Ovarian Cancer (OC) and its management
From a clinical perspective, however, these definitions may be arbitrary. Rather, sensitivity to platinum agents occurs across a spectrum, in which patients with a longer duration of remission following platinum-based treatment have a greater likelihood of response to additional platinum therapy [Bukowski 2007].
The main therapeutic regimens evaluated in ROC are:
Both agents were evaluated in a randomised phase III, multicenter study of patients with advanced epithelial ovarian carcinoma who had progressed during or after one platinum-based regimen. Response rate was 20.5% in topotecan-treated patients and 13.2% in placlitaxel-treated patients (p = 0.138). Disease stabilization for at least 8 weeks was noted in 30% of patients with topotecan and 33% of patients with paclitaxel. Median durations of response to topotecan and paclitaxel were 32 and 20 weeks, respectively (p = 0.222) and median time to progression was 23 and 14 weeks, respectively (p = 0.002). Median survival was 61 weeks for topotecan and 43 weeks for paclitaxel (p = 0.515). This trial was the basis for the approval of topotecan for the treatment of relapsed ovarian cancer [Huinink 1997].
In a phase III trial comparing PLD and topotecan in ROC after first-line platinum-based chemotherapy, PLD was associated with a reduction in the risk of death in the overall population and in the subset of patients with platinum-sensitive disease (18% and 30%, respectively) [Gordon 2004]. TTP in the evaluable population showed superiority of PLD over topotecan (hazard ratio [HR]=1.262; 90% CI: 1.062-1.500, p=0.026). Overall survival (OS) also favoured PLD in the intention-to-treat (ITT) population, OS all randomised HR: 1.23 (95% CI: 1.01-1.50, p=0.038) vs. OS HR: 1.216 (95% CI: 1.0-1.48, p=0.05). This trial was the basis for the approval of PLD for the treatment of advanced ovarian cancer after failure of a first-line platinum regimen in the European Union.
Gemcitabine has shown slightly lower response rates in phase II clinical trials [Poveda 2005; Colombo 2006] than PLD [Perez-Lopez 2007; Markman 2004; Gordon 2001; Lorusso 2004] or topotecan [McGuire 2000; Bookman 1998]. In a recent phase III trial, no statistically significant differences between gemcitabine and PLD were shown [Ferrandina 2008]. However, a survival advantage was found for PLD, and quality of life scores were better in patients treated with PLD. Gemcitabine is approved for ROC only in combination with carboplatin [Pfisterer 2006].
In randomised trials, platinum-based combinations provide superior benefit (response rate and progression-free survival) than single agents as second-line therapy in patients with platinum-sensitive ovarian cancer. This has been shown for platinum plus taxane vs. platinum in monotherapy, where mean PFS (13 vs. 10 months) and mean OS (29 vs. 24 months and median 2-year survival: 57% vs. 50%) favoured the combined treatment arm [Parmar 2003]. The comparison of carboplatin plus gemcitabine vs. carboplatin in monotherapy, where median PFS (8.6 vs. 5.8 months) also favoured the combined regimen. However, there was not a statistical difference in the overall survival between the two treatments (18.0 vs. 17.3 months; p=0.73). [Pfisterer 2006]. In addition, combination chemotherapy is more likely to decrease tumour burden and yield symptom control in patients with highly symptomatic disease.
One trial with PLD in combination as treatment of advanced ovarian cancer evaluated PLD plus carboplatin vs. carboplatin alone in patients with platinum-sensitive disease. The study was closed prematurely due to slow patient accrual [Alberts 2008]. The dose of PLD in the combination (30 mg/m2 every-4-weeks) was almost equivalent to that used in the Yondelis® phase III trial OVA-301 in ROC (30 mg/m2 every-3-weeks). The OVA-301 trial has compared the efficacy and safety of Yondelis®+PLD vs. PLD alone. This trial showed significant superiority of Yondelis® + PLD in terms of PFS (HR:0.79; 95% CI, 0.65 to 0.96; p=0.0190) [Monk 2010]. A recent trial has evaluated the carboplatinum-based doublets, PLD (30 mg/m2) plus carboplatin (AUC 5) every 4 weeks) vs. paclitaxel (175 mg/m2 over 3 hours) plus carboplatin (AUC 5) every 3 weeks in patients with platinum-sensitive disease.This non inferiority trial showed statistical differences in terms of PFS, with a reduction of 18% in the risk of recurrence, favouring the PLD-carboplatin combination (HR 0.82; p=0.005). OS data have not yet been published [Pujade-Lauraine 2010].