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Cardiovascular Disease in Cancer Survivors in 10'7, to 20'7, ofpatients 5 to 10 years after radiation therapy. branch blocks, and complete heart block. Up to 75% of long Pericardial calcification is not always present radiographically. term survivors of mediastinal radiation demonstrate conduc- Late constriction can occur in those who have not experienced tion abnormalities on ECG. The need for permanent pacing is acute pericarditis. more common after valve replacement surgery in patients who Radiation also damages the microvasculature, causing have received radiation therapy. endothelial dysfunction and ischemia that result in myocardial Coronary artery disease (CAD) occurs earlier and with fibrosis, diastolic dysfunction, and restrictive physiologr. increased incidence in patients treated with radiation ther- Radiation-induced cardiomyopathy presents similarly to pri apy. Coronary artery Iesions are typically ostial. long. smooth. mary restrictive cardiomyopathy. Diff'erentiating cardiomyo and concentric and have higher tibrotic content than typical pathy due to myocardial fibrosis fiom pericardial constriction atherosclerotic lesions. The incidence ofCAD is increased by is essential because the conditions have dilferent treatments traditional risk factors (e.g., smoking. dyslipidemia. and and outcomes (see Myocardial Disease). hypertension). and aggressive therapy to address these risk Although all cardiac l'alves may be affected by radiation factors is indicated. therapy, left sided involvement predominates. Valvular regur- Surgical outcomes for patients with radiation associated gitation due to tissue retraction is the most common valvular cardiovascular disease are significantly worse than in matched lesion in the first two decades after therapy, with later fibrosis cohorts. and radiation-associated aortic stenosis is associated and calcification leading to mixed regurgitation and stenosis with rnorse short-term and long-term cardiovascular mortal- (Figure 61). ity. Recent trials have suggested that percutaneous approaches Radiation causes fibrosis of the conduction system and to aortic valve replacement may be preferable in this group. may lead to sinus node dystunction, lascicular and bundle There is no consensus on cardiac testing after chest irra- diation in asymptomatic patients. Baseline evaluation includ ing echocardiography is reasonable, and several organizations A have recommended stress echocardiography at 5 to 10 years I 1?7 :at after completion of therapy or at age 30 years, whichever 13u/63 \ comes first. The role of serum biomarkers in surveillance is unclear, and their use is not recommended. Routine screening

in 10'7, to 20'7, ofpatients 5 to 10 years after radiation therapy. branch blocks, and complete heart block. Up to 75% of long Pericardial calcification is not always present radiographically. term survivors of mediastinal radiation demonstrate conduc- Late constriction can occur in those who have not experienced tion abnormalities on ECG. The need for permanent pacing is acute pericarditis. more common after valve replacement surgery in patients who Radiation also damages the microvasculature, causing have received radiation therapy. endothelial dysfunction and ischemia that result in myocardial Coronary artery disease (CAD) occurs earlier and with fibrosis, diastolic dysfunction, and restrictive physiologr. increased incidence in patients treated with radiation ther- Radiation-induced cardiomyopathy presents similarly to pri apy. Coronary artery Iesions are typically ostial. long. smooth. mary restrictive cardiomyopathy. Diff'erentiating cardiomyo and concentric and have higher tibrotic content than typical pathy due to myocardial fibrosis fiom pericardial constriction atherosclerotic lesions. The incidence ofCAD is increased by is essential because the conditions have dilferent treatments traditional risk factors (e.g., smoking. dyslipidemia. and and outcomes (see Myocardial Disease). hypertension). and aggressive therapy to address these risk Although all cardiac l'alves may be affected by radiation factors is indicated. therapy, left sided involvement predominates. Valvular regur- Surgical outcomes for patients with radiation associated gitation due to tissue retraction is the most common valvular cardiovascular disease are significantly worse than in matched lesion in the first two decades after therapy, with later fibrosis cohorts. and radiation-associated aortic stenosis is associated and calcification leading to mixed regurgitation and stenosis with rnorse short-term and long-term cardiovascular mortal- (Figure 61). ity. Recent trials have suggested that percutaneous approaches Radiation causes fibrosis of the conduction system and to aortic valve replacement may be preferable in this group. may lead to sinus node dystunction, lascicular and bundle There is no consensus on cardiac testing after chest irra- diation in asymptomatic patients. Baseline evaluation includ ing echocardiography is reasonable, and several organizations A have recommended stress echocardiography at 5 to 10 years I 1?7 :at after completion of therapy or at age 30 years, whichever 13u/63 \ comes first. The role of serum biomarkers in surveillance is unclear, and their use is not recommended. Routine screening d t- ,-tF. tr

in 10'7, to 20'7, ofpatients 5 to 10 years after radiation therapy. branch blocks, and complete heart block. Up to 75% of long Pericardial calcification is not always present radiographically. term survivors of mediastinal radiation demonstrate conduc- Late constriction can occur in those who have not experienced tion abnormalities on ECG. The need for permanent pacing is acute pericarditis. more common after valve replacement surgery in patients who Radiation also damages the microvasculature, causing have received radiation therapy. endothelial dysfunction and ischemia that result in myocardial Coronary artery disease (CAD) occurs earlier and with fibrosis, diastolic dysfunction, and restrictive physiologr. increased incidence in patients treated with radiation ther- Radiation-induced cardiomyopathy presents similarly to pri apy. Coronary artery Iesions are typically ostial. long. smooth. mary restrictive cardiomyopathy. Diff'erentiating cardiomyo and concentric and have higher tibrotic content than typical pathy due to myocardial fibrosis fiom pericardial constriction atherosclerotic lesions. The incidence ofCAD is increased by is essential because the conditions have dilferent treatments traditional risk factors (e.g., smoking. dyslipidemia. and and outcomes (see Myocardial Disease). hypertension). and aggressive therapy to address these risk Although all cardiac l'alves may be affected by radiation factors is indicated. therapy, left sided involvement predominates. Valvular regur- Surgical outcomes for patients with radiation associated gitation due to tissue retraction is the most common valvular cardiovascular disease are significantly worse than in matched lesion in the first two decades after therapy, with later fibrosis cohorts. and radiation-associated aortic stenosis is associated and calcification leading to mixed regurgitation and stenosis with rnorse short-term and long-term cardiovascular mortal- (Figure 61). ity. Recent trials have suggested that percutaneous approaches Radiation causes fibrosis of the conduction system and to aortic valve replacement may be preferable in this group. may lead to sinus node dystunction, lascicular and bundle There is no consensus on cardiac testing after chest irra- diation in asymptomatic patients. Baseline evaluation includ ing echocardiography is reasonable, and several organizations A have recommended stress echocardiography at 5 to 10 years I 1?7 :at after completion of therapy or at age 30 years, whichever 13u/63 \ comes first. The role of serum biomarkers in surveillance is unclear, and their use is not recommended. Routine screening d t- ,-tF. tr F{ 't: with nuclear medicine testing or coronary CT should be avoided. Statins. ACE inhibitors, and aldosterone antagonists. although effective for risk factor reduction. have not been

F{ 't: with nuclear medicine testing or coronary CT should be avoided. Statins. ACE inhibitors, and aldosterone antagonists. although effective for risk factor reduction. have not been .a f 3_ a_-- proved to prevent radiation-induced cardiovascular disease. TTY POITTS o Thoracic irradiation damages all cells, including those *.ff "{ of the pericardium, myocardium, valves, coronary vas 61 oP'1 culature, and conduction system, with clinical disease usually presenting t'vvo to three decades after treatment. B . In patients with a history of chest irradiation, tradi- I 127 :r: tional cardiovascular risk factors, such as smoking, dys \ 130/03 lipidemia, and hypertension, should be aggressively managed because of the increased risk for coronary artery disease.

61 oP'1 culature, and conduction system, with clinical disease usually presenting t'vvo to three decades after treatment. B . In patients with a history of chest irradiation, tradi- I 127 :r: tional cardiovascular risk factors, such as smoking, dys \ 130/03 lipidemia, and hypertension, should be aggressively managed because of the increased risk for coronary artery disease. tf ,G Card iotoxicity of Chemothera py 6W * Chemotherapy may cause reversible or dose dependent, irreversible cardiac injury (Table 43). Strategies to minimize cardiovascular risk should be considered before initiation of

tf ,G Card iotoxicity of Chemothera py 6W * Chemotherapy may cause reversible or dose dependent, irreversible cardiac injury (Table 43). Strategies to minimize cardiovascular risk should be considered before initiation of ,r ; FIGURE 61. Transesophageal echocardiogram in a patientwith previ0us chemotherapy, including optimizing treatment of traditional risk factors and identifying patients with the greatest long term risk (Table a4). Cardiotoxic therapies should be mini- mized if there are alternative therapies with equivalent mantle irradiation for Hodgkin lymphoma. The aortic valve leaflets are thickened, outcomes. and excursion is limited during systole (top panel). During diastole (bottom panel), Acute anthracycline toxicity, which can present as heart central aortic regurgitation (arow) is present. block, arrhythmias, heart failure, myocarditis, or pericarditis, 112

Cardiovascular Disease in Cancer Survivors TABTE 43. Cardiovascular Toxicities Associated with Chemotherapy Toxicity Class Drugs Left ventricular dysfunction Alkylating agents Cyclophosphamide, ifosfamide Anthracyclines Doxorubicin, epirubicin, idarubicin Antimicrotu bu lar agents Paclitaxel, docetaxel Monoclonal antibody Trastuzumab Proteasome inhibitor Bortezomib, carfilzomib Tyrosine kinase inhibitor Sunitinib schemia Antimetabolites 5-Fluorouracil, capecitabine Antimicrotubular agents Paclitaxel, docetaxel Monoclonal antibody Bevacizumab Tyrosine kinase inhibitors Erlotinib, sorafenib Hypertension Monoclonal antibody Bevacizumab Tyrosine ki nase inhibitors Sorafenib, sunitinib Venous th rom broembolism Alkylating agent Cisplatin Angiogenesis inhibitor Thalidomide Tyrosine kinase inhibitor Erlotinib Bradycardia/atrioventricular block Angiogenesis inhibitor Thalidomide Antimicrotubular agent Paclitaxel OT prolongation resulting in torsades de pointes Alkylating agent Oxaliplatin Anth racycline Aclarubicin Miscellaneous Arse n ic

TABTE 43. Cardiovascular Toxicities Associated with Chemotherapy Toxicity Class Drugs Left ventricular dysfunction Alkylating agents Cyclophosphamide, ifosfamide Anthracyclines Doxorubicin, epirubicin, idarubicin Antimicrotu bu lar agents Paclitaxel, docetaxel Monoclonal antibody Trastuzumab Proteasome inhibitor Bortezomib, carfilzomib Tyrosine kinase inhibitor Sunitinib schemia Antimetabolites 5-Fluorouracil, capecitabine Antimicrotubular agents Paclitaxel, docetaxel Monoclonal antibody Bevacizumab Tyrosine kinase inhibitors Erlotinib, sorafenib Hypertension Monoclonal antibody Bevacizumab Tyrosine ki nase inhibitors Sorafenib, sunitinib Venous th rom broembolism Alkylating agent Cisplatin Angiogenesis inhibitor Thalidomide Tyrosine kinase inhibitor Erlotinib Bradycardia/atrioventricular block Angiogenesis inhibitor Thalidomide Antimicrotubular agent Paclitaxel OT prolongation resulting in torsades de pointes Alkylating agent Oxaliplatin Anth racycline Aclarubicin Miscellaneous Arse n ic Tyrosine kinase inhibitor Vandetanib Atrial fibrillation Alkylating agents Cisplatin, cyclophosphamide, ifosfamide Anthracyclines Doxorubicin, aclacinomycin A, mitoxantrone Antimetabolites 5-Fluorouracil, leucovorin Histone deacetylase inhibitor Belinostat Microtubule agents Paclitaxel, docetaxel, gemcitabine

Tyrosine kinase inhibitor Vandetanib Atrial fibrillation Alkylating agents Cisplatin, cyclophosphamide, ifosfamide Anthracyclines Doxorubicin, aclacinomycin A, mitoxantrone Antimetabolites 5-Fluorouracil, leucovorin Histone deacetylase inhibitor Belinostat Microtubule agents Paclitaxel, docetaxel, gemcitabine Monoclonal antibodies Trastuzumab, etaracizumab Tyrosine kinase inhibitors Cetuximab, sunitinib, sorafenib, ibrutinib Monomorphic ventricula r tachycardia Anthracycl nesi Doxorubicin Antimetabolite 5-Fluorou raci I Miscellaneous Arsenic Monoclonal antibodies Nivolumab, trastuzu mab lnformat on from Tisdale JE, Chung MK, Campbeli KB, et al; American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology and Council on doi:1 0.1 1 61 /CIR.00OOOOOOOO0OOiO5

Miscellaneous Arsenic Monoclonal antibodies Nivolumab, trastuzu mab lnformat on from Tisdale JE, Chung MK, Campbeli KB, et al; American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology and Council on doi:1 0.1 1 61 /CIR.00OOOOOOOO0OOiO5 occurs in fewer than 1'2, of patients and may be reversible. TABLE 44. CancerTherapy-Associated FactorsThat lncrease Long-Term Cardiovascular Risk Chronic progressive anthracycline toxicity usually presents as dilated cardiomyopathy and is typically irreversible. It is most Anthracycline ortrastuzumab in patients with multiple cardiovascular risk factors closely linked with doxorubicin but may occur with epirubicin High-dose anthracycline (>-250 mg/m2 doxorubicin or and idarubicin. Chronic progressive toxicity has an early onset >600 mg/m2 epirubicin) (within 1 year of treatment) in 1.6"1' to 2.1% of patients and a late l Combination anthracycline and trastuzumab onset (after 1 year) in up to 5'7, ofpatients. Late onset chronic progressive toxicity is related to total cumulative dose. ln Combination anthracycline and radiation patients with a cumulative anthracycline dose of 550 mg/m2, Radiation of >30 Gy with the heart in the treatment field the incidence of heart failure is up to 26'ln, and toxicity may not 113