In this study, none of the 43 patients undergoing chemotherapy with doxorubicin developed clinical CTX. Although, we have identified some cases of subclinical CTX with both the cutoff points utilized (LV GLS relative reduction > 15 and > 12%). Advanced age and HTN were associated with the occurrence of subclinical CTX in univariate analysis.
Ventricular dysfunction and heart failure (HF) risks vary according to the cumulative dose of doxorubicin administered, ranging from 3 to 5% to 18–48% with doses of 400 mg/m2 and 700 mg/m2, respectively . A study conducted among 2625 patients undergoing treatment with anthracyclines showed that the incidence rate of CTX was 9% during a mean follow-up period of 5.2 years. The cumulative dose of doxorubicin was 359 (± 172) mg/m2 in the group with CTX and 299 (± 144) mg/m2 in the group without CTX (P < 0.001) .
An extensive systematic review that analyzed data from 18 studies and included approximately 23,000 patients treated with anthracyclines reported an incidence rate of 17.9% for ventricular dysfunction and 6.3% for clinical HF during a mean follow-up period of 9 years. The cumulative dose of anthracyclines was consistently reported across studies as an accurate and robust predictor of CTX .
We identified no cases of clinical CTX, which may be due to the short follow-up period (patients were followed up for 6 months after starting chemotherapy) and/or low cumulative dose of doxorubicin administered (248.4 ± 30.9 mg/m2). However, there were cases of subclinical CTX (the incidence rate was 14–39.5%, depending on the criterion used).
According to the ASE and EACVI Expert Consensus for Multimodality Imaging Evaluation of Adult Patients During and After Cancer Therapy, it was suggested that a relative reduction of LV GLS > 15% (compared with baseline) is a diagnostic criterion for subclinical CTX . In an Italian study analyzing strain as a guide for cardioprotective therapy in 116 patients with breast cancer, 19.8% of patients developed subclinical CTX (LV GLS reduction > 15% during a 3-month follow-up period). The prevention of clinical HF development could result from patients completing their chemotherapy after administering cardioprotective drugs (ramipril and carvedilol) .
The 1-year follow-up analysis of the Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes (SUCCOUR) study has been recently published. This was the first randomized clinical trial comparing a serial analysis (every 3 months) of LV GLS vs LVEF to monitor cardioprotective therapy. Overall, 331 patients undergoing doxorubicin treatment (mean dose of 218 mg/m2) were analyzed. LV GLS reduction ≥12% at any time (compared with baseline) was considered an indicator of subclinical CTX. The incidence rate of subclinical CTX was 29% in the LV GLS group, whereas clinical CTX was 13.7% in the LVEF-guided group . The study failed to meet the primary endpoint after the 1-year follow-up period, with no statistically significant difference in LVEF over the period evaluated (− 3.0% in the LVEF-guided group and − 2.7% in the LV GLS-guided group, P = 0.69). Cases of hospitalization for HF were rare (one in each group) . Patients in the LV GLS group were prescribed cardioprotective therapy twice as often as those in the LVEF group. The detection of subclinical CTX resulted in interrupted cancer treatment in five patients in the LV GLS group) and two patients in the LVEF group) . In addition to the higher risk of exposure to side effects and costs associated with cardiological treatment, patients in the LV GLS group had a higher risk of unfavorable cancer progression when chemotherapy was interrupted. Moreover, there were no differences in LVEF and LV GLS at the end of the 1-year follow-up period . Therefore, in the absence of definitive evidence, the LV GLS should be used judiciously in the clinical follow-up of cancer patients . Based on this study, the SBC adopted LV GLS change > 12% as a recommendation in the recently published Brazilian Positioning on the Use of Multimodality Imaging in Cardio-Oncology – 2021 . In this study, the incidence rate of subclinical CTX observed was similar to that found in the literature. The comparison of the two LV GLS cutoffs showed no differences in the occurrence of subclinical CTX.
A systematic review and meta-analysis published in 2014 analyzed the role of myocardial strain in the early detection of CTX during and after chemotherapy. This study evaluated 1504 patients and reported that a LV GLS reduction between 10 and 15% during chemotherapy appeared to be the most useful parameter to predict the future occurrence of CTX . Additionally, a systematic review and meta-analysis published by Oikonomou et al.  analyzed the role of LV GLS as a predictor of CTX. This analysis showed that the nine studies evaluating the percentage LV GLS variation had cutoff points that ranged from 2.3 to 15.9% (mean, 13.7%), with a sensitivity of 45 to 100% (mean, 86%) and specificity of 65 to 95% (mean, 79%) . However, due to the heterogeneity of the studies analyzed and the possible existence of publication bias (limited description of the population analyzed and lack of adjustment for relevant risk factors), the meta-analysis concluded that more robust prospective studies should be conducted to define the ideal cutoff point .
There is still no consensus in the literature on the best cutoff point for the percentage variation of LV GLS as a predictor of CTX. This study revealed no differences in the incidence of subclinical CTX with both cutoff points, probably due to the small sample size. There were no differences in the occurrence of subclinical CTX between the two-time intervals used.
Gripp et al. analyzed the role of LV GLS as a predictor of CTX in 49 patients with breast cancer undergoing chemotherapy and identified two cases of reduced LVEF in the third month of follow-up and another three in the sixth month. The authors suggested that if the LV GLS had been analyzed after each cycle of chemotherapy (3-week interval) rather than every 3 months (routine procedure), the change in strain would have probably occurred before the decrease in LVEF. Therefore, they recommend performing echocardiography after each cycle of chemotherapy , which does not corroborate the findings in this study.
To the best of our knowledge, no study has directly compared the two-time intervals for monitoring subclinical CTX. Despite the limitations of sample size and the short follow-up period, more frequent monitoring does not seem to benefit the diagnosis of CTX and is associated with increased costs.
In this study, advanced age and HTN were associated with the occurrence of subclinical CTX in univariate analysis. Similarly, a systematic review and meta-analysis by Lotrionte et al. showed that in addition to the cumulative anthracycline dose, extremes of age, HTN, diabetes mellitus, extremes of weight, radiotherapy, African-American ethnicity and severe comorbidities were predictors of anthracycline-induced CTX .
Henry et al. observed that 4.2% of 16,456 patients with breast cancer undergoing chemotherapy developed CTX. HTN was associated with the occurrence of CTX (relative risk, 1.28; 95% confidence interval, 1.09–1.51). In addition, younger individuals (age < 50 years) were less likely to develop CTX than older ones (age ≥ 65 years) , thereby corroborating the findings of this study. Therefore, serial LV GLS monitoring is useful for the follow-up of patients undergoing chemotherapy with anthracyclines. Despite the small sample size and being conducted at a single center, the present study indicated that quarterly monitoring was the most appropriate for clinical practice.
Intra-observer agreement was not analyzed. The low incidence of CTX in the analyzed sample was probably a result of the short follow-up period and the low cumulative dose of doxorubicin administered. Larger sample size may increase the impact of the conclusions of this study. The concomitant use of biomarkers and cardiac magnetic resonance imaging would provide additional value to the serial analysis of the strain as a predictor of CTX in suspected cases. High risk patients, specially those with cardiac structural diseases, were excluded from this analysis. This population could be the one that should be most beneficiated of the more frequent monitoring strategy. These observations should be analyzed in future studies to increase knowledge.
Competency in patient care
Monitoring the development of subclinical CTX in patients with breast cancer who undergo treatment with doxorubicin is pivotal to the cardiovascular management of these patients. This study suggests that quarterly monitoring of LV GLS is the most appropriate echocardiographic strategy.
Further studies with larger sample sizes and extended follow-up periods are required to validate the results of the present study. Early diagnosis and treatment of CTX is necessary for improving the outcomes in female patients with breast cancer undergoing chemotherapy. Serial LV GLS monitoring is useful in this scenario. Defining the optimal cutoff point for the relative variation in the LV GLS (compared with baseline) and ideal frequency of performing serial exams are necessary measures to establish routines, avoid unnecessary expenses, and provide better care to patients with breast cancer.