Kaye 2013.
| Methods | Open‐label multi‐centre phase II RCT (27 institutions in 9 countries in Western Europe, Eastern Europe, and Canada). Recruitment from February 2006 to November 2006 | |
| Participants | 149 women with a first relapse of histologically confirmed ovarian, fallopian, or primary peritoneal carcinoma (defined by at least 1 measurable lesion according to RECIST or elevated CA‐125 (GCIG criteria of ≥ 2 × upper limit of normal (ULN)), documented on 2 occasions > 1 week and < 3 months apart) Participants were required to have platinum‐sensitive disease (defined by initial response to platinum and a progression‐free interval of > 6 months after completion of a platinum‐based regimen). Other requirements included Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 and adequate haematological, renal, hepatic, and cardiac function. Median age (range) CT + P = 58.1 (26 to 76); CT 55.3 (19 to 83) WHO PS = 0 CT + P = 41/75 (55%); CT alone = 39/74 (52) WHO PS = 1: CT + P = 33/75 (45%); CT alone = 36/74 (48%) |
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| Interventions |
Comparison (cytotoxic chemotherapy (CT)) Carboplatin (AUC 5/q3wk with paclitaxel or AUC 4/q3wk with gemcitabine) with either paclitaxel (Taxol; 175 mg/m² q3wk) or gemcitabine (1000 mg/m² days 1 and 8, q3wk) Chemotherapy was administered for a maximum of 6 cycles. Intervention (chemotherapy + pertuzumab (CT + P)) Cytotoxic chemotherapy (CT) (as per comparison group) + pertuzumab (P) (840‐mg loading dose followed by 420 mg q3wk). After completion of chemotherapy or withdrawal of chemotherapy due to toxic effects, pertuzumab was administered for a further 11 cycles q3wk (resulting in a total of 17 cycles); pertuzumab treatment could be continued up to a maximum of 52 cycles. No participants were allowed to cross over to the intervention (chemotherapy + pertuzumab) arm at any stage. |
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| Outcomes |
Progression‐free survival (PFS) Median PFS (weeks) CT + P = 34.1 weeks vs C = 40.0 weeks; HR 1.17 (80% CI 0.92 to 1.49); P= 0.39727 Overall survival (OS) Median OS CT + P = 28.2 months vs CT= not reached; HR 1.02 (80% CI 0.74 to 1.41); P = 0.9262 ORR (overall response rate, as defined by RECIST or CA‐125) Toxicity (G3 or more) during chemotherapy
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| Notes | ClinicalTrials.gov identifier: NCT02004093 This study was mentioned as ongoing in the original version of this review; results have been published since that time. Funding source This study was sponsored by F. Hoffmann‐La Roche. Declarations of Interest Disclosure statement from the published paper "GR and VMN are employees of F. Hoffmann‐La Roche, and hold stocks or stock options in Roche Products. AS and MM are employees of Roche Diagnostics, and hold stocks or stock options in Roche Diagnostics. SBK and CJP have participated in Roche advisory boards and served as a consultant for F. Hoffmann‐La Roche. AD‐B, LG, GDC, VG, EN, and IV have no conflicts to declare". Survival data The published paper gives results for PFS and OS for both a 'Primary analysis' (conducted 1 year after the last participant was enrolled), and a 'Final analysis' (conducted 2 years after the last treatment was administered). We have used the data from the Final analysis in this review. Toxicity data This trial allowed participants in the intervention (pertuzumab + chemotherapy) arm to continue with pertuzumab beyond cycle 6 (the point at which both arms finished chemotherapy). For the main toxicity comparison analyses in this review, we have used toxicity data up to cycle 6 (although separate data for toxicity after cycle 6 are also reported in the published paper). |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomization was stratified by treatment‐free interval (TFI; 6–12 months versus > 12 months), measurable versus non‐measurable disease, chemotherapy regimen (carboplatin–paclitaxel versus carboplatin–gemcitabine) and territory (Eastern Europe versus Western Europe and Canada)". |
| Allocation concealment (selection bias) | Low risk | Personal communication with the Lead Project Statistician confirmed allocation concealment. |
| Blinding of participants and personnel (performance bias) Objective outcome measures (Overall Survival) | Low risk | Outcome unlikely to be affected by blinding |
| Blinding of participants and personnel (performance bias) Subjective outcome measures (PFS; Toxicity; QoL) | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) Objective outcome measures (overall survival) | Low risk | Outcome unlikely to be affected by blinding |
| Blinding of outcome assessment (detection bias) Subjective outcome measures (PFS, Toxicity, QoL) | High risk | Open‐label study |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Attrition and exclusions were reported. Participants were excluded from analyses if they did not receive at least 1 dose of the allocated trial medication (1/75 in the intervention group; 2/77 in the control group). |
| Selective reporting (reporting bias) | Low risk | Results for all major expected outcomes were reported. Seconday and exploratory outcomes that were not described in the publication are included in the ClinicalTrials.gov entry of this study (personal communication with the Lead Project Statistician). |
| Other bias | Unclear risk | This study was sponsored by F. Hoffmann‐La Roche. Several of the study investigators have financial links to either F. Hoffmann‐La Roche or Roche Diagnostics, which have been declared in the published paper (and are detailed in the Notes section of the study table above). |