Cardiotoxicity From Chemotherapy: Diagnosis and Monitoring (PDF)

Attikon National and Kapodistrian University Hospital University of Athens ΚΑΡΔΙΟΤΟΞΙΚΟΤΗΤΑ ΑΠΟ ΧΗΜΕΙΟΘΕΡΑΠΕΥΤΙΚΑ: διάγνωση και παρακολούθηση...

Attikon National and Kapodistrian University Hospital University of Athens ΚΑΡΔΙΟΤΟΞΙΚΟΤΗΤΑ ΑΠΟ ΧΗΜΕΙΟΘΕΡΑΠΕΥΤΙΚΑ: διάγνωση και παρακολούθηση ΚΑΛΛΙΟΠΗ ΚΕΡΑΜΙΔΑ, MD, PhD, FESC, FHFA, FICOS Καρδιολογικό τμήμα, Γενικό Αντικαρκινικό, Ογκολογικό νοσοκομείο, Άγιος Σάββας  Landmarks in the development of cancer therapeutics Herrmann J. Nature Reviews Cardiology volume 17, pages474–502(2020) Gottlieb R and Mehta P. Cardio-Oncology Principles, Prevention and Management  Childhood Cancer Survivors (CCSs) Five-year survival of children with cancer is ~ 85% in developed countries (1) > 50% of children receive AC and > 20% radiation to the chest Symptomatic cardiac dysfunction in up to 16% of AC exposed survivors but subclinical disease in > 50% (2, 3) The most serious CV consequence is cardiomyopathy 25 genes have been associated with AC toxicity Two have the strongest evidence: RARG and UGT1A6 (4, 5) 1. SEER Cancer Statistics Review, 1975-2014. 2017. 2. Lipshultz SE et al. Circulation. 2013;128:1927-1995. 3. Armstrong GT et al. N Engl J Med.2016;374:833-42. 4. Aminkeng F et al. Nat Genet. 2015;47:1079-84. 5. Visscher H et al. Pediatr Blood Cancer. 2013;60:1375-1381.  Childhood Cancer Survivors (CCSs) Mulrooney DA et al. BMJ 2009;339:b4606  CARDIOTOXICITY ✓ Myocardial dysfunction – Heart Failure ✓ Myocarditis ✓ Arrhythmias (including AF, QTc prolongation) ✓ Hypertension ✓ Vascular toxicity ✓ Valvular disease ✓ Pericardial disease PubMed entries overtime for cardiotoxicities Herrmann J et al. Eur Heart J. 2021 Dec 14:ehab674.  Chemotherapy induced heart failure Acute cardiotoxicity (during administration) => can affect access to lifesaving drugs Chronic cardiotoxicity (months or even years afterwards)=> can affect survival, morbidity and QoL  Chemotherapy induced heart failure Preclinical toxicity: histopathologically or biochemically detected Clinical toxicity: heart failure  2 types of cardiotoxicity Type I Type II Anthracyclines/anthraquinolones Biological agents Doxorubicin Monoclonal antibodies Mitoxantrone Trastuzumab Alemtuzumab Alkylating agents Interleukins Cyclophosphamide Interferon-α Ifosfamide Miscellaneous Mitomycin - Can be irreversible All- trans retinoic acids - Reversible Antimetabolites - Dose dependent Imatinib - Dose independent -Fluorouracil Structural changes: necrosis - Interference Pentostatin with myocardial Anti-microtubule structure or function Paclitaxel Vinca alkaloids More types of cardiotoxicity……. Witteles R. ACC 2018 A new classification of cardio-oncology syndromes de Boer RA, et al. Cardiooncology. 2021 Jun 21;7(1):24.  SEVERITY OF CARDIOTOXICITY Molecular mechanism of action Immediate and cumulative dose Method of administration Presence of any underlying predisposing cardiac condition Genetic pattern Age Concurrent or previous treatment with other antineoplastic medications or radiotherapy  CARDIO-ONCOLOGICAL JOURNEY Asymptomatic LV dysfunction Symptomatic LV dysfunction Cancer Cardiotoxic Subtle cardiac Completed toxicity Cardiotoxicity therapy diagnosis therapy Primordial Primary Secondary Tertiary prevention prevention prevention prevention  Subclinical damage Before any treatment (biomarkers, imaging) Clinical (symptomatic or Tertiary prevention asymptomatic) cardiotoxicity Effective surveillance strategies After the completion of treatment Baseline cardiotoxicity risk assessment Okwuosa TM, Keramida K, Filippatos G, Yancy CW. Eur J Heart Fail. 2020;10.1002/ejhf.1999. Čelutkienė J et al. Eur J Heart Fail. 2020;10.1002/ejhf.1957 DIAGNOSIS OF CARDIOTOXICITY Pathophysiological mechanisms and targets for new pharmacotherapies and for radiation induced toxicity Donis N. Expert Opin Pharmacother. 2018 Apr;19(5):431-442. Lancellotti P. European Heart Journal – Cardiovascular Imaging (2013) 14, 721–740  Types of cardiovascular imaging Echocardiography Cardiac magnetic resonance (CMR) Cardiac computed tomography (CCT) Nuclear/metabolic cardiac imaging (MUGA, ERNA) Echocardiography Čelutkienė J et al. Eur J Heart Fail. 2020;10.1002/ejhf.1957 Suboptimal reproducibility of 2D vs 3D Analysis time < 30 sec Feasibility > 90% Global longitudinal strain Keramida K, et al. Eur J Heart Fail 2019 Cut off value of relative % change of RV GLS for cardiotoxicity ≥ 14.8%  Focused echo in cardio-oncology Subtle cardiac toxicity Long-term Cancer Cardiotoxic surveillance diagnosis therapy Asymptomatic Cardiotoxicity LV dysfunction Symptomatic Complete LV dysfunction TTE FECO Proposed Focused Echo Protocols in Cardio-Oncology Keramida K et al. Echocardiography. 2020;00:1-10. Farmakis D, Keramida K, Filippatos G. Eur J Heart Fail. 2020;22(6):929-932. Cardiac magnetic resonance (CMR)  CMR indications in cardio-oncology Measurement of LV volumes and LVEF in challenging cases (poor echocardiographic images, discrepancy between measurements) RVEF assessment Differential diagnosis of LV dysfunction Clarification of the underlying mechanism of cardiotoxicity Early detection of cardiotoxicity Valvular disease Pericardial disease Cardiac masses, cardiac infiltration Vascular injury (small and large vessels)  CMR IN CARDIO-ONCOLOGY T1 mapping for dd in pericardial effusions  CMR limitations Lower availability Higher cost Safety (metallic implants) Claustrophobia Tachyarrhythmias (less reliable measurements) Time consuming Feasibility – advancement of CMR Cardiac computed tomography (CCT)  Cardiac computed tomography CT coronary angiography and calcium score in RT survivors for CAD risk Metastases to the heart (high spatial resolution) Useful adjunct to echocardiography in the evaluation of pericardial disease, especially when the diagnosis is unclear (eg loculated effusions, pericardial calcification, pericardial mass) In the pre-procedural assessment and procedural planning of catheter-based techniques for valvular disease (eg TAVR) Nuclear/metabolic cardiac imaging  Nuclear / Metabolic imaging LVEF measurement (MUGA) [highly reproducible] FDG-PET for ICIs-induced myocarditis 18F-FDG PET for cardiotoxicity surveillance Cardiac metastases Multimodality imaging  Choice of imaging modality for detecting cardiotoxicity depends on Clinical scenario (drug, possible cardiotoxicity) Local protocols Availability Local expertise Cost  Cardio-Oncological case 31 years old male, BSA 1.92m2 9/2019 mass in the left femur – knee (sarcoma?) Plan: [Adriamycin 30mg/m2 and cisplatin] x 3 Surgical resection [Adriamycin 30mg/m2, cisplatin, Methotrexate (MAP), Mifamurtide ([MTP-PE)] x 2 LVEF = 62% LV GLS = -19.6% RV GLS = -23.6% 27/12/2019 Surgical resection Biopsy: High malignancy osteosarcoma in the distal left femur 74% response to previous chemotherapy Grade II by Huvos system  24/2/2020 During chemotherapy (Adriamycin, methotrexate, cisplatin, mifamurtide) - Bradycardia (46bpm) - Shortness of breath/cough worsening in the flat position - Hypotension (93/70mmHg)  Cardio-oncology assessment after 2 days BP = 131/75mmHg, 66bpm Lab tests: (26/2/20) CRP = 7,78 NT-proBNP = 201,7 hs-TnT = 12,2 D-dimers = 1002 CT negative for pulmonary embolism  Baseline: 26/2/2020 LVEF = 62% LVEF = 50% LVGLS = -19.6% LVGLS = -16.5% RV GLS = -23.6% RV GLS = - 24% - Start ramipril 2,5mg od - C-O re-assessment before the next cycle of chemotherapy (echo, TnT and NT-proBNP) Definition of Cancer-Therapeutics Related Cardiac Dysfunction (CTRCD) Herrmann J et al. Eur Heart J. 2021 Dec 14:ehab674. Cardio-oncology assessment (3/3/2020)  Cardio-oncology assessment (3/3/2020) 3/3/2020 LVEF = 52% LVGLS = - 17.3% RV GLS = - 20% TnT = 16,4 NT-proBNP = 217 ✓ Up-titration of ramipril to 5mg od ✓ Start carvedilol 3.125mg bid ✓ C-O re-assessment before the next cycle of chemotherapy (echo, TnT and NT-proBNP) After 4 months (1/7/2020) Chemotherapy stopped on 5/2020 Since then patient only on mifamurtide till 10/2020 Asymptomatic BP = 139/92mmHg - Up-titration of Ramipril 10mg od - Up-titration of Carvedilol 6.25mg bid After 4 months (1/7/2020) After 4 months (1/7/2020) 1/7/2020 LVEF = 52% LVGLS = - 16.8% RV GLS = - 21.4% TREATMENT OF CARDIOTOXICITY  Treatment of Cardiotoxicity (LV dysfunction) 1. Non-pharmacologic therapy: risk factors control, diet/nutrition, exercise 2. Heart failure drug treatment 3. Myocarditis specific treatment 4. Devices (ICD, CRT, LVAD, BiVAD) 5. Transplantation  Treatment of Cardiotoxicity (LV dysfunction) 1. Non-pharmacologic therapy: risk factors control, diet/nutrition, exercise 2. Heart failure drug treatment 3. Myocarditis specific treatment 4. Devices (ICD, CRT, LVAD, BiVAD) 5. Transplantation Non-pharmacologic therapy D’ Ascenzi F. European Journal of Preventive Cardiology 2019  Treatment of Cardiotoxicity (LV dysfunction) 1. Non-pharmacologic therapy: risk factors control, diet/nutrition, exercise 2. Heart failure drug treatment 3. Myocarditis specific treatment 4. Devices (ICD, CRT, LVAD, BiVAD) 5. Transplantation  This statement analyzed the guidelines from: the American Society of Clinical Oncology (ASCO-2017 and ASCO-2018), the European Society for Medical Oncology (ESMO-2017 and ESMO-2020), and the European Society of Cardiology (ESC-2016). Alexandre J. J Am Heart Assoc. 2020;9:e018403. Alexandre J. J Am Heart Assoc. 2020;9:e018403. Myocarditis Immune checkpoint inhibitors mediated cardiotoxicities Lyon A. Lancet Oncology 2018  ICIs mediated myocarditis Incidence: 0,27 – 5% ↑Incidence in patient population with Diabetes, Hypertension, Sleep Apnea Fatality rates ranges between 36%and 67% depending on the treatment regimen Risk factors: 1. Combination therapy (4,74 fold increase compared to monotherapy) - increased risk of severe myocarditis - increased rates of co-occurring myasthenia gravis and myositis - increased mortality 2. Female gender 3. Age > 75 years Definition of ICIs associated myocarditis Herrmann J et al. Eur Heart J. 2021 Dec 14:ehab674. Myocarditis – A Proposed Definition Bonaca MP et al. Circulation. 2019;140:80–91 Definition of ICIs associated myocarditis Herrmann J et al. Eur Heart J. 2021 Dec 14:ehab674. Screening, Surveillance and Management of ICI- Associated Myocarditis Hu J. R., et al. (2019). Cardiovasc. Res. 115, 854–868. 10.1093/cvr/cvz026 AlexandreJ. J Am Heart Assoc. 2020;9:e018403. CARDIOTOXICITY QT prolongation Can be caused by several anticancer drugs ◆ High incidence with some drugs such as arsenic trioxide (26-93%) Can also be caused by electrolyte disturbances, predisposing factors and concomitant medications Can lead to life-threatening arrhythmias such as torsade de pointes Arrhythmias can occur before, during and shortly after treatment  CARDIOTOXICITY QT prolongation: risk factors Correctable Non-correctable Electrolyte imbalance Family history of sudden death Nausea / vomiting Personal history of syncope Diarrhea Baseline QTc interval prolongation Use of loop diuretics Female gender Hypokalemia (≤3.5 mEq/L) Advanced age Hypomagnesaemia (≤1.6 mg/dL) Heart disease Hypocalcemia (≤8.5 mg/dL) Myocardial infarction Hypothyroidism Impaired renal function Impaired hepatic function Concurrent use of QT-prolonging drugs Antiarrhythmic Antibiotics or antifungals Psychotropic or antipsychotic Antidepressant Antiemetic antihistamine Adapted from ESC Guidelines; European Heart Journal 2016 Definition of QTc prolongation Herrmann J et al. Eur Heart J. 2021 Dec 14:ehab674. Overview of the approach to QTc prolongation in cancer patients Herrmann J et al. Eur Heart J. 2021 Dec 14:ehab674. Definition of Hypertension in cancer patients Herrmann J et al. Eur Heart J. 2021 Dec 14:ehab674.  Vascular toxicities Herrmann J et al. Eur Heart J. 2021 Dec 14:ehab674.  Vascular toxicities Herrmann J et al. Eur Heart J. 2021 Dec 14:ehab674. Coronary artery disease  ACS in patients with cancer ❖The highest risk for arterial thrombosis occurs in the first month after diagnosis and levels off in six months. ❖Incidence of ACS in hematological malignancies 1.4-11.2%.1,2 ❖A 6 month cumulative incidence of arterial thromboembolism in 4.7% of cancer patients compared with 2.2% in control patients.3 ❖Risk for thromboembolism generally resolved by a year following cancer diagnosis and correlated with cancer stage.3 ❖In November 2009, the first cardiac catheterization laboratory in a cancer center in the world was opened at The University of Texas MD Anderson Cancer Center (a new field of interventional onco-cardiology). 1 ParkJY et al. Int J Cardiol 2018 2 Maynard C et al. Arch. Intern. Med. 2006 3Navi BB et al. J Am Coll Cardiol 2017  Causative factors for ACS in cancer: 1. Pre-existing CV risk factors 2. Cancer related mechanisms 3. Chemotherapeutic agents 4. Radiotherapy 5. Specific malignancies 6. Coronary tumor embolism 7. Coronary compression of a metastatic cardiac tumor Aronson D. Thrombosis Research 2018 Shared risk factors O Age O Gender ✓ Inflammation ✓ Hyperinsulinemia O Smoking ✓ Hyperglycemia O Obesity ✓ Oxidative stress ✓ Endothelial dysfunction O Sedentary lifestyle ✓ IGF-1 O Diabetes mellitus Ageing of the population Liu VY. Front. Cardiovasc. Med. 2018.  Pathophysiological mechanism of ACS Medication Mechanism 5-fluorouracil , capecitabine , sorafenib Coronary vasospasm nivolumab, pembrolizumab, atezolizumab Etoposide, bleomycin, bevacizumab and vinblastine Apoptosis of endothelial cells Bevacizumab, Lenalidomide ↓ endothelial NO production Gonadotropin releasing Accelerated progression of atherosclerosis hormone agonists , aromatase inhibitors (anastrozole, letrozole, exemestane) Rituximab Release of IL-6, TNF-a => vasoconstriction, PLT activation, plaque rupture Vincristine Cell-cycle arrest of endothelial cells Cisplatin Endothelial injury  The temporal onset of ischemia Medication Time 5-fluorouracil Infusion onset to several days following administration Vincristine Within hours of infusion Rituximab Infusion onset to several days following administration Cisplatin Infusion onset to several weeks following administration BCR-ABL directed TKI Infusion onset to a month after therapy Mohanty BD et al. Future Cardiol. 2017  Radiotherapy induced CAD Risk factors The anatomic location of radiotherapy: ✓Hodgkin disease ✓left breast cancer ✓pulmonary cancer Dosage of radiation: increased risk of 7.4% per Gy with no apparent threshold Concomitant use of chemotherapy Traditional risk factors (diabetes)  Radiotherapy induced CAD Coronary artery atherosclerosis seems to be triggered by radiation- induced damage of the endothelium. The mean time interval for the development of radiation induced CAD in relation to radiotherapy is approximately 82 months (range 59– 104). The increased incidence of ACS for breast cancer is obvious within the first 5 years after radiotherapy and continues into the third decade after it. CAD generally presents earlier in survivors of childhood malignancies.  Radiotherapy induced CAD ✓The distribution of CAD has been associated with the location of RT. ✓Left breast radiation is associated with disease of the mid and distal left anterior descending artery and distal diagonal branch ✓Ostial lesions are more common. ✓Two decades after RT for Hodgkin’s lymphoma, severe ostial stenosis of the left main and/or RCA is observed in up to 20% of patients. ✓Surgical revascularization can be challenging because of mediastinal fibrosis. ✓The use of internal mammary artery as a graft may not always be possible due to radiation disease with this vessel itself.  Specific malignancies Solid tumors: lung, gastric, and pancreatic cancers confer the highest risk. Advanced cancer stage is associated with higher risk. Myeloproliferative neoplasms (MPN), particularly polycythemia vera and essential thrombocythemia, are associated with increased thrombosis rate. Aronson D. Thrombosis Research 2018  Presentation of ACS in cancer patients The presenting symptoms of ACS in cancer patients are: dyspnea (44%) chest pain (30.3%) hypotension (23%) none (high prevalence of silent ischemia) 85% NSTEMI and 15% as STEMI 1/10 as takotsubo syndrome  Prognosis of ACS in cancer patients Cancer patients with STEMI have higher mortality and morbidity compared with those without cancer. Patients with recently diagnosed cancer ( 80% of patients received beta-blocker, only around 50% received antiplatelet, anticoagulant, and/or statin therapy. ❑ The in-hospital and 1-year mortality was 21.9% and 58.9%, respectively, of which 81.3% and 68.1% were non-cardiac in etiology. Park JY. JACC 2016 Treatment of ACS in cancer patients Among patients with ACS, treatment should be the same regardless of malignancy with some considerations for the oncologic patients. Each cancer patient with ACS should be considered for optimal medical therapy with antiplatelets, statins, ACEIs (or ARBs), mineralocorticoid receptor antagonists, and β-blockers.  Treatment of ACS in cancer patients Remember!!! The choice of antiplatelet and anticoagulant drugs should be individualized depending on the stage of cancer and the need for surgery after ACS and/or PCI. Ticagrelor and prasugrel should not be used owing to higher risk of bleeding in cancer patients. With chemotherapy, DAPT may need to be extended due to the delayed re- endothelialization of the stent. Some agents are thrombogenic, such as cisplatinum and thalidomide, and require an antithrombotic regimen. Others might induce TP, which hampers the use of DAPT.  PCI vs CABG -PCI might be preferred over CABG whenever possible, which is generally contraindicated due to the risk of metastatic dissemination during extracorporeal circulation (?). - Mediastinal fibrosis: may limit the number of redo surgeries, may increase surgical bleeding, and prolongs surgical duration - Internal mammary arteries may not be good grafts in these patients due to radiation damage. - Moreover, radiation- induced left subclavian artery disease may cause traditional steal phenomenon and flow limitation to the left internal mammary artery, and aortic calcification may challenge -bypasses (both saphenous and arterial). - CABG should be scheduled 2 to 6 weeks after ACS in clinically stable patients with cancer. - CABG should be performed in patients with a platelet count exceeding 50 000/μl. Banasiak W. POLISH ARCHIVES OF INTERNAL MEDICINE 2018 Pulmonary arterial hypertension PH pulmonary hypertension, CTEPH chronic thromboembolic pulmonary hypertension, LAM lymphangioleiomyomatosis, NF1 neurofibromatosis type 1, PTTM pulmonary tumor thrombotic microangiopathy Proposed management algorithm for dasatinib-induced pulmonary arterial hypertension (PAH) Weatherald J. Eur Respir J. 2017 Jul 27;50(1):1700217. Gevaert SA, et al. Eur Heart J Acute Cardiovasc Care. 2021 Oct 27;10(8):947-959. Cardio-oncology MDT  Cardio-oncology clinics European Journal of Heart Failure (2018)20,1732–1734 Lancelloti P et al. European Heart Journal (2018) 00, 1–8 Thank you very much for your attention