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Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer

  1. Theresa A Lawrie1,
  2. Andrew Bryant2,
  3. Alison Cameron3,*,
  4. Emma Gray4,
  5. Jo Morrison5

Editorial Group: Cochrane Gynaecological Cancer Group

Published Online: 9 JUL 2013

Assessed as up-to-date: 2 JUL 2013

DOI: 10.1002/14651858.CD006910.pub2


How to Cite

Lawrie TA, Bryant A, Cameron A, Gray E, Morrison J. Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD006910. DOI: 10.1002/14651858.CD006910.pub2.

Author Information

  1. 1

    Royal United Hospital, Cochrane Gynaecological Cancer Group, Bath, UK

  2. 2

    Newcastle University, Institute of Health & Society, Newcastle upon Tyne, UK

  3. 3

    University Hospitals Bristol NHS Foundation Trust, Department of Clinical Oncology, Bristol, UK

  4. 4

    Musgrove Park Hospital, The Beacon Centre, Taunton, Somerset, UK

  5. 5

    Musgrove Park Hospital, Department of Obstetrics and Gynaecology, Taunton, Somerset, UK

*Alison Cameron, Department of Clinical Oncology, University Hospitals Bristol NHS Foundation Trust, Bristol Haematology and Oncology Centre, Horfield Road, Bristol, BS2 8ED, UK. Alison.Cameron@UHBristol.nhs.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 9 JUL 2013

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Characteristics of included studies [ordered by study ID]
ASSIST-3 2007

MethodsPhase III multicentre RCT (ID not found on trial registries); abstract only; no further methodological details.


Participants247 women with PR ROC (resistant and refractory) with measurable disease (RECIST), who had progressed on 2 platinum regimens.


InterventionsArm 1: CAN (750 mg/m²) and carboplatin (AUC 5) (carbo)

Arm 2: PLD (50 mg/m²) IV q4wks until progression


OutcomesORR, PFS, safety and QoL


NotesPublished results included the following statements with little supporting data:

  • 'Overall median PFS was 3.5 months for both CAN/carbo and PLD' (no HRs given)';
  • 'Most common toxicities for CAN/carbo were haematologic and as expected for each drug alone'.


Overall median survival had not been reached at the time of the 2007 ASCO proceedings where these results were reported.

Subgroup analyses of women with time from last carbo dose (TFP) = 6 months 'reported large differences in ORR and QoL and statistical significance in PFS and survival' in favour of the experimental group (CAN/carbo), but this subgroup consisted of 19 women in each group and 58% (11/19) of the CAN/carbo arm were censored (compared with 3/19 in the PLD arm).

We emailed Dr Rose and Telik, Inc in November 2012 for further information and final survival and safety data but received no response.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskORR results differed between clinician and independent radiological assessments, however it is not stated which assessment was used in the analyses.

Incomplete outcome data (attrition bias)
All outcomes
High riskInsufficient data. The abstract states ' 25% of patients discontinued treatment without documented progression'. Final results not reported. Censoring imbalance.

Selective reporting (reporting bias)High riskPreliminary results were reported at ASCO 2007 with scant useful data. Overall survival was not reported.

Other biasHigh riskPublication bias. We were unable to obtain any useful data despite several attempts to contact the first author and Telik. We assessed the overall risk of bias of this study as high.

ASSIST-5 2010

MethodsPhase III multicentre RCT (US, Brazil, Belgium, UK). Accrual from Sept 2006 to June 2007. Followed up every 8 weeks. (ID: NCT00350948)


Participants125 women with PR ROC. Included if: ≥ 18 years old; 1 or 2 previous platinum-based chemo regimens given; measurable disease defined by RECIST; ECOG PS 0,1 or 2; and adequate bone marrow reserves and cardiac, renal and hepatic function were required. Bulky disease was defined as tumour mass ≥ 5cm.


InterventionsArm 1: CAN (1000 mg/m²) IVI for 30 min followed by PLD (50 mg/m²) on day 1 every 28 days

Arm 2: PLD (50 mg/m²) IVI for 60 min on day 1 every 28 days


OutcomesPrimary: PFS

Secondary: ORR, SAE (NCI-CTCAE v3.0)


NotesThis study was temporarily put on hold in June 2007 to review the results of the single-agent trial (ASSIST-1) in PR ROC was reviewed. The clinical hold was released in October 2007 but the sponsor decided not enrol any additional patients.

Patients requiring dose reductions for HFS and stomatitis were 15% and 4% respectively, in the intervention arm compared with 42% and 25% respectively in the PLD arm; i.e. CAN appeared to decrease the rate of HFS and stomatitis when combined with PLD. Premedication (ondansetron and IV corticosteroids) was the same in both arms.

For the exploratory subgroup of PR ROC women with platinum-refractory or primary platinum resistance (i.e. excluding secondary platinum resistance), the difference in PFS was significantly in favour of arm 1 (HR = 0.55; P value 0.0425). Also in this subgroup, median survival for arm 1 was 11.8 months versus 7.8 months in arm 2.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation with stratification for ECOG PS, prior best response to platinum-based chemotherapy and bulky disease.

Allocation concealment (selection bias)Low riskCentral allocation.

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

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskIt is not stated whether assessors were blind to group allocation.

Incomplete outcome data (attrition bias)
All outcomes
Low risk3/60 women in the PLD arm did not receive any study drug and so were not included in the SAE analyses.

Selective reporting (reporting bias)High riskOS was not reported as there was an insufficient number of death events at the time of reporting. We requested final OS data from Telik Inc but received no reply to our queries.

Other biasHigh riskThis trial closed early. Planned enrolment = 244, actual enrolment = 125. See notes above. As a result of the clinical hold, 35 patients (21 in combo arm and 14 in PLD arm) were not able to complete their assigned therapy as per protocol.

CALYPSO 2010

MethodsPhase III open-label multicentre non-inferiority RCT. Accrual from Apr 2005 to Sept 2007. (ID: NCT00538603)


Participants976 women with PS ROC (recurrence > 6 months after first or second line platinum-based chemotherapy and had received a taxane). included if ECOG ≤ 2; previous taxane therapy; measurable or assessable disease; life-expectancy of at least 12 weeks; and adequate bone marrow, renal and hepatic function. Patients with pre-existing peripheral neuropathy grade > 1 were excluded. 


InterventionsArm 1 (509 women): carbo (AUC 5) + PAC (175 mg/m²) q3wks 

Arm 2 (466 women): carbo (AUC 5) + PLD (30 mg/m²) q4wks

Premedication of antiemetics (5HT agonist) and dexamethasone was to given to all women; those in the carbo/PAC arm also received clemastine and ranitidine.


OutcomesPrimary: PFS

Secondary: OS, SAE, QoL (QLQ C30 and OV 28) assessed at baseline, 3,6, 9 and 12 months


NotesOverall, severe non-haematological toxicity occurred in 36.8% of the PAC/carbo arm compared with 28.4% of the PLD/carbo arm (P < 0.01). Significantly fewer severe allergic reactions (grade 3 to 4) were observed in the PLD/carbo arm than in the PAC/carbo arm: 2.4% versus 8.8%, respectively (P < 0.001) (see Joly 2011).

Significantly more women in the PAC/carbo arm discontinued treatment before six cycles had been completed (110/507 versus 70/466), mainly due to toxicity (73/507 women versus 27/466 women; P < 0.001).

In total, 90% of women received post-progression treatment, 69% received two or more lines. The proportion of women in the PAC/carbo arm who received PLD as post-study therapy (68%) was significantly higher than the proportion of women in the PLD/carbo arm who received PAC (43%; P < 0.001); this may have influenced OS HRs in the direction of the PAC/carbo arm.

We obtained unpublished data on non-haematological adverse effects (grade 3 to 4) from the investigators.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentrally randomised. Randomisation was in permuted blocks of 6, with stratification by measurable disease, treatment free interval (6-12 versus >12 months) and centre.

Allocation concealment (selection bias)Low riskCentral allocation.

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

Blinding of outcome assessment (detection bias)
All outcomes
Low riskEvaluation assessments were independently reviewed.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition for survival and toxicity outcomes. Regarding QoL data, 79% of women in the carbo/PAC arm and 84% of women in the carbo/PLD arm had QoL data at baseline and one other point in the study. The most complete data set (< 20% missing data) was available at 3 months post-randomisation, therefore we used these data.

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported.

Other biasLow riskBaseline characteristics were similar and arms were well balanced for stratification factors. Imbalance in treatment allocation (509 versus 467) was consistent with chance.

Colombo 2012

MethodsPhase III open-label RCT conducted in 22 countries; accrual between Nov 2005 and Mar 2009 ID: NCT00262990


Participants829 women with PR ROC following ≤ 3 platinum-taxane based regimens. Measurable and non-measurable disease (but CA125 elevated at baseline); ovarian, fallopian and primary peritoneal cancer included. Excluded if peripheral neuropathy, unresolved bowel obstruction or diarrhoea had within 7 days of start of treatment.


InterventionsArm 1: PAT (10 mg/m²) IVI q3wk

Arm 2: PLD (50 mg/m²) IVI q4wk

No routine premedication was given to either arm.


OutcomesPrimary: OS

Secondary: PFS, ORR, SAE


NotesWomen were assessed 8-weekly; median follow-up was 27 months.

Arms received a median of 4.5 and 3 cycles for PAT and PLD respectively.

Median TTP was 15.9 weeks for both arms.

Median time to death was 56.6 weeks versus 54.4 weeks in favour of PAT.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation.

Allocation concealment (selection bias)Low riskAllocation via an interactive voice response system.

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

Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinded central review of results.

Incomplete outcome data (attrition bias)
All outcomes
Low riskVery few women lost to follow-up and low attrition (< 20%) in most analyses. As with other studies, QoL data suffered from high attrition rates and therefore we could not use it in the meta-analyses.

Selective reporting (reporting bias)Low riskAll expected outcomes were reported.

Other biasLow riskBaseline characteristics were similar.

Gordon 2001

MethodsPhase III multicentre open-label RCT with 104 sites in USA and Europe that recruited participants between May 1997 to March 1999.


Participants481 women with ROC (PS or PR) who had recurred or failed first-line platinum-based chemotherapy; with measurable disease, or measurable and assessable disease; adequate bone marrow, renal, hepatic and cardiac function; Karnofsky performance status ≥ 60%; expected to live > 3 months


InterventionsArm 1: PLD 50 mg/m² IVI over 1 hour, q4wk

Arm 2: TOP 1.5 mg/m²/d IVI over 30 min x 5d, q3wk


OutcomesPrimary: PFS

Secondary: ORR, OS, SAE, QoL (QLQ-C30)


NotesSeven women received no treatment after randomisation and were excluded from most analyses.

G-CSF was given to women who experienced febrile neutropenia, prophylactically in the following cycles; 29.1 % TOP versus 4.6% PLD received G-CSF. The Investigators concluded that PLD was the treatment of choice among non-platinum agents for women with ROC, especially platinum-sensitive disease.

72% and 74% of women in the TOP and PLD groups, respectively, received prior taxane therapy.

Median TTP was 17 weeks versus 16.1 weeks in favour of the TOP arm.

Median time to death was 59.7 weeks versus 62.7 weeks in favour of the PLD arm.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation; stratified by platinum sensitivity and bulky disease.

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
Low riskIndependent radiological review used for primary outcome (PFS).

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition low for primary outcomes (high for QoL data).

Selective reporting (reporting bias)Low riskAll expected outcomes reported. Censoring = 13%.

Other biasLow riskBaseline characteristics were similar.

HeCOG 2010

MethodsPhase II RCT of the Hellenic Cooperative Oncology Group. Accrual from Oct 199 to Dec 2005. (ID: ACTRN12609000436279)


Participants189 women with PS ROC (≥ 6 months after platinum-based chemotherapy). Included if ECOG 0-2; life expectancy ≥ 3 months; and adequate bone marrow, renal, hepatic function. Patients with residual neurotoxicity from previous platinum and/or taxane chemotherapy and those with other cancers were excluded


InterventionsArm 1: carbo (AUC 5) + PAC 175 mg/m² over 3 hours, q3wks

Arm 2: carbo (AUC 5) + PLD 45 mg/m², q4wks

Standard premedication included dexamethasone, dyphenhydramine and ranitidine for both groups, although the PAC group received both an oral (12 hours prior) and an IV dose (30 min prior to PAC administration). Six cycles intended.


OutcomesPrimary: ORR (WHO criteria or CA-125 Rustin's criteria) and toxicity

Secondary: TTP, OS


Notes204 women were randomised but 15 were subsequently considered to be ineligible and excluded. Median follow-up 43.6 months (95% CI 0.1 to 74.8).

88% and 93% respectively received previous taxane-containing therapy.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation.

Allocation concealment (selection bias)Low riskCentral randomisation/allocation.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAssessor blinding not described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition (< 20%). Fifteen post-randomisation exclusions due to non-eligibility including other cancers, non-measurable disease without CA-125 elevations. Eleven lost medical records, (5 in CP arm and 6 in CLD arm); 8 and 5 women lost to follow-up respectively.

Selective reporting (reporting bias)Low riskAll pre-specified outcomes reported.

Other biasLow riskNone noted. Baseline characteristics were similar.

Kaye 2012

MethodsPhase II open-label multicentre RCT; 1:1:1 ratio (ID: NCT00628251)


Participants97 women with ROC within 12 months of receiving platinum-based chemotherapy with confirmed BRCA1/2 germline mutations; one or more measurable lesion; ECOG PS 0-2; estimated life expectancy ≥ 16 weeks; adequate bone marrow, hepatic and renal function. Excluded if previous PARP inhibitors or anthracyclines; brain metastases; other malignant disease; persistent toxic effects of treatment; LVEF < 50%


InterventionsArm 1: OLA 200 mg bd continuously (32 women)

Arm 2: OLA 400 mg bd continuously (32 women)

Arm 3: PLD 50 mg/m² IVI q4wk (33 women)


OutcomesPrimary: PFS (RECIST-assessed)

Secondary: ORR, duration of treatment response, tumour size, OS, SAE, QoL (FACT-O)


NotesPARP nuclear enzymes facilitate DNA repair. Olaparib is a PARP inhibitor selective for homologous-recombination-deficient cells, such as those with BRCA1/2 deficiency.

The primary outcome was reported for the olaparib arms combined and individually, versus the PLD arm. We used the results from the OLA 400 mg arm versus PLD. Median time to progression was 38 weeks versus 30 weeks in favour of OLA. Median time to death was not calculable for the OLA group and was 76 weeks for the PLD group (unpublished data).

Corticosteroids and serotonin antagonists were given to 22/33 (67%) and 14/33 (42%) of the women in the PLD group respectively versus 12.5 % and 12.5% of the OLA group respectively, but it was not possible to determine whether they were given as premedication or at another time (unpublished information).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated, block randomisation, stratified according to BRCA status and platinum sensitivity (≤ 6 months and > 6 months).

Allocation concealment (selection bias)Low riskAllocation via an Interactive Voice Response System

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

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk'Centrally reviewed tumour assessments' were used for analyses; investigator-assessed primary outcome; assessor blinding/independence not described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskIn the PLD arm, 5/33 discontinued treatment for unknown reasons versus 1/64 in the olaparib arm. Otherwise, attrition rates seem low.

Selective reporting (reporting bias)Low riskAll expected outcomes reported. Results are not reported for platinum-sensitive subgroups; these data were requested from the lead investigator on the 6/12/12.

Other biasLow riskBaseline characteristics were similar except that more women in Arm 2 had received > 2 prior chemotherapy regimens.

M200 2009

MethodsMulticentre open-label RCT; enrolment in USA from July 2007 to Oct 2008. (ID: NCT00635193)


Participants127 women with stage III/IV PS or PR ROC. Maximum of 2 prior chemotherapy treatments (at least one of which was platinum/taxane based); at least one measurable lesion to assess response by RECIST.


InterventionsVolociximab (M200) is an anti-angiogenic integrin inhibitor/monoclonal antibody. Two dosage regimes were tested combined with PLD versus PLD alone:

Arm 1: PLD 40 mg/m² q4wk (66 women)

Arm 2: M200 15 mg/kg qwk + PLD 40 mg/m² q4wk (34 women)

Arm 3: M200 15 mg/kg q2wk + PLD 40 mg/m² q4wk (27 women)


OutcomesEfficacy, safety and tolerability


NotesNo useable data. Results were reported as follows: 'The most common Grade 3 to 4 AEs (≥5% in any group) were abdominal pain, intestinal obstruction, ascites, fatigue, hypoalbuminemia, and cytopenias. The incidence of AEs was balanced across treatment groups. "There were no CRs; PRs were 16%, 18%, and 19%....Preliminary analysis of PFS suggested that there was a low probability of detecting a statistically significant difference in favor of V+PLD, so the study was closed to enrollment."


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNot described.

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

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskEfficacy and safety were not clearly detailed in the ASCO 2009 abstract which is the only publication for this study.

Selective reporting (reporting bias)Unclear riskBaseline data were not reported.

Other biasUnclear riskLimited information was available and results have not been published in full. Dr Obrocea of Abbott Laboratories was emailed on 28/11/2012 for final study data.

MITO-3 2008

MethodsPhase III multicentre RCT; accrual from Jan 2003 to Jan 2007.


Participants153 women with ROC that had relapsed within 12 months (PPS and PR ROC) of receiving one platinum/paclitaxel regimen. Women had measurable or assessable disease (RECIST), adequate hepatic, renal, cardiac and bone marrow function, no prior malignancies, and were expected to live > 3months.


InterventionsArm 1: GEM (1000 mg/m²) days 1, 5, 8, 15, q4wk

Arm 2: PLD (40 mg/m²) IVI, q4wk

Methylprednisolone 20 mg was given as premedication to the PLD arm.


OutcomesPrimary: TTP (time to progression)

Secondary: OS, ORR, SAE, QoL (QLQ-C30)


NotesTrial used a lower (40 mg/m²) dose of PLD to minimise SAEs.

Post-progression treatment was only documented in 36 participants so OS data difficult to interpret.

Median TTP was 20 weeks versus 16 weeks in favour of GEM.

Median time to death was 51 weeks versus 56 weeks in favour of PLD.

HR for OS and PFS not given but requested from Dr Ferrandina on 3/12/12.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation.

Allocation concealment (selection bias)Low riskRandom assignment by central telephone service.

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants and physicians not blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.

Selective reporting (reporting bias)Low riskPrimary outcome was TTP. PFS/OS were not reported clearly with HRs but we were able to obtain these from the investigators in January 2013.

Other biasLow riskTreatment groups were well balanced for baseline characteristics. 

Mutch 2007

MethodsPhase III open-label multicentre RCT; accrual from July 2002 to May 2004 at 44 sites in the USA.


Participants195 women with PR ROC who had received 1-2 prior platinum-based chemotherapy regimens with measurable (RECIST) or assessable disease (Zubrod performance status of 0 to 2 and adequate bone marrow, hepatic and neurological function.


InterventionsArm 1: GEM (1000 mg/m²) IV day 1, 8 q3wk

Arm 2: PLD (50 mg/m²) IV q4wk


OutcomesPrimary: PFS

Secondary: OS, SAE (NCI-CTCAE v 2.0) QoL (FACT-O)


NotesIf participants experienced disease progression, unacceptable toxicity or if cumulative PLD dose exceeded 500 mg/m², they crossed over to the alternative drug. Median follow-up was 29.2 months. 99% of women had received prior taxane.

Median TTP was 15.4 weeks versus 13.3 weeks in favour of the GEM arm.

Median time to death was 54.4 versus 57.9 weeks in favour of the PLD arm.

PFS and OS were not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation.

Allocation concealment (selection bias)Low riskCentral allocation.

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

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskIndependent assessment/blinding not described.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber of events/(total number evaluated) and censoring was not described for the primary outcome (PFS) or OS. Attrition for QoL outcomes not reported. Additional data requested from authors 4/12/12.

Selective reporting (reporting bias)High riskHRs, number of events, and censoring was not described for the primary outcome (PFS) or OS. Limited (non-comparative) QoL data reported. Additional data requested from authors 4/12/12.

Other biasLow riskBaseline characteristics were similar.

O'Byrne 2002

MethodsPhase III multicentre RCT. Accrual May 1997 to April 2000. (ID: NCT00653952)


Participants438 women with ROC (PS or PR) that had 1 prior course of platinum-based non-taxane containing chemotherapy and evaluable disease. Prior therapy with PLD or PAC was an exclusion criterion.


InterventionsArm 1: PLD 50 mg/m² IVI over 60 min q4wk (D)

Arm 2: Paclitaxel 175 mg/m² over 3 hours q3wk (P)


OutcomesOS, PFS and SAE


NotesThis study is listed as 'Terminated' on the NCT registry after enrolling 220 women. The only published report is an ASCO 2002 abstract which had no data that could be included in our meta-analyses. Results were reported as follows: 'A preliminary analysis indicates that the overall progression-free survival rates are similar between the two arms (D: 21.7 versus P: 22.4 weeks; P value 0.15). The overall response rates for D and P are 17.8% and 22.4%, respectively (P value 0.34). Median overall survival times are 45.7 weeks for D and 56.1 weeks for P (P value 0.44). No significant difference was seen in median progression-free or overall survival for platinum sensitive or refractory patients in either treatment arm. The overall number of adverse events was equivalent in either arm. Nausea and vomiting, stomatitis and plantar-palmar erythrodysesthesia were seen more frequently with D whereas alopecia, myalgia, arthralgia and paraesthesiae occurred more commonly with P. These findings clearly indicate that D has comparable efficacy to P in taxane naive patients with ROC. D may be particularly suitable for those patients with musculoskeletal disorders or for whom the prospect of alopecia has a significant adverse psychological effect.'


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described. Stratified prospectively for platinum sensitivity and bulky disease.

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 riskAssessor blinding not described.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information given to assess this risk.

Selective reporting (reporting bias)Unclear riskVery limited results were reported; see notes section above. Baseline characteristics stated as 'well-matched'.

Other biasHigh risk214 women were enrolled and yet the study was terminated. The reason for termination was 'poor accrual' and the final results for the 214 women were, to our knowledge, never published. Janssen Oncology emailed on 29/11/12 for more data (no response).

OVA-301 2010

MethodsPhase III multicentre RCT (21 countries); recruited from April 2005 to May 2007. Participants were followed up every 8 weeks.


Participants672 women with PR ROC (PFI < 6 months) and women with PS ROC (PFI ≥ 6 months), excluding platinum refractory patients. Planned enrolment was 650 women.

Included if measurable disease was present (defined by RECIST); only 1 prior platinum-based regimen received; ECOG PS 0,1 or 2; PFI based on radiological evaluation; no other major medical conditions.


InterventionsArm 1: Dexamethasone (IVI 20 mg) + PLD (30 mg/m²) IVI for 90 min +TBD (1.1 mg/m²) IVI for 3-hours, every 21 days

Arm 2: PLD (50 mg/m²) IVI for 90 min every 28 days


OutcomesPrimary: PFS

Secondary: OS, ORR, duration of response, SAE (NCI-CTCAE v3.0)

Tertiary: QoL


NotesGrowth factor was necessary in 42% arm 1 versus 17% arm 2 to treat neutropenia (precise figures were not given). There were more withdrawals in the TBD arm than the PLD alone arm due to patient choice or adverse events (126 versus 89 participants).

Dexamethasone was given to the TBD group only to reduce hepatic toxicity (personal communication).

When results were subgrouped by platinum sensitivity, only women in the PS ROC group experienced significantly longer PFS with arm 1; i.e. TBD + PLD offered no significant additional benefit over PLD alone for women with PR ROC. Similarly for OS, only the PPS ROC subgroup of arm 1 had a statistically significantly longer OS than the arm 2 subgroup (HR 0.59; 95% CI 0.42 to 0.82; P value 0.0015).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral block randomisation (1:1) with stratification by platinum sensitivity and ECOG PS.

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
Low riskIndependent radiological assessment and oncologist review.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll expected outcomes were reported, although missing data was >20% for QoL outcomes.

Selective reporting (reporting bias)Unclear riskThe reduced rate of PLD toxicity reported in the TBD + PLD arm could have been due to the premedication drug dexamethasone (and not TBD) that was given to the experimental group, or due to the lower dose of PLD used. This was not mentioned in any of the trial publications.

Other biasUnclear riskWomen in arm 2 had a significantly longer PFI than arm 1 (P value 0.009) which may have biased the survival data in the direction of PLD alone. When the investigators adjusted OS results for the PFI and other prognostic factors in ad hoc exploratory analyses, the adjusted OS produced a statistically significant result in favour of arm 1 (HR = 0.82; 95% CI 0.69 to 0.98; P value 0.0285).

PRECEDENT 2013

MethodsPhase II open-label multicentre RCT; randomisation ratio EC145 (Vintafolide) + PLD to PLD was 2:1; recruitment between Sept 2008 and June 2010 in USA, Canada and Poland.


Participants162 women with PR ROC (149 had measurable disease); ≥18 years; ECOG performance status of 0-2; measurable disease; ≤ 2 prior systemic cytotoxic regimens and adequate organ function. Excluded if prior exposure to PLD, folate-receptor (FR) targeted therapy or vinca-containing compounds; recent surgery; serious comorbidities; concurrent malignancy.


InterventionsArm 1 (100 women): EC145 (2.5 mg IV days 1,3 and 5, weeks 1 and 3, q4wk) + PLD (50 mg/m²) q4wk

Arm 2 (49 women): PLD (50 mg/m²) IV q4wk

EC145 is a folate-linked vinca alkaloid. Premedication was optional, but considered not necessary for EC145 administration.


OutcomesPrimary: PFS assessed within 12 months following completion of accrual using RECIST and clinical findings

Secondary: OS assessed within 18 months after PFS analysis; ORR; safety and tolerability; correlation between therapeutic response and 99mTc-EC20 levels.


NotesWe contacted the investigators, who gave us access to their unpublished manuscript and provided us with additional unpublished data.

The Independent radiologic committee (IRC) assessment in women with more than one CT scan correlation was 74%. PFS was not significantly different between the treatment groups for the IRC assessment except for the subgroup of folate-receptor positive women.

One woman in each group required growth factor support (unpublished data).

Median OS was unusually long in the PLD only arm (16.8 months)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation 2:1 EC145/PLD:PLD. Stratified according to primary or secondary platinum resistance, treatment centre, and baseline CA-125 (<200 versus ≥200 U/ml).

Allocation concealment (selection bias)Low riskCentral randomisation.

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

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessment was based upon investigator assessment using RECIST criteria, however blinded assessment was performed by an IRC to check for investigator bias.

Incomplete outcome data (attrition bias)
All outcomes
Low riskCensoring due to clinical progression was 12% and 10% for treatment arms respectively. Eight women in the EC145 arm were withdrawn from EC145 due to treatment related AEs (7.5%) but were included in ITT analyses. Women with non-measurable disease (13) were included in the safety analyses but excluded from the survival analyses.

Selective reporting (reporting bias)Low riskAll pre-specified outcomes reported. Sensitivity analysis performed for primary outcome.

Other biasLow riskBaseline characteristics were similar between the arms except for the number of tumour lesions, which was greater in the EC145 arm, however this was not a prognostic factor for shorter PFS.

SWOG S0200 2008

MethodsPhase III multicentre RCT. Accrual from Aug 2002 and Dec 2004. (ID:NCT00043082)


Participants61 women with PS ROC or peritoneal cancer; a progression-free and platinum-free interval of 6 to 24 months according to RECIST or GCIG CA-125 criteria; progression following first-line platinum based CT and up to 12 courses of non-platinum containing consolidation treatment;  Zubrod performance status 0-1.


InterventionsArm 1: PLD (30 mg/m²) IV plus carbo IV (AUC = 5 mg/mL/min) q4wk

Arm 2: carbo IV (AUC = 5 mg/mL/min) q4wk

Patients could receive a premed of intravenous dexamethasone (20 mg) plus IV granisetron before carbo dose, and further dexa on days 2,3, and 4.

G-CSF was allowed to treat G3 to 4 neutropenia when it occurred, and then subsequently to prevent it.


OutcomesPrimary: OS

Secondary: PFS, ORR, toxicity


NotesThe accrual goal was 900 but study was discontinued due to slow accrual.

Unpublished final survival data related to the 2010 publication was received from investigators on 13/12/12. PFS was significantly improved by the addition of PLD to carbo. The final OS was not statistically significantly different between treatment arms, in contrast to the earlier report of 2008 where OS was significantly longer in the PLD/carbo arm.

Despite using a lower dose of PLD, this trial had a relatively high rate of haematological SAEs (G3 to 4) in the PLD/carbo arm compared with the carbo alone arm (neutropenia 48% versus 3%; anaemia 16% versus 0%; thrombocytopenia 39% versus 10%). Eight women in the carbo arm had allergic reactions (any grade) compared with 0 in the PLD/carbo arm. The HFS rate was 3/31 (10%) in the PLD/carbo arm. The proportion of women in each group who received a dexamethasone premed was not described.

Investigators concluded that PLD/carbo dosing interval was more convenient than the PAC/carbo and GEM/carbo alternatives; that PLD was well tolerated with no significant HFS problems; and that 'administering PLD with carboplatin appears to substantially reduce the incidence of platinum-associated hypersensitivity reactions'.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation.

Allocation concealment (selection bias)Low riskCentral allocation.

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

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.

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

Selective reporting (reporting bias)Low riskFinal HRs for survival were not published, however the investigators provided us with these unpublished data.

Other biasUnclear riskThis study closed early due to insufficient accrual and the final sample size was not powered to detect a survival difference.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

ASSIST-1 2009RCT of canfosfamide versus topotecan or PLD, however allocation of the control intervention (TOP or PLD) depended on previous treatment and therefore was not a random process.

Cherchi 2003Not an RCT.

GOG0182/ICON 5A multicentre RCT to evaluate new platinum-based combination treatments, including PLD, GEM and TOP for first-line treatment of advanced stage OC, not relapsed OC.

Kavanagh 2004Not an RCT.

MITO-2 2011A multicentre RCT of carboplatin plus paclitaxel versus carboplatin plus PLD as first-line treatment for OC, not relapsed OC.

Palaia 2006Not an RCT.

Scarfone 2006Not an RCT.

 
Characteristics of ongoing studies [ordered by study ID]
ABT-888/NCT01113957

Trial name or titleA trial of ABT-888 in combination with temozolomide versus pegylated liposomal doxorubicin alone in ovarian cancer

MethodsPhase II open-label multicentre RCT

Participants150 women with recurrent high grade serous OC; must be PR or unable to tolerate platinum-based therapy

InterventionsABT-888 + temozolomide versus PLD

OutcomesPrimary: ORR based on tumour measurements and CA125 levels (assessed every 3 months for 3 years)

Secondary: PFS, OS, 12-month survival rate, 6-month PFS rate, duration of response, safety and tolerability, QoL

Starting dateMar 2010

Contact informationYan Luo (Abbott): yan.luo@abbott.com

NotesEnd date: Mar 2013

AGOG06-001

Trial name or titlePhase III RCT of maintenance pegylated liposomal doxorubicin (PLD)/carboplatin versus without in patients with advanced ovarian cancer. (ANZCTR reg. ID: ACTRN12607000329460)

MethodsOpen-label RCT; central, computerised, block randomisation with allocation concealment; stratified by residual tumour after primary surgery and baseline CA-125

Participants290 women with advanced OC in complete remission after first-line chemotherapy

InterventionsMaintenance PLD (30 mg/m²)/carboplatin (AUC 4) in 28-day cycles for 6 courses versus observation (no treatment) after complete remission of first-line chemotherapy

OutcomesPrimary: PFS

Secondary: OS, QoL, safety profile

Starting dateJune 2007

Contact informationTTY BIOPHARM and the Asian Gynecologic Oncology group (AGOG)

Chang Gung Memorial Hospital, Taiwan. DR C-H Lai: laich46@cgmh.org.tw

NotesAs at 16/11/12, 49 women enrolled.

ATI0918/NCT01715168

Trial name or titleA cross-over bioequivalence study of intravenously administered ATI0918 and DOXIL/CAELYX in patients with ovarian cancer

MethodsPhase I single-blind RCT

Participants40 women with ROC

InterventionsPLD (50 mg/m²) versus ATI-0918

OutcomesPharmaco-equivalence outcomes

Starting dateOct 2012

Contact informationKaren Kuhn: kkuhn@ockham.com

NotesMay 2013

AURELIA

Trial name or titleAURELIA: A study of Avastin (Bevacizumab) added to chemotherapy in patients with platinum-resistant ovarian cancer (NCT ID: NCT00976911)

MethodsPhase III open-label multicentre RCT

Participants300 women with PR ROC

InterventionsLD+paclitaxel+TOP versus BEV+LD+paclitaxel+TOP

OutcomesPrimary: PFS

Secondary: ORR, QoL, SAE

Starting dateOct 2009

Contact informationHoffmann-La Roche: genentechclinicaltrials@druginfo.com

NotesNCT00976911

End Date: Dec 2013

HECTOR

Trial name or titleTopotecan plus carboplatin (TC) versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or carboplatin plus pegylated doxorubicin (PLDC): a randomised phase III trial of the NOGGO-AGO-Germany-AGO Austria and GEICO-GCIG intergroup study (HECTOR)

MethodsPhase III multicentre RCT

Participants550 women with PS ROC.

InterventionsArm 1:TC

Arm 2: GC or PC or PLDC

OutcomesPrimary: PFS

Secondary: toxicity

Starting dateAccrual from Feb 2007 to Dec 2009

Contact informationSehouli@aol.com

NotesInterim data of the first 200 women were presented at ASCO 2012. However, approx. 78% of control arm received GC and it is not clear how many participants, if any, received the PLDC intervention. We emailed the lead investigator for more information on 13/11/12 and 30/11/12.

IMC-383/NCT00913835

Trial name or titleA study of liposomal doxorubicin with or without IMC-3G3 in platinum-refractory or resistant advanced ovarian cancer

MethodsPhase II open-label RCT

Participants125 women with ROC

InterventionsIMC-383 + LD versus LD

OutcomesPrimary: PFS

Secondary: OS, ORR, duration of response, SAE

Starting dateJun 2009

Contact informationClinicalTrials@ ImClone.com

NotesEnd Date: Oct 2011

INOVATYON

Trial name or titlePhase III international, randomised study of trabectedin plus pegylated liposomal doxorubicin (PLD) versus carboplatin plus PLD in patients with ovarian cancer progressing within 6-12 months of last platinum (ID: NCT01379989)

MethodsPhase III multicentre RCT

Participants558 women with ROC 6-12 months after completion of first line treatment with platinum-based chemotherapy

Interventionstrabectedin + PLD (30 mg/m²) versus carboplatin + PLD (30 mg/m²).

OutcomesPrimary: OS

Secondary: PFS, ORR, CA125, duration of response, time to subsequent CT, safety

Starting dateJun 2010

Contact informationNicoletta Colombo

NotesEnd Date: Dec 2017

Suspended due to the PLD shortage in 2011/12

MITO-8

Trial name or titleLiposomal doxorubicin versus carboplatin/paclitaxel in patients with ovarian cancer recurrence between 6 and 12 months after previous platinum based therapy: phase III randomised multicentre study (ID: NCT00657878)

MethodsPhase III open-label multicentre RCT

Participants250 women with PS ROC

InterventionsPLD 40 mg/m² (or GEM or TOP) followed by CP versus CP followed by PLD 40 mg/m² (or GEM or TOP)

OutcomesPrimary: OS

Secondary: PFS, QoL, ORR, toxicity

Starting dateApr 2008

Contact informationMarilina Piccirillo: marilina.piccirillo@usc-intnapoli.net

NotesEnd Date: Nov 2014. As at 8/3/13, 149 women were enrolled.

NCT01100372

Trial name or titleRandomised phase II AGO-study comparing combined liposomal doxorubicin (Myocet) and gemcitabine (Gemzar) With liposomal doxorubicin (Myocet) monotherapy in platinum-refractory and platinum-resistant epithelial cancer of the ovary, fallopian tube and the peritoneum (Other IDs: CDR0000669716/ MUI-AGO-10/ EUDRACT-2008-008746-20/ EU-21028)

MethodsPhase II open-label multicentre RCT

Participants154 women with PR ROC

InterventionsLD + GEM versus LD

OutcomesPrimary: CR, PR

Secondary: QoL, PFS, OS, toxicity

Starting dateJun 2009

Contact informationAlain Zeimet (Innsbruck Universitaetsklinik)

NotesMay 2014

NCT01666444

Trial name or titleVTX-2337 and pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer

MethodsPhase II double blind multicentre RCT

Participants210 women with PR ROC

InterventionsVTX-2337 + PLD versus PLD + placebo

OutcomesPrimary: OS

Secondary: PFS, toxicity, ORR, DCR

Starting dateAug 2012

Contact informationBradley Monk: bradley.monk@chw.edu

NotesEnd Date: Mar 2016

NGR018

Trial name or titlePhase II study of NGR-hTNF in combination with doxorubicin in platinum-resistant ovarian cancer (ID: NCT01358071)

MethodsPhase II open-label multicentre RCT

Participants100 women with PR ROC

InterventionsNGR-hTNF + PLD (50 mg/m²) or doxorubicin versus PLD (50 mg/m²) or doxorubicin

OutcomesPrimary: PFS

Secondary: OS, RR, DCR, DDC, safety and toxicity

Starting dateJun 2011

Contact informationAntonio Lambiase (MolMed)

NotesEnd Date: Dec 2012

PROCEED

Trial name or titleStudy for women with platinum resistant ovarian cancer evaluating EC145 in combination with Doxil

MethodsPhase III multicentre RCT

Participants640 women with PR ROC (including 500 folate-receptor positive women)

InterventionsEC145 + PLD (50 mg/m²) versus PLD (50 mg/m²) + placebo

OutcomesPrimary: PFS assessed at 6 week intervals to weeks 24 then at 8 week intervals using RECIST v1.1

Secondary: OS, SAE up to 26 months

Starting dateApr 2011

Contact informationBinh Nguyen (Endocyte)

NotesEnd Date: May 2015

PROVE

Trial name or titlePROVE A randomised phase II trial of standard carboplatin-based chemotherapy with or without panitumumab in platinum-sensitive recurrent ovarian cancer (NCT ID: NCT01388621)

MethodsPhase II open-label RCT

Participants140 women with ROC

InterventionsPanitumumab + carbo + PLD or GEM  versus  carbo + PLD or GEM

OutcomesPrimary: PFS

Secondary: OS, duration of response, SAE, translational research

Starting dateOct 2011

Contact informationSascha M Neugebauer; info@wisp.de

NotesEnd Date: Jul 2015

SGI-110/NCT01696032

Trial name or titleA randomised, controlled, open-label, phase 2 trial of SGI-110 and carboplatin in subjects with platinum-resistant recurrent ovarian cancer

MethodsPhase II open-label RCT

Participants116 women with PR ROC

InterventionsSGI-110 + carbo versus PLD (40 mg/m²) or TOP or paclitaxel

OutcomesPrimary; SAE, PFS, CA125

Secondary: ORR, duration of response, OS

Starting dateOct 2012

Contact informationAstex Pharmaceuticals; Medpace Recruitment Center

NotesEnd Date: Jul 2014

TRINOVA-2

Trial name or titleTrial IN OVArian cancer-2: A phase 3, randomised, double-blind trial of pegylated liposomal doxorubicin (PLD) plus AMG 386 or placebo in women with recurrent partially platinum sensitive or resistant epithelial ovarian, primary peritoneal, or fallopian tube cancer (ID: NCT01281254)

MethodsPhase III multicentre double-blind RCT

Participants380 women with recurrent PPS or PR epithelial ovarian, primary peritoneal or fallopian tube cancer

InterventionsAMG 386 + PLD (50 mg/m²) versus PLD (50 mg/m²) + placebo

OutcomesPrimary: OS

Secondary: PFS, ORR, CA125, duration of response, time to subsequent CT, safety

Starting dateJan 2011

Contact informationAMGEN

NotesEnd Date: Jun 2018

Suspended due to the PLD shortage

Volasertib/NCT01121406

Trial name or titlePhase II randomised trial of the polo-like kinase 1 inhibitor BI 6727 (Volasertib) monotherapy versus investigator´s choice chemotherapy in ovarian cancer patients resistant or refractory to platinum-based cytotoxic therapy

MethodsPhase II open-label multicentre RCT

Participants100 women with PR OC

InterventionsBI 6726 versus paclitaxel or GEM or TOP or PLD

OutcomesPrimary: DCR at week 24

Secondary: PFS, adverse events, QoL

Starting dateApr-10

Contact informationBoehringer Ingelheim Pharmaceuticals

NotesActive, not recruiting. End date: May-13

 
Comparison 1. PLD/carbo vs carbo ± other

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

 1 PFS3Hazard Ratio (Random, 95% CI)Subtotals only

    1.1 PLD/carbo vs carbo only
161Hazard Ratio (Random, 95% CI)0.52 [0.31, 0.88]

    1.2 PLD/carbo vs PAC/carbo
21164Hazard Ratio (Random, 95% CI)0.85 [0.74, 0.97]

 2 OS3Hazard Ratio (Random, 95% CI)Subtotals only

    2.1 PLD/carbo vs carbo only
161Hazard Ratio (Random, 95% CI)0.69 [0.40, 1.21]

    2.2 PLD/carbo vs PAC/carbo
21164Hazard Ratio (Random, 95% CI)1.01 [0.88, 1.17]

 3 SAE: Hand-foot syndrome (G3)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 PLD/carbo vs carbo only
161Risk Ratio (M-H, Random, 95% CI)2.91 [0.12, 68.66]

    3.2 PLD/carbo vs PAC/carbo
21140Risk Ratio (M-H, Random, 95% CI)4.30 [0.92, 20.15]

 4 SAE: Anaemia (G3/4)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 PLD/carbo vs carbo only
161Risk Ratio (M-H, Random, 95% CI)10.66 [0.61, 184.70]

    4.2 PLD/carbo vs PAC/carbo
21140Risk Ratio (M-H, Random, 95% CI)1.59 [1.02, 2.50]

 5 SAE: Febrile neutropenia (G3/4)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 PLD/carbo vs carbo only
1361Risk Ratio (M-H, Random, 95% CI)0.65 [0.03, 12.37]

    5.2 PLD/carbo vs PAC/carbo
1967Risk Ratio (M-H, Random, 95% CI)0.61 [0.31, 1.23]

 6 SAE: Neutropenia (G3/4)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 PLD/carbo vs carbo only
161Risk Ratio (M-H, Random, 95% CI)14.52 [2.04, 103.16]

    6.2 PLD/carbo vs PAC/carbo
21140Risk Ratio (M-H, Random, 95% CI)0.91 [0.60, 1.36]

 7 SAE: Thrombocytopenia (G3/4)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 PLD/carbo vs carbo only
161Risk Ratio (M-H, Random, 95% CI)3.87 [1.21, 12.36]

    7.2 PLD/carbo vs PAC/carbo
21140Risk Ratio (M-H, Random, 95% CI)2.69 [1.83, 3.96]

 8 SAE: Stomatitis/mucositis (G 3/4)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    8.1 PLD/carbo vs PAC/carbo
21140Risk Ratio (M-H, Random, 95% CI)2.27 [0.82, 6.29]

 9 SAE: Vomiting (G 3/4)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    9.1 PLD/carbo vs carbo only
161Risk Ratio (M-H, Random, 95% CI)2.91 [0.12, 68.66]

    9.2 PLD/carbo vs PAC/carbo
21140Risk Ratio (M-H, Random, 95% CI)1.40 [0.44, 4.42]

 10 SAE: Alopecia (G2)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    10.1 PLD/carbo vs PAC/carbo
21140Risk Ratio (M-H, Random, 95% CI)0.09 [0.06, 0.15]

 11 SAE: Neurological (G3/4)21140Risk Ratio (M-H, Random, 95% CI)0.20 [0.08, 0.50]

    11.1 PLD/carbo vs PAC/carbo
21140Risk Ratio (M-H, Random, 95% CI)0.20 [0.08, 0.50]

 12 SAE: Fatigue (G3/4)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    12.1 PLD/carbo vs carbo only
161Risk Ratio (M-H, Random, 95% CI)1.45 [0.26, 8.09]

    12.2 PLD/carbo vs PAC/carbo
21140Risk Ratio (M-H, Random, 95% CI)1.02 [0.66, 1.57]

 13 SAE: Arthralgia/myalgia (G3/4)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    13.1 PLD/carbo vs carbo only
161Risk Ratio (M-H, Random, 95% CI)0.32 [0.01, 7.63]

    13.2 PLD/carbo vs PAC/carbo
21140Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.67]

 14 SAE: Hypersensitivity reactions (HSR; G3/4)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    14.1 PLD/carbo vs carbo only
161Risk Ratio (M-H, Random, 95% CI)0.09 [0.01, 1.53]

    14.2 PLD/carbo vs PAC/carbo
21140Risk Ratio (M-H, Random, 95% CI)0.29 [0.15, 0.54]

 15 SAE: Treatment-related death1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    15.1 PLD/carbo vs PAC/carbo
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 16 QoL: Global health score (mean change)1Mean Difference (IV, Random, 95% CI)Totals not selected

 17 Discontinuation due to toxicity21150Risk Ratio (M-H, Random, 95% CI)0.38 [0.26, 0.57]

    17.1 PLD/carbo vs PAC/carbo
21150Risk Ratio (M-H, Random, 95% CI)0.38 [0.26, 0.57]

 18 Antibiotics required2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    18.1 PLD/carbo vs PAC/carbo
21144Risk Ratio (M-H, Random, 95% CI)1.12 [0.57, 2.21]

 19 G-CSF required1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    19.1 PLD/carbo vs PAC/carbo
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 20 Blood transfusion required2Risk Ratio (M-H, Random, 95% CI)Totals not selected

    20.1 PLD/carbo vs carbo only
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    20.2 PLD/carbo vs PAC/carbo
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 2. Other drug vs PLD

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

 1 PFS4Hazard Ratio (Random, 95% CI)Subtotals only

    1.1 GEM vs PLD
1153Hazard Ratio (Random, 95% CI)1.15 [0.78, 1.70]

    1.2 TOP vs PLD
1481Hazard Ratio (Random, 95% CI)1.12 [0.94, 1.34]

    1.3 OLA vs PLD
160Hazard Ratio (Random, 95% CI)0.86 [0.46, 1.62]

    1.4 PAT vs PLD
1828Hazard Ratio (Random, 95% CI)1.05 [0.89, 1.24]

 2 OS5Hazard Ratio (Random, 95% CI)Subtotals only

    2.1 GEM vs PLD
2348Hazard Ratio (Random, 95% CI)1.23 [0.81, 1.88]

    2.2 TOP vs PLD
1481Hazard Ratio (Random, 95% CI)1.23 [1.01, 1.50]

    2.3 OLA vs PLD
160Hazard Ratio (Random, 95% CI)1.01 [0.44, 2.29]

    2.4 PAT vs PLD
1828Hazard Ratio (Random, 95% CI)0.93 [0.79, 1.09]

 3 SAE: HFS (G3)5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 GEM vs PLD
2338Risk Ratio (M-H, Random, 95% CI)0.07 [0.01, 0.54]

    3.2 TOP vs PLD
1474Risk Ratio (M-H, Random, 95% CI)0.01 [5.69, 0.15]

    3.3 OLA vs PLD
164Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.65]

    3.4 PAT vs PLD
1811Risk Ratio (M-H, Random, 95% CI)0.01 [5.68, 0.15]

 4 SAE: Stomatitis (G3/4)5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 GEM vs PLD
2338Risk Ratio (M-H, Random, 95% CI)0.40 [0.08, 2.05]

    4.2 TOP vs PLD
1474Risk Ratio (M-H, Random, 95% CI)0.05 [0.01, 0.38]

    4.3 OLA vs PLD
164Risk Ratio (M-H, Random, 95% CI)0.2 [0.01, 4.01]

    4.4 PAT vs PLD
1811Risk Ratio (M-H, Random, 95% CI)0.05 [0.01, 0.20]

 5 SAE: Neutropenia (G3/4)5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 GEM vs PLD
2338Risk Ratio (M-H, Random, 95% CI)2.25 [1.46, 3.47]

    5.2 TOP vs PLD
1474Risk Ratio (M-H, Random, 95% CI)6.31 [4.46, 8.94]

    5.3 OLA vs PLD
164Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.31]

    5.4 PAT vs PLD
1811Risk Ratio (M-H, Random, 95% CI)0.30 [0.16, 0.56]

 6 SAE: Anaemia (G3/4)5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 GEM vs PLD
2338Risk Ratio (M-H, Random, 95% CI)1.33 [0.47, 3.73]

    6.2 TOP vs PLD
1474Risk Ratio (M-H, Random, 95% CI)5.16 [2.93, 9.10]

    6.3 OLA vs PLD
164Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 100.20]

    6.4 PAT vs PLD
1811Risk Ratio (M-H, Random, 95% CI)1.22 [0.62, 2.39]

 7 SAE: Thrombocytopenia (G3/4)4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 GEM vs PLD
2338Risk Ratio (M-H, Random, 95% CI)2.15 [0.32, 14.57]

    7.2 TOP vs PLD
1474Risk Ratio (M-H, Random, 95% CI)27.12 [8.69, 84.67]

    7.3 OLA vs PLD
164Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.89]

 8 SAE: Vomiting (G3/4)41213Risk Ratio (M-H, Random, 95% CI)1.39 [0.72, 2.65]

    8.1 GEM vs PLD
2338Risk Ratio (M-H, Random, 95% CI)1.03 [0.10, 11.12]

    8.2 OLA vs PLD
164Risk Ratio (M-H, Random, 95% CI)1.0 [0.22, 4.59]

    8.3 PAT vs PLD
1811Risk Ratio (M-H, Random, 95% CI)1.40 [0.84, 2.32]

 9 SAE: Fatigue/asthenia (G3/4)41213Risk Ratio (M-H, Random, 95% CI)1.49 [0.73, 3.03]

    9.1 GEM vs PLD
2338Risk Ratio (M-H, Random, 95% CI)3.44 [0.47, 24.92]

    9.2 OLA vs PLD
164Risk Ratio (M-H, Random, 95% CI)0.75 [0.18, 3.09]

    9.3 PAT vs PLD
1811Risk Ratio (M-H, Random, 95% CI)1.26 [0.82, 1.93]

 10 SAE: Neurological (G3/4)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    10.1 GEM vs PLD
1195Risk Ratio (M-H, Random, 95% CI)0.32 [0.01, 7.84]

    10.2 PAT vs PLD
1811Risk Ratio (M-H, Random, 95% CI)12.72 [3.03, 53.34]

 11 SAE: Alopecia (G2)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    11.1 TOP vs PLD
1474Risk Ratio (M-H, Random, 95% CI)4.75 [1.38, 16.30]

 12 SAE: Allergy (G3/4)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 13 SAE: Diarrhoea (G3/4)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    13.1 OLA vs PLD
164Risk Ratio (M-H, Random, 95% CI)0.2 [0.01, 4.01]

    13.2 PAT vs PLD
1811Risk Ratio (M-H, Random, 95% CI)11.64 [5.97, 22.69]

 14 Dose reductions4Risk Ratio (M-H, Random, 95% CI)Subtotals only

 15 Dose delays2Risk Ratio (M-H, Random, 95% CI)Subtotals only

 
Comparison 3. PLD + other drug vs PLD

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

 1 PFS3Hazard Ratio (Random, 95% CI)Subtotals only

    1.1 TBD/PLD vs PLD
1672Hazard Ratio (Random, 95% CI)0.79 [0.65, 0.96]

    1.2 CAN/PLD vs PLD
1125Hazard Ratio (Random, 95% CI)0.92 [0.58, 1.46]

    1.3 EC145/PLD vs PLD
1149Hazard Ratio (Random, 95% CI)0.63 [0.41, 0.97]

 2 PFS: PPS subgroup only1Hazard Ratio (Random, 95% CI)Subtotals only

    2.1 PLD/TBD vs PLD
1208Hazard Ratio (Random, 95% CI)0.65 [0.45, 0.93]

 3 OS3Hazard Ratio (Random, 95% CI)Subtotals only

    3.1 TBD/PLD vs PLD
1Hazard Ratio (Random, 95% CI)0.86 [0.72, 1.02]

    3.2 CAN/PLD vs PLD
1Hazard Ratio (Random, 95% CI)0.0 [0.0, 0.0]

    3.3 EC145/PLD vs PLD
1Hazard Ratio (Random, 95% CI)1.01 [0.68, 1.50]

 4 SAE: Anaemia (G3/4)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 TBD/PLD vs PLD
1663Risk Ratio (M-H, Random, 95% CI)2.54 [1.45, 4.43]

    4.2 CAN/PLD vs PLD
1122Risk Ratio (M-H, Random, 95% CI)1.93 [0.71, 5.22]

    4.3 EC145/PLD vs PLD
1157Risk Ratio (M-H, Random, 95% CI)0.53 [0.22, 1.28]

 5 SAE: Neutropenia (G3/4)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 TBD/PLD vs PLD
1663Risk Ratio (M-H, Random, 95% CI)2.80 [2.25, 3.48]

    5.2 CAN/PLD vs PLD
1122Risk Ratio (M-H, Random, 95% CI)2.19 [1.05, 4.59]

    5.3 EC145/PLD vs PLD
1157Risk Ratio (M-H, Random, 95% CI)1.07 [0.55, 2.08]

 6 SAE: Thrombocytopenia (G3/4)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 TBD/PLD vs PLD
1663Risk Ratio (M-H, Random, 95% CI)7.56 [3.67, 15.54]

    6.2 CAN/PLD vs PLD
1122Risk Ratio (M-H, Random, 95% CI)8.77 [1.16, 66.41]

    6.3 EC145/PLD vs PLD
1157Risk Ratio (M-H, Random, 95% CI)0.47 [0.12, 1.79]

 7 SAE: Vomiting (G3/4)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 TBD/PLD vs PLD
1663Risk Ratio (M-H, Random, 95% CI)4.81 [2.16, 10.70]

    7.2 CAN/PLD vs PLD
1122Risk Ratio (M-H, Random, 95% CI)1.46 [0.37, 5.85]

    7.3 EC145/PLD vs PLD
1157Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.45]

 8 SAE: HFS (G3)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    8.1 TBD/PLD vs PLD
1663Risk Ratio (M-H, Random, 95% CI)0.20 [0.11, 0.35]

    8.2 CAN/PLD vs PLD
1122Risk Ratio (M-H, Random, 95% CI)0.50 [0.15, 1.62]

    8.3 EC145/PLD vs PLD
1157Risk Ratio (M-H, Random, 95% CI)2.57 [0.59, 11.16]

 9 SAE: Stomatitis (G3/4)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    9.1 TBD/PLD vs PLD
1663Risk Ratio (M-H, Random, 95% CI)0.17 [0.05, 0.59]

    9.2 CAN/PLD vs PLD
1122Risk Ratio (M-H, Random, 95% CI)0.70 [0.20, 2.49]

    9.3 EC145/PLD vs PLD
1157Risk Ratio (M-H, Random, 95% CI)0.93 [0.30, 2.96]

 10 SAE: Alopecia (G2)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    10.1 TBD/PLD vs PLD
1663Risk Ratio (M-H, Random, 95% CI)0.90 [0.60, 1.34]

    10.2 CAN/PLD vs PLD
1122Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 11 SAE: Abdominal pain (G3/4)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    11.1 EC145/PLD vs PLD
1157Risk Ratio (M-H, Random, 95% CI)1.87 [0.41, 8.48]

 12 SAE: Neuropathy (G3/4)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    12.1 TBD/PLD vs PLD
1663Risk Ratio (M-H, Random, 95% CI)1.40 [0.85, 2.31]

    12.2 EC145/PLD vs PLD
1157Risk Ratio (M-H, Random, 95% CI)4.25 [0.23, 77.45]

 13 SAE-related death2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    13.1 TBD/PLD vs PLD
1663Risk Ratio (M-H, Random, 95% CI)2.48 [0.48, 12.68]

    13.2 EC145/PLD vs PLD
1157Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 14 Dose reductions1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    14.1 CAN/PLD vs PLD
1535Risk Ratio (M-H, Random, 95% CI)1.07 [0.53, 2.14]

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

    15.1 CAN/PLD vs PLD
1535Risk Ratio (M-H, Random, 95% CI)1.50 [1.00, 2.26]

 
Comparison 4. Exploratory analyses

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

 1 SAE: HFS (G3) subgrouped by PLD dose8Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 PLD < 50 mg/m2
41344Risk Ratio (M-H, Random, 95% CI)4.63 [1.32, 16.19]

    1.2 PLD ≥ 50 mg/m2
41544Risk Ratio (M-H, Random, 95% CI)50.75 [12.57, 204.97]

 2 SAE: Stomatitis (G3/4)72827Risk Ratio (M-H, Random, 95% CI)5.60 [2.10, 14.95]

    2.1 PLD < 50 mg/m2
31283Risk Ratio (M-H, Random, 95% CI)2.22 [0.87, 5.67]

    2.2 PLD ≥ 50 mg/m2
41544Risk Ratio (M-H, Random, 95% CI)12.19 [4.62, 32.20]

 
Summary of findings for the main comparison.

PLD/carbo compared with PAC/carbo for platinum-sensitive relapsed ovarian cancer

Patient or population: women with platinum-sensitive relapsed ovarian cancer

Settings: inpatient or outpatient setting

Intervention: PLD/carbo

Comparison: PAC/carbo

OutcomesIllustrative comparative survival or risk rates* (95% CI included for RR)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PAC/carboPLD/carbo

Progression-free survival Median PFS¹ = 40 weeks (9 months)Median PFS¹ = 48 weeks (11 months)HR 0.85 (0.74 to 0.97)1164
(2)
⊕⊕⊕⊕
high
P value 0.01. Low statistical heterogeneity between studies.

Overall survival Median OS¹ = 141 weeks (33 months)Median OS¹ = 132 weeks (31 months)HR 1.01 (0.88 to 1.17)1164
(2)
⊕⊕⊕⊝
moderate
P value 0.85. Low statistical heterogeneity between studies. We downgraded this evidence due to post-study treatment differences between the groups in the CALYPSO 2010 study which may have impacted the results in the direction of the PAC/carbo arm.

SAE - Hand-foot syndrome (grade 3)3 per 100013 per 1000

(3 to 60)
RR 4.30 (0.92 to 20.15)1140

(2)
⊕⊕⊕⊝
moderate
P value 0.06. We downgraded the quality of this evidence due to the rarity of grade 3 events in these two studies.

SAE - Hair loss (grade 2)²840 per 100076 per 1000

(50 to 126)
RR 0.09 (0.06 to 0.15)1140

(2)
⊕⊕⊕⊕
high
P < 0.00001.

Discontinuation due to toxicity 144 per 100055 per 1000
(37 to 82)
RR 0.38 (0.26, 0.57)1150
(2)
⊕⊕⊕⊕
high
P < 0.00001. Low statistical heterogeneity between studies.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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; HR: hazard ratio; PFS: progression-free survival; OS: overall survival; PLD: pegylated liposomal doxorubicin; PAC: paclitaxel; carbo: carboplatin

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.

 The basis of the assumed risk was the median control group risk across studies, and 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), unless otherwise noted.
¹ These illustrative values, rounded to the nearest week and month, are taken from CALYPSO 2010.
² Grade 2 is the highest grade of alopecia according to the CTCAE 2006.
 
Summary of findings 2.

PLD-based combination treatment compared with PLD alone for relapsed ovarian cancer

Patient or population: women with platinum-resistant (PR) or platinum-sensitive (PS) relapsed ovarian cancer

Settings: inpatient or outpatient setting

Intervention: PLD plus other drug

Comparison: PLD alone

OutcomesIllustrative comparative survival* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

PLD alonePLD plus other drug

PFS: PR and PS disease

TBD/PLD versusPLD
Median PFS = 25 weeksMedian PFS = 31 weeksHR 0.79 (0.65 to 0.96)672
(1)
⊕⊕⊕⊝
moderate
We downgraded this evidence as meta-analysis was not possible and subgroup analysis indicated that the survival benefit only related to the PPS subgroup. This finding therefore has limited clinical applicability as the standard treatment for the PS subgroup is PAC/carbo or PLD/carbo.

PFS: PPS disease only

PLD/TBD versusPLD
Median PFS = 24 weeksMedian PFS = 32 weeksHR 0.65 (0.45 to 0.93)208

(1)
⊕⊕⊕⊝
moderate
We downgraded this evidence as meta-analysis was not possible and the data was a subgroup analysis of the original study in which the sample sizes for the subgroup arms differed by 30%. This finding has limited clinical applicability as the standard treatment for the PPS subgroup is PAC/carbo or PLD/carbo.

OS: PR and PS disease

TBD/PLD versusPLD
Median OS = 81 weeks (19 months)Median OS = 95 weeks (22 months)HR 0.86 (0.72 to 1.02)672
(1)
⊕⊕⊕⊝
moderate
We downgraded this evidence as meta-analysis was not possible and PFI baseline characteristics differed between the groups (women in the PLD only arm had significantly longer PFIs; P value 0.008). This may have biased the results of this study in favour of the PLD only arm.

PFS: PR disease only

EC145/PLD versusPLD
Median PFS = 12 weeksMedian PFS = 21 weeksHR 0.63 (0.41, 0.97)149

(1)
⊕⊕⊝⊝
low
We downgraded this evidence as meta-analysis was not possible and the source of the data was a single, phase II open-label study.

OS: PR disease only

EC145/PLD versusPLD
Median OS = 72 weeksMedian OS = 60 weeksHR 1.01 (0.68, 1.50)149

(1)
⊕⊝⊝⊝
very low
We downgraded this evidence as meta-analysis was not possible and the source of the data was a single, phase II open-label study. The study was not powered to evaluate OS.

*The illustrative comparative survival times are derived from the OVA-301 2010 and PRECEDENT 2013 trial results and do not reflect a relative effect of the experimental intervention per se.
CI: confidence interval; RR: risk ratio; HR: hazard ratio; PFS: progression-free survival; OS: overall survival; PFI: platinum-free interval; PPS: partially platinum-sensitive; PR: platinum-resistant; PS: platinum-sensitive; PLD: pegylated liposomal doxorubicin; TBD: trabectedin; EC145: vintafolide

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.

 
Summary of findings 3.

Adverse events related to PLD dose (<50 mg/and 50 mg/) in studies that compared PLD alone with non-PLD agent/s for relapsed ovarian cancer

Patient or population: women with relapsed ovarian cancer

Settings: inpatient or outpatient setting

Intervention: PLD

Comparison: other non-PLD drug/s

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

non-PLD agent/sPLD alone

SAE: HFS (grade 3) subgrouped by PLD dose< 50 mg/PLD dose every 4 weeksRR 4.63 (1.32 to 16.19)

RR 50.75 (12.57 to 204.97)
1344

(4)

1544

(4)
⊕⊕⊕⊕
high

⊕⊕⊕⊕
high
Tests for subgroup differences were significant (P value 0.01).

< 1 per 10005 per 1000
(1 to16)

50 mg/PLD dose every 4 weeks

< 1 per 100051 per 1000
(13 to 205)

SAE: Stomatitis (grade 3 to 4) subgrouped by PLD dose<50 mg/PLD dose every 4 weekRR 2.22 (0.87 to 5.67)

RR 12.19 (4.62 to 32.20)
1283
(4)

1544

(4)
⊕⊕⊕⊕
high

⊕⊕⊕⊕
high
Tests for subgroup differences were significant (P value 0.01).

1 per 10002 per 1000
(1 to 6)

50 mg/PLD dose every 4 weeks

1 per 100012 per 1000
(5 to 32)

*The basis for the assumed risk is the median 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; PLD: pegylated liposomal doxorubicin

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.

 
Table 1. FIGO staging of ovarian cancer*

StageExtent of tumourSubstageDetails

ILimited to ovariesIaLimited to 1 ovary, no tumour on surface or capsule rupture, no positive ascites

IbLimited to both ovaries, no tumour on surface or capsule rupture, no positive ascites

IcStage Ia or Ib but with capsule ruptured, tumour on ovarian surface or positive peritoneal washings/ascites

IILimited to 1 or both ovaries with pelvic extensionIIaExtension, metastases to uterus, tubes, or a combination

IIbExtension to other pelvis tissues

II cStage IIa or IIb with tumour on the surface of 1 or both ovaries, or with capsule ruptured, or with positive peritoneal washings/ascites

IIILimited to abdomen with histologically confirmed peritoneal implants outside the pelvis or positive nodes, or both, or extension to small bowel or omentumIIIaTumour grossly limited to the true pelvis with negative regional lymph nodes, microscopic seeding of abdominal peritoneal surfaces or extension to small bowel or mesentery

IIIbMacroscopic metastases < 2 cm; negative regional lymph nodes

IIIcMacroscopic metastases > 2 cm or positive regional lymph nodes, or both

IVDistant metastasesGrowth outside the abdominal cavity (e.g. lung, liver parenchyma (superficial liver metastases is stage III))

 FIGO: International Federation of Gynaecology and Obstetrics. * From FIGO 2009.
 
Table 2. Platinum sensitivity status and median survival times in participants of included studies

Platinum-resistant data (PFI ≤6 months)

STUDY NAMEOther drug armPLD armN (other drug)N (PLD)Median TTP for other arm in weeks Median TTP for PLD arm in weeks Median TTD for other arm in weeks Median TTD for PLD arm in weeks Comment

Colombo 2012PATPLD4124161616575417% of these women had non-measurable disease.

Mutch 2007GEMPLD99961513545836% of these women with non-measurable disease.

Gordon 2001TOPPLD1251301494136It is unclear why survival in the PLD arm of this PR subgroup is so much shorter than that of the other trials.

ASSIST-3 2007CAN/carboPLDNANA1515NANALimited available data. Additional data were requested from Telik but not obtained.

Kaye 2012OLAPLD1614NANANANASmall study, subgroup data not available.

MITO-3 2008GEMPLD4343NANANANASubgroup data not available.

PRECEDENT 2013EC145/PLDPLD1004921126072Unpublished OS data. Study was not adequately powered to assess OS.

OVA-301 2010TBD/PLDPLD11812417166153Subgroup analysis was pre-planned for PFS but was exploratory for OS.

ASSIST-5 2010CAN/PLDPLD65602416NANAPre-planned subgroup analysis favoured the CAN/PLD group for PFS. Final OS results were not published. Additional data were requested from Telik but not obtained.

Partially platinum-sensitive data (PFI 6-12 months)

CALYPSO 2010PAC/carboPLD/carbo1831613840NANAPFS HR = 0.73 (95% CI 0.58 to 0.90, P value 0.004) from Gladieff 2012;

OS HR = 1.01 (0.80 to 1.28) from Wagner 2012.

OVA-301 2010TBD/PLDPLD1239032249671TTP data from Poveda 2011 and exploratory TTD data from Monk 2012. PFS HR = 0.65 (95% CI 0.45 to 0.92; P value 0.015; OS HR =0.64 (95% CI 0.47 to 0.86; P value 0.0027).

Platinum-sensitive data (PFI > 6months)

Gordon 2001TOPPLD111109232970108Exploratory analysis. The greatest effect was seen in the PPS subgroup (N=112; HR = 1.58, 95% CI 1.07-2.34; P value 0.021).

OVA-301 2010TBD/PLDPLD2152023932116103Subgroup analysis was pre-planned for PFS but was exploratory for OS.

SWOG S0200 2008carboPLD/carbo3031345177133Small study which closed early.

HeCOG 2010PAC/carboPLD/carbo96934651126106

CALYPSO 2010PAC/carboPLD/carbo5094664048141132

Platinum-resistant and platinum-sensitive data combined

MITO-3 2008GEMPLD767720165156PR + PPS.

Kaye 2012OLAPLD32333830NA76PR + PPS. Unpublished TTD data obtained from investigators. Phase II study not powered to assess survival.

Gordon 2001TOPPLD2352391716.16063PR + PS.

O'Byrne 2002PACPLD10710722225646PR + PS; preliminary data.

OVA-301 2010TBD/PLDPLD33733531259581PR + PS.

 Conversions from published data (months to weeks) were performed assuming one month to be 4.3 weeks, and then rounding the answer to the nearest week.
*This is from the comparison CAN versus active control (PLD and TOP data combined). The PLD group had an improved PFS compared with the TOP group but we were unable to obtain separate data.
Abbreviations: NA = not available; ; HR = hazard ratio; OS = overall survival; TTP = time to progression; TTD = time to death; PFI = platinum-free interval; PR = platinum-resistant (recurrence within 6 months of platinum-based therapy); PPS = partially platinum-sensitive (recurrence of 7 to 12 months of platinum-based therapy); PS = platinum-sensitive (recurrence >12 months after platinum-based therapy); PRef = platinum-refractory (recurrence within 1 month of, or during, platinum-based therapy); PLD = pegylated liposomal doxorubicin; GEM = gemcitabine; TOP = topotecan; TBD = trabectedin; CAN = canfosfamide; PAT = patupilone; OLA = olaparib; PAC = paclitaxel; carbo = carboplatin