Highlights
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TZ is associated with LV dysfunction leading to cardiotoxicity.
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Current literature examining RV parameters post-TZ chemotherapy is scarce.
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RV GLS and RV FWLS are significantly reduced post-TZ chemotherapy.
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RV subclinical damage occurs leading to the deformation of RV mechanics.
Abstract
Introduction
The survival rates of breast cancer patients have improved drastically in the past few decades due to advancements in anti-neoplastic drugs. Trastuzumab (TZ) chemotherapy is associated with left ventricular dysfunction leading to cardiotoxicity. Two-dimensional speckle-tracking echocardiography has demonstrated efficacy in predicting TZ-induced cardiotoxicity; however, its role in using right ventricular (RV) strain parameters remains unclear.
Methods
A comprehensive literature search spanning major electronic databases was conducted to identify studies comparing pre- and post-TZ chemotherapy RV strain parameters. The outcomes of interest included RV global longitudinal strain (GLS) and RV free-wall longitudinal strain (FWLS). Mean differences (MD) with 95% confidence intervals (CI) were pooled using the inverse-variance random-effects model. Statistical significance was set at p<0.05.
Results
Four studies involving 275 cancer patients were included. The mean age of the patients was 53.35 ± 11.1 years. The pooled analysis demonstrated significantly reduced RV GLS [MD: -1.94; 95% CI: -2.83, -1.05; p<0.01] and RV FWLS [MD: -2.05; 95% CI: -3.61, -0.50; p<0.01] on follow-up post-TZ chemotherapy compared to pre-TZ baseline values.
Conclusion
Following TZ-based chemotherapy, RV subclinical damage ensues without overt clinical signs, leading to the deformation of RV mechanics. This meta-analysis demonstrated a reduction in RV GLS and RV FWLS after TZ-based chemotherapy.
Graphical Abstract
Introduction
Breast cancer is the second most frequently diagnosed cancer worldwide and the most common cancer among women Incidence and prevalence estimates report approximately 2.3 million new cases and 685,000 deaths in 2020 The survival rates for breast cancer have greatly improved over the past decade, mainly owing to advancements in cancer treatment, such as antineoplastic drugs. However, the widespread use of these antineoplastic drugs has been associated with side effects such as cardiotoxicity, which has become a significant cause of increased mortality With the increasing number of long-term cancer survivors, cardiotoxicity induced by antineoplastic drugs has become a rapidly growing area of clinical interest Trastuzumab (TZ), a humanized IgG1 monoclonal antibody targeting the extracellular domain of HER2, has markedly improved the survival rate of patients with HER2-positive breast cancer Including this monoclonal antibody in standard chemotherapy regimens has significantly improved overall and disease-free survival rates. Despite these potential benefits, TZ administration has been linked to cardiotoxic effects, primarily affecting ventricular (LV) function These cardiotoxic effects can vary from temporary, asymptomatic changes to severe heart failure, which can undermine the effectiveness of cancer treatment and increase patient morbidity and mortality Early cardiotoxicity may be undetectable, but timely diagnosis is crucial for patients who exhibit early structural heart changes without symptoms of heart failure
Conventional methods for detecting cardiotoxicity have mostly focused on analyzing left ventricular function, primarily emphasizing left ventricular ejection fraction (LVEF) However, subclinical myocardial damage can occur before any noticeable changes in LVEF occur, underscoring the need for more sensitive diagnostic techniques. Speckle-tracking echocardiography may assess the global longitudinal strain (GLS) of the LV, which is a reliable indicator of subclinical cardiotoxicity A decline in LV GLS is an early indicator of myocardial dysfunction, even before any detectable changes in LVEF become apparent While the effects of TZ on LV function have been well established, its impact on right ventricular (RV) function is yet to be thoroughly studied Recent research has indicated that TZ can also adversely affect RV function, which is crucial for overall cardiac performance and patient outcome Studies have demonstrated that RV remodeling, assessed either through RV global longitudinal strain (RV GLS) or RV free wall longitudinal strain (RV FWLS), can develop during TZ treatment
This remodeling in RV functions often seems parallel to that in the LV, suggesting that TZ has a comprehensive myocardial impact. Therefore, our comprehensive systematic review and meta-analysis aimed to evaluate the efficacy of RV remodeling as an early predictor of TZ-induced chemotherapy-related cardiac dysfunction.
Materials and methods
This systematic review and meta-analysis was designed, conducted, and reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines ( Supplementary Table S1 )
Search strategy and study selection
A systematic literature search of major bibliographic databases (MEDLINE, Embase, Google Scholar, Scopus, Cochrane Library, and clinicaltrials.gov) was conducted from database inception until June 2024. The search strategy used keywords such as “right ventricular strain” and “trastuzumab”, in combination with the Boolean operators such as “AND” and “OR” ( Supplementary Table S2 ). We did not impose any restrictions on the publication year or language of publication. The search was aimed at identifying studies that evaluated echocardiographic RV strain parameters before and post-TZ chemotherapy.
Inclusion criteria (PECOS format):
- (i)
P (Population): Breast cancer patients
- (ii)
E (Exposure): TZ
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C (Comparator): Post-TZ chemotherapy patients
- (iv)
(Outcomes): RV GLS and RV FWLS
- (v)
S (Study Design): Randomized controlled trials or observational studies
Exclusion criteria:
We excluded studies (i) if they did not report pre- and post-TZ echocardiographic RV strain parameters in the same patient group; (ii) if they were of the following study design: reviews, case reports, case series, editorials, correspondence, viewpoints, expert opinions, in vitro models, and letters to editors; (iii) if they did not conduct a pre-TZ chemotherapy echocardiogram; and (iv) if they were conducted on animals.
Using the aforementioned search strategies, all relevant records were exported to EndNote X7 software (Clarivate Analytics, USA), and duplicates were removed. Two investigators (M.A. and M.D.T.) screened all articles using titles and abstracts and removed those that did not adhere to our predefined inclusion criteria. Subsequently, the full texts of the shortlisted articles were comprehensively assessed for inclusion in the meta-analysis. Any discrepancies or disagreements were resolved by discussion with a third investigator (H.J.) to reach a consensus. All the reference lists were manually screened to identify additional studies. There were no limitations imposed on the minimum sample size.
Data extraction and quality assessment
Two investigators (J.J. and M.A.) extracted the following data from an Excel spreadsheet: first author’s name, publication year, country of publication, sample size, mean age, mean body mass index, hypertension (%), diabetes mellitus (%), dyslipidemia (%), obesity (%), radiotherapy (%), anthracycline use (%), beta-blockers (%), angiotensin-converting enzyme inhibitor use (%), inclusion criteria, exclusion criteria, and outcomes of interest. A third reviewer (H.J.) further crosschecked the data extraction to ensure accuracy and validity. For conducting the quality assessment, two reviewers (M.A. and J.J.) independently utilized the Risk Of Bias In Non-Randomized Studies – of Interventions (ROBINS-I) The ROBINS-I assesses the risk of bias across seven domains, including confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of the reported result.
Data synthesis and analysis
The extracted data were analyzed using R version 4.3.3, using the “meta” and “metasens” packages. The mean differences (MD) between the post-TZ follow-up and pre-TZ baseline values were pooled for continuous outcomes. Inverse-variance random-effects models were used to pool the outcomes, and the statistical significance was set at p<0.05. To evaluate the statistical heterogeneity between the included studies, the Higgins I 2 metric was utilized with low (<25%), moderate (25-75%), and high (>75%) heterogeneity. A sensitivity analysis was performed using the leave-one-out method. Publication bias was evaluated visually using funnel plots for all the outcomes.
Results
Systematic literature search results
The preliminary search identified 83 articles. Following the removal of duplicates (n = 28), 55 articles were screened for title and abstract. After excluding irrelevant articles that did not meet the inclusion criteria (n = 32), 23 articles were subjected to a comprehensive full-text assessment, including a manual search of the reference lists of all studies. Nineteen studies were excluded for the following reasons: incorrect outcomes (n = 10) and incorrect study designs (n = 9). Finally, four studies were included in this meta-analysis. The systematic literature search process was visually depicted using the PRISMA flowchart [ Supplementary Figure S1 ].
Baseline study characteristics and quality assessment
This meta-analysis included four studies published between 2019 and 2024, with 275 participants. The mean age of the patients was 53.35 ± 11.1 years. One study was conducted in the United States, one in England, one in Brazil, and one in Italy The baseline characteristics of all studies are reported in Table 1 . The inclusion and exclusion criteria of the included studies are presented in Supplementary Table S3 .
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