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2011 ASCO: Additional Phase III Study Data Support the Potential Role of Avastin in Newly-Diagnosed & Recurrent Ovarian Cancer

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Positive results from two bevacizumab (Avastin®) phase III clinical studies were presented at the 2011 American Society of Clinical Oncology Annual Meeting on June 4. The data reported add to the growing body of evidence in support of bevacizumab use to treat recurrent and newly-diagnosed ovarian cancer.

Positive results from two bevacizumab (Avastin®) phase III clinical studies were presented at the 2011 American Society of Clinical Oncology Annual Meeting on June 4. The data reported add to the growing body of evidence in support of bevacizumab use to treat recurrent and newly-diagnosed ovarian cancer.

About Bevacizumab (Avastin®)

A diagram illustrating the role of the VEGF protein in the formation of new blood vessels that support tumor growth. Click on the picture above to view a video regarding the mechanism of action with respect to bevacizumab (Avastin®). (Photo: Genentech)

“Angiogenesis” refers to the process of new blood vessel formation. When tissues need more oxygen, they release molecules that encourage blood vessel growth. Angiogenesis is a normal and vital process in human growth and development, as well as in wound healing. Unfortunately, cancer tumors also utilize this same process to enhance their own blood supply in order to nourish their aberrant growth.

Ovarian cancer is associated with high concentrations of vascular endothelial growth factor (VEGF), a protein associated with tumor growth and spread. Studies have shown a correlation between a high concentration of VEGF and ascites  (excess fluid in the body cavity) development, disease worsening, and a poorer prognosis in women with ovarian cancer.[1-2]

Bevacizumab is a humanized monoclonal antibody designed to specifically bind to the VEGF protein, which plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels through angiogenesis. The drug interferes with the tumor blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. The tumor blood supply is thought to be critical to a tumor’s ability to grow and spread in the body (metastasize).

Bevacizumab is the first U.S. Food and Drug Administration (FDA) approved therapy designed to inhibit angiogenesis. Although FDA-approved for several forms of cancer, bevacizumab is not yet approved for the treatment of ovarian cancer. Patients treated with bevacizumab may experience side effects. In past clinical trials, some people treated with bevacizumab experienced serious and sometimes fatal side effects, related to gastrointestinal (GI) perforation, surgery and wound healing, and severe bleeding. For more information, review the Avastin BOXED WARNINGS and Additional Important Safety Information.

OCEANS Phase III Clinical Study: Women with Recurrent Platinum Sensitive Ovarian Cancer Experience 78% Response Rate & 52% Reduction In Disease Progression Risk

  • About the OCEANS Study

“OCEANS” is a multicenter, randomized, double-blind, placebo-controlled Phase III study in 484 women with platinum drug-sensitive recurrent ovarian, primary peritoneal or fallopian tube cancer.[3] Women in the OCEANS study received no more than one treatment regimen prior to study enrollment.  The OCEANS study randomized enrolled women to one of two clinical study arms:

Arm A: Intravenous carboplatin (area under the curve (AUC) 4; Day 1) + gemcitabine  (1,000 mg/m2; Day 1 & 8; brand name: Gemzar®) + placebo (Day 1) every 21 days x 6 cycles, followed by placebo maintenance every 21 days, until disease progression or unacceptable toxicity occurred.

Arm B: Carboplatin + gemcitabine + bevacizumab (15 mg/kg; Day 1) every 21 days x 6 cycles, followed by single agent bevacizumab maintenance every 21 days, until disease progression or unacceptable toxicity occurred.

The primary endpoint of the OCEANS study was progression free survival. The secondary endpoints of the study included overall survival, objective response, duration of response and safety profile.

  • OCEANS Study Data

Carol Aghajanian, M.D. speaks during the Oral Abstract Session: Gynecologic Cancer at the American Society of Clinical Oncology Annual Meeting on Saturday June 4, 2011. (Photo: ASCO/GMG/Silas Crews 2011)

Carol Aghajanian, M.D., chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center, presented the data from the OCEANS study comparing efficacy and safety of chemotherapy and antiangiogenic therapy in platinum drug-sensitive recurrent ovarian cancer.

Two hundred forty-two women were allocated to each study arm and the median follow-up period was 24 months. Patient characteristics were well-matched in the two treatment groups with regard to age (median age ~60), race (~91% white), performance status (~75%, PS = 0), histologic subtype (~80% serous), cytoreductive surgery (~11%), and platinum-free interval (defined as the time between finishing front-line platinum-based therapy and starting second-line chemotherapy) of more than 12 months (~60%). The study stratification variables were platinum-free interval (6 to 12 months vs. more than 12) and cytoreductive surgery for recurrent disease (yes vs. no).

The median number of chemotherapy cycles was six for each group, and a median of 11 cycles of bevacizumab or placebo was given. At least one-third of the patients received more than six cycles of carboplatin and gemcitabine, although slightly more of the placebo-treated group continued chemotherapy beyond six cycles.

Progression-free survival was significantly longer for women given bevacizumab (12.4 months vs. 8.4 months in the placebo-treated group (hazard ratio [HR]: 0.484; 95% confidence interval (CI) [0.388, 0.605]; p < 0.0001). These results were corroborated by the analyses of an independent review committee. Analyses according to platinum-free interval, cytoreductive surgery, age, and baseline performance status indicate a consistent benefit in all subgroups.

Objective response rate increased by 21.1% (p < 0.0001), from 57.4% in the placebo group to 78.5% in the bevacizumab treated group; duration of response increased from a median of 7.4 months to 10.4 months, respectively (HR: 0.534; 95% CI [0.408, 0.698]; p < 0.0001). Overall survival data are still premature, with median survival of 29.9 months in the placebo group and 35.5 months in the bevacizumab treatment group.

Sixty-five percent of the patients in the placebo group were withdrawn from the protocol due to disease progression, compared with only 41% of the treatment group, but 23% of the discontinuations in the bevacizumab group were due to adverse events, compared with only 5% in the placebo group. Much of this increase was due to grade 3 (or worse) adverse events; specifically hypertension and proteinuria associated with bevacizumab therapy. Overall, the safety profile of bevacizumab was consistent with past trials.

  • OCEANS Study Commentary

Dr. Aghajanian concluded that the OCEANS study results demonstrate a statistically significant and clinically relevant benefit when bevacizumab is added to carboplatin and gemcitabine. Aghajanian stated that this regimen should be considered a new option for the treatment of recurrent, platinum drug-sensitive ovarian cancer. As expected, the rate of adverse events was higher among patients who received bevacizumab, explained Dr. Aghajanian. “Hypertension and proteinuria were increased, but febrile neutropenia was the same in both arms.” “The safety data are reassuring and consistent with the known bevacizumab side-effect profile, and there were no new safety signals,” said Dr. Aghajanian.

“In advanced ovarian cancer, just as in advanced breast cancer, there is often an opportunity to intervene with different lines of chemotherapy,” said Andrew Seidman, M.D., attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Medical College of Cornell University. “There are many chapters in the story, so to speak,” said Dr. Seidman, who moderated a press briefing held in advance of the presentation. “We want to prolong each and every chapter in the disease, and make the story longer and ultimately improve survival. These trials results are certainly an important step in that direction.”

“Women with recurrent ovarian cancer need new treatment options, and it is therefore an important advance to halve the risk of disease progression in this incurable cancer,” said Hal Barron, M.D., chief medical officer and head of Roche Holdings Global Product Development. “These data add to the growing body of evidence supporting Avastin’s potential role in this disease, which includes two previously presented Phase III clinical trials [Gynecologic Oncology Group (GOG)-218 [4] & ICON7] in women with newly diagnosed ovarian cancer.”

In his discussion of the study, Anil K. Sood, M.D., professor and director of the Blanton-Davis Ovarian Cancer Research Program in the Departments of Gynecologic Oncology and Cancer Biology at the University of Texas M.D. Anderson Cancer Center, suggested that further understanding of the timing and dosing of bevacizumab should be pursued in light of (i) its great financial cost, and (ii) reports that inhibition of angiogenesis in animal models reduces primary cancer tumor growth, but accelerates invasion and metastasis — unintended consequences that might be linked to the failure of bevacizumab to extend overall survival in most clinical trials.

ICON7 Phase III Clinical Study:  Newly-Diagnosed Women with High-Risk Ovarian Cancer Experience 36% Reduction in Risk of Death

Gunnar Kristensen M.D., Ph.D. speaks during the Women's Cancers Press Briefing at the American Society of Clinical Oncology Annual Meeting on June 4, 2011. (Photo: ASCO/GMG/Scott Morgan 2011)

ICON7 was designed to investigate safety and efficacy of adding bevacizumab to standard chemotherapy in women with newly diagnosed ovarian cancer. [5] Gunnar Kristensen, M.D, Ph.D., senior consultant in the Department for Gynecologic Oncology of the Norwegian Radium Hospital located in Oslo, reported the Phase III clinical study results.

  • About the ICON7 Study

From December 2006 to February 2009, 1,528 women were randomized from 263 centers in 7 Gynecologic Cancer InterGroups. Eligible women with high-risk early FIGO (Federation of International Gynecology and Obstetrics) stage I or IIa (grade 3 or clear cell histology), capped ≤10%) or advanced (stage IIb-IV) epithelial ovarian, primary peritoneal or fallopian tube cancer were randomizsed (1:1) to one of two study arms:

Arm A: 6 cycles of 3 weekly chemotherapy (carboplatin AUC 5 or 6 and paclitaxel 175mg/m2) alone;  or

Arm B: Same chemotherapy as in Arm A, given concurrently with bevacizumab (7.5mg/kg) for 5 or 6 cycles, followed by continued 3-weekly single-agent bevacizumab maintenance therapy for 12 additional cycles (up to 12 months) or until disease progression (whichever event occurs first).

The baseline patient characteristics were balanced between both study arms: median age (57 years); ECOG Performance Status 0-1 (47%); high-risk early-stage disease (9%); poor prognosis patients (30%); histology (69% serous, 8% endometrioid, 8% clear cell).

  • Updated ICON7 Progression Free Survival Data

Data from the ICON7 study were presented for the first time at the 2010 European Society of Medical Oncology (ESMO) Congress. As reported at ESMO, chemotherapy-naïve ovarian cancer patients who received bevacizumab in combination with standard chemotherapy, and then continued with single agent bevacizumab maintenance therapy, experienced approximately 27% improvement (18.3 months versus 16 months) in the likelihood of living longer without the disease worsening (i.e., progression-free survival) compared to those women who received only chemotherapy (hazard ratio = 0.79, p=<0.0010), which corresponds to a 21% reduction in risk of cancer progression or death. The ICON7 data presented at ESMO was based upon mature progression-free survival results.

The updated ICON7 progression-free survival data presented at the ASCO annual meeting were consistent with the data reported last year at ESMO. In the updated analysis, women assigned to the bevacizumab arm experienced longer progression-free survival than those in the control group (19.8 months vs 17.4 months; HR, 0.87; p =.039). “There is a substantial prolongation of time to progression,” said Dr. Kristensen, adding that the gain was 2.4 months.

  • ICON7 Overall Survival Data Immature; But Clear Benefit To Women With “Poor Prognosis.” 

At a median follow-up of 28 months, there were fewer deaths among women who received bevacizumab than among those who received standard chemotherapy (178 vs 200). Although this represents a 15% overall reduction in mortality risk, the difference did not reach statistical significance (hazard ratio [HR], 0.85; P = .11). The final analyses for overall survival will be performed when 715 patient deaths have occurred. The current analysis was conducted because an interim analysis with at least 365 deaths was requested by the FDA and the European Medicines Agency for licensing consideration.

Although the overall survival data is not mature, a subgroup analysis of women with a “poor prognosis” (defined as FIGO stage III patients debulked to >1.0cm of visible diease or FIGO stage IV with debulking) was performed. Within this subgroup, there were 79 deaths within the bevacizumab arm and 109 deaths in the control arm. Based on this data, there was a 36% reduction in the risk of death (HR=0.64, 95% CI=0.48 to 0.85, p=0.0022 with p=0.015 for test for interaction (treatment/risk group)) among the poor prognosis subgroup.  This result was statistically significant. “We have previously shown that [the high-risk] group has a greater benefit from bevacizumab than the other patients,” said Dr. Kristensen. “For this group, there is a very clear gain for overall survival.”

  • ICON7 Study Commentary

“We conclude that the addition of concurrent and continued bevacizumab for 12 months does improve progression-free survival,” said Dr. Kristensen.  Kristensen also noted that, on the basis of an interim analysis involving approximately 53% of the number of deaths needed for the final analysis, there is an overall trend for improvement in overall survival.

“In this study, we see the ability of antiangiogenic therapy to delay the progression of ovarian cancer, this time in the first-line setting,” said Andrew Seidman, M.D. He added that previous studies have demonstrated the efficacy of bevacizumab in ovarian cancer. “These lend support to a potential role for bevacizumab as the first biologic agent to be used in this disease,” said Seidman, who moderated a press briefing during which study highlights were presented.

There are many strengths in a study like this, in that it addresses questions about the role of anti-VEGF therapies in this setting, said Anil Sood, M.D., who served as a discussant for this paper. “The randomized design is obviously a major strength.”

However, there are potential issues to examine, explained Dr. Sood. “One is the role of bevacizumab in the combination setting, compared with the maintenance setting.”

“How useful is bevacizumab in the combination setting up front? Is the real role for bevacizumab in the maintenance setting following initial chemotherapy,” he asked.

The issue of bevacizumab dosing was also raised by Dr. Sood. “One of the questions is whether higher doses are needed,” he said. “There are data emerging from other studies showing that lower doses are as efficacious, if not more so.”

References:

1/Rudlowski C, Pickart AK, Fuhljahn C, et. al. Prognostic significance of vascular endothelial growth factor expression in ovarian cancer patients: a long-term follow-up. Int J Gynecol Cancer. 2006 Jan-Feb;16 Suppl 1:183-9. PubMed PMID: 16515588.

2/Cooper BC, Ritchie JM, Broghammer CL, et. al. Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer. Clin Cancer Res. 2002 Oct;8(10):3193-7.  PMID: 12374688

3/Aghajanian C, Finkler NJ, Rutherford T, et. al. OCEANS: A randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC). J Clin Oncol 29: 2011 (suppl; abstr LBA5007)[2011 American Society of Clinical Oncology Annual Meeting].

4/ Burger RA, Brady MF, Bookman MA, et. al. Phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): a Gynecologic Oncology Group study [GOG 218 Abstract]. J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1).

5/Kristensen G, Perren T, Qian W., et. al. Result of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer. J Clin Oncol 29: 2011 (suppl; abstr LBA5006) [2011 American Society of Clinical Oncology Annual Meeting].

Additional Sources & Helpful Information:

Bevacizumab (Avastin®) Clinical Trial Information

Related WORD of HOPE Ovarian Cancer Podcast™

Related Libby’s H*O*P*E*™ Postings

Related Libby’s H*O*P*E*™ Videos

  • To view videos regarding bevacizumab (Avastin®), click here.


Access Pharma Commences European Phase II Study of ProLindac™ + Paclitaxel In Platinum-Sensitive Ovarian Cancer Patients

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Access Pharmaceuticals announces commencement of a Phase 2 combination trial for its second generation DACH-platinum cancer drug, ProLindac™ (formerly known as AP5346), in platinum-sensitive ovarian cancer patients. This trial is an open-label, Phase 2 study of ProLindac™ given intravenously with paclitaxel. The combination trial will be conducted in up to eight European participating centers.

Access Pharmaceuticals, Inc., a biopharmaceutical company leveraging its proprietary drug-delivery platforms to develop treatments in the areas of oncology, cancer supportive care and diabetes, announces commencement of a Phase 2 combination trial for its second generation DACH-platinum [the active part of the currently-marketed drug, oxaliplatin] cancer drug, ProLindac™ (formerly known as AP5346), in platinum-sensitive ovarian cancer patients. This trial is an open-label, Phase 2 study of ProLindac™ given intravenously with paclitaxel. The combination trial will be conducted in up to eight European participating centers.

“We are very pleased to be able to begin this trial, which will be the first of several ProLindac-based combination studies in a variety of indications,” said Prof. Esteban Cvitkovic, Vice Chairman Europe and Senior Director Clinical Oncology R&D, Access Pharmaceuticals, Inc. He continued, “The ambitious two-step design of the study will allow us to rapidly benchmark ProLindac/paclitaxel in a clinical setting where there is a clear need to establish an improved standard for long-term tumor responses. When treated using the current first-line combination of carboplatin/paclitaxel, more than half of patients with advanced ovarian cancer will relapse. There are very few second-line options. Approved agents for second-line and later therapy are currently focused primarily on the palliation of more resistant tumors. This lack of valid second-line options presents an opportunity to prove the role of ProLindac-based combinations in ovarian cancer.”

“After optimizing ProLindac’s scaled-up manufacturing process, we are pleased to be moving forward with its clinical development,” said Jeff Davis, President and CEO, Access Pharmaceuticals, Inc. He continued, “We think there is a significant clinical need and commercial opportunity for safer, more effective platinum drugs.”

Access Pharmaceuticals previously announced positive safety and efficacy results from its Phase 2 monotherapy clinical study of ProLindac™ in late-stage, heavily pretreated ovarian cancer patients. In this study, 66% of patients who received the highest dose achieved clinically meaningful disease stabilization according to RECIST [Response Evaluation Criteria in Solid Tumors] criteria, including sustained significant reductions in CA-125 (the established specific serum marker for ovarian cancer) observed in several patients. No patient in any dose group exhibited signs of acute neurotoxicity, which is a major adverse side-effect of the approved DACH platinum, Eloxatin®. ProLindac was very well tolerated, with only minor sporadic hematologic toxicity.

Access Pharmaceuticals is evaluating various indications where DACH platinum-based combinations have been proven active, such as hepatocarcinoma, biliary tree cancer and pancreatic cancer before deciding on an expanded Phase 2 program.

About ProLindac:

ProLindac™ is a novel DACH platinum prodrug that has completed a phase 2 monotherapy study in ovarian cancer patients. It is a polymer therapeutic that utilizes a safe, water-soluble nanoparticulate system to deliver DACH platinum to tumors, while reducing delivery to normal tissue, resulting in an increase in drug effectiveness and a significant decrease in toxic side-effects seen in the currently marketed DACH platinum, Eloxatin®.

For more information, please visit http://www.accesspharma.com/product-programs/prolindac/.

Source: Access Pharmaceuticals Commences ProLindac Phase 2 Combination Clinical Trial – Multicenter, Open-Label Trial to Target Platinum-Sensitive Ovarian-Cancer Patients, News Release, Access Pharmaceuticals, Inc., November 3, 2010.

Additional Information:


Two Combination Treatment Regimens Added to Updated NCCN Guidelines for Ovarian Cancer

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The National Comprehensive Cancer Network (NCCN) recently updated the NCCN Guidelines for Ovarian Cancer to include two additional combination treatment regimens for women with select types of recurring ovarian cancer.

The National Comprehensive Cancer Network (NCCN) recently updated the NCCN Clinical Practice Guidelines for Oncology™ for Ovarian Cancer to reflect the addition of two preferred combination regimens for a specific cohort of patients based on data from recent clinical research studies.

Key updates to the NCCN Guidelines include the addition of carboplatin (Paraplatin®, Bristol-Myers Squibb)/weekly paclitaxel (Taxol®, Bristol-Myers Squibb) and carboplatin/liposomal doxorubicin (Doxil®, Centocor Ortho Biotech) for cytotoxic therapy for patients with platinum-sensitive epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer that has recurred.

These modifications made to the NCCN Guidelines for ovarian cancer are based on results from recent studies in The Lancet and The Journal of Clinical Oncology demonstrating that both combination regimens improved median progression-free survival in women with specific types of recurring ovarian cancer as compared to conventional regimens. In addition, the carboplatin/weekly paclitaxel regimen improved overall survival.

Robert J. Morgan, Jr., M.D., F.A.C.P., Professor, Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center

“Ovarian cancer is a challenge to treat because by the time the majority of the women are diagnosed with the disease, it has already progressed to stage III or IV,” says Robert J. Morgan, MD, of City of Hope Comprehensive Cancer Center and the chair of the NCCN Guidelines Panel for Ovarian Cancer. “Although finding effective screening tools remains a priority, new treatment options for women with ovarian cancer such as the ones outlined in the updated NCCN Guidelines, remains imperative to making steady progress against the disease.”

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and the country’s fifth most common cause of cancer mortality in women. In the year 2009, there were more than 21,000 new diagnoses and nearly 15,000 deaths from this neoplasm in the United States.

The NCCN Clinical Practice Guidelines in Oncology™ are developed and updated through an evidence-based process with explicit review of the scientific evidence integrated with expert judgment by multidisciplinary panels of physicians from NCCN Member Institutions. The most recent version of this and all the NCCN Guidelines are available free of charge at NCCN.org.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives.

Sources:

M.D. Anderson Researchers Find GM-CSF and rIFN-gamma1b Plus Carboplatin Effective For the Treatment of Recurrent, Platinum-Sensitive Ovarian Cancer

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Researchers working in the Gynecologic Oncology Department of The University of Texas M.D. Anderson Cancer Center, reported Phase II clinical study results from their evaluation of the use of carboplatin, granulocyte-macrophage colony-stimulating factor (GM-CSF) and recombinant interferon gamma 1b (rIFN-gamma1b) in women with recurrent, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancer. …

Researchers working in the Gynecologic Oncology Department of The University of Texas M.D. Anderson Cancer Center, reported Phase II clinical study results from their evaluation of the use of carboplatin, granulocyte-macrophage colony-stimulating factor (GM-CSF) and recombinant interferon gamma 1b (rIFN-gamma1b) in women with recurrent, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancer.

As part of this Phase II clinical study, patients with recurrent, platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer were treated with subcutaneous GM-CSF and rIFN-gamma1b before and after intravenous carboplatin until their disease progressed or unacceptable toxicity occurred. All patients had measurable disease and a chemotherapy-free interval >6 months. Response was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and CA 125 blood serum levels. Between 2003 and 2007, 59 patients received a median of 6 cycles of therapy (range, 1 to 13 cycles). The median patient age at enrollment was 61 years (range, 35 to 79 years). The median patient time to disease progression prior to clinical study enrollment was 11 months (range, 6 to 58 months).

The M.D. Anderson researchers reported the following results:

Based upon the foregoing results, the researchers concluded that the pre- and post-carboplatin cytokine regimen resulted in a reasonable response and a hematologic profile that could invite further evaluation of its components in the treatment of patients with ovarian cancer.

Primary Source:  A phase II study of GM-CSF and rIFN-gamma1b plus carboplatin for the treatment of recurrent, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancer; Schmeler KM, Vadhan-Raj S, Ramirez PT et. al., Gynecol Oncol. 2009 Mar 3. [Epub ahead of print].