Single agent carboplatin versus carboplatin plus pegylated liposomal doxorubicin in recurrent ovarian cancer: Final survival results of a SWOG (S0200) phase 3 randomized trial

Abstract

Objectives-Randomized phase 3 trials have demonstrated the utility of a regimen of carboplatin plus pegylated liposomal doxorubicin (PLD) in recurrent ovarian cancer, and have provided provocative data suggesting a substantially lower risk of carboplatin-associated hypersensitivity if PDL is delivered in combination with the platinum agent.Methods-To further examine both of these clinically-relevant issues, the survival outcome (with longer follow-up) and hypersensitivity reaction profile of a previously reported phase 3 trial that compared single agent carboplatin (AUC 5) to carboplatin (AUC 5) plus PLD (30 mg/m 2 ) delivered on an every 4-week schedule in recurrent ovarian cancer (SWOG 0200) were re-analyzed.Results-In the limited number of patients (n=61) entered into this phase 3 study before closure by the SWOG Data Safety and Monitoring Committee due to insufficient accrual, there was an initially reported improvement in outcome associated with the combination regimen. With longer follow-up and additional events there is still a statistically-significant improved progression-free survival (median: 12 versus 8 months, p=0.02), but the previously observed impact of the two-drug regimen on overall survival is no longer apparent (median: 31 versus 18 months; p=0.2). While no Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. hypersensitivity reactions were reported in the carboplatin plus PLD arm (0/31), 9 of 30 patients (30%) of women randomized to single agent carboplatin experienced an allergic episode (p=0.0008), with 5 being ≥ grade 3 in severity. NIH Public AccessConclusion-Despite a favorable impact of carboplatin and PLD on progression-free survival in this trial, the effect on overall survival is not statistically significant. For currently unknown reasons, administering PLD with carboplatin appears to substantially reduce the incidence of platinumassociated hypersensitivity reactions.

Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective

“…The study was powered for pfs equivalence, but demonstrated that the median pfs was significantly superior for combination therapy. The os difference was not statistically different, however 26 . It is important to emphasize that both trials were underpowered to assess os and that survival data may have been confounded by contamination of the control arm through use of the experimental drug in the community.…”

“…It should be noted that the quality of the data at later time points was limited [25][26][27] , and as pointed out previously, was perhaps affected by nonrandom dropout, possibly obscuring qol benefits.…”

Management of Hypersensitivity to Platinum- and Taxane-Based Chemotherapy: cepo Review and Clinical Recommendations

“…The calypso study showed that hypersensitivity occurred more often among patients receiving a carboplatin-paclitaxel combination than among those receiving carboplatin combined with pegylated liposomal doxorubicin (18.8% vs. 5.6%) 15 . In a Southwest Oncology Group study, Markman et al 16 showed that, compared with single-agent carboplatin, the combination of pegylated liposomal doxorubicin and carboplatin reduced the frequency of hypersensitivity reactions (0% vs. 30%).…”

Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells

“…Ranges were selected from the results of 3-day cytotoxicity assays on parental cell lines (Table S3) For carboplatin and taxol a dose range of up to 20µg/ml and 120ng/ml respectively was deemed clinically relevant following pharmacokinetic studies for a dose of carboplatin at AUC 5 and taxol at 175mg/m 2 which are often administered to patients in clinical trials as single agents (du Bois et al 1997;Go et al 1999;ICON3 2002;Joerger et al 2006;Markman et al 2010;Mross et al 2000;Oguri et al 1988;Ozols et al 2003;Pfisterer et al 2006;Rowinsky 1997;Vasey et al 2004). …”