For advanced/metastatic LMS, doxorubicin, ifosfamide, gemcitabine, trabectedin, and docetaxel have shown activity. Landmark studies addressing the role of chemotherapy in uterine sarcoma are summarized in Table 33.3.

Single-agent doxorubicin was compared with a combination of doxorubicin and DTIC in a phase III trial in patients with various sarcomas including uterine LMS and carcinosarcoma. The overall response rate of 25 % was achieved in patients of uterine LMS treated with doxorubicin, and there was no further improvement with the addition of DTIC [17]. In another phase III trial, the addition of cyclophosphamide to doxorubicin did not improve outcomes in 104 women with uterine sarcomas [18]. Ifosfamide has shown single-agent activity in phase II trial, with a response rate of 6/32 (17.2 %) [19], while in combination with doxorubicin, an objective response of 30 % in LMS was achieved [20]. Liposomal doxorubicin, in a prospective phase II trial, achieved a 16 % response in first-line setting [21]. Gemcitabine studied in a second-line setting in a phase II trial achieved objective response in 20 % of women [22]. Gemcitabine, delivered as a fixed dose rate infusion, in combination with docetaxel, achieved objective response in 53 % of heavily pretreated women of LMS with uterine and non-uterine primary. However, the combination was found to be more toxic than doxorubicin alone [23]. In two other phase II studies, objective response of 36 % was seen in women on first-line therapy with this combination [24], while response was 27 % in women on second-line treatment [14].

Trabectedin is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata; it has covalent interaction with the minor groove of the DNA double helix and with adjacent nuclear proteins. The compound’s chemical interactions trigger a cascade of events that interfere with several transcription factors, DNA-binding proteins, and DNA repair pathways. Trabectedin also causes modulation of the production of cytokines and chemokines by tumor and normal cells, suggesting that the antitumor activity could also be attributed to changes in the tumor microenvironment. Trabectedin has been approved for soft-tissue sarcomas in Europe, based on objective response rates ranging from 4 % to 17 % in phase II trials. Another retrospective analysis of 56 women with uterine LMS reported a response rate of 20 %. In a study of trabectedin for advanced liposarcoma or LMS, the objective response rate was 5.6 % with the 24-h infusion schedule and 1.6 % with the weekly schedule. However, to date, there is insufficient evidence to support or refute the use of trabectedin in these patients [25–30].

The risk of disease recurrence is about 50–70 % even in completely resected patients [31, 32]. No prospective, randomized trial has shown a survival benefit from adjuvant therapy. The standard approach in completely resected, uterus-limited LMS is only observation. The current evidence for adjuvant therapy in surgically resected LMS is weak and is summarized in Table 33.4. A randomized phase III trial comparing doxorubicin with observation in women with uterine LMS or carcinosarcoma was conducted by the GOG [33]. In the subgroup of LMS, recurrence rate was 44 % with doxorubicin and 61 % with observation alone. Another retrospective analysis of 18 women with uterine sarcomas compared adjuvant doxorubicin, cisplatin, and pelvic radiation, with pelvic radiation alone [34]. The chemotherapy-radiation group had a recurrence rate of 38 %, with 72 % among women who had only radiation. Another prospective study in women with completely resected uterine LMS of all stages was conducted. They were treated with four cycles of adjuvant fixed dose rate gemcitabine plus docetaxel, and the median progression-free survival (PFS) exceeded 3 years, and 59 % were progression-free at 2 years. In another study in a group of 47 women, treated with four cycles of fixed dose rate gemcitabine plus docetaxel, followed by four cycles of doxorubicin, 78 % of women remained progression-free at 2 years, and median PFS was 39.3 months [35].

The potential targets that have been identified for therapy in LMS and in ESS are summarized in Table 33.5. Targeted agents of estrogen and progesterone receptors (ER and PR) like medroxyprogesterone, aromatase inhibitors (AI), and mifepristone are successful for treating patients with uterine LMS with indolent growth as studies have revealed ER/PR positivity of up to 18–80 % in various series. The studies are summarized in Table 33.5.