**5.1. Progesterone/progestin**

Progesterone/progestin has been proven to be an effective inhibitor (suppressor) of endome‐ trial carcinogenesis mediated through estrogen exposure [91, 92].

Many retrospective studies and clinical trials have been conducted to evaluate the role of multiple progestin-based hormonal therapy regimens in management of patients with recurrent endometrial cancer. The most commonly used regimens are megestrol acetate (MA) and medroxyprogesterone acetate (MPA).

In 1996, a meta-analysis of 6 randomized trials comprising a sum of 3339 patients with endometrial cancer failed to produce any survival benefits when adjuvant progesterone/ progestin therapy was administered [93]. Moreover, a successively reported randomized clinical trial recruiting more than 1000 patients with endometrial cancer also failed to produce any survival benefits when adjuvant progesterone/progestin therapy was administered [94]. Furthermore, in 2011, a recently published Cochrane meta-analysis demonstrated no survival benefits of adjuvant progesterone/progestin in 4556 patients with endometrial cancer [95]

#### **5.2. Selective estrogen receptor modulators (SERMs)**

The expression of ER in endometrial cancer justifies the use of selective estrogen receptor modulators (SERMS), such as tamoxifen and raloxifene [96]. The tamoxifen-induced increased risk of developing endometrial cancer is a well-known adverse effect and must always be considered in mind [97], as opposed to raloxifene that is not associated with any endometrial cancer risk.

Thigpen and partners [98] used adjuvant tamoxifen (2 doses of 20 mg/day) in management of patients with recurrent and advanced endometrial cancer. The response rate was 10%. The median progression-free survival and overall survival rates were roughly 2 and 9 months, respectively. Raloxifene produced equally unsatisfactory results.

Arzoxifene is a modified drug of raloxifene. Two phase II clinical trials by McMeekin et al. [99] and Burke et al. [100] explored the role of adjuvant arzoxifene (20 mg/day) for management of patients with recurrent, metastatic and advanced endometrial cancer. The response rates were 25% and 31%, respectively. The median response periods were approximately 19.3 and 12.9 months, respectively.

Rendina and associates [101] compared the efficacy of adjuvant tamoxifen versus MPA in patients with recurrent endometrial cancer, and response rates were roughly 53% and 56%, respectively.

Pandya et al. [102] randomized 20 patients and 42 patients with endometrial cancer to receive MA (standard progestin) and combination of MA plus tamoxifen, respectively. The response rates were 20% (1 complete and 3 partial responses) and 19% (1 complete and 7 partial responses), respectively. It was decided that the combination of MA plus tamoxifen did not yield clinical benefits over MA alone in management of patients with advanced endometrial cancer.

Whitney et al. [103] in a phase II trial of MPA (200 mg/week) plus tamoxifen (40 mg/day) in patients with advanced and recurrent endometrial cancer demonstrated a 33% response rate (13 partial and 6 complete responses among a total of 58 patients). The median progressionfree survival and overall survival were 3 month and 13 months, respectively. It was concluded that daily tamoxifen (40 mg/day) and alternating weekly MPA (200 mg/week) constitutes an effective therapeutic regimen in management of patients with recurrent and advanced endometrial cancer.

## **5.3. Gonadotropin-releasing hormone (GnRH) agonists**

Gonadotropin-releasing hormone (GnRH) agonists can effectively suppress estrogen produc‐ tion levels by ovarian cells ― a process mediated by down-regulation of GnRH receptors [87]. Multiple studies in the United Kingdom explored the usefulness of GnRH agonists in the management of patients with recurrent endometrial cancer [104, 105]. In a phase II clinical trial, 6 out of 17 patients (35%) experienced a response rate at a median of 20 months without drugrelated toxicities [104]. A long-term follow-up study, five years afterwards, the same research team documented that the response rate was 28% in 32 patients with recurrent endometrial cancer [105]. The response rate was higher in the previously irradiated regions (35%) versus non-irradiated regions (28%) of relapse. The study concluded that utilization of GnRH agonists greatly exhibit beneficial anti-cancer outcomes in patients with recurrent and advanced endometrial cancer, particularly in those patients who received previous radiation therapy.

Another GOG clinical trial explored the influence of Goserelin acetate (GnRH agonist) in 42 patients with advanced and recurrent endometrial cancer. A total of 5 patients (11%) experi‐ enced a response rate. The median progression-free survival and overall survival rates were roughly 2 and 7.3 months, respectively [106].

#### **5.4. Aromatase inhibitors (AIs)**

apy, hormonal therapy is hardly ever considered as one of the "primary" adjuvant treatment regimens in management of patients with endometrial cancer [86, 87]. Currently, hormonal therapy is largely employed for management of patients with poor performance status or recurrent/advanced/metastatic endometrial cancers, with the advantages of low morbidity,

The most frequently employed hormonal agents for management of endometrial cancer include: progesterone/progestin, selective estrogen receptor modulators (SERMs), gonadotro‐

Progesterone/progestin has been proven to be an effective inhibitor (suppressor) of endome‐

Many retrospective studies and clinical trials have been conducted to evaluate the role of multiple progestin-based hormonal therapy regimens in management of patients with recurrent endometrial cancer. The most commonly used regimens are megestrol acetate (MA)

In 1996, a meta-analysis of 6 randomized trials comprising a sum of 3339 patients with endometrial cancer failed to produce any survival benefits when adjuvant progesterone/ progestin therapy was administered [93]. Moreover, a successively reported randomized clinical trial recruiting more than 1000 patients with endometrial cancer also failed to produce any survival benefits when adjuvant progesterone/progestin therapy was administered [94]. Furthermore, in 2011, a recently published Cochrane meta-analysis demonstrated no survival benefits of adjuvant progesterone/progestin in 4556 patients with endometrial cancer [95]

The expression of ER in endometrial cancer justifies the use of selective estrogen receptor modulators (SERMS), such as tamoxifen and raloxifene [96]. The tamoxifen-induced increased risk of developing endometrial cancer is a well-known adverse effect and must always be considered in mind [97], as opposed to raloxifene that is not associated with any endometrial

Thigpen and partners [98] used adjuvant tamoxifen (2 doses of 20 mg/day) in management of patients with recurrent and advanced endometrial cancer. The response rate was 10%. The median progression-free survival and overall survival rates were roughly 2 and 9 months,

Arzoxifene is a modified drug of raloxifene. Two phase II clinical trials by McMeekin et al. [99] and Burke et al. [100] explored the role of adjuvant arzoxifene (20 mg/day) for management of patients with recurrent, metastatic and advanced endometrial cancer. The response rates were 25% and 31%, respectively. The median response periods were approximately 19.3 and

few drug-related side effects and relatively suboptimal therapeutic response [86, 87].

pin-releasing hormone (GnRH) agonists, and aromatase inhibitors [86-90].

trial carcinogenesis mediated through estrogen exposure [91, 92].

**5.1. Progesterone/progestin**

166 Contemporary Gynecologic Practice

cancer risk.

12.9 months, respectively.

and medroxyprogesterone acetate (MPA).

**5.2. Selective estrogen receptor modulators (SERMs)**

respectively. Raloxifene produced equally unsatisfactory results.

Aromatase inhibitors (AIs), such as anastrozole and letrozole, directly block the aromatase enzyme, and subsequently decrease the estrogen production and suppress its estrogen-driven neoplastic endometrial proliferation [87].

A phase II clinical trial by Rose and colleagues [107] studied the efficacy of anastrozole (1 mg a day for 28 days) in 23 patients with advanced or recurrent endometrial cancer. The response rate was 9% and progression-free interval ranged from 1 to 6 months. Despite the drug-related adverse events were well-tolerated, it was concluded that anastrozole does not offer any survival advantages.

Another multi-center phase II clinical trial by Ma and colleagues [108] studied the effect of letrozole in 28 patients with metastatic or recurrent endometrial cancer who previously received progestin-based and/or chemotherapy regimens. One patient (3.6%), two patients (7.1%) and eleven patients (39%) experienced a complete response, a partial response and a median 6.7-month stable disease, respectively. The median time to progression and overall survival were approximately 4 and 9 months, respectively. The most frequently encountered drug-related adverse events in a descending order were: hot flashes, grade I and II (28%), followed by fatigue and anemia

In short, it can be concluded that AIs greatly failed to offer survival benefits in management of patients with endometrial cancer
