- Email: [email protected]
Making of a Phase III Study in Recurrent Ovarian Cancer: The Odyssey of GOG 213
Current Trial Making of a Phase III Study in Recurrent Ovarian Cancer: The Odyssey of GOG 213 Robert L. Coleman Keywords: Bevacizumab, Carboplatin, Cytoreduction, Fallopian tube cancer, Paclitaxel, Peritoneal cancer Clinical Ovarian Cancer, Vol. 1, No. 1, 78-80, 2008; DOI: 10.3816/COC.2008.n.009
Introduction Clinicians and healthcare providers who interact with patients with ovarian cancer are well aware of the significant therapeutic challenge recurrent disease entails. The documented and largely unchanged disease-specific mortality rates over the past 3 decades, despite an expansion of therapeutic options, highlights an entity in dire need of further investigational exploration.1 This clinical trial summary outlines the key rationale, hypotheses, eligibility criteria, accrual goals, and statistical considerations for the Gynecologic Oncology Group (GOG) 213 trial, a randomized controlled clinical trial of carboplatin/paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian, peritoneal primary, and fallopian tube cancer. Study Rationale The study has 2 primary research objectives: (1) to evaluate the role of secondary cytoreductive surgery in patients with recurrent, platinum-sensitive ovarian cancer; and (2) to evaluate the merit of not only adding an antiangiogenic agent (bevacizumab) to combination paclitaxel and carboplatin but also the efficacy of maintenance bevacizumab until progression relative to control. The study’s bifactorial-like design (Figure 1) highlights the questions being addressed and, as such, designates “controls” for each question as (1) no surgery and (2) paclitaxel/carboplatin retreatment. In order to capture the disease spectrum of this group of patients with recurrent disease, the trial allows for investigator discretion as to the feasibility of surgical cytoreduction and, thus, is not strictly bifactorial, meaning not all patients will undergo double randomization. However,
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston Submitted: May 13, 2008; Accepted: May 16, 2008 Address for correspondence: Robert L. Coleman, MD, Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, 1155 Herman Pressler Dr, CPB 6.3271, Houston, TX 77030 Fax: 713-792-7586; e-mail: [email protected]
the study is designed to answer each question independently, allowing for closure of either randomization sequence when its accrual goals are met. The overall primary objective is survival. Rationale for Secondary Cytoreduction The role of tumor debulking as a strategy for primary disease management is consistently accepted, although the sequence relative to chemotherapy administration is fodder for some debate.2 The hypothesis, never tested in a prospective randomized clinical setting, is that cytoreduction improves outcome by reducing tumor bulk and, with it, potentially chemotherapy-resistant cell populations, resulting in more favorable chemotherapy efficacy. Inherent in the assumption is the codependency of surgery and chemotherapy: neither is completely efficacious without the other. The constitution of “optimal” surgery and “optimal” chemotherapy is persistently being revised: the former predominately by retrospective analyses, the latter by randomized clinical studies, such as the GOG 218 and International Collaborative Ovarian Neoplasm (ICON)–7 trials.3 However, it is clear that the odds for “optimal” patient outcome are heightened by aggressive postures from each modality. Cure is the goal. Although this same goal might canvas our approach to recurrent disease, it is well appreciated that, when ovarian malignancy recurs, very few patients will achieve it. Nonetheless, because patients with long disease-free survival represent a relatively “chemotherapysensitive” population, it is reasonable to reconsider surgery as a therapeutic option. Data to support the maneuver are scattered, highly biased, and nearly all retrospective, but each of the nearly 2dozen studies have raised the hypothesis that patients with selected presenting characteristics might benefit from secondary surgery.4,5 The 2 most consistent “favorable” criteria identified by multivariate analyses are prolonged treatment-free survival (first recurrence; varies from 6 months to 24 months) and postoperative tumor residuum, described as “< 0.5 mm,” “microscopic,” or “none.” Median overall survival (OS) of an individual study’s “optimal” cohort is generally 2-3 times the median survivorship of their “suboptimal” cohort. Other factors such as pretreatment with chemotherapy, presence of ascites, volume of presenting disease, number of sites, and histology have appeared in some reports, but these factors likely represent
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1941-4390, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Clinical Ovarian Cancer • June 2008
surrogates for one or both of the following: treatment-free survival or odds of complete resection. In light of these observations, the 2 primary factors described are the eligibility considerations for the surgical question in GOG 213. While treatment-free interval is usually easy to document (biomarker, imaging, symptoms, examination), preoperative factors associated with an “optimal” postoperative tumor residuum (defined as no visible disease) are trickier and, to some extent, surgeon-dependent. The recently completed DESKTOP-II trial is investigating the role of preoperative computed tomography imaging in order to predict optimal surgical outcome; unfortunately, reproducibility of imaging characteristics has been poor.6,7 GOG 213 enables the operating surgeon to establish candidacy for surgical cytoreduction based on the probability of attaining no visible postoperative tumor residuum. It is anticipated that the preoperative characteristics will be variable between and potentially within individual surgeons. Overall survival is the primary endpoint for the surgical question.
Figure 1 GOG 213 Trial Schema Women with recurrent ovarian, peritoneal primary, or fallopian tube cancer and a treatment-free interval q 6 months
Yes
No
Randomize Surgery
Surgical Candidate?
No Surgery
Randomize Carboplatin Paclitaxel
Carboplatin Paclitaxel Bevacizumab Maintenance Bevacizumab
Rationale for Chemotherapy The final iteration of the chemotherapy question proposed in GOG 213 resulted from nearly a decade of debate about what this question should be and how to best answer it. Those who are familiar with this trial’s early development might recall that the initial deliberations centered on not only single-agent platinum versus single-agent nonplatinum therapy but also treatment sequence and whether this question should be addressed in the phase III setting. Other contributing factors to development included the presentation and publication of ICON4, which solidified the control group to combination platinum and taxane treatment, the AGO/OVAR study demonstrating the merits of combination therapy (gemcitabine and carboplatin) over single-agent therapy (carboplatin) and the emergence of bevacizumab as an active agent in solid tumors despite being largely untested at the time in ovarian cancer.8-10 Nonetheless, through great effort on many fronts, the experimental arm was constructed with bevacizumab not only as a combination therapy with paclitaxel and carboplatin but also as a maintenance strategy until progression. It was believed that, with OS as the primary endpoint, maintenance biologic therapy for responding patients would be an important intervention given the natural history of recurrent disease. Finally, the choice of the experimental agent being tested in this protocol and the availability of tissue for some of the participants affords a unique opportunity to evaluate important translational (molecular and biochemical) determinants of outcome. In addition, several correlative questions have also been developed including treatment (surgery and/or chemotherapy) effect on quality of life, incidence of carboplatin hypersensitivity, and predictive models of response and progression-free survival. Hypotheses Being Tested The stated specific hypotheses of GOG 213 are (1) surgical secondary cytoreduction before adjuvant chemotherapy increases the duration of OS in patients with recurrent platinum-sensitive epithelial ovarian cancer, peritoneal primary, or fallopian tube cancer; (2) the addition of bevacizumab to second-line paclitaxel/carboplatin and maintenance phases of treatment increases the duration of OS
The trial schema for GOG 213 demonstrates the 2 primary randomizations. Patients considered candidates for surgery are randomized before chemotherapy randomization. Those not considered good candidates based on their distribution of recurrent disease would go directly to the chemotherapy randomization. The anticipated sample size to answer both questions is approximately 660 patients.
relative to second-line chemotherapy alone in patients with recurrent platinum-sensitive epithelial ovarian cancer, peritoneal primary, or fallopian tube cancer; (3) molecular and biochemical profiles can be identified that are associated with time to first disease recurrence or death; and (4) molecular determinants can be identified within patients with platinum-sensitive recurrent ovarian, peritoneal primary, or fallopian tube carcinoma, which predicts for sensitivity/resistance to combination chemotherapy with or without bevacizumab followed with or without maintenance bevacizumab therapy. Eligibility GOG 213 is a study of patients with traditionally defined platinum- and taxane-sensitive disease. Women with histologically confirmed primary recurrent ovarian, peritoneal, and fallopian tube cancer are eligible for participation if they have been diseasefree for ≥ 6 months after completion of their primary treatment strategy. This could have involved maintenance therapy, interval cytoreduction, or reassessment procedures as long as they were considered to be completely disease-free upon completion assessment. Recurrence can be defined by cancer antigen 125 criteria or clinically evident nonmeasurable or measurable disease by Response Evaluation Criteria in Solid Tumors. Patients must have adequate hematologic and biochemical parameters, be considered of adequate performance status (GOG performance status of 0-2), and have normal or medication-controlled hypertension. Principle exclusions include impending or apparent functional bowel dysregulation or obstruction; grade ≥ 2 neuropathy; previous treatment for recurrent disease, including surgery or chemotherapy; central nervous system disease; and cardiovascular abnormalities. All participants must have received a previous taxane and organoplatinum for treatment of their primary disease.
Clinical Ovarian Cancer • June 2008
79
Phase III Study in Recurrent Ovarian Cancer: GOG 213
Randomization Sequence, Accrual Goals, and Statistics Patients meeting eligibility for GOG 213 will first undergo an assessment of surgical candidacy. As stated, no specific predefined criteria are detailed—only that the surgical attempt, in the estimation of the surgeon, would likely render the patient disease-free. These individuals are then randomized to initial surgery versus direct participation in the chemotherapy randomization (no surgery). Patients completing surgery will join their cohorts, along with patients considered to be poor candidates for surgery, in a randomization between standard paclitaxel/carboplatin or paclitaxel/carboplatin/bevacizumab. Those in the latter arm responding with at least stable disease will then receive single-agent bevacizumab until disease progression. Treatment cycle length for both chemotherapy regimens is 21 days. Overall, it is anticipated that approximately 660 women will be needed to address the primary objectives of this study. In the surgical cohort, ≥ 250 events (deaths) are necessary to provide 80% power to address a 30% reduction in the hazard for death. The treatment effect is equivalent to increasing the percentage of patients surviving at 22 months (median) by 11.5% (from 50% to 61.5%). In the chemotherapy arm, ≥ 214 events (deaths) are required to provide 81% power to address a 25% reduction in the hazard of death. This is equivalent to increasing the expected proportion surviving 22 months to 9.5% (from 50% to 59.5%). A planned interim analysis will be performed when 110 deaths have occurred. The design allows for disproportional participation and may continue in either sequence when one side meets a targeted accrual. Final Considerations It is somewhat ironic that, although the widest array of potentially active agents as well as surgery is available for patients with recurrent platinum- and taxane-sensitive ovarian cancer, the data supporting the use of any particular strategy are so limited. Fortunately, efforts within the world’s cooperative groups and the pharmaceutical industry are addressing this obvious deficiency. While
80
it is unlikely that the need for further refinement will be abolished any time soon, it is clear that large carefully designed studies such as GOG 213, ICON6, DESKTOP-III, and others represent the greatest opportunity to measurably define the coming treatment standards for our patients. Acknowledgements Dr Coleman has received research support from Novartis Oncology, American BioScience, and Morphotek. He has also served as a paid consultant or been on the Advisory Board of Genentech BioOncology, GlaxoSmithKline, Eli Lilly, and Seattle Genetics and has been a member of the Speaker’s Bureau for GlaxoSmithKline, Ortho Biotech, and Eli Lilly. References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 58:71-96. 2. Bristow RE, Chi DS. Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta-analysis. Gynecol Oncol 2006; 103:1070-6. 3. Chi DS, Eisenhauer EL, Lang J, et al. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol 2006; 103:559-64. 4. Hauspy J, Covens A. Cytoreductive surgery for recurrent ovarian cancer. Curr Opin Obstet Gynecol 2007; 19:15-21. 5. Munkarah AR, Coleman RL. Critical evaluation of secondary cytoreduction in recurrent ovarian cancer. Gynecol Oncol 2004; 95:273-80. 6. Axtell AE, Lee MH, Bristow RE, et al. Multi-institutional reciprocal validation study of computed tomography predictors of suboptimal primary cytoreduction in patients with advanced ovarian cancer. J Clin Oncol 2007; 25:384-9. 7. Harter P, Bois AD, Hahmann M, et al. Surgery in recurrent ovarian cancer: the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) DESKTOP OVAR trial. Ann Surg Oncol 2006; 13:1702-10. 8. Burger RA, Sill MW, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group study. J Clin Oncol 2007; 25:5165-71. 9. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinumbased chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003; 361:2099-106. 10. Pfisterer J, Plante M, Vergote I, et al. 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. J Clin Oncol 2006; 24:4699-707.
Clinical Ovarian Cancer • June 2008
Introduction Clinicians and healthcare providers who interact with patients with ovarian cancer are well aware of the significant therapeutic challenge recurrent disease entails. The documented and largely unchanged disease-specific mortality rates over the past 3 decades, despite an expansion of therapeutic options, highlights an entity in dire need of further investigational exploration.1 This clinical trial summary outlines the key rationale, hypotheses, eligibility criteria, accrual goals, and statistical considerations for the Gynecologic Oncology Group (GOG) 213 trial, a randomized controlled clinical trial of carboplatin/paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian, peritoneal primary, and fallopian tube cancer. Study Rationale The study has 2 primary research objectives: (1) to evaluate the role of secondary cytoreductive surgery in patients with recurrent, platinum-sensitive ovarian cancer; and (2) to evaluate the merit of not only adding an antiangiogenic agent (bevacizumab) to combination paclitaxel and carboplatin but also the efficacy of maintenance bevacizumab until progression relative to control. The study’s bifactorial-like design (Figure 1) highlights the questions being addressed and, as such, designates “controls” for each question as (1) no surgery and (2) paclitaxel/carboplatin retreatment. In order to capture the disease spectrum of this group of patients with recurrent disease, the trial allows for investigator discretion as to the feasibility of surgical cytoreduction and, thus, is not strictly bifactorial, meaning not all patients will undergo double randomization. However,
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston Submitted: May 13, 2008; Accepted: May 16, 2008 Address for correspondence: Robert L. Coleman, MD, Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, 1155 Herman Pressler Dr, CPB 6.3271, Houston, TX 77030 Fax: 713-792-7586; e-mail: [email protected]
the study is designed to answer each question independently, allowing for closure of either randomization sequence when its accrual goals are met. The overall primary objective is survival. Rationale for Secondary Cytoreduction The role of tumor debulking as a strategy for primary disease management is consistently accepted, although the sequence relative to chemotherapy administration is fodder for some debate.2 The hypothesis, never tested in a prospective randomized clinical setting, is that cytoreduction improves outcome by reducing tumor bulk and, with it, potentially chemotherapy-resistant cell populations, resulting in more favorable chemotherapy efficacy. Inherent in the assumption is the codependency of surgery and chemotherapy: neither is completely efficacious without the other. The constitution of “optimal” surgery and “optimal” chemotherapy is persistently being revised: the former predominately by retrospective analyses, the latter by randomized clinical studies, such as the GOG 218 and International Collaborative Ovarian Neoplasm (ICON)–7 trials.3 However, it is clear that the odds for “optimal” patient outcome are heightened by aggressive postures from each modality. Cure is the goal. Although this same goal might canvas our approach to recurrent disease, it is well appreciated that, when ovarian malignancy recurs, very few patients will achieve it. Nonetheless, because patients with long disease-free survival represent a relatively “chemotherapysensitive” population, it is reasonable to reconsider surgery as a therapeutic option. Data to support the maneuver are scattered, highly biased, and nearly all retrospective, but each of the nearly 2dozen studies have raised the hypothesis that patients with selected presenting characteristics might benefit from secondary surgery.4,5 The 2 most consistent “favorable” criteria identified by multivariate analyses are prolonged treatment-free survival (first recurrence; varies from 6 months to 24 months) and postoperative tumor residuum, described as “< 0.5 mm,” “microscopic,” or “none.” Median overall survival (OS) of an individual study’s “optimal” cohort is generally 2-3 times the median survivorship of their “suboptimal” cohort. Other factors such as pretreatment with chemotherapy, presence of ascites, volume of presenting disease, number of sites, and histology have appeared in some reports, but these factors likely represent
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1941-4390, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
78
Clinical Ovarian Cancer • June 2008
surrogates for one or both of the following: treatment-free survival or odds of complete resection. In light of these observations, the 2 primary factors described are the eligibility considerations for the surgical question in GOG 213. While treatment-free interval is usually easy to document (biomarker, imaging, symptoms, examination), preoperative factors associated with an “optimal” postoperative tumor residuum (defined as no visible disease) are trickier and, to some extent, surgeon-dependent. The recently completed DESKTOP-II trial is investigating the role of preoperative computed tomography imaging in order to predict optimal surgical outcome; unfortunately, reproducibility of imaging characteristics has been poor.6,7 GOG 213 enables the operating surgeon to establish candidacy for surgical cytoreduction based on the probability of attaining no visible postoperative tumor residuum. It is anticipated that the preoperative characteristics will be variable between and potentially within individual surgeons. Overall survival is the primary endpoint for the surgical question.
Figure 1 GOG 213 Trial Schema Women with recurrent ovarian, peritoneal primary, or fallopian tube cancer and a treatment-free interval q 6 months
Yes
No
Randomize Surgery
Surgical Candidate?
No Surgery
Randomize Carboplatin Paclitaxel
Carboplatin Paclitaxel Bevacizumab Maintenance Bevacizumab
Rationale for Chemotherapy The final iteration of the chemotherapy question proposed in GOG 213 resulted from nearly a decade of debate about what this question should be and how to best answer it. Those who are familiar with this trial’s early development might recall that the initial deliberations centered on not only single-agent platinum versus single-agent nonplatinum therapy but also treatment sequence and whether this question should be addressed in the phase III setting. Other contributing factors to development included the presentation and publication of ICON4, which solidified the control group to combination platinum and taxane treatment, the AGO/OVAR study demonstrating the merits of combination therapy (gemcitabine and carboplatin) over single-agent therapy (carboplatin) and the emergence of bevacizumab as an active agent in solid tumors despite being largely untested at the time in ovarian cancer.8-10 Nonetheless, through great effort on many fronts, the experimental arm was constructed with bevacizumab not only as a combination therapy with paclitaxel and carboplatin but also as a maintenance strategy until progression. It was believed that, with OS as the primary endpoint, maintenance biologic therapy for responding patients would be an important intervention given the natural history of recurrent disease. Finally, the choice of the experimental agent being tested in this protocol and the availability of tissue for some of the participants affords a unique opportunity to evaluate important translational (molecular and biochemical) determinants of outcome. In addition, several correlative questions have also been developed including treatment (surgery and/or chemotherapy) effect on quality of life, incidence of carboplatin hypersensitivity, and predictive models of response and progression-free survival. Hypotheses Being Tested The stated specific hypotheses of GOG 213 are (1) surgical secondary cytoreduction before adjuvant chemotherapy increases the duration of OS in patients with recurrent platinum-sensitive epithelial ovarian cancer, peritoneal primary, or fallopian tube cancer; (2) the addition of bevacizumab to second-line paclitaxel/carboplatin and maintenance phases of treatment increases the duration of OS
The trial schema for GOG 213 demonstrates the 2 primary randomizations. Patients considered candidates for surgery are randomized before chemotherapy randomization. Those not considered good candidates based on their distribution of recurrent disease would go directly to the chemotherapy randomization. The anticipated sample size to answer both questions is approximately 660 patients.
relative to second-line chemotherapy alone in patients with recurrent platinum-sensitive epithelial ovarian cancer, peritoneal primary, or fallopian tube cancer; (3) molecular and biochemical profiles can be identified that are associated with time to first disease recurrence or death; and (4) molecular determinants can be identified within patients with platinum-sensitive recurrent ovarian, peritoneal primary, or fallopian tube carcinoma, which predicts for sensitivity/resistance to combination chemotherapy with or without bevacizumab followed with or without maintenance bevacizumab therapy. Eligibility GOG 213 is a study of patients with traditionally defined platinum- and taxane-sensitive disease. Women with histologically confirmed primary recurrent ovarian, peritoneal, and fallopian tube cancer are eligible for participation if they have been diseasefree for ≥ 6 months after completion of their primary treatment strategy. This could have involved maintenance therapy, interval cytoreduction, or reassessment procedures as long as they were considered to be completely disease-free upon completion assessment. Recurrence can be defined by cancer antigen 125 criteria or clinically evident nonmeasurable or measurable disease by Response Evaluation Criteria in Solid Tumors. Patients must have adequate hematologic and biochemical parameters, be considered of adequate performance status (GOG performance status of 0-2), and have normal or medication-controlled hypertension. Principle exclusions include impending or apparent functional bowel dysregulation or obstruction; grade ≥ 2 neuropathy; previous treatment for recurrent disease, including surgery or chemotherapy; central nervous system disease; and cardiovascular abnormalities. All participants must have received a previous taxane and organoplatinum for treatment of their primary disease.
Clinical Ovarian Cancer • June 2008
79
Phase III Study in Recurrent Ovarian Cancer: GOG 213
Randomization Sequence, Accrual Goals, and Statistics Patients meeting eligibility for GOG 213 will first undergo an assessment of surgical candidacy. As stated, no specific predefined criteria are detailed—only that the surgical attempt, in the estimation of the surgeon, would likely render the patient disease-free. These individuals are then randomized to initial surgery versus direct participation in the chemotherapy randomization (no surgery). Patients completing surgery will join their cohorts, along with patients considered to be poor candidates for surgery, in a randomization between standard paclitaxel/carboplatin or paclitaxel/carboplatin/bevacizumab. Those in the latter arm responding with at least stable disease will then receive single-agent bevacizumab until disease progression. Treatment cycle length for both chemotherapy regimens is 21 days. Overall, it is anticipated that approximately 660 women will be needed to address the primary objectives of this study. In the surgical cohort, ≥ 250 events (deaths) are necessary to provide 80% power to address a 30% reduction in the hazard for death. The treatment effect is equivalent to increasing the percentage of patients surviving at 22 months (median) by 11.5% (from 50% to 61.5%). In the chemotherapy arm, ≥ 214 events (deaths) are required to provide 81% power to address a 25% reduction in the hazard of death. This is equivalent to increasing the expected proportion surviving 22 months to 9.5% (from 50% to 59.5%). A planned interim analysis will be performed when 110 deaths have occurred. The design allows for disproportional participation and may continue in either sequence when one side meets a targeted accrual. Final Considerations It is somewhat ironic that, although the widest array of potentially active agents as well as surgery is available for patients with recurrent platinum- and taxane-sensitive ovarian cancer, the data supporting the use of any particular strategy are so limited. Fortunately, efforts within the world’s cooperative groups and the pharmaceutical industry are addressing this obvious deficiency. While
80
it is unlikely that the need for further refinement will be abolished any time soon, it is clear that large carefully designed studies such as GOG 213, ICON6, DESKTOP-III, and others represent the greatest opportunity to measurably define the coming treatment standards for our patients. Acknowledgements Dr Coleman has received research support from Novartis Oncology, American BioScience, and Morphotek. He has also served as a paid consultant or been on the Advisory Board of Genentech BioOncology, GlaxoSmithKline, Eli Lilly, and Seattle Genetics and has been a member of the Speaker’s Bureau for GlaxoSmithKline, Ortho Biotech, and Eli Lilly. References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 58:71-96. 2. Bristow RE, Chi DS. Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta-analysis. Gynecol Oncol 2006; 103:1070-6. 3. Chi DS, Eisenhauer EL, Lang J, et al. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol 2006; 103:559-64. 4. Hauspy J, Covens A. Cytoreductive surgery for recurrent ovarian cancer. Curr Opin Obstet Gynecol 2007; 19:15-21. 5. Munkarah AR, Coleman RL. Critical evaluation of secondary cytoreduction in recurrent ovarian cancer. Gynecol Oncol 2004; 95:273-80. 6. Axtell AE, Lee MH, Bristow RE, et al. Multi-institutional reciprocal validation study of computed tomography predictors of suboptimal primary cytoreduction in patients with advanced ovarian cancer. J Clin Oncol 2007; 25:384-9. 7. Harter P, Bois AD, Hahmann M, et al. Surgery in recurrent ovarian cancer: the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) DESKTOP OVAR trial. Ann Surg Oncol 2006; 13:1702-10. 8. Burger RA, Sill MW, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group study. J Clin Oncol 2007; 25:5165-71. 9. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinumbased chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003; 361:2099-106. 10. Pfisterer J, Plante M, Vergote I, et al. 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. J Clin Oncol 2006; 24:4699-707.
Clinical Ovarian Cancer • June 2008