Anthracycline-induced Cardiotoxicity, Cardiotoxicity
Conditions
Keywords
anthracycline, cardiotoxicity, cardiac magnetic resonance imaging
Brief summary
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: * other abnormal results in CMR * changes in troponin T and NT-pro-BNP * changes in global longitudinal strain in echocardiography and correlation with results of CMR * detection of new biomarkers in blood, urine, or stool
Detailed description
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.
Interventions
DIAGNOSTIC_TESTCMR based measurement of cardiotoxicity
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
OTHERbiosampling for scientific research in study-specific biobank
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.
Sponsors
Robert Bosch Gesellschaft für Medizinische Forschung mbH (RBMF)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\- Patients with a recommendation for antineoplastic therapy including at least four administrations of an anthracycline
Exclusion criteria
* Inability to provide informed consent * Prior administration of an anthracycline * Administration of cardiotoxic drugs within the last six months, such as: * High-dose cyclophosphamide (\>1,000 mg/m² or \>10 mg/kg) * HER2 inhibitors * VEGF inhibitors * BCR-ABL inhibitors * BRAF inhibitors * MEK inhibitors * Immune checkpoint inhibitors (CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors) * Planned invasive cardiac intervention during the study period * Cardiac involvement of an underlying disease, e.g. amyloidosis * Treatment with fewer than four administrations of anthracyclines * Treatment with a liposomal anthracycline formulation * Treatment in which anthracyclines are not administered in every chemotherapy cycle * Thoracic radiation involving the heart prior to anthracycline administration * Participation in another clinical study concurrently or within the last three months * Renal impairment with a GFR \< 30 ml/min/1.73 m² * Patients in the perioperative phase of liver transplantation * Contraindications to cardiac magnetic resonance imaging, such as metallic implants (e.g. cardiac pacemaker) * Pregnancy or breastfeeding * Hypersensitivity or intolerance to gadolinium-based contrast agents * Vulnerable populations (individuals unable to protect their own interests, prisoners)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of T2-weighted myocardial relaxation time in cardiac magnetic resonance imaging | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| abnormal CMR findings regarding morphology and function | 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. | 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. |
| abnormal CMR findings regarding late gadolinium enhancement (LGE) | 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. | 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. |
| abnormal CMR findings regarding additional parametric mapping (T1-weighted relaxation times, extracellular volume) | 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. | 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. |
| 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. | — |
Countries
Germany
Contacts
CONTACTMatthias Prof. Dr. med. Schwab
Outcome results
None listed