Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study

OBJECTIVES: To estimate the objective response rate and toxicity associated with alternating megestrol acetate (MA) and tamoxifen citrate (T) in women with endometrial carcinoma. METHODS: Consenting patients with measurable recurrent or advanced endometrial carcinoma were eligible if they had not received prior cytotoxic or hormonal treatment. MA 80 mg BID x 3 weeks alternating with T 20 mg BID x 3 weeks orally was given. RESULTS: Of 61 patients entered, 56 eligible patients were evaluable for toxicity and response. Fifteen patients responded (12 complete, 3 partial) for an overall response rate of 27% (90% Confidence Interval: 17-38%). In 8 of 15 (53%) responders, response duration exceeded 20 months. The response rate was 38% in patients with histologic grade 1 tumors (n = 16), 24% in those with grade 2 disease (n = 17), and 22% among patients with grade 3 disease (n = 23). Women less than or equal to 60 years (n = 16) appear to have a better response rate than those >60 years (n = 40), 44% versus 20%. The response rate in patients with extra pelvic disease (n = 42) was 31% as compared to 14% in those with strictly pelvic and/or vaginal disease (n = 14). The median progression-free survival (PFS) was 2.7 months and median overall survival was 14.0 months. Two patients experienced a grade 4 thromboembolic event. Additional toxicities included one of each grade 3 gastrointestinal, grade 3 neurologic, and grade 3 genitourinary. CONCLUSION: A regimen of alternating megestrol acetate and tamoxifen is active in treating endometrial cancer and may result in a prolonged complete response (CR) in some patients.     

Uterine pleomorphic rhabdomyosarcoma in a patient receiving tamoxifen therapy

INTRODUCTION: Tamoxifen has been used as adjuvant therapy for the treatment of breast cancer. Its use has been associated with the development of proliferative endometrial lesions such as polyps, hyperplasia, and carcinoma. Mesenchymal tumors including malignant mixed mullerian tumors, endometrial stromal sarcomas, adenosarcomas, and leiomyosarcomas have been more recently described with tamoxifen use. CASE REPORT: This report describes the first case of a pure uterine rhabdomyosarcoma in a patient receiving tamoxifen therapy. DISCUSSION: Although uterine rhabdomyosarcomas are rare tumors and may arise de novo, we discuss the possible role of tamoxifen in the development of these mesenchymal tumors.     

The prognostic value and clinical utility of estrogen and progesterone receptors in endometrial carcinoma

In the United States, endometrial carcinoma is the most common gynecologic malignancy, and accounts for 4,900 deaths per year in the United States. While this disease has relatively good cure rates, there is motivation to describe other determinants, which may help in the treatment of this disease. Attempts have been made to correlate hormone receptor status with disease-free intervals and survival in patients with endometrial carcinoma. The weight of evidence seems to support that of the two hormone receptors, progesterone is the more significant predictor of patient outcome. If hormone receptors are to be used in the management of endometrial carcinoma, they should be determined by immunohistochemistry. In the adjuvant setting, patients with progesterone positive tumors are more amenable to treatment with progestational agents than are patients with receptor negative tumors. Future areas of research include the use of tamoxifen and selective estrogen receptor modulators in the chemoprevention and treatment of endometrial carcinoma.     

Chemotherapy plus Sequential Hormonal Therapy for Advanced and Recurrent Endometrial Carcinoma: A Phase II Study

We evaluated the therapeutic value of sequential cyclical hormonal therapy (megestrol acetate, and tamoxifen citrate) plus single-agent chemotherapy (carboplatin) in the outpatient management of advanced or recurrent endometrial cancer. Carboplatin (300 mg/m²) was administered every 4 weeks for six courses or until disease progression. In addition, patients alternated megestrol acetate (80 mg orally twice daily) with tamoxifen citrate (20 mg orally twice daily) every 3 weeks. Thirteen of 18 (72.2%) patients were considered evaluable. Four patients (30.8%) had a complete response, six (46.2%) had a partial response, one (7.7%) had stable disease, and two patients (15.4%) progressed. Six of seven patients with vaginal disease responded. The median progression-free interval was 14 months for complete responders. Two patients (15.4%) are alive with no evidence of disease at 41 and 59 months. Seven of 13 patients experienced a hematologic toxicity (six grade 2, one grade 3); all resolved within 2 weeks. Dose reduction of carboplatin to 200 mg/m²was required in one patient. No other toxicities were encountered. The median survival for all patients is 11 months, and is 33 months for complete responders. We conclude that a regimen of carboplatin plus sequential hormonal therapy shows promise in this pilot study for the treatment of advanced or recurrent endometrial cancer.     

宫腔镜联合孕激素治疗年轻患者早期子宫内膜癌的疗效及预后分析

目的:探讨宫腔镜联合孕激素治疗年轻早期子宫内膜癌患者的疗效及预后。方法:回顾性分析四川大学华西第二医院2008年1月至2014年12月自愿接受宫腔镜联合孕激素治疗的年轻早期子宫内膜癌16例患者的临床资料,且随访资料完整。所有患者行宫腔镜下刮宫或宫腔镜下病灶切除+刮宫,其中7例联合口服醋酸甲羟孕酮(250 mg/d,MPA组),9例联合醋酸甲地孕酮(160 mg/d,MA组)治疗。比较两组患者缓解、复发及生育等情况。结果:随访中位时间为54个月(17~90个月),其中12例(75.0%)完全缓解,3例(18.8%)部分缓解,1例(6.2%)无反应,MPA组和MA组的完全缓解率分别为71.4%(5/7)和77.8%(7/9),差异无统计学意义(P0.05)。16例患者中有3例在完全缓解后复发(MPA组1例,MA组2例),复发平均时间为42个月。16例患者中有8例(50.0%)完成了妊娠(其中1例2次妊娠),有6次(66.6%)妊娠顺利生产,3次(33.3%)流产。结论:宫腔镜联合孕激素治疗对于年轻早期子宫内膜癌患者保守治疗是有效的,其中MPA和MA的治疗效果无明显差异,但均存在着一定的复发风险,所以应对其进行严格的筛选和严密的随访。     

Leiomyomatosis peritonealis disseminata and ovarian Brenner tumor associated with tamoxifen use

Abstract. Bristow RE, Montz FJ. Leiomyomatosis peritonealis disseminata and ovarian Brenner tumor associated with tamoxifen use.
Tamoxifen is frequently administered as adjuvant therapy for breast carcinoma and produces weak estrogen agonist effects in estrogen sensitive tissues. In addition to producing a measurable increase in the risk of endometrial carcinoma, tamoxifen has also been associated with increasing size of uterine leiomyomata as well as the development of new leiomyomata. As the indications for tamoxifen therapy expand, surveillance for additional potential associated adverse outcomes is warranted.
A 44-year-old woman with a history of bilateral breast carcinoma presented with leiomyomatosis peritonealis disseminata and a right ovarian Brenner tumor 18 months after beginning adjuvant tamoxifen therapy. Although a causal link cannot be proven, this case is the second reported association between leiomyomatosis peritonealis disseminata, an ovarian Brenner tumor, and tamoxifen use for the treatment of breast carcinoma. Given the hormonal sensitivity of leiomyomatosis peritonealis disseminata, both mutagenic and mitogenic effects of tamoxifen on this rare entity must be considered. In the setting of continued hormonal treatment for breast carcinoma, the management of leiomyomatosis peritonealis disseminata presents unique clinical challenges.     

Durable response of metastatic endometrial carcinoma to treatment with fulvestrant (Faslodex) after prior progestin and anastrozole therapy

BACKGROUND: Patients with metastatic endometrial carcinoma may respond to hormonal therapy with progestins. There is a need for new therapies for hormone-responsive disease. CASE: We report a patient with metastatic endometrial carcinoma to the lungs, who after progressing on progestin therapy, had a lengthy remission with anastrozole; upon further progression, fulvestrant (Faslodex) was instituted, with a resultant partial remission, which has been sustained for almost 3 years. CONCLUSION: In this case, fulvestrant therapy was successful even in the face of prior anastrozole and megestrol. The activity of fulvestrant in patients with metastatic endometrial carcinoma should be further explored, especially in situations in which the tumor is well differentiated and/or expresses hormone receptors.     

Endometrial stromal sarcoma: objective response to letrozole

BACKGROUND: Low-grade endometrial stromal sarcoma is generally an indolent tumor rich in estrogen and progesterone receptors. Objective responses to hormonal therapy, most commonly with megestrol acetate, have been reported. CASE: The patient is a 51-year-old woman who presented with low-grade endometrial stromal sarcoma confined to the uterus in 1991 and was treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. Approximately 5 years later, the patient had recurrent pelvic disease treated with radiation therapy, followed by an attempt at resection. She was treated with megestrol acetate during the period she received radiation therapy with poor tolerance. Tamoxifen was then given with no tumor response. Megestrol acetate was restarted with progression of disease in the pelvis and abdomen. Letrozole was then given at a daily dose of 2.5 mg with partial response for a duration of 9 months. CONCLUSION: Letrozole at a daily dose of 2.5 mg may be effective in low-grade endometrial stromal sarcoma with positive estrogen receptors.     

Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study

OBJECTIVES: The objectives of this study were to estimate the clinical response rate and toxicity of daily tamoxifen combined with intermittent weekly medroxyprogesterone acetate (MPA). METHODS: This study reports the results of 61 patients with measurable advanced or recurrent endometrial carcinoma enrolled on this study to be treated with tamoxifen 40 mg p.o. daily plus alternating weekly cycles of MPA 200 mg p.o. daily. RESULTS: One patient was excluded and two patients did not receive study treatment. The percent of patients responding (6 complete and 13 partial) was 33% (95% confidence interval [CI]: 21-46%) among 58 eligible patients who received therapy. Median progression-free survival (PFS) was 3 months and median overall survival (OS) was 13 months. CONCLUSION: The combination of daily tamoxifen and intermittent weekly medroxyprogesterone acetate is an active treatment for advanced or recurrent endometrial carcinoma. Further investigation of this combination is appropriate.     

Four case reports presenting new acquisitions on the association between breast and endometrial carcinoma

In recent years, the association between breast and endometrial cancer has been the subject of many studies. The present report describes four cases of this association in which tamoxifen had been administered to all of the patients. Data have been published regarding the possibility that tamoxifen may be responsible for the subsequent development of carcinoma of the corpus uteri in these patients. The authors intend to carry out a case-control study on patients treated with tamoxifen for breast carcinoma to reveal the possible presence of endometrial carcinoma.     

The use of megestrol acetate in the treatment of advanced malignant lesions of the endometrium

The use of megestrol acetate, an oral progestin, was evaluated in a group of patients with far advanced, endometrial carcinoma. Using strict criteria, over 40% of the patients achieved an objective remission at doses ranging from 80 to 160 mg per day.     

Tamoxifen-induced increase in cytosol progestin receptor levels in a case of metastatic endometrial cancer

A patient with endometrial carcinoma metastatic to the groin has had serial cytosol estrogen (ER_c) and progestin (PR_c) receptor determinations during hormonal therapy. The primary lesion was well differentiated and a left iliac node metastasis had high ER_c and borderline PR_c levels. PR_c levels increased substantially in a subsequently appearing right groin metastasis at three times during the clinical course when the patient was treated with the antiestrogen tamoxifen. The patient had a partial response to the first course of tamoxifen and at one later time briefly had stabilized disease on tamoxifen plus medroxyprogesterone acetate. Tamoxifen with and without progestin should be further evaluated in the treatment of endometrial carcinoma.     

Endometrial glandular dysplasia and endometrial intraepithelial neoplasia

PURPOSE OF REVIEW: In recent decades, progress has been made in defining endometrial precancers. Endometrial intraepithelial neoplasia has been widely accepted as a precancer of type I endometrial cancer, while endometrial glandular dysplasia is a newly described entity as a probable precancer of type II cancer. As endometrial intraepithelial neoplasia has been discussed more extensively in the literature, we focus more on the recent development of endometrial glandular dysplasia in this review. RECENT FINDINGS: Serous endometrial intraepithelial carcinoma was previously considered as a putative precancer for endometrial serous carcinoma or uterine papillary serous carcinoma. It is now considered as an early form of endometrial serous carcinoma, however. Endometrial glandular dysplasia was found to be a better candidate for precancer for both endometrial serous and clear cell carcinomas, which meets almost all recently defined criteria for precancer. Biomarkers of p53 and IMP3 are helpful for the early detection of endometrial glandular dysplasia as well as type II endometrial cancers. SUMMARY: Two types of endometrial cancers are derived from two different precancers. Type I endometrioid carcinoma develops from endometrial intraepithelial neoplasia, while type II derives most probably from endometrial glandular dysplasia. Recognition and correct detection of endometrial glandular dysplasia may deepen our understanding and improve prevention and clinical management for type II endometrial cancer.     

Treatment of recurrent and metastatic endometrial cancer with cisplatin, doxorubicin, cyclophosphamide, and megestrol acetate

The combination of cisplatin, doxorubicin, cyclophosphamide, and megestrol acetate was used to treat 15 patients with recurrent and metastatic endometrial cancer. Four patients had a complete response and one patient had a partial response, yielding a total response rate of 33%. Five patients had stable disease. The median survival for the whole group was 38 weeks. The median survival for responders was 60 weeks, and that for nonresponders was 21 weeks. The median progression-free survival for the whole group was 17 weeks. The median progression-free survival for responders was 32 weeks, and that for patients with stable disease was 25 weeks. The toxic reactions noted were primarily nausea, vomiting, and myelosuppression. The combination of cisplatin, doxorubicin, cyclophosphamide, and megestrol acetate has modest effectiveness in the treatment of metastatic or recurrent carcinoma of the endometrium.     

Pregnancy outcome in patients with stage 1a endometrial adenocarcinoma,who conservatively treated with megestrol acetate

Objective  

The most effective treatment of well-differentiated endometrial carcinoma is surgery. The aim of this study is the evaluation of megestrol acetate on young patients with well-differentiated endometrial cancer who wish to preserve their fertility, with regard to the receptors.     

Intraepithelial G3 adenocarcinoma of the endometrium after tamoxifen treatment

Case report In this paper we describe a case of endometrial carcinoma observed in a post-menopausal patient who was treated with tamoxifen for 5 years after a mastectomy for cancer. She came to our department because of vaginal bleeding 2 years after the end of tamoxifen treatment.Treatment She underwent hysteroscopy and a D and C. A polypoid endometrium completely filled the uterine cavity and was carefully removed by curettage; histology showed a highly undifferentiated neoplasia with a component of serous adenocarcinoma, which was likely to originate from endometrial polyps.Outcome The patient underwent radical hysterectomy, but no residual tumor was found in the uterus or in the tubes, ovary, or pelvic nodes, in spite of its low differentiation grade and high potential aggressiveness, and even though the patient was already symptomatic. Two years after surgery the patient is disease free, which is consistent with the evaluation of the surgical specimen, but unusual in poorly differentiated neoplasms.     

Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: A gynecologic oncology group study

Objectives

To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma.

Background

Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy.

Methods

We performed a randomized phase II trial of intravenous temsirolimus 25 mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20 mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma.

Results

There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded.

Conclusions

Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.     

Metabolic effects associated with high-dose continuous megestrol acetate administration in the treatment of endometrial pathology

OBJECTIVES: To determine the metabolic effects and efficacy of high-dose continuous megestrol acetate administration in the treatment of endometrial pathology. MATERIAL AND METHODS: 27 women with histologically proven endometrial pathology (endometrial hyperplasia and irregularly proliferative endometrium) were treated with megestrol acetate orally 160 mg/d given once-a-day for 3 months. In 5 of 27 patients the dose of megestrol acetate was increased to 320 mg/d to alleviate irregular uterine bleeding. Serum lipid profiles and fasting and 2-h postprandial serum glucose levels were studied at baseline and one week after the therapy was completed. RESULTS: HDL-cholesterol level significantly lowered from a mean of 50.4+/-11.1 mg/dL to 44.4+/-8.5 mg/dL after 3 months of megestrol acetate therapy (p<0.05). Serum total cholesterol level significantly lowered from a mean of 222.8+/-50.0 mg/dL to 192.7+/-36.5 mg/dL (p<0.05) and apolipoprotein A-I level from a median of 134 mg/dL to 116 mg/dL (p<0.05) after the therapy. Serum LDL-cholesterol, triglyceride, apolipoprotein B, fasting and 2-h postprandial glucose levels did not significantly change after the therapy (p>0.05). The median weight of patients was found to be 70 (53-110) kg before the therapy and 74 (56-111) kg after the therapy (p=0.001). CONCLUSIONS: The use of megestrol acetate, 160-320 mg/d, in the treatment of endometrial pathology is an effective method without marked harmful effects on serum lipid profiles or glucose levels but is associated with weight gain.     

Long-term effect of megestrol acetate in the treatment of endometrial hyperplasia

Fifty-two postmenopausal women who were poor surgical risks and had histologically proved adenomatous hyperplasia, atypical hyperplasia, or adenocarcinoma in situ of the endometrium were treated with megestrol acetate, 40 mg per day, continuously for 9 to 104 months (mean, 42 months). More than 90% of these women had complete remissions of the hyperplasia. Three women with carcinoma in situ were followed up for 57, 65, and 104 months, without recurrence of the disease. Four women required hysterectomy; none had invasive adenocarcinoma. No adverse side effects of the drug were observed. Thus, we conclude that the continuous use of megestrol acetate is an effective, safe, alternative form of therapy for endometrial hyperplasia in postmenopausal women.     

Does tamoxifen use affect prognosis in breast cancer patients who develop endometrial cancer?

OBJECTIVE: The use of tamoxifen to prevent breast cancer and decrease recurrence is not controversial. However, the effect that tamoxifen may have in women with a history of breast cancer in whom endometrial cancer develops is unclear. The purpose of this study was to estimate whether a history of tamoxifen use is a prognostic factor for such patients. METHODS: Between 1990 and 2002, patients seen at The University of Texas M. D. Anderson Cancer Center with a history of breast cancer who developed endometrial cancer were identified. Medical records were reviewed to identify clinical, pathologic, and outcome information. RESULTS: Eighty-nine patients with a history of breast cancer in whom endometrial carcinoma developed were identified. Fifty-two percent (46/89) had a history of tamoxifen use (median duration 48 months; range 2-120 months). There were no significant differences in the clinical or pathologic features between tamoxifen users and nonusers. A history of tamoxifen use was associated with a shorter interval from breast cancer to endometrial cancer diagnosis (77.2 versus 121.3 months for nonusers; P =.01). There was no significant difference in overall survival between tamoxifen users and nonusers (39.2 months versus 48.3 months, P =.27), and there was no difference in endometrial cancer-specific survival duration between tamoxifen users and nonusers (55.7 versus 51.0 months, P =.92). CONCLUSION: Among tamoxifen users, the interval from breast cancer to endometrial cancer diagnosis was significantly shorter than that in nonusers. In this cohort, a history of tamoxifen use was not associated with a worse overall or disease-specific survival.