Uterine sarcomas are rare, high-risk malignancies. Expert histologic review is important for accurate diagnosis. For high-grade leiomyosarcomas, the risk of recurrence is high after complete resection of uterus-limited disease; however, no adjuvant therapy has been proven to improve survival. Chemotherapy regimens with efficacy in treating advanced uterine leiomyosarcoma include gemcitabine-docetaxel, doxorubicin and ifosfamide. Uterine carcinosarcomas also carry a high risk of recurrence. Adjuvant chemotherapy is a standard approach for completely resected and metastatic carcinosarcoma. Active agents include carboplatin, cisplatin, ifosfamide and paclitaxel.
Introduction
Uterine sarcomas are a rare, heterogenous group of neoplasms. They vary in histologic appearance, risk of recurrence, and sensitivity to chemotherapy. Expert histologic review and management by clinicians experienced in the care of sarcomas is recommended. Uterine sarcomas may be classified as leiomyosarcomas, carcinosarcomas, endometrial stromal sarcomas, adenosarcomas, and high-grade undifferentiated sarcomas. Carcinosarcoma is considered by some to be a high-risk, de-differentiated variant of endometrial adenocarcinoma.
Uterine leiomyosarcoma
Chemotherapy for advanced, metastatic leiomyosarcoma
Important clinical studies aimed at identifying active agents in uterine leiomyosarcoma are presented in Table 1 . Doxorubicin has been a standard first-line treatment for advanced soft-tissue sarcoma. In a phase III trial that included women with uterine leiomyosarcoma, carcinosarcoma or other sarcoma, doxorubicin 60 mg/m 2 was compared with doxorubicin plus the addition of dimethyl triazenoimidazole carboxamide, achieving objective response in 16% of all women enrolled, with response of 25% among those with uterine leiomyosarcoma. The addition of dimethyl triazenoimidazole carboxamide did not significantly improve response rates. In a separate phase III trial, the addition of cyclophosphamide to doxorubicin did not improve outcomes among 104 evaluable women with uterine leiomyosarcoma, carcinosarcoma or other uterine sarcoma. Ifosfamide has single-agent activity, with a response rate of 17.2% (6 out of 35 women treated in a phase II trial). The combination of doxorubicin plus ifosfamide achieved objective response in 30% of women with uterine leiomyosarcoma. The incidence of grade 3 or 4 neutropaenia was 48%, and one woman died of sepsis.
| Reference | Agent | Trial design and population | Number of prior regimens | Response rate |
|---|---|---|---|---|
| Omura et al., 1983 | Doxorubicin 60 mg/m 2 with or without DTIC | Phase III, stage III and intravenous uterine sarcomas | 0 | Doxorubicin 13/80 (16.3%) Doxorubicinplus DTIC 16/66 (24.2%) P > 0.05 Doxorubicin response 7/28 (25%) of women with measurable uterine leiomyosarcoma |
| Muss et al., 1985 | Doxorubicin 60 mg/m 2 with or without cyclophosphamide 500 mg/m 2 | Phase III, advanced or recurrent uterine sarcoma (leiomyosarcoma or carcinosarcoma) | 0 | Doxorubicin 5/26 (19%) Doxorubicin plus cyclophosphamide 5/26 (19%) |
| Sutton et al., 1992 | Ifosfamide 1500 mg/m 2 × 5 days (1200 mg/m 2 if prior pelvic radiation) | Phase II | 0 | 6/35 (17%) |
| Sutton et al., 1996 | Ifosfamide 5 g/m 2 plus doxorubicin 50 mg/m 2 | Phase II, uterine leiomyosarcoma, 33 evaluable women | 0 | 10/33 (30.3%) |
| Look et al., 2004 | Gemcitabine 1000 mg/m 2 days 1, 8, 15 | Phase II, uterine leiomyosarcoma | 0–1 | 9/42 (20%) |
| Hensley et al., 2002 | Gemcitabine 900 mg/m 2 over 90 min days 1 and 8 plus docetaxel 100 mg/m 2 day 8 (25% lower doses if prior pelvic radiation) | Phase II uterine leiomyosarcoma, or non-uterine leiomyosarcoma | 0–2 | 18/34 (53%) |
| Hensley, 2008 | Gemcitabine 900 mg/m 2 over 90 min days 1 and 8 plus docetaxel 100 mg/m 2 day 8 | Phase II, uterine leiomyosarcoma | 0 | 15/42 (36%) |
| Hensley, 2008 | Gemcitabine 900 mg/m 2 over 90 min days 1 and 8 plus docetaxel 100 mg/m 2 day 8 | Phase II, uterine leiomyosarcoma | 1 | 13/48 (27%) |
| McMeekin, 2007 | Thalidomide 200–1000 mg daily | Phase II, uterine leiomyosarcoma | 1 | 0/29 (0%) |
| Muss, 1990 | Mitoxantrone 12 mg/m 2 | Phase II, uterine sarcomas | 0–1 | 0/12 (0%) |
| Sutton, 2005 | Liposomal doxorubicin 50 mg/m 2 | Phase II, uterine leiomyosarcoma | 0 | 5/32 (16%) |
| Gallup, 2003 | Paclitaxel 175 mg/m 2 (135 mg/m 2 for women who have undergone prior pelvic radiation | Phase II, uterine leiomyosarcoma | 0–1 | 4/48 (8%) |
| Sutton, 1999 | Paclitaxel 175 mg/m 2 | Phase II, uterine leiomyosarcoma | 0 | 3/33 (9%) |
| Thigpen, 1991 | Cisplatin 50 mg/m 2 | Phase II, uterine sarcomas | 0 | 1/33 (3%) |
| Thigpen, 1985 | Piperazinedione 50 mg/m 2 | Phase II, uterine sarcomas | 1 | 1/19 (5%) |
| Thigpen, 1996 | Etoposide intravenous 100 mg/m 2 | Phase II, uterine leiomyosarcoma | 0 | 0/28 (0%) |
| Rose, 1998 | Etoposide oral 50–60 mg/m 2 | Phase II, uterine leiomyosarcoma | 1 | 2/29 (7%) |
| Miller, 2000 | Topotecan 1.5 mg/m 2 daily for 5 days | Phase II, uterine leiomyosarcoma | 0 | 4/36 (11%) |
| Smith, 2002 | Trimetrexate 5 mg/m 2 daily for 5 days, every 14 days | Phase II, uterine leiomyosarcoma | 0–1 | 1/23 (4%) |
| Garcia-Carbonera, 2005 | Trabectedin 1.5 mg/m 2 intravenous over 24 h | Phase II, soft–tissue sarcoma | 0 | 6/35 (17%) |
| Ferriss, 2010 | Temozolomide, oral, various doses and schedules | Small retrospective study; one prospective | Variable; zero to three prior regimens in the prospective study | 2/6 (33%) |
| Anderson and Aghajanian, 2005 | 2/12 (16%) | |||
| Boyar, 2005 | 1/23 (4%) | |||
Gemcitabine was studied in a phase II trial of women with metastatic uterine leiomyosarcoma who had received zero to one prior chemotherapy regimens, and achieved objective response in 20%, with median duration of response being 4.8 months. Gemcitabine, delivered as a fixed dose-rate infusion, in combination with docetaxel, achieved objective response in 53% of women with leiomyosarcoma of uterine or non-uterine primary who previously underwent zero to two prior cytotoxic regimens. In two subsequent multi-institution, phase II studies for women with uterine leiomyosarcoma, this regimen achieved objective response in 36% of women who had not undergone prior chemotherapy, and in 27% of women who had undergone one prior chemotherapy treatment.
The Gynecologic Oncology Group has conducted several other phase II trials in uterine leiomyosarcoma to identify active agents. With the exceptions detailed above, the response rates have failed to exceed 10%. Inactive agents include thalidomide, cisplatin, piperazinedione, paclitaxel, etoposide, oral etoposide, trimetrexate, topotecan, and mitoxantrone. Liposomal doxorubicin, a formulation of doxorubicin with less risk for cardiotoxicity or alopecia, but with moderate risk for skin toxicity, was tested in a prospective phase II trial for uterine leiomyosarcoma, and achieved a 16% response among women who had no undergone prior chemotherapy treatment. Although this response rate is lower that what would be expected with doxorubicin, liposomal doxorubicin may be a treatment option for certain women with co-morbidities that preclude the use of doxorubicin.
Experience with cytotoxic agents tested in soft-tissue sarcoma trials may inform treatment options for women with uterine leiomyosarcoma. Docetaxel was compared with doxorubicin in a randomised phase II trial for advanced soft-tissue sarcoma. Doxorubicin achieved objective response in 30% of women, whereas women treated with docetaxel achieved no response. Trabectedin is approved for the treatment of soft-tissue sarcomas in Europe, based on objective response rates ranging from 4–17% in a number of phase II trials. In a study comparing two different doses and schedules of trabectedin for advanced liposarcoma or leiomyosarcoma in women who had received zero to two prior regimens, the objective response rate was 5.6% among women with the 24-h infusion schedule, and 1.6% among women with the weekly schedule. In contrast, a retrospective study of 56 women with uterine leiomyosarcoma who had received prior anthracycline treatment reported a response rate of 20% to treatment with trabectedin. Results of a prospective phase II study of trabectedin using the 24-h infusion schedule in women with uterine leiomyosarcoma and no prior treatment are awaited.
Temozolomide has been reported to have activity in soft-tissue sarcomas in small, retrospective studies. In one study, two responses were reported among six women, and two responses were reported among 12 women in another. In a prospective study, temozolomide was combined with thalidomide for advanced leiomyosarcoma, and responses were observed in one out of 23 women (4%).
Biomolecular treatments for uterine leiomyosarcoma
Trials investigating biomolecular treatments for uterine leiomyosarcoma are presented in Table 2 . In a phase I/II study, bevacizumab was added to gemcitabine and docetaxel for women with advanced soft-tissue sarcoma who had not undergone prior treatment. Responses were observed in 11 out of 25 women. Important toxicities included bowel perforation, pneumothorax, fatigue, wound dehiscence and haemorrhage. The Gynecologic Oncology Group is conducting a phase III placebo-controlled trial to determine whether the addition of bevacizumab to fixed-dose rate gemcitabine plus docetaxel improves response rates or progression-free survival in advanced uterine leiomyosarcoma.
| Reference | Agent | Trial design and population | Number of prior regimens | Response rate |
|---|---|---|---|---|
| Verschraegen et al., 2008 | Gemcitabine plus docetaxel plus bevacizumab, every 2 weeks | Phase I/II soft-tissue sarcoma | 0 | 11/25 (44%) |
| Hensley et al., 2009 | Sunitinib 50 mg daily, 4 weeks out of 6 | Phase II, uterine leiomyosarcoma | 1–2 | 2/23 (8.7%) 4/23 (17%) progression-free at 6 months |
| D’Adamo et al., 2005 | Doxorubicin 75 mg/m 2 plus bevacizumab 15 mg/kg | Phase II soft-tissue sarcoma; 11 out of 17 women had leiomyosarcoma; 7 out of 11 women had uterine leiomyosarcoma | 0–1 prior, non-anthracycline regimen | 2/17 (12%) |
| Maki et al., 2009 | Sorafenib 400 mg twice daily | Phase II soft-tissue sarcoma with histology-specific cohorts | 0–1 | 1/37 (2.7%) women in leiomyosarcoma cohort |
| Sleijfer et al., 2009 | Pazopanib 800 mg daily | Phase II soft-tissue sarcoma, histology-specific cohorts | 0–2 | 1/41 (2.4%) women in leiomyosarcoma cohort |
| O’Cearbhaill et al., 2010 | Aromatase inhibitors (letrozole or anastrozole or exemestane) | Retrospective, uterine leiomyosarcoma, small volume metastases, mostly hormone–receptor positive | Variable | 3/34 (9%) women with measurable disease. All three responses were among the women who were oestrogen–receptor positive |
Bevacizumab was added to doxorubicin for the treatment of advanced soft-tissue sarcoma (11 out of the 17 women had leiomyosarcoma) who had received zero to one prior regimens and had not previously taken anthracycline. Objective response was observed in only two out of 17 women (12%), which is lower than would be expected for response to doxorubicin in this population. Cardiac toxicity was observed in six women.
Multikinase inhibitors that affect the vascular endothelial growth factor pathway have also been investigated. Sunitinib was studied in a phase II trial designed with a dual end point of either objective response or stable disease at 6 months. Sunitinib failed to meet either criterion for activity: objective response was observed in 8.7%, and only four women (17%) remained progression-free at 6 months. Sorafenib was studied in a phase II trial for soft-tissue sarcomas who had received zero to one prior treatment regimens. Among the 37 women in the leiomyosarcoma cohort, objective response was observed in one woman (2.7%). Pazopanib was studied in a phase II study for women with soft-tissue sarcoma who had received zero to two prior regimens. Forty-one women with leiomyosarcoma were evaluated, and response was observed in one woman (2.4%).
Oestrogen receptors and progesterone receptors have been reported to be expressed in 7–71% of uterine leiomyosarcomas providing a rationale for testing aromatase inhibition in these tumours. Case reports have suggested activity. In one retrospective study, 9% of women had objective response, although women in the study had generally been selected for treatment because of small-volume and relatively indolent disease; thus, the outcomes observed cannot be definitively attributed to the aromatase inhibition treatment.
Chemotherapy for adjuvant treatment of completely resected leiomyosarcoma
Although most uterine leiomyosarcomas are limited to the uterus at the time of diagnosis, the risk for disease recurrence is estimated at 50–70%. No prospective, randomised trial has shown a survival benefit to adjuvant therapy. Although retrospective studies have suggested that adjuvant pelvic radiation might improve local control, a randomised phase III trial of adjuvant pelvic radiation compared with observation for women with early stage uterine sarcoma did not show improvement in local control or survival with pelvic radiation among women with leiomyosarcoma.
The Gynecologic Oncology Group conducted a randomised phase III trial of doxorubicin compared with observation for women with uterine leiomyosarcoma or carcinosarcoma. Adjuvant pelvic radiation was permitted at the clinician’s discretion. In the subgroup of women with leiomyosarcoma, recurrences were seen in 44% of women assigned to doxorubicin treatment and in 61% of women assigned to observation (not statistically significant in this small sample). A retrospective, case-control study evaluated recurrence rates among 18 women with uterine sarcoma (13 leiomyosarcomas) who had been treated with adjuvant doxorubicin, cisplatin and pelvic radiation, comparing recurrence rates with those women matched for age and histology who had received only pelvic radiation. The chemotherapy-radiation group had a recurrence rate of 38%, compared with 72% among women who had only radiation.
In a small prospective study women with completely resected stage I, II, III or IV uterine leiomyosarcoma were enrolled. All women were treated with four cycles of adjuvant fixed-dose rate gemcitabine plus docetaxel. Among all women, 45% remained disease-free at 2 years. Among the 18 women with uterus-limited disease, 59% were progression-free at 2 years. Median progression-free survival exceeded 3 years. Because of the efficacy of doxorubicin in advanced leiomyosarcoma, the subsequent study was designed to offer all women four cycles of fixed-dose rate gemcitabine plus docetaxel, followed by four cycles of doxorubicin. Forty-seven women with uterus-limited disease were enrolled. With median follow-up of 27.4 months, 78% of women remained progression-free at 2 years, and median progression-free survival was 39.3 months.
The standard approach to managing completely resected, uterus-limited leiomyosarcoma remains observation. A phase III randomised trial comparing adjuvant chemotherapy to a no-chemotherapy control group is needed.
Uterine leiomyosarcoma
Chemotherapy for advanced, metastatic leiomyosarcoma
Important clinical studies aimed at identifying active agents in uterine leiomyosarcoma are presented in Table 1 . Doxorubicin has been a standard first-line treatment for advanced soft-tissue sarcoma. In a phase III trial that included women with uterine leiomyosarcoma, carcinosarcoma or other sarcoma, doxorubicin 60 mg/m 2 was compared with doxorubicin plus the addition of dimethyl triazenoimidazole carboxamide, achieving objective response in 16% of all women enrolled, with response of 25% among those with uterine leiomyosarcoma. The addition of dimethyl triazenoimidazole carboxamide did not significantly improve response rates. In a separate phase III trial, the addition of cyclophosphamide to doxorubicin did not improve outcomes among 104 evaluable women with uterine leiomyosarcoma, carcinosarcoma or other uterine sarcoma. Ifosfamide has single-agent activity, with a response rate of 17.2% (6 out of 35 women treated in a phase II trial). The combination of doxorubicin plus ifosfamide achieved objective response in 30% of women with uterine leiomyosarcoma. The incidence of grade 3 or 4 neutropaenia was 48%, and one woman died of sepsis.
| Reference | Agent | Trial design and population | Number of prior regimens | Response rate |
|---|---|---|---|---|
| Omura et al., 1983 | Doxorubicin 60 mg/m 2 with or without DTIC | Phase III, stage III and intravenous uterine sarcomas | 0 | Doxorubicin 13/80 (16.3%) Doxorubicinplus DTIC 16/66 (24.2%) P > 0.05 Doxorubicin response 7/28 (25%) of women with measurable uterine leiomyosarcoma |
| Muss et al., 1985 | Doxorubicin 60 mg/m 2 with or without cyclophosphamide 500 mg/m 2 | Phase III, advanced or recurrent uterine sarcoma (leiomyosarcoma or carcinosarcoma) | 0 | Doxorubicin 5/26 (19%) Doxorubicin plus cyclophosphamide 5/26 (19%) |
| Sutton et al., 1992 | Ifosfamide 1500 mg/m 2 × 5 days (1200 mg/m 2 if prior pelvic radiation) | Phase II | 0 | 6/35 (17%) |
| Sutton et al., 1996 | Ifosfamide 5 g/m 2 plus doxorubicin 50 mg/m 2 | Phase II, uterine leiomyosarcoma, 33 evaluable women | 0 | 10/33 (30.3%) |
| Look et al., 2004 | Gemcitabine 1000 mg/m 2 days 1, 8, 15 | Phase II, uterine leiomyosarcoma | 0–1 | 9/42 (20%) |
| Hensley et al., 2002 | Gemcitabine 900 mg/m 2 over 90 min days 1 and 8 plus docetaxel 100 mg/m 2 day 8 (25% lower doses if prior pelvic radiation) | Phase II uterine leiomyosarcoma, or non-uterine leiomyosarcoma | 0–2 | 18/34 (53%) |
| Hensley, 2008 | Gemcitabine 900 mg/m 2 over 90 min days 1 and 8 plus docetaxel 100 mg/m 2 day 8 | Phase II, uterine leiomyosarcoma | 0 | 15/42 (36%) |
| Hensley, 2008 | Gemcitabine 900 mg/m 2 over 90 min days 1 and 8 plus docetaxel 100 mg/m 2 day 8 | Phase II, uterine leiomyosarcoma | 1 | 13/48 (27%) |
| McMeekin, 2007 | Thalidomide 200–1000 mg daily | Phase II, uterine leiomyosarcoma | 1 | 0/29 (0%) |
| Muss, 1990 | Mitoxantrone 12 mg/m 2 | Phase II, uterine sarcomas | 0–1 | 0/12 (0%) |
| Sutton, 2005 | Liposomal doxorubicin 50 mg/m 2 | Phase II, uterine leiomyosarcoma | 0 | 5/32 (16%) |
| Gallup, 2003 | Paclitaxel 175 mg/m 2 (135 mg/m 2 for women who have undergone prior pelvic radiation | Phase II, uterine leiomyosarcoma | 0–1 | 4/48 (8%) |
| Sutton, 1999 | Paclitaxel 175 mg/m 2 | Phase II, uterine leiomyosarcoma | 0 | 3/33 (9%) |
| Thigpen, 1991 | Cisplatin 50 mg/m 2 | Phase II, uterine sarcomas | 0 | 1/33 (3%) |
| Thigpen, 1985 | Piperazinedione 50 mg/m 2 | Phase II, uterine sarcomas | 1 | 1/19 (5%) |
| Thigpen, 1996 | Etoposide intravenous 100 mg/m 2 | Phase II, uterine leiomyosarcoma | 0 | 0/28 (0%) |
| Rose, 1998 | Etoposide oral 50–60 mg/m 2 | Phase II, uterine leiomyosarcoma | 1 | 2/29 (7%) |
| Miller, 2000 | Topotecan 1.5 mg/m 2 daily for 5 days | Phase II, uterine leiomyosarcoma | 0 | 4/36 (11%) |
| Smith, 2002 | Trimetrexate 5 mg/m 2 daily for 5 days, every 14 days | Phase II, uterine leiomyosarcoma | 0–1 | 1/23 (4%) |
| Garcia-Carbonera, 2005 | Trabectedin 1.5 mg/m 2 intravenous over 24 h | Phase II, soft–tissue sarcoma | 0 | 6/35 (17%) |
| Ferriss, 2010 | Temozolomide, oral, various doses and schedules | Small retrospective study; one prospective | Variable; zero to three prior regimens in the prospective study | 2/6 (33%) |
| Anderson and Aghajanian, 2005 | 2/12 (16%) | |||
| Boyar, 2005 | 1/23 (4%) | |||
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