Updates in chemotherapy in the treatment of advanced and recurrent endometrial cancer

There are several explanations for the slow development of use of chemotherapy in endometrial cancer. The historical use of radiation therapy, the activity and tolerability of progestins in patients with advanced or recurrent disease, and the perception that many patients with endometrial cancer are just too old or too sick to tolerate cytotoxic chemotherapy led to minimal enthusiasm. With nearly 7000 deaths estimated for 2004 from advanced or recurrent endometrial cancer, the identification of active agents and combination regimens, and data now showing superiority of chemotherapy to radiation therapy in some patients with advanced disease, chemotherapy is moving to the forefront in management of endometrial cancer. Phase II studies have identified several active agents including adriamycin, cisplatin, carboplatin, and paclitaxel. Several phase II and III trials have been subsequently performed showing that combination regimens, in general, produce improved response rates with limited improvements in progression-free survival (PFS) and survival as compared to single drug regimens in patients with advanced/recurrent disease. The GOG has conducted phase III trials comparing adriamycin (A) to adriamycin/cisplatin (AC) (GOG 107), AC to adriamycin/paclitaxel (AT) (GOG 163), and AC to paclitaxel/adriamycin/cisplatin (TAP) (GOG 177). The most recent trial, GOG 177 showed that the three drug TAP regimen produced significantly longer PFS (8.5 vs. 5.3 months) and survival (15.3 vs. 12.3 months) compared to AC(1). The three drug regimen required 2 days to deliver and the use of filgrastim. Toxicity was also more common with 30% of patients treated with TAP experiencing grade 2–3 neuropathy. Because of the convenience and toxicity profile, many have begun to use paclitaxel and carboplatin (TC) as the preferred regimen for patients with advanced or recurrent disease. As a single agent, paclitaxel has demonstrated impressive activity. Only a limited number of patients have been treated with TC in phase II series (~200), and only one small randomized phase II study compared TC to adriamycin and cisplatin(2). The combination of TC was feasible and active in these small series. It is noteworthy, that in the randomized phase III trial (GOG 163) comparing AC to AT, response, PFS, and survival were essentially the same. The GOG is currently conducting a randomized phase III trial comparing TAP to TC. The trial is a noninferiority study that will require 900 patients. Traditionally chemotherapy has been reserved for patients with advanced or recurrent disease thought to be incurable with surgery and radiation. More recently chemotherapy has been studied in upfront therapy in patients with previously untreated stage III/IV disease in phase II–III studies. Results from GOG trial 122, which compared whole abdominal radiation therapy (WAR) to AC have been presented in abstract form(3). With a median follow-up of 52 months, 24 months PFS (50% AC versus 46% WAR) and survival (70% AC vs. 59% WAR) were significantly longer with chemotherapy. Data also suggested that AC was more toxic despite having better DFS/OS, and overall 55% of these high-risk patients recurred or progressed. Perhaps the best way to treat patients with advanced disease is by a combination of chemotherapy with radiation. The GOG has conducted a phase III trial comparing volume directed radiation (pelvic ± extended field) followed by AC versus TAP to evaluate this strategy. Phase I studies of high-risk patients are being conducted through the GOG using WAR with concurrent weekly paclitaxel/cisplatin, and sequential AC followed by WAR. Which agents to combine with radiation and in what sequence (chemotherapy 1st, 2nd, sandwiched, or concurrent with radiation) remains to be defined. The role of chemotherapy for patients with endometrial cancer will continue to evolve. Future studies will need to compare chemotherapy to combination chemotherapy with radiation. Chemotherapy in patients with high-risk early stage will also need to be reassessed in a well-designed study. Finally, as specific molecular targets are identified, and genetic profiles classified, a more refined use of biologic agents combined with chemotherapy will need to be evaluated.