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Phase III Trial of Doxorubicin Plus Cisplatin With or Without Paclitaxel Plus Filgrastim in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study

From the Department of Medicine, University of Chicago, Chicago; Northwestern University Medical School and Center on Outcomes Research and Education, Evanston Northwestern Healthcare Research Institute, Evanston, IL; Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, Indiana University School of Medicine, Indianapolis, IN; Gynecologic Oncology, Riverside Methodist Hospital, Columbus, OH (affiliate of the Columbus Cancer Council); Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Wayne State University/Karmanos Cancer Institute, Detroit, MI; Division of Gynecologic Oncology, Ochsner Clinic Foundation, New Orleans, LA (affiliate of University of Mississippi); Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of California-Irvine Medical Center, Orange, CA; Department of Obstetrics, Gynecology, Reproductive Biology, Harvard Medical School, Massachusetts General Hospital Gillette Center for Women's Cancers, Boston, MA (affiliate of Tufts-New England Medical Center, Boston); Virginia Commonwealth Health Sciences Center, Richmond, VA; and Spartanburg Pathology Associates PA, Spartanburg, SC.

Address reprint requests to Denise Mackey, Administrative Assistant, Gynecologic Oncology Group, Four Penn Center, 1600 JFK Blvd, Suite 1020, Philadelphia, PA 19103. Address other correspondence to Gini F. Fleming, MD, Section of Medical Oncology, University of Chicago, 5841 S Maryland Ave, Room I-211, MC 2115, Chicago, IL 60637; e-mail: gfleming{at}medicine.bsd.uchicago.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
PURPOSE: To determine whether the addition of paclitaxel to doxorubicin plus cisplatin improves overall survival (OS) in women with advanced or recurrent endometrial carcinoma. Secondary comparisons included progression-free survival (PFS), response rate (RR), and toxicities.

PATIENTS AND METHODS: Eligible, consenting patients received doxorubicin 60 mg/m² and cisplatin 50 mg/m² (AP), or doxorubicin 45 mg/m² and cisplatin 50 mg/m² (day 1), followed by paclitaxel 160 mg/m² (day 2) with filgrastim support (TAP). The initial doxorubicin dose in the AP arm was reduced to 45 mg/m² in patients with prior pelvic radiotherapy and those older than 65 years. Both regimens were repeated every 3 weeks to a maximum of seven cycles. Patients completed a neurotoxicity questionnaire before each cycle.

RESULTS: Two hundred seventy-three women (10 ineligible) were registered. Objective response (57% v 34%; P < .01), PFS (median, 8.3 v 5.3 months; P < .01), and OS (median, 15.3 v 12.3 months; P = .037) were improved with TAP. Treatment was hematologically well tolerated, with only 2% of patients receiving AP, and 3% of patients receiving TAP experiencing neutropenic fever. Neurologic toxicity was worse for those receiving TAP, with 12% grade 3, and 27% grade 2 peripheral neuropathy, compared with 1% and 4%, respectively, in those receiving AP. Patient-reported neurotoxicity was significantly higher in the TAP arm following two cycles of therapy.

CONCLUSION: TAP significantly improves RR, PFS, and OS compared with AP. Evaluation of this regimen in the high-risk adjuvant setting is warranted, but close attention should be paid to the increased risk of peripheral neuropathy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
There is currently little hope for cure in patients with metastatic endometrial carcinoma. Selected patients will respond to hormonal therapy, particularly progestins^1,2; however, for most women with advanced disease, chemotherapy is currently the standard antineoplastic treatment option. Taxanes, anthracyclines, and platinum compounds represent the chemotherapeutic agents with the greatest activity in this disease. Response rates (RRs) for each agent range from 20% to 35%.^3–8 The combination of doxorubicin plus cisplatin (AP) has produced RRs of 40% to 46%, with reported median progression-free survival (PFS) ranging from 5.2 to 7.2 months in the three most recent Gynecologic Oncology Group (GOG) randomized trials.^7,9,10 Most recently, the GOG compared AP with doxorubicin plus paclitaxel 150 mg/m² as a 24-hour continuous infusion with filgrastim support, and there was no statistically significant improvement in objective RR, PFS, or overall survival (OS) between the regimens.¹⁰

In 2001, the GOG published the results of a dose-finding trial that combined cisplatin, doxorubicin, and a 3-hour infusion of paclitaxel (TAP) in chemotherapy-naïve patients with advanced endometrial carcinoma and other gynecologic malignancies.¹¹ In that trial, doxorubicin and cisplatin were administered on day 1, and paclitaxel, on day 2 because of previous reports suggesting that the cardiotoxicity associated with the paclitaxel + doxorubicin combination was decreased when these agents were administered 16 to 24 hours apart.¹² Even when low doses of the combination of TAP were used, filgrastim was required for hematopoietic support, and neurotoxicity became the dose-limiting toxicity. The recommended phase II doses were doxorubicin 45 mg/m², cisplatin 60 mg/m², and paclitaxel 160 mg/m² intravenously over 3 hours, with filgrastim 5 µg/kg given on days 3 to 12. Of 20 patients treated at this dose level, two (10%) developed grade 3 peripheral neuropathy.

The current trial was designed to compare the three-drug (TAP) combination with the two-drug (AP) combination in terms of RR, PFS, and OS. The cisplatin dose in the TAP regimen was decreased to 50 mg/m², with the expectation of decreasing the incidence of neurotoxicity, providing the same starting cisplatin dose in the two study arms.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
Chemotherapy-naïve women with histologically documented measurable stage III, stage IV, or recurrent endometrial carcinoma of any cell type, and a GOG performance status (PS) of 0 to 2 were eligible for this study. Prior therapy with radiation, hormones, or biologic agents was permitted, but these were to be discontinued before entry onto the study. At least 4 weeks were to have elapsed since completion of radiotherapy (RT) involving the whole pelvis or more than 50% of the spine. Adequate hematologic and end-organ function was required, with an absolute granulocyte count 1.5 x 10⁹/L, platelet count 100 x 10⁹/L, serum creatinine 1.6 mg/dL, ALT 3x upper limits of normal, bilirubin within institutional normal limits, and a left ventricular ejection fraction (LVEF) 50%. Patients with serious concomitant medical illnesses such as uncontrolled infection or angina, or serious neuropathy, were ineligible. Patients with a second malignancy other than nonmelanoma skin cancer were eligible only if they had been disease-free for at least 5 years. All patients provided written informed consent before study entry in accordance with US Federal, State, and institutional guidelines.

Patient Treatment and Evaluation
Pretreatment evaluation included a review of medical history and a physical examination, with assessment of PS, CBC with differential and platelets, serum sodium, potassium magnesium, blood urea nitrogen, creatinine, bilirubin and ALT, tumor measurements, ECG, measurement of LVEF, and, if clinically indicated, an audiogram. CBC with differential and platelets was to be repeated weekly. Physical examination, assessment of toxicities,and serum biochemistry tests were to be repeated each cycle. Tumor measurements by radiological examination were to be repeated every other cycle. LVEF was to be repeated after cycles 3 and 6. The Functional Assessment of Cancer Therapy (FACT)/GOG neurotoxicity subscale (FACT/GOG-NTX) was to be administered each cycle before chemotherapy administration. The scale is a brief assessment of pain, numbness and tingling in the extremities, and functional limitations caused by peripheral neuropathy from chemotherapy. The questionnaire consisted of 11 statements, such as, "I have numbness or tingling in my hands," which patients scored from zero (not at all) to four (very much) according to their experience.¹³

Treatment on the AP arm consisted of doxorubicin 60 mg/m² followed immediately by cisplatin 50 mg/m². Cisplatin was diluted in 250 mL 0.9% sodium chloride and infused over 1 hour. Patients who had received prior pelvic RT or who were older than 65 years were to receive a reduction in the starting dose of doxorubicin, to 45 mg/m². The TAP arm consisted of doxorubicin 45 mg/m² followed immediately by cisplatin 50 mg/m² on day 1, paclitaxel 160 mg/m² as a 3-hour infusion on day 2, and filgrastim administered at a dose of 5 µg/kg subcutaneously on days 3 to 12. There were no modifications to starting drug doses in the TAP arm based on age or prior pelvic RT. On both arms, women with a body-surface area greater than 2.0 m² were prescribed doses as though their body-surface area were 2.0 m². Treatment was repeated every 21 days and continued for seven cycles, or until disease progression or unacceptable toxicity. On the AP arm, doses were reduced for grade 3 or 4 granulocyte or platelet toxicity; filgrastim was to be added only if granulocyte toxicity persisted after the doxorubicin dose was reduced to 30 mg/m² and cisplatin was reduced to 30 mg/m². On the TAP arm, doses were reduced for grade 3 or 4 platelet toxicity or for grade 4 granulocyte toxicity, but not for asymptomatic grade 3 granulocyte toxicity. Grade 3 peripheral neuropathy on either arm required discontinuation of therapy until symptoms were no worse than grade 1, and paclitaxel and/or cisplatin doses were reduced for subsequent cycles. Protocol therapy was to be discontinued for recurrent grade 3 neurologic toxicity or for a drop in LVEF to less than 45%, a 20% decrease in absolute LVEF percentage points, or for any toxicity-related delay in treatment administration of more than 3 weeks.

All toxicities were graded using the Common Toxicity Criteria (CTC) version 2.0, and are tabulated for patients who received any amount of study chemotherapy.

Response was measured according to standard GOG response criteria. Complete response was defined as the disappearance of all gross evidence of disease for at least 4 weeks. Partial response was a 50% or greater reduction in the product of perpendicular diameters obtained from measurement of each lesion for at least 4 weeks. Increasing disease was a 50% or greater increase in the product of perpendicular diameters of any lesion, or the appearance of any new lesion within 8 weeks of study entry. Stable disease was disease meeting none of the above criteria. OS was defined as observed length of life from entry on the study to death or, for living patients, the date of last contact. PFS was defined as date from entry on study to the date of reappearance or increasing parameters of disease, death from any cause, or, for living patients, the date of last contact.

Statistical Analysis
The GOG Statistical and Data Center (SDC) randomly assigned therapy to each patient, with equal probability of assignment to each treatment regimen. The sequence of treatment assignments was concealed from institutions and patients until registration. Patient entry was accomplished by telephone registration with verification of eligibility.

Data were collected and reviewed centrally at the SDC. The study Chair reviewed patient data to assess protocol compliance, toxicity, and end points. Pathology materials, including slides documenting primary and metastatic disease, cell type, and grade, were collected at the SDC and reviewed by members of the GOG Pathology Committee. The GOG Gynecologic Oncology Committee centrally reviewed all patient eligibility data without knowledge of outcome.

The primary end point used to compare the treatment regimens was OS. Secondary end points were PFS and RR. This study was designed with a target accrual of 240 patients; with 12 months of follow-up, 175 deaths were expected. One hundred seventy-five events would provide statistical power of 85% to detect a proportional decrease of 33% in the hazard rate when testing at the .05 level.¹⁴ Considering the planned use of an interim futility analysis, a one-tail testing procedure was chosen for analysis of primary and secondary end points. For the purposes of this report, all significance levels are based on two-tail tests. This report includes 207 deaths, with a median follow-up of 32 months among living patients. Given the actual accrual and follow-up, the power to detect a 33% reduction in hazard is .89. An interim analysis of OS was completed when there were 99 reported deaths using an O'Brien and Fleming–type spending function¹⁵ and futility analysis.¹⁶

An intent-to-treat analysis was applied in all treatment group comparisons after excluding ineligible patients. A log-rank test¹⁷ stratified by PS (0 and 1 v 2) was used to test the independence of treatment with OS and PFS, and an exact test¹⁸ stratified by PS (0 and 1 v 2) and recurrent disease status was used to test the independence of treatment with objective response. The conditional maximum likelihood estimate of the common relative odds ratio adjusted for PS (0 v 1 v 2) and recurrent disease status (primary v recurrent) is reported with exact 95% confidence bounds.¹⁹ The product-limit method²⁰ was used to obtain PFS and OS life-table estimates. The treatment effect on PFS and survival, adjusting for PS, was estimated using a Cox proportional hazards model.²¹ The CIs in this report are not adjusted for interim analysis.

Patient-reported neurotoxicity symptoms were assessed with the neurotoxicity subscale of the FACT/GOG-NTX.¹³ The subscale score was computed when at least eight of the 11 items were answered. For the purposes of this study, the NTX score for the jth patient at the kth visit was calculated as

Where _ijk is equal to 1 when the ith item has valid response for the jth patient at the kth visit; otherwise, it is equal to 0, and s_ijk is the corresponding response. Thus, a score of 0 is consistent with asymptomatic individuals, and 44 reflects the worst possible score. For comparison with other FACT/GOG-NTX data, the scores can be transposed such that 0 corresponds to "very much" and 4 corresponds to "not at all." An independent two-tailed t test was used to analyze the treatment effect on NTX subscale scores at each assessment point. Due to the multiplicity of outcome measures, the P values were adjusted with idák's method,²² and are expressed as 1 – (1 – P)^1/k.

	RESULTS

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Between December 28, 1998, and August 14, 2000, 273 patients were enrolled onto this study. Seven patients on the AP arm and three on the TAP arm were ineligible on central pathology review because of inadequate documentation of endometrial carcinoma or stage (n = 4), wrong primary cancer (n = 3), or a second primary (n = 3). Two hundred sixty-three patients (129 on the AP arm and 134 on the TAP arm) were deemed eligible and are included in the primary survival analysis. Two hundred sixty eligible patients (129 on AP and 131 on TAP) received at least one cycle of therapy and were assessable for toxicity. Patient characteristics are shown in Table 1. The two arms were fairly well-balanced with respect to baseline characteristics, though the AP arm contained fewer African American patients and fewer patients with stage III disease, PS 0, and grade 3 histology.

Sixty patients (47%) on AP and 70 patients (52%) on TAP received all seven cycles of therapy. The reason for discontinuation of study therapy can be seen in Table 2. More patients on the TAP arm had treatment discontinued due to toxicity (24% v 9%), whereas more patients on the AP arm discontinued due to progressive disease (35% v 15%). Patients discontinued treatment due to toxicity for the following: neurotoxicity (10 on the TAP arm v none on the AP arm); decreased LVEF (two on TAP v one on AP); and other toxicity (20 on TAP v 11 on AP).

View larger version (16K): [in this window] [in a new window]   Fig 1. Progression-free (PF) survival by randomized treatment. AP, doxorubicin + cisplatin; TAP, doxorubicin + cisplatin + paclitaxel.

View larger version (15K): [in this window] [in a new window]   Fig 2. Survival by randomized treatment. AP, doxorubicin + cisplatin; TAP, doxorubicin + cisplatin + paclitaxel.

There seemed to be no difference between the two regimens in the reported lesser grades of cardiac toxicity experienced while on study, based on only 192 patients (93 on TAP, 99 on AP) who had values recorded both at baseline and after three cycles. There were 17% of patients with grade 1, and 11% with grade 2 declines in LVEF in the AP arm, as compared with 15% of patients with grade 1, and 10% with grade 2 declines in LVEF among patients on the TAP arm (Table 3). Median decrease in ejection fraction after three cycles of chemotherapy was 1 absolute percentage point on TAP and 2.5 absolute percentage points on AP. Three patients (2%) on TAP versus none on AP, developed grade 3 symptomatic congestive heart failure. They were aged 65, 65, and 69 years, respectively.

Neurotoxicity
Physician-assessed peripheral sensory neuropathy was more commonly reported in patients on the TAP regimen, with 12% CTC grade 3, and 27% grade 2, versus less than 1% grade 3 and 4% grade 2 with AP. Forty-seven patients (18%) were excluded from the analysis of patient-reported neurotoxicity for completing no more than one assessment, or for a missing baseline assessment. The average compliance for the seven assessments was 71%, ranging from 91% at baseline to 52% at the final assessment. The reasons for missing NTX assessments before cycles 1, 2, and 3 were not illness-related or treatment-related. From cycle 4 on, increasing numbers of patients did not complete the assessments because they were no longer receiving therapy, owing predominantly to progression (on the AP arm) or toxicity (on the TAP arm).

The patient-assessed FACT/GOG-NTX subscale scores are summarized and displayed in Table 4. These confirm the physician-assessed neuropathy scores, and show significantly more neuropathy with TAP than with AP. Before initiating treatment, approximately 28% of all patients responded "not at all" to all 11 items on the NTX subscale. Following two cycles of chemotherapy, patients on the TAP arm reported a significantly higher neurotoxicity score than did patients on the AP arm. Significant differences in the mean score were observed, and sustained following the second cycle of chemotherapy. Furthermore, patient-reported neurotoxicity increased significantly during the treatment period in the TAP arm, but not in the AP arm. Before cycle 6, the mean score in the TAP arm was 8.4 compared with 4.2 in the AP arm, with 5% of patients reportedly asymptomatic on the TAP arm compared with 15% of patients on the AP arm.

In an exploratory multivariate analysis using a Cox proportional hazards model, PS of 2, African American race, older age, prior RT, and AP treatment were associated with a higher death hazard. Similarly, PS of 2, increasing age, and AP treatment were associated with shorter PFS. Recurrent disease status was not a significant factor in the PFS and OS treatment comparisons.

	DISCUSSION

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TAP chemotherapy produced a superior RR and longer PFS and OS as compared with the AP combination. It could be questioned whether sequential therapy (eg, AP followed by paclitaxel) would have achieved similar OS. This trial did not include any specified cross-over, but information about first salvage therapy was collected. Twenty-six percent of patients on the AP arm received paclitaxel as part of their first salvage therapy (15% at progression, 11% before progression). Fifty-one percent of patients on the AP arm received any chemotherapy as part of their first salvage regimen (33% at progression, 18% before progression). It could be speculated that the low number of patients receiving paclitaxel as first salvage therapy contributed to the survival advantage produced by the three-drug regimen over the two-drug regimen. Possibly, endometrial cancer patients are often too ill to receive second-line chemotherapy, or possibly, the activity of paclitaxel in the setting of previously treated endometrial cancer was not fully appreciated during the time at which this trial was performed. Paclitaxel is the only chemotherapeutic agent that has consistently produced RRs greater than 20% in trials of endometrial cancer patients who have received prior chemotherapy. It is also possible that the lower doses of cisplatin received in the AP arm contributed to its decreased effectiveness (filgrastim therapy was not started in the AP arm until after a dose reduction of cisplatin to 30 mg/m²).

The three-drug regimen requires growth factor support to control hematologic toxicity. However, when filgrastim support is used, hematologic toxicity is not limiting; in fact, substantially more patients on the AP arm required dose reductions. Even elderly patients, who generally comprise a substantial fraction of the metastatic endometrial patient population, did not seem to suffer an excess of neutropenic fever with TAP chemotherapy.

Cardiac toxicity was a major concern when the TAP regimen was designed because of data on congestive heart failure in breast cancer patients treated with anthracycline/taxane regimens. In this study, the cardiac toxicity of the TAP regimen was not a major issue. There was no difference in ejection fraction declines between the regimens as viewed by percent grade 1 and 2 ejection fraction decline, or by percent change in ejection fraction after three cycles. Although three patients on TAP, compared with none on AP, developed grade 3 congestive heart failure, this was not statistically significant. Moreover, two of these cases occurred after completion of therapy (8 months and 2 months, respectively). The third case occurred in association with renal failure and aspiration pneumonia, and the ejection fraction recovered back to normal. The imbalance in the number of deaths to which treatment may have contributed (five on TAP v none on AP) is of note. Only two of the five deaths (neutropenic fever and AML) on TAP were clearly treatment-related. Moreover, the number of deaths reported with the identical AP regimen on prior GOG studies has been higher; for example, there were four patients (of 156 receiving AP) for whom treatment was believed to have contributed to death on GOG 163—the randomized trial immediately preceding GOG 177 (V. Brunetto, personal communication, Jan 2004).

Both grade 2 and grade 3 neurotoxicity may contribute substantially to a negative quality of life. The increase in CTC grade 3 neurotoxicity on the TAP arm was significant, and overall, 40% of patients on TAP, compared with 5% of patients on AP, suffered grade 2 or grade 3 neuropathy. The patient questionnaires reflect similar differences in symptomatic distress. The average difference between AP- and TAP-treated patients after cycle 2 was approximately 3 points on the NTX scale, and this difference persisted throughout therapy even though more patients dropped out of the TAP arm for neurotoxicity. This difference of three points represents 7% of the full range of the scale (0 to 44). Such differences are considered clinically meaningful.²³ A more detailed description of these FACT/GOG-NTX data will be reported elsewhere. Posttreatment neurotoxicity questionnaires were not administered; thus, the degree of and time to resolution of neurotoxicity in these patients is unknown. However, the current GOG trial testing TAP versus AP chemotherapy as an adjuvant in high-risk disease incorporates a patient-neurotoxicity questionnaire 6 months after completion of chemotherapy. While the addition of paclitaxel almost certainly accounts for much of the additional neurotoxicity seen with the TAP regimen, it should also be recalled that patients on TAP received more cisplatin because they required fewer dose reductions for hematologic toxicity.

It is interesting to note that a randomized study conducted by the GOG (Protocol 122), which used the identical AP regimen described in the current trial, reported that 7% of patients experienced grade 3 to 4 neurologic toxicity. This includes all (not only peripheral) neuropathy. While comparisons of toxicity rates across trials should be made with caution, it nonetheless seems likely that the peripheral neuropathy seen with AP chemotherapy in GOG 122 was greater than the 1% reported with AP chemotherapy in the current trial. GOG 122 prescribed seven cycles of AP chemotherapy with an additional cycle of cisplatin, and 63% of patients completed all eight cycles. It is unlikely that one additional cycle of cisplatin alone accounts for the potentially greater neurologic toxicity. The majority of patients on GOG 122 had stage III endometrial carcinoma, and none had prior pelvic RT. It could be hypothesized that they therefore required fewer dose reductions and received a higher cumulative cisplatin dose.

A variety of manipulations might be proposed to decrease the neurotoxicity of the TAP regimen. First, earlier and more aggressive dose modifications for grade 2 neuropathy could be instituted (the current trial did not require dose modifications until the neuropathy was grade 3). Second, the number of chemotherapy cycles could be modified. Seven cycles was chosen based solely on historical precedent; previous GOG protocols studying chemotherapy for advanced/recurrent endometrial carcinoma used seven cycles. Fewer cycles, for example two cycles beyond best response, might be equally effective. Finally, substitution of less neurotoxic drugs in the combination might be possible. Carboplatin and docetaxel have less neurotoxicity than cisplatin and paclitaxel, respectively. The antitumor activity of carboplatin in phase II trials of endometrial cancer seems similar to the activity of cisplatin; a phase II trial of decetaxel in previously treated endometrial cancer patients is currently underway through the GOG.

It is also possible that a platinum + taxane doublet could produce outcomes similar to those seen with three-drug therapy in endometrial cancer, possibly with less neurologic and gastrointestinal toxicity. The combination of paclitaxel + platinum has been reported in several phase II trials to produce RRs of 60% to 70%, which are comparable to those seen with TAP in the current study.^24,25 The GOG is currently comparing the combination of paclitaxel + carboplatin with triplet (TAP) chemotherapy in women with advanced or metastatic endometrial cancer. Meanwhile, the significant improvements in RR, PFS, and OS observed with TAP are very encouraging, and the GOG is currently comparing TAP with AP in women with stage III/early stage IV endometrial cancer. That trial has incorporated G-CSF into the AP arm, and it will be interesting to note whether rates of neurotoxicity will be higher than those observed in this study.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The following member institutions participated in this study: University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, Wayne State University, University of Minnesota Medical School, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group, PC, University of Washington, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University Medical Center, Wake Forest University School of Medicine, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-Presbyterian-St Luke's Medical Center, SUNY Downstate Medical Center, University of Kentucky, The Cleveland Clinic Foundation, State University of New York at Stony Brook, Washington University School of Medicine, Cooper Hospital/University Medical Center, Columbus Cancer Council, MD Anderson Cancer Center, University of Massachusetts Medical Center, Fox Chase Cancer Center, Medical University of South Carolina, Women's Cancer Center, University of Oklahoma, University of Virginia, University of Chicago, Tacoma General Hospital, Thomas Jefferson University Hospital, Mayo Clinic, Case Western Reserve University, Tampa Bay Cancer Consortium, North Shore University Hospital, Brookview Research Inc, and Ellis Fischel Cancer Center.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Gini F. Fleming, Bristol-Myers Squibb.

	Acknowledgment

 
We thank Helen Huang, MS, Biostatistician, Gynecologic Oncology Group Statistical and Data Center, for the expert assistance she provided in the analysis, and reporting of the neurotoxicity component of this manuscript.

	NOTES

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

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted July 25, 2003; accepted March 9, 2004.

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