Best Practices in Cardio-Oncology Olga Kristof, M.D., FACC

No disclosures

Contemporary cancer therapy has led to a 23% decrease in the cancer related mortality rate from 1991 to 2012, with an associated rapid increase in cancer survivorship (1). Patients undergoing cancer treatment and long-term cancer survivors remain at elevated risk for a variety of cardiovascular (CV) toxicities and CV disease (CVD) represents the main competing cause of death in cancer survivors across many primary malignancies (2, 3). Moreover, an increasing number of patients are receiving long–term, including lifelong, cancer therapies with potential CV adverse effects

Moreover, recent data demonstrate significantly higher CVD risk among survivors of lung, non-Hodgkin lymphoma and breast cancer, compared to non-cancer population, with poor overall survival in survivors who develop CVD (6), providing a rationale for proactive CV risk factor screening and treatment. Marginal (Kaplan-Meier) and (C–E) cause-specific (competing risk) cumulative incidence of cardiac events (CEs) in childhood cancer survivors stratified according to different treatment groups. (A) Marginal cumulative incidence for all CEs, stratified according to potential cardiotoxic (CTX) therapy or no CTX therapy, log-rank P < .001. (B) Marginal cumulative incidence for all CEs, stratified according to different CTX therapies, log-rank P < .001. (C) Cause-specific cumulative incidence for congestive heart failure, stratified according to different treatment groups, log-rank P < .001. (D) Cause-specific cumulative incidence for cardiac ischemia, stratified according to cardiac irradiation (RTX) or no RTX, log-rank P= .01. (E) Cause-specific cumulative incidence for valvular disease, stratified according to RTX or no RTX, log-rank P < .001. The shaded colorized background areas refer to the 95% CIs. Ant, anthracycline

 Previously, systemic chemotherapy with anthracyclines and radiation therapy were the only cancer treatments with significant cardiotoxicity. However, modern targeted cancer therapies, including HER2 inhibitors, tyrosine kinase inhibitors (TKIs), proteasome inhibitors, and immune checkpoint inhibitors, have all been associated with adverse cardiovascular events. 

Key clinical developments (FDA approval, clinical recognition of cancer-treatment related cardiotoxicity and introduction of LV monitoring in oncology practice) are symbolically represented on a timeline for 5 classes of cancer therapies. LV monitoring is not currently routine oncology practice for treatment with VEGF inhibitors, proteasome inhibitors or immune checkpoint inhibitors. Publication of relevant cardiology and oncology professional society statements that address LV dysfunction is marked on the timeline for each class of cancer treatment therapeutics that is included in the respective guidelines and statements.

Current clinical practices regarding LV dysfunction risk, screening and treatment, across different categories of cancer therapies, are shown using a simplified schema. ✔indicates existing data and statements/guidelines addressing specific cancer treatment category, ✔ * indicates major differences in the recommendations regarding LV dysfunction among guidelines andΟ indicates lack of data/recommendations.

Professional Societies Statements National Comprehensive Cancer Network (NCCN) Guidelines Survivorship: Anthracycline-Induced Cardiac Toxicity. Available online Armenian SH, Lacchetti C, Barac A et al. Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2017;35:893–911. Plana JC, Galderisi M, Barac A et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27:911–39. Zamorano JL, Lancellotti P, Rodriguez Muñoz D et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37:2768–801. 2013 ACCF/AHA guideline for the management of heart failure Several state-of-the-art or lit review papers . MD Anderson Practices in Onco-Cardiology CVD and Breast Cancer…: Scientific Statement from the AHA. Circ., 2018 Specific recommendations regarding dose-related toxicity, risk stratification and HF prevention strategies are lacking in the ACCF/AHA HF guidelines and we here summarize and contrast recent oncology (7, 8) and cardiology (9, 10) professional society statements and guidelines.

ASCO 2017 Which cancer patients are at increased risk for developing cardiac dysfunction? Which preventative strategies minimize risk prior to initiation of therapy? Which preventive strategies are effective in minimizing risk during the administration of potentially cardiotoxic cancer therapy? What are the preferred surveillance / monitoring approaches during treatment in patients at risk for cardiac dysfunction? What are the preferred surveillance/ monitoring approaches after treatment in patients at risk for cardiac dysfunction?

Anthracyclines are potent inhibitors of topoisomerase II, and thus DNA function, and for decades have been a crucial component of chemotherapy for many neoplastic conditions (Online Supplement). The main mechanism is by inhibition of Toposiomerase 2β, which is active in quiescent non-proliferating cells including cardiomyocytes, resulting in activation of cell death pathways and inhibition of mitochondrial biogenesis, and is now thought to be the key mediator of anthracycline-induced cardiotoxicity.

Anthracycline-induced cardiomyopathy (doxorubicin, daunorubicin, epirubicin, idarubicin) Cancers responsive to anthracyclines Cardiac event rates  carcinoma (breast, small cell lung, bladder, esophagus, stomach, liver, and thyroid), leukemia (AML and ALL), lymphomas (Hodgkin’s and non-Hodgkin’s, cutaneous T-cell lymphoma), sarcoma (osteogenic bone, soft tissue, and Ewing). 7% 150 mg/m2, 18% 350 mg/m2 65% at cumulative doses 550 mg/m2  98% of cases developing in the first year (median time 3.5 months)

Anthracycline-induced cardiomyopathy Risk markers cumulative dose, female gender, hypertension, valvular disease, baseline LV dysfunction, African-American ancestry, age >65 years or <18 years, renal failure, concomitant exposure to radiation and/or trastuzumab, possibly genetic factors.

Anthracycline Cardiotoxicity: An Update Heart Dec 21, 2017 Cancers responsive to anthracyclines include carcinoma (breast, small cell lung, bladder, esophagus, stomach, liver, and thyroid), leukemia (AML and ALL), lymphomas (Hodgkin’s and non-Hodgkin’s, cutaneous T-cell lymphoma), and sarcoma (osteogenic bone, soft tissue, and Ewing). Anthracycline-induced (doxorubicin, daunorubicin, epirubicin, idarubicin) cardiomyopathy is a disease spectrum ranging from development of heart failure (HF) with symptoms and clinical signs to asymptomatic decline in left ventricular ejection fraction (LVEF). Clinical HF may ensue in up to 5% of high-risk patients. Cardiac event rates on anthracycline therapy are 7%, 18%, and 65% at cumulative doses of 150 mg/m2, 350 mg/m2, and 550 mg/m2, respectively. Anthracycline chemotherapy was associated with an adjusted hazard ratio of 1.26 (confidence interval, 1.12-1.42) for development of congestive cardiac failure in 43,000 women (aged 66-70 years) with breast cancer over a median period of 53 months. In 2,625 cancer patients who received anthracycline (74% women; 51% breast cancer, and 28% non-Hodgkin’s lymphoma), incidence of cardiotoxicity was 9% with 98% of cases developing in the first year (median time 3.5 months). Pediatric populations receiving anthracycline chemotherapy remain at elevated risk of developing HF decades after receiving a cancer cure. Mechanism of toxicity: The main mechanism is by inhibition of Toposiomerase 2β,which is active in quiescent non-proliferating cells including cardiomyocytes, resulting in activation of cell death pathways and inhibition of mitochondrial biogenesis, and is now thought to be the key mediator of anthracycline-induced cardiotoxicity. Risk markers: These include cumulative dose, female gender, hypertension, valvular disease, baseline LV dysfunction, African-American ancestry, age >65 years or <18 years, renal failure, concomitant exposure to radiation and/or trastuzumab, and possibly genetic factors. LVEF and global longitudinal strain (GLS): There is no consensus on how best to monitor cardiotoxicity; however, monitoring LVEF remains the basis for identifying cardiotoxicity—baseline measurements and ongoing monitoring for patients receiving >200 mg/m2 is recommended. Delaying initiation of trastuzumab reduces incidence of LV dysfunction by 7% in one study and HF by 0.6%. A fall in GLS of 15% compared with baseline measurement is considered pathological and an early injury marker, which is predictive of LV systolic dysfunction. Cardiac biomarkers: Cardiac troponin and B-type natriuretic peptide have shown promise as indicators of cardiotoxicity. In one study of 81 breast cancer patients, a combination of GLS and high-sensitivity troponin I had 93% sensitivity and 91% negative predictive value for future cardiotoxicity. Anthracycline derivatives: Lipsomal encapsulated doxorubicin is associated with lower rates of HF and subclinical changes in LV dysfunction, but in the United States, its use is restricted to ovarian cancer, AIDS-related Kaposi sarcoma, and multiple myeloma after failure of at least one treatment. Dexarazoxane: Dexarazoxane has been shown to prevent anthracycline cardiotoxicity by minimizing or completely preventing fall in LVEF and reducing release of cardiac biomarkers. However, it fell out of favor after concerns that it dampened the anti-mitochondrial activity of anthracyclines and was associated with a signal of increased secondary malignancies in survivors of childhood leukemia and lymphoma. A reappraisal of data has led to an extended indication in pediatric patients receiving >300 mg/m2. Its clinical safety continues to be appraised. Therapy and prevention: angiotensin-converting enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARBs) and beta-blockers are utilized for both treatment and prevention of cardiotoxicity (i.e., asymptomatic LV dysfunction and HF), on the basis of small randomized clinical trials. However, there are no robust data to recommend a specific regimen, and ongoing studies (ICOS-ONE, PROACT, Cardiac CARE) should shed light on key questions including: a) how long should ACEI/ARBs and/or beta-blockers be continued following recovery of LV function, and b) to what degree should these medications prevent future presentations of HF? Primary prevention with statins: Preclinical studies suggest that statins could be protective in preventing anthracycline cardiotoxicity. Further randomized studies are needed to confirm these findings.

Anthracycline therapy is limited by dose-related cardiotoxicity, presenting as LV systolic dysfunction with or without clinical HF, with risk rising significantly after cumulative doxorubicin doses above 400 mg/m2

Radiation Induced Heart Disease: Dx and Mt

CAD Up to 85% Epicardial coronaries and microvascular d-se, sustained inflammation. Usually occurs 10 years after XRT Involves LM, ostial LAD, RCA. Lesions are longer, concentric, tubular Stress testing, CCTA, PTCA, CABG - could be challenging due to fibrosis of pericardium and mediastinum

Valvular HD 10 years: 26% AI, 39% MR, 16% TR, 7% PR 20 yrs: 60% AI, 16% AS, 52% MR, 26% TR, 12% PR Mean time 12 yrs post XRT Diffuse fibrosis of the valvular cusps or leaflets, with or without calcifications Left sided > right sided

PERICARDIAL DISEASE 6-30% Acute or chronic pericarditis, pericardial effusion, pericardial constriction Inflammation, impaired drainage, fibrotic changes to the parietal pericardium. Acute pericarditis is often self- limiting. Chronic is often effusive-constrictive Diagnosis: rule out other etiologies ECHO, CMR, CCTA MT: Anti-inflammatory, pericardiocentesis, pericardial window for recurrent, pericardial stripping for constrictive

Anticancer Agents Associated With Myocardial Infarction/Ischemia Chemotherapy Agents Frequency of Use Incidence (%) Prevention/Treatment Antimetabolites Capecitabine ++++ 3–9 Ischemia workup and treatment Flourouracil 1–68 Monoclonal antibody-based tyrosine kinase inhibitors Bevacizumab +++ 0.6–8.5 Small molecule tyrosine kinase inhibitors Nilotinib 5.0–9.4 Ponatinib + 12 Angiogenesis inhibitors Lenalidomide 0–1.9 Antimicrotubule agents Paclitaxel <1.5

Anticancer Agents Associated With HF/Left Ventricular Dysfunction Chemotherapy Agents Frequency of Use Incidence (%) Prevention/Treatment Anthracyclines Doxorubicin ++++ 3–26 Monitor EF, GLS, troponin dexrazoxane, cont infusion, liposomal Epirubicin + 0.9–3.3 Idarubicin ++ 5–18 Alkylating agents Cyclophosphamide 7–28 Ifosfamide +++ 17 Antimetabolites Decitabine 5 Clofarabine 27 Antimicrotubule agents Docetaxel 2.3–8.0 Anticancer Agents Associated With HF/Left Ventricular Dysfunction

Monoclonal antibody-based tyrosine kinase inhibitors Trastuzumab +++ 2–28 Avoid concomitant use with anthracyclines Bevacizumab ++ 1.0–10.9 Adotrastuzumab emtansine + 1.8 Pertuzumab 0.9–16.0 Small molecule tyrosine kinase inhibitors Pazopanib ++++ 0.6–11.0 Treat hypertension aggressively Ponatinib 3–15 Ischemia workup and treatment Sorafenib 1.9–11.0 Dabrafenib 8–9 Sunitinib 1–27 Dasatinib Lapatinib 0.9–4.9 Trametanib 7–11 Proteasome inhibitor Carfilzomib 7 Bortezomib 2–5 Miscellaneous

Anticancer Agents Associated With Hypertension Chemotherapy Agents Frequency of Use Incidence (%) Comments Monoclonal antibody-based tyrosine kinase inhibitors Early consultation with cardiologist Bevacizumab +++ 4–35 Ado-trastuzumab emtansine + 5.1 Monoclonal antibodies Alemtuzumab 14 Ibritumomab NA 7 Ofatumumab 5–8 Rituximab 6–12 mTor inhibitors Everolimus ++++ 4–13 Temsirolimus ++ Small molecule tyrosine kinase inhibitors Pazopanib 42 Ponatinib 68 Sorafenib 7–43 Sunitinib 5–24 Axitinib 40 Cabozantinib 33–61 Ibrutinib 17 Nilotinib 10–11 Ramucirumab 16 Regorafenib 30–59 Trametinib 15 Vandetanib 33 Ziv-aflibercept 41 Proteasome inhibitors Bortezomib 6 Carfilzomib 11–17 Antimetabolites Decitabine

Hypertension is a common toxicity of vascular endothelial growth factor signaling pathway (VSP) inhibitors, and requires aggressive management to avoid end-organ damage. Treatment of cancer therapy-induced hypertension frequently requires more than a single agent. An angiotensin-converting enzyme inhibitor is the preferred first-line therapy due to its beneficial effects on plasminogen activator inhibitor-1 expression and proteinuria.

Thromboembolism Low molecular weight heparin is the anticoagulant agent of choice in patients with malignancy. Compared with the general population, there are fewer data to support the use of direct oral anticoagulants (DOACs) as first-line agents in patients with malignancy; Subgroup Aristotle trial however, limited data suggest that warfarin and DOACs are of equal efficacy when oral anticoagulants are necessary in cancer patients

Pulmonary Hypertension 5 major etiological groups cancer or cancer treatment related potential etiologies: Group 1 Drug- and toxin-induced PH is classified as group 1. Group 2 CHF Group 3 Lung d-se Group 4 Cancer can cause PH through obstruction from organized fibrotic thrombi due to hypercoagulability, Group 5 Extrinsic compression of the pulmonary vessels from tumors such as pulmonary angiosarcoma or direct intravascular extension from large B cell lymphoma can also lead to group 5 Rare complication of Dasatinib therapy The DASISION (Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients) comparing dasatinib with imatinib showed that 14 (5%) of the 258 dasatinib patients developed PH, compared with 1 (0.4%) imatinib patient over a follow-up period of at least 5 years - 1 pt - RHC, potential PAH incidence overestimation Mechanism: SRC kinase is involved in regulation of smooth muscle proliferation and vasoconstriction so that its inhibition could lead to increased pulmonary vascular resistance

Thromboembolism release of prothrombotic factors, such as tissue factor, mucin, and cysteine protease, into the circulation to activate the clotting cascade higher in the first 6 months after cancer diagnosis and returns to baseline at 1 year higher with certain cancers (lung, pancreatic, colon/rectal, kidney, and prostate), with metastatic diseases with certain risk factors (use of central venous catheters, immobility, heart failure, atrial fibrillation, hypovolemia, and chemotherapy) VSP inhibitors increase the risk of thromboembolism by altering the vascular protective property of the endothelial cells incidence of all grade arterial thrombotic ranges from 1 to 11% use with caution or avoid with recent CV events in the preceding 6 to 12 months No data, reasonable to start on low dose ASA 75-100 prophylactically in high risk patients VSP should be discontinued in grade 3 or higher thromboembolic events low-dose aspirin may prevent cardiovascular events in patients receiving bevacizumab who are age $65 years with a prior history of ATEs

Thromboembolism Cisplatin. 16.7% incidence of thromboembolic events in 48 patients (Jacobson et al) 271 patients with urothelial transitional cell cancer - TE and vascular events in 12.9% of patients; The risk factors include CAD, immobility, prior history of thromboembolic events, and pelvic masses. vascular injury and induces platelet activation through a mechanism involving monocyte procoagulant activity Angiogenesis inhibitors Lenalidomide and its parent drug thalidomide transient elevation in factor VIII and von Willebrand Factor and a reduction in soluble thrombomodulin Increase the risk when combined with glucocorticoids and/or cytotoxic chemotherapy ( decadrone and doxorubicin) This risk is 3% to 75% for lenalidomide and 1% to 58% for thalidomide When thalidomide or lenalidomide was combined with steroids , the risk increased. Aspirin, warfarin with target international normalized ratio of 2.0 to 3.0, or therapeutic doses of LMWH can reduce the risk of venous thromboembolism. //rates of major bleeding complications are unknown; thus, the benefit of prophylaxis is not clear.

QTc prolongation QT prolongation following treatment with arsenic trioxide and TKIs Antiemetics, H2-blockers, proton pump inhibitors, antimicrobial agents, and antipsychotics Nausea, vomiting, and diarrhea following cancer therapy lead to loss of potassium and magnesium