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Pegylated liposomal doxorubicin for first-line treatment of epithelial ovarian cancer

  1. Theresa A Lawrie1,*,
  2. Roy Rabbie2,
  3. Clemens Thoma3,
  4. Jo Morrison4

Editorial Group: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group

Published Online: 21 OCT 2013

Assessed as up-to-date: 14 AUG 2013

DOI: 10.1002/14651858.CD010482.pub2


How to Cite

Lawrie TA, Rabbie R, Thoma C, Morrison J. Pegylated liposomal doxorubicin for first-line treatment of epithelial ovarian cancer. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD010482. DOI: 10.1002/14651858.CD010482.pub2.

Author Information

  1. 1

    Royal United Hospital, Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group, Bath, UK

  2. 2

    Epsom and St Helier University Hospitals NHS Trust, Department of Respiratory Medicine, London, UK

  3. 3

    University of Oxford, Nuffield Department of Obstetrics & Gynaecology, Oxford, UK

  4. 4

    Musgrove Park Hospital, Department of Gynaecological Oncology, Taunton, Somerset, UK

*Theresa A Lawrie, Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group, Royal United Hospital, Education Centre, Bath, BA1 3NG, UK. tess@lawrie.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 21 OCT 2013

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Characteristics of included studies [ordered by study ID]
GOG0182/ICON 5 2009

MethodsInternational phase III RCT (Australia, New Zealand, United Kingdom and Italy). Accrual from January 2001 to September 2004


Participants4100 women with EOC or primary peritoneal carcinoma. Women had to have FIGO stage III or IV and optimal (≤ 1 cm) or suboptimal residual disease. Other inclusion criteria included GOG performance status ≤ 2, absolute neutrophil count ≥ 1500/microL, platelets ≥ 100,000/microL and creatinine ≤ 1.5× institutional upper limit of normal (ULN), bilirubin ≤ 1.5× ULN, AST and alkaline phosphatase ≤ 2.5× ULN and baseline sensory or motor neuropathy grade 1 or lower, according to National Cancer Institute Common Toxicity Criteria version 2. Patients with history of breast cancer were eligible, provided they were disease -free for at least 3 years without contraindications for protocol-based chemotherapy. Patients who had early-stage synchronous endometrial cancer were also eligible, provided was no more than minimum invasion was noted without high-grade features.


InterventionsFive treatment arms with 8 cycles (C1-8) each:
1. Carbo AUC 6/PAC 175 mg/m² (C1-8); administered on day 1 (D1) (control arm).
2. Carbo AUC 5/PAC 175 mg/m² (C1-8; D1) plus gemcitabine 800 mg/m² (C1-8; D1/8).
3. Carbo AUC 5/PAC 175 mg/m² (C1-8; D1) plus PLD 30 mg/m² alternate cycles (C1/3/5/7; D1) (experimental arm).
4. Carbo AUC 5/topotecan 125 mg/m² (C1-4; Carbo D3, topotecan D1/2/3) followed by Carbo AUC 6/PAC 175 mg/m² (C5-8; D1).
5. Carbo AUC 6/gemcitabine 1000 mg/m² (C1-4; Carbo D8, gemcitabine D1/8) followed by Carbo AUC 6/paclitaxel 175 mg/m² (C5-8; D1).


OutcomesPrimary: PFS, OS.

Secondary: toxicity (graded according to National Cancer Institute Common Toxicity Criteria version 2.0), complications, dose intensity, cumulative dose delivery.


NotesOverall, approximately 30% of women had suboptimal cytoreduction and < 25% had measurable residual disease. For the purposes of this review, we extracted data for arms 1 (864 women) and 3 (862 women). We were unable to obtain additional data from the study authors


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated stratified block randomisation

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskIndependent evaluation not described

Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition

Selective reporting (reporting bias)Low riskPrespecified and expected outcomes were reported

Other biasUnclear riskAlternate dosing of PLD limits interpretation of these data

Baseline characteristics of groups were similar

MITO-2 2011

MethodsOpen-label, multi-centre phase III RCT (Italy, Portugal, Turkey). Accrual dates January 2003 to November 2007, with median follow-up time of 40 months


Participants820 women with cytological or histological diagnosis of EOC (stage Ic to IV FIGO). Included if < 75 years, Eastern Cooperative Oncology Group performance status ≤ 2, life expectancy ≥ 3 months and adequate bone marrow, kidney and liver function


InterventionsStandard arm: Carbo AUC 5 and PAC 175 mg/m²

Experimental arm: Carbo AUC 5 and PLD 30 mg/m² (diluted in 250 mL 5% glucose and infused over 60 minutes, after completion of Carbo treatment)


OutcomesPrimary: PFS

Secondary: OS, treatment activity, toxicity (according to National Cancer Institute Common Toxicity Criteria version 2.0), QoL (EORTC QLQ-C30 questionnaire)


NotesIncluded stage Ic and II. Overall, approximately 46% had suboptimal cytoreduction (residual disease > 1 cm) and 18% had no surgery

We obtained updated, unpublished survival data (August 2013) from the investigators for this review


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated minimisation method

Allocation concealment (selection bias)Low riskCentral telephone assignment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskIndependent evaluation not described

Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition except for QoL data

Selective reporting (reporting bias)Low riskPrespecified and expected outcomes were reported

Other biasLow riskBaseline characteristics of groups were similar

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Pontamianou 2005Not an RCT

SWOG S9912 2009Not an RCT

 
Comparison 1. PLD combination versus PAC/carbo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 PFS2Hazard Ratio (Random, 95% CI)Subtotals only

    1.1 PLD/carbo versus PAC/carbo
1820Hazard Ratio (Random, 95% CI)1.01 [0.85, 1.19]

    1.2 PLD/PAC/carbo versus PAC/carbo
11726Hazard Ratio (Random, 95% CI)0.98 [0.88, 1.09]

 2 OS2Hazard Ratio (Random, 95% CI)Subtotals only

    2.1 PLD/carbo versus PAC/carbo
1820Hazard Ratio (Random, 95% CI)0.94 [0.78, 1.13]

    2.2 PLD/PAC/carbo versus PAC/carbo
11726Hazard Ratio (Random, 95% CI)0.95 [0.84, 1.08]

 3 PFS: subgroup analyses1Hazard Ratio (Random, 95% CI)Subtotals only

    3.1 No residual disease
1298Hazard Ratio (Random, 95% CI)0.93 [0.67, 1.29]

    3.2 Residual disease ≤ 1 cm
1149Hazard Ratio (Random, 95% CI)1.39 [0.96, 2.01]

    3.3 Residual disease > 1 cm
1227Hazard Ratio (Random, 95% CI)0.92 [0.70, 1.22]

    3.4 No cytoreductive surgery
1146Hazard Ratio (Random, 95% CI)1.01 [0.72, 1.41]

    3.5 Stage I/II only
1153Hazard Ratio (Random, 95% CI)0.96 [0.56, 1.65]

    3.6 Stage III/IV only
1667Hazard Ratio (Random, 95% CI)0.99 [0.84, 1.16]

    3.7 Age < 70 years
1721Hazard Ratio (Random, 95% CI)0.95 [0.80, 1.13]

    3.8 Age ≥ 70 years
199Hazard Ratio (Random, 95% CI)1.42 [0.92, 2.19]

 4 OS: subgroup analyses1Hazard Ratio (Random, 95% CI)Subtotals only

    4.1 No residual disease
1298Hazard Ratio (Random, 95% CI)0.79 [0.49, 1.27]

    4.2 Residual disease ≤ 1 cm
1149Hazard Ratio (Random, 95% CI)1.48 [0.94, 2.34]

    4.3 Residual disease > 1 cm
1227Hazard Ratio (Random, 95% CI)0.82 [0.60, 1.11]

    4.4 No cytoreductive surgery
1146Hazard Ratio (Random, 95% CI)1.05 [0.73, 1.50]

    4.5 Stage I/II only
1153Hazard Ratio (Random, 95% CI)0.82 [0.38, 1.76]

    4.6 Stage III/IV only
1667Hazard Ratio (Random, 95% CI)0.94 [0.78, 1.14]

    4.7 Age < 70 years
1721Hazard Ratio (Random, 95% CI)0.95 [0.77, 1.17]

    4.8 Age ≥ 70 years
199Hazard Ratio (Random, 95% CI)0.87 [0.53, 1.43]

 5 Febrile neutropenia (grade 3/4)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 PLD/carbo versus PAC/carbo
1803Risk Ratio (M-H, Random, 95% CI)0.51 [0.18, 1.49]

    5.2 PLD/PAC/carbo versus PAC/carbo
11726Risk Ratio (M-H, Random, 95% CI)2.25 [1.72, 2.94]

 6 Neutropenia (grade 3/4)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 PLD/carbo versus PAC/carbo
1803Risk Ratio (M-H, Random, 95% CI)0.87 [0.75, 1.01]

    6.2 PLD/PAC/carbo versus PAC/carbo
11726Risk Ratio (M-H, Random, 95% CI)1.13 [1.06, 1.22]

 7 Anaemia (grade 3/4)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 PLD/carbo versus PAC/carbo
1803Risk Ratio (M-H, Random, 95% CI)2.74 [1.54, 4.88]

    7.2 PLD/PAC/carbo versus PAC/carbo
11726Risk Ratio (M-H, Random, 95% CI)1.79 [1.40, 2.30]

 8 Thrombocytopenia (grade 3/4)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    8.1 PLD/carbo versus PAC/carbo
1803Risk Ratio (M-H, Random, 95% CI)8.09 [3.93, 16.67]

    8.2 PLD/PAC/carbo versus PAC/carbo
11726Risk Ratio (M-H, Random, 95% CI)1.73 [1.49, 2.01]

 9 Alopecia (grade 2)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    9.1 PLD/carbo versus PAC/carbo
1803Risk Ratio (M-H, Random, 95% CI)0.09 [0.06, 0.14]

   9.2 PLD/PAC/carbo versus PAC/carbo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 10 Vomiting (grade 3/4)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    10.1 PLD/carbo versus PAC/carbo
1803Risk Ratio (M-H, Random, 95% CI)1.47 [0.56, 3.82]

   10.2 PLD/PAC/carbo versus PAC/carbo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 11 Stomatitis (grade 3/4)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    11.1 PLD/carbo versus PAC/carbo
1803Risk Ratio (M-H, Random, 95% CI)2.06 [0.19, 22.58]

 12 Hand-foot syndrome (grade 3/4)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    12.1 PLD/carbo versus PAC/carbo
1803Risk Ratio (M-H, Random, 95% CI)0.77 [0.27, 2.20]

   12.2 PLD/PAC/carbo versus PAC/carbo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 13 Neuropathy (grade 3/4)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    13.1 PLD/carbo versus PAC/carbo
1803Risk Ratio (M-H, Random, 95% CI)0.09 [0.01, 0.66]

    13.2 PLD/PAC/carbo versus PAC/carbo
11726Risk Ratio (M-H, Random, 95% CI)1.05 [0.89, 1.23]

 14 Allergic reaction (grade 3/4)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    14.1 PLD/carbo versus PAC/carbo
1803Risk Ratio (M-H, Random, 95% CI)0.93 [0.38, 2.25]

   14.2 PLD/PAC/carbo versus PAC/carbo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 15 Fatigue (grade 3/4)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    15.1 PLD/carbo versus PAC/carbo
1803Risk Ratio (M-H, Random, 95% CI)1.03 [0.45, 2.34]

   15.2 PLD/PAC/carbo versus PAC/carbo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 16 Treatment-related death1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    16.1 PLD/carbo versus PAC/carbo
1803Risk Ratio (M-H, Random, 95% CI)0.51 [0.09, 2.79]

   16.2 PLD/PAC/carbo versus PAC/carbo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 17 Dose delays1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    17.1 PLD/carbo versus PAC/carbo
13636Risk Ratio (M-H, Random, 95% CI)3.01 [2.61, 3.47]

   17.2 PLD/PAC/carbo versus PAC/carbo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 18 Discontinuation due to toxicity or refusal2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    18.1 PLD/carbo versus PAC/carbo
1811Risk Ratio (M-H, Random, 95% CI)1.83 [1.09, 3.07]

    18.2 PLD/PAC/carbo versus PAC/carbo
11726Risk Ratio (M-H, Random, 95% CI)1.30 [0.98, 1.74]

 
Summary of findings for the main comparison.

PLD/carbo compared with PAC/carbo for first-line treatment of epithelial ovarian cancer

Patient or population: women with newly diagnosed EOC (stage Ic to IV)

Settings: hospital

Intervention: PLD (30 mg/m²)/carbo every three weeks

Comparison: PAC/carbo every three weeks

OutcomesAssumed risk*Corresponding riskRelative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)

PFS¹HR 1.01

(0.85 to 1.19)
820

(1)
⊕⊕⊕⊕
high

OS²HR 0.94

(0.78 to 1.13)
820

(1)
⊕⊕⊕⊕
high

Anaemia (grade 3/4)37 per 1000100 per 1000

(57 to 181)
RR 2.74

(1.54 to 4.88)
803
(1)
⊕⊕⊕⊕
high

Thrombocytopenia (grade 3/4)20 per 1000162 per 1000

(79 to 333)
RR 8.09

(3.93 to 16.67)
803
(1)
⊕⊕⊕⊕
high

Alopecia (grade 2)595 per 100054 per 1000

(36 to 83)
RR 0.09

(0.06 to 0.14)
803
(1)
⊕⊕⊕⊕
high

Neuropathy (grade 3/4) 29 per 10003 per 1000

(0 to 19)
RR 0.09

(0.01 to 0.66)
803
(1)
⊕⊕⊕⊕
high

*The assumed risk is the median risk for the control group in the one included study. CI: Confidence interval; HR: Hazard Ratio; 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.

 ¹Relative median PFS in MITO-2 2011 (all participants) was 16.8 months and 19.0 months for PAC/carbo and PLD/carbo, respectively (published 2011 data). MITO-2 2011 also performed exploratory analyses of a high-risk group (defined as stage IV, or stage III with residual disease > 1 cm). The relative median PFS for this high-risk group was 11 versus 11.8 months for PAC/carbo and PLD/carbo, respectively (unpublished 2013 data).
²Relative median OS in MITO-2 2011 (all participants) was 53.2 months and 61.6 months for PAC/carbo and PLD/carbo, respectively (published 2011 data). The relative median PFS for the high-risk group defined above was 29 months versus 30.3 months for PAC/carbo and PLD/carbo, respectively (unpublished 2013 data).