Cardiotoxicity Induced By Epirubicin-based Chemotherapy For Early Stage Breast Cancer Patients With Diabetes And The Protection Of Dexrazoxane

Part 1 Cardiotoxicity induced by epirubicin-based chemotherapy in early stage Breast Cancer PatientsObjective:Breast cancer is one of the most common malignances among women. The anthracyclines including doxorubicin and epirubicin, have been effectively applied in the treatment of breast cancer and are components of many adjuvant and palliative regimens. The application of anthracyclines is, however, limited by cumulative, dose-related progressive myocardial damage that can lead to chronic heart failure (CHF), reduced quality of life, and even death. As an increasing in survival of breast cancer, the impacts of treatment methods on cardiovascular health are attracting more attention in clinic. The cardiac abnormalities resulting from anthracycline therapy could be persistent, progressive and irreversible. Thus, it is necessary to monitor and prevent the early cardiac toxicity of anthracycline.Recent reports have demonstrated that some improved screening techniques may facilitate rapid detection of cardiac toxicity, allowing chemotherapeutic doses to be tailored to patient tolerance. Serial noninvasive surveillance for anthracycline cardiotoxicity has previously centered on the echocardiographic assessment of LV systolic function. However, changes in these indices are usually symptomatic of significant myocardial dysfunction, and thus do not contribute to the early diagnosis of subclinical myocardial dysfunction. Tissue Doppler imaging (TDI) is a relatively potent echocardiographic technique. Several parameters of TDI velocity analysis have been shown to be useful predictors of long-term prognosis, provides independent and incremental prognostic information in a number of major cardiac diseases, including heart failure, acute myocardial infarction, and hypertension. Some researches have comfirmed that TDI could help to observe the earliest stage of cardiac dysfuntion brought by anthracycline, which manifests myocardial inotropic dysfunction followed by diastolic dysfuntion. Thus, application of this technology may improve the evaluation of cardiac function during anthracycline therapy. However, its associated research in China is still rare until now. The ventricular diastolic or contraction function alteraitions caused by anthracycline often happened in late stage, so the positive rate is low in short-term observation. By contrast, the cardiac electrophysiological changes appear earlier, and the positive rate is high. Among the indicators of cardiac electrophysiological activity, heart rate variability (HRV) have relatively high specificity and repeatability. HRV could be effected by anthracycline medicines as their side-effect on autonomic nerve. Many studies have provided some evidence that the doxorubicin chemotherapy could decrease the HRV of breast cancer patients, in addition, as the accumulated doses increase, the HRV tends to be progressively lower. The alteration of HRV happens earlier with high positive rate, which makes it a sensitive indicator of cardiac toxicity. However, anthracycline's effect on autonomic nerve still lack attention in China.In this study, early stage breast cancer female patients received chemotherapy based on epirubicin were observed to evaluate their cardiac effect on autonomic nerve, echocardiography and TDI examinations as well as SOD and MDA assessments before and after medicine administration, aiming at assessing the safety of the epirubicin-based adjuvant chemotherapy.Methods:40 cases of early stage breast cancer female patients without any cardiovascular hazard risk were recruited to receive the chemotherapy. All patients received 80 mg/m2 epirubicin and 500 mg/m2 cyclophosphamide by intravenous infusion every 3 weeks for a total of six cycles. Before and after chemotherapy, all patients received physical examination, including measurement of height, weight and blood pressure, a resting 12-lead electrocardiogram and 24-hour dynamic electrocardiogram, tissue Doppler imaging (TDI) and transthoracic echocardiographic examination was performed. Blood samples were collected for assaying the oxidative stress markers. 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.Result:Before and after the chemotherapy,the SOD level in serum was decreased while MDA was increased, significantly. The differences of other indices including HRV and TDI are all not of statistical significance.Conculsions:In patients without apparent CVD risk factor, the standard dose of epirubicin adjuvant chemotherapy did not induce significant deterioration of HRV and any systolic or diastolic function parameters in TDI, indicating that no detectable myocardial injury was induced by this treatment. Within the limitations of our small scale single center study, these results could provide some reassurance regarding potential cardiac complications associated with a standard adjuvant low-dose epirubicin regimen. This study also indicated that epirubicin reduced free radical scavenging, which could lead to cardiomyocyte injury as a result of excess lipid peroxide.Part 2 Cardiotoxicity induced by epirubicin-based chemotherapy in early stage Breast Cancer Patients with concurrent DiabetesObjective:The occurrence of cardiactoxicity resulting from anthracycline is related to some hazard factors, which means that the patients who pocess these factors are vulnerable to myocardial damage. These hazard factors mainly include age, gender, total cumulative dose of anthracycline, prior irradiation therapy, and predisposition to heart disease. Patients with a medical history of diabetes mellitus,hypertension, obesity and heart disease are also found to be related with the increase of anthracycline cardiac toxicity.Diabetes mellitus (DM) is a well-known risk factor for the development of heart failure, and has been recognised as a coronary heart disease by the American Heart Association (AHA). Numerous studies have demonstrated an association between type 2 diabetes 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. However, although the studies on age, gender, accumulated doses and combined breast radiotherapy have been rather clear, there are rare research on DM and hypertension. In addition, among the studies targeting early stage breast cancer patients received adjuvant chemotherapy, no matter prospective or retrospective study, the patients who have cardiovascular disease hazard risks are excluded. Thus, in the future, large-scale, prospective studies to comprehensively evaluate the cardiovascular disease (CVD) risk burden associated with modern adjuvant therapy are urgently required.In order to investigate the mechanisms by which chemotherapy aggravates cardiac damage in patients with type 2 diabetes mellitus (DM2), this study recruited female patients diagnosed with early stage breast cancer and DM2 to evaluate cardiac damage after chemotherapy with epirubicinMethods:40 female early stage breast cancer patients with DM2 were recruited to receive the chemotherapy.40 age-matched female early stage breast cancer patients without DM2 were recruited as controls (NDM). All patients received 80 mg/m2 epirubicin and 500 mg/m2 cyclophosphamide by intravenous infusion every 3 weeks for a total of six cycles. Before and after chemotherapy, all patients received physical examination, including measurement of height, weight and blood pressure, a resting 12-lead electrocardiogram and 24-hour dynamic electrocardiogram, tissue Doppler imaging (TDI) and transthoracic echocardiographic examination was performed. Blood samples were collected for assaying the oxidative stress markers. 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.ResuIt:After chemotherapy, the SDNN, SDANN, RMSSD, pNN50, LF, HF, Ea and serum SOD got significantly lower while the LF/HF, E/Ea, Tei index and MDA got higher. Sa, EF showed no difference. Compared to NDM patients, the baseline of SDNN, SDANN, RMSSD, pNN50, LF, HF, Ea and serum SOD in DM2 patients were lower while E/ Ea,Tei index were higher, but the differences of Sa or EF were not significant. However, after chemotherapy, compared to NDM patients, the decrease of SDNN, SDANN, RMSSD, pNN50, LF, HF, Ea and serum SOD got more significant, likewise, LF/HF, E/Ea, Tei index and serum MDA got more significant.Conclusion:This study showed that patients with DM2, in comparison to patients without DM2, had apparent oxidative stress injury, impaired antioxidant capacity, autonomic nerve dysfunction and diastolic dysfunction at baseline. Anthracycline-based chemotherapy further reduced the capacity to clear free radicals and accumulation of lipid peroxidation products, leading to cardiomyocyte injury which further aggravated autonomic nerve dysfunction and diastolic dysfunction. These results indicated that hyperglycemia, hyperlipidemia and other cardiovascular risk factors might play an important role in the exacerbation of myocardial damage by anthracycline chemotherapy.Part 3 Dexrazoxane Protects Breast Cancer Patients with Diabetes from chemotherapy Induced CardiotoxicityObjective:Co-administration of the cardioprotective agent dexrazoxane (Cardioxane, ICRF-187) with each dose of anthracycline has been shown to significantly reduce cardiotoxicity in several randomized controlled studies?In this population dexrazoxane facilitates the safe administration of anthracyclines without compromising their efficacy.Breast cancer patients have been reported to have a significantly worse cardiovascular risk profile than age/gender-matched controls, leading to development of the "Multiple-Hit" hypothesis. 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 presence of modifiable risk factors all contribute to either overt CVD or an elevated risk of future CVD during early breast cancer.In this study, breast cancer patients with DM received epirubicin-based chemotherapy were observed, among these patients somewere randomly to receive dexrazoxane. To evaluate their cardiac autonomic nerve function before and after medicine administration, echocardiographic and oxidative stress index, aiming at assessing the value of dexrazoxane in the epirubicin-based adjuvant chemotherapy and revealing the effects of cardiovascular hazard factor in aggravating the myocardial damage brought by chemotherapy.Methods:80 female breast cancer patients with DM2 were randomly assigned to receive the chemotherapy only or chemotherapy plus dexrazoxane.. All patients received 80 mg/m2 epirubicin and 500 mg/m2 cyclophosphamide by intravenous infusion every 3 weeks for a total of six cycles. The group assigned to receive chemotherapy alone received placebo 30 min prior to epirubicin administration. The group assigned to receive chemotherapy plus dexrazoxane received 800 mg/m2 dexrazoxane 30 min prior to epirubicin administration. Before and after chemotherapy, all patients received physical examination, including measurement of height, weight and blood pressure, a resting 12-lead electrocardiogram and 24-hour dynamic electrocardiogram, echocardiographic examination was performed. Blood samples were collected for assaying the oxidative stress markers. 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.Results:There was no difference in baseline HRV?systole or diastole function between the two DM2 groups. Patients receiving chemotherapy alone experienced significantly greater reductions in SDNN?SDANN?RMSSD? pNN50?LF?HF?and Ea, and significantly greater elevations in LF/HF?E/ Ea and Tei index in comparison to patients receiving chemotherapy plus dexrazoxane. After chemotherapy SOD was significantly reduced and serum MDA was significantly increased in the two groups. Serum SOD levels were comparable between the two groups before and after chemotherapy, MDA levels were comparable between the two groups before chemotherapy, while serum MDA was significantly higher after chemotherapy in the chemotherapy alone group in comparison to the group that received dexrazoxane.Conculsions:Dexrazoxane protects against cardiotoxicity induced by epirubicin-based chemotherapy in breast cancer patients with concurrent DM2. Thus the mechanism by which dexrazoxane protects myocardium does not involve the activity of radical scavenging enzymes, but instead involves reduced production of oxygen free radicals, reduced lipid peroxidation, reduced oxidative stress, and thereby inhibition of anthracycline cardiotoxicity.. These observations support the "multiple hit" model of myocardial damage caused by the combination of hyperglycemia, hyperlipidemia, and anthracycline cardiotoxicity.Therefore, although dexrazoxane can reduce myocardial damage to some extent, it cannot completely prevent this damage.