A Phase II Study of Combination Therapy With Paclitaxel, Carboplatin and Megesterol Acetate for the Management of Advanced Stage or Recurrent Carcinoma of the Endometrium

Endometrial cancer is the most common gynecologic malignancy with 40,100 new cases diagnosed and 6,800 deaths attributable to this malignancy in 2003. Most patients diagnosed with endometrial cancer have early stage disease that is amenable to treatment with hysterectomy and bilateral salpingo-oophorectomy with excellent clinical outcomes. Surgical staging has improved accuracy over clinical staging for defining a low risk population of patients who have favorable long-term outcomes with surgery alone. However, approximately 15% of patients will have evidence of Stage III or IV disease at the time of initial diagnosis and 15% of surgical Stage I/II patients will have recurrent disease. Radiation therapy will be effective in patients with disease confined to the pelvis; however, patients with metastatic disease will require more systemic therapy in order to control disease.

Multiple chemotherapeutic agents including cisplatin, doxorubicin HCL, paclitaxel, carboplatin, and oral etoposide, alone and in combination, have been studied for persistent, advanced or recurrent endometrial cancer. A phase III study by the Gynecologic Oncology Group (GOG) compared doxorubicin with and without cisplatin (GOG 107) for patients with advanced or recurrent endometrial cancer. A higher response rate (45% vs. 27%) was noted for combination therapy and has been considered by many to be the standard chemotherapy regimen for treatment of patients with advanced endometrial cancer. However, clinical trials have continued to define the optimal chemotherapy regimen for this disease. Recently, the use of whole abdominal radiation therapy in the adjuvant setting for advanced endometrial cancer was demonstrated to be inferior to the combination of cisplatin and doxorubicin. The predicted 2-year survival of 70% for patients receiving the chemotherapeutic regimen was superior to patients that received radiation therapy (59%)(p<0.01).

Hormonal and cytotoxic chemotherapy agents are utilized in patients with metastatic or recurrent disease not amenable to radiation therapy. Hormonal agents have been used in this disease process since it has been demonstrated to be a hormonal responsive tumor. Notably, a correlation between histologic grade and the presence or absence of hormonal receptors has been noted, with well differentiated tumors more likely to express hormone receptors than those with poor histology. Furthermore, the presence of estrogen receptors (ER) and progesterone receptors (PR) varies with tumor histology. ER has been reported to be present between 70% and 87% of endometrioid adenocarcinoma and 0 and 24% in UPSC; while, PR has ranged from 67% to 91% in endometrioid tumors and 0 and 19% in UPSC.

Various progestins have been investigated including Megace (megesterol acetate) and Provera (medroxyprogesterone acetate) for the treatment of endometrial cancer. These agents are generally well tolerated and have been reported to have response rates of 15-30% with long-term complete responses not uncommonly experienced. Furthermore, median survival in patients treated with progestins ranges from 9 to 20 months.

As paclitaxel has been noted to be active in ovarian cancer and other malignancies, it seems reasonable to evaluate its utility for endometrial cancer. Accordingly, single agent paclitaxel was administered to 30 chemotherapy naïve patients with advanced or recurrent endometrial cancer. The overall response rate was 36% when patients received a 24-hour infusion of paclitaxel. Furthermore, paclitaxel given as a 3-hour infusion demonstrated a response between 27 to 37% in patients that had failed prior chemotherapy.