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© 2001 American Society for Clinical Oncology Tamoxifen in the Treatment of Advanced or Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group StudyFrom the Division of Oncology, Department of Medicine, University of Mississippi School of Medicine, Jackson, MS; Gynecologic Oncology Group, Roswell Park Cancer Institute, Buffalo, NY; Wake Forest School of Medicine and Brookview Research, Inc, Winston-Salem, and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC; and Riverside Methodist Hospital, Columbus, OH. Address reprint requests to Gynecologic Oncology Group Administrative Office, Suite 1945, 1234 Market St, Philadelphia, PA 19107; email JTTHIGPEN{at}worldnet.att.net
PURPOSE: In two large Gynecologic Oncology Group studies of patients with advanced or recurrent endometrial carcinoma and no previous systemic therapy, progestins have demonstrated activity against advanced or recurrent endometrial carcinoma with response rates between 15% and 25%. Tamoxifen has been reported as variously active or inactive with or without previous systemic therapy. The purpose of this study was to determine whether tamoxifen exhibits enough activity in patients with advanced or recurrent endometrial carcinoma, who have not received systemic therapy, to warrant a phase III trial. PATIENTS AND METHODS: Sixty-eight eligible patients with advanced or recurrent endometrial carcinoma received oral tamoxifen 20 mg bid until toxicity was unacceptable or disease progressed. RESULTS: Three complete (4%) and four partial (6%) responses were observed for an overall response rate of 10% (90% confidence interval [CI], 5.7% to 17.9%). Patients with tumors that were more anaplastic tended to respond less frequently. The median progression-free survival for all 68 eligible patients was 1.9 months (90% CI, 1.7 to 3.2 months). The median survival was 8.8 months (90% CI, 7.0 to 10.1 months). CONCLUSION: Tamoxifen demonstrated modest activity at best against endometrial carcinoma and does not warrant further investigation as a single agent for this disease. Ongoing trials will assess the sequential use of tamoxifen and progestational agents.
ENDOMETRIAL CARCINOMA is the most common invasive neoplasm of the female genital tract, accounting for more than 37,400 new cases in 1999 according to the American Cancer Society.1 Fewer than 6,500 deaths will occur from this disease, however, because it is most commonly diagnosed as a result of bleeding while the disease is still limited to the corpus. For patients unfortunate enough to develop disseminated or recurrent disease, limited options for systemic therapy are available.2,3 Because endometrial carcinoma is susceptible to hormonal influences in some cases, progestational agents4,5 and tamoxifen6,7 have been used in patients with recurrent or disseminated disease. Large trials of oral progestins have yielded response rates ranging from 15% to 25%, whereas studies of tamoxifen have been too small to provide reliable estimates. The present study was undertaken to determine whether tamoxifen has sufficient activity against endometrial carcinoma to warrant a large-scale, phase III investigation.
Between October 15, 1987, and June 14, 1991, member institutions of the Gynecologic Oncology Group (GOG) entered 73 patients with advanced or recurrent endometrial carcinoma onto GOG Protocol 81-F to evaluate the efficacy of tamoxifen. Patients had to meet the following criteria: histologically documented, advanced (stage III or IV) or recurrent endometrial carcinoma not controllable with surgery and/or radiotherapy; no previous exposure to systemic therapy; at least one marker lesion measurable clinically in two dimensions for the assessment of response; a GOG performance status of 0, 1, or 2 (equivalent to Karnofsky performance status score of 50 or better); no contraindication to the use of tamoxifen; no history of a previous invasive malignancy other than endometrial carcinoma; complete recovery from previous surgery; and freedom from evidence of infection. Pretreatment laboratory data must have included a leukocyte count greater than 3,000/dL, a platelet count greater than 100,000/dL, a creatinine level less than 2.0 mg/dL, and AST, alkaline phosphatase, and bilirubin levels less than twice normal. Written informed consent that fulfilled all institutional, state, and federal regulations was obtained from all patients before entry onto the study. Patients received tamoxifen 20 mg orally bid with monthly reassessment. Treatment was continued until toxicity was unacceptable, diseased progressed, or the patient died or was lost to follow-up. Frequency of response was the primary end point for assessment of therapeutic activity. The study was designed to limit the width of the 90% CI to less than 20%. Response was defined according to standard GOG criteria. A complete response indicated that all evidence of disease had disappeared, and that this status was maintained until at least a second assessment 1 month later. A partial response indicated a reduction of at least 50% in the product of perpendicular diameters of 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 was indicated if one or more lesions demonstrated an increase of at least 50% in the product of perpendicular diameters or if one or more new lesions had appeared within 1 month of the initiation of therapy. Progression-free survival (PFS) and overall survival also were assessed. PFS was defined as the minimum period from entry onto the study to evidence of disease progression, death from any cause, or the last contact if the patient was alive and progression-free. Overall survival was defined as the period from entry onto the study to death from any cause or the last contact. The analyses of survival, PFS, and response were based on all of the patients registered onto this study who were deemed eligible, regardless of the duration of treatment. The analyses also included examination of the pretreatment patient characteristics and evaluation of toxicity. The CI of the responding proportion is based on the inversion of the Score test.8 Cumulative probabilities of surviving were estimated with the Kaplan-Meier method,9 and a log-rank test10 was used to test the independence between pretreatment patient characteristics and risk of death.
Patient Characteristics A total of 73 patients were entered onto the study. Of these, five were deemed ineligible after central pathology review. One patient had a carcinosarcoma, two patients had adenocarcinoma of the cervix, and two patients had insufficient documentation of primary endometrial cancer. The patient characteristics of the 68 eligible patients are summarized in Table 1. The overall characteristics for these study patients are similar to those described for the population of patients with endometrial carcinoma as a whole: most patients were postmenopausal, they had received surgery and/or radiotherapy for limited disease that had recurred subsequently, and they tended to demonstrate higher-grade lesions consistent with advanced or recurrent disease.
Duration of Treatment The median duration of treatment on the study was 58 days, and 85% of patients received more than 21 days of treatment. The reasons for termination of treatment were progression (84%), death from cancer (9%), death from intercurrent disease (4%), and withdrawal from the study (3%). The two patients who withdrew from treatment on the study without evidence of new disease demonstrated rapid deterioration of their health status, which was thought to be unrelated to the study treatment.
Response
PFS and Overall Survival PFS and overall survival are displayed in Fig 1. The median duration of PFS was 1.9 months (90% CI, 1.7 to 3.2 months), and the median duration of overall survival was 8.8 months (90% CI, 7.0 to 10.1 months). Survival was slightly shorter among women with tumors that were more anaplastic. This difference, however, was not statistically significant (Table 2). There was a significant difference in overall survival when patients were compared according to their initial performance score (P < .001). Patients who were fully active (performance score, 0) had a median survival of 30.6 months. This is considerably longer than the survival of patients with performance scores of 1 or 2, who had median survivals of 9.7 and 2.5 months, respectively.
Adverse Effects The most frequently reported adverse event was gastrointestinal toxicity (6%), primarily including nausea or vomiting. Two patients (3%) developed anemia, one patient experienced grade 2 thrombophlebitis, one patient had grade 1 hot flashes, and one patient experienced grade 2 fatigue. In no patient was the study treatment reported a contributing factor in the cause of death.
The GOG experience with hormonal therapy for advanced or recurrent endometrial carcinoma has focused on the use of progestational agents.4,5 In the first of these studies, administration of medroxyprogesterone acetate (MPA) 150 mg orally per day produced 32 complete and 26 partial responses among 331 patients, for an overall response rate of 18%.5 This represented a lower response rate than had been reported previously.11,12 The observed median PFS and overall survival of 4 and 10.5 months, respectively, also were less impressive than in previous reports.5,11,12 In the second GOG trial, patients who received either MPA 1,000 mg/d or MPA 200 mg/d had 15% and 25% response rates, respectively.4 That study demonstrated no benefit from a five-fold increase in the MPA dose. In these studies, response was associated with histologic grade. Among patients with histologic grade 1, 2, and 3 tumors, the percentage who responded to MPA was 37%, 23%, and 9%, respectively.4 The frequency of response was slightly higher within each grade level compared with this study. Although estrogen and progesterone receptor status also correlated with response in both trials, receptor data were not available for all patients and were not controlled for interlaboratory variation. These two trials established the value of progestins in the treatment of advanced or recurrent endometrial carcinoma, although at a lower level of activity than indicated in the previously published literature. Tamoxifen also has been suggested as a potentially effective hormonal therapy for endometrial carcinoma. Three previous phase II trials of doses ranging from 20 mg to 60 mg bid have produced mixed results; two of the studies demonstrated reasonable activity and one demonstrated no activity.6,7 The trials were small and had no requirement for absence of previous exposure to systemic therapy. The current trial was undertaken to determine whether tamoxifen has sufficient activity (defined as a 20% or better response rate) to warrant a phase III investigation. The results of this trial demonstrate that the drug has, at best, modest activity with an overall response rate of 10%. PFS was relatively short and overall survival was similar to that demonstrated by progestins. Despite the similarity of overall survival, progestins remain the preferred hormonal therapy for endometrial carcinoma, particularly for women with progestin receptor–positive tumors. It is unclear whether tamoxifen has any role to play in second-line hormonal manipulation for patients who respond to progestins and subsequently relapse. If tamoxifen is to be considered for use in second-line therapy, the focus should be patients with grade 1 and 2 tumors. Preliminary studies have suggested that sequential administration of tamoxifen and progesterone may provide effective treatment for advanced endometrial cancer. Progesterones seem to work through the progesterone receptors. Prolonged administration of progesterone diminishes progesterone receptor concentrations. However, tamoxifen promotes progesterone receptor expression, which in turn may enhance or prolong the response to progesterone.13 This thesis is under investigation by the GOG. The GOG has no plans to explore further the use of tamoxifen as a single agent in endometrial carcinoma.
The following institutions participated in this study (National Cancer Institute grant numbers are in parentheses): Duke University Medical Center (CA 12534); University of Rochester Medical Center (CA 12482); University of Minnesota Medical School (CA 23088); University of California Medical Center at Los Angeles (CA 13630); The Milton S. Hershey School of Medicine of the Pennsylvania State University (CA 16386); Georgetown University Hospital (CA 16938); 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); Illinois Cancer Council (CA 27806); Stanford University Medical Center (CA 35640); Eastern Virginia Medical School (CA 40296); Cleveland Clinic Foundation (unfunded); State University of New York at Stony Brook (unfunded); Washington University School of Medicine (unfunded); Cooper Hospital University Medical Center; Columbus Cancer Council (unfunded); and University of Massachusetts Medical Center.
Please see the Appendix for grant support information.
1. Landis SH, Murray T, Bolden D, et al: Cancer statistics, 1999. CA Cancer J Clin 49: 8-31, 1999 2. Lentz SS: Advanced and recurrent endometrial carcinoma: Hormonal therapy. Semin Oncol 21: 100-106, 1994 3. Muss HB: Chemotherapy of metastatic endometrial cancer. Semin Oncol 21: 107-113, 1994
4.
Thigpen JT, Brady MF, Alvarez RD, et al: Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: A dose-response study by the Gynecologic Oncology Group. J Clin Oncol 17: 1736-1744, 1999 5. Thigpen T, Blessing J, DiSaia P, et al: Oral medroxyprogesterone acetate in advanced or recurrent endometrial carcinoma: Results of therapy and correlation with estrogen and progesterone receptor levels—The Gynecologic Oncology Group experience, in Baulier E, Iacobelli S, McGuire W (eds): Endocrinology and Malignancy. Pearl River, NY, Parthenon Publishers, 1986, pp 446-454 6. Thigpen T, Vance R, Lambuth B, et al: Chemotherapy for advanced or recurrent gynecologic cancer. Cancer 60: 2104-2116, 1987[Medline] 7. Slavik M, Petty W, Blessing J, et al: Phase II clinical study of tamoxifen in advanced endometrial adenocarcinoma: A Gynecologic Oncology Group study. Cancer Treat Rep 68: 809-811, 1984[Medline] 8. Agresti A, Coull BA: Approximate is better than exact for the interval estimation of binomial proportions. The Am Statistician 52: 119-126, 1998 9. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 10. Peto R, Peto J: Asymptotically efficient rank invariant procedures. J R Stat Soc (series A) 135: 185-261, 1972 11. Kauppila A: Progestin therapy of endometrial, breast, and ovarian carcinoma: A review of clinical observations. Acta Obstet Gynecol Scand 63: 441-450, 1984[Medline] 12. Reifenstein EC Jr: Hydroxyprogesterone caproate therapy in advanced endometrial cancer. Cancer 27: 485-502, 1971[Medline]
13.
Mortel R, Levy C, Wolff JP, et al: Female sex steroid receptors in postmenopausal endometrial carcinoma and biochemical response to an antiestrogen. Cancer Res 41: 1140-1147, 1981 Submitted February 9, 2000; accepted August 22, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
