient was lost to follow-up. All remaining patients were followed up for 126 days (Figure 1). Baseline Demographic Characteristics of the Patients There was no significant difference in the average age, duration of observation, body mass index, rate of smoking

55.11 6 2.36 126 24.93 6 1.22 0

53.47 6 5.45 126 24.89 6 1.03 0

40 (100)

40 (100)

10 (25) 30 (75)

9 (22.5) 31 (77.5)

P . 0.05, in comparison with the DM2 chemotherapy alone group. BMI, body mass index; ECOG, eastern cooperative oncology group; PS, performance status.

behavior, ECOG and tumor stage between the 2 patient groups (Table 1). Duration of DM2 and Medication History There was no significant difference in the duration of DM2, diabetes medication or proportion of patients taking each medication. There was also no significant difference in the received dose of epirubicin or cyclophosphamide between the 2 groups (Table 2). Clinical Characteristics of the Patients There was no significant difference in serum levels of glycosylated hemoglobin, total cholesterol, triglyceride, blood pressure and C-reactive protein between the 2 patient groups before or after chemotherapy (Table 3). Safety At the end of the course of chemotherapy, there was no tumor-related death, tumor recurrence or symptoms of heart failure were reported.

TABLE 2. Patient medical history

Duration of DM2, y Medication for DM2, % Biguanides Sulfonylureas Insulin Statins Cumulative chemotherapy Epirubicin, mg/m2 Cyclophosphamide, mg/m2 FIGURE 1. Study flowchart.

408

DM2, chemotherapy alone (n 5 40)

DM2, chemotherapy + dexrazoxane (n 5 40)

6.68 6 2.75

7.03 6 3.08

60 53.33 66.67 83.33

56.67 60 73.33 90

480 3000

480 3000

P . 0.05, in comparison with the DM2 chemotherapy alone group.

Volume 349, Number 5, May 2015

Cardiotoxicity of Chemotherapy in Diabetes

TABLE 3. Patient clinical characteristics before and after chemotherapy DM2, chemotherapy alone (n 5 40) Pre-C HbA1c, % tCHOL, mmol/L TG, mmol/L SBP/DBP, mm Hg

7.48 5.74 1.83 128.68 79.78 4.65

CRP, mg/L

6 6 6 6 6 6

0.53 1.31 0.22 5.30 5.59 0.82

DM2, chemotherapy + DEX (n 5 40)

Post-C 7.48 5.67 1.83 130.38 78.85 4.59

6 6 6 6 6 6

0.55 1.12 0.19 4.57 3.37 0.97

Pre-C 7.47 5.83 1.88 132.88 78.46 4.72

6 6 6 6 6 6

0.13 0.94 0.22 4.85 4.88 1.18

Post-C 7.43 5.81 1.83 129.69 79.47 4.46

6 6 6 6 6 6

0.14 0.90 0.25 5.43 4.01 1.01

P . 0.05, in comparison with prechemotherapy. P . 0.05, in comparison with the DM2 chemotherapy alone group. CRP, C-reactive protein; DBP, diastolic blood pressure; HbA1c, glycosylated hemoglobin; Pre-C, prechemotherapy; Post-C, postchemotherapy; SBP, systolic blood pressure; tCHOL, total cholesterol; TG, triglyceride.

Systolic/Diastolic Function With Conventional and TDI ECG On completion of the course of chemotherapy, Ea was decreased, and E/Ea and Tei index were increased in the 2 patient groups (Table 4). There was no difference in baseline systole or diastole function between the 2 patient groups. After chemotherapy, the group of patients receiving chemotherapy alone group exhibited a greater reduction in Ea and greater elevation in E/Ea and Tei indices than patients receiving chemotherapy plus DEX. Systolic/diastolic function before and after chemotherapy (:Ea, :E/Ea and :Tei) also differed between the 2 patient groups (Table 5). SOD and MDA On completion of the course of chemotherapy, serum SOD was significantly decreased, and MDA was significantly increased all groups (Table 6). Serum SOD levels were comparable between the 2 patient groups before and after chemotherapy. Baseline serum MDA levels were also comparable between the 2 patient groups, whereas serum MDA levels after chemotherapy were significantly higher in patients receiving chemotherapy alone than patients receiving chemotherapy and DEX. MDA level before and after chemotherapy (:MDA) also differed significantly between the 2 patient groups (Table 7).

DISCUSSION In this study, the authors found that DEX protects against chemotherapy-induced cardiotoxicity in patients with breast cancer with concurrent DM2. To the best of the authors’ knowl-

edge, the authors present the first report of the cardioprotective effect of DEX in chemotherapy in patients with breast cancer with concurrent DM2. Patients with breast cancer have been reported to have a significantly worse cardiovascular risk profile than age/gender-matched controls, leading to development of the “multiple hit” Hypothesis.33–35 In middle-aged and elderly women who are already are at risk for CVD, the direct and indirect effects of adjuvant therapy, coupled with an unhealthy lifestyle, and the presence of modifiable risk factors all contribute to either overt CVD or an elevated risk of future CVD during early breast cancer. The authors found that chemotherapy treatment in patients with DM2 significantly elevated the E/Ea and Tei index, significantly decreased Ea, but did not alter Sa or EF, indicating that chemotherapy significantly worsened the impairment of diastolic function in patients with DM2. As CVD accounts for about 65% of diabetes-related mortalities, the American Heart Association considers diabetes to be equivalent to coronary heart disease.26 In particular, diabetes is a risk factor for heart failure, and the Framingham Heart Study revealed that the frequency of heart failure is doubled in diabetic men and increased 5 folds in diabetic women.36 Both laboratory and clinical data support the notion that the diabetic milieu can induce functional and structural changes in cardiomyocytes, leading to progressive deterioration of regional and global diastolic dynamics. In the early stages of the disease, diastolic dysfunction is the only abnormality,37 and substructural changes in the cardiomyocytes are detectable only by very sensitive methods such as TDI.38 The prevalence of diastolic dysfunction in patients with DM2 was found to be as high as

TABLE 4. Systolic/diastolic function with conventional and TDI ECG DM2, chemotherapy alone (n 5 40) Pre-C E/A EF Sa Ea E/Ea Tei index

0.96 0.65 8.30 11.08 6.48 0.45

6 6 6 6 6 6

0.20 0.08 3.13 2.65 0.58 0.02

Post-C 0.98 0.65 7.93 6.84 10.21 0.59

6 6 6 6 6 6

0.18 0.13 2.39 1.62a 1.06a 0.02a

DM2, chemotherapy + DEX (n 5 40) Pre-C 0.96 0.63 8.91 11.96 6.51 0.44

6 6 6 6 6 6

0.10 0.18 3.26 2.15 0.37 0.02

Post-C 0.97 0.64 8.14 9.23 7.87 0.53

6 6 6 6 6 6

0.08 0.16 2.18 1.09a,b 1.07a,b 0.02a,b

P , 0.05, in comparison with respective prechemotherapy. P , 0.05, in comparison with the respective DM2 chemotherapy alone group (Post-C). A, transmitral late diastolic peak flow velocity; Pre-C, prechemotherapy; Post-C, postchemotherapy; E, transmitral early diastolic peak flow velocity; Ea, early diastolic peak velocity of mitral annulus; EF, ejection fraction; Sa, systolic peak velocity of mitral annulus. a b

Copyright © 2015 by the Southern Society for Clinical Investigation.

409

Sun et al

TABLE 5. Difference of systolic/diastolic function before and after chemotherapy DM2, chemotherapy DM2, chemotherapy + alone (n 5 40) DEX (n 5 40) :E/A :EF :Sa :Ea :E/Ea :Tei

0.012 0.004 20.374 24.232 3.731 0.145

6 6 6 6 6 6

0.056 0.1297 3.4645 2.921 1.181 0.029

0.006 0.019 20.773 22.726 1.354 0.080

6 6 6 6 6 6

0.057 0.135 4.081 2.309a 1.085a 0.031a

P , 0.05, in comparison with the DM2 chemotherapy alone group. A, transmitral late diastolic peak flow velocity; E, transmitral early diastolic peak flow velocity; Ea, early diastolic peak velocity of mitral annulus; EF, ejection fraction; Sa, systolic peak velocity of mitral annulus. a

30%–60% in some studies.39 The authors noticed significant reduction of serum SOD activity and significantly increased serum MDA levels after chemotherapy treatment, indicating that chemotherapy reduces free radical scavenging, which can lead to cardiomyocyte injury as a result of excess lipid peroxide.40 In patients administered cardioprotective DEX before anthracycline chemotherapy, serum MDA levels, Ea, E/Ea and Tei index were significantly improved, in comparison with patients given anthracycline chemotherapy alone, although serum SOD was not affected. There was no change in E/A within the DEX treatment in comparison with DEX-untreated arm. E/A is an index of cardiac LV diastolic function assessed by conventional echocardiography. However, this method is vulnerable to mitral transvalvular pressure, cardiac preload and afterload, heart rate, advanced age, various disease states and many other factors. As it can be hard to distinguish the normalization of pseudo ratio, Doppler’s E/Ea allows earlier and more accurate evaluation of LV diastolic dysfunction than E/A.8 Thus, the mechanism by which DEX protects the myocardium may not involve SOD, but instead represents reduced reactive oxygen species production and oxidative damage, thereby inhibiting anthracycline cardiotoxicity.41 The authors also observed that despite administration of DEX, anthracycline-based chemotherapy still significantly elevated serum MDA levels, significantly reduced Ea and significantly increased E/Ea and Tei index in comparison with prechemotherapy levels. These observations indicate increased lipid peroxidation and impaired diastolic function, supporting the “multiple hit” model of myocardial damage caused by the combination of hyperglycemia, hyperlipidemia and anthracycline cardiotoxicity. In addition, Zhang et al42 recently reported that anthracycline doxorubicin-induced cardiotoxicity was

mediated by topoisomerase-IIb in a mouse model. Therefore, although DEX can reduce myocardial damage to some extent, it cannot completely prevent this damage. The authors recommend that a formal baseline CVD risk assessment be performed before adjuvant therapy. All women should be counseled about the value of a healthy lifestyle, unfavorable risk factors should to be managed and proactive treatment of modifiable risk factors should also be undertaken. For example, patients with DM2 should receive medication and life-style advice to reduce blood sugar and blood lipids, ideally before the initiation of adjuvant therapy. Study Limitations The authors have not provided insight into the pathophysiology of anthracycline-induced cardiomyopathy, and coronary artery disease was ruled out only by resting electrocardiogram and echocardiography, without the use of stress tests including imaging tests. Therefore, the authors cannot be entirely confident that all patients with epicardial coronary artery disease were excluded. Additionally, although the TDI parameters seem to be less load dependent than those of conventional blood flow Doppler, assessment of subclinical LV dysfunction based on tissue velocities may be limited. Newer echocardiographic parameters, such as real-time 3-dimensional echocardiography, strain, strain rate or speckle tracking may identify chemotherapyinduced subclinical myocardial dysfunction in serial measurements, and thus, represents a promising diagnostic tool in these patients. The patients in this study were given epirubicin plus cyclophosphamide, and the impact of cyclophosphamide on the myocardium cannot be completely excluded. Goldberg et al reviewed 14 cases of cyclophosphamide cardiotoxicity and considered more than 1.55 g$m22$d21 to be the critical doses for the onset of fatal cardiomyopathy, and symptoms were acute, usually occurring within 1 to 3 weeks.43,44 In their study, the authors administered cyclophosphamide at 0.5 g$m22$d21 and observed the symptoms within 126 days. Therefore, the authors presume that the myocardial damage detected in this study is epirubicin related. As blood changes reflect impact of the drug on all tissues, and we cannot sample the blood directly from heart, the evaluation of SOD and MDA in serum to reflect the changes of heart is a flaw of their study design. However, the authors use SOD and MDA in serum as oxidative damage makers and speculate the similar relative patterns of oxidative damage induced in hearts after anthracycline chemotherapy.22 The MDA level was estimated by the level of thiobarbituric acid reactive substances present in the sample, detected based on the conversion of thiobarbituric acid to a fluorescent product.32 Although the sample size was relatively small, all patients were recruited from a single site, and the observation duration was short, this preliminary study may serve to provide a basis

TABLE 6. Assessment of oxidative damage markers DM2, chemotherapy alone (n 5 40)

SOD, U/mL MDA, nmol/L

DM2, chemotherapy + DEX (n 5 40)

Pre-C

Post-C

Pre-C

Post-C

129.99 6 8.44 6.88 6 0.53

67.86 6 24.54a 18.89 6 2.10a

132.56 6 9.35 7.03 6 0.57

76.61 6 29.58a 13.32 6 2.33a,b

P , 0.05, in comparison with respective prechemotherapy. P , 0.05, in comparison with the respective DM2 chemotherapy alone group (Post-C). Pre-C, prechemotherapy; Post-C, postchemotherapy; MDA, malondialdehyde; SOD, superoxide dismutase.

a b

410

Volume 349, Number 5, May 2015

Cardiotoxicity of Chemotherapy in Diabetes

TABLE 7. Difference of oxidative damage markers before and after chemotherapy DM2, chemotherapy DM2, chemotherapy + alone (n 5 40) DEX (n 5 40) :SOD :MDA

262.129 6 28.901 12.018 6 2.288

255.951 6 30.215 6.284 6 2.564a

P , 0.05, in comparison with the DM2 chemotherapy alone group. MDA, malondialdehyde; SOD, superoxide dismutase.

a

for further research, and the results should be verified by larger trials with higher event numbers. In conclusion, the authors found that DEX protects against cardiotoxicity induced by epirubicin-based chemotherapy in patients with breast cancer with concurrent DM2, supporting the multiple hit theory. In patients with DM2, a CVD risk factor, anthracycline-based chemotherapy significantly exacerbated myocardial damage, which was not completely prevented by simultaneous administration of DEX. It is thus important to control blood sugar and blood lipids to attenuate DM2 in administration of epirubicin-based chemotherapy. REFERENCES 1. O’Shaughnessy J, Twelves C, Aapro M. Treatment for anthracyclinepretreated metastatic breast cancer. Oncologist 2002;7(suppl 6):4–12. 2. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003;97:2869–79. 3. Bird BR, Swain SM. Cardiac toxicity in breast cancer survivors: review of potential cardiac problems. Clin Cancer Res 2008;14:14–24. 4. Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010;55:213–20. 5. Airoldi M, Amadori D, Barni S, et al. Clinical activity and cardiac tolerability of non-pegylated liposomal doxorubicin in breast cancer: a synthetic review. Tumori 2011;97:690–2.

13. Sanderson JE. Heart failure with a normal ejection fraction. Heart 2007;93:155–8. 14. Wang M, Yip G, Yu CM, et al. Independent and incremental prognostic value of early mitral annulus velocity in patients with impaired left ventricular systolic function. J Am Coll Cardiol 2005; 45:272–7. 15. Su HM, Lin TH, Voon WC, et al. Differentiation of left ventricular diastolic dysfunction, identification of pseudonormal/restrictive mitral inflow pattern and determination of left ventricular filling pressure by Tei index obtained from tissue Doppler echocardiography. Echocardiography 2006;23:287–94. 16. Erdogan D, Yucel H, Alanoglu EG, et al. Can comprehensive echocardiographic evaluation provide an advantage to predict anthracyclineinduced cardiomyopathy? Turk Kardiyol Dern Ars 2011;39:646–53. 17. Lopez M, Vici P, Di Lauro K, et al. Randomized prospective clinical trial of high-dose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas. J Clin Oncol 1998;16:86–92. 18. Swain SM, Whaley FS, Gerber MC, et al. Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 1997; 15:1333–40. 19. Hasinoff BB. The interaction of the cardioprotective agent ICRF-187 [+)-1,2-bis(3,5-dioxopiperazinyl-1-yL)propane); its hydrolysis product (ICRF-198); and other chelating agents with the Fe(III) and Cu(II) complexes of adriamycin. Agents Actions 1989;26:378–85. 20. Ichikawa Y, Ghanefar M, Bayeva M, et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 2014;124:617–30. 21. Sterba M, Popelová O, Vávrová A, et al. Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid Redox Signal 2013;18: 899–929. 22. Dickey JS, Gonzalez Y, Aryal B, et al. Mito-tempol and dexrazoxane exhibit cardioprotective and chemotherapeutic effects through specific protein oxidation and autophagy in a syngeneic breast tumor preclinical model. PLoS One 2013;8:e70575.

6. Khasraw M, Bell R, Dang C. Epirubicin: is it like doxorubicin in breast cancer? A clinical review. Breast 2012;21:142–9.

23. Jirkovský E, Lencová-Popelová O, Hroch M, et al. Early and delayed cardioprotective intervention with dexrazoxane each show different potential for prevention of chronic anthracycline cardiotoxicity in rabbits. Toxicology 2013;311:191–204.

7. Tassan-Mangina S, Codorean D, Metivier M, et al. Tissue Doppler imaging and conventional echocardiography after anthracycline treatment in adults: early and late alterations of left ventricular function during a prospective study. Eur J Echocardiogr 2006;7:141–6.

24. Marty M, Espie M, Llombart A, et al. Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracyclinebased chemotherapy. Ann Oncol 2006;17:614–22.

8. Mercuro G, Cadeddu C, Piras A, et al. Early epirubicin-induced myocardial dysfunction revealed by serial tissue Doppler echocardiography: correlation with inflammatory and oxidative stress markers. Oncologist 2007;12:1124–33.

25. Ryberg M, Nielsen D, Cortese G, et al. New insight into epirubicin cardiac toxicity: competing risks analysis of 1097 breast cancer patients. J Natl Cancer Inst 2008;100:1058–67.

9. Lotrionte M, Cavarretta E, Abbate A, et al. Temporal changes in standard and tissue Doppler imaging echocardiographic parameters after anthracycline chemotherapy in women with breast cancer. Am J Cardiol 2013;112:1005–12. 10. Di Lisi D, Bonura F, Macaione F, et al. Chemotherapy-induced cardiotoxicity: role of the tissue Doppler in the early diagnosis of left ventricular dysfunction. Anticancer Drugs 2011;22:468–72. 11. Kalay N, Basar E, Ozdogru I, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2006;48:2258–62. 12. Yu CM, Sanderson JE, Marwick TH, et al. Tissue Doppler imaging a new prognosticator for cardiovascular diseases. J Am Coll Cardiol 2007;49:1903–14.

Copyright © 2015 by the Southern Society for Clinical Investigation.

26. Doyle JJ, Neugut AI, Jacobson JS, et al. Chemotherapy and cardiotoxicity in older breast cancer patients: a population-based study. J Clin Oncol 2005;23:8597–605. 27. Grundy SM, Benjamin IJ, Burke GL, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134–46. 28. Boyle P, Boniol M, Koechlin A, et al. Diabetes and breast cancer risk: a meta-analysis. Br J Cancer 2012;107:1608–17. 29. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539–53. 30. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echo-

411

Sun et al

cardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–63. 31. Erdogan D, Caliskan M, Yildirim I, et al. Effects of normal blood pressure, prehypertension and hypertension on left ventricular diastolic function and aortic elastic properties. Blood Press 2007;16:114–21. 32. Qi B, Ji Q, Wen Y, et al. Lycium barbarum polysaccharides protect human lens epithelial cells against oxidative stress-induced apoptosis and senescence. PLoS One 2014;9:e110275. 33. Jones LW, Haykowsky MJ, Swartz JJ, et al. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol 2007;50: 1435–41. 34. Jones LW, Haykowsky M, Peddle CJ, et al. Cardiovascular risk profile of patients with HER2/neu-positive breast cancer treated with anthracycline-taxane-containing adjuvant chemotherapy and/or trastuzumab. Cancer Epidemiol Biomarkers Prev 2007;16:1026–31. 35. Jones LW, Haykowsky M, Pituskin EN, et al. Cardiovascular reserve and risk profile of postmenopausal women after chemoendocrine therapy for hormone receptor–positive operable breast cancer. Oncologist 2007;12:1156–64. 36. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979;241:2035–8.

412

37. Nunes S, Soares E, Fernandes J, et al. Early cardiac changes in a rat model of prediabetes: brain natriuretic peptide overexpression seems to be the best marker. Cardiovasc Diabetol 2013;12:44. 38. Miki T, Yuda S, Kouzu H, et al. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail Rev 2013;18:149–66. 39. Di Bonito P, Moio N, Cavuto L, et al. Early detection of diabetic cardiomyopathy: usefulness of tissue Doppler imaging. Diabet Med 2005;22:1720–5. 40. Simunek T, Sterba M, Popelova O, et al. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Rep 2009;61:154–71. 41. Lebrecht D, Geist A, Ketelsen UP, et al. Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats. Br J Pharmacol 2007;151:771–8. 42. Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012;18:1639–42. 43. Goldberg MA, Antin JH, Guinan EC, et al. Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood 1986;68:1114–8. 44. Senkus E, Jassem J. Cardiovascular effects of systemic cancer treatment. Cancer Treat Rev 2011;37:300–11.

Volume 349, Number 5, May 2015