Current Research on the Use of Hormonal Therapy in the Treatment of Advanced or Recurrent Endometrial Cancer

INTRODUCTION

Endometrial cancer is now the most common pelvic cancer in American women, with an estimated incidence of over 40000 for the year 2004 and an estimated 7090 deaths from the disease’. While patients with low grade cancers can often be cured by surgery, with or without radiotherapy, patients with advanced or recurrent endometrial cancer have a poor prognosis despite surgical treatment and irradiation. Though chemotherapy has proven to be a more effective method of treatment, its high toxicity profile makes it problematic, as the majority of patients with endometrial cancer are elderly. Hormonal therapy using progesterone derivatives is of great interest as it has a low toxicity profile (i.e. edema, weight gain, gastrointestinal disturbances and thromboembolic events) and is therefore a desirable option for elderly patients or patients with medical co-morbidities.

There is an undeniable link between hyperestrogenic states and endometrial cancer. Although there have certainly been cases of endometrial cancer in patients with normal estrogen levels, many of the risk factors associated with endometrial cancer (nulliparity, late menopause, obesity) are due to increased levels of estrogen2. Numerous studies have tried to manipulate the hormonal nature of the cancer by using the various hormonal receptors in the tumor in a manner leading to tumor cell death. Below are the results of various hormonal therapies that have been studied in the treatment of advanced and recurrent endometrial cancer (summarized in Table 1).

PROGESTERONE DERIVATIVES

Following early research in the 1950s establishing the role of estrogen in the etiology of endometrial cancer, Kelly and Baker, in 1961, first introduced the concept of treating patients with advanced endometrial cancer with a progesterone derivative3. Kelly and Raker saw objective regressions in 6 of 21 patients with advanced endometrial cancer following treatment with various doses and formulations of progesterone derivatives. Since then, research has continued looking toward various progesterone derivatives, various doses of those derivatives, and, most recently, adjunctivc therapies to enhance the effects of the progestins. A problem with treating endometrial cancer with progestins is the down-regulation of progesterone receptors that has been found to occur with prolonged progestin treatment. In Gynecologic Oncology Group (GOG) protocol 121, high doses of megestrol acetate (MA) were given to investigate if high-dose progestin therapy was more effective then previously investigated historical controls4. Subsequently, the high- dose MA therapy did not lead to improved outcomes for patients with endometrial cancer compared to previously documented lower-dose regimens. The phenomenon of progesterone response being unrelated to dose intensity was echoed by another study, GOG protocol 81, that investigated the difference in response to 200 mg/day of oral MPA vs. 1000 mg/day of oral MPA.5 This study demonstrated that, in fact, the patients receiving the lower dose of MPA had a trend toward longer progression-free survival and a better overall survival then the higher dose group. Additionally, this study showed a significant difference in response rates between patients that had progesterone receptor-positive tumors vs. progesterone receptor-negative tumors, 37% vs. 8% respectively, prompting the idea that increasing progesterone receptors can lead to increased efficacy of progesterone.

Tamoxifen citrate (TAM), an anti-estrogen that has proven valuable in breast cancer treatment, has been investigated as an adjunct to progestin therapy due to its proven ability to increase progesterone receptors. When tamoxifen binds to cytosolic estrogen receptors, the TAM-rcceptor complex then translocates to the nucleus and causes an increase in production of progesterone receptors and a decrease in es trogen receptors. Through a scries of studies in the early 1980s it was shown that TAM treatment caused an increase in functional progesterone receptors in en dometrial cancer specimens6- 8. The use of tamoxifen as a single-agent treatment of advanced or recurrent endomctrial cancer was studied in GOG protocol 81F^sup 9^. In this phase II study, tamoxifen was found to have only a 10% overall response rate, a short progression-free survival and an overall survival comparable to that of progestins alone. Although this determined that it was not an effective treatment as a single agent, further investigation was still warranted for its possible role in combination with progesterone.

Table 1 Comparison of trials of hormonal therapy for endometrial cancer

Using TAM as an adjunct to increase progesterone receptors has been investigated as a means of increasing the efficacy of progesterone treatment. A study by Zaino et al. showed that in nude mice the combination of TAM and medroxyprogesterone acetate (MPA) led to a greater reduction in tumor size then MPA alone10. An ECOG study comparing the response of MA alone to the combination of MA and tamoxifen was conducted in 2001, but failed to accrue enough patients, so the MA only arm was discontinued11. Because of the poor patient accrual, the authors could not statistically compare the two arms, but MA alone and TAM + MA showed similar response rates (20% and 19% respectively). Early this year, two separate phase II trials were published which examined the use of combination regimens of TAM and progestins for the treatment of advanced endometrial cancer. Exploring the idea that TAM’s effect of increasing progesterone receptors would increase the effectiveness of progesterone, both of these studies sought to investigate a combination of agents that may lead to better results then each agent produced alone. GOG protocol 119 utilized a regimen of daily tamoxifen and daily MPA on alternating weeks, while GOG protocol 1.53 investigated a program of daily MA (a different progesterone) for 3 weeks alternating with daily TAM for 3 weeks (the results of all the above mentioned trials are summarized in Table 1)12,13 Although each of these trials used different progesterones, they both achieved similar results.

Both regimens achieved progression-free survival lengths similar to each other and to previous experience, with their respective progesterone as a single agent. However, GOG 153 demonstrated a median overall survival (14 months) that was considerably longer then was previously shown with MA alone (7.6 months), while GOG 119 showed only a mild improvement in median overall survival when compared with the lower dose MPA used in GOG 81 (12.8 months vs. 11.1 months, respectively). Both GOG 119 and GOG 153 showed improvements in overall response rate compared to progestin alone; however, it is notable that their 95% confidence intervals both overlap the response rates of both MPA and MA alone, thus challenging the superiority of combination therapy. Of note was the significant improvement in duration of overall response in GOG 153 compared to GOG 121 (28 months vs. 8.9 months). Since GOG 153 was based on the premise that tamoxifen would help to maintain progesterone receptors for increased progesterone responsiveness, the difference supports this previous hypothesis.

A notable difference was observed between the previous single agent treatments and the regimens examined in GOG 153 in the response of higher grade cancers. When the response by each grade of cancer is compared (see Table 2), the alternating MA and TAM regimen in GOG 153 demonstrated a sizeable improvement in response to grade 3 cancers compared to the use of MA alone (22% vs. 8%). Unfortunately, GOG 119 did not present data comparing response by grade, but the results of GOG 153 indicate an enhanced response with tamoxifen due to a possible induction of progesterone receptors that were not present in tumors prior to treatment or due to an effect distinct from progesterone receptors. With these studies promising survival data and limited adverse events, the use of progesterone and tamoxifen certainly deserves further phase III trials and continued investigation.

Table 2 Response of endometrial cancer by grade of tumor to hormonal therapy

DANAZOL

Danazol was investigated in a previous phase II trial, since it had success as a therapy for endometrial hyperplasia and had promising in wrro findings . A IT-alpha-ethinyltestoterone derivative, this agent hoth affects pituitary gonadotropins and hinds to progesterone, androgcn and glucocorticoid receptors, In vitro, it was shown to inhibit endometrial tumor cell migration and invasive activity’15. Unfortunately, none of the participants in this study responded to danazol. Of the 22 patients that were evaluated for response, the hest response seen was sthle disease in six patients (27%). Notably, four of the six patients that achieved stable disease had progesterone-receptor positive tumors. Unexpectedly, four patients were removed from the study because of elevated liver enzymes (SCOT > 3 times the starting value) and these four patients had stable disease as their hest response. Unfortunately, this study was very disappointing, since danazol was shown to he an ineffective agent against endometrial cancer, despite the encour\aging m vitro and pre-malignant clinical results.

SELECTIVE ESTROGEN-RECEPTOR MODULATORS

Selective estrogen-reccptor modulators (SERM) are ER ligands that have hoth agonistic and antagonistic effects depending on tissue16. For example TAM is a first generation SERM that, hesides the actions on the endometrial estrogen receptor discussed above, also has antagonistic action in the breast and agonist functions in the bone and the cardiovascular system. The third generation SERM arzoxifene has shown estrogen receptor antagonism in endometrial tissues and was shown in an animal model to completely block uterine growth’17. Following preclinical studies showing strong estrogen antagonism, two phase Il trials (a trial by McMeekin et al. and a trial conducted by Eli Lilly that remains unpublished) were carried out looking at the efficacy of arzoxifene in the treatment of advanced or recurrent endometrial cancer16,18. Arzoxifene showed very promising results, with a 31% response rate in the McMcckin trial and a 25% overall response rate in the Eli Lilly trial. Although response by tumor grade data was not presented, both trials found that the progestogeii’Sensitive tumors responded to therapy better then the progestogen-resistant tumors (36% in McMeekin et al, and 34% in Eli Lilly), and McMeekin found that all of the responses occurred in progestogen -scnsitive tumors.

Eli Lilly’s trial was significant in that it found a 17.6 month overall survival, which is longer then any of the other trials presented in this review, but this difference may be due to more favorable patient prognostic factors that remain unreported. However, with a reported response duration of 19.3 months, this agent may be an effective agent for treatment and warrants further study.

GONADOTROPIN-RELEASING HORMONE AGONISTS

Gonadotropin-releasing hormone (OnRH) agonists have shown efficacy in many pre-mcnopausal disorders, such as endometriosis and uterine fihromas, due to their ability to inhibit estrogen secretion. GnRH agonists have been receiving attention as possible therapy for advanced and recurrent endometrial cancer due to the discovery of GnRH receptors in endometrial cancer tissue, GnRH’s actions on the pituitary to decrease endogenous cstrogen, and m vitro inhibition of estrogenstimulated endometrial tumor cell growth19. Three different GnRH analogues (leuprolide, triptorelin, and goserclin acetate) have been investigated in studies with very conflicting results.

Leuprolide was recently studied in two separate studies with contradictory results. A study of 32 patients by Jeyarajah et ai. found promising results with a 28% overall response rate, including a 33% response of grade 3 tumors20. However, a trial by Covens et al. demonstrated disappointing results, with all 25 patients showing no response to the treatment21. In a letter to the editor supporting the Covens et al, study, a group from the Cleveland Clinic reported that they had given the same treatment regimen to nine women with no responses22. With such a large discrepancy between studies, further study is needed to clarify the efficacy of this agent.

Triptorelin, another GnRH agonist, showed only a modest response compared to the Jeyarajah study in a trial performed by Lhommc et ai. Lhomme et al, found an 8.7% overall response rate to triptorelin, with only one of their 23 patients evaluated for efficacy having a partial response and one of the patients having a complete response23. The GnRH agonist goserelin was also examined in a GOG trial and had an 11% overall response rate, comparable to that of triptorelin24.

It is questionable how efficacious GnRH agonists truly are. While leuprolide historically showed very good results, recent data has shown it to be ineffective. Additionally, two other GnRH agonists that have been investigated showed unimpressive response rates that did not warrant further investigation. GnRH agonists are good theoretical agents as they have fairly low toxicity profiles, and are easy to administer as they are usually monthly intramuscular shots of controlled-release medication. Since the exact mechanism of GnRH agonists on endometrial cancer has yet to be elucidated, further examination of its true action upon the tumor cells may help to clarify the setting in which these agents would be optimal.

AROMATASE INHIBITORS

Aromatase is an enzyme essential for the conversion of adrenal androstenedione to estrodiol. Since estrogen stimulation furthers tumor progression and aromatase was found to be elevated in endometrial cancer stroma, it was postulated that an aromatase inhibitor could be an effective treatment of endometrial cancer. Theoretically, by blocking a step in the production of endogenous estrogen (both peripherally and within the tumor itself), continued estrogen stimulation of endometrial tissues could be halted. Since anastrazole was shown to have an improved survival compared to MA for breast cancer, a phase II trial was done to determine the efficacy of anastrazole in advanced and recurrent endometrial cancer25,26. Anastrazole, as a treatment for endometrial cancer, however, was not as promising as hoped. Of the 23 patients that took part in this trial, only two partial responses (9%) were demonstrated and the median progression-free survival and overall survival were only 1 month and 6 months, respectively. The authors also carried out a multivariate analysis adjusting for prognostic factors, and the expected response rate was still less then 15%. Since there were no patients with grade 1 tumors entered into the study, it cannot be determined if anastrazole could be an effective treatment for well-differentiated cancers. However, anastrazole’s inadequate response against poorly differentiated cancers leaves little need for continued research for high grade tumors.

CONCLUSION

Although chemotherapy has proven to have a higher response then any of the studies presented in this review, the low toxicity and easy administration associated with hormonal therapy is very appealing considering the demographics of patients with endometrial cancer. Although danazol and anastrazole proved to be ineffective, continued investigations into progestins, tamoxifen, SERMs and GnRH agonists are warranted. As the above therapies continue to be pursued and refined, there will hopefully be continued improved response rates and better understanding of the settings in which these treatments can be optimized. Additionally, as more is learned about the actions of these treatments and the targets they are affecting, better treatments and regimens can be conceived. Future research should aim to advance further development of these therapies and understand the optimal settings for these agents, as well as to determine the most optimal combinations in modulating the receptors.

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Genoa G. Ferguson and Thomas J. Herzog

Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, MO, USA

Copyright CRC Press Sep 2004