Transcript Diapositive 1 - metcardio.org

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]
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
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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).
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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.
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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
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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.
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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.
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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.
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BASELINE CHARACTERISTICS
Chemotherapy with
Chemotherapy without
non-pegylated
non-pegylated
P value
liposomal doxorubicin* liposomal doxorubicin*
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
Patients
0.434
Diabetes mellitus
2 (6.9%)
2 (8.7%)
Oral hypoglycemic agents
0
1 (4.3%)
Insulin
0
1 (4.3%)
Diet therapy
0.580
Smoking
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%)
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BASELINE CHARACTERISTICS
Chemotherapy with
Chemotherapy without
non-pegylated
non-pegylated
P value
liposomal doxorubicin* liposomal doxorubicin*
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
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%)
1.0
Medical therapy
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CHEMOTHERAPY REGIMENS
NON-PEGYLATED
EPIRUBICIN-BASED
LIPOSOMAL DOXORUBICIN-
REGIMEN
P value
BASED REGIMEN
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
-
-
5-fluorouracyl
-
5000±600
-
Anthracyclines
517±49
1000±120
<0.001
5034±760
5000±600
0.867
776±73
-
Cumulative doses per patient (mg/m2)
Cyclophosphamide
Docetaxel
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ECHOCARDIOGRAPHY RESULTS
• Repeated-measure analysis showed that a nonpegylated 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).
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LOCF TDI DATA
Chemotherapy with
Chemotherapy without
non-pegylated
non-pegylated liposomal
liposomal doxorubicin*
doxorubicin*
0.796
Lateral wall Em/Am ratio
2 (8.7%)
2 (10.0%)
1.0-2.0
16 (69.6%)
12 (60.0%)
>2.0
5 (21.7%)
6 (30.0%)
<1.0
P value
0.012
Septal Em/Am ratio
<1.0
12 (52.2%)
2 (10.0%)
1.0-2.0
10 (43.5%)
17 (85.0%)
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
>2.0
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LOCF ECHOCARDIOGRAPHIC DATA
Chemotherapy with
Chemotherapy without
non-pegylated
non-pegylated liposomal
liposomal doxorubicin*
doxorubicin*
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
0.347
E/A ratio
<1.0
5 (21.7%)
2 (10.0%)
1.0-2.0
18 (78.3%)
18 (85.0%)
0
1 (5.0%)
217.6±34.0
218.5±37.6
>2.0
Deceleration time (ms)
P value*
*at bivariate/interaction testing
0.935
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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).
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PEAK FOLLOW-UP BIOMARKERS
Glucose (mg/dL)
Creatinine (mg/dL)
Creatinine kinase (IU/L)
Cardiac troponin T (ng/mL)
NT-pro-BNP (ng/mL)
P value*
Chemotherapy with non-
Chemotherapy without
pegylated liposomal
non-pegylated liposomal
doxorubicin*
doxorubicin*
107.4±16.7
109.4±25.6
0.765
0.8±0.2
0.8±0.1
0.383
76.2±60.2
122.8±81.1
0.043
0.008±0.004
0.011±0.005
0.032
99.5±64.9
162.9±77.0
0.006
*at bivariate/interaction testing
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CORRELATION ANALYSIS FOR TDI
LVEF (%)
LV enddiastolic
diameter
LV endsystolic
diameter
E wave
Lateral wall Em wave
R=0.403
P=0.070
R=-0.611
P=0.003
R=-0.544
P=0.011
R=0.399
P=0.024
R=-0.641
P=0.010
R=-0.493
P=0.002
Lateral wall Am wave
R=0.258
P=0.153
R=0.480
P=0.083
R=0.412
P=0.143
R=-0.461
P=0.004
R=0.294
P=0.308
R=0.368
P=0.025
Septal Em wave
R=0.195
P=0.241
R=-0.360
P=0.119
R=-0.423
P=0.063
R=0.441
P=0.006
R=-0.525
P=0.002
R=-0.386
P=0.018
Septal Am wave
R=0.359
P=0.027
R=0.310
P=0.058
R=0.540
P=0.046
R=-0.438
P=0.007
R=0.509
P=0.019
R=0.218
P=0.195
Lateral S wave
R=0.485
P=0.002
R=-0.446
P=0.011
R=-0.524
P=0.015
R=-0.112
P=0.506
R=-0.577
P=0.031
R=-0.458
P=0.042
Septal S wave
R=0.560
P<0.001
R=-0.464
P=0.008
R=-0.704
P=0.003
R=0.323
P=0.165
R=-0.700
P=0.004
R=-0.340
P=0.037
RV S wave
R=0.431
P=0.008
R=-0.290
P=0.063
R=-0.283
P=0.070
R=0.225
P=0.224
R=-0.473
P=0.006
R=-0.503
P=0.024
A wave
Deceleration
time
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MULTIVARIABLE ANALYSIS FOR
ECHOCARDIOGRAPHIC RESULTS
LVEF (%)
LV end-diastolic diameter
LV end-systolic diameter
E wave
A wave
Deceleration time
Lateral wall Em wave
Lateral wall Am wave
Septal Em wave
Septal Am wave
Lateral S wave
Septal S wave
RV S wave
P value for chemotherapy regimen
0.892
0.013
0.017
0.939
0.896
0.618
0.892
0.934
0.604
0.358
0.400
0.559
0.481
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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.
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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.
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