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Non-pegylated liposomial doxorubicin is less cardiotoxic than epirubicin in women with breast cancer: evidence from the LITE randomized study. Giuseppe Biondi Zoccai, MD University of Modena and Reggio Emilia [email protected] - PowerPoint PPT Presentation
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Non-pegylated liposomial doxorubicin is less cardiotoxic than epirubicin in
women with breast cancer: evidence from the LITE randomized study
Giuseppe Biondi Zoccai, MDUniversity of Modena and Reggio Emilia
for the LITE (Liposomial doxorubicin–Investigational chemotherapy–Tissue doppler imaging Evaluation) Investigators: Marzia LOTRIONTE, MD, Giovanni
PALAZZONI, MD, Antonio ABBATE, MD, Eugenia DE MARCO, MD, Rosaria NATALI, MD, Silvia DI PERSIO, RN, and Francesco LOPERFIDO, MD
1
BACKGROUND• Cardiomyopathy following anthracycline chemotherapy
may have ominous clinical implications in cancer patients. • With the improved success of cancer treatments, more
cases of late chemotherapy-related cardiac morbidity and mortality are seen.
• The efficacy and safety of chemotherapy regimens is however often assessed only on the basis of cancer-free survival and on immediate chemotherapy toxicity (which does not take into account late cardiac [or pulmonary] toxicity).
2
BACKGROUND (2)• In terms of cardiac toxicity, subclinical toxicity may precede
clinically evident toxicity by several years, and thus clinically-based approaches are highly insensitive to assess cardiac toxicity in the short- to mid-term.
• Anthracyclines are available in different formulations, and are administered as part of complex chemotherapy regimens in which multiple drugs with potential cardiotoxicity are given.
• Liposomial anthracyclines have the potential for more selective uptake by cancer cells and reduced cardiac toxicity.
3
BACKGROUND (3)• We thus designed an independent randomized clinical
trial to specifically address cardiac safety using a highly sensitive approach (serial echocardioDoppler studies) and comparing a non-pegylated liposomial doxorubicin (Myocet)-based regimen vs a standard epirubicin-based as neoadjuvant or adjuvant strategies in women with non-metastatic breast cancer.
• ClinicalTrials.gov identifier: NCT00531973
4
METHODS• Women with non-metastatic breast cancer and indication
to anthracycline chemotherapy for neoadjuvant or adjuvant therapy were randomized to a non-pegylated liposomial doxorubicin-based chemotherapy regimen or a standard epirubicin-based chemotherapy regimen (and radiotherapy as per standard of care at our center).
• Baseline, post-chemotherapy and follow-up Doppler echocardiogram included standard left ventricular systolic and diastolic parameters, as well as tissue Doppler imaging (TDI) systolic and diastolic parameters.
5
METHODS (2)• The primary end-points of the study were the changes from
baseline to mid-term follow-up of TDI systolic function parameters, given their superior sensitivity and spatial resolution.
• Additional data on standard systolic and diastolic echocardiographic parameters were also appraised.
• Comparisons between treatment groups were based on Student t test or ANOVA for repeated measures for continuous variables, and 2 or Fisher exact tests for categorical variables. Last observation carried forward (LOCF) method was used for echocardiographic data.
6
RESULTS• A total of 52 women were included, 29 randomized to
non-pegylated liposomial doxorubicin and 23 to epirubicin, who were followed for an average of 23 months since starting chemotherapy.
7
BASELINE CHARACTERISTICSChemotherapy with
non-pegylated
liposomal doxorubicin*
Chemotherapy without
non-pegylated
liposomal doxorubicin*
P value
Patients 29 23 -
Age (years) 46.9±8.5 45.8±7.7 0.633
Family history of heart disease 7 (24.1%) 8 (34.8%) 0.400
Arterial hypertension 6 (20.7%) 3 (13.0%) 0.714
Dyslipidemia 12 (41.4%) 7 (30.4%) 0.416
Diabetes mellitus 0.434
Diet therapy 2 (6.9%) 2 (8.7%)
Oral hypoglycemic agents 0 1 (4.3%)
Insulin 0 1 (4.3%)
Smoking 0.580
Current smoker 5 (17.2%) 6 (26.1%)
Former smoker 3 (10.3%) 1 (4.3%)
Never a smoker 21 (72.4%) 16 (69.6%)8
BASELINE CHARACTERISTICSChemotherapy with
non-pegylated
liposomal doxorubicin*
Chemotherapy without
non-pegylated
liposomal doxorubicin*
P value
Height (cm) 161.6±8.6 162.4±6.2 0.691
Weight (kg) 64.9±11.9 64.2±14.1 0.851
Body surface area (m2) 1.71±0.16 1.68±0.20 0.520
Body mass index 24.6±4.6 24.5±4.8 0.934
Baseline ST-T changes at ECG 6 (20.7%) 1 (4.3%) 0.117
Medical therapy
Angiotensin-converting enzyme inhibiotors 1 (3.4%) 0 1.0
Angiotensin II receptor blockers 3 (10.3%) 2 (8.7%) 1.0
Antidepressants 1 (3.4%) 0 1.0
Aspirin 1 (3.4%) 1 (4.3%) 1.0
Beta-blockers 4 (13.8%) 2 (8.7%) 0.682
Calcium channel antagonists 1 (3.4%) 0 1.0
Statins 1 (3.4%) 1 (4.3%) 1.09
CHEMOTHERAPY REGIMENS
NON-PEGYLATED
LIPOSOMAL DOXORUBICIN-
BASED REGIMEN
EPIRUBICIN-BASED
REGIMEN
P value
Cumulative doses per cycle (mg/m2)
5-fluorouracyl - 833±100 -
Anthracyclines 86±8 167±20 <0.001
Cyclophosphamide 869±87 833±100 0.208
Docetaxel 129±12 - -
Cumulative doses per patient (mg/m2)
5-fluorouracyl - 5000±600 -
Anthracyclines 517±49 1000±120 <0.001
Cyclophosphamide 5034±760 5000±600 0.867
Docetaxel 776±73 -
10
ECHOCARDIOGRAPHY RESULTS• Repeated-measure analysis showed that a non-
pegylated liposomial doxorubicin (Myocet)-based chemotherapy regimen was associated with more favorable changes in:– TDI septal Em/Am (p=0.012),– end-diastolic diameter (-4.4 mm, p=0.005), – end-systolic diameter (-4.4 mm, p=0.003).
11
LOCF TDI DATA
Chemotherapy with
non-pegylated
liposomal doxorubicin*
Chemotherapy without
non-pegylated liposomal
doxorubicin*
P value
Lateral wall Em/Am ratio 0.796
<1.0 2 (8.7%) 2 (10.0%)
1.0-2.0 16 (69.6%) 12 (60.0%)
>2.0 5 (21.7%) 6 (30.0%)
Septal Em/Am ratio 0.012
<1.0 12 (52.2%) 2 (10.0%)
1.0-2.0 10 (43.5%) 17 (85.0%)
>2.0 1 (4.3%) 1 (5.0%)
Lateral S wave (cm/s) 10.5±1.8 10.2±2.6 0.585
Septal S wave (cm/s) 13.9±2.5 18.8±22.8 0.297
RV S wave (cm/s) 1.3±0.5 1.3±0.4 0.309
12
LOCF ECHOCARDIOGRAPHIC DATAChemotherapy with
non-pegylated
liposomal doxorubicin*
Chemotherapy without
non-pegylated liposomal
doxorubicin*
P value*
Time to follow-up (months) 20.5±9.0 25.5±7.6 0.057
LVEF (%) 64.4±3.9 63.6±5.1 0.565
LV end-diastolic diameter (mm) 45.9±4.4 47.4±4.8 0.003
LV end-systolic diameter (mm) 27.4±3.4 29.1±5.0 0.005
E wave 71.2±14.8 78.4±13.3 0.104
A wave 65.0±15.9 69.0±18.9 0.102
E/A ratio 0.347
<1.0 5 (21.7%) 2 (10.0%)
1.0-2.0 18 (78.3%) 18 (85.0%)
>2.0 0 1 (5.0%)
Deceleration time (ms) 217.6±34.0 218.5±37.6 0.935
*at bivariate/interaction testing13
RESULTS• At multivariable analysis concomitantly adjusting for
age, diabetes mellitus, and follow-up duration, chemotherapy including non- pegylated liposomial doxorubicin was associated with more beneficial changes in left ventricular end-diastolic diameter (p=0.013) and end-systolic diameter (p=0.017).
14
PEAK FOLLOW-UP BIOMARKERS
Chemotherapy with non-
pegylated liposomal
doxorubicin*
Chemotherapy without
non-pegylated liposomal
doxorubicin*
P value*
Glucose (mg/dL) 107.4±16.7 109.4±25.6 0.765
Creatinine (mg/dL) 0.8±0.2 0.8±0.1 0.383
Creatinine kinase (IU/L) 76.2±60.2 122.8±81.1 0.043
Cardiac troponin T (ng/mL) 0.008±0.004 0.011±0.005 0.032
NT-pro-BNP (ng/mL) 99.5±64.9 162.9±77.0 0.006
*at bivariate/interaction testing15
CORRELATION ANALYSIS FOR TDI
LVEF (%)LV end-diastolic diameter
LV end-systolic
diameterE wave A wave Deceleration
time
Lateral wall Em wave R=0.403 P=0.070
R=-0.611 P=0.003
R=-0.544 P=0.011
R=0.399P=0.024
R=-0.641 P=0.010
R=-0.493P=0.002
Lateral wall Am wave R=0.258P=0.153
R=0.480P=0.083
R=0.412 P=0.143
R=-0.461P=0.004
R=0.294P=0.308
R=0.368 P=0.025
Septal Em wave R=0.195P=0.241
R=-0.360P=0.119
R=-0.423P=0.063
R=0.441P=0.006
R=-0.525P=0.002
R=-0.386P=0.018
Septal Am wave R=0.359P=0.027
R=0.310P=0.058
R=0.540P=0.046
R=-0.438P=0.007
R=0.509P=0.019
R=0.218P=0.195
Lateral S waveR=0.485P=0.002
R=-0.446P=0.011
R=-0.524P=0.015
R=-0.112P=0.506
R=-0.577P=0.031
R=-0.458P=0.042
Septal S waveR=0.560P<0.001
R=-0.464P=0.008
R=-0.704P=0.003
R=0.323P=0.165
R=-0.700P=0.004
R=-0.340P=0.037
RV S waveR=0.431P=0.008
R=-0.290P=0.063
R=-0.283P=0.070
R=0.225P=0.224
R=-0.473P=0.006
R=-0.503P=0.024
16
MULTIVARIABLE ANALYSIS FOR ECHOCARDIOGRAPHIC RESULTS
P value for chemotherapy regimen
LVEF (%) 0.892
LV end-diastolic diameter 0.013
LV end-systolic diameter 0.017
E wave 0.939
A wave 0.896
Deceleration time 0.618
Lateral wall Em wave 0.892
Lateral wall Am wave 0.934
Septal Em wave 0.604
Septal Am wave 0.358
Lateral S wave 0.400
Septal S wave 0.559
RV S wave 0.481
17
LIMITATIONS• The study compares 2 different chemotherapy
regimens based on liposomial doxorubicin or epirubicin, but differences include also doses, and concomitant treatments
• Data on oncologic outcomes are still under collection and not included in the present report.
• The limited sample size strongly limits the statistical power for comparisons of cardiovascular or oncologic outcomes.
18
CONCLUSIONS• When sensitive tests are used, subclinical
differences in cardiac toxicity can be measured. These differences are small but likely to have a clinical impact over the long-term.
• Some differences in TDI can be seen earlier than changes in global LV systolic function (measured as LVEF), however TDI changes do not occur before changes in LV volumes, and are not independent of changes in LV volumes.
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CONCLUSIONS (2)
• In this pilot clinical trial comparing two different chemotherapy strategy in women with breast cancer, the regimen based on non-pegylated liposomial doxorubicin appeared to be less cardiotoxic than the epirubicin-based treatment.
20
Thank you for your attention
For any correspondence: [email protected]
For these and further slides on these topics feel free to visit the metcardio.org website:http://www.metcardio.org/slides.html