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Adding Another Standard to Platinum-sensitive Recurrent Ovarian Cancer
Abstract & commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman serves on the scientific/advisory board of Centocor.
Synopsis: Combination pegylated liposomal doxorubicin and carboplatin was found to be superior to paclitaxel and carboplatin in platinum-sensitive recurrent ovarian cancer and with a better therapeutic index
Source: Pujade-Lauraine E, et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 2010 May 24; Epub ahead of print.
To assess the efficacy and toxicity of combination pegylated liposomal doxorubicin (PLD) and carboplatin against industry-standard paclitaxel and carboplatin, patients with histologically proven ovarian cancer with recurrence more than 6 months after first- or second-line platinum- and taxane-based therapies were randomly assigned by stratified blocks to CD (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m2) every 4 weeks or CP (carboplatin AUC 5 plus paclitaxel 175 mg/m2) every 3 weeks for at least 6 cycles. The primary endpoint was progression-free survival (PFS); secondary endpoints were toxicity, quality of life, and overall survival. Overall, 976 patients were recruited. With median follow-up of 22 months, PFS for the CD arm was statistically superior to the CP arm (hazard ratio, 0.821; 95% confidence interval [CI], 0.72-0.94; P < 0.005); median PFS was 11.3 vs 9.4 months, respectively. Severe non-hematologic toxicity (36.8% vs 28.4%; P < 0.01) leading to early discontinuation (15% vs 6%; P < 0.001) occurred more frequently in the CP arm. More frequent grade 2 or greater alopecia (83.6% vs 7%), hypersensitivity reactions (18.8% vs 5.6%), and sensory neuropathy (26.9% vs 4.9%) were observed in the CP arm; more hand-foot syndrome (grade 2-3, 12.0% vs 2.2%), nausea (35.2% vs 24.2%), and mucositis (grade 2-3, 13.9% vs 7%) in the CD arm. The authors conclude that the new combination has clinical efficacy and a better toxicity profile than paclitaxel and carboplatin.
This study represents an important advance in our approach for women with recurrent platinum-sensitive ovarian cancer because it is one of the few trials not only adequately powered to address the question of non-inferiority, but also one conducted in a patient population that is reflective of patients we see day to day. These distinctions are important to realize because they stand in contrast to the other trials conducted in platinum-sensitive recurrent ovarian cancer patients where the control arm is predominately a single-agent platinum or a non-platinum agent, and in a population that has not universally been previously exposed to a taxane. These two features have limited the interpretation and exportability of results in previous efforts. The issue of non-inferiority is also one not to be overlooked. Such trial designs are unpopular for many reasons; they are usually larger, more time-consuming, and expensive, only to conclude that the experimental regimen is no worse that a treatment standard. Indeed, in a negative trial powered only for superiority, we are often left to make the erroneous interpretation that the treatment arms are "likely" not different. This trial helped to answer both: non-inferiority of the new arm and superiority. Unfortunately, the short-term metric, progression-free survival, in an open-label study may be influenced by many factors other than treatment effect, which has tempered the enthusiasm of our regulatory agencies (e.g., FDA) in using this outcome to approve new clinical entities. Nevertheless, as the survival data mature in the current study, we are encouraged by the rigor with which this study was undertaken, its outcomes for survival and toxicity, and that availability of the agents, which allows our patients to have another option in the treatment of their disease.