Regular articleArzoxifene as therapy for endometrial cancer
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.
References (55)
- et al.
A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometriuma Gynecologic Oncology Group study
Gynecol Oncol
(1996) - et al.
Phase II study of paclitaxel as salvage treatment in advanced endometrial cancer
Ann Oncol
(1996) The epidemiology of polycystic ovary syndromeprevalence and associated disease risks
Endocrinol Metab Clin North Am
(1999)- et al.
Differential effect of forms A and B of human progesterone receptor on estradiol-dependent transcription
J Biol Chem
(1994) - et al.
RU486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism
J Biol Chem
(1994) - et al.
Clarke-Pearson DL. Influence of cytoplasmic steroid receptor content on prognosis of early stage endometrial carcinoma
Am J Obstet Gynecol
(1985) - et al.
A phase II study of leuprolide in advanced/recurrent endometrial cancer
Gynecol Oncol
(1997) - et al.
Long-term follow-up of gonadotrophin-releasing hormone analog treatment for recurrent endometrial cancer
Gynecol Oncol
(1996) - et al.
The pharmacology and clinical uses of tamoxifen
Pharmacol Ther
(1984) - et al.
Adjuvant tamoxifen in early breast canceroccurrence of new primary cancers
Lancet
(1989)