The Risk And Predictive Factors Of Chemotherapy-Related Cardiotoxicity

Currently, the most commonly used chemotherapy drugs including anthracyclines such as Pirarubicin, Doxorubicin, paclitaxel drugs such as Paclitaxel or Docetaxel, as well as with representatives of trastuzumab for targeted anticancer drugs. These drugs often have excellent anticancer performance, but the potential cardiotoxicity after treatment limits their wider clinical applications. Chemotherapy-mediated cardiotoxicity is difficult to detect for its variety of clinical manifestations. Chemotherapy-mediated cardiotoxicity presentation of progressive, irreversible, seriously affecting the quality of life of cancer patients and even endangers the lives of patients, so early detection and early prevention is very important for patients. The common means of monitoring cardiac function for cancer patients with chemotherapy including electrocardiogram, echocardiogram, blood biochemistry, such as c Tn T, BNP, EMB, but no sensitive indicator of a reliable prediction of cardiac toxicity occurred in current clinical practice. Therefore, early detection of chemotherapy-related cardiotoxicity and periodic assessment of cardiac function using ECG, serum marker testing during chemotherapy has become the consensus of oncologists and cardiologists.The purpose of this study was to assess the incidence of cardiotoxicity in patients with early breast cancer in the clinical practice and to find the potential risk factors. At the same time, the study is to investigate the early diagnosis value of ECG and Tβ4 in chemotherapy-mediated cardiotoxicity.1.This study was to start from clinical practice to assess the cardiotoxicity incidence among the patients with early breast cancer in the real world and to identify some possible risk factors. Selected 415 patients with early breast cancer in the department of breast cancer of Affiliated Hospital of the PLA Military Academy of Medical Sciences, according to whether the event met the diagnostic criteria cardiotoxicity after chemotherapy were divided into groups with no cardiac toxicity to cardiac toxicity group, using the cross-sectional study design. According to the use of trastuzumab, also divided into targeted group and conventional chemotherapy group. Observed indicators Include age, BMI, ER, PR, the history of hypertension, the history of coronary atherosclerotic heart disease, the history of diabetes, the tumor location, the clinical stage(AJCC cancer Staging); type of chemotherapy; past history of radiation therapy. Using SPSS 20.0 statistical software package to establish a database, the survival rate is calculated using the Kaplan-Meier method, using COX survival analysis comparing cardiac toxicity events. The results: 1. All 415 patients enrolled in the study, the total of 72 patients(17.35%) have appeared in the event of cardiotoxicity. Receiving trastuzumab treatment in patients with early breast cancer, the incidence of cardiotoxicity events to reach 23% was significantly higher than the 10.78%(p <0.01). Trastuzumab(HR: 3.90; 95% CI: 2.31 to 6.58) and the use of anthracyclines(HR: 1.08; 95% CI: 0.50 to 2.34) significantly increase the risk of cardiotoxicity, between the two groups there are statistically significant; 3. Anthracycline drug use within 4 cycles(Epirubicin less than 300 mg / m2, Pirarubicin less than 200 mg / m2) did not significantly increase their risk of cardiotoxicity(HR: 1.08; 95% CI: 0.50 to 2.34); 4. Multivariate analysis found that large doses of anthracyclines(HR: 2.59; 95%CI: 1.27 to 5.29), use of trastuzumab(HR: 3.90; 95% CI: 2.31 to 6.58), previous history of coronary heart disease(HR: 2.54; 95% CI: 1.16 to 5.56), combination with radiotherapy(HR: 1.74; 95% CI: 1.07 to 2.83) and other factors may increase the risk of cardiotoxicity, there are statistically significant. Conclusion: 1. The chemotherapy-related cardiotoxicity is greatly underestimated in clinical practice. The coincidence was significantly higher than the result of clinical trials. 2. On the basis of the conventional chemotherapy plus trastuzumab and other targeted drugs may increase the risk of cardiotoxicity.3. Previous history of coronary heart disease, joint anthracyclines and adjuvant radiotherapy are the high-risk factors for early breast cancer patients. These patients should closely monitor changes in their cardiac function.2.The study also determines if ECG is associated with cardiotoxicity in HER2-positive early breast cancer patients undergoing trastuzumab and conventional chemotherapy. Selected 199 HER2-positive early breast cancer patients in the department of breast cancer of Affiliated Hospital of the PLA Military Academy of Medical Sciences for prospective nested case-control study. With ST segment changes, T wave changes(increase, decrease and inversion), QRS wave changes and arrhythmias as the main standard ECG abnormalities. All subjects take electrocardiogram examination before and after chemotherapy. Assess cardiac function once every four weeks. Using multivariate analysis, to compare the differences of cardiotoxicity group and no cardiotoxicity group by ECG abnormalities, calculate the sensitivity and specificity of the diagnosis of cardiac toxicity occurred, assess their predictive value. The results: 1. A total of 199 cases of HER2-positive breast cancer patients eventually enrolled. 124 cases of patients during the treatment appeared abnormal ECG changes, of which 86 patients showed transient ECG abnormalities. 2.The most common ECG abnormalities are non-specific ST-T changes, a total of 108 cases have appeared in patients with T-wave changes alone or ST segment abnormalities. Secondly, respectively ST-T segment(26 cases), leads to abnormal voltage change(29 cases), block(six cases), sinus arrhythmia(12 cases). 3.The proportion of non-specific ST-T changes in the group of patients with cardiotoxicity appear significantly higher than in patients without cardiotoxicity(71.43% vs. 49.68% p <0.01), other ECG difference was not statistically different between the two groups. 4.ECG abnormalities occurring in the early stage of chemotherapy is an independent predictor of cardiac toxicity events. Throughout the follow-up, the possibility of cardiotoxicity ECG abnormalities increased by 1.7 times, 2 times the risk of ECG abnormalities in patients with 2-fold increase. 5.ECG abnormalities occur more times, then the greater the likelihood of cardiotoxicity events occur, and both were significantly correlated. An electrocardiographic abnormality in patients with more than four times the sensitivity of diagnosis of cardiac toxicity was 50%, specificity of 83%. Conclusion: 1.This study demonstrated that the using of ECG for early detection of trastuzumab-related cardiotoxicity has good prospects for high-risk patients, the diagnostic value worth more step studying. 2.ECG changes for detecting subclinical cardiac toxicity have a good sensitivity. The consecutive ECG abnormalities should lead to doctor’s attention. Early intervention for cardiovascular physicians is good to avoid future incidents of possible cardiotoxicity, so that the patients get more benefits.3.The study is to value the diagnostic value of serum Tβ4 level on chemotherapy-related cardiotoxicity of breast cancer. Selected 129 HER2-positive early breast cancer patients in the department of breast cancer of Affiliated Hospital of the PLA Military Academy of Medical Sciences for prospective nested case-control study. All patients enrolled were complete electrocardiogram, echocardiogram, troponin and other cardiac function as baseline examinations. During chemotherapy, detection of serum Tβ4 levels weekly, echocardiographic examination once every three months. Patients tested before each cycle of chemotherapy treatment and chemotherapy first six days of fasting venous blood 4ml, natural cohesion 30 min,-8, 4000 rpm 15min serum was separated by centrifugation, aliquot and tested-80. Compare the relationship between serums Tβ4 during every cycle of chemotherapy and analyze the relationship between serum levels of Tβ4 and cardiotoxicity occurred. The results: Follow-up to January 2014, a total of 129 cases of breast cancer patients entering the final group, complete follow-up. The level of Tβ4 differences between groups with and without cardiotoxicity was statistically significant cardiotoxicity, Tβ4 with cardiotoxicity group were significantly higher than those without cardiotoxicity. After chemotherapy, Tβ4 in cardiotoxicity group was progressively increased, a significant increase compared to the increased rate of non-toxic group, with statistical significance. 3.Area under the curve after chemotherapy(AUC) was 0.83(95% CI: 0.71-0.94). Considering the ROC curve set the level of serum Tβ4 6000 pg / ml for the diagnosis of cardiotoxicity critical point, the diagnosis of breast cancer cardiotoxicity sensitivity and specificity were 72.22%, 85.60%. Conclusion: 1. Observed the change of Tβ4 levels in the different cycles of chemotherapy in the larger sample size, confirming the serum Tβ4 of patients with cardiotoxicity significantly increased compared with the previous level, suggesting that Tβ4 is practicable for early detection the cardiotoxicity in early breast cancer. Dynamic monitoring of serum levels of Tβ4 need further follow-up value of the patient’s condition monitoring cardiotoxicity, efficacy assessment, prognosis in breast cancer after chemotherapy, its diagnostic value to be further confirmed.Our study focuses firstly on the clinical practice, the incidence of chemotherapy related cardiotoxicity is much higher than expected. Clinical trials about cardiotoxicity are in the undervalued. Then the research on cardiac function in patients with EBC undergoing anticancer therapy change after statistical analysis, screening out the previous history of coronary heart disease, combined with anthracycline and trastuzumab drug, radiotherapy and other factors. In the cross-sectional study, accept the anti-tumor treatment, EBC patients have the abnormal high ratio of ECG increased significantly. Combined with ECG for the special status of subclinical cardiac function change, we conducted a prospective nested case-control study, found that ECG for the early detection of cardiotoxicity of chemotherapeutic drugs have good prospects, for predicting subsequent cardiac toxicity occurred abnormal ECG sensitivity of 50%, specificity of 83%, one of the more reliable predictor for chemotherapy related cardiotoxicity. Previous study showed that T beta 4 plays an important role in the repair of injury of heart very much, but T beta 4 in chemotherapy has not been reported in cardiotoxicity. The innovation of this research will be the T beta 4 as a new serum biomarkers for early diagnosis and prediction of cardiac toxicity of chemotherapeutic agents, found that serum T beta 4 levels have important value in the early diagnosis of cardiac toxicity, the sensitivity was 72.22%, specificity was 85.60%. The study on cardiotoxicity of chemotherapeutic agents in early detection and early diagnosis of a series of study, improve the reference for clinical practice, and lays the foundation for the next research.