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Originally published as JCO Early Release 10.1200/JCO.2006.06.0913 on September 11 2006 © 2006 American Society of Clinical Oncology. 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
From the Klinik für Gynäkologie und Geburtshilfe Campus Kiel, Universitätsklinikum Schleswig-Holstein, Kiel; Dr Horst Schmidt Klinik (HSK), Wiesbaden; Universitäts-Frauenklinik, Tübingen; St Vincentius-Krankenhäuser, Karlsruhe; Frauenklinik Klinikum Großhadern der Ludwig-Maximilians-Universität, München; Universitäts-Frauenklinik, Magdeburg; Klinikum rechts der Isar der Technischen Universität, München; Frauenklinik der Westfälischen Wilhelms-Universität, Münster; Frauenklinik Medizinische Hochschule, Hannover; KKS Marburg, Klinikum der Philipps-Universität Marburg, Germany; University of British Columbia, Vancouver; Centre Hospitalier Universitaire De Quebec, Quebec; Hamilton Regional Cancer Center, Hamilton, Ontario; Saskatoon Cancer Center, University of Saskatchewan; QEII Health Sciences, Halifax; National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada; University Hospital, Leuven, Belgium; Hospital Central De Asturias, Oviedo Asturias, Spain; Medical University, Gdansk, Poland; and the Eli Lilly and Co, Indianapolis, IN Address reprint requests to Jacobus Pfisterer, MD, PhD, Klinik für Gynäkologie und Geburtshilfe, Campus Kiel, Universitätsklinikum Schleswig-Holstein, Michaelisstr 16, D-24105 Kiel, Germany; e-mail: jpfisterer{at}e-mail.uni-kiel.de
PURPOSE: Most patients with advanced ovarian cancer develop recurrent disease. For those patients who recur at least 6 months after initial therapy, paclitaxel platinum has shown a modest survival advantage over platinum without paclitaxel; however, many patients develop clinically relevant neurotoxicity, frequently resulting in treatment discontinuation. Thus, an alternative regimen without significant neurotoxicity was evaluated by comparing gemcitabine plus carboplatin with single-agent carboplatin in platinum-sensitive recurrent ovarian cancer patients. METHODS: Patients with platinum-sensitive recurrent ovarian cancer were randomly assigned to receive either gemcitabine plus carboplatin or carboplatin alone, every 21 days. The primary objective was to compare progression-free survival (PFS). RESULTS: Three hundred fifty-six patients (178 gemcitabine plus carboplatin; 178 carboplatin) were randomly assigned. Patients received a median of six cycles in both arms. With a median follow-up of 17 months, median PFS was 8.6 months (95% CI, 7.9 to 9.7 months) for gemcitabine plus carboplatin and 5.8 months (95% CI, 5.2 to 7.1 months) for carboplatin. The hazard ration (HR) for PFS was 0.72 (95% CI, 0.58 to 0.90; P = .0031). Response rate was 47.2% (95% CI, 39.9% to 54.5%) for gemcitabine plus carboplatin and 30.9% (95% CI, 24.1% to 37.7%) for carboplatin (P = .0016). The HR for overall survival was 0.96 (95% CI, 0.75 to1.23; P = .7349). While myelosuppression was significantly more common in the combination, sequelae such as febrile neutropenia or infections were uncommon. No statistically significant differences in quality of life scores between arms were noted. CONCLUSION: Gemcitabine plus carboplatin significantly improves PFS and response rate without worsening quality of life for patients with platinum-sensitive recurrent ovarian cancer.
Despite progress in the first-line treatment of ovarian cancer, the majority of patients relapse and die within 5 years.1,2 Retrospective studies of platinum-based, second-line therapies have led to the identification of two subgroups of patients with recurrent ovarian cancer: those with so-called platinum-resistant disease and those with platinum-sensitive disease.3,4 Platinum-sensitive disease is characterized by a response to first-line platinum-based therapy and a relapse-free period of at least 6 months after the last platinum treatment. Retreatment with a single-agent platinum has long been considered to be standard therapy for these patients, and based on its favorable therapeutic profile, carboplatin has become the agent of choice. In a recently published pooled analysis of three randomized phase III trials, the Arbeitsgemeinschaft Gynäkologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and International Collaborative Ovarian Neoplasm (ICON) collaborators demonstrated that, compared with conventional platinum-based therapies, paclitaxel plus platinum yielded significant improvements in progression-free survival (hazard ratio [HR], 0.76; 95% CI, 0.66 to 0.89; P = .0004) and overall survival (HR, 0.82; 95% CI, 0.69 to 0.97; P = .02) in patients with platinum-sensitive recurrent ovarian cancer.5 Global quality of life did not differ significantly between the arms, but 20% of patients receiving paclitaxel platinum reported grade 2 to 4 neurotoxicity compared with 1% receiving conventional platinum therapy. Because many patients in that study did not receive paclitaxel as first-line treatment, these neurotoxicity figures with second-line paclitaxel platinum might underestimate the true incidence. In fact, OVAR 2.2, the AGO-OVAR part of the ICON4 study, was discontinued early after slow recruitment due to the investigators' concern that retreatment with paclitaxel would lead to an excess of neurotoxicity after first-line platinum paclitaxel, and a considerable proportion of otherwise eligible patients could not be entered at recurrence because of persistent neurotoxicity from their first-line therapy. In general, ovarian cancer patients relapsing after first-line platinum paclitaxel therapy are at risk for significant neurotoxicity when retreated with the same regimen due to the cumulative neurotoxicity of both platinum and paclitaxel.6 When administered in the first-line setting in a recent AGO-OVAR study, paclitaxel with carboplatin or cisplatin was associated with grade 1 to 4 neurotoxicity in the majority of patients (75% and 83%, respectively).1 In the same study, neurotoxicity slowly resolved after therapy discontinuation, but it also persisted in 20% of patients for 2 years or longer. Thus, although the efficacy of platinum paclitaxel readministration appears promising for platinum-sensitive ovarian cancer patients, the frequency of clinically significant residual neurotoxicity after first-line treatment underscores the need for an active platinum-based combination therapy that is not associated with this toxic effect. The nucleoside analog gemcitabine has shown promising single-agent activity in phase II studies of recurrent ovarian cancer, including patients with prior platinum and/or taxane exposure.7-9 Thus, the AGO-OVAR investigators conducted a phase I/II study of gemcitabine plus carboplatin in patients with platinum-sensitive recurrent ovarian cancer to determine recommended doses to give in combination and to provide some preliminary information on efficacy.10 Results showed a high response rate (62.5%) and encouraging progression-free and overall survival with acceptable toxicity. Based on the considerations herein, a randomized phase III study was initiated to compare the efficacy of gemcitabine plus carboplatin with carboplatin alone in patients with platinum-sensitive recurrent ovarian cancer. The primary objective was to compare progression-free survival between treatment arms. Secondary objectives included comparisons of response rate, duration of response, overall survival, quality of life, and toxicity. Important parts of this final analysis have been presented at the 40th Annual Meeting of the American Society of Clinical Oncology in 2004 and the 10th Biennial Meeting of the International Gynecologic Cancer Society in 2004.11,12
Patients Women at least 18-years-old with recurrent ovarian cancer at least 6 months after completion of first-line, platinum-based therapy were eligible. In addition, patients were required to have measurable or assessable lesions per Southwest Oncology Group criteria,13 an Eastern Cooperative Oncology Group performance status of 0 to 2, adequate bone marrow reserve (absolute neutrophil count [ANC]  1.5 x109/L and platelets 100 x109/L), an estimated glomerular filtration rate (GFR) greater than 50 mL/min, no serious concomitant systemic disorders incompatible with the study, and an estimated life expectancy 12 weeks or longer. Written informed consent was obtained from all patients before enrollment. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. Before patient entry, the appropriate institutional ethics committee for each participating institution approved the protocol.
Procedures Patients in the experimental arm received gemcitabine 1,000 mg/m2 on days 1 and 8 and carboplatin area under the curve (AUC) 4 mg/mL/min on day 1.10 Patients in the control arm received carboplatin AUC 5 on day 1, based on the Calvert formula.14 The AUC calculation was based on GFR calculation according to the formula of Jelliffe.15 Cycles were repeated every 21 days for six cycles in the absence of progressive disease or unacceptable toxicity. At the investigator's discretion, benefiting patients could receive a maximum of 10 cycles of therapy.
Cycles could be postponed up to 2 weeks due to toxicity, and longer toxicity-related delays led to treatment discontinuation. Treatment resumed after recovery from nonhematologic and hematologic toxicities (ANC Patients were assessed before random assignment, before every cycle during treatment, and every 2 to 3 months after treatment for at least 2 years. The baseline assessment included medical history, physical examination, blood counts and chemistries, and radiologic studies to establish extent of tumor burden. Within 2 weeks before enrollment and before every cycle, quality of life was assessed using the EORTC Quality of Life Questionnaires QLQ-C30 and QLQ-OV28, version 2.16,17 Toxicity was assessed every cycle and 30 days after the last treatment; blood counts were obtained on days 1 and 8 of each cycle. Progression-free survival was defined as the time from the date of random assignment to the date of disease progression or death from any cause. Progressive disease was based on clinical and/or radiologic evaluation. Progressive disease was not based on CA-125 elevation without other clinical or radiologic evidence of disease progression. Duration of response was measured from the date of first response to the date of disease progression or death due to any cause. Overall survival was measured from the date of random assignment to the date of death from any cause. All randomly assigned patients were eligible for efficacy evaluation based on an intent-to-treat analysis. Response was measured according to standard Southwest Oncology Group criteria.13 Patients with quality of life data at baseline and postbaseline were included in the quality of life analyses, and changes were measured from baseline to treatment discontinuation between and within arms. All patients receiving at least one dose of study drug were included in the toxicity analysis, which was graded according to the National Cancer Institute Common Toxicity Criteria version 2.18,19
Statistical Analyses
The study was not powered to detect differences in overall survival. In order to detect a 25% improvement in overall survival (that is assuming a HR of 0.80), the power would have been only 55% with an
For time-to-event parameters, Kaplan-Meier estimations were used and log-rank
Role of the Funding Source
From September 1999 to April 2002, 366 patients were enrolled. Figure 1 shows the trial profile; 10 patients did not fully meet the eligibility criteria and were not randomly assigned. Seven randomly assigned patients did not receive study therapy due to patient decision, ineligibility, or thrombocytopenia. The treatment arms were well balanced for baseline patient and disease characteristics (Table 1).
Of the 1,849 total cycles administered, 961 cycles were in the gemcitabine plus carboplatin arm, and 888 cycles were in the carboplatin arm (Table 2). Patients in the gemcitabine plus carboplatin arm received 75.6% of the planned mean dose of gemcitabine (92.8% on day 1 and 63.4% on day 8) and 96.2% of the planned dose of carboplatin. Patients in the carboplatin arm received 98.2% of the planned dose.
Grade 3/4 hematologic toxicities were significantly more frequent in the gemcitabine plus carboplatin arm than the carboplatin arm; neutropenia was the predominant toxicity (Table 3). Although the use of granulocyte growth factors was significantly higher in the gemcitabine plus carboplatin arm (23.6%) than the carboplatin arm (10.1%), the frequency of febrile neutropenia and use of intravenous antibiotic treatment did not differ significantly between arms. Patients in the gemcitabine plus carboplatin arm received more RBC (27.0%) and platelet transfusions (8%) than those in the carboplatin arm (6.7% and 3%, respectively). Fewer than 8% of patients in either arm received erythropoietin for anemia. Few patients discontinued treatment due to hematologic events (such as complicated neutropenia or thrombocytopenia) in either arm (5.1% in the gemcitabine plus carboplatin arm; 4.0% in the carboplatin arm). The overall incidence of grade 3/4 nonhematologic toxicities was modest with less than 5% of patients on either arm having nausea, vomiting, motor or sensory neuropathy, or renal toxicity (Table 3). Of note, grade 2 alopecia was reported in 14.3% of gemcitabine plus carboplatin patients and 2.3% of carboplatin patients.
For the progression-free survival assessment, 325 events were observed. With a median follow-up of 17 months, the HR for progression-free survival was 0.72 (95% CI, 0.58 to 0.90; log-rank P = .0031), indicating a 28% reduction in the progression-free event rate. Median progression-free survival was 8.6 months (95% CI, 7.9 to 9.7 months) for the gemcitabine plus carboplatin arm and 5.8 months (95% CI, 5.2 to 7.1 months) for the carboplatin arm (Fig 2). Overall survival was assessed when 71% of the study population had died. The HR for overall survival was 0.96 (95% CI, 0.75 to 1.23; log-rank P = .7349). Median overall survival was 18.0 months (95% CI, 16.2 to 20.2 months) for the gemcitabine plus carboplatin arm and 17.3 months (95% CI, 15.2 to 19.3 months) for the carboplatin arm (Fig 3). Response rate was significantly higher in the gemcitabine plus carboplatin arm than the carboplatin arm (47.2% v 30.9%; P = .0016; Table 4). Median duration of response was 8.4 months (95% CI, 7.6 to 9.6 months) in the gemcitabine plus carboplatin arm and 7.3 months (95% CI, 5.9 to 8.2 months) in the carboplatin arm (log-rank P = .2511).
Employing the Cox proportional hazards model, a univariate analysis assessed the effect of prespecified prognostic factors on progression-free survival (Table 5). Platinum-free interval was an important prognostic factor individually (P = .0015). Adjusting the effect of this factor on treatment showed that the positive effect of gemcitabine plus carboplatin was maintained when adjusting for platinum-free interval (adjusted HR, 0.71; 95% CI, 0.57 to 0.88; Table 5).
To illustrate the effect of prespecified prognostic factors on progression-free survival, forest plots were constructed (Fig 4). Of note, improved progression-free survival was maintained in patients who received platinum-taxane therapy in the first-line setting and in patients whose platinum-free interval was less than 12 months.
A total of 152 patients (85.4%) in the gemcitabine plus carboplatin arm and 147 patients (826%) in the carboplatin arm completed a quality of life questionnaire at baseline and at least one postbaseline questionnaire. For all scales/items, there were no statistically significant treatment differences for baseline scores between arms, as well as for score changes from baseline to treatment discontinuation between arms (Fig 5).
There were no major differences in postprogression therapy between treatment arms: 135 patients (75.8%) in the gemcitabine plus carboplatin arm received additional chemotherapy, compared with 129 patients (72.5%) in the carboplatin arm. Detailed information was available for 68 patients (38%) in the gemcitabine plus carboplatin arm and for 71 patients (40%) in the carboplatin arm. Twenty patients (29%) in the gemcitabine plus carboplatin arm versus 16 patients (23%) in the carboplatin arm received platinum again, 20 patients (29%) versus 15 patients (21%) received topotecan, 10 patients (15%) versus 13 patients (18%) received anthracyclines, eight patients (12%) versus three patients (4%) received etoposide, eight patients (12%) versus 14 patients (20%) received alkylating agents, one patient (1%) versus five patients (7%) received taxanes, and no patients (0%) versus four patients (6%) received gemcitabine, respectively.
As epithelial ovarian cancer has frequently followed a trajectory more like a chronic illness than an immediate life-threatening disease, the long-term treatment complications associated with improved survival are increasingly becoming clinically relevant. While platinum taxane-based regimens have improved the clinical outcome of ovarian cancer patients, their widespread use as first-line treatments and their cumulative neurotoxicity limit their utility for patients with recurrent ovarian cancer, the majority of whom are platinum sensitive at their first relapse.1,2 Thus, there is an urgent need to identify new platinum-based combination therapies in platinum-sensitive recurrent ovarian cancer that prolong overall and progression-free survival and palliate cancer symptoms with acceptable toxicity and quality of life. This is the first randomized phase III study comparing gemcitabine plus carboplatin with carboplatin in platinum-sensitive recurrent ovarian cancer patients. This study demonstrates that the regimen of gemcitabine plus carboplatin is feasible and significantly increases progression-free survival and response rates in this patient population. In addition, based on the Cox model analysis, the treatment effect of gemcitabine plus carboplatin persisted even when adjusted for significant prognostic factors like prior taxane use and platinum-free interval. This is in accordance with the ICON4/AGO-OVAR 2.2 study, where progression-free survival was longer in patients treated with the combination carboplatin plus paclitaxel than in patients treated with carboplatin alone, irrespective of previous exposure to taxane and time since completion of last chemotherapy.5 This study did not show significant improvement in overall survival with gemcitabine plus carboplatin, but it was not designed and powered to do so. In trials of patients with advanced, incurable cancers, improvement in survival can be easily obscured by poststudy therapy on study discontinuation; furthermore, overall survival reflects all administered lines of therapy and not a specific regimen. The Third International Ovarian Cancer Consensus Conference of the Gynecologic Cancer Intergroup 2004 has stated that it is not possible to standardize treatment for recurrence in ovarian cancer patients, and that progression-free survival is an important end point for the management of ovarian cancer patients and for the assessment of new treatments.21 In addition, there is evidence from other tumor types (for example, colon cancer) that progression-free and overall survival are highly correlated, both within patients and trials.22 Therefore, progression-free survival is an adequate and clinically relevant end point in ovarian cancer trials. While hematologic toxicity was significantly higher with gemcitabine plus carboplatin, the toxicity profile was acceptable, as the increased toxicity was associated with improved efficacy, infrequent clinically significant sequelae (for example, febrile neutropenia), and no diminution of quality of life. Despite that the majority of patients were previously exposed to platinum taxane regimens in the first-line setting, the incidence of significant neurotoxicity was low and comparable between arms. As platinum paclitaxel regimens are the cornerstone of first-line treatment of ovarian cancer, residual neurotoxicity and increased risk for neurotoxicity must be considered when selecting second-line therapy. The high frequency of neurotoxicity observed with paclitaxel-platinum therapy in the aforementioned ICON4/AGO-OVAR 2.2 study highlights the need to consider prior therapy and the efficacy and safety of new therapy when palliation for patients with incurable malignancies is required. Of note, the treatment effect of gemcitabine plus carboplatin on progression-free survival in our study (HR, 0.72) is comparable with the AGO-OVAR 2.2/ICON 4 analyses (HR, 0.76).5 Our study demonstrates also an improvement in progression-free survival that is maintained in patients whose platinum-free interval was less than 12 months and in patients who received first-line taxane therapy. This study clearly demonstrates that gemcitabine plus carboplatin is superior to carboplatin in terms of progression-free survival and response rate. Finally, relative to therapy with taxanes, gemcitabine plus carboplatin exhibited a preferable toxicity profile as evidenced by greatly diminished neuropathy and alopecia, which are of importance for the affected women. Therefore, gemcitabine plus carboplatin represents a new treatment option for patients with platinum-sensitive recurrent ovarian cancer.
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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,999 (C)
The following physicians/centers enrolled two or more patients (presented in alphabetical order): A. de Barros Lopes (Gateshead, United Kingdom), J. Bentley (Halifax, Canada), G.S. Bhattacharyya (Calcutta, India), A. du Bois (Wiesbaden, Germany), G. P. Breitbach (Neunkrichen, Germany), B. Brückner (Bonn, Germany), S. Cai (Shanghai, China), M. Carey (London, Canada), H. Chalchal (Regina, Canada), N. Colombo (Milano, Italy), S. Costa (Frankfurt, Germany), J. D' Dubuc (Montreal, Canada), D.C. Doval (Dehli, India), W. Faught (Ottawa, Canada), S. Fine (Mississauga, Canada), V.P. Gangadharan (Trivandrum, India), K. Govind Babu (Bangalore, India), I. Gröll de Rivera (Ebersberg, Germany), F. Hilpert (Kiel, Germany), H. Hirte (Hamilton, Canada), M. Hummel (Bad Säckingen, Germany), Ch. Jackisch (Münster, Germany), J. Jeffrey (Kingston, Canada), R. Kimmig (München, Germany), W. Knapp (Delmenhorst, Germany), A. Kobierska (Gdansk, Poland), O. Kramer (Waiblingen, Germany), R. Kreienberg (Ulm, Germany), P. Krezdorn (Sigmaringen, Germany), W. Kuhn (München, Germany), U. Kullmer (Lich, Germany), T. Le (Saskatoon, Canada), U. Lee (Surrey, Canada), L. Leuschner-Richter (Husum, Germany), H.J. Lück (Hannover, Germany), C. Mangioni (Monza, Italy), F. Melchert (Mannheim, Germany), S. Nag (Pune, India), H Nöschel (Jena, Germany), A.M. Oza (Toronto, Canada), M. Plante (Quebec, Canada), P. Prem Kumar (Hyderabad, India), J. Quaas (Greifswald, Germany), A.A. Ranade (Pune, India), G. Reinelt (Mühlacker, Germany), B. Richter (Dresden, Germany), K. J. Roozendaal (Amsterdam, Netherlands), F. Salas (Lima, Peru), D. Schwörer (Offenburg, Germany), A. Stähle (Karlsruhe, Germany), K. Swenerton (Vancouver, Canada), Ch. Uleer (Osnabrück, Germany), I. Vergote (Leuven, Belgium), U. Wagner (Tübingen, Germany), W. Weise (Magdeburg, Germany), B. Wojtkowiak (Mayen, Germany), S.S. Yoshida (Windsor, Canada), W. Zhang (Beijing, China).
published online ahead of print at www.jco.org on September 11, 2006. Supported by Lilly Deutschland GmbH, Bad Homburg, Germany. Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004 and at the 10th Biennial Meeting of the International Gynecologic Cancer Society, Edinburgh, Scotland, October 3-7, 2004. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. du Bois A, Lück HJ, Meier W, et al: A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95:1320-1329, 2003 2. Ozols RF, Bundy BN, Greer BE, et al: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gyncologic Oncology Group study. J Clin Oncol 21:3194-3200, 2003 3. Markman M, Rothman R, Hakes T, et al: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 9:389-393, 1991[Abstract] 4. Gore ME, Fryatt I, Wiltshaw E, et al: Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol 36:207-211, 1990[CrossRef][Medline] 5. Parmar MK, Ledermann JA, Colombo N, 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 361:2099-2106, 2003[CrossRef][Medline] 6. Armstrong DK: Relapsed ovarian cancer: Challenges and management strategies for a chronic disease. Oncologist 7:20-28, 2002 (suppl 5) 7. Lund B, Hansen OP, Theilade K, et al: Phase II study of gemcitabine (2',2'-ifluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 86:1530-1533, 1994 8. Lund B, Neijt JP: Gemcitabine in cisplatin-resistant ovarian cancer. Semin Oncol 2372-2376, 1996 9. Shapiro JD, Millward MJ, Rischin D, et al: Activity of gemcitabine in patients with advanced ovarian cancer: Responses seen following platinum and paclitaxel. Gynecol Oncol 63:89-93, 1996[Medline] 10. du Bois A, Lück HJ, Pfisterer J, et al: Second-line carboplatin and gemcitabine in platinum- sensitive ovarian cancer: A dose-finding study by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Ovarian Cancer Study Group. Ann Oncol 12:1115-1120, 2001 11. Pfisterer J, Plante M, Vergote I, et al: Gemcitabine/carboplatin vs. carboplatin in platinum sensitive recurrent ovarian cancer: Results of a gynecologic cancer Intergroup randomized phase III trial of the AGO-OVAR, the NCIC CTG and the EORTC GCG. J Clin Oncol 22:450s, 2004 (abstr 5005) 12. Pfisterer J, Vergote I, du Bois A, et al: Combination therapy with gemcitabine and carboplatin in recurrent ovarian cancer. Int J Gynecol Cancer 15:36-41, 2005 (suppl 1)[CrossRef][Medline] 13. Green S, Weiss GR: Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 10:239-253, 1992[CrossRef][Medline] 14. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989[Abstract] 15. Jelliffe RW: Creatinine clearance: Beside estimate. Ann Intern Med 79:604-605, 1973[CrossRef][Medline] 16. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376,1993 17. Greimel E, Bottomley A, Cull A, et al: An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-OV28) in assessing the quality of life of patients with ovarian cancer. Eur J Cancer 39:1402-1408, 2003[CrossRef][Medline] 18. National Cancer Institute: Cancer Therapy Evaluation Program: Common Toxicity Criteria. Http://ctep.cancer.gov/reporting/ctc.html 19. Trotti A, Byhardt R, Stetz J, et al: Common toxicity criteria: Version 2.0: An improved reference for grading the acute effects of cancer treatment: Impact on radiotherapy. Int J Radiat Oncol Biol Phys 47:13-47, 2000[CrossRef][Medline] 20. Freedman LS: Tables of the number of patients required in clinical trials using the logrank test. Stat Med 1:121-129, 1982[Medline] 21. Thigpen T, Stuart G, du Bois A, et al: Clinical trials in ovarian carcinoma: Requirements for standard approaches and regimens. Ann Oncol 16:viii13-viii19, 2005 (suppl 8) 22. Sargent DJ, Wiand HS, Haller DG, et al: Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: Individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 23:8664-8670, 2005 Submitted February 8, 2006; accepted June 29, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= .05 and 352 deaths. 
2 tests compared the distribution between groups. For progression-free survival, separate univariate Cox models were fitted individually for each covariate. Factors that showed individual prognostic value (P < .05) were added to a model with treatment to assess the effect of treatment when adjusting for any significant univariate prognostic factors. Covariates included age (> 60 v 
60), performance status (0 v 1-2), prior platinum therapy (platinum plus nonpaclitaxel v platinum plus paclitaxel), disease status (bidimensionally measurable v assessable), and duration of platinum-free interval (6 to 12 months v > 12 months). Response rates were compared using an unadjusted normal approximation for the difference of two binomial proportions, and 95% CIs were constructed. Changes in QLQ-C30 and QLQ-OV28 baseline scores were compared within and between arms using a paired t-test and an analysis of variance (ANOVA). All analyses were done with SAS version 8.2 (SAS Institute, Cary, NC). 
