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Heart function after epirubicin‐treatment for breast cancer – A study of Tissue‐Doppler echocardiography

Jon Michael Appel

Summary

Background

Breast cancer is the most common cancer in women with a lifetime-risk of approximately 10%.Development of adjuvant chemotherapy has improved prognosis for high-risk patients. Epirubicinand other anthracyclines are effective components in breast cancer treatment-regimens and intreatment of other cancers, but they have serious side effects, most important, cardiotoxicity withlate development of heart failure. This side effect is dose related and in certain conditions the risk ofheart failure can approach 50%. The risk was previously regarded as negligible among individualstreated with low doses, as used in adjuvant treatment of breast cancer. New studies, however, raiseconcern that there is a risk of late development of myocardial dysfunction even after low-dosetreatment. An alternative treatment regimen where methotrexate substitutes epirubicin (CMF) hasbeen tested but turned out to be inferior to the epirubicin-based regimen (CEF) in terms of survivaland recurrence rate.Early studies showed that late development of heart failure was preceded by a reduction in leftventricular ejection fraction, EF measured with radio-nuclide ventriculography (MUGA). Themonitoring of the cardiac function has therefore traditionally included measurements of EF, butparameters of the diastolic function have been suggested as more sensitive. Myocardial velocitiesmeasured with tissue-Doppler are sensitive parameters of the myocardial function and are affectedearly in several heart diseases. Theses parameters contain prognostic information in diverse settings.Based on pathophysiological assumptions we hypothesized that assessment of the longitudinal heartfunction would expose possible functional impairment when using tissue-Dopplerechocardiography early or years after adjuvant epirubicin-treatment.

Methods

1. We re-analyzed raw data from MUGA-studies from 34 patients selected retrospectively.They had all completed high dose epirubicin-based chemotherapy for advanced breastcancer, were examined with MUGA prior to, and after chemotherapy and were followedclinically for late development of heart failure.2. Longitudinal heart function was examined prospectively in other 80 consecutive breastcancer patients undergoing epirubicin-based adjuvant chemotherapy. Tissue-Doppler andconventional echocardiography were applied before starting and approximately one weekafter ending chemotherapy. From the hospital staff we recruited 34 healthy volonteers ascontrols.3. We searched registries for diagnoses and outcome for 980 breast cancer patients who, 10 to20 years previously, participated in a randomized trial comparing epirubicin-based adjuvantchemotherapy against a methotrexate-based regimen. From this population 77 individualswere examined with tissue-Doppler and conventional echocardiography, radionuclideventriculography and NT-proBNP. The epirubicin-treated group. Meaurements from theCEF-group were compared to the CMF-group and to baseline-values from participants inprotocol 2.4. We recruited 34 healthy women among the hospital staff. They were examined twice withtissue-Doppler and conventional echocardiography with a 6 weeks interval.

Results

1. Whereas EF declined considerably during high-dose epirubicin treatment (-9.7% ±6.8, p<0.001) filling and emptying rates only showed minor, but statistically significant reductions.Cumulated dose and systolic baseline blood pressure correlated to the risk of heart failure.Individuals could be divided into a low-risk group with EF above 50% after ending epirubicin treatment and a high-risk group with EF values below 50% (log Rank 4.048, p0.044, HR 3.31). Diastolic parameters from MUGA did not possess prognostic information.2. Apart from a marginal decrease in A/E-ratio (-0.07 ±0.2, p 0.02) there were no significantchanges in any of several parameters of systolic and diastolic heart function during adjuvanttreatment with epirubicin.3. Analyses based on diagnoses from national registries showed a similar risk of heart failureand ischemic heart disease in the two treatment groups ((Logrank test, χ² 0.07, p 0.93).Incidence of heart failure in the total population was 2.6/1000/year at risk. The risk of IHDwas not increased in patients who had received radiation therapy (Logrank test, χ² 0.527, p0.468). In the sample of survivors there were no differences in multiple heart functionparameters from tissue-Doppler echocardiography, conventional echocardiography andMUGA. Although within normal range, plasma NT-proBNP values were higher in the CEFgroup(CI 105-226%, p 0.03).4. Compared to conventional echocardiograhy, tissue-Doppler variables were very feasible andhighly reproducible in a normal population. A considerable time-to-time variability oftissue-Doppler measurements was noted in healthy individuals.

Conclusions

High-dose epirubicin treatment for breast cancer is associated with decreasing heart function and ahigh risk of development of heart failure. Measurements of the left ventricular ejection fraction, EF,after ended treatment provide important prognostic information regarding the risk, permitting acloser follow-up of high-risk patients.