Current Cardio-Oncology Guidelines focus on the diagnosis, treatment and surveillance of patients with high or very high cardiovascular risk. Therefore, low risk patients can be misdiagnosed. In this study, we aimed to assess the prevalence and the long-term effects of late cardiotoxicity among breast cancer survivors without pre-existing heart disease and CV risk factors. The main finding of our study was the high prevalence of LVSD (32.5%) and of late cardiotoxicity (10%) in patients considered of low cardiovascular risk. Previous studies, particularly of pediatric cancers survivors, report a similar prevalence of late cardiotoxicity.(33) However, other studies report prevalence between 1.6 and 5% and as high as 36%.(8, 30) These differences between studies highlight the importance of standardizing the definition of ATC-associated cardiotoxicity when conducting research in cancer survivors, even in the low risk population.
GLS, which is nowadays considered a more sensitive parameter to monitor the left ventricular systolic function, was inferior to -20 in more than a half of the study group which may indicate subclinical dysfunction in this low risk population.
In addition, our study showed that the longitudinal evaluation of patients with low cardiovascular risk was poor: only 52.5% of the patients were evaluated with echocardiography after finishing the treatment with anthracyclines. At T1 five patients already had LVSD which was not properly treated which should raise concern in the need of a Cardio-Oncology unit in the hospitals with an Oncology Department. At T2, 32.5% of patients had LVSD – this finding should raise the concern of performing cardiac evaluation in all patients that were exposed to anthracyclines, even in the low risk patients. The results of our study, suggests that despite the low risk of cardiotoxicity, all patients exposed to anthracyclines, especially with high doses, should be carefully monitored. The cardiotoxic effects of ATC increase with cumulative dose. Doxorubicin is associated with a 5% incidence of congestive HF when a cumulative lifetime dose of 400 mg/m2 is reached, and higher doses lead to an exponential increase in risk, up to 48% at 700 mg/m2.(34) High-dose ATC in a doxorubicin regiment is considered when the cumulative dose is greater than 250 mg/m2, and in an epirubicin-based treatment when superior to 600 mg/m2. (35) In this study, the mean cumulative dose of the doxorubicin-based treatment was 392 ± 26.5 mg/m2 and in the epirubicin-based regiment the cumulative dose was in mean 478 ± 50.9 mg/m2. In this way, the patients that received a doxorubicin- based chemotherapy did regiments with high-dose ATC, on the contrary patients with epirubicin-based treatment received low-dose ATC. However, there were no significant differences regarding the variation of LVEF according to the classes of ATC. Also, this analysis did not find higher cumulative doses of ATC to be associated with the variation of LVEF and with the developing of cardiotoxicity. These findings were not expected and might be explained by the small sample size of our study. Nevertheless, other studies, namely Yoon et al. and Qin et al. also did not find higher cumulative ATC doses to be associated with LV dysfunction.(36, 37)
Two studies of chemotherapy-treated BC survivors reported a lower prevalence of LVSD (15% and 8%) compared to this study (32.5%).(26, 27) This discrepancy is probably explained by the fact that the patients in our research were submitted to greater cumulative doses of ATC (429 ± 57.3mg/m2) when compared to the cumulative doses reported in the mentioned studies: 238 mg/m2 and 294 mg/m2. Distinct research methodology between the studies and small sample size in this analysis might also explain the different results. Recent studies reported differences in RV systolic function between ATC treated patients and controls. In our study, no differences were found in TAPSE between the study and control group, which might be associated to the limited sample size. (15, 16)
The median difference in LVEF between baseline (T0) and the end of treatment (T1) was a reduction of 3%, however this was not statistically significant. Similar results were reported by other studies, but it should be noted that patients’ characteristics and the types of malignancies vary. (28–30) Furthermore, the two patients that developed acute cardiotoxicity at T1 recovered normal LVEF. This study found a significant median decreased in LVEF of 7% from T0 to T2 and of 4% between T1 and T2. These findings suggest a worsening in cardiac function in BC survivors probably related to the cardiac toxic effects of chemotherapy since these patients were of low cardiovascular risk.
Although advanced age is a risk factor for developing cardiotoxicity, this study did not find older age to be associated with the variation of LVEF and with the developing of cardiotoxicity.(8) This might be related to the exclusion of patients older than 65 years from this study and to small sample.
Furthermore, this study also did not find significant results regarding the variation of LVEF according to treatment characteristics, namely left-sided radiation. Even though this might be explained by the small sample size, more recent studies obtained similar results. A potential reason for this finding might be the use of modern radiotherapy, resulting in a lower heart dose, especially in left-sided breast cancer.(27, 29, 37)
Few patients developed CV risk factors, namely hypertension and dyslipidemia. One patient that developed late cardiotoxicity experienced an arrythmia episode, a stroke, and subsequently a cardiovascular hospitalization. These findings might be related to aging and unhealthy lifestyle and not to cardiotoxic effects of chemotherapy. (38)
Limitations:
The main limitation of the study is the sample size. In the longitudinal evaluation, missing data restricted the analysis, because only twenty-one patients were screened at the end of treatment (T1) and several parameters, such as GLS, were not evaluated. Furthermore, interobserver variability and subjective interpretation of echocardiographic parameters constituted a serious limitation in this assessment. This weakness was surpassed by the comparison with the control group, where all echocardiographic analyses were performed by a single experienced cardiologist. Therefore, studies with larger sample size are required to further evaluate the effects and predictors of late cardiotoxicity in women without previous CV risk factors.