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Cochrane Database of Systematic Reviews

First‐line chemotherapy in low‐risk gestational trophoblastic neoplasia

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DOI:
https://doi.org/10.1002/14651858.CD007102.pub4Copy DOI
Database:
  1. Cochrane Database of Systematic Reviews
Version published:
  1. 09 June 2016see what's new
Type:
  1. Intervention
Stage:
  1. Review
Cochrane Editorial Group:
  1. Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group

Copyright:
  1. Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Authors

  • Theresa A Lawrie

    Cochrane Gynaecological, Neuro‐oncology and Orphan Cancer Group, 1st Floor Education Centre, Royal United Hospital, Bath, UK

  • Mo'iad Alazzam

    Correspondence to: Gynaecological Oncology Division, Beacon Hospital, Dublin, Ireland

    [email protected]

    [email protected]

  • John Tidy

    Obstetrics & Gynaecology, Sheffield Teaching Hospitals Foundation NHS Trust, Sheffield, UK

  • Barry W Hancock

    School of Medicine and Biomedical Sciences, Sheffield University, Sheffield, UK

  • Raymond Osborne

    Division of Gynecology‐Oncology, Toronto‐Sunnybrook Regional Cancer Centre, Toronto, Canada

Contributions of authors

Mo'iad Alazzam: protocol development, methodological quality assessment, retrieval of papers, data extraction, data analysis and writing the review.
John Tidy: protocol development, methodological quality assessment, data extraction and revision of the review. Barry Hancock: content expert and revision of the review.
Ray Osborne: content expert, contributed to writing discussion and revision of the review.
Tess Lawrie: co‐ordination of the review updates, methodological quality assessment, retrieval of papers, data extraction, data analysis and updating the review.

Sources of support

Internal sources

  • Sheffield Teaching Hospitals NHS Trust, UK.

External sources

  • 10/4001/12 National Institute for Health Research (NIHR) Cochrane Programme Grant Scheme, UK., UK.

    This review received methodological and statistical support as part of the 10/4001/12 NIHR Cochrane Programme Grant Scheme ‐ Optimising care, diagnosis and treatment pathways to ensure cost effectiveness and best practice in gynaecological cancer: improving evidence for the NHS.

Declarations of interest

Ray Osborne was an primary investigator of a study that has been included in this review (Osborne 2011). He was not involved in the consideration or assessment of this study for inclusion.

Acknowledgements

We thank the following people:

  • Jo Morrison, Clare Jess, Gail Quinn, and Jane Hayes at the Cochrane Gynaecological, Neuro, and Orphan Cancer Review Group in Bath for their advice and support throughout the review process;

  • Jo Platt for conducting the updated 2016 search and sifting the initial results;

  • Alison Little (Sheffield University) and Anne Oestmann (Cochrane Gynaecological Cancer Collaborative Review Group) for their assistance in developing the search strategy process and literature search for the original review; and

  • The authors of Lertkhachonsuk 2009 and Yarandi 2008 for providing additional data.

  • The 2012 review update received methodological and statistical support as part of the 10/4001/12 NIHR Cochrane Programme Grant Scheme ‐ Optimising care, diagnosis and treatment pathways to ensure cost effectiveness and best practice in gynaecological cancer: improving evidence for the NHS.

  • This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Gynaecological, Neuro‐oncology and Orphan Cancer Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Version history

Published

Title

Stage

Authors

Version

2016 Jun 09

First‐line chemotherapy in low‐risk gestational trophoblastic neoplasia

Review

Theresa A Lawrie, Mo'iad Alazzam, John Tidy, Barry W Hancock, Raymond Osborne

https://doi.org/10.1002/14651858.CD007102.pub4

2012 Jul 11

First‐line chemotherapy in low‐risk gestational trophoblastic neoplasia

Review

Mo'iad Alazzam, John Tidy, Barry W Hancock, Raymond Osborne, Theresa A Lawrie

https://doi.org/10.1002/14651858.CD007102.pub3

2009 Jan 21

First line chemotherapy in low risk gestational trophoblastic neoplasia

Review

Mo'iad Alazzam, John Tidy, Barry W Hancock, Raymond Osborne

https://doi.org/10.1002/14651858.CD007102.pub2

2008 Apr 23

First line chemotherapy in low risk gestational trophoblastic neoplasia

Protocol

Mo'iad Alazzam, John Tidy, Barry W Hancock, Raymond Osborne

https://doi.org/10.1002/14651858.CD007102

Differences between protocol and review

In the protocol and the original 2009 review, we included non‐randomised studies (NRS) as well as RCTs. For the updated and revised review, we included only RCTs.

Keywords

MeSH

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Study flow diagram of the original 2009 review*The original 2009 review Included four non‐RCTs (Abrao 2008; Kohorn 1996; Smith 1982; Wong 1985) in the qualitative and three (Abrao 2008 not included) in the quantitative meta‐analysis). These non‐RCTs were excluded in the updated review.
Figures and Tables -
Figure 1

Study flow diagram of the original 2009 review

*The original 2009 review Included four non‐RCTs (Abrao 2008; Kohorn 1996; Smith 1982; Wong 1985) in the qualitative and three (Abrao 2008 not included) in the quantitative meta‐analysis). These non‐RCTs were excluded in the updated review.

Study flow diagram of the updated search conducted from January 2010 to February 2012.
Figures and Tables -
Figure 2

Study flow diagram of the updated search conducted from January 2010 to February 2012.

Study flow diagram for the updated search conducted from Feb 2012 to January 2016.
Figures and Tables -
Figure 3

Study flow diagram for the updated search conducted from Feb 2012 to January 2016.

Chemotherapy treatment comparisons of included RCTs (solid lines) and ongoing RCTs (dotted lines)
Figures and Tables -
Figure 4

Chemotherapy treatment comparisons of included RCTs (solid lines) and ongoing RCTs (dotted lines)

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 5

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

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 1 Primary cure (remission).
Figures and Tables -
Analysis 1.1

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 1 Primary cure (remission).

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 2 Failure of first line therapy.
Figures and Tables -
Analysis 1.2

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 2 Failure of first line therapy.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 3 Chemotherapy cycles to primary cure.
Figures and Tables -
Analysis 1.3

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 3 Chemotherapy cycles to primary cure.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 4 Adverse effects: Nausea.
Figures and Tables -
Analysis 1.4

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 4 Adverse effects: Nausea.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 5 Adverse effects: Vomiting.
Figures and Tables -
Analysis 1.5

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 5 Adverse effects: Vomiting.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 6 Adverse effects: Diarrhoea.
Figures and Tables -
Analysis 1.6

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 6 Adverse effects: Diarrhoea.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 7 Adverse effects: Constitutional.
Figures and Tables -
Analysis 1.7

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 7 Adverse effects: Constitutional.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 8 Adverse effects: Alopecia.
Figures and Tables -
Analysis 1.8

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 8 Adverse effects: Alopecia.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 9 Adverse effects: Mucositis/stomatitis.
Figures and Tables -
Analysis 1.9

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 9 Adverse effects: Mucositis/stomatitis.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 10 Adverse effects: Dermatological.
Figures and Tables -
Analysis 1.10

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 10 Adverse effects: Dermatological.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 11 Adverse effects: Neutropenia.
Figures and Tables -
Analysis 1.11

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 11 Adverse effects: Neutropenia.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 12 Adverse effects: Thrombocytopenia.
Figures and Tables -
Analysis 1.12

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 12 Adverse effects: Thrombocytopenia.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 13 Adverse effects: Anaemia.
Figures and Tables -
Analysis 1.13

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 13 Adverse effects: Anaemia.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 14 Adverse effects: Hepatotoxicity.
Figures and Tables -
Analysis 1.14

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 14 Adverse effects: Hepatotoxicity.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 15 Adverse effects: Haemoptysis.
Figures and Tables -
Analysis 1.15

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 15 Adverse effects: Haemoptysis.

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 16 Severe adverse events (≥G3).
Figures and Tables -
Analysis 1.16

Comparison 1 Methotrexate vs. Actinomycin D, Outcome 16 Severe adverse events (≥G3).

Actinomycin D compared with methotrexate (MTX) for low‐risk gestational trophoblastic neoplasia (GTN)

Patient or population: women withe low‐risk GTN

Settings: outpatient or hospital

Intervention: actinomycin D (Act D)

Comparison: MTX

Outcomes

Illustrative Assumed risk*

(Act D)

Illustrative Corresponding risk

(MTX)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Primary cure (remission)

824 per 1000

536 per 1000

(470 to 618)

RR 0.65 (0.57 to 0.75)

577 women (6 studies)

⊕⊕⊕⊝
moderate1

Act D is probably more likely to achieve a primary cure than MTX.

55% of the data came from trials of weekly IM MTX, which may be less effective than the 5‐ or 8‐day MTX regimens.

Failure of first‐line therapy

154 per 1000

547 per 1000 (279 to 1000)

RR 3.55 (1.81 to 6.95)

577 women (6 studies)

⊕⊕⊕⊝
moderate1

Act D as a first‐line treatment is probably less likely to fail than MTX.

59% of the data came from trials of weekly IM MTX, which may be less effective than the 5‐ or 8‐day MTX regimens.

Severe adverse events (≥ grade 3)

142 per 1000

50 per 1000

(11 to 235)

RR 0.35 (0.08 to 1.66)

515 women (5 studies)

⊕⊕⊝⊝

low1,2

There may be little or no difference between interventions overall. However, the point estimate and subgroup analyses favoured MTX. SAEs occurred in 3 out of 6 studies, but one study did not contribute to the meta‐analysis due to insufficient data.

Nausea

462 per 1000

282 per 1000

(134 to 582)

RR 0.61 (0.29 to 1.26)

466 women (4 studies)

⊕⊕⊕⊝
moderate1

There is probably little or no difference between MTX and Act D for nausea.

Alopecia

Subtotals only

⊕⊕⊝⊝

low1,2

Data on alopecia were not pooled due to substantial subgroup differences. However, in general the evidence suggested that there may be little or no difference between MTX and Act D regimens with regard to alopecia, except for the five‐day Act D regimen, which may be more frequently associated with alopecia than the 8‐day MTX regimen.

*The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (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: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

IM = intramuscular; SAE = severe adverse effects

1 Downgraded for clinical or statistical inconsistency

2 Downgraded for imprecision

Figures and Tables -
Table 1. FIGO anatomical staging *

Stage I

Disease confined to the uterus

Stage II

GTN extends outside of the uterus, but is limited to the genital structures (adnexae, vagina, broad ligament)

Stage III

GTN extends to the lungs with or without known genital tract involvement

Stage IV

All other metastatic sites

*FIGO 2009
GTN:

Figures and Tables -
Table 1. FIGO anatomical staging *
Table 2. Modified WHO Prognostic Scoring System as adapted by FIGO for GTN

Scores

0

1

2

4

Age (years)

< 40

≥ 40

Antecedent pregnancy

mole

abortion

term

Interval months from index pregnancy

< 4

4–6

7–12

> 12

Pretreatment serum hCG (IU/L)

< 103

103 to 104

104 to 105

> 105

Largest tumour size (including uterus)

< 3

3cm to 4 cm

≥ 5 cm

Site of metastases

lung

spleen, kidney

gastrointestinal

liver, brain

Number of metastases

1to 4

5 to 8

> 8

Previous failed chemotherapy

single drug

≥ 2 drugs

To stage and allot a risk factor score, a patient's diagnosis is allocated to a stage as represented by a Roman numeral I, II, III, and IV. This is then separated by a colon from the sum of all the actual risk factor scores expressed in Arabic numerals, i.e., stage II:4, stage IV:9. This stage and score will be allotted for each patient.(FIGO 2009). A score ≤ 6 indicates low‐risk; > 6 indicates high‐risk.

hCG = human chorionic gonadotrophin; IU = Internationa Units

Figures and Tables -
Table 2. Modified WHO Prognostic Scoring System as adapted by FIGO for GTN
Table 3. Other first‐line chemotherapy regimens described

Drug

Study

Comment

Intravenous (IV) methotrexate (100, 150, or 300 mg/m²) with folinic acid rescue 24 hours later, repeated weekly

Bagshawe 1976

The original Bagshawe regimen.

Bolus (100 mg/m² IV or IM) and 12‐hour continuous methotrexate infusion (200 mg/m²) with folinic acid rescue 24 hours later, repeated fortnightly

Garrett 2002

Combined 5‐day methotrexate (day 1 to 5) and 5‐day actinomycin D (day 15 to 19), repeated every 28 days

Abrao 2008; Smith 1975; Rose 1989

Associated with a high incidence of toxicity.

High‐dose methotrexate (600 mg/m²)

Elit 1994

Did not effect a higher cure than other methotrexate regimens.

Etoposide (oral and parenteral)

Hitchins 1988; Wong 1984; Wong 1986; Baptista 2012

Reported to be highly effective but not widely used for low‐risk GTN due to the high risk of side‐effects, particularly alopecia.

Fluorouracil

Sung 1984; Song 1998

Used in China for several decades, mainly because of its low cost, but is not favoured elsewhere.

Intra‐lesional methotrexate infusion

Su 2001

Not favoured in Europe or North America.

Chinese preparations

Wang 1998

Not favoured in Europe or North America.

GTN = gestational trophoblastic neoplasia

Figures and Tables -
Table 3. Other first‐line chemotherapy regimens described
Comparison 1. Methotrexate vs. Actinomycin D

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Primary cure (remission) Show forest plot

6

577

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.57, 0.75]

1.1 Weekly IM MTX vs. pulsed IV Act D

3

393

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.48, 0.80]

1.2 Five‐day IM MTX vs. pulsed IV Act D

1

75

Risk Ratio (M‐H, Random, 95% CI)

0.76 [0.57, 1.00]

1.3 Eight‐day IM MTX‐FA vs. 5‐day IV Act D

1

45

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.40, 0.81]

1.4 Eight‐day IM MTX‐FA vs. pulsed IV Act D

1

64

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.50, 0.93]

2 Failure of first line therapy Show forest plot

6

577

Risk Ratio (M‐H, Random, 95% CI)

3.55 [1.81, 6.95]

2.1 Weekly IM MTX vs. pulsed IV Act D

3

393

Risk Ratio (M‐H, Random, 95% CI)

3.54 [1.12, 11.16]

2.2 Five‐day IM MTX vs. pulsed IV Act D

1

75

Risk Ratio (M‐H, Random, 95% CI)

3.2 [1.17, 8.78]

2.3 Eight‐day IM MTX‐FA vs. 5‐day IV Act D

1

45

Risk Ratio (M‐H, Random, 95% CI)

18.58 [1.16, 297.18]

2.4 Eight‐day IM MTX‐FA vs. pulsed IV Act D

1

64

Risk Ratio (M‐H, Random, 95% CI)

3.25 [1.19, 8.90]

3 Chemotherapy cycles to primary cure Show forest plot

4

Mean Difference (IV, Random, 95% CI)

Subtotals only

3.1 Weekly IM MTX vs. pulsed IV Act D

2

346

Mean Difference (IV, Random, 95% CI)

3.04 [0.93, 5.14]

3.2 Five‐day IM MTX vs. pulsed IV Act D

1

75

Mean Difference (IV, Random, 95% CI)

‐2.20 [‐2.87, ‐1.53]

3.3 Eight‐day IM MTX‐FA vs. 5‐day IV Act D

1

45

Mean Difference (IV, Random, 95% CI)

0.63 [‐0.27, 1.53]

4 Adverse effects: Nausea Show forest plot

4

466

Risk Ratio (M‐H, Random, 95% CI)

0.61 [0.29, 1.26]

4.1 Weekly IM MTX vs. pulsed IV Act D

3

391

Risk Ratio (M‐H, Random, 95% CI)

0.42 [0.11, 1.62]

4.2 Five‐day IM MTX vs. pulsed IV Act D

1

75

Risk Ratio (M‐H, Random, 95% CI)

1.18 [0.72, 1.93]

5 Adverse effects: Vomiting Show forest plot

3

420

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.32, 1.73]

5.1 Weekly IM MTX vs. pulsed IV Act D

2

345

Risk Ratio (M‐H, Random, 95% CI)

0.56 [0.24, 1.32]

5.2 Five‐day IM MTX vs. pulsed IV Act D

1

75

Risk Ratio (M‐H, Random, 95% CI)

1.43 [0.50, 4.05]

6 Adverse effects: Diarrhoea Show forest plot

3

419

Risk Ratio (M‐H, Random, 95% CI)

1.43 [0.85, 2.41]

6.1 Weekly IM MTX vs. pulsed IV Act D

2

344

Risk Ratio (M‐H, Random, 95% CI)

1.34 [0.57, 3.16]

6.2 Five‐day IM MTX vs. pulsed IV Act D

1

75

Risk Ratio (M‐H, Random, 95% CI)

1.5 [0.58, 3.85]

7 Adverse effects: Constitutional Show forest plot

3

420

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.84, 1.19]

7.1 Weekly IM MTX vs. pulsed IV Act D

2

345

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.79, 1.18]

7.2 Five‐day IM MTX vs. pulsed IV Act D

1

75

Risk Ratio (M‐H, Random, 95% CI)

1.10 [0.78, 1.55]

8 Adverse effects: Alopecia Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

8.1 Weekly IM MTX vs. pulsed IV Act D

1

131

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.27, 1.83]

8.2 Five‐day IM MTX vs. pulsed IV Act D

1

75

Risk Ratio (M‐H, Random, 95% CI)

1.33 [0.41, 4.30]

8.3 Eight‐day IM MTX‐FA vs. 5‐day IV Act D

1

49

Risk Ratio (M‐H, Random, 95% CI)

0.03 [0.00, 0.53]

9 Adverse effects: Mucositis/stomatitis Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

9.1 Weekly IM MTX vs. pulsed IV Act D

1

216

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.39, 2.17]

9.2 Eight‐day IM MTX‐FA vs. 5‐day IV Act D

1

49

Risk Ratio (M‐H, Random, 95% CI)

0.14 [0.03, 0.54]

10 Adverse effects: Dermatological Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

10.1 Weekly IM MTX vs. pulsed IV Act D

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

11 Adverse effects: Neutropenia Show forest plot

4

469

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.48, 1.45]

11.1 Weekly IM MTX vs. pulsed IV Act D

2

345

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.38, 1.15]

11.2 Five‐day IM MTX vs. pulsed IV Act D

1

75

Risk Ratio (M‐H, Random, 95% CI)

2.0 [0.43, 9.20]

11.3 Eight‐day IM MTX‐FA vs. 5‐day IV Act D

1

49

Risk Ratio (M‐H, Random, 95% CI)

2.44 [0.27, 21.89]

12 Adverse effects: Thrombocytopenia Show forest plot

3

338

Risk Ratio (M‐H, Random, 95% CI)

0.76 [0.16, 3.55]

12.1 Weekly IM MTX vs. pulsed IV Act D

1

214

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.12, 1.11]

12.2 Five‐day IM MTX vs. pulsed IV Act D

1

75

Risk Ratio (M‐H, Random, 95% CI)

2.5 [0.74, 8.50]

12.3 Eight‐day IM MTX‐FA vs. 5‐day IV Act D

1

49

Risk Ratio (M‐H, Random, 95% CI)

0.27 [0.01, 6.41]

13 Adverse effects: Anaemia Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

13.1 Weekly IM MTX vs. pulsed IV Act D

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

14 Adverse effects: Hepatotoxicity Show forest plot

2

263

Risk Ratio (M‐H, Random, 95% CI)

2.57 [0.39, 16.88]

14.1 Weekly IM MTX vs. pulsed IV Act D

1

214

Risk Ratio (M‐H, Random, 95% CI)

1.43 [0.56, 3.61]

14.2 Eight‐day IM MTX‐FA vs. 5‐day IV Act D

1

49

Risk Ratio (M‐H, Random, 95% CI)

10.68 [0.63, 179.70]

15 Adverse effects: Haemoptysis Show forest plot

2

206

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.30, 3.31]

15.1 Weekly IM MTX vs. pulsed IV Act D

1

131

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.13, 2.94]

15.2 Five‐day IM MTX vs. pulsed IV Act D

1

75

Risk Ratio (M‐H, Random, 95% CI)

2.0 [0.30, 13.38]

16 Severe adverse events (≥G3) Show forest plot

5

515

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.08, 1.66]

16.1 Weekly IM MTX vs. pulsed IV Act D

3

391

Risk Ratio (M‐H, Random, 95% CI)

0.61 [0.35, 1.04]

16.2 Five‐day IM MTX vs. pulsed IV Act D

1

75

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

16.3 Eight‐day IM MTX‐FA vs. 5‐day IV Act D

1

49

Risk Ratio (M‐H, Random, 95% CI)

0.12 [0.02, 0.88]

Figures and Tables -
Comparison 1. Methotrexate vs. Actinomycin D