FOCUS SEMINAR: CARDIO-ONCOLOGY STATE-OF-THE-ART REVIEW Cardiovascular Complications of Cancer Therapy Best Practices in Diagnosis, Prevention, and Management: Part 2 Hui-Ming Chang, MD, MPH, a Tochukwu M. Okwuosa, DO, b Tiziano Scarabelli, MD, PHD, c Rohit Moudgil, MD, PHD, d Edward T.H. Yeh, MD a ABSTRACT In this second part of a 2-part review, we will review cancer or cancer therapy–associated systemic and pulmonary hypertension, QT prolongation, arrhythmias, pericardial disease, and radiation-induced cardiotoxicity. This review is based on a MEDLINE search of published data, published clinical guidelines, and best practices in major cancer centers. Newly developed targeted therapy can exert off-target effects causing hypertension, thromboembolism, QT prolongation, and atrial fibrillation. Radiation therapy often accelerates atherosclerosis. Furthermore, radiation can damage the heart valves, the conduction system, and pericardium, which may take years to manifest clinically. Management of pericardial disease in cancer patients also posed clinical challenges. This review highlights the unique opportunity of caring for cancer patients with heart problems caused by cancer or cancer therapy. It is an invitation to action for cardiologists to become familiar with this emerging subspecialty. (J Am Coll Cardiol 2017;70:2552–65) © 2017 by the American College of Cardiology Foundation. SYSTEMIC HYPERTENSION H ypertension (HTN) is the most common cardiovascular comorbidity reported in cancer registries, with a prevalence of 37% (1). Early diagnosis and treatment is essential because HTN is a major risk factor for the development of chemotherapy-induced cardiotoxicity (2). In addi- tion, suboptimal blood pressure control may lead to premature discontinuation of chemotherapy, thus affecting cancer therapy directly (2,3). INCIDENCE. Vascular endothelial growth factor signaling pathway inhibitors. Bevacizumab, sor- afenib, and sunitinib target the vascular endothelial growth factor signaling pathway (VSP) to achieve their therapeutic efficacy at the expense of increased blood pressure (4) (Table 1). The incidences of HTN reported in different trials range from 4% to 35% for bevacizumab (5–8), 7% to 43% for sorafenib (9–13), and 5% to 24% for sunitinib (14–18). Although treat- ment with antihypertensive medications is usually adequate to allow for continuation of cancer therapy, severe HTN requiring hospitalization or discontinua- tion of therapy occurred in 1.7% of bevacizumab- treated patients (19). Proteasome inhibitors. HTN, including hyperten- sive crisis or emergency, was observed during treatment with proteasome inhibitors, primarily car- filzomib. In the ENDEAVOR (Carfilzomib and Dexa- methasone versus Bortezomib and Dexamethasone From the a Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, Missouri; b Division of Cardiology, Rush University Medical Center, Chicago, Illinois; c Division of Cardiology, Virginia Common Wealth University, Richmond, Virginia; and the d Department of Cardiology, University of Texas, MD Anderson Cancer Center, Houston, Texas. Dr. Yeh has received support from the National Institutes of Health (HL126916); and is the Frances T. McAndrew Chair in the University of Missouri, School of Medicine. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received August 1, 2017; revised manuscript received September 24, 2017, accepted September 26, 2017. Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster. JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 70, NO. 20, 2017 ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2017.09.1095
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J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 0 , N O . 2 0 , 2 0 1 7
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FOCUS SEMINAR: CARDIO-ONCOLOGY
STATE-OF-THE-ART REVIEW
Cardiovascular Complications ofCancer TherapyBest Practices in Diagnosis, Prevention, and Management: Part 2
Hui-Ming Chang, MD, MPH,a Tochukwu M. Okwuosa, DO,b Tiziano Scarabelli, MD, PHD,c Rohit Moudgil, MD, PHD,d
Edward T.H. Yeh, MDa
ABSTRACT
Fro
Ca
Ric
Dr
the
co
Ma
In this second part of a 2-part review, we will review cancer or cancer therapy–associated systemic and pulmonary
hypertension, QT prolongation, arrhythmias, pericardial disease, and radiation-induced cardiotoxicity. This review is
based on a MEDLINE search of published data, published clinical guidelines, and best practices in major cancer
centers. Newly developed targeted therapy can exert off-target effects causing hypertension, thromboembolism,
QT prolongation, and atrial fibrillation. Radiation therapy often accelerates atherosclerosis. Furthermore, radiation can
damage the heart valves, the conduction system, and pericardium, which may take years to manifest clinically.
Management of pericardial disease in cancer patients also posed clinical challenges. This review highlights the unique
opportunity of caring for cancer patients with heart problems caused by cancer or cancer therapy. It is an invitation
to action for cardiologists to become familiar with this emerging subspecialty. (J Am Coll Cardiol 2017;70:2552–65)
© 2017 by the American College of Cardiology Foundation.
SYSTEMIC HYPERTENSION
H ypertension (HTN) is the most commoncardiovascular comorbidity reported incancer registries, with a prevalence of 37%
(1). Early diagnosis and treatment is essential becauseHTN is a major risk factor for the development ofchemotherapy-induced cardiotoxicity (2). In addi-tion, suboptimal blood pressure control may lead topremature discontinuation of chemotherapy, thusaffecting cancer therapy directly (2,3).
INCIDENCE. Vascular endothe l ia l growth factors igna l ing pathway inh ib i tors . Bevacizumab, sor-afenib, and sunitinib target the vascular endothelialgrowth factor signaling pathway (VSP) to achieve
m the aCenter for Precision Medicine, Department of Medicine, Unive
rdiology, Rush University Medical Center, Chicago, Illinois; cDivision o
hmond, Virginia; and the dDepartment of Cardiology, University of Te
. Yeh has received support from the National Institutes of Health (HL
University of Missouri, School of Medicine. All other authors have repo
ntents of this paper to disclose.
nuscript received August 1, 2017; revised manuscript received September
their therapeutic efficacy at the expense of increasedblood pressure (4) (Table 1). The incidences of HTNreported in different trials range from 4% to 35% forbevacizumab (5–8), 7% to 43% for sorafenib (9–13),and 5% to 24% for sunitinib (14–18). Although treat-ment with antihypertensive medications is usuallyadequate to allow for continuation of cancer therapy,severe HTN requiring hospitalization or discontinua-tion of therapy occurred in 1.7% of bevacizumab-treated patients (19).
Proteasome inh ib i tors . HTN, including hyperten-sive crisis or emergency, was observed duringtreatment with proteasome inhibitors, primarily car-filzomib. In the ENDEAVOR (Carfilzomib and Dexa-methasone versus Bortezomib and Dexamethasone
rsity of Missouri, Columbia, Missouri; bDivision of
f Cardiology, Virginia Common Wealth University,
xas, MD Anderson Cancer Center, Houston, Texas.
126916); and is the Frances T. McAndrew Chair in
rted that they have no relationships relevant to the
24, 2017, accepted September 26, 2017.
AB BR E V I A T I O N S
AND ACRONYM S
AF = atrial fibrillation
CAD = coronary artery disease
CTA = computed tomography
angiography
DOAC = direct oral
anticoagulant
DVT = deep vein thrombosis
ECG = electrocardiography
LMWH = low molecular weight
heparin
PE = pulmonary embolism
PH = pulmonary hypertension
QTc = corrected QT
RR = relative risk
TdP = torsades de pointes
TKI = tyrosine kinase inhibitor
VSP = vascular endothelial
growth factor signaling
ay
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for Relapsed Multiple Myeloma Patients) and ASPIRE(Carfizomib, Lenalidomide, and Dexamethasone vsLenalidomide and Dexamethasone in Subjects withRelapsed Multiple Myeloma) studies, the incidence ofHTN in patients receiving carfilzomib was 17% and11%, respectively (20,21). Of these events, 3% to 6%were reported as grade $3 and <2% were fatal (20).Hence, blood pressure monitoring should be regularlyperformed in all patients receiving carfilzomib. IfHTN cannot be adequately controlled, carfilzomibshould be withheld and possibly discontinued.Rechallenge should be considered only after risk/benefit assessment (20).
PATHOPHYSIOLOGY. Vascular endothelial growthfactor (VEGF) enhances the production of nitric oxideand prostacyclin while decreasing endothelin-1 gen-eration (22). VSP inhibitors affect normal vascularhomeostasis by interfering with production of nitricoxide (NO) in the arteriolar walls (23). Inhibition ofNO leads to vasoconstriction, increased peripheralvascular resistance, and increased blood pressure(23). Bevacizumab reduced endothelial nitric oxidesynthase activity leading to HTN (24). Although VEGFis believed to affect the renin-angiotensin system(25), anti-VEGF therapy did not alter serum cate-cholamine, renin, and aldosterone levels (26). Tela-tinib, a potent inhibitor of VEGFR, induces capillaryrarefaction (27). Carfilzomib reduces the vasodilatoryresponse of acetylcholine and induces vasospasm,which can be treated with nitroglycerin (28–30). Thus,peripheral vasoconstriction due to impairment ofendothelial function is likely to be the mechanism ofcarfilzomib-induced hypertension.
DIAGNOSIS AND TREATMENT. HTN is defined asblood pressure $140/90 mm Hg, based on an averageof 2 or more BP readings on 2 or more visits. Clinicalevaluation of HTN should include identification ofthe cause(s) of hypertension and assessment of car-diovascular risk factors (31) (Central Illustration). HTNmost commonly occurs within the first month oftreatment (32). In cancer patients, the temporal as-sociation of blood pressure elevation with new cancertreatment easily established the diagnosis.
Treatment of cancer therapy-induced HTNfrequently requires more than a single agent.Angiotensin-converting enzyme inhibitors (ACEIs) arethe preferred first-line therapy due to their beneficialeffects on plasminogen activator inhibitor-1 expres-sion and proteinuria (24). ACEIs also increase therelease of endothelial NO and decrease catabolism ofbradykinin (4). ACEIs have been shown to significantlyimprove overall survival in metastatic renal cell car-cinoma patients treated with sunitinib (33). Another
consideration in choosing antihypertensiveagents is to minimize harmful drug–drug in-teractions, particularly with sorafenib. Sincesorafenib is metabolized via the cytochromep450 system (mainly CYP3A4), drugs thatinhibit the CYP3A4 isoenzyme, such as diltia-zem and verapamil, should be avoided.Although HTN is considered as an undesirableside effect of cancer therapy, the increase inblood pressure has been shown to predict ef-ficacy of cancer treatment (4).
PULMONARY HYPERTENSION
Pulmonary hypertension (PH) is a disease ofthe pulmonary vasculature classified into 5major etiological groups (34). Drug- andtoxin-induced PH is classified as group 1.Cancer can cause PH through obstruction ofpulmonary artery from organized fibroticthrombi due to hypercoagulability, which isclassified as group 4 (35,36). Extrinsic
compression of the pulmonary vessels from tumorssuch as pulmonary angiosarcoma or direct intravas-cular extension from large B cell lymphoma can alsolead to group 5 PH (37).Dasatinib was first reported to cause PH in 2009 in achronic myeloid leukemia patient (38). A French reg-istry reported that 9 patients treated with dasatinibsubsequently developed moderate to severe PH; theincidence was estimated to be 0.45% (39). A total of 8patients showed functional improvement 4 monthsafter cessation of dasatinib therapy. In an Americanstudy of 41 patients with dasatinib-induced PH, partialor complete reversal of PH was seen followingdiscontinuation of dasatinib (40). The DASISION(Dasatinib Versus Imatinib Study in Treatment-NaïveChronic Myeloid Leukemia Patients) comparing dasa-tinib with imatinib showed that 14 (5%) of the 258dasatinib patients developed PH, compared with 1(0.4%) imatinib patient over a follow-up period of atleast 5 years (41). However, only 1 dasatinib-treatedpatient received right heart catheterization that didnot support the diagnosis of PH. Thus, the incidence of5% PH with dasatinib therapy is most likely an over-estimation. Inhibition of SRC kinase by dasatinib wasimplicated in the development of PH (39). SRC kinaseis involved in regulation of smooth muscle prolifera-tion and vasoconstriction so that its inhibition couldlead to increased pulmonary vascular resistance (39).
Transthoracic echocardiography is the screeningtool of choice for PH. A ventilation–perfusion scanand right heart catheterization are necessary toestablish the diagnosis of PH. A high index of
pathw
TABLE 1 Anticancer Agents Associated With Hypertension
Chemotherapy AgentsFrequencyof Use
Incidence(%) Comments
Monoclonal antibody-based tyrosine kinase inhibitors Pre-treatment risk assessment
BP goal <140/90 mm Hg
Weekly BP monitoring in 1st cycle
Every 2–3 weeks BP monitoringfor duration of therapy
Initiate BP treatment whendiastolic BP increases by20 mm Hg
More than 1 anti-HTN medicationmay be needed
Avoid diltiazem and verapamilwith sorafenib
Hold chemotherapy as the lastresort
Hold bevacizumab if systolicBP >160 mm Hg or diastolicBP >100 mm Hg
Early consultation withcardiologist
Bevacizumab þþþ 4–35
Ado-trastuzumabemtansine
þ 5.1
Monoclonal antibodies
Alemtuzumab þ 14
Ibritumomab NA 7
Ofatumumab þ 5–8
Rituximab þþþ 6–12
mTor inhibitors
Everolimus þþþþ 4–13
Temsirolimus þþ 7
Small molecule tyrosine kinase inhibitors
Pazopanib þþþþ 42
Ponatinib þ 68
Sorafenib þþþþ 7–43
Sunitinib þþþþ 5–24
Axitinib þþþþ 40
Cabozantinib NA 33–61
Ibrutinib þþþþ 17
Nilotinib þþþþ 10–11
Ramucirumab þ 16
Regorafenib þþþþ 30–59
Trametinib þþþþ 15
Vandetanib NA 33
Ziv-aflibercept þ 41
Proteasome inhibitors
Bortezomib þþ 6
Carfilzomib þþ 11–17
Antimetabolites
Decitabine þþ 6
Frequency of use was determined using inpatient and outpatient doses dispensed at MD Anderson Cancer Centerduring the time period of January 1, 2014, through December 21, 2014. þ ¼ <1,000 dosesdispensed; þþ ¼ 1,000–5,000 doses dispensed; þþþ ¼ 5,000–10,000 doses dispensed;and þþþþ ¼ >10,000 doses dispensed (4,55,72).
BP ¼ blood pressure; HTN ¼ hypertension.
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suspicion and prompt diagnosis are necessary toprevent further deterioration. PH can be managed bywithholding dasatinib and treating with alternativetyrosine kinase inhibitors (TKIs), followed by treat-ment with sildenafil, an endothelial antagonist, or acalcium-channel blocker (39). Patient should befollowed monthly with echocardiogram for serialassessment of pulmonary artery pressure. Cancertherapy can be continued with alternative TKIs. Thus,dasatinib-induced PH has a relatively good prognosisif diagnosed and treated early.
PERICARDIAL DISEASES
Pericardial effusion, a manifestation of late-stagemalignancies, develops in 5% to 15% of patientswith cancer (42). The most common malignancies
associated with pericardial effusions are lung cancer,breast cancer, leukemia, and lymphoma (42–44).Pericardial effusion caused by breast cancer orlymphoma had better prognosis compared withlung cancer (45). Malignant effusions with negativecytology in early pericardiocentesis usually becomepositive over time. The pericardial space can beinvaded by direct tumor extension or metastaticspread via lymphatics or blood. Pericardial effusioncan also develop as a result of chemotherapy or ra-diation therapy, or from opportunistic infections (46).
Chemotherapies associated with pericardial dis-eases include anthracyclines, cyclophosphamide,cytarabine, imatinib, dasatinib, interferon-a, arsenictrioxide, and less frequently, docetaxel and5-fluorouracil (47). All-trans retinoic acid causes asyndrome characterized by fever, hypotension, acuterenal failure, and pericardial effusion. High-dosebusulfan can cause pericardial and endomyocardialfibrosis 4 to 9 years after treatment (48).
Pericardial disease (effusion and/or constriction)can occur in 6% to 30% of patients after radiationtherapy (49–51). It is the most common manifestationof radiation-induced heart disease, which usuallyoccurs as a result of fibrinous exudates to thepericardial surface, as well as fibrotic changes tothe parietal pericardium. Acute pericarditis can occurwithin days to months following radiation therapy;it is often self-limiting. Chronic pericarditis is oftencharacterized as effusive-constrictive.DIAGNOSIS AND TREATMENT. An electrocardiogramis useful in the diagnosis of acute pericarditis, usuallyin the setting of recent radiation therapy. However,echocardiography is the imaging modality of choice inthe diagnosis of pericardial effusion and cardiac tam-ponade. Patients are often asymptomatic with small tomoderate pericardial effusion, but can present withdyspnea, cough, tachycardia, pulsus paradoxus, andhypotension with impending cardiac tamponade.Echocardiographic features of cardiac tamponadeinclude increase mitral inflow with expiration, dia-stolic compression of the right ventricle, late diastoliccollapse of the right atrium, plethora of inferior venacava, and abnormal ventricular septal motion. Emer-gency pericardiocentesis should be carried outpromptly when cardiac tamponade is suspected.
Pericardiocentesis should be carried out for cardiactamponade, large pericardial effusions ($2 cm), or fordiagnostic purposes. Factors that carried poorerprognosis for 2-year survival after pericardiocentesisfor malignant effusions included age >65 years,platelet counts <20,000, lung cancer, presence ofmalignant cells in the effusion, and drainage duration(45). Pericardial fluid should be sent to for chemistry,
CENTRAL ILLUSTRATION Management of Cancer Therapy–Induced Cardiovascular Complications
Radiation sequelae
Management of cancer or cancer-therapy associated cardiovascular (CV) complications
Hypertension Thromboembolism QT prolongation
Blood pressure (BP) goal<140/90 mm Hg
Monitor weekly
Monitor every 2-3 weeks during therapy
Initiate treatment when diastolic BP increases
by 20 mm Hg
Identify, modifyand treat CV risk factors
CV Monitoring:Yearly:
ECG, Echo if indicated
5 years after radiation:ECG, Echo
10 years after radiation: ECG, Echo, stress test,
or coronary CT
VSP and angiogenesis inhibitors increase risk
Deep venous thrombosisor pulmonary embolism
diagnostics
Anti-coagulateas necessary
Direct oral anticoagulant (limited data)
Take bleeding precautions
Diagnosis with Tangent method & Fridericia
correction
Correct low potassiumor magnesium
Remove QT-prolonging medications
Chang, H.-M. et al. J Am Coll Cardiol. 2017;70(20):2552–65.
Best practices in the management of cancer therapy–induced HTN, thromboembolism, QT prolongation, and radiation-induced complications. BP ¼ blood pressure;
CT ¼ computed tomography; CV ¼ cardiovascular; ECG ¼ electrocardiography; Echo ¼ echocardiography; HTN ¼ hypertension; VSP ¼ vascular endothelial growth
factor signaling pathway.
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microbiology, and cytology. If pericardiocentesisis performed, the drain should be left in place for 3 to5 days, and a surgical pericardial window should beconsidered if the output drainage is still high 6 to7 days after pericardiocentesis. Effusions are morelikely to recur with percutaneous pericardiocentesiscompared with pericardiotomy, even though therewas no difference in length of stay or intensive careunit admission with either approach (46).
Rarely, pericardial effusions are managed withintrapericardial injection of chemotherapeuticagents. In a small series of patients treated withintrapericardial cisplatin for malignant pericardialeffusion, 93% and 83% were free of hemodynamicallysignificant recurrent pericardial effusions at 3 and6 months, respectively (52,53). Intrapericardial bev-acizumab was used to achieve sustained remission in7 patients (54). However, the preferred managementfor recurrent pericardial effusion is still surgery (55).
THROMBOEMBOLISM
It is well established that cancer itself predisposespatients to thromboembolic events (56). However,
there are considerably more data on venous thanarterial thromboses (57,58). Thrombosis in cancerpatients is most likely due to release of prothromboticfactors, such as tissue factor, mucin, and cysteineprotease, into the circulation to activate the clottingcascade (56). The risk of arterial thromboembolism ishigher in the first 6 months after cancer diagnosis andreturns to baseline at 1 year (59). The risk of throm-boembolism is higher with certain cancers (lung,pancreatic, colon/rectal, kidney, and prostate), withmetastatic diseases, and with certain risk factors (useof central venous catheters, immobility, heart failure,atrial fibrillation, hypovolemia, and chemotherapy)(57,60).
PATHOPHYSIOLOGYAND INCIDENCE. VSP inhibitors. VSPinhibitors are known to increase the risk of throm-boembolism by altering the vascular protectiveproperty of the endothelial cells (Table 2) (61). Endo-thelial injury couples with hypercoagulability andhemodynamic changes followed by thrombosis.Meta-analyses of major VSP inhibitor trials demon-strated an increased risk of thromboembolic events(61–63). The incidence of all grade arterial thrombotic
TABLE 2 Anticancer Agents Associated With Thromboembolism
Chemotherapy AgentsFrequencyof Use
Incidence(%) Comments
Alkylating agents Risk factors: cancer types, metastaticdisease, central venous catheter, heartfailure, immobility, AF, previoushistory of thromboembolism,chemotherapy, hormonal therapy, oldage, female
Diagnosis: compressionultrasonography, spiral CT, MR
Treatment options: aspirin, warfarin,LMWH
Limited data with DOAC
Cisplatin þþþ 8.5–16.7
Angiogenesis inhibitors
Lenalidomide þþþ 3–75
Thalidomide þþ 1–58
Pomalidomide þ 3
Histone deacetylase inhibitor
Vorinostat þþþþ 4.7–8.0
Monoclonal antibody against VEGF
Bevacizumab þþþ 6.0–15.1
mTOR inhibitors
Everolimus þþþþ 1–4
Small molecule tyrosine kinase inhibitors
Axitinib þþþþ 3
Dabrafenib þþþþ 7
Erlotinib þþþþ 3.9–11.0
Nilotinib þþþþ 1–10
Pazopanib þþþþ 1–5
Ponatinib þ 5
Sunitinib þþþþ 3
Trametinib þþþþ 7
Ziv-aflibercept þ 9
See Table 1 for frequency of use description (55,72).
AF ¼ atrial fibrillation; CT ¼ computed tomography; DOAC ¼ direct oral anticoagulant; LMWH ¼ low molecularweight heparin; MR ¼ magnetic resonance.
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events in patients on VSP inhibitors ranges from 1% to11% (64). A higher risk of arterial thrombotic eventswas reported in several meta-analyses of VSP inhibi-tor trials (61–63). In a meta-analysis of 10,255 patientstreated with sorafenib or sunitinib, the incidence ofarterial thrombotic events was 1.4% with a relativerisk of 3.03 when compared with the control group(63). More recently, a meta-analysis of 38,078 pa-tients from all eligible VSP inhibitor trials observed asignificantly higher risk of myocardial infarction(relative risk [RR]: 3.54) and arterial thromboticevents (RR: 1.80) in the population studied. However,no significant difference in stroke risk was foundbetween these 2 groups (61).
Several meta-analyses failed to establish increasedrisk in venous thromboembolism in patients treatedwith a VSP inhibitor compared with the control group(65–67). Subsequently, a meta-analysis of all eligibletrials of patients treated with VSP inhibitors showedthat the RRs for deep vein thrombosis (DVT) andpulmonary embolism (PE) were insignificant at 1.14and 1.18, respectively (61). Although cancer itself is arisk factor for venous thromboembolism, it is notclear whether VSP inhibitors exaggerate this risk (68).Cisp lat in . Jacobson et al. (69) found a 16.7% inci-dence of thromboembolic events in 48 patients
treated with cisplatin and radiotherapy for cervicalcancer. In another study of 271 patients with urothe-lial transitional cell cancer, cisplatin-based chemo-therapy was associated with thromboembolic andvascular events in 12.9% of patients; 8.5% of themhad DVT or PE. The risk factors include coronary ar-tery disease (CAD), immobility, prior history ofthromboembolic events, and pelvic masses. Cisplatincauses vascular injury (70) and induces platelet acti-vation through a mechanism involving monocyteprocoagulant activity (71).Angiogenes is inh ib i tors . Lenalidomide and itsparent drug thalidomide increase the risk of throm-boembolism when combined with glucocorticoidsand/or cytotoxic chemotherapy. This risk is 3% to 75%for lenalidomide and 1% to 58% for thalidomide (72).A systematic review demonstrates that patientswith multiple myeloma treated with thalidomide- orlenalidomide-based regimens are at higher risk fordeveloping venous thromboembolism (73). Newlydiagnosed patients have higher risk than patientswho were previously treated. When thalidomide orlenalidomide was combined with dexamethasone anddoxorubicin, the risk increased. Aspirin, warfarinwith target international normalized ratio of 2.0 to3.0, or therapeutic doses of low molecular weightheparin (LMWH) can reduce the risk of venousthromboembolism. However, rates of major bleedingcomplications are unknown; thus, the benefit ofprophylaxis is not clear. Thalidomide causes a tran-sient elevation in factor VIII and von WillebrandFactor and a reduction in soluble thrombomodulin,which may explain the increase in thromboembolism(73,74).
Histone deacety lase inh ib i tor . Vorinostat, usefulin the treatment of cutaneous T-cell lymphoma, isknown to increase the risk of thromboembolism incancer patients (72,75). The rates of PE and DVT withthis agent were reported to be 5% and 8%, respec-tively (76).
DIAGNOSIS, PREVENTION, AND MANAGEMENT. DVTis usually diagnosed by compression ultrasonographyand PE by spiral computed tomography angiography(CTA). Ventilation-perfusion scan is employed lessfrequently for diagnosis of PE due to lower sensitivityand specificity compared with CTA, but is still utilizedwith compression ultrasonography in patients withrenal dysfunction. Magnetic resonance pulmonaryangiography is considered in patients who are allergicto iodinate contrast media (72,77).
Prevention strategies should be chosen accordingto specific anticancer drug. The goal is to use thesafest form of prophylaxis that reduces the risk of
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thromboembolism to #10%. Prevention should betailored to the presence of risk factors, such asobesity, prior episodes, central venous catheter use,comorbid conditions, surgery, use of erythropoietinand tamoxifen, and concomitant therapy with high-dose dexamethasone and/or doxorubicin. For pri-mary prevention, all hospitalized patients shouldreceive either LMWH or unfractionated heparin (78).The Khorana VTE risk assessment model for cancerpatients may be utilized in the ambulatory setting.This model uses site of cancer, blood cell counts, andbody mass index to determine a patient’s risk. A scoreof 3 or higher confers a 7.1% to 41% risk of symp-tomatic VTE, and prophylaxis may be reasonable inthese patients (78,79).VSP inh ib i tors . Prior to initiation of VSP inhibitortherapy, cardiovascular risk factors should beaggressively managed (80). A history of prior arterialthromboembolic event (ATE) is not an absolutecontraindication to VSP inhibitor therapy; however,VSP inhibitors should be used with caution or avoidedin patients with recent cardiovascular events in thepreceding 6 to 12 months. There are no standardguidelines for management of ATEs in patients takingVSP inhibitors, so management of such events shouldbe based on standard medical practice (81). VSP in-hibitor therapy should be discontinued in grade 3 orhigher thromboembolic events (4,82). Increased riskof hemorrhage with VSP inhibitor is not a contrain-dication to the use of thrombolytic or anticoagulationtherapy when medically appropriate; however, thesepatients should be closely monitored. Following res-olution of acute events, restarting VSP inhibitorshould be based on individualized risk–benefitanalysis.
Data from multiple trials have led to widespreaduse of aspirin for both primary and secondary pre-vention of arterial ischemia (83,84). Although thereare no controlled studies to determine the benefit ofaspirin in patients taking VSP inhibitors, it isreasonable to start low-dose aspirin prophylacticallyin high-risk patients (e.g., patients with previousATEs or based on Framingham risk assessment).Furthermore, low-dose aspirin may prevent cardio-vascular events in patients receiving bevacizumabwho are age $65 years with a prior history of ATEs (9).
Angiogenes i s inh ib i tors . Observational studies ofthalidomide- and lenalidomide-based regimens inmultiple myeloma patients have demonstrated effi-cacy of prophylaxis with aspirin (81 to 325 mg),warfarin, or LMWH (77,85). Single-agent lenalidomidedoes not constitute a high risk of VTE, and prophy-laxis is not recommended in this setting. Aspirin is an
appropriate prophylaxis in patients receiving lenali-domide with low-dose dexamethasone, melphalan, ordoxorubicin; the incidence of VTE was reducedto <10% with aspirin (86–88). The addition of high-dose dexamethasone carries additional risk andlikely warrants the use of more aggressive prophy-laxis, such as LMWH or full-dose warfarin.
One randomized study compared the use ofaspirin and fixed low-dose warfarin versus LMWH toprevent thromboembolism in 667 previously un-treated multiple myeloma patients receivingthalidomide-containing regimens with or withoutbortezomib (89). Patients were randomized to aspirin(100 mg/day), warfarin (1.25 mg/day), or LMWH(enoxaparin 40 mg/day). There was no difference inthe prevention strategies tested. In the case of single-agent thalidomide, low-dose aspirin should beconsidered (90). LMWH or full-dose warfarin isrecommended in patients receiving angiogenesisinhibitors with dexamethasone, doxorubicin, ormultiagent chemotherapy.
Once the diagnosis of VTE is made, the treatmentgoal should be to relieve symptoms and to preventpropagation. Patients should be treated in accordancewith the American College of Chest Physicians guide-lines (81). If a patient develops VTE while on chemo-therapy, the therapy should be held and standardanticoagulation, preferably LMWHs, should be initi-ated (91). Thrombolytic therapy should be consideredif clinically indicated. Cancer therapy can be reinstatedafter the patient is stable and therapeutic anti-coagulation is achieved. Anticoagulation should becontinued as long as the patient has active malignancyand therapy is not otherwise contraindicated (78).Anticoagulation should be avoided in the presence ofintracranial bleeding, recent surgery, pre-existingbleeding diathesis such as thrombocytopenia,platelet count <50,000/ml, or coagulopathy (90).
USE OF DIRECT ORAL ANTICOAGULANTS IN CANCER.
Although direct oral anticoagulants (DOACs), such asdabigatran, rivaroxaban, apixaban, are the preferredoral anticoagulant for the treatment of VTE in pa-tients without cancer, there is limited data for DOACin cancer patients (92,93). Most trials that comparedthe safety and efficacy of DOAC with warfarin haveexcluded cancer patients or included a small numberof them. Most of the included cancer patients hadcompleted cancer therapy, and active cancer patientswere excluded.
As already discussed, LMWH is the anticoagulantagent of choice in patients with malignancy.Compared with the general population, there arefewer data to support the use of DOACs as first-line
TABLE 3 Anticancer Agents Associated With QT Prolongation
Chemotherapy AgentsFrequencyof Use
Incidence(%) Comments
Histone deacetylase inhibitors Tangent method of QTmeasurement
Fridericia correction formula
Correct low K or Mg
Remove QTc prolongingmedications
QTc >500 ms or >60 ms abovebaseline associated with TdP
TdP reported for arsenictrioxide, sunitinib, pazopanib,vandetanib, vemurafenib
Belinostat þ 4–11
Vorinostat þþþþ 3.5–6.0
Chemicals
Arsenic trioxide þþ 26–93
Small molecule tyrosine kinase inhibitors
Dabrafenib þþþþ 2–13
Dasatinib þþþþ <1–3
Lapatinib þþþþ 10–16
Nilotinib þþþþ <1–10
Vandetanib þþþþ 8–14
BRAF inhibitor
Vemurafenib þþþþ 3
See Table 1 for frequency of use description (55,72).
K ¼ potassium; Mg ¼ magnesium; QTc ¼ corrected QT interval; TdP ¼ torsades de pointes.
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agents in patients with malignancy; however, limiteddata suggest that warfarin and DOACs are of equalefficacy when oral anticoagulants are necessary incancer patients. Compared with warfarin, therapeuticefficacy with DOACs occurs within 1 to 4 h afteringestion. A subgroup analysis of cancer patients inthe ARISTOTLE (Apixaban for Reduction in Strokeand Other Thromboembolic Events in Atrial Fibrilla-tion) trial evaluated DOACs for patients with non-valvular atrial fibrillation (94). At baseline, there were1,236 (6.8%) patients with a history of cancer and 157(12.7%) had active cancer or treated within 1 year.This study did not show a difference in stroke orsystemic embolization between apixaban andwarfarin in cancer patients. Another small prospec-tive study suggests that rivaroxaban is safe andeffective for treatment of cancer-associated VTE (95).
QT PROLONGATION
QT interval prolongation is caused by abnormality indepolarization/repolarization that can lead to tor-sades de pointes (TdP) and sudden death (96). ThehERG potassium channel is the molecular target fordrugs that prolong the QT interval (2,97–100). Cancerpatients are more prone to develop QT prolongationfollowing treatment with arsenic trioxide and TKIs(Table 3). Antiemetics, H2-blockers, proton pump in-hibitors, antimicrobial agents, and antipsychoticsalso contribute to prolonging the QT interval (2). Inaddition, nausea, vomiting, and diarrhea followingcancer therapy lead to loss of potassium and magne-sium, which also prolongs the QT interval.
INCIDENCE. Arseni c tr iox ide . Arsenic trioxide isused for the treatment of acute promyelocytic leu-kemia. The U.S. Multicenter Study of Arsenic Trioxidereported the incidence of corrected QT (QTc) interval>500 ms to be 40% (101); other trials reported in-cidences of QT prolongation with arsenic trioxideranging from 26% to 93% (72,102). The QT intervalbecame prolonged 1 to 5 weeks after arsenic trioxidetreatment, and returned to baseline 8 weeks aftercessation of therapy (101).
Smal l molecu le TKI inh ib i tors . A total of 4.4% ofpatients treated with TKIs developed all-grade QTcprolongation, and 0.8% developed seriousarrhythmia (98). However, the incidence of QT pro-longation is not affected by the duration of therapy(98). The most common drugs that prolongs QTcwhen used in conjunction with sunitinib are dom-peridone or loperamide (103); nonetheless, therewere no high-grade arrhythmias or sudden cardiacdeaths associated with sunitinib use. Pazopanib andaxitinib only confer <1% risk of high-grade QTc pro-longation in the absence of TdP. Unfortunately, QTintervals were not available in studies on sorafeniband cediranib (104–106). High-grade QT prolongationis a significant adverse effect of vandetanib therapy.In a trial for metastatic medullary thyroid cancer, theincidence of high-grade QTc prolongation is 8% (107).A meta-analysis reported similar incidence of QTcprolongation for vandetanib (98). This effect is dose-dependent, with the reported incidence of 3.6% forlow dose and 12.2% for high dose. The incidence of QTprolongation is 10% for nilotinib to 10% and 16% forlapatinib, according to package insert.
Histone deacetylase inhibitor and BRAF inhibitor. Theincidence of QTc prolongation with vorinostat rangedfrom 3.5% to 6% (72). In an open-label study in pa-tients with the BRAF (V600) mutation, vemurafeniblengthened QTc to >500 ms in 3% of patients (108).
DIAGNOSIS. The QT interval varies with heart rateand has to be adjusted by the RR interval to calculateQTc (109). The Fridericia formula, in which QT isdivided by the cubic root of the RR interval, is rec-ommended by the U.S. Food and Drug Administrationfor heart rate correction (110). QTc interval isconsidered normal at <430 ms in male and <450 msin female patients. Common Terminology Criteria forAdverse Events version 4 defines grade 1 QTc pro-longation as 450 to 480 ms, grade 2 as 481 to 500 ms,and grade 3 as QTc >501 ms. QTc $501 ms or >60 mschange from baseline and TdP or sudden death aredefined as grade 4. QTc >500 ms or >60 ms abovebaseline have been associated with increased risk forTdP (111).
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MANAGEMENT. A baseline electrocardiography (ECG)should be obtained in all patients and electrolyteabnormalities (particularly hypokalemia and hypo-magnesemia) should be corrected prior to startingtreatment (112). It is important to identify drug–druginteractions that prolong the QTc interval. Importantmedications to consider are domperidone, ondanse-tron, palonosetron, granisetron, prochlorperazine,olanzapine, escitalopram, venlafaxine, sertraline, andmirtazapine (98). ECG should be repeated at 7 daysafter initiation of therapy, according to drug packageinserts, and following any dosing changes (55).The 2016 Canadian Cardiovascular Society guidelinesupports baseline ECG and periodic monitoring ofthe QTc interval in cancer patients receivingQT-prolonging agents (113). Treatment should bestopped if the QTc is >500 ms on monitoring (112).
TdP should be managed with 2 g of intravenous(IV) magnesium as the initial drug of choice regard-less of serum magnesium level. Nonsynchronizeddefibrillation may be indicated. Overdrive pacing(with short-term pacing rates of 90 to 110 ms) may beused to shorten QTc; it is useful when TdP is precip-itated by bradycardia. IV isoproterenol titrated toheart rates >90 ms is indicated when temporarypacing is not immediately available. All electrolyteabnormalities should be corrected and QT prolongingmedications should be discontinued (114).
ARRHYTHMIAS
Bradyarrhythmias or tachyarrhythmias (includingbradycardia or heart block, as well as atrial fibrillation[AF] and supraventricular or ventricular arrhythmias)can be associated with cancer or chemotherapy.
BRADYCARDIA AND HEART BLOCK. Infiltration ofthe AV nodes by lymphoma or amyloidosis cancause bradyarrhythmias or heart block (115,116). Vagalparaganglioma, a rare tumor of the neuroendocrinesystem, can cause significant heart block (117), and10% of patients with catecholamine-secretingtumors have bradycardia and heart block (118,119).Bradycardia and/or heart block can also be seen inpatients with neck mass, with involvement ofthe vagus nerves (120). Although uncommon, brady-cardia and heart block have been linked to cisplatin,irinotecan, paclitaxel, mitoxantrone (and rarely,doxorubicin), octreotide, thalidomide, methotrexate,5-fluorouracil, and arsenic trioxide (60,72). Ethanol,which is injected percutaneously for treatment ofhepatocellular carcinoma, can cause sinus brady-cardia and heart block (121).Management . The majority of patients with brady-cardia secondary to chemotherapy are asymptomatic
(60). Symptoms associated with bradycardia includefatigue, dizziness, as well as pre-syncope/syncope.Treatment of heart block depends on the type ofescape rhythm present. Junctional escape rhythmrequires pacemaker only if symptoms are present,whereas ventricular escapes are unstable and requirepacemaker implantation.
When a clear offending drug is identified, alterna-tive therapy should be considered. However, if thereis no substitution, the patient can be closely moni-tored while undergoing chemotherapy. When brady-cardia is caused by thalidomide without a treatmentalternative, permanent pacemaker implantation maybe necessary to allow for continuation of therapy(122,123). In some cases, the heart block will resolvewith treatment of the primary malignancy (60,115).Pacemaker placement in patients with persistentsymptomatic bradycardia and heart block shouldfollow American College of Cardiology/AmericanHeart Association guidelines (124). In cancer patientswith ongoing infection, a temporary pacemaker maybe placed and left in place for a few days until theinfection is controlled (60,124). The use of isoproter-enol to maintain higher heart rates can also beconsidered. The final decision should be made afterconsultation between the cardiologist and oncologist.
TACHYARRHYTHMIAS. Tachyarrhythmias, such assupraventricular arrhythmias, AF, as well as life-threatening and non–life-threatening ventricular ar-rhythmias, could occur in cancer patients. A recentstudy of patients diagnosed with cancer afterimplantable cardioverter-defibrillator implantationfound that the frequency of ventricular tachycardiaand ventricular fibrillation increased significantly af-ter diagnosis, representing a 10-fold increase inarrhythmia burden (125). The incidence of ventriculararrhythmias is significantly higher in patients withstage IV cancer than in those with earlier stages. Themost common malignancies associated with ventric-ular arrhythmias are skin, prostate, and breast can-cers. Causations of ventricular arrhythmias in cancerpatients include QTc-prolonging chemotherapeuticagents, inflammation in advanced cancer (126), directcardiac involvement by tumor, metabolic de-rangements relating to nausea/vomiting/diarrhea,decreased oral intake, and electrolyte abnormalities.
A large epidemiological study of 24,125 patientswith newly diagnosed cancer found a 2.4% baselineprevalence of AF, with an additional 1.8% increasedincidence after cancer diagnosis (127). Another studythat examined 28,333 patients with AF compared with282,260 patients without AF found the prevalence ofcolorectal cancer to be 0.59% in patients with AF and
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only 0.05% in those without AF (128). Another studyfound post-operative AF to be more common afterbreast and colorectal cancer surgery (3.6%) comparedwith noncancer surgery (1.6%) (129). Thus, cancer isassociated with a higher risk of AF. In patients whoare post-thoracic surgery for lung cancer, AF wasassociated with higher post-operative mortality andwas associated with 4-fold higher mortality in 5-yearsurvivors after adjustments for other risk factors.
AF in cancer patients is associated with advancedage, hypoxia, increased sympathetic drive caused bypain as well as physical and emotional stress, and/orparaneoplastic conditions such as autoimmune re-actions against atrial structures (130). In addition,cancer drugs known to be associated with AF includecisplatin, 5-fluorouracil, doxorubicin, paclitaxel/docetaxel, ifosfamide, gemcitabine, and mitoxan-trone (131). Interleukin-2, with or without interferon,has been associated with AF in patients with meta-static renal cell cancer (132). The mechanisms of AFinduced by interleukin-2 are unclear, but are likelyrelated to elevations in plasma cytokine concentra-tions with these agents (133). Inflammation appears tobe a common denominator leading to AF in most ofthese conditions (131).
Ibrutinib, a Bruton kinase inhibitor useful in thetreatment of chronic lymphocytic leukemia, issignificantly associated with AF (134). In the RESO-NATE (Ibrutinib versus Ofatumumab in Patients withRelapsed or Refractory Chronic Lymphocytic Leuke-mia) trial, 3% of patients receiving ibrutinib devel-oped AF, whereas the ofatumumab arm had no AF(135). In another study of 56 patients, AF occurred 3to 8 months after initiation of ibrutinib, and 76% ofthem developed AF within the first year on this drug(136). Patients were managed with dose reductionand/or anticoagulation (137); however, the clinicalexperience is still limited to make a generalrecommendation.Management . Management of tachyarrhythmias incancer patients is similar to those for noncancer pa-tients. A useful approach is to distinguish dysrhyth-mias resulting from chemotherapy and metabolicabnormalities from those associated with structuralcardiac abnormalities. Active intervention is requiredwhen the arrhythmia results in significant hemody-namic abnormality, or when the rhythm disturbancebecomes life threatening. The use of antiarrhythmicdrugs for management of dysrhythmias during cancertherapy poses a particular challenge because of drug–drug interactions. Coadministration of chemotherapyand antiarrhythmic drugs may lead to increased druglevels due to impaired cytochrome p450 metabolismor P-glycoprotein–mediated transport inhibition
(138). Furthermore, both chemotherapy and antiar-rhythmic drugs increase the risk of bradycardias andQT prolongation. In general, Class 1A, 1C, and IIIantiarrhythmic drugs are more likely to cause druginteractions and QT prolongation, whereas class 1Bdrugs are less likely to do so. Among the beta-blockerclass of drugs, metoprolol, atenolol, and pindolol areless likely to cause drug interactions compared withcarvedilol, propranolol, or nadolol. Recommenda-tions for managing drug–drug interactions for sometargeted therapies were recently published by Asnaniet al. (138).
The decision to anticoagulate in cancer patientswith AF should be individualized after consultationwith the oncologist. The use of CHA2DS2-VASc(congestive heart failure, hypertension, age $75years, diabetes, previous stroke, vascular disease,age 65 to 74, and female sex) and HAS-BLED (Hyper-tension, Abnormal Renal/Liver Function, Stroke,Bleeding History or Predisposition, Labile Interna-tional Normalized Ratio, Elderly, Drugs/Alcohol)scores has not been validated in cancer patients(139). Furthermore, cancer generally creates a pro-thrombotic milieu, whereas cancer therapy oftenincrease the bleeding risk due to induction ofthrombocytopenia (56). Thus, a careful balance be-tween risk/benefit and involvement of patient andfamily in decision making is essential.
CARDIOVASCULAR DISEASE WITH
RADIATION THERAPY
Radiation therapy affects all cardiac structuresincluding the pericardium, epicardial and microvas-cular circulation, conduction system, and themyocardium (140). Patients can present with acutepericarditis immediately following radiation therapyor chronic pericarditis decades after radiation therapy(Table 4). Valvular heart disease and coronary arterydisease usually presents 5 to 10 years after radiationtherapy. We recommend an echocardiogram 5 yearsafter radiation therapy and a stress test or coronaryCTA 10 years after radiation therapy (55).
CAD is a major cardiovascular complication ofradiation therapy. Women with left chest radiationhave increased risk of cardiovascular complicationscompared with right-sided radiation (141). Higherdoses of radiation were associated with increased riskof major coronary events in women treated for breastcancer (142). This risk began within the first 5 yearsafter radiation therapy and continued until the thirddecade. This study was based on older radiationtechniques involving external beam radiation therapywith higher radiation doses. Newer radiation
TABLE 4 Radiation-Induced Heart Disease: Diagnosis and Management
Pericardial Disease
Prevalence 6%–30%
Description Pericarditis (acute or chronic), pericardial effusion, pericardial constrictionMost common manifestation of radiation-induced heart disease, and a diagnosis of exclusion. Due to inflammation and impaired
drainages to the pericardial surface, fibrotic changes to the parietal pericardium. Acute pericarditis is often self-limiting. Chronicpericarditis is often effusive-constrictive.
Diagnosis Diagnosis of exclusion after other causes of pericardial disease have been ruled outEchocardiogram, cardiac magnetic resonance imaging, cardiac CT
Management Anti-inflammatory drugs for pericarditisPericardiocentesis for large effusions or tamponadePericardial window for recurrent pericardial effusionsPericardial stripping for constrictive pericarditis
Coronary Artery Disease
Prevalence Up to 85%
Description Due to epicardial coronary arteries and microcirculatory damage, and sustained inflammation. Usually occurs 10 yrs after radiationtherapy. Involves the LM, ostial LAD, and RCA. Lesions are longer, concentric, and tubular.
Diagnosis Stress echocardiography (could also screen for other causes of RIHD, other than CAD); or stress perfusion imaging; cardiac CTA;possible role for coronary calcium screening
Management Percutaneous coronary angioplasty or coronary artery bypass graft (challenging surgery due to fibrosis of pericardium andmediastinum). Aggressive cardiovascular risk factor modification
Valvular Heart Disease
Prevalence 10 yrs: 26% AI, 39% MR, 16% TR, and 7% PR20 yrs: 60% AI, 16% AS, 52% MR, 26% TR, and 12% PR
Description Mean time interval of 12 yrs after radiation. Diffuse fibrosis of the valvular cusps or leaflets, with or without calcification; no post-inflammatory changes noted. Left-sided valves > right-sided valves. Initial regurgitation related to valve retraction, later stenosisrelated to thickening/calcification
Diagnosis Echocardiogram, cardiac magnetic resonance imaging
Management Serial monitoring with timing of surgery as in ACC/AHA guidelinesValve replacement is preferred over valve repairConsider TAVR, if mediastinum and cardiac anatomy is not amenable to open heart surgery
Conduction System Abnormalities
Prevalence Up to 5%
Description A-V nodal block (including high-degree block), bundle branch block (right > left), fascicular blockTachycardia can be persistent, usually a result of autonomic dysfunction, similar to denervated hearts. Persistent tachycardia could
increase risk of tachycardia-induced cardiomyopathy.
Diagnosis ECG, telemetry/ambulatory Holter monitor
Management Permanent pacemaker for high-degree A-V blockICD for life-threatening arrhythmia, sudden death, or secondary preventionConsider subpectoral approach for device implantation, if subcutaneous involvement of thoracic radiation
Cardiomyopathy
Prevalence Up to 10%
Description Diastolic dysfunction > systolic dysfunction; right ventricle > left ventricleDue to increased fibrosis in all 3 layers of the ventricular walls (epicardium, myocardium, and endocardium). May lead to restrictive
cardiomyopathy, and rarely to systolic dysfunction.
Diagnosis Echocardiogram, cardiac magnetic resonance imaging
Management Slow upward titration of ACEI, beta-blockade, and aldosterone inhibitors in patients with reduced left ventricular systolic function;optimize risk factors for diastolic dysfunction, exercise training
Inotropic support, VAD, heart transplantation
Data from Filopei et al. (49), Jaworski et al. (50), Zamorano et al. (139), Gonzaga et al. (149), Ong et al. (150), and Curigliano et al. (151).
ACC ¼ American College of Cardiology; ACEI ¼ angiotensin-converting enzyme inhibitors; AHA ¼ American Heart Association; AI ¼ aortic insufficiency; AS ¼ aortic stenosis;CAD ¼ coronary artery disease; CTA ¼ computed tomography angiography; ECG ¼ electrocardiogram; ICD ¼ implantable cardioverter-defibrillator; LAD ¼ left anteriordescending artery; LM ¼ left main artery; PR ¼ pulmonary regurgitation; RCA ¼ right coronary artery; RIHD ¼ radiation-induced heart disease; TAVR ¼ transcatheter aorticvalve replacement; TR ¼ tricuspid regurgitation; VAD ¼ ventricular assist device; other abbreviations as in Table 2.
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techniques, including deep inspiration breath-holdgating, accelerated partial breast irradiation, and useof modern 3-dimensional planning, came with lessradiation dosage and may ameliorate dreaded car-diovascular complications. Proton beam therapy is
purported to offer a great potential to minimize therisk of cardiovascular events by keeping the meanheart dose at #1 Gy (143). A Surveillance, Epidemi-ology, and End Results Program database study of29,102 patients diagnosed with breast cancer from
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2000 to 2009 showed a small increase in percuta-neous coronary intervention procedures afterradiation therapy: 5.5% versus 4.5% for left- versusright-sided breast cancer. In those who underwentpercutaneous coronary intervention, left-sidedbreast cancer carried a significantly higher risk ofcardiac mortality compared with right-sided breastcancer (144).
Cardiovascular risk factors, such as HTN, diabetesmellitus, dyslipidemia, and obesity, have been shownto significantly increase the risk of cardiovasculardisease and the associated complications of radio-therapy (145). The risks are magnified after chemo-therapy and/or with 2 or more cardiovascular riskfactors. Annual follow-up is recommended byordering ECG or echocardiogram as clinically indi-cated. The echocardiography consensus statementrecommends evaluation based on signs and symp-toms as stated in the previous text, and functionalnoninvasive stress testing within 5 to 10 years ofcompletion of chest radiation therapy (47). Perfusionabnormalities on single-photon emission computedtomography perfusion imaging does not alwayscorrelate with presence of CAD associated withradiotherapy (146). The role of coronary artery
calcium scoring as well as coronary CTA in screeningfor radiation-induced CAD has not been defined. In astudy by Hancock et al. (147), a significant proportionof patients who experienced a fatal myocardialinfarction because of radiation-induced CAD had noprior symptoms of angina or heart failure. Futureresearch efforts should aim to better identify thissubset of patients.
Autonomic dysfunction is sequelae of radiationtherapy (148). Elevated resting heart rate and heartrate recovery that worsened with time after radiationwere demonstrated in Hodgkin lymphoma survivorswho were referred for stress testing. Abnormal heartrate recovery was associated with an increase in all-cause mortality (age-adjusted hazard ratio: 4.60)(148). These patients could be managed with beta-blockers, such as atenolol. The diagnosis, preven-tion, and management for other radiation-inducedcardiovascular complications are summarized inTable 4.
ADDRESS FOR CORRESPONDENCE: Dr. Edward T.H.Yeh, Department of Medicine, University of Missouri,1 Hospital Drive, MA412, Columbia, Missouri 65212.E-mail: [email protected].
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KEY WORDS cancer therapy,cardiovascular complication, hypertension,radiation therapy, thromboembolism
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