Abstract: We included two large trials. One trial compared three-weekly PLD and carboplatin (PLD/carbo) with PAC/carbo. The other trial included four experimental arms, one of which was PLD plus PAC/carbo, that were compared with the standard PAC/carbo regimen. We did not combine results of these two trials in the meta-analysis. We considered the two studies to be at low risk of bias. For the comparison PLD/carbo versus PAC/carbo (820 women; stages Ic to IV), no statistically significant differences in progression-free survival (PFS) (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.85 to 1.19) or overall survival (OS) (HR 0.94, 95% CI 0.78 to 1.13) were noted between study arms. Severe anaemia (risk ratio [RR] 2.74, 95% CI 1.54 to 4.88) and thrombocytopenia (RR 8.09, 95% CI 3.93 to 16.67) were significantly more common with PLD/carbo, whereas alopecia (RR 0.09, 95% CI 0.06 to 0.14) and severe neurotoxicity (RR 0.09, 95% CI 0.01 to 0.66) were significantly more common with PAC/carbo. Quality of life scores were not significantly different. For the comparison PLD/PAC/carbo versus PAC/carbo (1726 women; stage III/IV), it is important to note that PLD was given for alternate cycles only (i.e. every 6 weeks). No statistically significant difference in PFS (HR 0.98, 95% CI 0.88 to 1.09) or OS (HR 0.95, 95% CI 0.84 to 1.08) between these two treatment arms was reported. However, women in the triplet arm experienced significantly more severe haematological adverse events (anaemia, thrombocytopenia, neutropenia and febrile neutropenia) compared with those given standard treatment. No RCTs evaluated single-agent PLD for first-line treatment of EOC. PLD/carbo is a reasonable alternative to PAC/carbo for the first-line treatment of EOC. Although three-weekly PLD/carbo may be associated with increased dose delays and discontinuations compared with the standard PAC/carbo regimen, it might be more acceptable to women who wish to avoid alopecia or those at high risk of neurotoxicity. No survival benefits appear to be associated with the alternating triplet regimen, and the additional toxicity associated with adding PLD to PAC/carbo limits further investigation. Further studies are needed to establish the safest, most effective PLD/carbo regimen for newly diagnosed disease.

Plain-language summary: One study compared PLD plus carbo given to women every three weeks versus the standard treatment (paclitaxel (PAC)/carbo every three weeks), and the other added PLD to the standard treatment and compared it with standard treatment only (the latter study also included other treatments not relevant to this review). These studies spanned three years and included 820 and 4100 women, respectively. Most women in these studies had advanced cancer and had undergone surgery to remove as much of the cancer as possible. Key findings Women receiving the PLD/carbo treatment and those given the standard treatment survived for a similar period, but PLD/carbo caused more women to experience low blood counts (anaemia and low platelets) that often led to a delay in treatment or the need to stop treatment. However, PLD/carbo caused far fewer women to experience hair loss and neuropathy (nerve damage causing symptoms such as tingling, numbness, pain, loss of sensation and/or coordination), and so it might help women who find these side effects unacceptable or intolerable. We concluded that three-weekly PLD/carbo is a reasonable alternative to standard platinum-based treatment for newly diagnosed EOC, but more research is needed to establish the safest and most effective dosage and dose frequency. Adding PLD to standard treatment (PAC/carbo) every six weeks did not help women with newly diagnosed ovarian cancer survive longer and was associated with worse effects on blood counts that increased the chance of infection; therefore this triple drug treatment cannot be recommended. Quality of the evidence We considered the evidence related to survival of women after they are treated with PLD/carbo or PAC/carbo, and the evidence related to adverse drug effects to be of high quality.