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

Background Epithelial ovarian cancer (EOC) is often diagnosed at an advanced stage, requiring primary cytoreductive surgery and combination chemotherapy for its first-line management. Currently, the recommended standard first-line chemotherapy is platinum-based, usually consisting of carboplatin and paclitaxel (PAC/carbo). Pegylated liposomal doxorubicin (PLD) is an improved formulation of doxorubicin that is associated with fewer and less severe side effects than are seen with non-modified doxorubicin. In combination with carboplatin, PLD has recently been shown to improve progression-free survival compared with PAC/carbo in women with relapsed, platinum-sensitive EOC. It is therefore important to know whether any survival benefit can be attributed to PLD when it is used in the first-line setting. Objectives To evaluate the role of PLD, alone or in combination, in first-line chemotherapy for women with EOC. Search methods We searched The Cochrane Gynaecological Cancer Group's Trial Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE from January 1990 to February 2013. In addition, we searched online trial registries for ongoing trials and abstracts of studies presented at relevant scientific meetings from 2000 onwards. Selection criteria We included all randomised controlled trials (RCTs) that compared PLD alone or in combination with other agent/s (e. g. carboplatin) versus other agent/s for first-line chemotherapy in women with EOC who may or may not have undergone primary cytoreductive surgery. Data collection and analysis Two review authors independently selected trials, extracted data and assessed the risk of bias for each included trial. We obtained updated trial data when possible. Main results 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. Authors' conclusions 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.