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Journal of Clinical Oncology, Vol 25, No 19 (July 1), 2007: pp. 2811-2818 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.6735 Randomized Phase III Trial of Gemcitabine Compared With Pegylated Liposomal Doxorubicin in Patients With Platinum-Resistant Ovarian Cancer
From the Washington University School of Medicine, St. Louis, MO; Eli Lilly & Co, Indianapolis, IN; Texas Oncology Cancer Center, Austin; Sammons Cancer Center, Baylor University Medical Center, Dallas, TX; University of Oklahoma Health Sciences Center, Oklahoma City, OK; Carilion GYN Oncology Associates, Roanoke, VA; Carolinas Medical Center, Charlotte; and the Duke University Medical Center, Durham, NC Address reprint requests to David G. Mutch, MD, Washington University School of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, 4911 Barnes Jewish Hospital Plaza, St Louis, MO 63110; e-mail: mutchd{at}msnotes.wustl.edu
Purpose: Ovarian cancer (OC) patients experiencing progressive disease (PD) within 6 months of platinum-based therapy in the primary setting are considered platinum resistant (Pt-R). Currently, pegylated liposomal doxorubicin (PLD) is a standard of care for treatment of recurrent Pt-R disease. On the basis of promising phase II results, gemcitabine was compared with PLD for efficacy and safety in taxane-pretreated Pt-R OC patients. Patients and Methods: Patients (n = 195) with Pt-R OC were randomly assigned to either gemcitabine 1,000 mg/m2 (days 1 and 8; every 21 days) or PLD 50 mg/m2 (day 1; every 28 days) until PD or undue toxicity. Optional cross-over therapy was allowed at PD or at withdrawal because of toxicity. Primary end point was progression-free survival (PFS). Additional end points included tumor response, time to treatment failure, survival, and quality of life. Results: In the gemcitabine and PLD groups, median PFS was 3.6 v 3.1 months; median overall survival was 12.7 v 13.5 months; overall response rate (ORR) was 6.1% v 8.3%; and in the subset of patients with measurable disease, ORR was 9.2% v 11.7%, respectively. None of the efficacy end points showed a statistically significant difference between treatment groups. The PLD group experienced significantly more hand-foot syndrome and mucositis; the gemcitabine group experienced significantly more constipation, nausea/vomiting, fatigue, and neutropenia but not febrile neutropenia. Conclusion: Although this was not designed as an equivalency study, gemcitabine and PLD seem to have a comparable therapeutic index in this population of Pt-R taxane-pretreated OC patients. Single-agent gemcitabine may be an acceptable alternative to PLD for patients with Pt-R OC.
Ovarian cancer (OC) is the leading cause of gynecologic cancer mortality in the United States.1-3 In 2006, an estimated 20,180 new cases of OC were diagnosed, resulting in approximately 15,310 deaths.1 Long-term survival for advanced-stage disease is only 30%, even among women who have had optimal cytoreduction and front-line combination therapy.4,5 OC patients experiencing a late relapse (> 6 months) after first-line platinum treatment are considered to be platinum sensitive. These women usually demonstrate a response to subsequent chemotherapy with or without secondary cytoreductive surgery.6 Platinum-sensitive patients receiving platinum-based combination regimens also show prolonged survival and progression-free survival (PFS) intervals when compared with single-agent chemotherapy.7-9 Treatment strategies are less clear for OC patients experiencing progressive disease (PD) after a treatment-free interval of less than 6 months. By convention, these patients are considered platinum resistant (Pt-R). Recurrent Pt-R patients have limited treatment options and are typically treated sequentially with multiple single-agent regimens. Nonplatinum and nontaxane chemotherapy options that are used in this setting include topotecan, gemcitabine, and pegylated liposomal doxorubicin (PLD).10 Considerations in the choice of second-line chemotherapy include assessment of efficacy, cumulative adverse effects, and the optimal sequencing of available agents. PLD is approved by the US Food and Drug Administration for use in patients with OC whose disease has progressed or recurred after platinum-based chemotherapy. A large phase III study demonstrated that single-agent PLD had an efficacy and safety profile equivalent to topotecan,11 another nonplatinum, nontaxane chemotherapy agent approved for recurrent OC. PLD has become a commonly used treatment option for patients with recurrent Pt-R OC. Gemcitabine has been studied extensively in the phase II recurrent setting as a single agent12-17 and in combination regimens.18-23 In each of these trials, gemcitabine was active and generally well tolerated. Given the promising results of gemcitabine in the treatment of OC and the need to better define its role in the treatment of this disease relative to other available agents, comparison to PLD was warranted. This randomized, multicenter, open-label, phase III trial was designed to compare the efficacy and safety of gemcitabine versus PLD in women with recurrent Pt-R OC disease.
This phase III, centrally randomized, multicenter, open-label comparative trial included 44 independent investigative sites in the United States. A total of 195 patients were randomly assigned to either the gemcitabine or PLD treatment arms. The study was performed in accordance with principles of good clinical practices, applicable laws and regulations, and the Declaration of Helsinki. Informed consent was obtained from all patients entered onto the trial. Each institution obtained institutional review board approval of the protocol before study initiation.
Eligibility Criteria Patients were excluded if they had received prior radiation to the breast, skin, head, or neck within the past 3 years or any previous abdominal or pelvic radiation therapy. Other key exclusion criterion included tumor of low malignancy potential and prior PLD or gemcitabine treatment. Concurrent use of low-dose corticosteroid or hormone replacement therapy was acceptable, but patients taking tamoxifen were excluded.
Treatment Plan
Dose Modification Dose modifications were accomplished by dose/cycle delay or reduction. Cytokines were allowed among patients demonstrating neutropenia (> 7 days) or febrile neutropenia. Dose adjustments were based on absolute neutrophil counts, platelets, and nonhematologic toxicities. Patients who had drug therapy withheld could have therapy resumed if toxicities resolved to  grade 2.
Patient Assessment
Statistical Analysis The primary efficacy analysis was a comparison of PFS between the two treatment arms using the log-rank test. The intent-to-treat population, which included all of the randomly assigned patients, was used for the primary analysis. The PFS curve was estimated for each treatment arm using the Kaplan-Meier method.28 The multiple Cox regression model was used to explore the impact of certain prognostic factors on PFS. Overall survival (OS), which was defined as the duration from random assignment to death, was analyzed in the same fashion. The analyses of PFS and time to treatment failure (defined as duration from random assignment to the earliest of PD, death, discontinuation as a result of toxicity, or starting of poststudy therapies for OC) were performed when the prespecified number (n = 148) of events, including progressions and deaths, was reached in February 2005. The trial remained open to follow-up for survival and other information until February 2006. Data collected up to February 2006 were included in the analysis of OS. A 95% CI for the response rate was calculated using the exact method based on the binomial distribution, and comparison between treatment arms was performed using Fisher's exact test. The disease control rate, which was the percentage of all patients with confirmed complete response, partial response, or stable disease (SD), was analyzed in the same way. Analysis of disease control rate was not planned in the original protocol but was performed ad hoc. Descriptive statistics were provided for QOL data. Two-sided Fisher's exact test was used to test the difference between incidences of selected toxicities. Unless otherwise stated, all tests of hypotheses were conducted at the significance level of P = .05.
Patient Characteristics Between July 9, 2002 and May 21, 2004, a total of 195 patients were enrolled, including 96 patients to the PLD arm and 99 patients to the gemcitabine arm. Table 1 lists the patient demographics for the trial. In comparing patient characteristics, both treatment arms had similar distributions based on age, Zubrod performance status, response to prior platinum therapy, receipt of prior taxane therapy, and diagnosis based on either measurable disease or CA-125. In the gemcitabine/PLD group, 60.6% had received one prior platinum regimen, and 39.4% had received two prior regimens. The distribution in the PLD/gemcitabine group was slightly higher for patients who had received only one prior platinum regimen compared with two prior regimens (67.7% v 32.3%, respectively). The median treatment-free interval from the last prior therapy (ie, the stop date of the last prior therapy to the first dose date of study drug) was 4.3 months for PLD/gemcitabine and 3.5 months for gemcitabine/PLD. Compliance for patients offered the FACT-O questionnaire at enrollment was slightly lower (90.6%) for the PLD group compared with the gemcitabine group (94.9%); however, the baseline FACT-O scores were similar between treatment groups. The median CA-125 value for assessable patients at baseline was higher for the gemcitabine group (525.2 U/mL) compared with the PLD group (291.3 U/mL). The median follow-up time for this trial was 29.2 months.
Treatment Administration During initial treatment, the median number of treatment cycles received was four cycles (range, one to 21 cycles) in the gemcitabine arm and three cycles (range, one to 13 cycles) in the PLD arm. Median number of doses received for the gemcitabine and PLD arms was eight and three doses, respectively. The mean dose-intensity (defined as the actual dose administered divided by planned dose) was 90.8% for gemcitabine and 92.4% for PLD. The percentage of cycles with dose reductions was 14.5% for gemcitabine and 9.0% for PLD. Cross-over therapy was administered to 130 patients, with 66 patients receiving gemcitabine and 64 patients receiving PLD. During cross over, the median number of treatment cycles received was five cycles (range, one to 21 cycles) in the gemcitabine arm and two cycles (range, one to 11 cycles) in the PLD arm. Median number of doses received for the gemcitabine and PLD arms was 8.5 and two, respectively. The mean dose-intensity was 92.1% for gemcitabine and 92.6% for PLD. The percentage of cycles with dose reduction was 13.7% for gemcitabine and 12.4% for PLD.
Efficacy
To explore the impact of certain prognostic factors on survival, a stepwise selection method (P = .20 for entry and P = .10 for stay) was used to build a Cox regression model. Factors considered were age, number of prior chemotherapies, number of prior platinum regimens, response to prior platinum therapy, disease measurability at baseline, baseline CA-125, and baseline Zubrod performance status. For PFS, only baseline CA-125 was a significant predictor. Patients who had higher than the median baseline CA-125 level had a higher risk of progression or death compared with the subgroup with a lower CA-125 level. After adjusting for CA-125, the hazard ratio of gemcitabine versus PLD was 0.98 (95% CI, 0.7 to 1.4). For OS, both baseline CA-125 and performance status were significant prognostic factors. Higher CA-125 level and higher performance status (1 or 2) were associated with higher risk of death. After adjusting for baseline CA-125 level and performance status, the hazard ratio of gemcitabine versus PLD was 0.98 (95% CI, 0.7 to 1.4). Clinical response results for both initial and cross-over treatment arms are listed in Table 2. During initial treatment, overall response rates (ORRs) for gemcitabine and PLD were not statistically different (P = .589). In subgroups of patients with measurable disease, the ORR for the gemcitabine arm (n = 65) was 9.2% compared with 11.7% for the PLD arm (n = 60), and the ORRs were not statistically different (P = .772). During cross-over treatment, ORR for all patients and for patients with measurable disease was comparable to the results observed in the initial treatment phase and was not statistically different between treatment arms. However, when patients with SD were included, the disease control rate (complete response + partial response + SD) trended higher for gemcitabine (60.6%) compared with PLD (46.9%) but was not statistically different (P = .063). A similar trend in disease control was seen in the cross-over treatment arms.
QOL The original plan for QOL assessment called for examination of FACT-O score change over time from baseline to study end. Subsequent study amendments did not permit appropriate follow-up to this end point. Using a multivariate Cox regression model, post hoc analyses of QOL results focused on the relationship between baseline FACT-O total score and treatment outcome for both PFS and OS. In addition to treatment, baseline FACT-O scores (categorized as less than or greater than the median) were included in both outcome models. FACT-O score was not a significant predictor for PFS but was significant for OS (P = .0003, hazard ratio = 0.54; higher baseline FACT-O score was associated with lower hazard). In both models, the treatment effects are comparable after adjusting for the baseline FACT-O score.
Toxicity
Primary nonhematologic events during initial treatment included fatigue, constipation, nausea/vomiting, dyspnea, and mucositis. Only patients in the PLD group (n = 19) experienced grade 2 or 3 hand-foot syndrome (palmar-plantar erythrodysesthesia [PPE]) during initial treatment. Also, grade 2 or 3 mucositis was significantly higher with PLD compared with gemcitabine (P = .003). More patients in the gemcitabine group experienced grade 2, 3, or 4 constipation (P = .004), grade 2, 3, or 4 nausea and vomiting (P = .008), and grade 2, 3, or 4 fatigue (P = .043) compared with PLD patients. Among grade 3 or 4 hematologic events, neutropenia was significantly (P = .003) more common with gemcitabine (n = 38; 38.4%) compared with PLD (n = 18; 18.8%). However, febrile neutropenia was equal in both arms. During cross-over treatment, toxicities were similar to those observed during the initial treatment phase. Fatigue (grade 2, 3, or 4) was significantly higher (P = .009) with gemcitabine (n = 38) compared with PLD (n = 22). Interestingly, PPE was similar in both arms (13 patients in gemcitabine arm and 11 patients in PLD arm; P = .8222). Among grade 3 or 4 hematologic events, neutropenia was more common with gemcitabine (P = .007). However, the incidence of febrile neutropenia was not statistically different between arms (P = .325).
The standard of care for initial management of OC includes platinum- and taxane-based chemotherapy. Although the initial response rate to chemotherapy is high, some patients experience relapse quickly and are not good candidates for re-treatment with these agents. Therefore, identification of active agents in patients with Pt-R disease is important. Ideally, second-line agents should lack cross resistance to previous agents. And, because of the palliative nature of second-line treatment, these agents should also have a favorable toxicity profile. The current study suggests that single-agent gemcitabine may be an acceptable alternative to PLD for patients with recurrent Pt-R OC. Several agents have been evaluated through nonrandomized phase II studies of patients with Pt-R OC. However, a limited number of randomized trials have compared outcomes of single agents in this patient population.7,11,29-38 In general, these studies showed no statistical difference in the therapeutic index among the treatment options. Notable exceptions were agents not considered to be standard treatment for Pt-R OC. (eg, treosulphan or luteinizing hormone-releasing hormone analogs).30,32 In one phase III study, ten Bokkel et al37 suggested that topotecan and paclitaxel were equivalent agents in Pt-R OC patients. However, this study lacked current clinical relevance because patients did not receive prior taxane therapy. In contrast, 99% of patients in our trial received taxane therapy before enrollment. The largest randomized phase III study of recurrent OC to date compared topotecan and PLD.11 This study provided a subset analysis of survival for Pt-R patients in which a survival benefit was not demonstrated for either agent. However, only 74% of the women treated with PLD had received prior taxane therapy. Patients receiving topotecan had significantly (P < .007) more grade 3 and 4 hematologic adverse events, whereas the most common adverse events for patients receiving PLD were PPE and stomatitis. Our study demonstrated comparable efficacy outcomes for gemcitabine and PLD. Response rates in the overall populations and in the subset of patients with measurable disease were largely consistent with data from prior trials using single-agent PLD11,39 and gemcitabine.12-17 Given that most patients with Pt-R OC experience rapid PD and desire active treatment for disease control, disease stabilization may be beneficial in this patient population.40 Importantly, the current study suggests that treatment with gemcitabine trends toward a higher rate of SD (Table 2). Additionally, there were no statistically significant differences between agents for PFS, the primary end point of this study, and for OS. However, OS data should be interpreted with caution as a result of the cross-over treatment design of the study because OS results can be potentially altered by subsequent treatment therapies. Because available second-line agents have similar antitumor activity, current treatment options for Pt-R disease are often guided by consideration for toxicity. Both gemcitabine and PLD showed manageable toxicity profiles. Gemcitabine produced significantly more neutropenia, whereas PLD therapy resulted in PPE (Table 3). The toxicity profiles for each agent are consistent with earlier trials.11,33 As expected given prior clinical studies, grade 2 or 3 PPE was not observed in patients receiving gemcitabine as initial treatment. In addition, 17.2% of gemcitabine-treated patients (11 of 64 patients) crossing over to PLD therapy experienced grade 2 or 3 PPE, which was similar to the incidence of grade 2 or 3 PPE in the initial PLD treatment group (19 of 96 patients; 19.8%). The incidence of PPE observed in these two treatment groups was slightly lower than that reported in other studies using a PLD dose of 50 mg/m2 every 21 or 28 days.11,39,41 Interestingly, approximately 20% of patients (13 of 66 patients) who crossed over to gemcitabine therapy after initial PLD treatment experienced grade 2 or 3 PPE. Further analysis showed that only two of these patients had experienced grade 2 or 3 PPE during the initial treatment phase with PLD. Thus, 11 PLD/gemcitabine cross-over patients reported grade 2 or 3 PPE symptoms as a new adverse event after cross over to gemcitabine therapy. However, for nine of these 11 PLD/gemcitabine cross-over patients with new grade 2 or 3 PPE, the PPE adverse events were reported on day 1 of gemcitabine cross-over therapy. These results suggest that much of the PPE observed in the PLD/gemcitabine cross-over group may be a result of latent or delayed toxicity secondary to initial PLD treatment. In a nonrandomized phase II study, Markman et al42 reported a lower incidence of grade 2 PPE (12%) using PLD 40 mg/m2 every 28 days. In that study, no grade 3 or 4 PPE events were observed. However, the median number of cycles received was two (range, one to 12 cycles), and 12% of the patients (six of 49 patients) required dose adjustments. The apparent higher incidence of PPE observed in our study may be related to multiple factors, including the study dose of PLD (50 mg/m2). This dose was chosen because it was used in all previous randomized trials and is approved by the US Food and Drug Administration. Patients still suffering from taxane- or platinum-induced sensory neuropathy may be at higher risk for more severe PPE secondary to PLD. Certainly, this is an issue for patients with Pt-R disease who may begin salvage chemotherapy while still experiencing persistent neurologic toxicity. The current study includes the second largest population of well-defined patients with Pt-R disease enrolled onto a randomized clinical trial. The trial design reflects current clinical practice, with almost all patients previously treated with both platinum and taxane as primary therapy. Although the current study did not meet the primary end point of improved PFS, it suggests that gemcitabine was similar in activity to PLD in the Pt-R setting with manageable toxicities. However, because this trial was not designed as an equivalency study, caution must be exercised in interpreting these data. Our results suggest that gemcitabine is another option to consider for taxane-pretreated Pt-R OC patients.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Mauro Orlando, Eli Lilly & Co; Tiana Goss, Eli Lilly & Co; Yanping Wang, Eli Lilly & Co; Martin Marciniak, Eli Lilly & Co Leadership: N/A Consultant: David G. Mutch, Genentech, GlaxoSmithKline; Alan N. Gordon, Eli Lilly & Co Stock: Mauro Orlando, Eli Lilly & Co; Tiana Goss, Eli Lilly & Co; Martin Marciniak, Eli Lilly & Co Honoraria: David G. Mutch, GlaxoSmithKline, Merck & Co; Alan N. Gordon, Johnson & Johnson Research Funds: David G. Mutch, Eli Lilly & Co, Aventis, GlaxoSmithKline; Michael G. Teneriello, US Oncology; Alan N. Gordon, Eli Lilly & Co, Johnson & Johnson Testimony: N/A Other: David G. Mutch, GlaxoSmithKline, Merck & Co
Conception and design: David G. Mutch, Alan N. Gordon Administrative support: David G. Mutch, Mauro Orlando, Tiana Goss Provision of study materials or patients: David G. Mutch, Michael G. Teneriello, Alan N. Gordon, Scott D. McMeekin, R. Wendel Naumann, Angeles Alvarez Secord Collection and assembly of data: David G. Mutch, Mauro Orlando, Tiana Goss, Dennis R. Scribner Jr, R. Wendel Naumann Data analysis and interpretation: David G. Mutch, Mauro Orlando, Tiana Goss, Yanping Wang, Martin Marciniak Manuscript writing: David G. Mutch, Mauro Orlando, Tiana Goss, Alan N. Gordon, Yanping Wang, Martin Marciniak Final approval of manuscript: David G. Mutch, Mauro Orlando, Michael G. Teneriello, Alan N. Gordon, Scott D. McMeekin, Yanping Wang, Dennis R. Scribner Jr, Martin Marciniak, R. Wendel Naumann, Angeles Alvarez Secord
We thank Matthew Monberg, John Gill, and Haoyue Zeigler for assistance with this article and Jeffery Bloss for significant contributions to the initial development of this clinical trial.
Supported by Eli Lilly & Co. Presented in part at the 29th European Congress on Clinical Oncology, October 30-November 3, 2005, Paris, France; and at the 37th Annual Meeting of the Society of Gynecologic Oncologists, March 22-26, 2006, Palm Springs, CA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
18 years of age and had a documented pathologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Prior platinum-based chemotherapy was required, and no more than two prior regimens were allowed. Pt-R disease was based on the most recent exposure to a platinum-based regimen and was defined as PD within 6 months of completing the prior therapy. Other inclusion criteria included presence of measurable disease
