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Phase I Trial of Escalating Doses of Paclitaxel Combined With Fixed Doses of Cisplatin and Doxorubicin in Advanced Endometrial Cancer and Other Gynecologic Malignancies: A Gynecologic Oncology Group Study

From the Departments of Medicine and Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Chicago, Chicago, IL; Ohio State University, James Cancer Hospital and Solove Research Institute, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbus, OH; Division of Gynecologic Oncology, University of Washington School of Medicine, Seattle, WA; Division of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA; Gynecologic Oncology, Indiana University Medical School, Indianapolis, IN; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA; Department of Medicine, Washington University School of Medicine, St. Louis, MO; Division of Gynecologic Oncology, University of Massachusetts, Memorial Hospital, Worcester, MA; University of Mississippi School of Medicine, Jackson, MS; and Chemotherapeutics and Research, Gynecologic Oncology Center, Mercy Medical Center, Baltimore, MD.

Address reprint requests to Gynecologic Oncology Group Administrative Office, 1234 Market St, Suite 1945, Philadelphia, PA 19107.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers.

PATIENTS AND METHODS: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m² and 45 mg/m², whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m². Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not.

RESULTS: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma.

CONCLUSION: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m², doxorubicin 45 mg/m², and paclitaxel 160 mg/m² with G-CSF support is recommended for further testing.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ALTHOUGH THE majority of patients with endometrial cancer present with potentially curable early-stage disease, an estimated 6,300 patients in the United Stated died of advanced disease in 1998.¹ Although it cannot generally be cured with chemotherapy, metastatic endometrial cancer is a chemosensitive disease. The optimal regimen has not been determined.

In 1993, the Gynecologic Oncology Group (GOG) reported a 45% response rate (including 22% complete responses)² for the combination of 60 mg/m² doxorubicin (A) with 50 mg/m² cisplatin (P) in advanced or recurrent endometrial carcinoma. This was significantly superior to the 27% response rate obtained in the arm using doxorubicin alone. Similarly, the European Organization for Research and Treatment of Cancer-Gynecologic Cancer Cooperative Group reported in a randomized trial a 63% response rate and 13-month median survival with a doxorubicin/cisplatin doublet versus a 19% response rate and 8-month median survival in the doxorubicin-only arm.³ More recently, the GOG evaluated single-agent paclitaxel (T) 250 mg/m² as a 24-hour continuous infusion with granulocyte colony-stimulating factor (G-CSF) support in chemotherapy-naive patients with advanced endometrial carcinoma. An overall response rate of 36% with 14% complete responses was observed.⁴ Subsequent trials have also documented the activity of a 3-hour infusion of paclitaxel. A response rate of 37% has been reported for patients with previous cisplatin therapy.^5,6 The goal of this trial was to develop a tolerable regimen combining all three drugs (cisplatin, doxorubicin, and paclitaxel) for further testing in patients with endometrial cancer.

Previous pelvic radiation therapy (RT) may have an impact on ability to tolerate myelosuppressive chemotherapy.⁷ Phase I studies often exclude such patients, and they are treated with required dose reductions on many phase II and phase III trials. At least 50% of patients on previously published GOG trials for advanced endometrial cancer had received prior pelvic RT.^4,8 To insure that the maximum-tolerated dose (MTD) in the target population was not overestimated, patients with and without previous pelvic RT were escalated in separate cohorts. Essentially, two parallel phase I trials were performed. The MTD was to be determined in both cohorts with and without the use of G-CSF.

A final separate cohort including patients both with and without previous pelvic RT was treated at the recommended phase II doses, but with the schedule of administration changed so that doxorubicin and cisplatin were given day 1 and paclitaxel was given on day 2, because an early report from Italy suggested that the cardiac toxicity of paclitaxel/doxorubicin combinations might be decreased when administration of the agents was separated by 24 hours.⁹ Particular attention was paid to obtaining serial ejection fraction measurements in this cohort.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility
Patients were eligible for the study if they had a histologically confirmed recurrent or metastatic gynecologic malignancy or bladder cancer that was refractory to or inappropriate for local therapy. Patients deemed to be at high risk for recurrence with radiation alone were also permitted to enroll in the neoadjuvant setting. Patients with epithelial ovarian cancer were excluded, as it was felt that they should be treated on ongoing phase III GOG studies. No previous cytotoxic chemotherapy was permitted unless it was given as a radiation sensitizer.

Other eligibility criteria included age 18 years, GOG performance status 2, left ventricular ejection fraction (LVEF) 50%, absolute neutrophil count (ANC) 1,500/µL, platelet count more than 100,000/µL, serum bilirubin 1.5 times upper limit of institutional normal, serum transaminases three times upper limits of institutional normal, and creatinine 1.5 mg/dL or calculated creatinine clearance 60 mL/min. Patients were also excluded for preexisting peripheral neuropathy grade 2.

At least 4 weeks were to have elapsed since any previous radiation treatment. Neither measurable nor nonmeasurable but assessable disease was required, allowing for treatment of patients with documented intraperitoneal disease that could not be radiologically assessed. Written, informed consent was obtained from all patients before entry on study, fulfilling all institutional, state, and federal regulations.

Drug Administration
Doxorubicin was given either as a slow intravenous (IV) push or as a 30-minute IV drip. Paclitaxel was diluted in 1,000 mL of 0.9% sodium chloride and given as a 3-hour IV infusion. Paclitaxel premedication consisted of dexamethasone 20 mg by mouth 14 and 7 hours before paclitaxel, and diphenhydramine 50 mg IV with either cimetidine 300 mg, ranitidine 50 mg, or famotidine 20 mg IV 30 minutes before paclitaxel. Cisplatin was diluted in 250 mL 0.9% sodium chloride and infused for 60 minutes, with a further 1,000 mL of 0.9% sodium chloride suggested as postcisplatin hydration. Recommended antiemetic therapy was to include a serotonin receptor antagonist.

For those dose levels that included G-CSF, it was given as a daily subcutaneous injection at a dose of 5 µg/kg. Injections started the day after chemotherapy and continued until a postnadir ANC 1,500/µL was obtained on two successive measurements, or for 10 days in the absence of a discernible nadir. G-CSF was discontinued at least 24 hours before the next dose of chemotherapy. Re-treatment required the same laboratory parameters as initial treatment except that a WBC count of 2,500/µL was acceptable in lieu of an ANC of 1,500/µL to avoid the need for rapid turnaround of differential counts.

Drug Sequence and Timing
For the lowest dose levels, all three drugs were infused on the same day, in the sequence of doxorubicin followed by paclitaxel followed by cisplatin. At paclitaxel doses of 125 mg/m² and higher, doxorubicin followed by paclitaxel was given on day 1 and cisplatin was administered on day 2. For the final dose level, doxorubicin followed by cisplatin was given on day 1, and paclitaxel was administered on day 2. Treatments were repeated every 21 days.

Study Design
Dose levels are listed in Table 1. Dose escalation was performed separately in two cohorts of patients. Patients on cohort 1 were required to have had previous radiation therapy including the whole pelvis; patients on cohort 2 were not permitted to have previous radiation treatment that encompassed more than 10% of the bone marrow. Initially, the dose of cisplatin was fixed at 60 mg/m², and attempts were made to escalate the starting doses of doxorubicin (45 mg/m²) and paclitaxel (90 mg/m²) without the use of G-CSF. Subsequently, all patients received G-CSF. Doses of cisplatin (60 mg/m²) and doxorubicin (45 mg/m²) were fixed, and the paclitaxel dose was escalated. A final dose level was added that included patients with or without previous pelvic RT. The drug doses used were the recommended phase II doses determined in the second half of the trial, but the days of drug administration were changed. Patients with a body-surface area over 2.0 m² were given doses as though they had a body surface area of 2.0 m². At least three patients were treated at each dose level at which the first treatment cycle produced no dose-limiting toxicities (DLTs).

Patient Evaluation
Baseline evaluation included a history, physical examination, complete blood cell count with differential and platelet count, serum chemistries, urinalysis, ECG, chest x-ray, LVEF, and tumor measurements. During treatment, complete blood cell count was performed three times a week, and days of neutropenia were counted starting with the first day that toxicity was noted and ending the day before documented resolution. Physical examination with toxicity evaluation and serum chemistries was repeated weekly. Tumor response evaluation and LVEF were repeated every two cycles.

In general, patients with progressive disease or nonhematologic DLT were taken off the study. Patients whose LVEF decreased to less than 45% or who had a decrease by 20% or more of their baseline value were also removed from the study. Patients with hematologic DLT could be retreated at the previous dose level or with the addition of G-CSF if they seemed to be responding or had received only one cycle of therapy.

In those patients with measurable disease, response was assessed according to standard GOG criteria. Complete response was the disappearance of all clinical and laboratory signs and symptoms of active disease for a minimum of 4 weeks. Partial response was a 50% or greater reduction in the product of cross-sectional diameters obtained from measurement of each lesion being followed lasting at least 4 weeks. Progressive disease was a 50% or greater increase in the product of the cross-sectional diameters of any lesion or the appearance of any new lesion. Stable disease was disease not meeting any of the above criteria.

The cumulative dose of doxorubicin was not to exceed 420 mg/m² in any patient. Patients whose disease was neither measurable nor nonmeasurable but assessable (such as those with intraperitoneal disease documented at the time of surgery that was not evident on imaging studies) were permitted to receive a maximum of five cycles of therapy.

Statistics
To investigate the relationship between patient characteristics and hematologic toxicity, we fit a generalized linear model¹¹ with gamma errors and a log link to both ANC and platelet nadirs on cycle 1. Covariates included age, previous pelvic RT (yes/no), G-CSF (yes/no), sequence of drug administration (ATP v APT) and dose level (seven-level factor). Smoothed plots of the residuals versus both the predicted values and the covariates were used to verify the adequacy of the models. Estimates are presented in exponentiated form (ie, percentage change in the mean) together with approximate 95% confidence intervals (CI) and two-sided P values for testing the null hypothesis that the underlying coefficient is equal to zero.

We examined the possible effects of age, paclitaxel dose, and sequence of drug administration on cardiac toxicity by fitting a linear regression model (using Ordinary Least Squares [OLS]) to the change in ejection fraction from baseline to after cycle two. The effects of dose were modeled in two ways, first by including a seven-level factor distinguishing each dose combination and second by including both paclitaxel and doxorubicin dose as continuous covariates. P values given are for testing the null hypothesis that the underlying coefficient is equal to zero and are two-sided.

Cumulative hematologic toxicity at the recommended phase II dose was examined by regressing both log ANC nadir and log platelet nadir on treatment cycle. Both models were fitted using the Generalized Estimating Equations approach¹² with Gaussian errors, an exchangeable correlation structure, and the so-called robust variance estimator. Estimates of the change in log nadir per cycle are presented, together with a 95% CI and a two-sided P value for testing the null hypothesis that the underlying slope is equal to zero.

Cumulative cardiac toxicity was investigated by estimating the mean absolute change in ejection fraction over the entire course of therapy. This was done by regressing LVEF on cycle (using OLS) separately for each patient, and then computing the unweighted average of these individual slopes. This provides a consistent estimate for the mean change despite the presence of informative censoring.¹³ The resulting estimate is presented together with a 95% CI and P value obtained from the appropriate t distribution.

	RESULTS

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Eighty-one patients received 320 cycles of chemotherapy (median, four per patient) on this trial between April 1995 and February 1998. Their characteristics are listed in Table 2. Nine dose levels were tested, with paclitaxel doses ranging from 90 to 250 mg/m². Dose levels are listed in Table 1. One patient experienced an acute hypersensitivity reaction during the first minute of paclitaxel infusion despite appropriate premedication and was not rechallenged. She was not considered assessable for response or toxicity. Three patients died during the study, two of possible toxicity and one of probable progressive disease. Details are given below.

Hematologic Toxicity
Neutropenia was dose-limiting when G-CSF was not added in both the cohort with previous pelvic RT and the cohort without previous pelvic RT. Cumulative neutrophil and platelet toxicities observed are listed in Table 3. Protocol-defined hematologic DLTs (cycle 1 events that limited dose escalation) are listed in Table 4. Hematologic toxicities were not dose-limiting when G-CSF was used. There was minimal neutropenia (median days grade 4 ANC after cycle one of 0) at the recommended phase II dose of paclitaxel 160 mg/m².

Cumulative neutrophil toxicity was not observed. However, platelet counts tended to decrease with successive cycles. At the 160 mg/m² paclitaxel dose (a dose at which no patient received any dose reductions on any cycle of therapy), there was an average decrease of 0.16 log units (95% CI, -0.23 to -0.08; P < .01), corresponding to a 15% reduction per cycle.

Effects of Previous Pelvic RT
Across all dose levels, the mean cycle 1 ANC nadir for patients with previous pelvic RT was estimated to be 58% lower (95% CI, 8% to 81% decrease; P = .029) than that for patients without previous RT. No statistically significant effect of previous RT on platelet nadir was observed (P = .182).

Effects of Age
A 10-year increase in age was associated with a 27% reduction in mean cycle 1 ANC nadir (95% CI, 7% to 43% decrease; P = .011). This effect seemed to be constant over the full range of ages treated (28 to 87 years). The effect of age on mean cycle 1 platelet nadir was only an 11% decrease per decade of age (95% CI, 3% to 18% decrease; P = .007). Of the 10 patients aged 70 years, three were treated with paclitaxel 160 mg/m² and doxorubicin 45 mg/m² (dose levels 6 and 9). None experienced hematologic DLT in any cycle. They completed one, four, and six cycles of therapy and were removed from treatment for patient request, cardiac ischemia without decreased ejection fraction, and grade 3 neurotoxicity, respectively.

Neurotoxicity
Peripheral neuropathy was the nonhematologic DLT. This, along with other nonhematologic toxicities, is summarized in Table 5. Only peripheral neuropathy and arthralgia/myalgia seemed to be related to paclitaxel dose. No neuropathy greater than grade 1 was observed until the paclitaxel dose reached 160 mg/m². Neuropathy tended to become more severe after multiple cycles of therapy. Two of 20 patients developed grade 3 peripheral neuropathy at a paclitaxel dose of 160 mg/m². In one patient, it was initially noted after cycle 3, although the patient received six total cycles of therapy, and the other had gradually worsening symptoms that progressed to grade 3 after her eighth cycle.

One patient with no previous RT treated at dose level 7 died in her sleep after cycle 5. She was not neutropenic, had a decreasing CA-125, and had no clinical evidence of congestive heart failure. Her baseline LVEF was 63%; it had decreased to 52% after two cycles, to 50% after three cycles, and was still 50% after four cycles. Because the patient seemed to be doing very well clinically, she was allowed to remain on the study despite the decrease by 21% of baseline ejection fraction. An autopsy was obtained, and cause of death was felt to be left ventricular hypertrophy with biventricular dilatation. In the opinion of the medical examiner, coronary atherosclerosis was probably a more important contribution to death than cardiotoxic drugs. However, a contribution of chemotherapy cannot be excluded.

Other Nonhematologic Toxicities
Nausea, vomiting, renal insufficiency, and electrolyte abnormalities were sporadically severe. These toxicities are common with regimens containing doxorubicin and cisplatin and did not seem to be related to paclitaxel dose. One patient had a grade 2 allergic reaction during the first minute of paclitaxel infusion and was not rechallenged. Reasons for discontinuation of therapy at the recommended phase II dosage (160 mg/m² paclitaxel) are given in Table 7.

	DISCUSSION

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Although previous pelvic RT is widely accepted as a risk factor for myelosuppression, few studies have attempted to compare MTDs in patients with and without pelvic RT. One study of doxorubicin and dose-escalated cyclophosphamide with G-CSF in patients with prostate cancer concluded that hematologic toxicity overall did not differ in patients with previous pelvic RT, although they had a lower MTD.⁷ We observed lower median cycle 1 neutrophil nadirs in these patients at all dose levels. Interestingly, platelet nadirs seemed unaffected by previous pelvic RT.

The effect of age on chemotherapy-related myelosuppression may vary from drug to drug and could be associated with age-related impairment in hepatic or renal function^14-16 or with a decrease in bone marrow reserve.¹⁷ We observed a progressive decrease in neutrophil nadirs with increasing age. The effect on platelet nadirs was minimal. Five of the 20 patients treated at the recommended phase II dose were 65 years of age or older, and three were older than 70 years. None experienced any hematologic dose-limiting toxicity. This is important, because the frequency of endometrial cancer increases with age. We believe older patients may be started on the same doses as younger patients, although this will need to be monitored as the regimen undergoes wider testing.

Peripheral neurotoxicity was dose-limiting for the TAP regimen, although it was rarely severe after the first cycle. The relationship of neurotoxicity to duration of paclitaxel infusion remains unclear. The European-Canadian randomized trial of paclitaxel dose (135 and 175 mg/m²) and infusion duration (3 v 24 hours) suggested that neurotoxicity with single-agent paclitaxel was significantly related to dose and not to duration of infusion.¹⁸ However, a large National Surgical Adjuvant Breast and Bowel Project trial comparing 3-hour with 24-hour paclitaxel infusions at 250 mg/m² found more severe neurotoxicity with the shorter infusion (22% v 13%).¹⁹

Peripheral neuropathy is a toxicity of great concern because it has a major impact on patients’ quality of life, may appear only after multiple cycles of therapy, and is often slowly and incompletely reversible. Unfortunately, grading of neuropathy is not straightforward, and comparisons between studies should be made with caution. One recent report found an interobserver agreement between neurologists of only 45.9% using the National Cancer Institute of Canada common toxicity criteria²⁰ (which are identical to the GOG common toxicity criteria used in our study). In our trial, the doses of paclitaxel and cisplatin were separated by 1 day at doses of paclitaxel 135 mg/m² to minimize any neurotoxicity that might be related to simultaneous high-peak concentrations of both cisplatin and paclitaxel. We found a 10% incidence of grade 3 neuropathy at the recommended phase II dose of 160 mg/m². A total of 20 patients were treated at that dose, and 14 received four or more cycles.

Cardiac toxicity was another concern in the design of the TAP regimen. Two early reports on the combination of bolus doxorubicin (50 to 60 mg/m²) and 3-hour paclitaxel (155 to 200 mg/m²) in metastatic breast cancer noted excellent antitumor activity, but a 20% incidence of clinical congestive heart failure was also observed at median cumulative doxorubicin doses of 480 mg/m² and 392 mg/m².^21,22 It was suggested that this might be related to increased area under the curve of doxorubicin or the potentially cardiotoxic metabolite, doxorubicinol, when paclitaxel was combined with doxorubicin.^23,24 Not all subsequent studies reported such a high incidence of cardiac dysfunction,^9,25-28 and sequential combinations of doxorubicin and paclitaxel (in which administration of the two drugs is separated by weeks) have not been found to increase cardiotoxicity.²⁹ LVEF is an imperfect predictor of congestive heart failure.³⁰ One instructive study obtained three sequential radionuclide angiocardiographic measures of LVEF separated by an average of only 4 days on each of 20 patients. The mean variability was reported to be 4.4% ± 3.6%, and five of 20 patients had a greater than 10% change in LVEF between two evaluations.³¹ However, assessing LVEF declines is a reasonable means of comparing the cardiotoxicity of different regimens, and by this measure we did not find any difference between those patients who received paclitaxel and doxorubicin on the same day, and those who received paclitaxel the day after doxorubicin.

Thirteen (20%) of 64 patients on our trial who had two or more ejection fractions experienced a decline to less than 45% or by 20% or more of their baseline value, which were the criteria for removal from study. We observed no clinical congestive heart failure, although one patient died suddenly of cardiac causes, which were believed to be unrelated to her chemotherapy.

Our paclitaxel dose of 160 mg/m² is somewhat lower than the usual dose of 175 mg/m². However, any difference in efficacy is likely to be small. This study was not designed to evaluate response, and many of the patients entered, particularly among those with no previous pelvic RT, had neither measurable nor nonmeasurable but assessable disease. The responses are tabulated only for those 40 patients with measurable disease and must be interpreted with caution, as they represent a small group of patients with mixed tumor histologies (Table 8). Nonetheless, the regimen clearly demonstrates activity.

The TAP three-drug combination was designed to incorporate the three categories of agents with the highest documented activities in endometrial cancer. In compilations of available trials of single agents in chemotherapy-naive patients, doxorubicin and cisplatin produced response rates of 26% and 21%, respectively.^32,33 Other categories of drugs, including antimetabolites and alkylating agents, appeared less active. As noted above, early trials with paclitaxel reported response rates of approximately 35%.^4-6

One goal of developing combination regimens is to determine the most active combination for testing in high-risk early disease with the hope of producing an improvement in survival. The sequential use of single agents or so-called doublets is also an option in the adjuvant setting. For example, the sequential addition of single-agent paclitaxel to the doxorubicin/cyclophosphamide doublet has recently been shown to produce an overall survival benefit in patients with node-positive breast cancer without added cardiac toxicity.³⁴ Results of ongoing and recently completed large adjuvant breast cancer trials comparing sequential with combination chemotherapy may help guide adjuvant drug development in other tumor types. However, because molecular and pharmacokinetic interactions vary with different combinations, it may be difficult to come to a generalized conclusion about how adjuvant regimens should be designed.

A second role of combination therapy is for the palliation of advanced disease. In this setting the toxicity of therapy must be carefully weighed against the limited benefits. Multiagent regimens tend to be more toxic than single-agent therapy, although this is, of course, dependent on the dose of the single agent. Certainly, there are examples, such as the use of methotrexate, vinblastine, doxorubicin, and cisplatin for advanced urothelial cancers, in which a combination became standard because it demonstrated a survival advantage over less toxic alternatives in randomized trials (in this case, single-agent cisplatin or the three-drug combination of cisplatin, cyclophosphamide, and doxorubicin).^35,36 Moreover, careful quality-of-life studies are starting to demonstrate that there is an association between symptom improvement and objective tumor regression, which might make the use of somewhat more toxic but more active regimens worthwhile even in the absence of a survival benefit.³⁷ These issues can only be resolved in the setting of a randomized trial. Other three-drug taxane/anthracycline/platinum triplets, such as carboplatin/epirubicin/paclitaxel,³⁸ have been reported and might offer less neurologic, though not less hematologic, toxicity. A platinum/taxane doublet would entirely eliminate cardiac toxicity and has produced preliminary promising results in patients with advanced papillary serous endometrial cancer.³⁹ All regimens used in metastatic endometrial cancer need to take into account the nature of the population, which is predominantly elderly and frequently has marrow compromise from previous pelvic irradiation.

The recommended phase II TAP regimen (paclitaxel 160 mg/m² for 3 hours, doxorubicin 45 mg/m² and cisplatin 60 mg/m², with G-CSF) is suitable for further testing in high-risk early-stage and metastatic endometrial cancer. An ongoing GOG trial is testing this combination (with a cisplatin dose of only 50 mg/m²) against the two-drug combination of doxorubicin and cisplatin in patients with advanced endometrial cancer. Neurotoxicity is being assessed by questionnaire. LVEF is being monitored at baseline and after three and six cycles of chemotherapy. This will allow definitive determination of whether a 3-hour paclitaxel infusion enhances doxorubicin cardiotoxicity.

APPENDIX
The following Gynecologic Oncology Group institutions participated in this study: Indiana University Medical Center, Washington University, University of Chicago, University of Washington Medical Center, Fox Chase Cancer Center, Columbus Cancer Council, and Emory University Clinic.

	ACKNOWLEDGMENTS

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

We thank L. Philip Schumm for statistical assistance and Jan-Marie McEvilly for data management support.

	REFERENCES

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Submitted November 16, 1999; accepted October 5, 2000.

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