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Comparison 1 Doxorubicin versus epirubicin, Outcome 1 Clinical heart failure.
Figures and Tables -
Analysis 1.1

Comparison 1 Doxorubicin versus epirubicin, Outcome 1 Clinical heart failure.

Comparison 1 Doxorubicin versus epirubicin, Outcome 2 Tumour response.
Figures and Tables -
Analysis 1.2

Comparison 1 Doxorubicin versus epirubicin, Outcome 2 Tumour response.

Comparison 1 Doxorubicin versus epirubicin, Outcome 3 Progression‐free survival.
Figures and Tables -
Analysis 1.3

Comparison 1 Doxorubicin versus epirubicin, Outcome 3 Progression‐free survival.

Comparison 1 Doxorubicin versus epirubicin, Outcome 4 Overall survival.
Figures and Tables -
Analysis 1.4

Comparison 1 Doxorubicin versus epirubicin, Outcome 4 Overall survival.

Comparison 1 Doxorubicin versus epirubicin, Outcome 5 Adverse effects: leukopenia grade 3 or 4.
Figures and Tables -
Analysis 1.5

Comparison 1 Doxorubicin versus epirubicin, Outcome 5 Adverse effects: leukopenia grade 3 or 4.

Comparison 1 Doxorubicin versus epirubicin, Outcome 6 Adverse effects: nausea / vomiting grade 3 or 4.
Figures and Tables -
Analysis 1.6

Comparison 1 Doxorubicin versus epirubicin, Outcome 6 Adverse effects: nausea / vomiting grade 3 or 4.

Comparison 1 Doxorubicin versus epirubicin, Outcome 7 Adverse effects: alopecia grade 3 or 4.
Figures and Tables -
Analysis 1.7

Comparison 1 Doxorubicin versus epirubicin, Outcome 7 Adverse effects: alopecia grade 3 or 4.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 1 Clinical heart failure.
Figures and Tables -
Analysis 2.1

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 1 Clinical heart failure.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 2 Heart failure combined.
Figures and Tables -
Analysis 2.2

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 2 Heart failure combined.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 3 Tumour response.
Figures and Tables -
Analysis 2.3

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 3 Tumour response.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 4 Progression‐free survival.
Figures and Tables -
Analysis 2.4

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 4 Progression‐free survival.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 5 Overall survival.
Figures and Tables -
Analysis 2.5

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 5 Overall survival.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 6 Adverse effects: anaemia grade >=3.
Figures and Tables -
Analysis 2.6

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 6 Adverse effects: anaemia grade >=3.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 7 Adverse effects: thrombocytopenia grade >=3.
Figures and Tables -
Analysis 2.7

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 7 Adverse effects: thrombocytopenia grade >=3.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 8 Adverse effects: neutropenia grade 4.
Figures and Tables -
Analysis 2.8

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 8 Adverse effects: neutropenia grade 4.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 9 Adverse effects: neutropenic fever (fever >=38, neutropenia grade 4, IV antibiotics and/or hospitalisation).
Figures and Tables -
Analysis 2.9

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 9 Adverse effects: neutropenic fever (fever >=38, neutropenia grade 4, IV antibiotics and/or hospitalisation).

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 10 Adverse effects: nausea/vomiting grade >=3.
Figures and Tables -
Analysis 2.10

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 10 Adverse effects: nausea/vomiting grade >=3.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 11 Adverse effects: stomatitis/mucositis grade >=3.
Figures and Tables -
Analysis 2.11

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 11 Adverse effects: stomatitis/mucositis grade >=3.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 12 Adverse effects: diarrhoea grade >=3.
Figures and Tables -
Analysis 2.12

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 12 Adverse effects: diarrhoea grade >=3.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 13 Adverse effects: asthenia/fatigue grade 3.
Figures and Tables -
Analysis 2.13

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 13 Adverse effects: asthenia/fatigue grade 3.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 14 Adverse effects: cutaneous grade 3.
Figures and Tables -
Analysis 2.14

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 14 Adverse effects: cutaneous grade 3.

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 15 Adverse effects: infection grade >=3.
Figures and Tables -
Analysis 2.15

Comparison 2 Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet), Outcome 15 Adverse effects: infection grade >=3.

Table 1. Criteria list for the assessment of methodological quality of included studies

Item ID

Description

Implementation

Patient selection

Note: all criteria were scored yes (+), no (‐) or unclear (?)

a

Was the allocation of participants to treatment groups randomised?

A random (unpredictable) assignment sequence must have been applied.

b

Was the treatment allocation concealed?

Allocation must have been performed by a person not responsible for determining eligibility of patients for inclusion.

Interventions

c

Was the care provider blinded to the intervention?

Adequate information about blinding must have been provided.

d

Was the patient blinded to the intervention?

Adequate information about blinding must have been provided.

Outcome assessments (for each outcome separately)

e

Was the outcome assessor blinded to the intervention?

Adequate information about blinding must have been provided.

f

Were patients lost to follow‐up described and acceptable?

For each outcome measure the number of evaluated patients must be mentioned. If the percentage of non‐evaluable patients does not exceed 20% a "yes" (+) is scored.

Figures and Tables -
Table 1. Criteria list for the assessment of methodological quality of included studies
Table 2. Quality assessment of included studies

Study

a

b

c

d

e

f

Intervention

Batist 2001

+

?

?

?

Clinical heart failure, subclinical heart failure, tumour response, PFS: +; adverse effects: ?

Clinical heart failure, subclinical heart failure, tumour response, PFS, OS, adverse effects: +

Doxorubicin versus liposomal‐encapsulated doxorubicin (myocet).

Brambilla 1986

+

?

?

?

Clinical heart failure, subclinical heart failure, tumour response, PFS: ?

Clinical heart failure: ?; subclinical heart failure, PFS: ‐; tumour response, OS: +

Doxorubicin versus epirubicin.

Chan 2004

+

?

?

?

Clinical heart failure, subclinical heart failure, tumour response, PFS, adverse effects: ?

Clinical heart failure, subclinical heart failure, tumour response, PFS, OS, adverse effects: +

Epirubicin versus liposomal‐encapsulated doxorubicin (myocet).

FESG 1998

+

?

?

?

Clinical heart failure, tumour response, PFS, adverse effects: ?

Clinical heart failure, tumour response, PFS, OS: +; adverse effects: ‐

Doxorubicin versus epirubicin.

Gasparini 1991

+

?

?

?

Clinical heart failure, tumour response, PFS, adverse effects: ?

Clinical heart failure, tumour response, PFS, OS, adverse effects: +

Doxorubicin versus epirubicin.

Harris 2002

+

?

?

?

Clinical heart failure, adverse effects: ?; subclinical heart failure, tumour response, PFS: +

Clinical heart failure, subclinical heart failure, tumour response, PFS, OS, adverse effects: +

Doxorubicin versus liposomal‐encapsulated doxorubicin (myocet).

IMBSWE 1988

+

?

?

?

Clinical heart failure, tumour response, adverse effects: ?

Clinical heart failure, tumour response, PFS, OS, adverse effects (with the exeption of alopecia: ‐): +

Doxorubicin versus epirubicin.

Mouridsen 1984

+

?

?

?

Clinical heart failure, tumour response, PFS: ?

Clinical heart failure, tumour response, PFS, OS: ‐

Doxorubicin versus epirubicin.

Figures and Tables -
Table 2. Quality assessment of included studies
Table 3. Descriptive results of survival in epirubicin vs doxorubicin

Study

Progr‐free survival

Overall survival

Brambilla 1986

Not evaluated in review.

Median: in epirubicin group > 16 months (7‐25+), in doxorubicin group > 18 months (6‐28+) (no significant difference)

FESG 1988

Median: in epirubicin group 220 days (30‐1230), in doxorubicin group 270 days (30‐1380) (no significant difference)

Median: in epirubicin group 450 days (20‐1582), in doxorubicin group 530 days (36‐1681) (no significant difference)

Gasparini 1991

In epirubicin group range 2 to 11 months, in doxorubicin group 3 to 14 months (P=0.91)

Median: in epirubicin group 12 months, in doxorubicin group 11 months (no significant difference)

IMBSWE 1988

Median: in epirubicin group 273 days, in doxorubicin group 314 days (P=0.59)

Median: in epirubicin group 591 days, in doxorubicin group 613 days (P=0.75)

Mouridsen 1987

No significant differences between both treatment groups (P=0.41)

No significant differences between both treatment groups (P=0.90)

Figures and Tables -
Table 3. Descriptive results of survival in epirubicin vs doxorubicin
Table 4. Adverse effects: epirubicin versus liposomal‐encapsulated doxorubicin (myocet)

Adverse effect

n/N myocet pts

n/N epirubicin pts

RR (95% CI)

P‐value

Anaemia grade >=3

19/80

11/80

1.73 (0.88 ‐ 3.39)

0.11

Thrombocytopenia grade >=3

3/80

2/80

1.50 (0.26 ‐ 8.74)

0.65

Neutropenia grade 4

66/80

52/80

1.17 (1.05 ‐ 1.53)

0.01

Prolonged neutropenia grade 4 (>=7 days)

20/80

24/80

0.83 (0.50 ‐ 1.38)

0.48

Febrile neutropenia (fever >=38 C, neutropenia grade 4, IV antibiotics and/or hospitalisation)

4/80

1/80

4.00 (0.46 to 35.01)

0.21

Infection grade >=3

5/80

1/80

5.00 (0.60 ‐ 41.85)

0.14

Nausea / vomiting grade >=3

16/80

15/80

1.07 (0.57 ‐ 2.01)

0.84

Stomatitis / mucositis grade 3

5/80

0/80

11.00 (0.62 ‐ 195.69)

0.10

Diarrhoea grade 3

1/80

1/80

1.00 (0.06 ‐ 15.71)

1.00

Asthenia / fatigue grade 3

0/80

1/80

0.33 (0.01 ‐ 8.06)

0.50

Cutaneous grade 3

0/80

1/80

0.33 (0.01 ‐ 8.06)

0.50

Injection site toxicity grade 3

0/80

1/80

0.33 (0.01 ‐ 8.06)

0.50

Figures and Tables -
Table 4. Adverse effects: epirubicin versus liposomal‐encapsulated doxorubicin (myocet)
Comparison 1. Doxorubicin versus epirubicin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical heart failure Show forest plot

5

1036

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.12, 1.11]

2 Tumour response Show forest plot

5

1036

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.82, 1.08]

3 Progression‐free survival Show forest plot

2

Hazard ratio (Random, 95% CI)

1.05 [0.76, 1.44]

4 Overall survival Show forest plot

2

Hazard ratio (Random, 95% CI)

0.95 [0.65, 1.39]

5 Adverse effects: leukopenia grade 3 or 4 Show forest plot

2

546

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.31, 0.80]

6 Adverse effects: nausea / vomiting grade 3 or 4 Show forest plot

2

546

Risk Ratio (M‐H, Random, 95% CI)

0.77 [0.61, 0.97]

7 Adverse effects: alopecia grade 3 or 4 Show forest plot

3

796

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.52, 1.38]

Figures and Tables -
Comparison 1. Doxorubicin versus epirubicin
Comparison 2. Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical heart failure Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

0.20 [0.05, 0.75]

2 Heart failure combined Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

0.38 [0.24, 0.59]

3 Tumour response Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.80, 1.26]

4 Progression‐free survival Show forest plot

2

hazard ratio (Random, 95% CI)

1.01 [0.83, 1.24]

5 Overall survival Show forest plot

2

hazard ratio (Random, 95% CI)

1.12 [0.83, 1.53]

6 Adverse effects: anaemia grade >=3 Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.61, 1.13]

7 Adverse effects: thrombocytopenia grade >=3 Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

1.09 [0.60, 1.97]

8 Adverse effects: neutropenia grade 4 Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.72, 0.94]

9 Adverse effects: neutropenic fever (fever >=38, neutropenia grade 4, IV antibiotics and/or hospitalisation) Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.53, 1.45]

10 Adverse effects: nausea/vomiting grade >=3 Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.44, 0.98]

11 Adverse effects: stomatitis/mucositis grade >=3 Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

0.58 [0.32, 1.05]

12 Adverse effects: diarrhoea grade >=3 Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.12, 0.87]

13 Adverse effects: asthenia/fatigue grade 3 Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.52, 1.41]

14 Adverse effects: cutaneous grade 3 Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.08, 5.45]

15 Adverse effects: infection grade >=3 Show forest plot

2

521

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.21, 2.89]

Figures and Tables -
Comparison 2. Conventional doxorubicin versus liposomal‐encapsulated doxorubicin (myocet)