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The goal of the trial is the early detection of cardiotoxicity in patients treated with anthracycline-based chemotherapy. Current diagnostics, such as troponin T, NT-pro-BNP, electrocardiogram, and echocardiography, are not able to identify early myocardial damage. Therefore, this study aims to identify early myocardial damage by using cardiac magnetic resonance imaging.
The primary endpoint of this study is the change in relaxation times in CMR before, during, and after therapy.
Furthermore, the study analyzes:
The goal of the trial is the early detection of cardiotoxicity in patients treated with anthracycline-based chemotherapy as standard of care therapy. For clarification: Standard anthracycline-based chemotherapy is administered independently of the study and is not the subject of this study, but rather is its basis. No investigational medicinal products are being tested in this clinical trial; instead only diagnostic procedures are being investigated.
Since current diagnostic methods-such as troponin T, NT-proBNP, electrocardiography, and echocardiography-are limited in their ability to detect early myocardial injury, the study aims to identify early myocardial damage using cardiac magnetic resonance imaging (CMR).
Enrolled participants will be stratified into risk groups using the HFA-ICOS score and-depending on the risk category-monitored according to current ESC guidelines using electrocardiography, echocardiography, and serial measurements of troponin T and NT-proBNP.
Preclinical data suggest that anthracyclines may impair myocardial function not only as a result of cumulative dosage over time but also during the early stages of therapy. The investigators therefore evaluate the use of CMR for the early detection of myocardial alterations during anthracycline therapy.
CMR examinations will be scheduled according to the administered cumulative dose of anthracyclines. Following a baseline evaluation prior to the initiation of therapy, the first follow-up CMR examination will be performed after approximately half of the preplanned cumulative anthracycline dose has been administered. A third CMR examination will be conducted after completion of therapy. Twelve months after therapy completion, an end-of-study CMR examination will be performed to assess persistent myocardial changes.
The primary endpoint is the measurement of myocardial relaxation times. Given the early time point of evaluation, additional CMR parameters will also be analyzed, including variations in cardiac morphology, cardiac function, late gadolinium enhancement, and myocardial perfusion.
Currently, both the proportion of participants potentially affected by early myocardial alterations during anthracycline therapy and the underlying pathophysiological mechanisms remain unclear. The study therefore seeks to identify biomarkers or genetic polymorphisms associated with an increased risk of early myocardial injury. For this purpose, blood, urine, and stool samples will be collected for inclusion in a biobank and analyzed for polymorphisms or mutations in genes such as CYBA, RAC2, NCF4, ABCC1, ABCC5, ABCB4, SLC22A17, SLC22A7, SLC28A3, SLC10A2, HAS3, CBR3, RARG, CELF4, and SLC22A3. In addition, anthracycline metabolites and cytokine profiles, such as IL-6 and TNF-α, may be measured.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Serial cardiac magnetic resonance imaging (CMR) | Experimental | In this study, cardiac magnetic resonance imaging (CMR) is used as the primary tool for detecting possible anthracycline-induced cardiotoxicity without affecting standard oncological therapy. Before starting anthracycline-based therapy, a baseline CMR is performed, supplemented by echocardiography (TTE), ECG, and biomarker determination. Further CMR examinations are performed for mid-point analysis after half of the planned chemotherapy cycles, as well as 12-14 weeks and 12 months after the end of therapy. The timing depends on the individual chemotherapy regimen, with CMR scheduled on the same day always taking place before anthracycline administration. The CMR examinations are used for structural and functional assessment of the heart and are combined with other diagnostic procedures (TTE, ECG, biomarkers, biosampling) to detect early changes in heart function and systematically monitor the course of potential cardiotoxic effects during therapy. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CMR based measurement of cardiotoxicity | Diagnostic Test | CMR is performed on a 1.5T Siemens Magnetom Aera. The examination follows clinically established protocols for assessing cardiac morphology and function using HASTE and CINE-SSFP sequences. CINE and late gadolinium enhancement (LGE) images of the short axis are taken every 10 mm from the base of the heart to the apex (6 mm slice, resolution 1.2 × 1.8 mm). LGE images are acquired 5-10 minutes after administration of gadolinium. T1 mapping is performed using a MOLLI sequence before and 20 minutes after contrast agent administration, T2 mapping using an ECG-triggered T2-prepared SSFP sequence before contrast agent administration. The evaluation is performed independently by two examiners with manual marking of endocardial and epicardial boundaries. Left ventricular volumes and ejection fraction are calculated using the summation method, and LGE is visually quantified and classified. In addition, T1, ECV, and T2 maps are created from motion-corrected images and global values are calculated |
| Measure | Description | Time Frame |
|---|---|---|
| Change of T2-weighted myocardial relaxation time in cardiac magnetic resonance imaging | T2 mapping using an ECG-triggered T2-prepared SSFP sequence before contrast agent administration. The evaluation is performed independently by two examiners with manual marking of endocardial and epicardial boundaries. | Baseline (before anthracycline administration), after 4-9 weeks (depending on the anthracycline-based treatment regimen used), 3 months after completion of therapy, and 12 months after completion of therapy. |
| Measure | Description | Time Frame |
|---|---|---|
| abnormal CMR findings regarding morphology and function | CMR is performed on a 1.5T Siemens Magnetom Aera. The examination follows clinically established protocols for assessing cardiac morphology and function using HASTE and CINE-SSFP sequences. | Baseline (before anthracycline administration), after 4-9 weeks (depending on the anthracycline-based treatment regimen used), 3 months after completion of therapy, and 12 months after completion of therapy. |
| Measure | Description | Time Frame |
|---|---|---|
| Validation and/or identification of novel biomarkers on collected biomaterials (blood, stool, urin) using genetic testing, metabolomics, and cytokine analyses. | As part of the study, additional biomaterial (blood, urine, stool) will be collected at defined time points. A study-specific biobank will be created. Blood samples will be taken at baseline, mid-point analysis, and 3 and 12 months after the end of therapy. The methods used will analyze the DNA, RNA, and protein levels of the stored tissue material and perform functional tests. Genetic variants will be detected using established methods such as real-time PCR methods, mass spectrometric detection or nanofluid technology, as well as DNA microarrays or genome sequencing. Endogenous metabolites or metabolite profiles as well as drug concentrations and their metabolites can be detected in blood, urine, and, if necessary, stool using various mass spectrometric methods as well as biochemical assays. The cytokine profile can be analyzed in plasma isolated from blood samples. Proinflammatory cytokines in doxorubicin-induced cardiotoxicity have been described and should therefore be determined. |
Inclusion Criteria
- Patients with a recommendation for antineoplastic therapy including at least four administrations of an anthracycline
Exclusion Criteria
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Matthias Prof. Dr. med. Schwab | Contact | 0049 + 0711-8101 3700 | matthias-schwab@ikp-stuttgart.de |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Robert Bosch Gesellschaft für Medizinische Forschung mbH | Recruiting | Stuttgart | 70376 | Germany |
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No investigational medicinal products are being tested in this clinical trial; instead only diagnostic procedures are being investigated. Study population is defined as patients who are to be treated with at least 4 cycles of anthracycline-based chemotherapy. The anthracycline-based chemotherapy is standard of care therapy and is administered independently of the study. The standard anthracycline-based chemotherapy is not the subject of this study, but rather is its basis.
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| biosampling for scientific research in study-specific biobank | Other | As part of the study, additional biomaterial (blood, urine, stool) will be collected at defined time points. A study-specific biobank will be created. Blood samples will be taken at baseline, mid-point analysis, and 3 and 12 months after the end of therapy. The methods used will analyze the DNA, RNA, and protein levels of the stored tissue material and perform functional tests. Genetic variants will be detected using established methods such as real-time PCR methods, mass spectrometric detection or nanofluid technology, as well as DNA microarrays or genome sequencing. Endogenous metabolites or metabolite profiles as well as drug concentrations and their metabolites can be detected in blood, urine, and, if necessary, stool using various mass spectrometric methods as well as biochemical assays. The cytokine profile can be analyzed in plasma isolated from blood samples. Proinflammatory cytokines in doxorubicin-induced cardiotoxicity have been described and should therefore be determined. |
|
| abnormal CMR findings regarding late gadolinium enhancement (LGE) | CMR is performed on a 1.5T Siemens Magnetom Aera. CINE and late gadolinium enhancement (LGE) images of the short axis are taken every 10 mm from the base of the heart to the apex (6 mm slice, resolution 1.2 × 1.8 mm). LGE images are acquired 5-10 minutes after administration of gadolinium. | Baseline (before anthracycline administration), after 4-9 weeks (depending on the anthracycline-based treatment regimen used), 3 months after completion of therapy, and 12 months after completion of therapy. |
| abnormal CMR findings regarding additional parametric mapping (T1-weighted relaxation times, extracellular volume) | CMR is performed on a 1.5T Siemens Magnetom Aera. T1 mapping is performed using a MOLLI sequence before and 20 minutes after contrast agent administration. | Baseline (before anthracycline administration), after 4-9 weeks (depending on the anthracycline-based treatment regimen used), 3 months after completion of therapy, and 12 months after completion of therapy. |
| Troponin T and NT-proBNP levels before, during, and after completion of anthracycline-based chemotherapy, correlated with CMR findings | Baseline (before anthracycline administration), after 4-9 weeks (depending on the anthracycline-based treatment regimen used), 3 months after completion of therapy, and 12 months after completion of therapy. |
| Echocardiographically assessed global longitudinal strain before, during, and after completion of anthracycline-based chemotherapy, correlated with CMR findings. | Baseline (before anthracycline administration), after 4-9 weeks (depending on the anthracycline-based treatment regimen used), 3 months after completion of therapy, and 12 months after completion of therapy. |
| Baseline (before anthracycline administration), after 4-9 weeks (depending on the anthracycline-based treatment regimen used), 3 months after completion of therapy, and 12 months after completion of therapy. |
| ID | Term |
|---|---|
| D066126 | Cardiotoxicity |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D064420 | Drug-Related Side Effects and Adverse Reactions |
| D064419 | Chemically-Induced Disorders |
| D011832 | Radiation Injuries |
| D014947 | Wounds and Injuries |
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