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Chapter 8: Interactions between Cancer, cancer treatment, and myocardial ischemia - Ronald J. Krone - Preet Paul Singh - Chiara Melloni Cardio-Oncology Eds: Kimmick, Lenihan, Sawyer, Mayer, Hershman Chapter 8: Interactions between Cancer, cancer treatment, and myocardial ischemia - Ronald J. Krone - Preet Paul Singh - Chiara Melloni Cardio-Oncology Eds: Kimmick, Lenihan, Sawyer, Mayer, Hershman The age groups where cancer is more common are also the age groups where CAD is common. After age 25, cardiac disease, primarily CAD, and malignancy are the two most common causes of death in adults.1,2 Age Specific Death Rate 4500 deaths per 100,000 persons 4000 3500 3000 2500 2000 1500 1000 500 0 25-34 35-44 45-54 55-64 65-74 75-84 85 and older Malignancy 8.8 28.8 111.6 300.1 666.1 1202.3 1729.5 Heart Disease 7.6 25.8 61.6 186.6 409.2 1172.0 4285.2 Age Groups Driver JA, et aI Incidence of cardiovascular disease and cancer in advanced age: prospective cohort study. BMJ 20 08;337:a2467. Share risk factors Coronary Disease and Cancer • Shared risk factors – – – – – Age Smoking Obesity Diabetes Lack of physical activity • Mechanisms in Common – Inflammation (found in obesity, smoking, diabetes, hypertension) – Oxidative stress (lipid peroxidation, toxins, smoking) Koene RJ, et al. Shared Risk Factors in Cardiovascular Disease and Cancer. Circulation 2016;133:1104-14 Risk Factors Risk Factors for coronary disease Age Smoking history (any smoking) Family history of coronary disease (coronary interventions, coronary bypass, myocardial infarctions in relatives < 55 years of age Diabetes-especially insulin requiring Lipid Profile (need not be fasting-2 hours after a meal) Peripheral vascular disease (carotid and/or femoral bruits) Coronary calcifications (can be seen on non-contrast CT examinations of the chest) Risk can be evaluated at http://my.americanheart.org/cvriskcalculator and http://www.cardiosource.org/scienceand-quality/practice-guidelines-and-qualitystandards/2013-prevention-guideline-tools.aspx Risk factors for cancer also are in Red Koene RJ, et al. Shared Risk Factors in Cardiovascular Disease and Cancer. Circulation 2016;133:1104-14. Interactions between therapies Cancer therapy can affect coronary arteries • 5-FU,capecitabine, paxitaxil and docetaxel cause endothelial injury and vasospasm • Cisplatin especially with bleomycin and vinblastine causes endothelial damage and can cause coronary vasospasm • Sunitinib and sorafanib plus other TKIs can cause progression of coronary disease • Bevacizumab associated with increased coronary events • Hormonal therapy associated with myocardial infarctions and angina • Radiation causes endothelial injury and ultimately coronary stenosis Coronary calcifications are often visible on standard CTs CT of chest showing calcium in RCA and LAD coronary arteries CT of chest showing calcium in Left Main and proximal LAD coronary arteries Drugs commonly used in cancer patients that are CYP3A4 substrates • • • • • • • • • • • • • • • • Chemotherapeutic Agents etoposide doxorubicin ifosfamide Antibiotics vincristine busulfan everolimus Anti-Inflammatory agents cyclosporine tacrolimus sirolimus Other Medications alprazolam carbamazepine Macrolide tamoxifen imidazoles Targeted anti-neoplastic agents imatinib ibrutinib: olaparib: ruxolitinib: sunitinib bosutinib The commonly used statins, simvastatin and atorvastatin are CYP3A4 inhibitors and interact with the cancer drugs above. Pravastatin and rosuvastatin are not CYP3A4 inhibitors and do not interact. The Coronary Vessels • The left main divides into the Anterior descending and circumflex arteries which supply most of the heart. • The Anterior Descending usually supplies the septum, the apex and much of the anterolateral wall • The circumflex supplies the lateral wall and a variable amount of the inferior wall • The Right coronary supplies the right ventricle and the inferior septum and a variable amount of the inferior-posterior and occasionally lateral wall ACS in the Cancer Patient A different risk/benefit ratio • the algorithms that guide ACS management may not apply in the setting of ongoing cancer management.. • Decision-making needs to consider multiple CONSIDER acuity/severity of the cardiac condition • the stage, treatment plan, and goals of care for the cancer. • This requires active communication between the oncologist and the cardiologist, • Issues: for the oncologist and cardiologist: – The severity and acuity of the coronary disease, – the severity and stage of the cancer, – the renal function which may be damaged with repeated PCI procedures, the anticipated long term toxicity of the cancer therapy, – the likelihood of developing severe thrombocytopenia on treatment, – the need for cancer surgery within 6 months of the cardiac • In a patient actively receiving cancer therapy, the primary indication for urgent revascularization is acute coronary syndrome (ACS), where the risks of inaction are high. Criteria for high risk NSTE-ACS with indication for invasive management Primary • Relevant rise or fall in troponin • Dynamic ST- or T-wave changes (symptomatic or silent) • Continuing or recurrent pain Secondary • Diabetes mellitus • Renal insufficiency (eGFR <60 mL/min/1.73 m²) • Reduced LV function (ejection fraction <40%) • Early post infarction angina • Recent Percutaneous coronary intervention (PCI) • Prior Coronary artery bypass graft surgery (CABG) • Intermediate to high GRACE risk score68 http://www.outomes.org/grace. MACE after surgery after Percutaneous Coronary Interventions with stentsthe importance of time from procedure <30 Days 30 to 90 3 3-6 6-12 >12 days months months Months months 50% 14% 4% 35% 13% 15% 6% 9% Time from PCI MACE after Bare Metal Stent MACE after Drug Eluting Stent van Kuijk JP et al. Timing of noncardiac surgery after coronary artery stenting with bare metal or drug-eluting stents. Am J Cardiol 2009;104:1229-34. Recommendations for timing of surgery after previous Percutaneous Coronary Intervention (PCI) Type of PCI 2014 ESC/ESA Guidelines103 2014 ACC/AHA Guidelines108 Bare Metal 4 weeks to 3 months (I,B) ≥30 days (I, B) ≥12 months (IIa, B) ≥12 months (I, B) Stent Drug Eluting Stent First ≥6 months (IIb, B) Generation 2nd and 3rd ≥6 months (IIa, B) generation DES Balloon ≥2 weeks (IIa, B) ≥2 weeks (I, C) angioplasty Kristensen SD,, et al. 2014 ESC/ESA Guidelines on non-cardiac surgery: Eur Heart J 2014;35:2383-431. Fleisher LA, et al. 2014 ACC/AHA Evaluation and Management of Noncardiac Surgery JACC 2014;64:e77-e137. Revascularization for Chronic Stable Angina in a patient with Cancer Revascularization could be considered in a patient with chronic stable coronary disease where complex cancer surgery is needed and the patient would be unable to tolerate the procedure unless some revascularization was done in advance (usually limited to severe left main disease or very proximal anterior descending involving the left main). This will of course delay the cancer surgery Modified from ESC/ESA Guidelines on non-cardiac surgery in patients with coronary stenosis Low-Risk Surgery <1% Superficial surgery Intermediate – Risk 1-5% High-risk > 5% Breast Surgery Intraperitoneal splenectomy, Hiatal hernia repair, cholecystectomy Head and neck surgery Major abdominal surgery involving pancreas, liver etc Esophagectomy Endocrine Thyroid Hip and spine surgery Repair of perforated bowel Pulmonary or liver transplant Pneumonectomy Major urological surgery Non-Major intra thoracic Total Cystectomy Adrenal resection Cardiac toxicities associated with 5FU and capecitabine 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Vasospasm Angina Pectoris Acute coronary syndrome Myocardial infarction Acute myocarditis Takotsubo stress cardiomyopathy Global cardiomyopathy. Sinus Bradycardia Ectopic ventricular beats Prolonged QT with torsade de Point Ventricular tachycardia Cardiogenic shock Sudden death Acute pericarditis Most Common cardiac responses to 5-FU • Vasospasm with angina • Angina without clear vasospasm • Myocardial infarction • Management is empirical and uncertain. Pretreatment with calcium channel blockers and nitrates have been advised but patients should be monitored in hospital and infusion stopped at first sign of vasospasm. Protection unpredictable and often unsuccessful. Radiation and Cardiac disease • Toxicities seen in cardiac structures in the radiation beam – Carotid Arteries – Coronary Arteries (Stenosis-accelerated atherosclerosis) • Left main • proximal Right • left anterior descending – Mitral Valve (calcification and stenosis) – Aortic Valve (calcification and stenosis) – Pericardial (calcification and fibrosis-constriction or effusion/tamponade) – Ventricular myocardium (usually right ventricle) Long Latency after Radiation • Prolonged follow-up is needed • Those at greatest risk-treated as children and those with Hodgins lymphoma (HL) treated with “mantle radiation.” • 111 survivors treated for HL followed with Coronary CTA – At 5 years 15% had lesions – At 10 years 34% had lesions Girinsky T et al. Prospective coronary heart disease screening in asymptomatic Hodgkin lymphoma patients Int J Rad Onc, Biol Phys 2014;89:59-66 Summary • We have described areas where collaboration between the cardiologist and oncologist are essential – Acute coronary syndrome – Chronic stable coronary disease –evaluation for cancer surgery – 5-FU and Capecitabine--vasospasm, angina – Radiation-long term surveillance