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Keywords:

  • bevacizumab;
  • Gynecologic Oncology Group;
  • stromal ovarian tumors;
  • survival

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

The Gynecologic Oncology Group conducted this phase 2 trial to estimate the antitumor activity of bevacizumab and to determine the nature and degree of toxicity in patients with recurrent sex cord-stromal tumors of the ovary.

METHODS

A prospective, multi-institutional cooperative group trial was performed in women with recurrent, measurable ovarian stromal tumors. Patients were allowed to have unlimited prior therapy, excluding bevacizumab. Bevacizumab 15 mg/kg was administered intravenously on day 1 of every 21-day cycle until patients developed disease progression or adverse effects that prohibited further treatment. The primary endpoint was the response rate (RR). Inhibin A and B levels were measured before each cycle, and the values were examined in relation to response and progression.

RESULTS

Thirty-six patients were enrolled, and all were eligible and evaluable. Patients received a median of 9 cycles of treatment (range, 2-37 cycles). Six patients (16.7%) had partial responses (90% confidence interval, 7.5%-30.3%), 28 patients (77.8%) had stable disease, and 2 patients (5.6%) had progressive disease. This met the criterion for declaring the regimen active. The median progression-free survival was 9.3 months, and the median overall survival was not reached in during reporting period. Two grade 4 toxicities occurred, including hypertension and proteinuria; and the most common grade 3 toxicities were hypertension (n = 5) and pain (n = 5). Inhibin A and B values were lower in patients who responded to treatment.

CONCLUSIONS

Bevacizumab has activity in the treatment of recurrent sex cord-stromal tumors of the ovary, and its toxicity is acceptable. Further investigation is warranted. Cancer 2014;120:344–351. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Sex cord-stromal tumors (SCSTs) of the ovary are rare neoplasms that account for less than 5% of all ovarian malignancies.[1-3] This group of ovarian stromal tumors includes granulosa cell tumors, granulosa cell-theca cell tumors, Sertoli-Leydig cell tumors (androblastomas), steroid (lipid) cell tumors, gynandroblastomas, unclassified sex cord-stromal tumors, and sex cord tumors with annular tubules. SCSTs tend to have an indolent course compared with epithelial ovarian cancer and can recur decades after their initial diagnosis and treatment. Unfortunately, these tumors are particularly resistant to chemotherapy, and treatment of recurrent disease is difficult, even with the use of surgery, radiotherapy, chemotherapy, and hormonal agents.[4-6] Therefore, the investigation of novel therapeutic approaches is warranted based on the limited efficacy of these standard treatment options.

The tumor biology of SCSTs suggests the importance of angiogenesis in tumor development and progression. These tumors are known to be vascular and can present with hemoperitoneum in up to 30% of patients.[5] Lymph node metastases are extremely rare, yet distant metastases are common, further suggesting that hematogenous spread predominates and that angiogenesis may play an important role in these tumors.[7, 8] A recent case series of 8 patients who were treated at a single institution suggested that bevacizumab is active in the setting of recurrent disease, but the study included multiple regimens with and without cytotoxic therapy and was retrospective in nature. That report also suggested that vascular endothelial growth factor overexpression and microvessel density were associated with worse outcomes and a more aggressive phenotype, although the sample size was too small to calculate statistical significance.[8] Together, these observations suggest that antiangiogenic agents, such as bevacizumab, may have a role in treating women with SCSTs. However, the body of literature surrounding these characteristics is limited, and, to our knowledge, no prospective study of any antiangiogenic agent in SCSTs has been performed to date.

Because SCSTs are uncommon, clinical trials exploring therapeutic options have been limited. Performing these trials in a cooperative group setting, such as the Gynecologic Oncology Group (GOG), allows for rapid accrual and evaluation. The primary objective of our phase 2 study was to estimate the antitumor activity of bevacizumab by assessing the frequency of objective responses in patients who had recurrent SCSTs of the ovary with measurable disease. The secondary objectives were to examine overall survival (OS) and progression-free survival (PFS) and to determine the nature and degree of toxicity in these patients. A translational research objective was to determine the association of inhibin A and inhibin B with response to treatment.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Eligibility Criteria

Eligible patients had a histologically confirmed diagnosis of recurrent ovarian stromal tumor, including granulosa cell tumor, granulosa cell-theca cell tumor, Sertoli-Leydig cell tumor (androblastoma), steroid (lipid) cell tumor, gynandroblastoma, unclassified sex cord-stromal tumor, or sex cord tumor with annular tubules. Because some patients had experienced multiple episodes of recurrent disease before enrolling in this protocol, any histologic confirmation of recurrent SCST was considered sufficient for enrollment, and a repeat biopsy was not mandated. Central pathologic review confirmed the diagnosis of ovarian SCST. Patients were eligible if they had measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1, defined as at least 1 lesion that could be accurately measured in at least 1 dimension (the greatest dimension to be recorded), with each target lesion ≥20 mm when measured by conventional techniques, including palpation, plain radiograph, computerized tomography, or magnetic resonance imaging, or ≥10 mm when measured by spiral computed tomography. Other eligibility criteria included a GOG performance status of 0, 1, or 2; adequate hematologic, renal, and hepatic function; and patients of childbearing potential with a negative pregnancy test had to agree to practice an effective means of birth control. There were no restrictions on prior therapy, but patients could not have previously received bevacizumab.

Study Design

This GOG prospective, multi-institutional, phase 2 trial was designed to estimate the antitumor activity of bevacizumab by assessing the frequency of objective response, to examine OS and PFS, and to determine the nature and degree of toxicity in these patients. Patients were to receive bevacizumab intravenously at a dose of 15 mg/kg every 21 days until they developed disease progression or prohibitive toxicity. Bevacizumab was provided by the manufacturer free of charge to the patients. Each 21-day period was considered 1 cycle. Serum inhibin A and B levels were measured during every cycle of treatment. The study received local institutional review board approval at participating institutions, and all patients gave written informed consent according to institutional and federal guidelines before treatment.

Treatment Plan and Dose Modification

Toxicity was monitored with history, physical examination, and laboratory assessment before each treatment cycle, with adverse events defined and graded according to National Cancer Institute Common Toxicity Criteria version 3.0. Guidelines were established for dose delays and dose reductions for hematologic and nonhematologic toxicity.

Patient Assessment

Activity of bevacizumab was assessed according to RECIST, either by clinical evaluation, computed tomography, or magnetic resonance imaging, at baseline and before every other cycle for the measurement of target lesions, the classification of clinical response, and the determination of disease progression. Therapy was discontinued for disease progression, unacceptable toxicity, receipt of other anticancer therapy, or voluntary withdrawal.

Statistical Analysis

The primary objective of the study was to evaluate the efficacy of the study agent as assessed by objective tumor responses. The tumor response rate (RR) was used as the primary endpoint, rather than survival or PFS, for 2 reasons. First, there are limited prior data serving as a reference for PFS and OS in this disease setting, so these endpoints cannot be used to define the activity of the agent. Second, an objective response is 1 meaningful way to assess antitumor activity, and setting a low threshold for tumor response (5%) enabled us to have reasonable probability (α = 10%) of ruling out truly inactive agents for further investigation.

The targeted accrual for the first stage was 19 patients but was allowed to deviate for administrative purposes. With 24 eligible and evaluable patients, more than 1 patient responding was required to go on to the second stage. The cumulative targeted accrual for the second stage was 34 patients but was allowed to deviate. With 36 eligible and evaluable patients, more than 3 patients with responses were required to declare the agent sufficiently active to warrant further evaluation.

The study was designed to limit the expected probabilities of type I and II errors to no greater than 10% under the assumed accrual ranges of 15 to 22 patients (first stage) and 30 to 37 patients (cumulatively after the second stage). By using the method of Chen and Ng,[9] if the true RR was 5%, then the study design limited the average probability (across the accrual range) of incorrectly designating the treatment as active to 10%. Conversely, if the true RR was 20%, then the average probability of correctly classifying the treatment as active was 90%.

Kaplan-Meier estimates were used for PFS and OS, and exact confidence intervals (CIs) were used for binary parameters. The primary endpoint was the RR, which was evaluated in a 2-stage design (with power of 0.90 for an RR of 20% and α = .10 for an RR of 5%). The reverse Kaplan-Meier method was used to calculate median follow-up.[10]

Inhibin A and inhibin B values were measured every cycle of treatment. We determined that a few inhibin A and inhibin B values were less than the cutoff; in these cases, the cutoff value was used for calculation. We also determined that several inhibin B values were above the cutoff; in these cases, the cutoff value was used for analysis. Results were similar when these values were excluded from the analysis and when 0.5 times the lower cutoff and 1.5 times the upper cutoff were used. Analyses of time point-specific values were done using medians and rank-based (nonparametric) methods. Medians of the 25th and 75th percentiles were used for summary statistics, and Wilcoxon rank-sum tests were used to compare groups. Summary statistics and comparison of inhibin A and inhibin B values between responders and nonresponders are presented for only the first 4 cycles, because the number of patients with available data decreased from 32 patients with available data in cycle 1 to 22 patients with available data in cycle 5. Joint models of both longitudinal inhibin values and PFS also were used in random effects models to model the inhibin values over time and in proportional hazards models. Natural log inhibin values were used in these joint models.[11]

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Patient Characteristics

From September 2008 through January 2011, 36 patients were enrolled, all of whom were eligible and evaluable. Patient characteristics of the study group are listed in Table 1. The GOG performance status was zero in 30 patients (83.3%) and 1 in 6 patients (16.7%). Of the 36 patients, 32 patients had granulosa cell tumors (88.9%), and 4 patients had an unclassified SCSTs (11.1%). When the referring pathology diagnosis was compared with central pathology review, 33 of 36 patients (91.7%) had concordant results. All 3 patients for whom a different diagnosis was rendered by central pathology review were ultimately determined to have SCST, unclassified; these patients had initial diagnoses of granulosa cell tumor, Sertoli-Leydig cell tumor, and unknown, respectively. Thirty-three of the 36 patients (91.7%) had received prior chemotherapy, with a median of 2 prior regimens. Six patients had previously received radiotherapy (16.7%). None had received prior immunotherapy.

Table 1. Patient Characteristics
CharacteristicNo. of Patients (%)
Age, y 
30-391 (2.8)
40-498 (22.2)
50-5912 (33.3)
60-6911 (30.6)
70-794 (11.1)
Race 
Unspecified2 (5.6)
Asian1 (2.8)
African-American3 (8.3)
White30 (83.3)
Ethnicity 
Hispanic2 (5.6)
Non-Hispanic30 (83.3)
Unspecified4 (11.1)
No. of prior chemotherapy regimens 
03 (8.3)
112 (33.3)
214 (38.9)
34 (11.1)
42 (5.6)
61 (2.8)

Treatment Administration

In total, 491 cycles of bevacizumab were administered, with a median of 9 treatment cycles per patient (range, 2-50 treatment cycles, with the maximum received by 1 patient who remained on the study).

Activity of Bevacizumab

The activity of bevacizumab was analyzed in the 36 enrolled patients. Six patients had a partial response (16.7%; 90% CI, 7.5%-30.3%), 28 patients had confirmed stable disease (77.8%), and 2 patients had progressive disease (5.6%). This RR met the criteria to declare the agent active. For the 6 patients who had partial responses, the median time to response was 8.2 months (25th to 75th percentile, 1.5-14.4 months), and the duration of response was 18.6 months (25th to 75th percentile, 17.9-27.2 months). The median PFS was 9.3 months, and the median OS was not reached at a median follow-up of 32.5 months. Graphs of the Kaplan-Meier estimates of PFS and OS for the study population are provided in Figures 1 and 2.

image

Figure 1. This is the Kaplan-Meier estimate of progression-free survival for the study population.

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image

Figure 2. This is the Kaplan-Meier estimate of overall survival for the study population.

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One patient remained on the study after 50 cycles with a partial response as of December 2012. Five patients remained alive without progression, 23 patients remained alive with disease progression, and 8 patients died, including 5 because of disease, 1 because of treatment and disease, and 2 whose cause of death is pending.

Toxicity

The safety of bevacizumab in all 36 patients was analyzed descriptively, as indicated in Table 2, and the events listed were reported as at least possibly related to study drug. Grade 3 adverse events at least possibly related to bevacizumab included hypertension (n = 5), pain (n = 5), dyspnea, dyspnea + hypoxia, leukopenia, anemia, hypophosphatemia, proteinuria, coagulation, tinnitus, constipation and distension, fatigue, genitourinary/renal, hematoma, and syncope (n = 1 each). Two grade 4 toxicities were observed: hypertension and proteinuria. All cardiac events were related to hypertension, and the gastrointestinal event was an incarcerated hernia that required emergent surgery. There were no gastrointestinal perforations. Four of 36 patients (11%) came off study because of toxicity.

Table 2. Adverse Events by Number of Episodes
 No. of Episodes 
Adverse Event Category012345Total
  1. Abbreviations: CTC, Common Terminology Criteria for Adverse Events.

Leukopenia322110036
Thrombocytopenia288000036
Anemia217710036
Other hematologic332100036
Allergy/immunology2311200036
Auditory/ear290610036
Cardiac156951036
Coagulation350010036
Constitutional12101310036
Dermatologic1714410036
Endocrine332100036
Gastrointestinal6101550036
Genitourinary/renal295110036
Hemorrhage1718010036
Infection2301120036
Lymphatics314100036
Metabolic1310832036
Musculoskeletal305100036
Neurosensory2113110036
Other neurologic2212110036
Ocular/visual306000036
Pain1111680036
Pulmonary1220130036
Sexual/reproductive324000036
Syndromes351000036
Vascular350100036
Death, not CTC coded350000136

Inhibin A and Inhibin B

The median inhibin A value was 12 pg/mL at cycle 1 (baseline) and decreased slightly across the following 3 cycles to 12 pg/mL, 11 pg/mL, and 9 pg/mL. Inhibin A values were lower (although the difference was not statistically significant; P = .100) at baseline in responders versus nonresponders (median, 6 pg/mL vs 15 pg/mL); and the values in cycles 2, 3, and 4 were statistically significantly lower in patients who responded to treatment (median, 2 pg/mL) than in those who did not respond to treatment (median, 30 pg/mL, 32 pg/mL, and 34 pg/mL in cycles 2, 3, and 4, respectively) (Table 3). The median inhibin B value was 217 pg/mL at cycle 1 (baseline) and decreased after treatment to 168 pg/mL, 169 pg/mL, and 169 pg/mL in cycles 2, 3, and 4, respectively. Inhibin B values were lower (although the difference was not statistically significant; P = .100) at baseline in responders versus nonresponders (median, 61 pg/mL vs 308 pg/mL); and the values in cycles 2, 3, and 4 were statistically significantly lower in patients who responded to treatment than in those who did not respond to treatment (this difference was significant in cycles 2, 3, and 4) (Table 4). Results from the joint models of inhibin and PFS indicated a nonstatistically significant increased hazard of progression or death with increasing levels of inhibin A or inhibin B. For inhibin A, a 1-unit increase in the log inhibin A level was associated with a hazard rate of 1.15 (95% CI, 0.96-1.38; P = .129). For inhibin B, a 1-unit increase in the log inhibin B levels was associated with a hazard rate of 1.09 (95% CI, 0.89-1.33; P = .424).

Table 3. Summary Statistics of Inhibin A: Overall and by Responder Status
    Complete or Partial Response 
 All PatientsNonrespondersResponders 
  Inhibin A Level, pg/mL Inhibin A Level, pg/mL Inhibin A Level, pg/mL 
CycleNo.Median25th-75th %tileNo.Median25th-75th %tileNo.Median25th-75th %tilePa
  1. Abbreviations: &tile, percentile.

  2. a

    P values are for the difference between responders and nonresponders (exact Wilcoxon rank-sum test).

131124-5826154-80562-10.100
232124-8128306-104421-4.020
331114-8526327-125522-4.011
43293-9227345-141521-2.008
Table 4. Summary Statistics of Inhibin B: Overall and by Responder Status
    Complete or Partial Response 
 All PatientsNonrespondersResponders 
 Inhibin B Level, pg/mLInhibin B Level, pg/mLInhibin B Level, pg/mL 
CycleNo.Median25th-75th %tileNo.Median25th-75th %tileNo.Median25th-75th %tilePa
  1. Abbreviations: &tile, percentile.

  2. a

    P values are for the difference between responders and nonresponders (exact Wilcoxon rank-sum test).

13221763-4922730891-54256148-141.100
23616835-7783023671-9596225-55.005
33316940-83327274122-150063615-69.008
43316862-81827274102-150065715-97.007

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Bevacizumab administered as a single agent appears to be active and to have acceptable toxicity in women with recurrent SCSTs of the ovary. This represents a significant advance for women who have this rare disease, in whom effective treatment options are quite limited and disease is often chemorefractory. Previously, the only options for systemic therapy included combined bleomycin, etoposide, and cisplatin; paclitaxel plus carboplatin; and hormone therapy.[4, 5, 12, 13] The ability to use bevacizumab as an effective means of controlling tumor progression is a meaningful addition to the short list of therapeutics available for these patients.

Pretreatment inhibin A and inhibin B values were lower in patients who responded to therapy than in those who did not respond, although the differences were not statistically significant (P = .100). These values were significantly lower postbaseline in patients who responded to bevacizumab than in those who did not respond. These data suggest that further investigation into the potential prognostic and predictive relevance of inhibins is warranted. Patients with high inhibin levels may have a more aggressive tumor type that will not respond to bevacizumab or other treatments, whereas patients with lower levels may be good candidates for certain treatments, as observed in this study. However, the conclusions drawn from these pilot data need to be carefully considered, because this is a small study, and further investigation is required before it is used as a guideline. It is also interesting that the trend of inhibin A and B levels followed the pattern of disease response, although this did not reach statistical significance. The hazard level associated with progression or death was higher with increasing inhibin A than with increasing inhibin B, but neither trend reached significance; therefore, the results do not suggest that inhibin A is a better marker than inhibin B. It is possible that the high percentage of stable disease in this study precluded the changing levels of inhibin A and B from reaching significance. It has been suggested that inhibins A and B may represent effective markers for after progression or response of disease on therapy, like CA 125 in epithelial ovarian cancer, but further evaluation of the accuracy of this correlation is needed.[14, 15] The use of high inhibin levels to triage patients away from bevacizumab, however, is a new concept that bears further investigation.

The histology of most of these patients was granulosa cell tumor, which reflects the relative frequency of this histologic subtype. Although care must be taken in generalizing the results from this report to all patients with stromal ovarian tumors, it is likely that the results of this trial do apply to other histologic subtypes of stromal ovarian tumors based on historic findings of similar responses among patients with various subtypes of stromal tumors.[3, 4, 6, 12, 13]

In this study, the tumor RR was used as the primary endpoint, rather than survival or PFS, for several reasons. The RR represents a clinically meaningful decision criterion for determining whether the therapy was effective or ineffective when deciding on continuation into the second stage of the study and when deciding on the success of the overall study. There are limited prior data in this patient population, which precluded the use of PFS or OS to judge the activity of the agent in this disease setting. Instead, the objective response was used, and a relatively low threshold for tumor response (5%) enabled us to have reasonable probability (α = 10%) of ruling out truly inactive agents for further investigation. A prior GOG trial in previously treated patients with stromal tumors evaluated bleomycin, etoposide, and cisplatin.[12] The observed RR in that trial was 37.5% (9 of 24 patients). However, in that study, patients were required to be chemotherapy-naive, whereas the current study allowed patients to receive any number of prior chemotherapy regimens. It is important to note that no biologic agent has been prospectively studied in patients with SCSTs before this trial. Therefore, the tumor RR was chosen as the primary endpoint, because it is a more clinically useful parameter for gauging the activity of bevacizumab in this specific disease setting.

Because the rationale for this study was to identify an antivascular agent for future combination with cytotoxic chemotherapy, and not simply its utility as monotherapy, the criteria to declare this agent interesting based on an objective RR were set lower than the criteria for identifying an agent with monotherapy activity. Therefore, the null hypothesis was set at 5%; if bevacizumab yielded an RR ≤5%, then it would not be of interest to evaluate further in combination with other agents. Therefore, although the RR was less than the conventionally accepted rate of 20% to declare an agent active, bevacizumab met the conditions of this trial to declare it as an active agent.

A substantial percentage of our patients experienced stable disease. To determine stable disease in this clinical trial required imaging studies that documented stable disease followed by confirmed imaging after 2 additional treatment courses. Because courses were 3 weeks apart, this implies at least 12 weeks of stable disease. The possibility exists that the indolent nature of this disease may lead to a suggestion that the drug was responsible for stable disease when, in fact, tumor biology was responsible for the large percentage of patients who experienced stable disease. In the absence of a randomized trial comparing therapy with a placebo arm, however, this is impossible to determine with certainty. However, the eventual progression or death from disease of 29 patients and the median PFS of 9.3 months suggest that this disease grows and does not simply remain dormant, leading to our opinion that the substantial rate of stable disease in this trial truly represents drug effect. Previous reports on “active” agents for stromal ovarian tumors reported a PFS of 14 to 19.6 months in patients with recurrent, measurable disease.[4, 12, 13] The long median time to progression in those patients with stable disease, as well as a PFS comparable to that described in the published literature for “active” compounds in stromal ovarian tumors,[4, 12, 13] leads to the conclusion that the response rate, PFS, and time to progression do represent real drug effects rather than indolent tumor behavior.

The toxicity profile described in this study is typical for bevacizumab, and represents findings that would be expected. Bevacizumab appears to be tolerable in patients with recurrent SCSTs.

To conduct meaningful clinical trials in rare tumors outside of a cooperative group setting is difficult. The short accrual time required to complete this trial highlights the feasibility of efficiently completing clinical trials in patients with rare tumors in a cooperative group setting. Furthermore, the finding of activity in this tumor, which, historically, has been relatively chemoresistant, underscores the importance of allocating resources to perform cooperative group trials in rare tumors, because this substantially moves the field forward. An additional strength of running trials in the cooperative group setting is the ability to assemble historic data sets against which future trial results can be judged; this trial is the first step in doing so for SCSTs of the ovary.

The results from this clinical trial indicate that bevacizumab has activity in the treatment of recurrent SCSTs of the ovary and that toxicity is acceptable in this treatment setting. Inhibin A and inhibin B levels appear to be associated with response to therapy. Further investigation is warranted, and combination therapy with a cytotoxic, targeted, or hormone agent may be an upcoming investigation in this cooperative group setting. In addition, a randomized phase 2 study comparing paclitaxel and carboplatin with bleomycin, etoposide, and cisplatin in patients with newly diagnosed, advanced, and recurrent chemotherapy-naive stromal ovarian tumors is currently underway within this cooperative group, further refining optimal therapy for patients with these rare tumors.

FUNDING SUPPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517).

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Linda Van Le is on the Advisory Board of Biologics, Inc. Mario Leitao has received compensation as a consultant and speaker from Intuitive Surgical Corporation.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES