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عجب عجاب لو ترى عيناكا ولعل ما في النفس من آياته *** حاولت تفسيرا لها أعياكا ً والكون مشحون بأسرار إذا *** ياشافي المراض : من أرداكا؟ قل للطبيب تخطفته يد الردى *** قل للمريض نجا وعوفي بعد ما *** عجزت فنون الطب : من عافاكا؟ من بالمنايا ياصحيح دهاكا؟ قل للصحيح يموت ل من علة ***للشاعر إبراهيم علي بديوي ) سوداني (
Chemotherapy Induced Cardotoxicity By Salah Mabrouk Assisstant lecturer of Medical Oncology SECI, Assiut University
Pathogenesis Multiple mechanisms appear to be involved1. Free Radical formation: –Enzymatic reaction in mitochondria. –Non-enzymatic reaction with Iron.2. Cytochrome C release apoptotic signal.3. Fewer antioxidant defenses, highly oxidative metabolism.4. Anthracycline affinity for cardiolipin, results in drug accumulation.5. Genetic polymorphisms in NAD(P)H oxidase and Doxorubicin efflux transporters
I- Free radical formation Enzymatic reaction in mitochondria Anthracyclines might undergo redox activation* through their interaction with several flavoprotein oxidoreductasesThis semiquinone can rapidly auto-oxidize using molecular oxygen (O2) as an electron acceptor, returning to the parent compound which is then available for a new redox cycle. This reaction leads to the formation of superoxide anion (O2−), Driven by superoxide dismutases (SOD), or spontaneously in acidic pH, superoxide anion is converted into hydrogen peroxide (H2O2) which, in the presence of traces of transition metals such as iron or copper, will be converted to the very reactive oxidizing species, hydroxyl radical (HO).
I- Free radical formation B- Non-enzymatic reaction with IronAnthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell.These complexes are apt to generate ROS in the presence or the absence of reducing components.
• Free radicals – Molecules containing an odd number of electrons • H2O2, hydroxyl radicals – Are highly reactive and damaging to tissues such as proteins, lipids, and nucleic acids, leading to modifications that are more likely to have an effect on the nucleus, the sarcoplasmic reticulum, or the mitochondria – cellular organelles that are in close proximity to the site of generation of ROS – Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal. Apoptosis hypothesis for the cardiotoxicity of anthracyclines. Apaf-1, Apoptotic protease activating factor-1; TNF/FAS-R, tumor necrosis factor/Fas receptor.
Risk factors for anthracycline-induced cardiotoxicityTreatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors (hypertension, diabetes, increasing total cholesterol, Obesity and Smoking) Gender, female sex.
Treatment related risk factors1- Cumulative dose• Can occur at any dose• Highly variable –Serious adverse effects may occur with small dose –>no adverse effects with very high dose• The standard cumulative dosesDoxorubicin : 450–550 mg/m2Epirubicin : 900–1000 mg/m2, why???
Induction Treatment Of AMLCumulative doses of anthracyclines•ADR & DNR: - 450 mg/m 2 if CP A is a ls o give n. - 550 mg/m 2 if not.•Ida rubicin: 75 mg/m 2 .•Mitoxa ntrone : 140 mg/m 2 .
Doxorubicin versus Epirubicin cumulative doseson a mg/m2 basis, Epirubicin is less cardiotoxic thandoxorubicin, and can, therefore, be administered athigher cumulative doses (up to a total of 900 mg/m2versus a total of 450 mg/m2 for doxorubicin beforecardiotoxicity limits further therapy).However, to achieve the same clinical benefit asdoxorubicin, epirubicin tends to be given at 25–50%higher doses, which potentially negates theadvantages of any higher cumulative dose threshold. van Dalenet al, Cochrane Database Syst Rev (2006)
Treatment related risk factors2- Dosing schedule• Single large dose > smaller, frequent dosing• The dose every 3 weeks > weekly doses• Bolus injection (peak levels) > continuous infusion
Treatment related risk factors3- History of mediastinal irradiation • Amplifies preexisting CAD • Exacerbation of vascular injury • Pericardial effusion • Pericardial fibrosis (restrictive disease) • Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications (cyclophosphomides, actinomycin D, bleomycin, cisplatin, methotraxate, trastuzumab)
Patient related risk factorsCumulative probability of developing doxorubicin-induced chronic heart failure  1- Age of patient Barrett-Lee, P. J. et al. Ann Oncol 2009 0:mdn728v1-728; doi:10.1093/annonc/mdn728
Patient related risk factors2- Preexisting cardiovascular disease or cardiac risk factorsHypertensionDiabetesincreasing total cholesterol)ObesitySmoking
Patient related risk factors3- Gender, female sex. Controversy?????
Type I and Type II Treatment-Related Cardiotoxicity Type I – Cumulative-dose related – Irreversible (cell death) – Typical biopsy changes – Doxorubicin is the model Type II – Not cumulative-dose related – Largely reversible (cell dysfunction) – Absence of anthracycline-like biopsy changes – Trastuzumab is the model
Stages• Acute Toxicity– Rare– Directly connected with the administration of a single dose or after a course of the antibiotic• Often asymptomatic and rarely fatal• Synergistic action between drug and hypokalemia• Tends to be reversible, and usually transient.• Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration. The most common ECG abnormalities reported are1. Nonspecific ST-T wave changes2. Decreased QRS voltage3. Sinus tachycardia4. Supraventricular tachyarrhythmia5. Premature ventricular and atrial contractions6. T-wave abnormalities7. QT interval prolongation8. Rarely, sudden death and life-threatening ventricular arrhythmias
• Subacute Toxicity– Occurs days to weeks post treatment– Rare and often asymptomatic– Includes 1. Toxic pericarditis 2. Toxic Myocarditis
Chronic CardiotoxicityInclude:1. Contractile dysfunction (CHRONIC CARDIOMYOPATHY)2. Heart failureThis is the most severe form of doxorubicincardiotoxicityCardiomyopathy is DOSE-RELATED.Morphologic damage increases progressivelywith increasing doses
Diagnosis and monitoringClinical pictureElectrocardiogram (ECG)EchocardiogramLaboratory markers • Troponin I & T • B-type natriuretic peptide (BNP)Cardiac biopsyMulti Gated Acquisition (MUGA) scan
EchocardiographyBenefitsProvides a wide spectrum of information on cardiacmorphology and functionDoes not expose patients to ionising radiationTissue Doppler imaging may improve detection of systolic anddiastolic dysfunctionLimitationsImage quality limits use in some patientsLVEF measurements time consuming and operator dependentNot sensitive for the early detection of preclinical cardiacdiseaseBoth FS( fractional shortening ) and LVEF are affected bypreload and afterload
Biomarkers 1. Cardiac troponin I (TnI&T), a contractile protein in the myocardium. 2. B-type natriuretic peptide (BNP), cardiac hormoneBenefits Troponin is a highly specific and sensitive biomarker for detection of myocardial damage Potentially useful screening tool It can be used to predict, at a very early stage, the development of future ventricular dysfunction, as well as its severity .Limitation Data regarding clinical value are limited
Magnetic resonance imagingBenefit Valuable tool to assess myocardial function and damageLimitations High costs of repeated examinations Limited availability
Computed tomographyBenefits Image quality similar to magnetic resonance imaging with Lower costLimitations High radiation dose Limited availability
ScintigraphyBenefit Sensitive method to detect myocyte damage in patients after doxorubicin therapyLimitation Larger prospective trials required to ascertain potential role
Multiple uptake gated acquisition scan (MUGA scan)Benefits Well-established and well-validated method to determine ejection fraction Can also assess regional wall motion and diastolic function (nonstandard)Limitations No information on valve function LVEF measurements are not sensitive for the early detection of preclinical cardiac disease
Prevention1. Screening for risk factors and prevention of cardiac events2. Dose limitation(< 550mg /m2 )3. Dosing Schedules modification4. Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)5. Use agents to prevent the cardiotoxicity6. Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment:1. ≤ 30%→Don’t give anthracyclines.2. 30%–50%→ give with monitoring of LVEF .3. ≥ 50% →repeat evaluation at 250–300 mg/m2 and again at 450 mg/m2 cumulative dose: • A 10% decrease in LVEF or a drop from ≥ 50% to ≤ 50% or from 30%–50% to ≤ 30% → stop anthracyclines
Dose limitationkeep the total lifetime cumulative dose belowthe recommended threshold.– 550 mg/m2 for doxorubicin– 900 mg/m2 for epirubicin.– When combined with paclitaxel, the cumulative doxorubicin dose should not exceed 360 mg/m2, and doxorubicin should be given before paclitaxel.
Dosing Schedules It should be as possible in:• Smaller, frequent dosing• Weekly doses• Continuous infusion, controversy???
Liposomal preparations of athracyclinesFigure : Liposomes – (left) = aqueous soluble drug encapsulated in aqueous compartment; (centre)= a hydrophobic drug in the liposome bilayer;(right) C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure : Accumulation of liposomes within solid tumours —(left) liposomes in normal tissue(right) liposome extravasation from the disorganisedtumour vasculature
There are two formulations of liposomalanthracyclines:1. Nonpegylated.2. Pegylated.N.B. : Peg =polyethylene glycolNon-toxic and non-immunogenicHydrophilic (aqueous-soluble)Highly flexible – provides for surface treatment or bioconjugation
Types of liposomal anthracyclines include: – Liposomal daunorubicin (DaunoXome®) – Pegylated liposomal doxorubicin (Doxil® or Caelyx ®)Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin, but with less cardiac toxicity.
Liposomal preparations of athracyclines (Caelyx®) Liposomes are preferentially taken up by tissues enriched in phagocytic reticuloendothelial cells In many trials, it appears to be as effective as standard doxorubicin Side effects:mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxane®)Dexrazoxane is an oral iron chelatorIt prevents the formation of the semiquinone-ironwhich leads to reactive oxygen productionIt has been tested in multiple clinical trials and hasbeen shown to reduce cardiac toxicityThe recommended dosage ratio ofdexrazoxane:doxorubicin is 10:1; doxorubicin shouldbe given within 30 minutes of giving dexrazoxane
Anthracycline Cardiotoxicity : Effects of Different Drugs, Scheduling, and Cardiac P rotection with Dexrazoxane 15 Epirubicin 1000 mg/m2 4 Epirubicin < 900 mg/m2 Dauno 1000 mg/m2 12 Dauno 500 mg/m2 1.5Doxo (400-499 mg/m2) + Dexrazoxane 1 Doxo low dose weekly > 600 mg/m2 5.4 Doxo bolus > 550 mg/m2 10 Doxo 1000 mg/m2 20 Doxo 500 mg/m2 7 0 5 10 15 20 25 CH (%) FHensley M et al J Clin Oncol 1999; 17(10):3333-3355 L
ASCO RecommendationsNot recommended for initial therapyBreast patients receiving more than 300mg/m2 of doxorubicinConsideration in patients with othermalignancies receiving more than 300 mg/m2of doxorubicin
Dexrazoxane and response to chemotherapySome data suggests that dexrazoxane maydecrease response to chemotherapyOne phase III trial published by Swain in1997 showed a significant decrease inresponse in the dexrazoxane group.There has been no difference in overallsurvival or progression free survival in thistrial
New prevention strategies In addition to new biomarkers for risk stratification, there are new potential approaches to prevention of anthracycline cardiotoxicity. These include1. Angiotensin-converting enzyme (ACE) inhibitors2. Angiotensin II receptor blockers (ARBs)3. Carvedilol.
ACE inhibitors They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress.Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF.Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockersARBs have been found to have intrinsicantioxidant and mediate a cardioprotectionNakamae and colleagues found that valsartansignificantly reduced changes in the leftventricular end-diastolic diameter.
Recovery of LV dysfunction with standard HF therapy Jensen, et al. Annals of Oncology. 2002. 13:499-709.
CarvedilolCarvedilol blocks beta1, beta2 and alpha1adrenoceptors and has potent antioxidant and anti-apoptetic properties. Early research in animals has shown that the use ofcarvedilol can prevent chemotherapeuticcardiotoxicity. Kalay and associates conducted the first humanclinical trial investigating the prophylactic use ofcarvedilol in this clinical setting.Further large randomised trials are needed???
5-FLUOROURACIL (5-FU)INCIDENCE: 1.6%–68%Onset:– in the first 72 hours of the initial treatment cycleRisk factors– Infusional administration– concurrent radiotherapy– pre-existing cardiac diseasePathogenesis:– coronary spasm
5-FLUOROURACIL (5-FU) Characteristics:• The second most common• Not dose related• Clinically ranges from angina pectoris within hours of a dose to myocardial infarction.• Capecitabine (Xeloda), the oral prodrug of 5- FU, is also reported to have similar cardiac toxic effects.
5-FLUOROURACIL (5-FU)Prevention and management.Careful clinical monitoringAdministration of 5-FU should be stopped immediately inpatients who develop a cardiac event.These patients should not be retreated with this agent.The role of prophylactic calcium channel blockers andnitrates remains unclear.Most patients respond to conservative antianginaltherapy and supportive care.
CYCLOPHOSPHAMIDEIncidence: • 25% • The life-threatening incidence is 5% to 10% of patients.Pathogenesis– It causes cardiac necrosis, may be related to acrolein– also cause ischemic cardiac toxicity.Risk factors– High dose regimens carry greater risk i.e after the use of very high does (120-140mg/kg) in preparation for bone marrow transplant.– Prior treatment with anthracycline or mediastinal irradiation
ManifestationMinor toxicities – Minor ECG changes • ST-T wave segment changes • Supraventricular arrhythmias– Pericarditis-with or without effusionSevere toxicities:– ECG voltage loss– Progressive heart failure– Pericarditis with or without tamponadeN.B,: Ifosfamide (Ifex) belongs to the same class of drugs and in one series isreported to have had significant cardiotoxicity in 17% of patients treated with the drug
CYCLOPHOSPHAMIDEPrevention and management.There are no established guidelines.Baseline MUGA scan or ECHO are done to measure leftejection fraction prior to transplant (Exclusion criteria – EF <50%)Close clinical monitoring of patients for signs and symptoms ofcongestive heart failure.If suspect, further therapy should be stopped and a completeevaluation, including ECG and an echocardiogram, performed toassess LVEF.These patients should be treated symptomatically for congestiveheart failure.Repeat treatment with an alkylating agent can be instituted onceLVEF returns to ≥ 50%.
Vinca alkaloids, bleomycin, and cisplatin Pathogenesis: – Vasospasm, in addition to electrolyte wasting with cisplatin. Manifestation: – MI – Arrhythmia with cisplatin – Autonomic cardioneuropathy with Vinca alkaloids – Raynaud phenomenon
TaxanesIncidence : 0.5%Pathogenesis:– It may be related to the cremaphor vehicle in paclitaxelManifestations:– Hypotension– Hypertension– Atrial and ventricular arrhythmia sp. Bradycardia– Myocardial infarctionTaxanes interfere with the metabolism and excretionof anthracycline and potentiate its cardiotoxicity.
TaxanesPrevention and management.No risk factors; however, patients with underlyingcardiac disease should be clinically monitoredAsymptomatic bradycardia→ No any intervention.neither be stopped nor the dose reduced in thesepatients.Symptomatic cardiac dysfunction → supportive tttSlow infusion of paclitaxel and doxorubicin orincreased time (24 h) between doxorubicin andpaclitaxel treatments decreased cardiotoxicity.Newer paclitaxel formulations, such as nanoparticlealbumin-bound paclitaxel
Trastuzumab Incidence:• 2% risk of developing cardiac dysfunction if used alone• Increased risk if given with doxorubicin andcyclophosphosphamide (16-27%)• Increased risk if given with paclitaxel (2-13%) • Manifestation: Cardiomyopathy Arrythmias
Trastuzumab (Herceptin®)• Risk factors for the cardiomyopathy: If given with doxorubicin If prior chest radiation therapy If diabetes If history heart valve disease If history heart artery disease • In other words, risk if prior heart disease • Not dose related.
Type Type I (myocardial damage) Type II (myocardial dysfunction) Agent Doxorubicin Trastuzumab Response May stabilize, but underlying damage appears to be permanent High likelihood of recovery to and irreversible; recurrence in Therapy months or years may be related to sequential cardiac stress Dose Cumulative, dose related Not dose related Free radical formation, oxidative Blocked ErbB2 signalingMechanism stress/damage Decreased ejection fraction by Decreased ejection fraction by Cardiac ultrasound or nuclear ultrasound or nuclear determination: testing determination: global decrease in global decrease in wall motion wall motion High probability of recurrent Effect of dysfunction that is progressive, Increasing evidence forRechallenge may result in intractable heart the relative safety of rechallenge; failure and death additional data neededEffect of late sequential High Low
Algorithm for continuation and discontinuation of trastuzumab based oninterval left ventricular ejection fraction (LVEF) assessments.
RITUXIMABIncidence: 25%Include:– Reversible or transient infusion-related hypotension– Arrhythmia– Acute myocardial infarction, ventricular fibrillation, and cardiogenic shock.Most of these reactions (80%) occur during thefirst infusion and may be associated with acytokine-release phenomenon
RITUXIMABPrevention and management.Discontinued in patients who develop significantarrhythmia or other severe cardiotoxicity.Careful monitoring during and after infusion iswarranted, especially in patients with pre-existingcardiac disease.It is recommended that patients avoid takingantihypertensive medication the morning of rituximabinfusion and delay taking these drugs until all transientcardiac side effects of rituximab have completelyresolved.
Sunitinib Sunitinib caused mitochondrial injury Release of cytochrome CCaspase activation ATP depletion Apoptosis Necrosis LV Myocyte loss dysfunction
Imatinib ER stress response JNK BAX activation Release of cytochrome CCaspase activation ATP depletion Apoptosis Necrosis LV Myocyte loss dysfunction
NilotinibQT prolongation ( 2.1%)sudden death (0.6% )Nilotinib prolongs the QT interval in a concentration-dependent manner.Rare– myocardial ischemia– atrial fibrillation– pericardial effusion– Cardiomegaly– bradycardia
DasatinibBoth pericardial effusions and cardiacfailure associated with dasatinib therapymay be caused by similar mechanismsto those associated with imatinibarrhythmia and palpitations. Severepericardial effusionsQT prolongation
Bevacizumab (Avastin®)Heart Attacks and Chemotherapy• May occur with bevacizumab (Avastin®) Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth.Avastin can cause heart attacks, angina, CHF, high blood pressure, strokes, and clotsRisk is 2%, especially if prior heart diseaseRisk is 14%, if given together with doxorubicin
Bevacizumab (Avastin®)• Heart toxicity can manifest as: Decreased muscle function (EF) Congestive heart failure Rhythm problems High blood levels of heart enzymes, such as troponin T and troponin I High blood levels of heart hormones, such as BNP Inflammation of the pericardium Inflammation of the heart muscle
ARSENIC TRIOXIDEArsenic trioxide is a novel agent currently used invarious hematologic malignancies.Incidence: 8-55%It is associated with prolongation of the QT interval andpotentially serious cardiac arrhythmia.Cardiotoxicity associated with arsenic trioxide is usuallyacute and occurs during or immediately after infusion.Hypokalemia or hypomagnesemia predisposes patientsto the cardiotoxic effects of arsenic trioxide.
Prevention and management. A baseline ECG should be done before starting therapy toassess the rhythm pattern and QT interval.This monitoring should be repeated weekly during inductionand biweekly during consolidation.If the QT interval is > 500 ms, the patient should beevaluated for potential risk versus benefit with furthertherapy.Prior to each infusion, electrolytes should be checked andcorrected if low. Recommended levels of potassium and magnesium are > 4mEq/L and > 1.8 mg/dL, respectively.Patients who develop cardiac symptoms should behospitalized with close cardiac monitoring and correction ofelectrolytes.Arsenic trioxide can usually be restarted once the QTcinterval is < 460 ms.
THALIDOMIDEThalidomide is an immunomodulatory agent currentlyused in the treatment of multiple myeloma and othermalignancies.It is rarely associated with any cardiovascular sideeffects, but recently, pulmonary hypertension hasoccurred in a patient receiving thalidomide .Both symptoms and pulmonary pressure resolvedafter cessation of thalidomide.The exact etiology of this phenomenon remainsunclear. Patients typically complain of shortness ofbreath and dyspnea on exertion.
THALIDOMIDEPrevention and management. High-resolution computed tomography (CT) and D-dimer should be performed to rule out pulmonary embolism. Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure. Further therapy with thalidomide should be stopped, as this is a reversible phenomenon
MITOXANTRONEThe recommended maximum cumulative dose of mitoxantrone is 140 mg/m2The cumulative dose is lower with prior anthracycline therapy
Other drugsBusulfan (Myleran): Cardiac tamponade or endomyocardial fibrosisBleomycin Pulmonary fibrosis:
Radiation Therapy• Factors that increase the risk of heart damage:1. Extent of the coronary arteries in the field2. Total radiation dose3. Radation dose per fraction4. Anterior fields versus tangential fields5. Patient age, especially under 20 years6. Concomitant doxorubicin7. Usual heart risk factors
Radiation Therapy• Coronary artery disease Increased risk if combined with doxorubicin• Pericarditis, acute or chronic• Pericarditis and myocarditis• Cardiomyopathy• Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy• Use cardiac blocking during therapy• Limit the concomitant use of doxorubicin (although it can be used before or after)• Minimize all other atherosclerotic risk factors