Of all the gynecologic malignancies, the management of endometrial cancer has undergone the most dramatic shift in recent years. There has been an introduction and acceptance of minimally invasive surgical techniques, more common use of surgical staging with pelvic and para-aortic lymphadenectomy, and greater consideration to remove or debulk i.p. metastases (akin to ovarian cancer debulking surgery). A better understanding of uterine factors, including tumor grade, depth of invasion, lymph vascular space invasion, and cervical involvement, and how surgical staging can define risk strata have altered the use of adjuvant therapy. Today, there is less use of pelvic radiation therapy, and when radiation is used a substitution to vaginal cuff brachytherapy is more common. Most dramatic has been the introduction of chemotherapy into the first-line management of patients with high-risk disease. Chemotherapy was traditionally reserved to treat incurable patients with disseminated or recurrent endometrial cancer, often after the failure of hormonal therapy.
Phase II trials have identified doxorubicin, paclitaxel, and the platinum agents cisplatin and carboplatin as the most active agents in patients with persistent or recurrent disease () [12
]. Two studies demonstrated a higher response rate (RR) with the combination of cisplatin and doxorubicin, albeit with a lesser effect on progression-free survival (PFS) and overall survival (OS) than with single-agent doxorubicin. The Gynecologic Oncology Group (GOG) study 107 showed a doubling of the complete RR (19% versus 8%) and a longer PFS interval (median, 5.7 months versus 3.8 months; hazard ratio [HR], 0.736; confidence interval [CI], 0.577–0.939; p
= .014) with the combination [13
]. The European Organization for Research and Treatment of Cancer similarly showed a higher RR (43% versus 17%) and modestly better survival favoring the combination [14
]. As a result of these studies, the doublet regimen became a standard for advancement in many future phase III studies.
Response rate to single-agent chemotherapy in chemotherapy-naïve endometrial carcinoma patients
Paclitaxel as a single agent has been evaluated in advanced/recurrent disease patients, showing RRs of 37% (no prior therapy) and 25% (one prior chemotherapy, 40 of 44 patients treated with doxorubicin–platinum chemotherapy), making this agent the most active reported in phase II studies [15
]. The GOG subsequently compared doxorubicin–cisplatin with doxorubicin–paclitaxel, and demonstrated nearly identical RRs, PFS intervals, and OS times in patients with advanced/recurrent disease [17
]. In the GOG 177 study, a phase III trial comparing doxorubicin–cisplatin alone with doxorubicin–cisplatin plus paclitaxel, for the first time, a significantly greater RR (57% versus 34%), PFS interval (median, 8.3 months versus 5.3 months), and OS time (median, 15.3 months versus 12.3 months) with combination chemotherapy using the three-drug paclitaxel–doxorubicin–cisplatin (TAP) regimen were observed [18
]. Despite the superior outcomes noted with the three-drug TAP regimen, neurotoxicity and a 3-day schedule have limited enthusiasm for its use. The GOG recently completed a ~1,300 patient trial (GOG 209) comparing TAP with paclitaxel–carboplatin in patients with advanced/recurrent measurable disease or those with advanced disease treated in an adjuvant setting. The results of the GOG 209 trial, which completed enrollment in April 2009, are maturing.
In all, the GOG has published four phase III trials in patients with advanced/recurrent disease including >1,200 patients. RRs of 25%–57%, with the best complete RR of only 22%, were reported [19
]. The population of patients with advanced or recurrent, measurable disease included in those trials was relatively heterogeneous and included patients with stage III, stage IV, and recurrent disease and all tumor grades and histologic types, and 55% had received prior radiation therapy. Factors independently associated with longer survival included white/Hispanic race, better performance status, stage III disease, no prior radiation therapy, and endometrioid tumor histology [17