1. Cardio-toxicity of anti-cancer therapyBy
Baher Ahmed Elgohari
Assistant lecture of Clinical Oncology and Nuclear Medicine
Mansoura University
27\12\2015

2. Introduction:
Cancer treatment had made a dramatic advances in the management and in the prognosis improvement of the patient.They are not lacking a harmful effect on different body systems as on the cardiovascular system.
Cardio-toxicity is one of the most significant adverse effects of cancer treatment, and is responsible for considerable morbidity and mortality. The most frequent and serious is heart failure with ventricular systolic dysfunction.
Other toxic effects include hypertension, thromboembolic disease, pericardial disease, arrhythmias and myocardial ischemia.

3. Definition of Cardio-toxicity
Cardiomyopathy characterised by a decrease in LVEF that was either global or more severe in the septum
Symptoms of CHF
Associated signs of CHF, including S3 gallop,tachycardia, or both.
Decline in LVEF of at least 5% to less than 55% with signs
or symptoms of CHF, or a decline in LVEF of at least 10% to below 55% without signs or symptoms

4. What are the anti-cancer therapies associated with cardio-toxicity?
Chemotherapeutic Agents
Targeted Therapies
Hormonal Therapies as SERMs and AIs
Radiation Therapy

5. A.Chemotherapeutic Agents
Anthracycline (Doxorubicin,Epirubicin,Mitoxantrone)
Alkylating Agents (Cyclophosphamide,Cisplatin,Ifosfamide)
Antimetabolites (5-Fluorouracil,Capecitabine)
Antimicrotubules (Paclitaxol,Doxcetaxol)
Vince Alkaloids (Vincristine, Vinblastine,Vinoralbine)
Others (Etoposide)

6. B. Targeted Therapies Trastuzumab Lapatinib Bevacizumab Sunitinib
Sorafinib
Imatinib
Rituximab
Erlotinib

7. Type I and Type II Drugs Type I drugs as Anthracyclines:
Related to cell lose .
Cumulative dose .
Irreversible damage .
Type II drugs as Trastuzumab:
Related to cellular dysfunction(mitochondrial and protein alternation)
not cumulative dose related .
Reversible damage.

8. Anthracyclines and cytotoxic agents with cumulative dose related cardiotoxicity (Type I)
A. Anthracycline induced cardiomyopathy
Characteristics and course
1.Acute :Within the first week ,in the form of transient depression in myocardial contractility,usually reversible when discontinue treatment
2.Early-onset, chronic progressive ,<1 year after the completion of treatment, in the form of dilated cardiomyopathy, usually progressive
3.Late-onset, chronic progressive cardio-toxicity ≥1 year after the completion of anthracycline treatment , in the form of dilated cardiomyopathy, usually progressive

9. Risk factors for anthracycline-induced cardiotoxicity
Treatment related:
Cumulative dose
Intravenous bolus administration
Higher single doses
History of prior irradiation
The use of other concomitant agents known to have cardiotoxicity including cyclophosphamide, trastuzumab and paclitaxel
Increased length of time since completion of chemotherapy
Patient related:
Female gender
Underlying CV disease
Age (young and elderly)
Increase in cardiac biomarkers, as troponins and natriuretic peptides, during and after administration ,
Hypertension, diabetes mellitus, preexisting cardiac disease,
Trisomy 21; African American ancestry; HFE gene mutation (hemochromatosis )

10. Molecular Mechanisms of Anthracycline Cardio-toxicity:
Anthracyclines are DNA intercalating agents that form a ternary complex with topoisomerase 2 which is an enzyme transiently breaks the DNA backbone to untangle the super- coiled DNA complex in a process required for transcription, replication, and recombinationDNA damage response, eventually leads to mitochondrial dysfunction and accumulation of reactive oxygen species.
Also cause the formation of reactive oxygen species inside the cardio-myocyte, especially in mitochondria.
Anthracyclines induce the intracellular accumulation of iron and form complexes with it, further inducing the production of free oxygen radicals via metal- catalyzed oxidoreductions.
Alter the activity of cardiac fibroblasts and the turnover of the myocardial extracellular matrix. Doxorubicin enhances the expression of MMP2 and MMP9, thus weakening the collagenous matrix and contributing to myocardial remodelling.
Other cellular changes depleted cardiac stem cells , impaired DNA synthesis , impaired cell signaling that triggers cell death , altered gene expression.
Anthracyclines also induce a local immune response.

11. The recommended maximum lifetime cumulative dose for :
The risk of clinical cardiotoxicity increases with a cumulative dose. Studies evaluating cumulative probability of doxorubicin-induced HF have found rates in the range of 3%– 5% with 400 mg/m2, 7%–26% at 550 mg/m2 and 18%–48% at 700 mg/m2.
The recommended maximum lifetime cumulative dose for :
Doxorubicin is 400–550 mg/m2.
Epirubicin mg/m2 .
Mitoxantrone 160 mg/m2.

12. Monoclonal antibodies and targeted agents not associated with cumulative dose-related cardio-toxicity: type II agents
Trastuzumab, a humanized monoclonal antibody against the extracellular domain IV of HER/ErbB2 arise from impairment of contractility rather than loss of myocytes, and the release of troponin
Pertuzumab is more recent anti-HER2 antibody that binds to the domain II of the receptor.
A third HER2- targeting agent is lapatinib, a small molecule inhibitor of the intracellular tyrosine kinase domain of HER2.
Trastuzumab only disrupts ligand-independent HER2 signaling;
Pertuzumab interferes with the formation of ligand- induced HER2 heterodimers.
Lapatinib a ects both ligand- triggered and ligand-independent HER2 signaling .
Intrestingly, lapatinib seems to be less toxic than trastuzumab.
Cardio-toxicity of HER2-targeting drugs has been ascribed to the inhibition of fundamental actions of neuregulin-1 in the heart . Neuregulin-1 acts on cardiac cells via ErbB4/ErbB4 homodimers and ErbB4/ErbB2 heterodimers to elicit protective pathways in response to stress .
By blocking neuregulin-1 effects in the heart, HER2 inhibitors may make it more vulnerable to noxious stimuli.

15. Antiangiogenic Drugs:
Induce type II cardiotoxicity
In particular, bevacizumab, sorafenib, and sunitinib are now widely used in oncology; more recently, pazopanib.
All these drugs interfere with vascular endothelial growth factor (VEGF) signaling.
As VEGF contributes to cardiomyocyte function and growth on the one hand and to the integrity and expansion of the coronary and systemic circulation on the other one , it is not surprising that VEGF antagonism may lead to cardiovascular side effects, principally hypertension, thromboembolism, LV dysfunction, and HF .

17. Cardiac Ischemia Alkylating agents : Antimetabolites:
LVD has been associated with cyclophosphamide therapy in 7%–28% of patients. In addition, there are reports of pericardial effusions and myopericarditis . The risk of cardio-toxicity appears to be dose related (≥150 mg/kg and 1.5 g/m2/day).
Another alkylating agent, Ifosfamide, can induce the onset of HF, with a dose–response trend (doses ≥12.5 g/ m2)
Antimetabolites:
The incidence of cardiac events associated with 5-FU varies in the literature ranging anywhere from 1% to 68% . Cardiac toxicity typically occurs with early onset (within 2– 5 days of starting therapy). Ischemic electrocardiogram (ECG) changes have been reported in up to 68% . Coronary artery thrombosis, arteritis and vasospasm secondary to drug exposure have been proposed as the most likely underlying mechanisms.
Microtubules Inhibitors:
Paclitaxel administration has been associated with cases of myocardial ischemia and infarction.

18. Hormonal therapy: Targeted agents:
Aromatase inhibitors (AIs) are an established component of the treatment of postmenopausal hormone receptor-positive breast cancer. Cardiac events, including myocardial infarction and cardiac failure, have been reported at low differential changes in lipid profile have been proposed as an etiology for these observations; however, a strong signal linking (AIs) and relevant changes in lipid levels are lacking .
SERMs (Tamoxifen) linked with cardiac events by thromboembolic events
Targeted agents:
Whether novel molecular therapies increase the risk of cardiac ischemia is not clear. In an evaluation of the VEGF receptor antagonist sunitinib, 18% of 68 patients studied were noted to have an increases in cardiac troponins, possibly serving as a biomarker of myocyte damage

19. Early detection of anticancer drug-induced cardiotoxicity(LVD)
1.Echocardiography:
Advantage:
Non-invasive and low cost
Morphological and functional assessment: systolic (LVEF, LV fractional shortening, systolic wall thickness) and diastolic parameters (E/A ratio, isovolumic relaxation time, pulmonary venous flow pattern)
Information on valve structure and pericardium
Disadvantage:
Operator-dependent

20. 2. Multiple-gated acquasition scan (MUGA)
Advantage:
Well validated for determining LVEF
Low intra- and inter-observer variability High reproducibility
Disadvantage:
Underestimates ventricular volumes Overestimates LVEF in smaller ventricles (children and women)
Radiation exposure
Low temporal and spatial resolution
No information on valve function
Little information on diastolic function
Limited predictive value for early detection of subclinical damage

21. 3. Cardiac MRI
Advantage:
High reproducibility
Functional and myocardial perfusion assessment Identification of post-MI scarring and viable myocardium
Tissue characterisation
Disadvantage:
High cost
Especially when repeat exams are required
Limited availability

22. Advantage: 4.Electrocardiogram Non-invasive
Low cost for arrhythmia screening
Prolonged QT interval is recognized as a marker of cardiotoxicity
Disadvantage :
No information on LVEF
QT values subject to problems with measurement, analysis and interpretation, and to intra- and inter-observer variability

23. 5. Noval Technique:
Contrast Echocardiography
Real-time three- dimensional (3D) echocardiography
Doppler and strain rate imaging
Cardiac markers :
More sensitive ,more specific.
Example :Troponin help earliest phase, long before any reduction in LVEF has occurred.

24. Cardio-protection of anthracycline type I toxicity
Reduction of risk factors (stop smoking,control dyslipidemia)
Cumulative dose limitation
Modification of infusion schedules
Alternate molecules:
Epirubicin
Pegylated and non pegylated liposomal formulations
Reduce cardiac wall stress:
control hypertension
beta blockers
ACEIs,ARBs
Carvedilol: blocker of beta1,beta 2 and alpha 1 adrenoreceptor ,antioxidant effect and antiapoptotic effect

25. 6.Cardio-protection:
Dexrazoxane :
EDTA-like chelating agent, is also cardio-protective.
Indicated only in metastatic breast cancer received >300mg\m2 doxorubicin.
Not recommended for use in women who are initiating treatment with doxorubicin.
Given at a dose of 10 times the anthracycline dose and within 30 minutes of anthracycline administration.

27. Management of trastuzumab cardiotoxicity
This involves two aspects:
Stopping and restarting rule
Treatment of cardiac disfunction

29. All patients with HF and an LVEF <40% should be treated with an ACE-I in combination with a BB unless a specific contraindication exists
ACE-Is should be used in all asymptomatic patients with LVD and an ejection fraction <40%
ACE-I should be considered if LVEF is <50%.
BB should be considered in all patients with asymptomatic LVD and an LVEF <40%

30. Management of ischemic events related to antimetabolites and paclitaxol:
Baseline ECG evaluation
Frequent vital sign monitoring is recommended during chemotherapeutic agent infusion
Monitoring of BNB and troponin I

31. Management to patient receiving anti-angiogenic agents:
Individuals should be considered at risk in case of:
Systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg; diabetes mellitus; established CV disease including any history of ischemic stroke, cerebral hemorrhage or transient ischemic attack; myocardial infarction, angina, coronary revascularization, or HF; peripheral artery disease; subclinical organ damage previously documented by ECG or echocardiogram revealing left ventricular hypertrophy; cigarette smoking; dyslipidemia.
Repeated BP measurements are recommended.
Aggressive management of BP elevations is recommended to prevent clinically limiting complications,preferred antihypertensives are ACEIs and dihydropyridine calcium channel blockers.
There are no evidence-based guidelines

32. cardio-toxicity induced by radiotherapy
This was evident in many trials especially in breast cancer and hodgkin lymphoma
Risk factors:
Dose >30–35 Gy
Dose per fraction >2 Gy
Large volume of irradiated heart
Younger age at exposure
Longer time since exposure
Use of cytotoxic chemotherapy
Endocrine therapy or trastuzumab
Presence of other risk factors such as diabetes, hypertension, dyslipidaemias, obesity, smoking .

33. Various structures are affected by radiotherapy
Coronary arteries :premature coronary arteries,atherosclerosis of left anterior descending
Pericarditis:acute or chronic (6-12 months after radiotherapy)
Myocarditis
Valvular stenotic or regurgitant lesion especially mitral and aortic valve
Fibrosis of conducting system
Indirect effect due to irradiation of adjacent structures as lung and mediastinal fibrosis,hypothyroidism.

34. Recommendation to reduce cardiac toxicity during radiotherapy:
Use of modern radiotherapy technique (3D- conformal,IMRT)
Use of proper type of radiation and energy
Cardiac sparing lead block
Normal tissue complication probability(NTCP):V25<10%
Maximum heart distance if no 3D conformal for every 1 cm increase there is an increase of mean heart dose by 2.9%

35. Treatment as non irradiated heart .
Monitor of cardiac function :no current recommendations.

36. Thank You