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

gbiondizoccai@gmail.com

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 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 -

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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).

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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

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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).

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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

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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

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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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Thank you for your attention

For any correspondence: gbiondizoccai@gmail.com

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