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Oral Medroxyprogesterone Acetate in the Treatment of Advanced or Recurrent Endometrial Carcinoma: A Dose-Response Study by the Gynecologic Oncology Group

From the Division of Oncology, University of Mississippi School of Medicine, Jackson, MS; Gynecologic Oncology Group, Roswell Park Cancer Institute, Buffalo, and Comprehensive Gynecology, Crouse Irving Memorial Hospital, Syracuse, NY; Department of Gynecologic Oncology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL; Bowman Gray School of Medicine, Carolina Gynecologic Oncology, Winston-Salem, and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC; Division of Gynecologic Oncology, University of California, Irvine Medical Center, Irvine, CA; and Division of Gynecologic Oncology, Eastern Virginia Medical School, Norfolk, VA.

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

	ABSTRACT

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PURPOSE: Progestins have definite activity against advanced or recurrent endometrial carcinoma. Both parenteral and oral progestins yield similar serum levels and response rates, which range from 18% to 34%. The one major study that used oral medroxyprogesterone acetate (MPA) noted a response rate at the lower end of the range (18%) and much poorer progression-free and overall survival times (4 and 10.5 months, respectively) than previously reported. The present study sought to confirm this earlier study of oral MPA, to assess the importance of prognostic factors such as histologic grade and receptor levels, and to determine whether a higher dose of MPA would yield a higher response rate.

PATIENTS AND METHODS: Two hundred ninety-nine eligible women with advanced or recurrent endometrial carcinoma were randomized to receive oral MPA either 200 mg/d or 1,000 mg/d until unacceptable toxicity intervened or their disease progressed.

RESULTS: Among 145 patients receiving the low-dose regimen, there were 25 complete (17%) and 11 partial (8%) responses for an overall response rate of 25%. The 154 patients receiving the high-dose regimen experienced 14 (9%) complete and 10 (6%) partial responses for an overall response rate of 15%. Median durations of progression-free survival were 3.2 months and 2.5 months for the low-dose and high-dose regimens, respectively. Median survival durations were 11.1 months and 7.0 months, respectively. The adjusted relative odds of responding to the high-dose regimen compared with the low-dose regimen was 0.61 (90% confidence interval, 0.36 to 1.04). Prognostic factors having a significant impact on the probability of response included initial performance status, age, histologic grade, and progesterone receptor concentration. Compliance with oral therapy was documented with serum levels 1 month after starting therapy, when possible. MPA levels were commensurate with the assigned dose and schedule.

CONCLUSION: Oral MPA is active against endometrial carcinoma. Response to progestin therapy is more frequent among patients with a well-differentiated histology and positive progesterone receptor status. This study provides no evidence to support the use of MPA 1,000 mg/d orally instead of MPA 200 mg/d orally. In fact, the trends suggest the opposite. The use of oral MPA 200 mg/d is a reasonable initial approach to the treatment of advanced or recurrent endometrial carcinoma, particularly those lesions that are well-differentiated and/or progesterone receptor-positive (> 50 fmol/mg cytosol protein). Patients with poorly differentiated and/or progesterone receptor levels less than 50 fmol/mg cytosol protein had only an 8% to 9% response rate.

	INTRODUCTION

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ENDOMETRIAL CARCINOMA, the most common invasive neoplasm of the female genital tract, will account for more than 34,900 new cases in 1997, according to estimates by the American Cancer Society.¹ Despite the relatively high frequency of this type of cancer, fewer than 6,000 deaths are estimated because the disease is usually diagnosed while it is still limited to the corpus of the uterus because of vaginal bleeding. Unfortunately, women who present with disseminated disease or who have recurrence at distant sites after initial surgical resection have few options for systemic therapy.^2,3 Because endometrial carcinoma is susceptible to hormonal influences in a significant proportion of cases, progestational agents have been used successfully as a treatment for patients with recurrent or disseminated disease. Initial studies of progestins in endometrial carcinoma used parenteral forms,⁴ but a more recent report focuses on the use of oral progestins.⁵ The demonstration that serum concentrations of medroxyprogesterone acetate (MPA) are similar whether given by parenteral or oral routes supports the use of oral progestins.⁶ The present study was undertaken to determine whether an increased dose of oral progestin could improve the observed response rate in endometrial carcinoma.

	PATIENTS AND METHODS

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Between October 1985 and May 1989, member institutions of the Gynecologic Oncology Group (GOG) entered 324 patients with advanced or recurrent endometrial carcinoma onto GOG Protocol 81 to evaluate the relative efficacy of two dose levels of MPA. Patients were required to have histologically documented endometrial carcinoma that was either advanced (stage III or IV) or recurrent and not amenable to control with surgery and/or radiotherapy. Patients were also required to exhibit at least one marker lesion clinically measurable in two dimensions for the purpose of response assessment. Pretreatment laboratory assessment must have included a leukocyte count greater than 3,000/dL, a platelet count greater than 100,000/dL, a creatinine concentration less than 2.0 mg/dL, and AST, alkaline phosphatase, and bilirubin levels less than twice normal. Patients were also required to have a GOG performance status score of 0, 1, or 2 (equivalent to a Karnofsky score of 50% or better), no contraindication to the use of progestins, no history of a previous invasive malignancy other than endometrial carcinoma, and no prior exposure to systemic therapy for malignancy. Complete recovery from prior surgery and freedom from evidence of infection were also required. Written informed consent was obtained from all patients before entry onto the study, fulfilling all institutional, state, and federal regulations.

Oral MPA in a dose of either 200 mg/d or 1,000 mg/d was assigned to each patient when she was registered to the study. The study drug was provided free of charge by the Upjohn Pharmaceutical Company in bottles of 100- to 200-mg tablets. Tissue receptor content was assessed before the study, whenever possible, at the institution's local laboratory. Treatment assignments were permutated randomly within blocks defined by the institutions and receptor status. Patients were reassessed monthly, and treatment continued until unacceptable toxicity intervened, progression of disease occurred, the patient died, or the patient was lost to follow-up. To assess compliance with oral therapy, patients who had not discontinued treatment because of progression of toxicity were required to submit a serum sample 1 month after starting therapy. The serum levels of MPA were assessed on these samples in a central laboratory at Upjohn Pharmaceuticals.

The protocol did not designate a salvage regimen therapy for patients who developed evidence of progressive disease. Investigators were encouraged to enter relapsing patients onto a GOG trial of chemotherapy, but not all patients qualified for one of these trials.

The primary end point for assessing therapeutic efficacy in this study was objective response. Progression-free survival and overall survival were also assessed. Response was defined according to standard GOG criteria. Complete response required the disappearance of all evidence of disease and the maintenance of this status until at least a second assessment 1 month later. Partial response necessitated at least a 50% reduction in the product of perpendicular diameters of each and every measurable lesion with no appearance of a new lesion; this response had to be maintained until at least a second assessment 1 month later. Increasing disease indicated that one or more lesions had demonstrated at least a 50% increase in the product of perpendicular diameters or that one or more new lesions had appeared within 1 month of initiating therapy. Stable disease met none of the above criteria.

Progression-free survival was defined as the period from registration onto the study to disease progression or to the time that the patient died from any cause or was last contacted. Overall survival was defined as the period from registration onto the study until the patient died from any cause or was last contacted.

Assuming the true probability of responding to the low-dose regimen was 20%, this study was designed to have an 85% chance of detecting a two-fold increase in the relative odds of responding (20% v 33%) among those treated on the high-dose regimen. The type I error for the one-sided question was set to 0.05.

The study design provided no planned early-stopping rules. However, when the accrual was 90% complete it was noted that even if all the future patients to be entered onto the high-dose regimen responded and all of the future patients to be entered onto the low-dose regimen did not respond, the trial would not conclude that the higher dose was superior. Because there was no desire to investigate whether increasing the MPA dose to 1,000 mg/d could be less effective, the trial was closed. Although early closure based on response can slightly distort the survival and progression-free survival comparisons, the usual estimates and significance tests are provided.

The analyses of response, progression-free survival, and overall survival included all eligible patients, and the treatment groups were compared on an intent-to-treat basis. For the analysis of response, those patients who demonstrated no clinical response and those who died or became noncompliant before clinical reassessment were classified as nonresponders.

Pearson's test⁷ was used to assess the hypothesis of independence between response and categorical patient characteristics. A Cochran-Armitage trend test⁷ was used when the characteristic was an order categorical variable and its use is noted in the text. A log-rank test⁸ was used to assess the hypothesis of independence between a categorical patient characteristic and time to failure. Linear logistic regression⁹ or a proportional hazards¹⁰ model was used to estimate relative odds or relative hazard (risk) in the presence of other covariates when the response was categorical or a time to failure, respectively. Progesterone receptor concentrations were included in the multivariate models by specifying either categorical covariates that indicated whether the value was missing or the quartile of the known values. The product-limit¹¹ method was used to compute the cumulative proportion surviving over time. Other statistical procedures are noted in the text.

The analysis of this trial included examination of several aspects: pretreatment characteristics of the patient population, evaluation of the serum MPA levels obtained after 1 month of therapy, assessment of response as well as progression-free and overall survival, and evaluation of the toxicity on each of the two regimens.

	RESULTS

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Patient Characteristics
A total of 324 patients were entered onto the study (Table 1). Of these, 25 were deemed to be ineligible after detailed pathology and clinical history review for the following reasons (Table 2): eight patients had a previous primary malignancy other than endometrial carcinoma; seven patients had a malignancy of the uterine corpus other than endometrial carcinoma; six patients had a malignancy originating in a primary site other than the endometrium; one patient had inadequate pathologic material to document endometrial carcinoma; one patient had incomplete documentation of her clinical history; one patient had no clinically measurable disease; and one patient had stage II disease.

The patient characteristics of the 299 eligible patients are listed in Table 2. Briefly, there were no appreciable differences between the patients on the two regimens with regard to age, performance status, prior treatment with surgery and/or radiotherapy, stage, cell type, or histologic grade. Although information regarding estrogen and progesterone receptor status of the endometrial carcinoma was not available for all patients, no appreciable differences were observed between the two regimens with regard to receptor status for the 132 patients who had data available for both estrogen and progesterone receptors. The overall patient profile for the study population was similar to that described for the population of patients with endometrial carcinoma as a whole: mostly postmenopausal patients who had received surgery and/or radiotherapy for limited disease and had subsequently had recurrence and who demonstrated, for the most part, higher-grade lesions consistent with advanced or recurrent disease.

Serum Levels of MPA
Patients entered onto the study were to have serum levels of MPA drawn 1 month after starting treatment. Because of the rapid onset of progression or death, serum levels were determined on only 187 (62%) of the patients. These data are summarized in Table 3. Although a small minority of patients demonstrated low serum MPA levels, as indicated by the low end of the two ranges in Table 3, most patients had levels commensurate with the dose level of MPA to which they had been assigned. The median level for the high-dose group was 3.4 times higher than the median for the low-dose group, and there was a significant difference (P < .001, Kruskal-Wallis Rank test) between the two treatment groups with regard to known serum MPA levels.

Response
The frequency of response is listed by treatment group in Table 4. Among the 145 patients receiving the low-dose regimen, there were 25 (17%) complete responses and 11 (8%) partial responses; 109 patients (75%) demonstrated no response. Among the 154 patients receiving the high-dose regimen, there were 14 (9%) complete responses and 10 (6%) partial responses; 130 patients (84%) had no response. The overall response rates (complete plus partial; 25% and 16% for low- and high-dose regimens, respectively) favored the low-dose regimen. The crude relative odds of responding to the high-dose regimen was 0.56. Several pretreatment prognostic factors, including stage of disease, performance status, histologic grade, cell type, prior surgery, prior radiotherapy, and age, were considered in a multivariate logistic model to account for the lower response rate among those on the high-dose regimen. After adjusting for the effects of tumor grade, progesterone receptor status, age, and performance status, the response rate remained notably poorer among those treated with the high-dose regimen. The adjusted estimate of the relative odds was 0.61 (90% confidence interval, 0.36 to 1.04, P = .93, one-tailed test).

The association (univariate) between response and several pretreatment patient characteristics is displayed in Table 5. Among the eligible patients entered onto this study, the frequency of response decreased slightly with increasing age. The women who were younger than 60 years when they entered the study demonstrated a 27% (17 of 62 patients) response rate. The response rate was 23% (27 of 118) among those 60 to 69 years old and only 13% (16 of 119) among those older than 69 years. There was a statistically significant (P = .017) trend for the response rate to decline with older age. Response did not vary by body weight.

The initial performance status is widely regarded as a prognostic factor. However, in this study there was only marginal evidence (P = .051) for a difference in response rates between groups, and there was no evidence for a consistent trend (P = .168). The highest response rate was observed in those with a normal performance status (28%; 26 of 94). The response rate was moderately better than that for those who were symptomatic:15% (20 of 137 patients) for those with performance status 1 and 20% (14 of 68 patients) for those with performance status 2.

The association between response and the histologic grade of the primary tumor is also presented in Table 5. Those patients with well-differentiated primary tumors tended to respond more frequently than those with poorer differentiation. The response rates were 37% (22 of 59 patients), 23% (26 of 113), and 9% (12 of 127) for those with grade 1, 2, or 3, respectively. There was a statistically significant (P < .001) and consistent trend for the response rate to decrease with decreasing differentiation of the primary tumor.

Although estrogen and progesterone receptor concentrations were not required and were not performed at a central reference laboratory, pretreatment levels, performed at the entering institutions, were available for 132 of the 299 eligible patients (Table 5). Patients were considered receptor positive if they had more than 10 femtomoles of estrogen receptors per milligram of cytosol protein and 50 femtomoles of progesterone receptors per milligram cytosol protein. There was a noteworthy correlation between response and receptor status. The response rate was 8% (seven of 86 patients) for patients who were progesterone receptor-negative and 37% (17 of 46) for patients who were progesterone receptor-positive (P < .001). Likewise, the response rate was 7% (four of 55) for patients who were estrogen receptor-negative and 26% (20 of 77) for patients who were estrogen receptor-positive (P = .005). In either case, the odds of response were greater among patients with receptor-positive tumors.

There was also a noteworthy correlation between estrogen receptor level and progesterone receptor level (P < .001; Spearman's rank correlation, 0.663). Patients with high progesterone receptor levels also tended to have high estrogen levels and vice versa. For this reason, these two markers may not be independent predictors for response. When progesterone and estrogen levels were considered simultaneously in a multivariate model, once the prognostic value of the progesterone receptor for predicting response was accounted for, there was little additional prognostic information gleaned from the estrogen level.

The estimated treatment effect was consistent across the strata of patients who were progesterone receptor-negative and receptor-positive. There were 86 patients classified as progesterone receptor-negative. Within this stratum, the response rates were 14% (six of 43 patients) and 2% (one of 43) for the low-dose and high-dose regimens, respectively. Within the stratum of progesterone receptor-positive patients, the response rates were 48% (10 of 21 patients) and 28% (seven of 25) for the low-dose and high-dose regimens, respectively. In each stratum, those patients treated with the lower dose responded more frequently than those treated with the high-dose regimen.

There was a marked association between receptor status and tumor grade. Those patients with more differentiated tumors, on average, also had higher concentrations of estrogen and progesterone receptors. The median concentrations of progesterone receptors were 79, 18, and 7.2 fmol/mg cytosol protein for grade 1, 2, and 3 tumors, respectively. Likewise, the median concentrations of estrogen receptors were 36.0, 13.0, and 9.9 fmol/mg cytosol protein for grade 1, 2, and 3 tumors, respectively. These associations between tumor grade and progesterone receptor levels (P = .002, Kruskal-Wallis rank sum test) and estrogen receptor levels (P = .049) were statistically significant. After tumor grade was adjusted for, progesterone receptor concentration remained an important predictor for response.

The association between actual serum MPA levels and response was assessed. After tumor grade, receptor status, age, and performance status were adjusted for, there was no evidence that serum MPA level was associated with the odds of response.

Progression-Free and Overall Survival
Progression-free and overall survival times are depicted graphically in Figs 1 and 2. The median progression-free survival time was 3.2 months for the low-dose regimen and 2.5 months for the high-dose regimen. For, The median overall survival time was 11.1 months for the low-dose regimen and 7.0 months for the high-dose regimen.

View larger version (15K): [in this window] [in a new window]   Fig 1. Progression-free survival by treatment.

View larger version (14K): [in this window] [in a new window]   Fig 2. Survival by treatment.

On average, the overall survival and progression-free survival were longer for those assigned to the low-dose regimen than for those assigned to the high-dose regimen. After the initial performance status, progesterone-receptor level, tumor grade, and age were adjusted for, the risk of death was 31% greater (P = .026) for those on the high-dose regimen than for those on the low-dose regimen. Similarly, the risk of first progression or death was 35% (P = .014) greater for those on the high-dose regimen. The median survival times and the corresponding 95% confidence intervals for the eligible patients classified by various pretreatment characteristics are listed in Table 5. There was a statistically significant difference (P = .021) in survival among age groups. This was primarily because of the poor survival (median, 6.8 months) among those patients aged 70 years or older compared with those younger than 60 years (median, 9.8 months) and those 60 to 69 years old (median, 9.4 months). There was also a consistent decline (P < .001) in the duration of overall survival in patients with poorer initial performance scores.

When patients were compared by the histologic grade of their primary tumor, those with grade 1 tumors exhibited the longest survival (median, 18.8 months). This was significantly longer than the survival for those with grade 2 (median, 7.5 months; P = .030) or grade 3 (median, 6.9 months; P < .001) tumors.

When considered individually, the progesterone and estrogen receptor concentrations were each associated with overall survival. Survival tended to be longer among those women with higher concentrations of receptors. However, the association of receptor concentrations with survival was not independent. When the prognostic value of progesterone receptor concentrations for predicting survival was accounted for, there was little additional value of estrogen receptor concentrations in the model. The median survival for women with less than 50 fmol/mg cytosol protein was 6.8 months. Those patients with higher concentrations of progesterone receptors survived significantly (P = .001) longer (median, 12.1 months). Even after tumor grade was adjusted for, higher progesterone receptor concentration was associated with longer progression-free and overall survival.

As with response, the association between serum MPA levels and overall survival was assessed. Serum MPA levels demonstrated no significant association with duration of survival. Patients with no reported levels did exhibit much poorer survival than those for whom values were reported, but this was expected because the lack of assessment for serum MPA was primarily because of early progression or death.

Adverse Effects
Adverse effects for 296 patients who received any study treatment are listed in Table 6. Adverse effects were not common with either of the two regimens, and no differences in toxicity were noted between the two arms of the study. The most commonly reported adverse events are listed in Table 6. The most frequent adverse event was thrombophlebitis, which occurred in 14 (5%) of the 296 patients who received any study treatment (5% in the low-dose arm and 4% in the high-dose arm). If one considers only grade 3 to 4 thrombophlebitis, there was a 2% incidence in both arms and in the overall study population. In four patients (1%), pulmonary emboli were observed. Although other adverse events were reported, such as gastrointestinal upset, somnolescence, and fatigue, none occurred in more than 3% of the patients and none were severe.

	DISCUSSION

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Early studies of progestational agents in the treatment of endometrial carcinoma used parenteral forms and reported response rates in approximately one third of cases of advanced or recurrent disease.¹² A review of these studies noted a range of response duration from 16 to 28 months and a range of survival times from 18 to 33 months. Some trials included in this review focused on selected groups of favorable patients with disease duration of more than 3 years at the time of initiation of hormonal treatment.¹³ The experience of the GOG in a more recent trial (GOG Protocol 48) involving unselected patients with advanced or recurrent disease, however, suggested a lower overall response rate of 18% (32 complete and 26 partial responses among 331 patients with measurable disease) and shorter median progression-free and overall survival times of 4 and 10.5 months, respectively.⁵ In addition to no selection for favorable characteristics, the GOG trial differed from the earlier studies in its choice of the dose and schedule of the progestational agent. MPA was the progestin selected for study both because it had been a commonly used agent in earlier trials of parenteral treatment and because it was available through Upjohn Pharmaceuticals as a 50-mg tablet. The dose of 50 mg three times daily was based on the results of a GOG pilot study which showed that this dose and schedule achieved serum levels similar to those seen with parenteral schedules of MPA used in earlier trials.⁶

A more detailed analysis of patient characteristics in GOG Protocol 48 revealed a correlation between histologic grade and the frequency of response, between estrogen and progesterone receptor levels and histologic grade, and between receptor positivity (defined as an estrogen receptor level > 10 fmol/mg cytosol protein and a progesterone receptor level > 50 fmol/mg cytosol protein) and response to hormonal therapy (T. Thigpen, personal communication). These correlations have been noted in other studies.^14-21 The lack of patient selection for favorable characteristics is the most likely explanation for the lower response rate and much shorter progression-free and overall survival times reported in the GOG trial.

The present study confirms the original GOG observations in Protocol 48 with regard to response rate and to progression-free and overall survival times. As in Protocol 48, the majority of the patients in this trial had grade 2 or 3 lesions. A majority (86 [65%] of 132) demonstrated low progesterone receptor concentrations. This was expected because poorly differentiated tumors exhibit low levels of one or both receptors (< 10 fmol/mg cytosol protein for estrogen receptor and < 50 fmol/mg cytosol protein for progesterone receptor). Response did correlate with both histologic grade and receptor levels and was lower (60 [20%] of 299) than the 34% reported in earlier studies. As in GOG Protocol 48, progression-free and overall survival times were considerably shorter than those observed in the earlier reports, with medians of 2.9 months and 8.6 months.

Monitoring compliance to oral medication remains difficult. Although pill counting can be implemented in the clinic, it is well known that this procedure is susceptible to error when the patient is either negligent or chooses to be deceitful. To address this concern, each patient in this study was to have serum MPA levels assayed by a centralized laboratory after completing 1 month of study treatment. Unfortunately, advanced endometrial cancer is often a rapidly progressing disease and many patients failed to complete 1 month of treatment because of early progression. Therefore, serum MPA levels were not assessed in all patients. Among those assayed, blood levels were commensurate with the dose and schedule of MPA. Although a few patients may have been noncompliant on the basis of low serum levels, the median serum MPA level was 3.4 times greater among the patients treated at the higher dose than those treated at the lower dose.

Another reasonable concern that has been raised about oral progestin therapy, however, is that, despite the earlier pilot study of the GOG which showed that parenteral and oral therapy yielded similar blood levels of MPA, exposure of the carcinoma to progestin may be inadequate. This concern raised the question as to whether higher doses of MPA could yield superior results. Supporting this theory were reports of improved response rates with higher doses of progestins in patients with metastatic breast carcinoma.²² The present study presents evidence that no such dose-response relationship exists for endometrial carcinoma treated with MPA, at least at the limits of doses from 200 mg/d to 1,000 mg/d. In fact, the trends, if anything, suggest the opposite. The multivariate comparisons of response, progression-free survival, and overall survival indicate that there is no advantage to the higher-dose regimen.

To ensure that no relationship between exposure to progestins and response was missed, the data were analyzed for an association between serum MPA level and response rate, progression-free survival, and overall survival. No relationship was found. Thus, there seems to be no advantage to the administration of doses of MPA greater than 200 mg/d orally.

The present study does provide evidence that receptor levels, particularly progesterone receptor levels, can improve predictability of response to progestin therapy. The comparative response rates for progesterone receptor-positive and -negative patients of 37% and 8%, respectively, are similar to those reported in GOG Protocol 48 (40% v 12%). Although these response rates are not as impressive as the difference between progesterone receptor-positive and -negative patients (86% v 7%) reported in a summary of other studies in the literature,²³ the observed difference is still substantial and is based on a significantly larger patient sample.

In conclusion, two successive GOG studies have now shown that oral progestins are clearly active against endometrial carcinoma. Benefit seems to be greatest in those patients with either lower-grade tumors or progesterone receptor-positive tumors, as evidenced by a progesterone receptor level of more than 50 fmol/mg cytosol protein. The results from this study indicate that prescribing doses as large as 1,000 mg of MPA daily is not necessary, and there is some evidence that larger doses may actually be detrimental.

Regardless of dose and schedule, oral progestin therapy seems to be well tolerated, with thrombophlebitis, the most frequent adverse effect, occurring in only 5% of patients. The use of oral MPA 200 mg/d as the initial systemic therapy for advanced or recurrent endometrial carcinoma, particularly in those with well-differentiated or progesterone receptor-positive neoplasms, is a reasonable approach.

	APPENDIX Participating Institutions and the National Cancer Institute Grants

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Participating... REFERENCES

 
The following is a list participating institutions and the National Cancer Institute grants supporting this study: University of Alabama at Birmingham (CA 12484), Duke University Medical Center (CA 12534), Temple University Health Science Center Hospital (CA 27816), University of Rochester Medical Center (CA 12482), Walter Reed Army Medical Center (CA 23501), University of Minnesota Medical School (CA 23088), Colorado Foundation for Medical Care (CA 15975), University of Miami School of Medicine (CA 37234), The Milton S. Hershey School of Medicine of the Pennsylvania State University (CA 16386), Georgetown University Hospital (CA 16938), University of Cincinnati College of Medicine (unfunded), University of North Carolina School of Medicine (CA 23073), University of Iowa Hospitals and Clinics (CA 19502), University of Texas Health Science Center at Dallas (CA 28160), Indiana University Medical Center (CA 21720), Bowman Gray School of Medicine of Wake Forest University (CA 21946), State University of New York at Syracuse (unfunded), The Albany Medical College of Union University (CA 27469), University of California Medical Center at Irvine (CA 23765), Tufts New England Medical Center (CA 37569), Illinois Cancer Council (CA 27806), Stanford University Medical Center (CA 35640), State University of New York Downstate Medical Center (CA 34477), Eastern Virginia Medical School (CA 40296), Cleveland Clinic Foundation (unfunded), The Johns Hopkins Oncology Center (unfunded), State University of New York at Stony Brook (unfunded) and Pennsylvania Hospital (unfunded).

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Participating... REFERENCES

 
1. Parker SL, Tong T, Bolden S, et al: Cancer Statistics 1997 [published erratum appears in CA 47:68, 1997]. CA Cancer J Clin 47:5-27, 1997[Medline]

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6. Sall S, DiSaia P, Morrow CP, et al: A comparison of medroxyprogesterone serum concentrations by the oral or intramuscular route in patients with persistent or recurrent endometrial carcinoma. Am J Obstet Gynecol 135:647-650, 1979[Medline]

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12. Kauppila A: Progestin therapy of endometrial, breast, and ovarian carcinoma: A review of clinical observations. Acta Obstet Gynecol Scand 63:441-450, 1984[Medline]

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14. Billiet G, De Hertogh R, Bonte J, et al: Estrogen receptors in human uterine adenocarcinoma: Correlation with tissue differentiation, vaginal karyopyknotic index, and effect of progestogen on anti-estrogen treatment. Gynecol Oncol 14:33-39, 1982[Medline]

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17. Janne O, Kauppila A, Kontula K, et al: Female sex steroid receptors in normal, hyperplastic, and carcinomatous endometrium: The relationship to serum steroid hormones and gonadotropins and changes during medroxyprogesterone acetate administration. Int J Cancer 24:545-554, 1979[Medline]

18. Benraad TJ, Friberg LG, Koenders AJ, et al: Do estrogen and progesterone receptors (E2R and PR) in metastasizing endometrial cancer predict the response to gestagen therapy? Acta Obstet Gynecol Scand 59:155-159, 1980[Medline]

19. Martin PM, Rolland PH, Ganxamerre M, et al: Estradiol and progesterone receptors in normal and neoplastic endometrium: Correlations between receptors, histopathological examinations and clinical responses under progestin therapy. Int J Cancer 23:321-329, 1979[Medline]

20. Creasman WT, McCarty KS Sr, Barton TK, et al: Clinical correlates of estrogen- and progesterone-binding proteins in human endometrial adenocarcinoma. Obstet Gynecol 55:363-370, 1980[Medline]

21. McCarty KS Jr, Barton TK, Fetter BF, et al: Correlation of estrogen and progesterone receptors with histologic differentiation in endometrial adenocarcinoma. Am J Pathol 96:171-183, 1979[Abstract]

22. Cavalli F, Goldhirsch A, Jungi F, et al: Randomized trial of low- versus high-dose medroxyprogesterone acetate in the induction treatment of postmenopausal patients with advanced breast cancer. J Clin Oncol 2:414-419, 1984[Abstract]

23. Thigpen T, Vance R, Lambuth B, et al: Chemotherapy for advanced or recurrent gynecologic cancer. Cancer 60:2104-2116, 1987 (suppl 8) [Medline]

Submitted June 10, 1998; accepted February 1, 1999.

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