Special Feature
Expanding the Treatment Options for Recurrent Ovarian Cancer Patients
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 is on the speaker's bureau for GlaxoSmithKline, Bristol-Myers Squibb, and Ortho Biotech.
Despite the grim statistics, recurrent ovarian cancer is somewhat distinguished from other solid tumors in its ability to retain and regain some "sensitivity" to chemotherapy long into its natural progression. Patients who are of good performance status and otherwise unburdened by cumulative toxicity of prior therapy are frequently interested in trying alternative agents in the hopes that these agents may retard tumor growth. This is particularly highlighted in proprietary marketing data which demonstrate that the most rapidly growing cohort of patients undergoing therapy are those receiving their third or more course of chemotherapy for recurrent disease. In this phenotype lies tremendous opportunity to evaluate new agents in several different populations based on important clinical parameters such as the length of time to first or second recurrence and previous drug exposure. As such, more than 150 clinical studies of all phases are underway in women with recurrent ovarian cancer (see www.clinicaltrials.gov).
Ultimately, the goal of this research is to extend the lives of women with this disease. Traditionally, phase III clinical investigation was primarily relegated to newly diagnosed disease, where promising agents were tested against clinical standards to determine if sufficient improvements in outcomes justified regimen alteration. This has been a successful exercise where new agents such as paclitaxel and docetaxel have entered into primary therapy regimes,1,2 intraperitoneal therapy has been justified,3 and several more toxic—but not more active—triple-drug regimens avoided in primary management programs.4 In recent years, however, similar intention has been advocated in the realm of recurrent disease, where a clear road map of "best" or "most active" therapy is lacking. While many studies in this setting show agents with "promise" (see Table 1), close scrutiny of eligibility criteria makes cross trial comparisons hazardous and inconclusive. The most accurate way to distinguish an individual drug or drug combination's impact is to place it head-to-head with another agent with a "track record" in a specific setting. Since there is no "standard of care" in recurrent ovarian cancer, the benchmark is usually an agent, which has a broad FDA label in the setting. New agents being evaluated in this mechanism are often under the registration process. Currently, nearly two dozen phase III clinical studies are underway or have been recently completed. While the success of the new drug application is measured against a frequently moving yardstick, the explosion of new drug applications (NDAs) has ushered in an expansion of potential options for patients.
Recently, the results of an important clinical study were published which appears to fulfill this important end point. Pfisterer and colleagues randomized 356 women with recurrent ovarian cancer to either single-agent carboplatin or combination carboplatin and gemcitabine with the intent to evaluate primarily, progression-free survival. Preclinically, the combination of platinum and gemcitabine has been shown to have synergistic cytotoxic effects and in early clinical evaluation among platinum-sensitive patients (those with a platinum-free interval of ≥ 6 months), efficacy.5,6 Given the mounting evidence that time-to-treatment progression (from the completion of primary therapy) is relevant to the probability of subsequent response with platinum, the investigators stratified enrollment to those with recurrence intervals between 6 and 12 months and more than 12 months. All patients in this study were deemed as potentially platinum-sensitive by traditional criteria and were to have either measurable or assessable disease in which response could also be evaluated. The dose of carboplatin was reduced in the combination arm based on previous phase II data suggesting more toxicity at higher doses when combined with gemcitabine.6 In addition, since patients could have been previously treated with a front-line regimen not including paclitaxel, strata were defined by primary therapy. The study was powered to detect a reduction in the hazard for progression of 29% (HR, 0.71) as quantified by an extension from 6 months (control) to 8.5 months (experimental). In order to evaluate the impact of toxicity, a quality-of-life measure was done.
Overall, more than 96% patients received their entire planned carboplatin dose as intended; approximately 75% received their planned dose of gemcitabine. Hematological toxicity was significantly greater (all parameters, P < 0.001) in the combination arm compared to single-agent carboplatin. In addition, more red blood cell and platelet transfusions were required and more granulocyte growth factor use was administered in the combination. However, febrile neutropenia and use of antibiotics was similar between the arms. Non-hematological toxicities were infrequent, mild and no different between cohorts. Importantly, despite these differences there was no measurable change in patient's reported quality of life.
The primary end point of the study was progression-free survival. At the time of the report, 325 events had been observed. The median follow-up was 17 months. The HR for progression-free survival was 0.72 (95% CI, 0.58-0.90; P = 0.0031) and remained so after adjustment of the platinum-free interval prior to registration. The experimental arm was associated with a median time to progression of 8.6 months compared to 5.8 months for single agent carboplatin. There was no difference, however, in overall survival (HR, 0.96; 95% CI, 0.75-1.23, median survival: 18 months, combination vs 17.3 months, single agent), although the study was underpowered to detect a difference. Response rate was also improved for the combination arm (47% vs 31%; P = 0.0016). In the multivariate analysis of factors affecting progression-free survival, only the treatment arm and platinum-free interval were significant. Subgroup analysis confirmed the effect was conserved across a number of variables including platinum-free interval, prior exposure to taxane, performance status and age. The authors concluded that the combination of carboplatin and gemcitabine was superior to carboplatin alone in patients with potentially platinum-sensitive disease and may be the preferred regimen in this setting given it toxicity profile.
The context of this study is important to understand, as the number of comparable trials in the literature is low. To date there are only 3 phase III studies in platinum-sensitive cohorts which have been published (see Table 2).7-9 A brief review of the findings relative to their primary endpoints demonstrates a confusing picture, as there is no consistent message of efficacy. Details of eligibility criteria for these trials are vastly different as are the cohort population with only the study reported by Pfisterer being closely representative of patients undergoing therapy in 2006. Nonetheless, there are important take-home messages raised by these studies. First, the impact of prior therapy may be relevant to the regimen under study and must be considered prospectively in the analysis. Future trials will be less heterogeneous as worldwide, the standards for primary therapy are becoming consistent. Second, platinum is an important agent even after pre-exposure. The current study would suggest that combination gemcitabine and carboplatin is specifically more active than a single agent carboplatin in the setting of platinum-sensitive recurrent disease however, issues related to sequence are unanswered. Third, progression-free survival is an important landmark for efficacy and acceptable for new drug registration by the United States FDA. Many have called for overall survival to be the principle end point of clinical investigation in recurrent disease. However, the benchmark may be too great given the expanding market of options following study completion. In this most recent trial, follow-up therapy was recorded in a subset of patients demonstrating a large range of sequenced agents. It is not possible to precisely define post-study therapy, as these decisions are made in consideration of issues not entirely defined by efficacy parameters, such as schedule, cumulative toxicity, and patient interest. Factors such as these can confound the survival end point and increase a type II statistical error. Lastly, defining the best option for women with recurrent cancer is a laudable and necessary exercise. We should be unsatisfied with our current offerings for these patients. While this current study appears to help, the combination is not curing more patients. Much more discovery and investigation is needed.
Many new drugs, delivery mechanisms and strategies are on the horizon. The field of translational medicine is bringing new compounds and technology to the bedside.10 It is our hope and intention is that future studies will define patient-specific therapy with curative intent.
References
- McGuire WP, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334:1-6
- Vasey PA, et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst. 2004;96:1682-1691.
- Jaaback K, Johnson N. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev. 2006;(1):CD005340.
- Bookman MA. GOG0182-ICON5: 5-arm phase III randomized trial of paclitaxel (P) and carboplatin (C) vs combinations with gemcitabine (G), PEG-lipososomal doxorubicin (D), or topotecan (T) in patients (pts) with advanced-stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma. Proc Am Soc Clin Oncol. 24:Abstr 5002,2006.
- Rose PG, et al. Gemcitabine reverses cisplatin resistance: demonstration of activity in platinum- and multidrug-resistant ovarian and peritoneal carcinoma. Gynecol Oncol. 2003;88:17-21.
- du Bois A, et al. Second-line carboplatin and gemcitabine in platinum sensitive ovarian cancer—a dose-finding study by the Arbeitsgemeinschaft Gynakologische Onkologie (AGO) Ovarian Cancer Study Group. Ann Oncol. 2001;12:1115-1520.
- Bolis G, et al. Carboplatin alone vs carboplatin plus epidoxorubicin as second-line therapy for cisplatin- or carboplatin-sensitive ovarian cancer. Gynecol Oncol. 2001;81:3-9.
- Parmar MK, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361:2099-2106.
- Pfisterer J, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24:4699-4707.
- Landen CN, Jr., et al. Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery. Cancer Res. 2005;65:6910-6918.
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