Regular article
Arzoxifene as therapy for endometrial cancer

https://doi.org/10.1016/S0090-8258(03)00343-3Get rights and content

Abstract

Objective

Arzoxifene, an orally active third-generation selective estrogen-receptor modulator (SERM), opposes the action of estrogen on the breast and endometrium but exerts an estrogen-agonist effect on bone and the lipid profile. Since this is an appealing combination for hormonal therapy of estrogen-related cancers, we initiated testing the potential of arzoxifene in women with treatment-refractory endometrial cancer.

Methods

Two phase I studies were conducted to evaluate the safety and pharmacokinetics of single and multiple doses of arzoxifene. In addition, two multi-institutional phase II trials have been completed on 100 women with metastatic or recurrent endometrial cancer.

Results

No serious adverse events were observed in the single-dose phase I study, the principal side effect being hot flashes in 5/15 healthy volunteers. In the second phase I study, conducted in 32 women with metastatic breast cancer, one patient had a serious, possibly drug-related adverse reaction (pulmonary embolism). The two multi-institutional trials demonstrated significant activity at 20 mg/day in patients with metastatic or recurrent endometrial cancer. Observed clinical response rates were 25 and 31%, with a median response duration of 19.3 and 13.9 months, respectively. Progression of the disease was stabilized in a substantial number of women. Toxicity was mild, except for two cases of pulmonary embolism that might have been drug related.

Conclusions

Further investigation is warranted to verify these preliminary response rates and the clinical significance of the stable disease cases, to compare clinical outcomes with those in progestin-treated women, and to elucidate the mechanisms of SERM action in this disease.

Introduction

Endometrial cancer is the most common gynecologic malignancy and the fourth most common cancer in women, with an estimated incidence of 36,000 cases and 6500 deaths in the United States in 2001. Outcome is heavily influenced by initial stage, histologic type, and tumor grade, with overall survival ranging from 36 to 95%, depending upon the subset of patients analyzed. The prognosis is better in women whose tumors are confined to the uterus (Stage I) or who have adenocarcinomas with 50% or more gland-forming tissue (grades 1 or 2). Conversely, extrauterine disease, deep myometrial penetration, and a serous, clear-cell, or grade 3 histology convey a poorer prognosis [1], [2].

Endometrial cancer is largely a disease of peri- and postmenopausal women, with a median age at diagnosis of about 60 years. The typical symptom of postmenopausal bleeding frequently leads to diagnosis at an early stage. Most patients are considered curable by surgery or surgery plus radiotherapy. Although treatment failure is rare in low-risk patients, it is estimated that 20% of patients (half of whom were diagnosed in Stage I) will still die of the disease. The majority of relapses occur in women with advanced-stage disease or where the primary tumor has high-risk features. Late recurrence is uncommon, and most treatment failures occur within 3 years of the original diagnosis [1], [3].

Treatment of advanced or recurrent disease is currently unsatisfactory. Although a number of new chemotherapeutic agents has been tested, the mainstay of cytotoxic treatment remains platinum or anthracycline therapy, or both. Despite the use of combination regimens, average response rates remain near 30%, with a duration of response or median survival of 7 months or less [1]. Recent studies performed in the United States and Italy have shown that paclitaxel is also an active cytotoxic agent for endometrial cancer [4], [5]. To date, however, cytotoxic therapy has made little impact on disease-free or overall survival. Given the age and likelihood of concurrent disease in the postmenopausal patient population, the toxicities associated with cytotoxic agents must always be taken into consideration. As an alternative, use of hormonal therapy is preferable in certain subgroups of patients [2], [6].

Section snippets

Steroid hormone receptors in endometrial cancer

The normal endometrium is a hormonally responsive tissue. The growth and glandular proliferation caused by estrogenic stimulation is balanced in the normal menstrual cycle by the action of progesterone. Excessive estrogen exposure is associated with the majority of known risk factors for endometrial cancer, including the use of unopposed exogenous estrogen to treat menopausal symptoms, early age at menarche, late menopause, and nulliparity, as well as obesity via the conversion of

Current status of hormonal therapy

The mainstay of hormonal therapy for patients with progressive or refractory disease has been progestogens. Activity was documented as early as 1961 [19]. Fifteen to twenty percent of patients achieve some response to hormonal agents, although the response is seldom complete. The duration of remission varies considerably but is usually in the range of 6–8 months [1], [6], [20]. Initial hormonal studies employed hydroxyprogesterone caproate, but subsequent trials used oral medroxyprogesterone

Toxicity and side effects of hormonal therapy

Although progestogens are relatively well tolerated, they commonly cause increased appetite, weight gain, and fluid retention. Significant cardiovascular side effects have also been reported. A GOG study on high-dose megestrol acetate in endometrial cancer reported thrombosis as the most severe toxicity [21]. While not significantly different than in the control arm, cardiovascular complications were also reported to be higher in progestogen-treated patients in a large, randomized, adjuvant

Selective estrogen-receptor modulators

Selective estrogen-receptor modulators (SERMs) are nonsteroidal compounds that bind to the ER with high affinity and display tissue- and cell type-specific ER agonism or antagonism [30], [31], [32], [33], [34], [35].

Single-dose phase I study

In a phase I study, 15 healthy infertile female volunteers received a single daily dose of arzoxifene. Doses ranging from 10 to 1000 mg were tested. The primary goals of the study were to evaluate the safety and pharmacokinetics of arzoxifene in this dose range. No serious adverse events were observed in this study. The principal side effect was the occurrence of hot flashes in five women. Arzoxifene was rapidly absorbed and had a half-life of 40–50 h. A detailed pharmacokinetic analysis was

Conclusions

Preliminary observations derived from these trials suggest that arzoxifene therapy can produce objective clinical responses in both progestogen-sensitive and progestogen-refractory tumors. The observed response rates appear to be higher than those reported for traditional progestational agents and for tamoxifen. The long response duration and number of clinically important stable disease cases are both surprising observations when compared to the outcomes of other trials of hormonal agents.

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