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Review
, 2013 (7), CD006910

Pegylated Liposomal Doxorubicin for Relapsed Epithelial Ovarian Cancer

Affiliations
Review

Pegylated Liposomal Doxorubicin for Relapsed Epithelial Ovarian Cancer

Theresa A Lawrie et al. Cochrane Database Syst Rev.

Abstract

Background: Ovarian cancer is the eighth most common cancer in women and it is usually diagnosed at an advanced stage. The majority of ovarian tumours are epithelial in origin. Women with relapsed epithelial ovarian cancer (EOC) often have a reduced performance status with a limited life expectancy, therefore maintaining quality of life with effective symptom control is the main purpose of treatment. Drug treatment of relapsed disease is directed by the platinum-free interval: relapsed platinum-sensitive disease is usually re-treated with platinum-based therapy and platinum-resistant disease challenged with non-platinum drugs. However, the side-effects of chemotherapy agents may be severe and optimal treatment regimens are unclear. Pegylated liposomal doxorubicin (PLD), which contains a cytotoxic drug called doxorubicin hydrochloride is one of several treatment modalities that may be considered for single-agent treatment of relapsed EOC, or used in combination with other drugs.

Objectives: To assess the efficacy and safety of PLD in women with relapsed epithelial ovarian cancer (EOC).

Search methods: We searched the Cochrane Gynaecological Cancer Group (CGCG) trials register, CENTRAL, MEDLINE and EMBASE from 1990 to February 2013. We also searched online registers of clinical trials, abstracts of scientific meetings and reference lists of included studies.

Selection criteria: Randomised controlled trials (RCTs) that evaluated PLD in women diagnosed with relapsed epithelial ovarian cancer.

Data collection and analysis: Two review authors independently abstracted data to a pre-designed data collection form and assessed the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions guidelines. Where possible, we pooled collected data in meta-analyses using RevMan 5.2 software.

Main results: We included 14 RCTs that evaluated PLD alone or in combination with other drugs. Four RCTs contributed no data to the meta-analyses. Two studies compared PLD plus carboplatin (carbo) to paclitaxel (PAC)/carbo in women with platinum-sensitive relapsed EOC. Overall survival (OS) was similar for these treatments, however progression-free survival (PFS) was longer with PLD/carbo (1164 participants; hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.74 to 0.97; I² = 7%; P value 0.01). PLD/carbo was associated with significantly more anaemia and thrombocytopenia than PAC/carbo, whereas PAC/carbo was associated with significantly more alopecia, neuropathies, hypersensitivity reactions and arthralgias/myalgias. PLD/carbo was well-tolerated and women receiving this treatment were significantly less likely to discontinue treatment than those receiving PAC/carbo (two studies, 1150 participants; risk ratio (RR) 0.38, 95% CI 0.26 to 0.57; I² = 0%; P < 0.00001).Five studies compared other agents to PLD alone. None of these agents were associated with significantly better survival or severe adverse-event profiles than PLD. Topotecan and gemcitabine were associated with significantly more haematological severe adverse events than PLD, and patupilone was associated with significantly more severe neuropathies and diarrhoea. Severe hand-foot syndrome (HFS) occurred consistently more frequently with PLD than the other drugs.Three studies compared PLD combination treatment to PLD alone. Two combinations resulted in a significantly longer PFS compared with PLD alone: trabectedin (TBD)/PLD (one study, 672 women; HR 0.79, 95% CI 0.65 to 0.96; P value 0.02) and vintafolide (EC145)/PLD (one study, 149 women; HR 0.63, 95% CI 0.41 to 0.97; P value 0.04). TBD/PLD appeared to benefit the partially platinum-sensitive subgroup only. Further studies are likely to have an important impact on our confidence in these estimates. TBD/PLD was associated with significantly more haematological and gastrointestinal severe adverse events than PLD alone, whereas EC145/PLD appeared to be well-tolerated.For platinum-resistant relapsed EOC, the median PFS and OS for single-agent PLD across seven included studies was 15 weeks and 54 weeks, respectively. Severe HFS occurred significantly more frequently in women receiving a 50 mg/m² dose of PLD than those receiving less than 50 mg/m² (17% versus 2%, respectively; P value 0.01).

Authors' conclusions: In platinum-sensitive relapsed epithelial ovarian cancer, PLD/carbo is more effective than PAC/carbo and is better tolerated; PLD/carbo should therefore be considered as first-line treatment in women with platinum-sensitive relapsed EOC. PLD alone is a useful agent for platinum-resistant relapsed EOC, however it remains unclear how it compares with other single agents for this subgroup and in what order these agents should be used. There is insufficient evidence to support the use of PLD in combination with other agents in platinum-resistant relapsed EOC.

Conflict of interest statement

None known.

Figures

Figure 1
Figure 1
Study flow diagram of searches to 15 October 2012.
Figure 2
Figure 2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Analysis 1.1
Analysis 1.1
Comparison 1 PLD/carbo vs carbo ± other, Outcome 1 PFS.
Analysis 1.2
Analysis 1.2
Comparison 1 PLD/carbo vs carbo ± other, Outcome 2 OS.
Analysis 1.3
Analysis 1.3
Comparison 1 PLD/carbo vs carbo ± other, Outcome 3 SAE: Hand‐foot syndrome (G3).
Analysis 1.4
Analysis 1.4
Comparison 1 PLD/carbo vs carbo ± other, Outcome 4 SAE: Anaemia (G3/4).
Analysis 1.5
Analysis 1.5
Comparison 1 PLD/carbo vs carbo ± other, Outcome 5 SAE: Febrile neutropenia (G3/4).
Analysis 1.6
Analysis 1.6
Comparison 1 PLD/carbo vs carbo ± other, Outcome 6 SAE: Neutropenia (G3/4).
Analysis 1.7
Analysis 1.7
Comparison 1 PLD/carbo vs carbo ± other, Outcome 7 SAE: Thrombocytopenia (G3/4).
Analysis 1.8
Analysis 1.8
Comparison 1 PLD/carbo vs carbo ± other, Outcome 8 SAE: Stomatitis/mucositis (G 3/4).
Analysis 1.9
Analysis 1.9
Comparison 1 PLD/carbo vs carbo ± other, Outcome 9 SAE: Vomiting (G 3/4).
Analysis 1.10
Analysis 1.10
Comparison 1 PLD/carbo vs carbo ± other, Outcome 10 SAE: Alopecia (G2).
Analysis 1.11
Analysis 1.11
Comparison 1 PLD/carbo vs carbo ± other, Outcome 11 SAE: Neurological (G3/4).
Analysis 1.12
Analysis 1.12
Comparison 1 PLD/carbo vs carbo ± other, Outcome 12 SAE: Fatigue (G3/4).
Analysis 1.13
Analysis 1.13
Comparison 1 PLD/carbo vs carbo ± other, Outcome 13 SAE: Arthralgia/myalgia (G3/4).
Analysis 1.14
Analysis 1.14
Comparison 1 PLD/carbo vs carbo ± other, Outcome 14 SAE: Hypersensitivity reactions (HSR; G3/4).
Analysis 1.15
Analysis 1.15
Comparison 1 PLD/carbo vs carbo ± other, Outcome 15 SAE: Treatment‐related death.
Analysis 1.16
Analysis 1.16
Comparison 1 PLD/carbo vs carbo ± other, Outcome 16 QoL: Global health score (mean change).
Analysis 1.17
Analysis 1.17
Comparison 1 PLD/carbo vs carbo ± other, Outcome 17 Discontinuation due to toxicity.
Analysis 1.18
Analysis 1.18
Comparison 1 PLD/carbo vs carbo ± other, Outcome 18 Antibiotics required.
Analysis 1.19
Analysis 1.19
Comparison 1 PLD/carbo vs carbo ± other, Outcome 19 G‐CSF required.
Analysis 1.20
Analysis 1.20
Comparison 1 PLD/carbo vs carbo ± other, Outcome 20 Blood transfusion required.
Analysis 2.1
Analysis 2.1
Comparison 2 Other drug vs PLD, Outcome 1 PFS.
Analysis 2.2
Analysis 2.2
Comparison 2 Other drug vs PLD, Outcome 2 OS.
Analysis 2.3
Analysis 2.3
Comparison 2 Other drug vs PLD, Outcome 3 SAE: HFS (G3).
Analysis 2.4
Analysis 2.4
Comparison 2 Other drug vs PLD, Outcome 4 SAE: Stomatitis (G3/4).
Analysis 2.5
Analysis 2.5
Comparison 2 Other drug vs PLD, Outcome 5 SAE: Neutropenia (G3/4).
Analysis 2.6
Analysis 2.6
Comparison 2 Other drug vs PLD, Outcome 6 SAE: Anaemia (G3/4).
Analysis 2.7
Analysis 2.7
Comparison 2 Other drug vs PLD, Outcome 7 SAE: Thrombocytopenia (G3/4).
Analysis 2.8
Analysis 2.8
Comparison 2 Other drug vs PLD, Outcome 8 SAE: Vomiting (G3/4).
Analysis 2.9
Analysis 2.9
Comparison 2 Other drug vs PLD, Outcome 9 SAE: Fatigue/asthenia (G3/4).
Analysis 2.10
Analysis 2.10
Comparison 2 Other drug vs PLD, Outcome 10 SAE: Neurological (G3/4).
Analysis 2.11
Analysis 2.11
Comparison 2 Other drug vs PLD, Outcome 11 SAE: Alopecia (G2).
Analysis 2.12
Analysis 2.12
Comparison 2 Other drug vs PLD, Outcome 12 SAE: Allergy (G3/4).
Analysis 2.13
Analysis 2.13
Comparison 2 Other drug vs PLD, Outcome 13 SAE: Diarrhoea (G3/4).
Analysis 2.14
Analysis 2.14
Comparison 2 Other drug vs PLD, Outcome 14 Dose reductions.
Analysis 2.15
Analysis 2.15
Comparison 2 Other drug vs PLD, Outcome 15 Dose delays.
Analysis 3.1
Analysis 3.1
Comparison 3 PLD + other drug vs PLD, Outcome 1 PFS.
Analysis 3.2
Analysis 3.2
Comparison 3 PLD + other drug vs PLD, Outcome 2 PFS: PPS subgroup only.
Analysis 3.3
Analysis 3.3
Comparison 3 PLD + other drug vs PLD, Outcome 3 OS.
Analysis 3.4
Analysis 3.4
Comparison 3 PLD + other drug vs PLD, Outcome 4 SAE: Anaemia (G3/4).
Analysis 3.5
Analysis 3.5
Comparison 3 PLD + other drug vs PLD, Outcome 5 SAE: Neutropenia (G3/4).
Analysis 3.6
Analysis 3.6
Comparison 3 PLD + other drug vs PLD, Outcome 6 SAE: Thrombocytopenia (G3/4).
Analysis 3.7
Analysis 3.7
Comparison 3 PLD + other drug vs PLD, Outcome 7 SAE: Vomiting (G3/4).
Analysis 3.8
Analysis 3.8
Comparison 3 PLD + other drug vs PLD, Outcome 8 SAE: HFS (G3).
Analysis 3.9
Analysis 3.9
Comparison 3 PLD + other drug vs PLD, Outcome 9 SAE: Stomatitis (G3/4).
Analysis 3.10
Analysis 3.10
Comparison 3 PLD + other drug vs PLD, Outcome 10 SAE: Alopecia (G2).
Analysis 3.11
Analysis 3.11
Comparison 3 PLD + other drug vs PLD, Outcome 11 SAE: Abdominal pain (G3/4).
Analysis 3.12
Analysis 3.12
Comparison 3 PLD + other drug vs PLD, Outcome 12 SAE: Neuropathy (G3/4).
Analysis 3.13
Analysis 3.13
Comparison 3 PLD + other drug vs PLD, Outcome 13 SAE‐related death.
Analysis 3.14
Analysis 3.14
Comparison 3 PLD + other drug vs PLD, Outcome 14 Dose reductions.
Analysis 3.15
Analysis 3.15
Comparison 3 PLD + other drug vs PLD, Outcome 15 Dose delays.
Analysis 4.1
Analysis 4.1
Comparison 4 Exploratory analyses, Outcome 1 SAE: HFS (G3) subgrouped by PLD dose.
Analysis 4.2
Analysis 4.2
Comparison 4 Exploratory analyses, Outcome 2 SAE: Stomatitis (G3/4).

Update of

  • Cochrane Database Syst Rev. doi: 10.1002/14651858.CD006910

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