Perspectives on monitoring and diagnosis of chemotherapy-induced cardiotoxicity

Abstract

The study included all patients at risk for chemotherapy-related cardiotoxicity, without exclusions based on the type of cancer, reflecting the institution’s epidemiology with a predominance of breast cancer. Myocarditis was not an exclusion; its absence may reflect underdiagnosis. Age, although a known risk factor, showed no significant differences, and no upper chemotherapy dose limits were imposed to better capture real-world scenarios. A typographical error in the patient count was amended to 195. Limitations include its retrospective design, selection bias, and incomplete dose data. A prospective multicenter registry is underway to enhance diagnostic accuracy, include diverse types of cancer, and improve generalizability.

Key Words: Cardiotoxicity; Chemotherapy; Echocardiography; Global longitudinal strain; Myocarditis; Risk assessment

Core Tip: The accurate identification and monitoring of chemotherapy-related cardiotoxicity demand inclusive patient selection and robust diagnostic strategies. Our study demonstrates that real-world cohorts often reflect local epidemiological patterns rather than exclusionary criteria, underscoring the need for comprehensive inclusion of both solid and hematologic malignancies. Retrospective designs, while valuable, may overlook subclinical conditions such as myocarditis and lack precise chemotherapy dose tracking. Integrating advanced imaging, standardized biomarker surveillance, and multicenter collaboration in prospective registries can close these gaps, enhance diagnostic certainty, and improve risk stratification. Such approaches will strengthen cardio-oncology practice and optimize long-term cardiovascular outcomes in cancer patients.

TO THE EDITOR

Study context and methodological remarks

We appreciate the interest shown in our article[1]. We are grateful for the thoughtful comments and the opportunity to provide clarifications regarding the study’s methodology, inclusion criteria, and interpretation of findings. Our study included all patients deemed at risk for chemotherapy-related cardiotoxicity, regardless of the type of cancer. The inclusion criteria were defined by the presence of baseline and follow-up echocardiographic evaluations with valid measures of left ventricular ejection fraction using the modified Simpson’s biplane method[2] and Global Longitudinal Strain[3] assessed with a consistent echocardiographic software version, as this is essential for comparability and accuracy. No exclusions were made based on the nature of the malignancy—solid or hematological—or its frequency; therefore, rare tumor types or hematologic malignancies were not deliberately excluded. However, the final cohort reflected a predominance of patients with breast cancer and lymphomas. This trend aligns with the local epidemiological patterns observed in our institution, where breast cancer is the most common malignancy among women and one of the leading causes of cancer-related morbidity. Furthermore, our institution is not a primary reference center for hematologic malignancies, which are frequently managed in specialized facilities in the region. As a result, our sample naturally overrepresented patients with solid tumors, particularly breast cancer, and underrepresented those with hematologic cancers. We acknowledge this as a limitation in terms of generalizability to other cancer populations, and we appreciate the opportunity to clarify that this pattern is reflective of real-world institutional referrals and not of an exclusionary selection process.

In addition, it is worth clarifying that we did not exclude patients based on the presence of myocarditis. Our retrospective design relied on available clinical documentation, laboratory data, and imaging reports. Upon thorough review, no patients were found to have a confirmed diagnosis of infective or viral myocarditis during the chemotherapy treatment or follow-up period. Nonetheless, we recognize that subclinical myocarditis or underdiagnosis could have occurred. The absence of such findings in the medical records does not rule out their possible presence in a broader or more intensively follow-up cohort. This reflects an intrinsic limitation of retrospective chart reviews, where diagnoses not explicitly investigated or documented may remain undetected. We agree with the observation that myocarditis can mimic or overlap with chemotherapy-related cardiotoxicity[4], and we consider this a relevant limitation of our study. To address this, future cohorts are being designed to incorporate cardiac magnetic resonance imaging (MRI) and systematic biomarker surveillance (e.g., troponins, NT-proBNP) to enhance diagnostic accuracy and rule out differential diagnoses with greater certainty.

METHODOLOGICAL CLARIFICATIONS AND STUDY LIMITATIONS

With regard to age, we acknowledge it as a well-established risk factor for chemotherapy-induced cardiotoxicity. In our cohort, patients who developed cardiotoxicity were slightly older than those who did not; however, this difference did not reach statistical significance in the comparative analysis (P > 0.05). This result is reported in the Results section of the article. Although our sample size may not have been large enough to detect subtle age-related differences in cardiotoxicity risk, age remains a central variable in the Mayo Clinic Cardiotoxicity Risk Score, which we used for baseline risk stratification[5]. We appreciate the attention to this variable, and we are addressing it in ongoing prospective studies where larger sample sizes and multivariate models will be employed to better delineate age-related trends.

Regarding chemotherapy dosing, we did not impose upper limits on cumulative dose as a selection criteria. Our aim was to reflect real-world clinical scenarios and capture a broad range of cardiotoxicity risk, rather than restrict inclusion to those within strict guideline-defined dose thresholds. Consequently, some patients may have received cumulative doses approaching or exceeding traditional cardiotoxicity limits[6]. This heterogeneity increases the ecological validity of our findings and allows us to explore cardiotoxic outcomes across diverse treatment exposures. That said, the retrospective nature of the study limited our ability to retrieve complete cumulative dose data for all patients—particularly those treated in multiple institutions. This limitation is acknowledged in Discussion and has informed our decision to incorporate detailed chemotherapy records in our prospective registry currently under development.

We sincerely apologize for the inconsistency noted in the manuscript’s text, which erroneously reports the final sample as 194 patients. The correct number is 195, as indicated in Table 1 and our internal database. This discrepancy was a typographical oversight introduced during the final stages of manuscript revision. We confirm that all statistical analyses were conducted using the correct sample size (n = 195) using the statistical software R (version 4.2.0), and this minor error does not affect the validity of the results, or the conclusions drawn. To illustrate the negligible effect on descriptive statistics, the reviewer correctly notes that the prevalence of Hypertension shifts minutely from 25.77% (n = 194) to 25.64% (n = 195). Given the large sample size and the context of clinical epidemiology, this difference is well below the threshold for clinical relevance and does not change the interpretation of any baseline characteristic or comparative test (where all P values remain unchanged). We appreciate the input for identifying this detail and are willing to issue a formal erratum or corrected version if requested by the editorial office.

INTERPRETATION AND CLINICAL RELEVANCE

In addition, it is worth clarifying that we did not exclude patients based on the presence of myocarditis. Our retrospective design relied on available clinical documentation, laboratory data, and imaging reports. Upon thorough review, no patients were found to have a confirmed diagnosis of infective or viral myocarditis during the chemotherapy treatment or follow-up period. Nonetheless, we recognize that subclinical myocarditis or underdiagnosis could have occurred. The possibility of subclinical myocarditis is rooted in the current understanding that chemotherapy-related cardiotoxicity is a continuum, often beginning with asymptomatic myocardial injury. The absence of such findings in the medical records does not rule out their possible presence in a broader or more intensively follow-up cohort.

This reflects an intrinsic limitation of retrospective chart reviews, where the diagnostic yield is strictly dependent on the data systematically collected in routine clinical practice. Diagnoses not explicitly investigated or documented, such as those requiring advanced imaging like cardiac MRI or systematic, high-frequency surveillance of advanced biomarkers (e.g., highly sensitive troponins), may remain undetected. We agree with the observation that myocarditis can mimic or overlap with chemotherapy-related cardiotoxicity, and we consider this a relevant limitation of our study. To address this, future cohorts are being designed to incorporate cardiac MRI and systematic biomarker surveillance (e.g., troponins, NT-proBNP) to enhance diagnostic accuracy and rule out differential diagnoses with greater certainty.

CONCLUSION

Our study reflects real-world clinical scenarios and highlights both the strengths and limitations of retrospective assessments of chemotherapy-related cardiotoxicity. By clarifying our inclusion criteria, methodological choices, and acknowledged constraints, we aim to reinforce the robustness of our findings while recognizing areas for future improvement. The planned development of a multicenter prospective registry with standardized imaging and biomarker protocols represents our commitment to advancing methodological rigor and enhancing the generalizability of our research. We strongly believe that these efforts will contribute to providing valuable insights into the complex interplay between cancer therapies and cardiovascular outcomes.

ACKNOWLEDGEMENTS

We acknowledge the collective contributions of our co-authors and research collaborators, whose commitment and expertise made this study possible.