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Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, Friedlander M, Colombo N, Fowler JM, Argenta PA, De Geest K, Mutch DG, Burger RA, Swart AM, Trimble EL, Accario-Winslow C, Roth LM. Evaluation of New Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer: A Phase III Trial of the Gynecologic Cancer InterGroup. J Clin Oncol. 2009;27(9):1419-25.
Purpose To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel. Patients and Methods Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons. Results Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup. Conclusion Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.
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Bookman
Burger
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Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, Friedlander M, Colombo N, Fowler JM, Argenta PA, De Geest K, Mutch DG, Burger RA, Swart AM, Trimble EL, Accario-Winslow C, Roth LM. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the Gynecologic Cancer Intergroup. J Clin Oncol. 2009 Mar 20;27(9):1419-25.
PURPOSE: To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel. PATIENTS AND METHODS: Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons. RESULTS: Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup. CONCLUSION: Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.
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Bookman
Burger
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Liao S, Darcy K, Randall LM, Tian C, Monk BJ, Burger RA, Fruehauf JP, Barrett RJ, Peters WA, Stock RJ, Stanbridge E. Prognostic relevance of carbonic anhydrase IX in high-risk, early-stage cervical cancer: A Gynecologic Oncology Group study. Gynecol Oncol. 2009 Feb;112(2):S15-S16.
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Burger
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Greer BE, Bundy BN, Ozols RF, Fowler JA, Clarke-Pearson D, Burger RA, Mannel R, DeGeest K, Hartenbach EM, Baergen RN, Copeland LJ. Implications of second-look laparotomy in the context of optimally resected stage III ovarian cancer: A non-randomized comparison using an explanatory analysis: A Gynecologic Oncology Group study. Gynecol Oncol. 2005 Oct;99(1):71-9.
Objective. A non-randomized comparison of outcome in women undergoing second-look laparotomy (SLL) or clinical follow-up, after receiving six cycles of combination chemotherapy with paclitaxel plus either cisplatin or carboplatin, for optimally resected stage III ovarian cancer. Methods. Prior to chemotherapy randomization, patients chose whether or not to undergo SILL; this was a stratification factor to insure balance of treatment assignment. Any subsequent therapy was physician-directed. Explanatory analysis replaced intent-to-treat because of a higher likelihood of detecting SLL effect in the presence of noncompliance. Results. There were 393 patients (median age: 54) who Elected SLL and 399 (median age: 59) who Elected No SLL. The former group was more likely to have gross residual disease at initial surgery than the latter group (69% versus 60%, respectively). In the Elected SLL group, 59 (15%) patients subsequently refused surgery, in nine (2%) surgery was contraindicated, and 31 (8%) relapsed or died prior to the procedure. Cancer was found in 46% of 294 (75%) patients undergoing SLL. Since early failures (prior to SLL) do not address benefit, such patients (SLL: 32; No SLL: 33), defined as progression-free survival (PFS) < 6 months, were excluded from analysis. The adjusted relative risk of progression is 0.89 (95% confidence interval: 0.75, 1.07); the difference in median PFS is 1.0 month (SLL: 23.9 months; No SLL: 22.9 months). The survival rate curves are superimposable. Conclusion. In the context of a non-randomized comparison, the performance of a SLL was not associated with longer survival. (c) 2005 Elsevier Inc. All rights reserved.
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Ozols
Burger
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Burger RA, Sill M, Monk BJ, Greer B, Sorosky J. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology Group (GOG) study. J Clin Oncol (Meeting Abstracts). 2005 June 1, 2005;23(16_suppl):5009-.
5009 Background: Development of targeted therapeutics is considered critical to improve outcomes for patients with EOC/PPC. Vascular Endothelial Growth Factor (VEGF) appears to be a promoter of tumor progression via induction of angiogenesis. Bevacizumab is a recombinant humanized anti-human VEGF monoclonal antibody recently FDA-approved to treat metastatic colorectal cancer. Methods: Eligible patients had persistent or recurrent EOC/PPC after receiving 1-2 prior cytotoxic regimens, measurable disease, and GOG performance status [≤] 2. Treatment consisted of bevacizumab 15 mg/kg IV Q 3 weeks until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at 6 months, objective response rate, and toxicity by NCI criteria. The single-stage design limits the probability of declaring the agent active to 10% when inactive according to both tumor response and PFS at 6 months but is capable of detecting activity on either scale with 90% power. Results: From 4/02 to 8/04, 64 patients were enrolled. Two were excluded for wrong primary and borderline histology; thus, the sample included 62 patients. Median age was 57 (range 18-79) years, and prior treatment consisted of 1 or 2 regimens in 23 and 39 patients, respectively. The median disease free interval from completion of primary cytotoxic chemotherapy to first recurrence was 6.5 months. Early results showed some patients had confirmed objective responses and PFS in some was at least 6 months. The following grade 3 or 4 toxicities were observed: allergy (1 grade 3), cardiovascular (4 grade 3; 1 grade 4), gastrointestinal (3 grade 3), hepatic (1 grade 3), pain (2 grade 3), and pulmonary (1 grade 4). As of 11/15/04, 36 patients were off study, including 29 for disease progression and 1 for toxicity in 33 cases reported. Conclusions: Preliminary evidence exists for objective responses to bevacizumab, presumably a cytostatic agent. Efficacy and toxicity data for this study is expected to reach maturity and be analyzed in March, 2005, and comprehensive results will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech BioOncology
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Burger
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