Non-pegylated liposomial doxorubicin is less cardiotoxic than epirubicin in women with breast cancer: evidence from the LITE randomized study

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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
• gbiondizoccai_at_gmail.com
• for the LITE (Liposomial doxorubicinInvestigation
  al chemotherapyTissue 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 non-pegylated liposomal doxorubicin Chemotherapy without non-pegylated liposomal doxorubicin P value
Patients 29 23 -
Age (years) 46.98.5 45.87.7 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)
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BASELINE CHARACTERISTICS
Chemotherapy with non-pegylated liposomal doxorubicin Chemotherapy without non-pegylated liposomal doxorubicin P value
Height (cm) 161.68.6 162.46.2 0.691
Weight (kg) 64.911.9 64.214.1 0.851
Body surface area (m2) 1.710.16 1.680.20 0.520
Body mass index 24.64.6 24.54.8 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) 1.0
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CHEMOTHERAPY REGIMENS
NON-PEGYLATED LIPOSOMAL DOXORUBICIN-BASED REGIMEN EPIRUBICIN-BASED REGIMEN P value
Cumulative doses per cycle (mg/m2)
5-fluorouracyl - 833100 -
Anthracyclines 868 16720 lt0.001
Cyclophosphamide 86987 833100 0.208
Docetaxel 12912 - -
Cumulative doses per patient (mg/m2)
5-fluorouracyl - 5000600 -
Anthracyclines 51749 1000120 lt0.001
Cyclophosphamide 5034760 5000600 0.867
Docetaxel 77673 -
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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 (p0.012),
• end-diastolic diameter (-4.4 mm, p0.005),
• end-systolic diameter (-4.4 mm, p0.003).

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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
lt1.0 2 (8.7) 2 (10.0)
1.0-2.0 16 (69.6) 12 (60.0)
gt2.0 5 (21.7) 6 (30.0)
Septal Em/Am ratio 0.012
lt1.0 12 (52.2) 2 (10.0)
1.0-2.0 10 (43.5) 17 (85.0)
gt2.0 1 (4.3) 1 (5.0)
Lateral S wave (cm/s) 10.51.8 10.22.6 0.585
Septal S wave (cm/s) 13.92.5 18.822.8 0.297
RV S wave (cm/s) 1.30.5 1.30.4 0.309
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LOCF ECHOCARDIOGRAPHIC DATA
Chemotherapy with non-pegylated liposomal doxorubicin Chemotherapy without non-pegylated liposomal doxorubicin P value
Time to follow-up (months) 20.59.0 25.57.6 0.057
LVEF () 64.43.9 63.65.1 0.565
LV end-diastolic diameter (mm) 45.94.4 47.44.8 0.003
LV end-systolic diameter (mm) 27.43.4 29.15.0 0.005
E wave 71.214.8 78.413.3 0.104
A wave 65.015.9 69.018.9 0.102
E/A ratio 0.347
lt1.0 5 (21.7) 2 (10.0)
1.0-2.0 18 (78.3) 18 (85.0)
gt2.0 0 1 (5.0)
Deceleration time (ms) 217.634.0 218.537.6 0.935
at bivariate/interaction testing
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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 (p0.013) and end-systolic
  diameter (p0.017).

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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) 107.416.7 109.425.6 0.765
Creatinine (mg/dL) 0.80.2 0.80.1 0.383
Creatinine kinase (IU/L) 76.260.2 122.881.1 0.043
Cardiac troponin T (ng/mL) 0.0080.004 0.0110.005 0.032
NT-pro-BNP (ng/mL) 99.564.9 162.977.0 0.006
at bivariate/interaction testing
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CORRELATION ANALYSIS FOR TDI
LVEF () LV end-diastolic diameter LV end-systolic diameter E wave A wave Deceleration time
Lateral wall Em wave R0.403 P0.070 R-0.611 P0.003 R-0.544 P0.011 R0.399 P0.024 R-0.641 P0.010 R-0.493 P0.002
Lateral wall Am wave R0.258 P0.153 R0.480 P0.083 R0.412 P0.143 R-0.461 P0.004 R0.294 P0.308 R0.368 P0.025
Septal Em wave R0.195 P0.241 R-0.360 P0.119 R-0.423 P0.063 R0.441 P0.006 R-0.525 P0.002 R-0.386 P0.018
Septal Am wave R0.359 P0.027 R0.310 P0.058 R0.540 P0.046 R-0.438 P0.007 R0.509 P0.019 R0.218 P0.195
Lateral S wave R0.485 P0.002 R-0.446 P0.011 R-0.524 P0.015 R-0.112 P0.506 R-0.577 P0.031 R-0.458 P0.042
Septal S wave R0.560 Plt0.001 R-0.464 P0.008 R-0.704 P0.003 R0.323 P0.165 R-0.700 P0.004 R-0.340 P0.037
RV S wave R0.431 P0.008 R-0.290 P0.063 R-0.283 P0.070 R0.225 P0.224 R-0.473 P0.006 R-0.503 P0.024
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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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