Faculty Publications

The objective of the current study was to determine the prognostic significance of a pretreatment serum CA 125 level in patients with advanced epithelial ovarian carcinoma (EOC) who received treatment with a standard chemotherapy regimen. METHODS: Patients with International Federation of Gynecology and Obstetrics stage III/IV ovarian carcinoma who were on 1 of 7 Gynecologic Oncology Group (GOG) phase 3 trials and received treatment with a standard regimen of intravenous cisplatin and paclitaxel were included. A Cox regression model was used to assess the impact of CA 125 levels drawn before the initiation of chemotherapy on progression-free survival (PFS) both overall and by subgroup, including surgical debulking status, disease stage, and histologic subtype. RESULTS: In total, 1299 patients who were on the cisplatin/paclitaxel arms of the GOG trials were eligible. The median CA 125 level was 246 U/mL. Only 7.6% of patients had a normal CA 125 level (<= 35 U/mL). The lowest median CA 125 level was observed in the group with mucinous tumors; however, 69% of women who had mucinous tumors had abnormal CA 125 levels. Shorter PFS was observed with increasing CA 125 and persisted in multivariate analysis. Overall and in the serous subgroup, a 1-fold increase in CA 125 level was associated with a 7% increase in the hazard of disease progression (P < .001). This association was even more pronounced in patients who had stage III disease that was debulked to microscopic disease (15%; P = .003) and in patients who had endometrioid tumors (17%; P = .001). CONCLUSIONS: A normal CA 125 level in the setting of advanced EOC was rare even after surgical debulking. The pretreatment CA 125 level was an independent predictor of PFS in patients with advanced EOC who received a standard chemotherapy regimen, particularly in the setting of disease that was debulked to a microscopic residual and in the serous or endometrioid subtypes. Cancer 2009;115:1028-35. (c) 2009 American Cancer Society.

Objective. The unique characteristics of cancer, particularly issues involving the use of surrogate endpoints in clinical trials, present special challenges in the development ofcancerdrugs. In response, the U.S. Food and Drug Administration (FDA) has partnered with the American Society of Clinical Oncology, the American Association for Cancer Research, and the American Society of Hematology to conduct public workshops evaluating potential endpoints for drug approvals for the most common tumor types. Methods. A workshop evaluating potential endpoints in ovarian cancer drug research was held in Bethesda, Maryland, in April 2006. Invited experts presented research findings and discussed endpoints in trials of drugs for treatment of Stage III and IV ovarian cancer. Results. The panel responded to specific questions from FDA, discussing use of progression-free survival as a surrogate for overall survival and use of CA-125 levels as an indicator of response. Panel members also addressed endpoints in first-line therapy, second-line and subsequent therapy, and maintenance therapy. Conclusion. Expert commentary provided by panel members will inform FDA's draft guidance on clinical endpoints for cancer drug approvals and will be discussed at meetings of the FDA's Oncologic Drugs Advisory Committee. FDA intends to develop a set of principles that can be used to define efficacy standards for drugs used to treat ovarian and other cancers. (c) 2007 Elsevier Inc. All rights reserved.

Purpose Conflicting results on prognostic factors for advanced epithelial ovarian cancer ( EOC) have been reported because of small sample size and heterogeneity of study population. The purpose of this study was to identify factors predictive of poor prognosis in a similarly treated population of women with advanced EOC. Patients and Methods A retrospective review of demographic, pathologic, treatment, and outcome data from 1,895 patients with International Federation of Gynecology and Obstetrics stage III EOC who had undergone primary surgery followed by six cycles of intravenous platinum/paclitaxel was conducted. A proportional hazards model was used to assess the association of prognostic factors with progression-free survival ( PFS) and overall survival ( OS). Results Increasing age was associated with increased risks for disease progression ( HR = 1.06; 95% CI, 1.02 to 1.11 for an increase every 10 years) and death ( HR = 1.12; 95% CI, 1.06 to 1.18). Mucinous or clear-cell histology was associated with a worse PFS and OS compared with serous carcinomas. Patients with performance status ( PS) 1 or 2 were at an increased risk for recurrence compared with PS 0 ( HR = 1.12; 95% CI, 1.01 to 1.24). Compared with patients with microscopic residual disease, patients with 0.1 to 1.0 cm and > 1.0 cm residual disease had an increased risk of recurrence ( HR = 1.96; 95% CI, 1.70 to 2.26; and HR = 2.36; 95% CI, 2.04 to 2.73, respectively) and death ( HR = 2.11; 95% CI, 1.78 to 2.49; P < .001; and HR = 2.47; 95% CI, 2.09 to 2.92, respectively). Conclusion Age, PS, tumor histology, and residual tumor volume were independent predictors of prognosis in patients with stage III EOC. These data can be used to identify patients with poor prognosis and to design future tailored randomized clinical trials.

Objective. Platinum/Paclitaxel-based chemotherapy is a current treatment for advanced epithelial ovarian cancer. We sought to explore the association between weight change during treatment and survival, as well as the association between pre-chemotherapy body mass index (BMI) and survival. Methods. A retrospective data review was conducted of 792 advanced ovarian cancer patients who participated in a phase III randomized trial of cisplatin/paclitaxel versus carboplatin/paclitaxel. Pre-chemotherapy BMI was calculated following surgery. Weight change was defined as the ratio of body weight at completion of protocol therapy to pre-chemotherapy body weight. Progression-free survival (PFS) and overall survival (OS), classified by BMI or relative weight change, were estimated by Kaplan-Meier, and associations were assessed using a Cox model controlled for known prognostic variables (age, race, performance status, histology, tumor grade, tumor residual and treatment group). Results. There was no association between pre-chemotherapy BMI and survival. There was a significant relationship between median OS and weight change as follows: > 5% decrease=48.0 months; 0-5% decrease=49.3 months; 0-5% increase=61.1 months; and > 5% inerease=68.2 months. Adjusted for covariates, the relative risk of death increased by 7% for each 5% decrease in body weight (HR=0.93, 95% CI=0.88-0.99; p=0.013). Conclusions. Change of body weight during primary chemotherapy was a strong prognostic factor for overall survival. Loss of body weight during primary therapy is an indicator for poor OS; weight gain is an indicator for improved survival. This study supports the development of strategies to minimize weight loss that can be assessed in a prospective, randomized study to improve patient outcomes. (c) 2007 Elsevier Inc. All rights reserved.

BACKGROUND: Ovarian cancer is treated with surgery followed by combination chemotherapy with paclitaxel plus carboplatin. In an effort to improve outcomes, clinical trials are evaluating the following strategies: maintenance therapy; intraperitoneal drug administration; new combinations; novel cytotoxics; combination chemotherapy for recurrent disease; and molecular-targeted therapies. PATIENTS AND METHODS: Clinical trials evaluating the above strategies are being performed in ovarian cancer in patients with: (1) previously untreated advanced ovarian cancer; (2) platinum-sensitive recurrent disease; and (3) platinum-resistant recurrent disease. RESULTS: Combination chemotherapy regimens are superior to single-agent therapy in recurrent ovarian cancer. Molecular-targeted therapy has produced objective responses in previously treated patients. Maintenance therapy of any type has not been shown to prolong survival. Intraperitoneal therapy has resulted in improved survival with considerable toxicity in patients with small-volume stage III disease. CONCLUSIONS: Numerous novel clinical strategies are being evaluated in ovarian cancers that have the potential to improve outcomes compared to standard therapy.

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.

Most patients with advanced ovarian cancer achieve a clinical complete remission following cytoreductive surgery and chemotherapy with paclitaxel plus carboplatin. However, a majority of these patients will ultimately recur, and second-line treatment for this group of patients is an important aspect of management of this disease as well as an area of active clinical investigation. Until recently, for patients with platinum-sensitive ovarian cancer (more than 6-month disease-free interval), chemotherapy with single-agent carboplatin was frequently recommended. However, two recent prospective randomized trials have shown that combination chemotherapy produces higher response rates and improvement in progression-free survival compared with treatment with single-agent carboplatin. One trial compared treatment with paclitaxel plus a platinum compound with re-treatment with platinum, and a second trial compared carboplatin plus gemcitabine re-treatment against carboplatin in patients with platinum-sensitive recurrent ovarian cancer. Both trials showed a 3-month improvement in progression-free survival in patients treated with the combination, as well as acceptable toxicity. In the absence of a prospective randomized trial comparing these two regimens in patients with platinum-sensitive recurrent ovarian cancer, the choice of which combination to use may depend on toxicity considerations.

The Gynecol. Oncol. Group (GOG) has conducted a series of randomized trials in advanced ovarian cancer patients, both with early-stage disease (FIGO stages I and II) and advanced-stage disease (FIGO stages III and IV). In patients with early-stage disease, the current std. of therapy is three cycles of paclitaxel and carboplatin-based combination chemotherapy. In patients with advanced-stage ovarian cancer, the GOG std. is six cycles of the same regimen. The GOG has also performed prospective randomized trials of consolidation and maintenance therapy with i.p. (IP) radioisotomes and addnl. cycles of paclitaxel, resp. Neither of these modalities has shown improvement in survival. In addn., the GOG has performed randomized trials of IP chemotherapy, and while it has been demonstrated that the regimens that included IP cisplatin led to improved outcomes, the toxicity of this approach has precluded widespread acceptance of this modality. Currently, the GOG is performing addnl. pilot studies to evaluate less toxic IP regimens. The GOG has also been at the forefront of developing new combination chemotherapy regimens based on the activity of second-line agents, such as topotecan, gemcitabine, and encapsulated doxorubicin. The GOG is also exploring mol.-targeted therapies in phase II trials with the goal of ultimately incorporating biol. therapies in newly diagnosed patients with advanced disease. [on SciFinder (R)]