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Gemcitabine vs Pegylated Liposomal Doxorubicin in Patients with Platinum-resistant Ovarian Cancer
Abstract & Commentary
By Robert L. Coleman, MD, Professor & Director, Clinical Research Department of Gynecologic Oncology, University of Texas; M.D. Anderson Cancer Center, Department of Gynecologic Oncology, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationship to this field of study.
Synopsis: Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer.
Source: Mutch DG, et al. J Clin Oncol. 2007;25:2811-2828.
Ovarian cancer patients relapsing within 6 months of their primary therapy represent among the most challenging patients to treat. Generally, in this setting, most patients have only been exposed to one or two agents, yet they are phenotypically resistant to most chemotherapeutics, making drug discovery of paramount importance. Several clinical studies have targeted this patient population to evaluate the potential efficacy of newer agents. Based on promising early clinical reports with the nucleoside analog, gemcitabine, Mutch and colleagues conducted a randomized phase III clinical trial of this agent compared with a clinical standard, pegylated liposomal doxorubicin (PLD). Patients were eligible if they had epithelial ovarian, primary peritoneal or fallopian tube cancer, which had recurred within 6 months of their most recent exposure to platinum. Primary therapy was to be "platinum-based" and patients could not have received more than 2 prior therapies. Both measurable and evaluable (biomarker CA125 greater than or equal to 100 U/mL) disease was allowed. FDA-approved dosing of PLD (50 mg/m2 every 28 days) was mandated in the control arm; standard dosing of gemcitabine (1000 mg/m2 days 1 and 8 every 21 days) was administered in the experimental arm. The primary efficacy endpoint was progression-free survival (PFS) and the sample size was determined based on an anticipated reduction in the hazard for progression of 37.5% (HR: 0.625). All analyses were performed under the intent-to-treat policy. Overall, 195 patients were randomly allocated (1:1) to one of the two treatment regimens. Both PFS and overall survival (OS) were statistically similar between the two agents. In addition, response rates in both measurable and non-measurable cohorts were similar. The PLD group suffered significantly higher "hand-foot" syndrome and mucositis; the gemcitabine group experienced significantly more non-complicated myelosuppression, constipation, nausea/vomiting and fatigue. The authors concluded that the two agents have a comparable "therapeutic index" and that gemcitabine may be an acceptable alternative to PLD in this cohort of patients.
While this large and highly anticipated study appears to have missed its primary endpoint, it is an informative clinical trial nonetheless and further solidifies a common use of administering single agent gemcitabine to patients with recurrent ovarian cancer. At the time of this publication, no previous phase III studies had been reported with single agent gemcitabine in any setting of recurrence and this trial joins just one other evaluating gemcitabine in combination with carboplatin in platinum-sensitive recurrent ovarian cancer.1 A subsequent second single-agent study of PLD vs gemcitabine has been recently presented with similar findings. The impact and effort of this trial is important to gauge against the relative paucity of similar data in the literature. Surprising to many, there have been very few randomized clinical trials exclusively in this population of patients (platinum-resistant disease) and given the relatively poor anticipated performance, it is understandable that superiority was not achieved.2
There are a few items about the trial, which warrant some discussion. First, the study allowed for both primary and secondary platinum-resistance. These two groups were slightly imbalanced by randomization and may represent different cohorts of patients. Currently, we do not have an accurate methodology to risk stratify recurrent patients where the underlying probability of response to treatment is equal. This is best controlled by balanced randomization and adequate sampling. Second, since the two regimens have a different schedule, the assessment of efficacy was made after 3 cycles of PLD but 4 cycles of gemcitabine. This could lead to an important imbalance of primary endpoint detection (bias) if there is a relational effect of the amount of chemotherapy exposure to response. However, in the studied population, this risk is likely low. Third, the doses and schedules of both agents have been altered somewhat in day-to-day clinical practice based on observed toxicities. While the higher dose of PLD was mandated by FDA for investigation, the much more tolerable lower dose (40 mg/m2) is almost exclusively used in the USA. Efficacy at this dose is not well studied, but was the subject of the more recently unpublished phase III study mentioned previously. Similarly, gemcitabine, which is administered to patients at all phases of their recurrence, has been shown to be quite tolerable in every 14 day dosing.3
Finally, even if the trial had met its primary endpoint, the frequent cross-over would likely have removed any benefit to, arguably, the ultimate endpoint, overall survival. In the context of clinical investigation, this is a difficult issue with which to wrestle. While we should be striving for the recognition of agents that "really matter" to this ultimate endpoint (as opposed to the addition of "me-too" therapeutics), it is a very difficult benchmark to move and broadening the menu of "active" agents does allow for customization of therapy based on individual patient characteristics and concurrent toxicities. Fortunately, several clinical studies are nearing completion to help clarify and illuminate this menu of options.