amp monitoring of chemotherapy Cardiovascular complications of Chemotherapy LV dysfunction Vasospasm and ischemia Hypertension VTE Conduction disease Arrhythmias Cardiac effects of Chemotherapy ID: 184771
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Slide1
MUGA scans &monitoring of chemotherapySlide2Slide3
Cardiovascular complications of ChemotherapySlide4Slide5
LV dysfunctionVasospasm and ischemiaHypertensionVTEConduction diseaseArrhythmias
Cardiac effects of ChemotherapySlide6
Chemotherapeutic agents associated with LV dysfunction
Anthracyclines
Doxorubicin (Adriamycin)
Epirubicin (Ellence)
Idarubicin
(
Idamycin
PFS)
Alkylating agents
Cyclophosphamide (Cytoxan)
Ifosfamide
(
Ifex
) AntimetabolitesClofarabine (Clolar) Antimicrotubule agentsDocetaxel (Taxotere)
Monoclonal antibody-based tyrosine kinase inhibitorsBevacizumab (Avastin)Trastuzumab (Herceptin) Proteasome inhibitorBortezomib (Velcade) Small molecule tyrosine kinase inhibitorsDasatinib (Sprycel)Imatinib mesylate (Gleevec)Lapatinib (Tykerb)Sunitinib (Sutent)
Yeh et al, Circulation 2004Slide7
Chemotherapeutic agents associated with Ischemia
Antimetabolites
Capecitabine (Xeloda)
Flurouracil (Adrucil)
Mab based-TKI
Bevacizumab (Avastin)
Small molecule TKI
Erlotinib (Tarceva)
Sorafenib (Nexavar)
Antimicrotubule agents
Paclitaxel (Taxol)
Docetaxel (Taxotere)Slide8
Chemotherapeutic agents associated with Hypertension
Mab based-TKI
Bevacizumab (Avastin)
Small molecule TKI
Sorafenib (Nexavar)
Sunitinib (Sutent)Slide9
Chemotherapeutic agents associated with venous thromboembolism
Alkylating agents
Cisplatin
Angiogenesis inhibitors
Lenalidomide (Revlimid)
Thalidomide (Thalomid)
Small molecule TKI
Erlotinib (Tarceva)
Histone deacetylase inhibitor
Vorinostat (Zolinza)Slide10
Chemotherapeutic agents associated with conduction disease/bradycardia
Angiogenesis inhibitors
Thalidomide (Thalomid)
Antimicrotubule agents
Paclitaxel (Taxol)Slide11
Chemotherapeutic agents associated with QTc prolongation
Histone deacetylase inhibitor
Vorinostat (Zolinza)
Misc
Arsenic trioxide
Small molecule tyrosine kinase inhibitors
Dasatinib (Sprycel)
Lapatinib (Tykerb)
Nilotinib (Tasigna)Slide12
LV dysfunction and chemotherapySlide13
Type 1
Type II
Doxorubicin
Trastuzumab
Cellular destruction
Cellular dysfunction
Cumulative /Dose dependent
Non-cumulative
/Non dose dependent
Usually irreversible
Usually reversible.
Types of
cardiotoxicity
Ewer 2008Slide14
AnthracyclinesSlide15
Dose related toxicity
Incidence of Doxorubicin-induced HF is
3% to 5% with 400 mg/m2,
7% to 26% at 550 mg/m2,
18% to 48% at 700 mg/m2
Maximum lifetime cumulative dose for doxorubicin is 400 to 550 mg/m2 .
Epirubicin
or
Idarubicin
appear to have less incidence of HF Slide16
Risk factors for anthracycline toxicity
Cumulative dose;
intravenous bolus administration;
higher single doses;
history of prior irradiation;
the use of other concomitant cardiotoxic agents
female gender;
Underlying cardiovascular disease; age (young and old age
increased length of time since anthracycline completionSlide17
Anthracycline
CardiotoxicitySlide18Slide19
TrastuzumabSlide20
Source and actions of NRG-1 in the heart
Lemmens, K., K. Doggen, and G.W. De Keulenaer, Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation, 2007. 116(8): p. 954-60.Slide21
Electron microscopy evaluation of
endomyocardial biopsy on a patient who
developed Trastuzumab-induced cardiac
toxicity.
Guarneri, V., et al., Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience. J Clin Oncol, 2006. 24(25): p. 4107-15.
Enlarged and edematous vacuole
Pleomorphic mitochondrion
Z band widening and splittingSlide22
Wide variation in definition of cardiotoxicity.
Wide range of incidence of asymptomatic LV dysfunction (3.2% - 33%)Slide23
Copyright ©2010 American College of Cardiology Foundation. Restrictions may apply.
Cardinale, D. et al. J Am Coll Cardiol 2010;55:213-220
Percentage of Responders According to the Time Elapsed From AC Administration and Start of HF TherapySlide24
Guidelines….(depends on who you ask)Slide25
So, how do you define cardiotoxicity?Slide26
The oncologist’s perspectiveSlide27Slide28Slide29Slide30
ACC/AHA?Slide31
Stages in the evolution of HF and recommended therapy by stage.
et al. Circulation 2001;104:2996-3007
Copyright © American Heart AssociationSlide32
ACC/AHA/ASNC guidelines for the use of radionuclide imaging for diagnosis of causes of cardiomyopathy
Circulation 2003, 108:1404-1418Slide33
Normal LVEF >50% at baselineBaseline MUGA within first 100 mg/m2 in all patients. Next MUGA 200-300 mg/m2. Next MUGA 450 mg /m2(400 mg/m2 if high risk- Cyclophosphamide, CAD, abnormal ECG, mediastinal radiation)
MUGA prior to every dose >450 mg/m2
DISCONTINUE IF
EF reduces ≥ 10% from baseline AND reaches ≤ 50%
ANSC - monitoring Doxorubicin therapy with serial resting RNA
Schwartz RD et al, Amer J. Med. 82;1109 -1118, 1987Slide34
Abnormal LVEF <50% at baselineBaseline MUGA within first 100 mg/m2 in all patients. Serial MUGAs prior to each subsequent dose. DISCONTINUE if LVEF ≥10% from baseline or absolute LVEF ≤ 30%
ASNC - monitoring Doxorubicin therapy with serial resting RNASlide35
Monitoring
Assessment of EF at 0, 3, 6, 9, 12 months
MUGA or Echo with Tissue Doppler assessment
Use the same modality in follow up
If >10% absolute LVEF reduction but >50% EF, please follow up with yearly echos .
If >10% reduction to <50%, please institute heart failure therapy and refer to a Cardiologist.
If hypertension or DM coexist, please consider ACEI as first line. Slide36Slide37
MUGAs are not perfectSlide38
LVEF = (ED counts – Background counts)- (ES counts – Background Counts)
(ED counts – Background counts)
Calculating EFSlide39
DigoxinHeparinHydralazinePenicillinQuinidinePrazosinMethyldopaQuinidine
Poor RBC
labellingSlide40
Inclusion of LA in ES ROIInclusion of ascending aorta in ROIBackground too dark (falsely low counts)Anterior wall motion abnormality. Temporal smoothing of LV volume curve.
Understimation
of EFSlide41
Exclusion of LV apex in ES ROIBackground counts too high. Inferoposterior wall motion abnormality. Overestimation of EFSlide42
MUGA
Pros
Cons
Easy
Inaccurate in many situations (Arrhythmias, drugs, inaccurate ROIs)
“Highly reproducible”
Radiation exposure.
“Low
interobserver
and
intraobserver
variability. “
Costly –
Medicare $291.3SPECT MUGA $759Standardized against contrast ventriculography EF. Low temporal and spatial resolution.Slide43
Radionuclide diastolic assessment
No change in EF , but indices of early diastolic function, showed a significant decrease.
1/3 peak filling rate/ the end-diastolic count (EDC) (1/3 PFR/EDC)
1/3 filling fraction (1/3 FF).
Delayed time to peak filling – (Normal is less than 180 ms)
Angiology 1999, Jan;50(1):37-45.
Early detection of anthracycline-induced cardiotoxicity by radionuclide angiocardiography.
Suzuki J, et alSlide44
Salerno M. Multi-modality imaging of diastolic function. J Nucl Cardiol. 2010;17:316–27
Count time curves from a patient prior to (
A
) and after (
B
) anthracycline treatment, with marked reduction in the slope of the curve (TPFR) representing abnormal diastolic filling Slide45
3 D TTESlide46Slide47
Ho C Y , Solomon S D Circulation 2006;113:e396-e398
Copyright © American Heart AssociationSlide48
Early detection using TDI: Clinical studies
42 Women , mean age 47± 9 years
25 % women developed Trastuzumab mediated cardiac toxicity at 3 months.
TDI parameters: (S′), early diastolic (e′), and late diastolic (a′) velocities.
Doppler-independent strainSlide49
Significant difference in the lateral S′ between normals and pts with LV dysfn.Both peak global longitudinal and radial strain decreased as early as 3 months in the CM group Biomarkers did not predict injuryMUGA EF was decreased in all 10 at 6 month follow up.
ResultsSlide50
www.clinicaltrials.gov>28 open studies looking at monitoring of cardiotoxicity. 11 looking at CMRI with 4 actively recruiting.
Future directions