Therapeutic Options for Recurrent Ovarian Cancer Expand
Abstract & Commentary
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationship to this field of study.
Synopsis: Gemcitabine did not provide a clinical advantage over pegylated liposomal doxorubicin in terms of time to progression, overall survival or quality of life in ovarian cancer patients relapsing within 12 months of primary therapy. However, gemcitabine should be considered among the available agents for this cohort.
Source: Ferrandina G, et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol. 2008;26:890-896.
The principal purpose of this clinical study was to evaluate the efficacy of gemcitabine relative to a clinical standard therapy, pegylated liposomal doxorubicin (PLD) in women with ovarian cancer relapsing within a year of primary treatments. The authors chose to evaluate only those patients with measurable or evaluable recurrent disease, in whom no other therapy for recurrence had been administered. The trial design was randomized (1:1) and balanced between the two treatment arms. The agents (gemcitabine and PLD) were administered in clinical relevant doses every 28 days; of note PLD was administered at 40 mg/m2. The primary efficacy metric was time to treatment progression (TTP); however, overall survival (OS), toxicity and quality of life (QoL) were also considered. The study was powered to detect and increase in TTP with gemcitabine from 12 to 19 weeks (HR = 0.63). Overall 153 patients were enrolled; 143 were evaluable for safety. The two agents were generally well tolerated with expected greater myelosuppression (grade 3/4 neutropenia) following gemcitabine and non-significantly higher hand-foot syndrome with PLD. The resulting quality of life based on these toxicities favored PLD, however. Efficacy evaluation in the intent-to-treat population demonstrated the two agents were very similar in regards to the primary endpoint (TTP of gemcitabine to PLD: 20 vs 16 weeks, P = 0.41). Overall clinical response (29% vs 16%, P = 0.06) and OS (51 vs 56 weeks, P = 0.048) were also similar between the two agents; a subgroup analysis suggested that OS was significantly longer in patients relapsing between 7-12 months when given PLD, but the reasons for this observation are limited by lack of post-progression therapy information. The authors conclude there is not superiority of gemcitabine relative to PLD and both should be considered options in women with ovarian cancer relapsing under 1 year from primary therapy.
Commentary
In the September 2007 issue of OB/GYN Clinical Alert, I reported on a similar study of these two agents in a randomized Phase III study reported by Mutch et al, in the Journal of Clinical Oncology. The current paper is important to additionally report for several reasons relevant to the practicing clinician. First, the study is somewhat "cleaner" in that the population is more homogeneous than the prior report. All patients in the current study were assessable or measurable and relied less on biomarker data for evaluation of the efficacy endpoints. This is important because CA125 is known to be somewhat unreliable early in therapy with regard to response following PLD therapy. An additional measure of homogeneity in the current study was the use of patients failing only one prior regimen of therapy. This helps to standardize the underlying probability of response expected among the randomized cohorts; the prior study included some patients who had already been treated with recurrence therapy. Indeed, about one-third of patients were enrolled at the third-line in the prior report. Second, the current study included patients considered primarily platinum-resistant (treatment free 0-6 months post therapy) and intermediate sensitive (TFI of 7-12 months) making the inference more robust. Only platinum-resistant patients were included in the prior study. And finally, the dosing of PLD in the two studies was significantly different. It is suspected that more than 80 percent of PLD administered nation-wide is dosed as was done in this report. The reduced dose (40 mg/m2) has never been prospectively evaluated relative to the package insert (FDA approved at 50 mg/m2) yet toxicity has guided clinicians to the lower dose for tolerance. The current study suggests there is little risk in this modification, as inspection of these results across other studies with this dosing appears consistent.
Recurrent ovarian cancer therapy is rooted deeply in considerations of both clinical efficacy and toxicity. Given the difficulty of demonstrating agent superiority in these women, important measures of toxicities and how patients experience these are critical to making good treatment recommendations. The current report is a model of how this investigation should proceed.
Suggested Reading
- Coleman RL, et al. Early changes in CA125 after treatment with pegylated liposomal doxorubicin or topotecan do not always reflect best response in recurrent ovarian cancer patients. Oncologist. 2007;12:72-78.
- Mutch DG, et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2007;25:2811-2818.
- Markman M, et al. Phase 2 trial of liposomal doxorubicin (40 mg/m(2)) in platinum/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. Gynecol Oncol. 2000;78:369-372.
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