Scolaris Content Display Scolaris Content Display

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison: 1 Analysis of Overall Survival, outcome: 1.1 OS ‐ all ‐ same recruitment period between the 2 arms (HD9).
Figures and Tables -
Figure 3

Forest plot of comparison: 1 Analysis of Overall Survival, outcome: 1.1 OS ‐ all ‐ same recruitment period between the 2 arms (HD9).

Forest plot of comparison: 2 Analysis of Progression Free Survival, outcome: 2.1 PFS ‐ all ‐ same recruitment period between the 2 arms (HD9).
Figures and Tables -
Figure 4

Forest plot of comparison: 2 Analysis of Progression Free Survival, outcome: 2.1 PFS ‐ all ‐ same recruitment period between the 2 arms (HD9).

Comparison 1 Analysis overall survival, Outcome 1 OS ‐ all ‐ same recruitment period between the 2 arms (HD9).
Figures and Tables -
Analysis 1.1

Comparison 1 Analysis overall survival, Outcome 1 OS ‐ all ‐ same recruitment period between the 2 arms (HD9).

Comparison 1 Analysis overall survival, Outcome 2 OS subgrouped by stage of disease.
Figures and Tables -
Analysis 1.2

Comparison 1 Analysis overall survival, Outcome 2 OS subgrouped by stage of disease.

Comparison 1 Analysis overall survival, Outcome 3 OS subgrouped by treatment.
Figures and Tables -
Analysis 1.3

Comparison 1 Analysis overall survival, Outcome 3 OS subgrouped by treatment.

Comparison 1 Analysis overall survival, Outcome 4 OS subgrouped by number of cycles of escalated BEACOPP.
Figures and Tables -
Analysis 1.4

Comparison 1 Analysis overall survival, Outcome 4 OS subgrouped by number of cycles of escalated BEACOPP.

Comparison 1 Analysis overall survival, Outcome 5 OS subgrouped by length of follow‐up.
Figures and Tables -
Analysis 1.5

Comparison 1 Analysis overall survival, Outcome 5 OS subgrouped by length of follow‐up.

Comparison 1 Analysis overall survival, Outcome 6 OS subgrouped by radiotherapy.
Figures and Tables -
Analysis 1.6

Comparison 1 Analysis overall survival, Outcome 6 OS subgrouped by radiotherapy.

Comparison 1 Analysis overall survival, Outcome 7 OS ‐ all recruited patients (HD9) with potential risk of bias due to different time periods of recruitment.
Figures and Tables -
Analysis 1.7

Comparison 1 Analysis overall survival, Outcome 7 OS ‐ all recruited patients (HD9) with potential risk of bias due to different time periods of recruitment.

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 1 PFS ‐ all ‐ same recruitment period between the 2 arms (HD9).
Figures and Tables -
Analysis 2.1

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 1 PFS ‐ all ‐ same recruitment period between the 2 arms (HD9).

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 2 PFS subgrouped by stage of disease.
Figures and Tables -
Analysis 2.2

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 2 PFS subgrouped by stage of disease.

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 3 PFS subgrouped by treatment.
Figures and Tables -
Analysis 2.3

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 3 PFS subgrouped by treatment.

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 4 PFS subgrouped by number of cycles of escalated BEACOPP.
Figures and Tables -
Analysis 2.4

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 4 PFS subgrouped by number of cycles of escalated BEACOPP.

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 5 PFS subgrouped by length of follow‐up.
Figures and Tables -
Analysis 2.5

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 5 PFS subgrouped by length of follow‐up.

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 6 PFS subgrouped by type of radiotherapy.
Figures and Tables -
Analysis 2.6

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 6 PFS subgrouped by type of radiotherapy.

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 7 PFS ‐ all recruited patients (HD9) with potential risk of bias due to different time periods of recruitment.
Figures and Tables -
Analysis 2.7

Comparison 2 Analysis of progression‐free survival (PFS), Outcome 7 PFS ‐ all recruited patients (HD9) with potential risk of bias due to different time periods of recruitment.

Comparison 3 Analysis of treatment‐related mortality, Outcome 1 Treatment‐related mortality.
Figures and Tables -
Analysis 3.1

Comparison 3 Analysis of treatment‐related mortality, Outcome 1 Treatment‐related mortality.

Comparison 3 Analysis of treatment‐related mortality, Outcome 2 TRM subgrouped by stage of disease.
Figures and Tables -
Analysis 3.2

Comparison 3 Analysis of treatment‐related mortality, Outcome 2 TRM subgrouped by stage of disease.

Comparison 3 Analysis of treatment‐related mortality, Outcome 3 TRM subgrouped by number of cycles of escalated BEACOPP.
Figures and Tables -
Analysis 3.3

Comparison 3 Analysis of treatment‐related mortality, Outcome 3 TRM subgrouped by number of cycles of escalated BEACOPP.

Comparison 3 Analysis of treatment‐related mortality, Outcome 4 TRM subgrouped by type of radiotherapy.
Figures and Tables -
Analysis 3.4

Comparison 3 Analysis of treatment‐related mortality, Outcome 4 TRM subgrouped by type of radiotherapy.

Comparison 4 Analysis of secondary malignancies, Outcome 1 Secondary malignancies.
Figures and Tables -
Analysis 4.1

Comparison 4 Analysis of secondary malignancies, Outcome 1 Secondary malignancies.

Comparison 4 Analysis of secondary malignancies, Outcome 2 SM subgrouped by stage of disease.
Figures and Tables -
Analysis 4.2

Comparison 4 Analysis of secondary malignancies, Outcome 2 SM subgrouped by stage of disease.

Comparison 4 Analysis of secondary malignancies, Outcome 3 SM subgrouped by treatment.
Figures and Tables -
Analysis 4.3

Comparison 4 Analysis of secondary malignancies, Outcome 3 SM subgrouped by treatment.

Comparison 4 Analysis of secondary malignancies, Outcome 4 SM subgrouped by number of cycles of escalated BEACOPP.
Figures and Tables -
Analysis 4.4

Comparison 4 Analysis of secondary malignancies, Outcome 4 SM subgrouped by number of cycles of escalated BEACOPP.

Comparison 4 Analysis of secondary malignancies, Outcome 5 SM subgrouped by type of radiotherapy.
Figures and Tables -
Analysis 4.5

Comparison 4 Analysis of secondary malignancies, Outcome 5 SM subgrouped by type of radiotherapy.

Comparison 4 Analysis of secondary malignancies, Outcome 6 SM subgrouped by length of follow‐up.
Figures and Tables -
Analysis 4.6

Comparison 4 Analysis of secondary malignancies, Outcome 6 SM subgrouped by length of follow‐up.

Comparison 5 Analysis of AML or MDS, Outcome 1 AML or MDS.
Figures and Tables -
Analysis 5.1

Comparison 5 Analysis of AML or MDS, Outcome 1 AML or MDS.

Comparison 5 Analysis of AML or MDS, Outcome 2 AML/MDS subgrouped by stage of disease.
Figures and Tables -
Analysis 5.2

Comparison 5 Analysis of AML or MDS, Outcome 2 AML/MDS subgrouped by stage of disease.

Comparison 5 Analysis of AML or MDS, Outcome 3 AML/MDS subgrouped by treatment.
Figures and Tables -
Analysis 5.3

Comparison 5 Analysis of AML or MDS, Outcome 3 AML/MDS subgrouped by treatment.

Comparison 5 Analysis of AML or MDS, Outcome 4 AML/MDS subgrouped by number of cycles of escalated BEACOPP.
Figures and Tables -
Analysis 5.4

Comparison 5 Analysis of AML or MDS, Outcome 4 AML/MDS subgrouped by number of cycles of escalated BEACOPP.

Comparison 5 Analysis of AML or MDS, Outcome 5 AML/MDS subgrouped by type of radiotherapy.
Figures and Tables -
Analysis 5.5

Comparison 5 Analysis of AML or MDS, Outcome 5 AML/MDS subgrouped by type of radiotherapy.

Comparison 5 Analysis of AML or MDS, Outcome 6 AML/MDS subgrouped by length of follow‐up.
Figures and Tables -
Analysis 5.6

Comparison 5 Analysis of AML or MDS, Outcome 6 AML/MDS subgrouped by length of follow‐up.

Comparison 6 Analysis of fertility, Outcome 1 Secondary amenorrhoea.
Figures and Tables -
Analysis 6.1

Comparison 6 Analysis of fertility, Outcome 1 Secondary amenorrhoea.

Comparison 7 Analysis of anaemia, Outcome 1 Anaemia.
Figures and Tables -
Analysis 7.1

Comparison 7 Analysis of anaemia, Outcome 1 Anaemia.

Comparison 8 Analysis of infection, Outcome 1 Infection.
Figures and Tables -
Analysis 8.1

Comparison 8 Analysis of infection, Outcome 1 Infection.

Comparison 9 Analysis of neutropenia, Outcome 1 Neutropenia.
Figures and Tables -
Analysis 9.1

Comparison 9 Analysis of neutropenia, Outcome 1 Neutropenia.

Comparison 10 Analysis of thrombocytopenia, Outcome 1 Thrombocytopenia.
Figures and Tables -
Analysis 10.1

Comparison 10 Analysis of thrombocytopenia, Outcome 1 Thrombocytopenia.

Comparison 11 Analysis of alopecia, Outcome 1 Alopecia.
Figures and Tables -
Analysis 11.1

Comparison 11 Analysis of alopecia, Outcome 1 Alopecia.

Comparison 12 Analysis of constipation, Outcome 1 Constipation.
Figures and Tables -
Analysis 12.1

Comparison 12 Analysis of constipation, Outcome 1 Constipation.

Comparison 13 Analysis of mucositis, Outcome 1 Mucositis.
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Analysis 13.1

Comparison 13 Analysis of mucositis, Outcome 1 Mucositis.

Comparison 14 Analysis of nausea/vomiting, Outcome 1 Nausea/vomiting.
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Analysis 14.1

Comparison 14 Analysis of nausea/vomiting, Outcome 1 Nausea/vomiting.

Comparison 15 Analysis of neurologic toxicity, Outcome 1 Neurologic.
Figures and Tables -
Analysis 15.1

Comparison 15 Analysis of neurologic toxicity, Outcome 1 Neurologic.

Comparison 16 Analysis of pain, Outcome 1 Pain.
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Analysis 16.1

Comparison 16 Analysis of pain, Outcome 1 Pain.

Comparison 17 Analysis of respiratory, Outcome 1 Respiratory.
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Analysis 17.1

Comparison 17 Analysis of respiratory, Outcome 1 Respiratory.

Comparison 18 Analysis of skin, Outcome 1 Skin.
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Analysis 18.1

Comparison 18 Analysis of skin, Outcome 1 Skin.

Comparison 19 Analysis of heart disease, Outcome 1 heart.
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Analysis 19.1

Comparison 19 Analysis of heart disease, Outcome 1 heart.

Comparison 20 Analysis of freedom from first progression, Outcome 1 Freedom from first progression.
Figures and Tables -
Analysis 20.1

Comparison 20 Analysis of freedom from first progression, Outcome 1 Freedom from first progression.

Comparison 21 Analysis of complete response (CR) rate, Outcome 1 CR.
Figures and Tables -
Analysis 21.1

Comparison 21 Analysis of complete response (CR) rate, Outcome 1 CR.

Summary of findings for the main comparison. Escalated BEACOPP versus chemotherapy including ABVD

Comparison of chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for people with early unfavourable or advanced stage Hodgkin lymphoma

Patient or population: Patients with early unfavourable or advanced stage HL
Setting: Hospitals
Intervention: BEACOPP
Comparison: ABVD

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with ABVD

Risk with BEACOPP

Mortality
follow up: median 5 years

Study population1

HR 0.74
(0.57 to 0.97)

3142
(5 RCTs)

⊕⊕⊕⊕
HIGH

To provide correct results by using the GRADE software, we calculated mortality instead of overall survival

120 per 1000

90 per 1000
(70 to 117)

Progression, relapse or death
follow up: median 5 years

Study population3

HR 0.54
(0.45 to 0.64)

3142
(5 RCTs)

⊕⊕⊕⊝
MODERATE3

To provide correct results by using the GRADE software, we calculated progression, relapse or death instead of progression‐free survival

250 per 1000

144 per 1000
(121 to 168)

Adverse event: treatment‐related mortality

follow up median 5 years

Study population

RR 2.15
(0.93 to 4.95)

2700
(4 RCTs)

⊕⊕⊝⊝
LOW 4

5 per 1000

11 per 1000
(5 to 25)

Adverse event: secondary malignancies

follow up median 5 years

Study population

RR 1.00
(0.68 to 1.48)

3332
(5 RCTs)

⊕⊕⊝⊝
LOW 5, 6

29 per 1000

29 per 1000
(20 to 42)

Adverse event: secondary malignancies: AML or MDS

Study population

RR 3.90
(1.36 to 11.21)

3332
(5 RCTs)

⊕⊕⊝⊝
LOW 4

3 per 1000

10 per 1000
(3 to 29)

Adverse event: infertility (secondary amenorrhoea)

follow up median 5 years

Study population

RR 1.37
(0.83 to 2.26)

106
(1 RCT)

⊕⊝⊝⊝
VERY LOW 4, 7

In the text referred to as infertility.

375 per 1000

514 per 1000
(311 to 847)

Quality of life

Not reported

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 we estimated the risk of mortality after 5 years in the ABVD arm as being 12%

2 we estimated the risk of progress, relapse or mortality after 5 years in the ABVD arm as being 25%

3 one level down due to the open‐label design of the included trials which could lead to performance or detection biases

4 two levels down due to very few events and wide confidence intervals (imprecision)

5 one level down due to few events and wide confidence intervals (imprecision)

6 one level down due to indirect results (follow‐up period not long enough to detect meaningful differences)

7 one level down due to indirect results (secondary amenorrhoea measured instead of infertility) (indirectness)

Figures and Tables -
Summary of findings for the main comparison. Escalated BEACOPP versus chemotherapy including ABVD
Table 1. The escalated BEACOPP regimen

Drug

Single Dose (mg/m2)

Route

Days given*

Bleomycin

10

IV

8

Etoposide

200

IV

1 to 3

Doxorubicin

35

IV

1

Cyclophosphamide

1200

IV

1

Vincristine

1.4

IV

8

Procarbazine

100

P.O.

1 to 7

Prednisone

40

P.O.

1 to 14

G‐CSF

SC

from day 8

*the regimen was repeated on day 22

IV: intravenously, P.O.: orally, SC: subcutaneous

Figures and Tables -
Table 1. The escalated BEACOPP regimen
Table 2. Adverse events (reported by two trials)

Name of trial

Adverse event

Experimental arm (N)

Control arm (N)

GHSG HD14

Gastrointestinal, others

43/744

14/757

Urogenital tract

0/744

2/757

Drug fever

17/744

6/757

Allergy

12/744

2/757

GSM‐HD 2008

Gastrointestinal, others

9/156

3/166

Fever of unknown reason

2/156

1/166

Others

16/156

1/166

Figures and Tables -
Table 2. Adverse events (reported by two trials)
Comparison 1. Analysis overall survival

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 OS ‐ all ‐ same recruitment period between the 2 arms (HD9) Show forest plot

5

3142

Hazard Ratio (Fixed, 95% CI)

0.74 [0.57, 0.97]

2 OS subgrouped by stage of disease Show forest plot

5

3142

Hazard Ratio (Fixed, 95% CI)

0.75 [0.57, 0.97]

2.1 early unfavourable stage

1

1623

Hazard Ratio (Fixed, 95% CI)

1.02 [0.54, 1.91]

2.2 advanced stage

4

1519

Hazard Ratio (Fixed, 95% CI)

0.70 [0.52, 0.93]

3 OS subgrouped by treatment Show forest plot

5

3142

Hazard Ratio (Fixed, 95% CI)

0.75 [0.57, 0.97]

3.1 only ABVD regimen

4

2700

Hazard Ratio (Fixed, 95% CI)

0.83 [0.60, 1.14]

3.2 ABVD including regimen

1

442

Hazard Ratio (Fixed, 95% CI)

0.62 [0.40, 0.96]

4 OS subgrouped by number of cycles of escalated BEACOPP Show forest plot

5

3142

Hazard Ratio (Fixed, 95% CI)

0.75 [0.57, 0.97]

4.1 eight cycles of escalated BEACOPP

1

442

Hazard Ratio (Fixed, 95% CI)

0.62 [0.40, 0.96]

4.2 four cycles of escalated BEACOPP

3

1077

Hazard Ratio (Fixed, 95% CI)

0.76 [0.52, 1.12]

4.3 two cycles of escalated BEACOPP

1

1623

Hazard Ratio (Fixed, 95% CI)

1.02 [0.54, 1.91]

5 OS subgrouped by length of follow‐up Show forest plot

5

3142

Hazard Ratio (Fixed, 95% CI)

0.75 [0.57, 0.97]

5.1 short‐term follow‐up (median length up to 5 years)

4

2700

Hazard Ratio (Fixed, 95% CI)

0.83 [0.60, 1.14]

5.2 long‐term follow‐up (median length 10 years)

1

442

Hazard Ratio (Fixed, 95% CI)

0.62 [0.40, 0.96]

6 OS subgrouped by radiotherapy Show forest plot

5

3132

Hazard Ratio (Fixed, 95% CI)

0.75 [0.57, 0.97]

6.1 without radiotherapy

1

549

Hazard Ratio (Fixed, 95% CI)

0.71 [0.42, 1.20]

6.2 with radiotherapy

4

2583

Hazard Ratio (Fixed, 95% CI)

0.76 [0.56, 1.02]

7 OS ‐ all recruited patients (HD9) with potential risk of bias due to different time periods of recruitment Show forest plot

5

Hazard Ratio (Fixed, 95% CI)

0.66 [0.52, 0.84]

Figures and Tables -
Comparison 1. Analysis overall survival
Comparison 2. Analysis of progression‐free survival (PFS)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 PFS ‐ all ‐ same recruitment period between the 2 arms (HD9) Show forest plot

5

3142

Hazard Ratio (Fixed, 95% CI)

0.54 [0.45, 0.64]

2 PFS subgrouped by stage of disease Show forest plot

5

3142

Hazard Ratio (Fixed, 95% CI)

0.54 [0.45, 0.64]

2.1 early unfavourable stage

1

1623

Hazard Ratio (Fixed, 95% CI)

0.47 [0.31, 0.71]

2.2 advanced stage

4

1519

Hazard Ratio (Fixed, 95% CI)

0.56 [0.46, 0.67]

3 PFS subgrouped by treatment Show forest plot

5

3142

Hazard Ratio (Fixed, 95% CI)

0.54 [0.45, 0.64]

3.1 only ABVD regimen

4

2700

Hazard Ratio (Fixed, 95% CI)

0.55 [0.45, 0.67]

3.2 ABVD including regimen

1

442

Hazard Ratio (Fixed, 95% CI)

0.50 [0.34, 0.72]

4 PFS subgrouped by number of cycles of escalated BEACOPP Show forest plot

5

3142

Hazard Ratio (Fixed, 95% CI)

0.54 [0.45, 0.64]

4.1 eight cycles of escalated BEACOPP

1

442

Hazard Ratio (Fixed, 95% CI)

0.50 [0.34, 0.72]

4.2 four cycles of escalated BEACOPP

3

1077

Hazard Ratio (Fixed, 95% CI)

0.58 [0.46, 0.72]

4.3 two cycles of escalated BEACOPP

1

1623

Hazard Ratio (Fixed, 95% CI)

0.47 [0.31, 0.71]

5 PFS subgrouped by length of follow‐up Show forest plot

5

3142

Hazard Ratio (Fixed, 95% CI)

0.54 [0.45, 0.64]

5.1 short‐term follow‐up (median length up to 5 years)

4

2700

Hazard Ratio (Fixed, 95% CI)

0.55 [0.45, 0.67]

5.2 long‐term follow‐up (median length 10 years)

1

442

Hazard Ratio (Fixed, 95% CI)

0.50 [0.34, 0.72]

6 PFS subgrouped by type of radiotherapy Show forest plot

5

Hazard Ratio (Fixed, 95% CI)

0.54 [0.45, 0.64]

6.1 without radiotherapy

1

Hazard Ratio (Fixed, 95% CI)

0.58 [0.39, 0.86]

6.2 with radiotherapy

4

Hazard Ratio (Fixed, 95% CI)

0.53 [0.44, 0.64]

7 PFS ‐ all recruited patients (HD9) with potential risk of bias due to different time periods of recruitment Show forest plot

5

Hazard Ratio (Fixed, 95% CI)

0.51 [0.43, 0.60]

Figures and Tables -
Comparison 2. Analysis of progression‐free survival (PFS)
Comparison 3. Analysis of treatment‐related mortality

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment‐related mortality Show forest plot

4

2700

Risk Ratio (M‐H, Fixed, 95% CI)

2.15 [0.93, 4.95]

2 TRM subgrouped by stage of disease Show forest plot

4

2700

Risk Ratio (M‐H, Fixed, 95% CI)

2.15 [0.93, 4.95]

2.1 early unfavourable stage

1

1623

Risk Ratio (M‐H, Fixed, 95% CI)

9.15 [0.49, 169.58]

2.2 advanced stage

3

1077

Risk Ratio (M‐H, Fixed, 95% CI)

1.69 [0.69, 4.13]

3 TRM subgrouped by number of cycles of escalated BEACOPP Show forest plot

4

2700

Risk Ratio (M‐H, Fixed, 95% CI)

2.15 [0.93, 4.95]

3.1 four cycles of escalated BEAOPP

3

1077

Risk Ratio (M‐H, Fixed, 95% CI)

1.69 [0.69, 4.13]

3.2 two cycles of escalated BEACOPP

1

1623

Risk Ratio (M‐H, Fixed, 95% CI)

9.15 [0.49, 169.58]

4 TRM subgrouped by type of radiotherapy Show forest plot

4

2700

Risk Ratio (M‐H, Fixed, 95% CI)

2.15 [0.93, 4.95]

4.1 without radiotherapy

1

549

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.26, 2.71]

4.2 with radiotherapy

3

2151

Risk Ratio (M‐H, Fixed, 95% CI)

6.13 [1.38, 27.26]

Figures and Tables -
Comparison 3. Analysis of treatment‐related mortality
Comparison 4. Analysis of secondary malignancies

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Secondary malignancies Show forest plot

5

3332

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.68, 1.48]

2 SM subgrouped by stage of disease Show forest plot

5

3332

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.68, 1.48]

2.1 early unfavourable stage

1

1528

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.45, 1.76]

2.2 advanced stage

4

1804

Risk Ratio (M‐H, Fixed, 95% CI)

1.06 [0.66, 1.70]

3 SM subgrouped by treatment Show forest plot

5

3332

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.68, 1.48]

3.1 only ABVD

4

2605

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.59, 1.61]

3.2 ABVD including regimen

1

727

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.57, 1.92]

4 SM subgrouped by number of cycles of escalated BEACOPP Show forest plot

5

3332

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.68, 1.48]

4.1 eight cycles of escalated BEACOPP

1

727

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.57, 1.92]

4.2 four cycles of escalated BEAOPP

3

1077

Risk Ratio (M‐H, Fixed, 95% CI)

1.09 [0.52, 2.29]

4.3 two cycles of escalated BEACOPP

1

1528

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.45, 1.76]

5 SM subgrouped by type of radiotherapy Show forest plot

5

3332

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.68, 1.48]

5.1 without radiotherapy

1

549

Risk Ratio (M‐H, Fixed, 95% CI)

1.25 [0.50, 3.13]

5.2 with radiotherapy

4

2783

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.62, 1.46]

6 SM subgrouped by length of follow‐up Show forest plot

5

3332

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.68, 1.48]

6.1 short‐term follow‐up (median length up to 5 years)

4

2605

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.59, 1.61]

6.2 long‐term follow‐up (median length 10 years)

1

727

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.57, 1.92]

Figures and Tables -
Comparison 4. Analysis of secondary malignancies
Comparison 5. Analysis of AML or MDS

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 AML or MDS Show forest plot

5

3332

Risk Ratio (M‐H, Fixed, 95% CI)

3.90 [1.36, 11.21]

2 AML/MDS subgrouped by stage of disease Show forest plot

5

3332

Risk Ratio (M‐H, Fixed, 95% CI)

3.90 [1.36, 11.21]

2.1 early unfavourable stage

1

1528

Risk Ratio (M‐H, Fixed, 95% CI)

5.01 [0.24, 104.25]

2.2 advanced stage

4

1804

Risk Ratio (M‐H, Fixed, 95% CI)

3.77 [1.22, 11.64]

3 AML/MDS subgrouped by treatment Show forest plot

5

3332

Risk Ratio (M‐H, Fixed, 95% CI)

3.90 [1.36, 11.21]

3.1 only ABVD

4

2605

Risk Ratio (M‐H, Fixed, 95% CI)

2.45 [0.71, 8.49]

3.2 ABVD including regimen

1

727

Risk Ratio (M‐H, Fixed, 95% CI)

7.84 [1.04, 59.29]

4 AML/MDS subgrouped by number of cycles of escalated BEACOPP Show forest plot

5

3332

Risk Ratio (M‐H, Fixed, 95% CI)

3.90 [1.36, 11.21]

4.1 eight cycles of escalated BEACOPP

1

727

Risk Ratio (M‐H, Fixed, 95% CI)

7.84 [1.04, 59.29]

4.2 four cycles of escalated BEAOPP

3

1077

Risk Ratio (M‐H, Fixed, 95% CI)

2.03 [0.51, 8.05]

4.3 two cycles of escalated BEACOPP

1

1528

Risk Ratio (M‐H, Fixed, 95% CI)

5.01 [0.24, 104.25]

5 AML/MDS subgrouped by type of radiotherapy Show forest plot

5

3332

Risk Ratio (M‐H, Fixed, 95% CI)

3.90 [1.36, 11.21]

5.1 without radiotherapy

1

549

Risk Ratio (M‐H, Fixed, 95% CI)

2.01 [0.37, 10.87]

5.2 with radiotherapy

4

2783

Risk Ratio (M‐H, Fixed, 95% CI)

5.27 [1.34, 20.74]

6 AML/MDS subgrouped by length of follow‐up Show forest plot

5

3332

Risk Ratio (M‐H, Fixed, 95% CI)

3.90 [1.36, 11.21]

6.1 short‐ term follow‐up (median length up to 5 years)

4

2605

Risk Ratio (M‐H, Fixed, 95% CI)

2.45 [0.71, 8.49]

6.2 long‐ term follow‐up (median length 10 years)

1

727

Risk Ratio (M‐H, Fixed, 95% CI)

7.84 [1.04, 59.29]

Figures and Tables -
Comparison 5. Analysis of AML or MDS
Comparison 6. Analysis of fertility

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Secondary amenorrhoea Show forest plot

1

106

Risk Ratio (M‐H, Fixed, 95% CI)

1.37 [0.83, 2.26]

Figures and Tables -
Comparison 6. Analysis of fertility
Comparison 7. Analysis of anaemia

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Anaemia Show forest plot

3

2425

Risk Ratio (M‐H, Fixed, 95% CI)

10.67 [7.14, 15.93]

Figures and Tables -
Comparison 7. Analysis of anaemia
Comparison 8. Analysis of infection

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Infection Show forest plot

3

2425

Risk Ratio (M‐H, Fixed, 95% CI)

3.73 [2.58, 5.38]

Figures and Tables -
Comparison 8. Analysis of infection
Comparison 9. Analysis of neutropenia

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Neutropenia Show forest plot

2

519

Risk Ratio (M‐H, Fixed, 95% CI)

1.80 [1.52, 2.13]

Figures and Tables -
Comparison 9. Analysis of neutropenia
Comparison 10. Analysis of thrombocytopenia

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Thrombocytopenia Show forest plot

3

2425

Risk Ratio (M‐H, Fixed, 95% CI)

18.12 [11.77, 27.92]

Figures and Tables -
Comparison 10. Analysis of thrombocytopenia
Comparison 11. Analysis of alopecia

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Alopecia Show forest plot

3

2425

Risk Ratio (M‐H, Fixed, 95% CI)

1.98 [1.78, 2.21]

Figures and Tables -
Comparison 11. Analysis of alopecia
Comparison 12. Analysis of constipation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Constipation Show forest plot

2

923

Risk Ratio (M‐H, Fixed, 95% CI)

1.19 [0.56, 2.55]

Figures and Tables -
Comparison 12. Analysis of constipation
Comparison 13. Analysis of mucositis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mucositis Show forest plot

3

2425

Risk Ratio (M‐H, Fixed, 95% CI)

8.04 [3.72, 17.38]

Figures and Tables -
Comparison 13. Analysis of mucositis
Comparison 14. Analysis of nausea/vomiting

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Nausea/vomiting Show forest plot

3

2425

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.68, 1.01]

Figures and Tables -
Comparison 14. Analysis of nausea/vomiting
Comparison 15. Analysis of neurologic toxicity

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Neurologic Show forest plot

3

2425

Risk Ratio (M‐H, Fixed, 95% CI)

2.04 [1.19, 3.50]

Figures and Tables -
Comparison 15. Analysis of neurologic toxicity
Comparison 16. Analysis of pain

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Pain Show forest plot

3

2425

Risk Ratio (M‐H, Fixed, 95% CI)

2.62 [1.76, 3.90]

Figures and Tables -
Comparison 16. Analysis of pain
Comparison 17. Analysis of respiratory

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Respiratory Show forest plot

3

2549

Risk Ratio (M‐H, Fixed, 95% CI)

1.80 [1.01, 3.20]

Figures and Tables -
Comparison 17. Analysis of respiratory
Comparison 18. Analysis of skin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Skin Show forest plot

2

2227

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.45, 2.34]

Figures and Tables -
Comparison 18. Analysis of skin
Comparison 19. Analysis of heart disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 heart Show forest plot

2

1823

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [0.21, 5.10]

Figures and Tables -
Comparison 19. Analysis of heart disease
Comparison 20. Analysis of freedom from first progression

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Freedom from first progression Show forest plot

1

331

Hazard Ratio (Fixed, 95% CI)

0.46 [0.27, 0.78]

Figures and Tables -
Comparison 20. Analysis of freedom from first progression
Comparison 21. Analysis of complete response (CR) rate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 CR Show forest plot

5

3427

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [1.01, 1.06]

Figures and Tables -
Comparison 21. Analysis of complete response (CR) rate