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. 2014 Jan;6(1):21–28. doi: 10.1177/1758834013513314

Current and future options in the management and treatment of uterine sarcoma

Khalid El-Khalfaoui 1,✉, Andreas du Bois 2, Florian Heitz 3, Christian Kurzeder 4, Jalid Sehouli 5, Philipp Harter 6
PMCID: PMC3866995  PMID: 24381658

Abstract

Uterine sarcomas are rare aggressive mesenchymal tumours with limited prognosis. They encompass various histological subtypes such leiomyosarcoma, endometrial stromal sarcoma and undifferentiated sarcomas with different surgical and medical strategies. Current evidence of surgery, adjuvant and palliative therapy is reported.

Keywords: chemotherapy, endometrial stromal sarcoma, surgery, uterine leiomyosarcoma, uterine sarcoma

Introduction

Uterine sarcomas are uncommon aggressive mesenchymal tumours, which comprise only about 3% of all uterine malignancies [D’Angelo and Prat, 2010]. The incidence of uterine sarcomas varies between 0.5 and 3.3 cases per 100,000 women per year [Harlow et al. 1986]. Uterine sarcomas include different histological entities. The most frequent type is leiomyosarcoma (LMS) in about 60% of cases, followed by endometrial stromal tumours (ESS), undifferentiated uterine sarcomas (UUS), and pure heterologous sarcomas. Mixed epithelial and mesenchymal tumours are adenosarcoma (with and without sarcomatous component) and carcinosarcoma (mixed mullerian tumours). Carcinosarcoma are of epithelial origin, as shown by in vitro data, immunohistochemical and molecular studies [Amant et al. 2005]. Therefore, uterine carcinosarcoma are counted as undifferentiated epithelial uterine carcinoma and should not be classified into the sarcoma group.

In this paper we therefore focus on mesenchymal uterine tumours like LMS, endometrial stromal sarcoma and undifferentiated stromal sarcoma.

Uterine LMS

LMS represents the most common uterine sarcoma. It accounts for about 1% of all uterine malignancies [Amant et al. 2005]. The incidence of LMS in series of hysterectomies performed for presumed uterine leiomyomas is approximately 0.1–0.3% [Leibsohn et al. 1990]. In most cases firm diagnosis cannot be made preoperatively. Most women with LMS lack symptoms or present with a rapidly enlarging pelvic mass [Ramondetta, 2006; Zivanovic et al. 2009; Vrzic-Petronijevic et al. 2006].

Some 60% of women with LMS present with a disease limited to the uterus at first diagnosis [Major et al. 1993]. Cure rates of these patients range from 20 to 60% depending on the success of the primary resection [Ramondetta, 2006; Gadducci A et al. 2008]. Relapse rate is approximately 70% for stage I and II. The site of metastasis or recurrence is often distant due to haematogenous spread into the lungs or liver [Ramondetta, 2006; Major et al. 1993]. Therefore, complete radiologic staging at first diagnosis and at relapse including computerized tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen and pelvis is mandatory. Although several prognostic factors in addition to tumour stage have been examined, results are inconclusive and play only a limited role for treatment decision [Ramondetta, 2006; Major et al. 1993; Akhan et al. 2005; Gadducci et al. 2008].

Surgical treatment

The cornerstone of the treatment in LMS is surgery. The resection of the localized disease by hysterectomy is regarded as gold standard. Total abdominal hysterectomy and bilateral salpingo-oophorectomy is considered to be the standard surgical treatment [Vrzic-Petronijevic et al. 2006; Ramondetta L et al. 2006; Gadducci A et al. 2008, Zivanovic et al. 2009]. Pelvic and para-aortic lymphadenectomy is not routinely indicated. The incidence of lymphatic spread is only about 3% in early stage uterine LMS [Gadducci et al. 2008; Vrzic-Petronijevic et al. 2006; Giuntoli et al. 2003; Leitao et al. 2003]. However, lymph-node involvement is often present in advanced disease. Ovarian preservation can be considered in premenopausal patients with early stage LMS of the uterus [Gadducci A et al. 1996a]. Many LMS are diagnosed after surgical intervention of presumed leiomyoma or hysterectomy. Morcellation of the tumour or uterus in total, for example, during laparoscopic assisted supracervical hysterectomy increases the rate of the abdominopelvic dissemination causing an iatrogenic advanced stage disease. This translates to a worse progression-free survival (PFS) and overall survival (OS). Thus, before performing surgery with morcellation, women have to be informed in detail about the possibility of tumour dissemination and prognosis deterioration via iatrogenic advanced stage disease [Park et al. 2011].

Medical therapy

Uterine LMS is an aggressive malignancy with a high risk of local and distant relapse even in completely resected tumours. Postoperative pelvic radiation therapy has been compared with observation for localized disease of uterine sarcoma including LMS stage I or II [Reed et al. 2008]. Neither PFS, nor OS nor pelvic control was improved by radiotherapy. Therefore, radiation therapy is not indicated in patients with stage I or II LMS after complete resection.

So far, only one randomized trial for localized LMS has been performed comparing doxorubicin (60 mg/m2, every 3 weeks for 8 courses) with observation [Omura et al. 1985]. Differences in PFS and OS were not significant, but there was a trend favouring chemotherapy (relapse rate 44% versus 61%). A recently updated meta-analysis showed an improvement of prognosis by chemotherapy; mainly combination chemotherapies including doxorubicin and ifosfamid regimen in patients with complete resection of soft tissue sarcoma were reported [Pervaiz et al. 2008]. But because this meta-analysis included several non-LMS trials it is difficult to draw any definitive conclusion for this entity.

A prospective phase II trial testing the combination chemotherapy of gemcitabine and docetaxel followed by doxorubicin in stage I/II disease reported promising results regarding activity (2 year PFS: 78%) [Hensley et al. 2013]. The combination of carboplatin and pegylated liposomal doxorubicin also demonstrated activity in another phase II trial [Harter et al. 2011].

Adjuvant chemotherapy with doxorubicin, ifosfamide and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas was evaluated in another randomized clinical phase III trial. A significant improvement of the 3-year PFS was detected in the cohort treated with combined modalities: 51% [95% confidence interval (CI): 34–69%) versus 40% (95%CI: 25–58%) in the radiotherapy group (p = 0.048). OS differences were not significant. However, this regimen showed remarkable toxicity including two therapy related fatal events in the combined modality arm [Pautier et al. 2012].

Treatment of recurrent LMS

If surgery remains a treatment option at advanced stage or at relapse has to be discussed on an individual basis [Leitao et al. 2003, 2012; Zivanovic et al. 2009].

There is a lack of clinical trials that have dealt only with pure recurrent LMS sarcoma. Most available data are from studies with metastatic uterine sarcoma and recurrence. This is probably explained by the rarity of the disease.

A randomized phase II clinical trial compared gemcitabine versus gemcitabine and docetaxel in the metastatic situation of soft tissue sarcomas. The trial’s conclusion was that the combination therapy was superior to monochemotherapy with gemcitabine. The median PFS was 6.2 months for gemcitabine–docetaxel versus 3.0 months for gemcitabine (p = 0.02). The median OS was 17.9 months for combination therapy versus 11.5 months for monochemotherapy (p = 0.03). However, more than 40% of the patients had to stop therapy as result of toxicity [Maki et al. 2007].

A randomized phase II trial included patients with advanced or recurrent liposarcoma or LMS after failure of prior antracycline and ifosfamide therapy. Compared were two schedules with trabectidin monotherapy: 24-hour intravenous of 1.5 mg/m2 infusion once every 3 weeks versus 3-hour infusion of 0.58 mg/m2 weekly. This clinical trial showed a clinical benefit for trabectidin given to patients in the 24 hours regimen. Median PFS was 3.3 months versus 2.3 months [hazard ratio (HR): 0.755; 95%CI: 0.574–0.992; p = 0.0418]. Median OS was 13.9 months versus 11.8 months (HR: 0.843; 95%CI: 0.653–1.090; p = 0.1920) [Demetri et al. 2009].

The only randomized double blind, placebo-controlled phase III trial in patients with metastatic and recurrent nongastrointestinal stromal tumour soft tissue sarcoma was a trial with pazopanib. It showed a significant increase in PFS by a median of 3 months compared with placebo (4.6 months versus 1.6 months; HR: 0.31, 95%CI: 0.24–0.40; p < 0.0001). OS was 12.5 months for pazopanib versus 10.7 months with placebo (HR: 0.86, 95%CI: 0.67–1.1; p = 0.25). Pazopanib is a new oral treatment option, after previous chemotherapy for metastatic nongastrointestinal stromal tumour, nonadipocytic soft tissue sarcoma [Van der Graaf et al. 2012].

Ridaforolimus is a mammalian target of rapamycin (mTOR) inhibitor, which was investigated in a clinical phase II trial including patients with advanced bone and soft tissue sarcomas. It showed a good clinical benefit rate (CBR) defined as complete response (CR), partial response (PR) or stable disease (SD) of ≥16 weeks. In the subgroup of LMS was the highest CBR reported with about 33.3% [Chawla et al. 2012]. A subsequent phase III trial investigated the efficacy of ridaforolimus as maintenance therapy after chemotherapy. The study met its primary endpoint of independent radiologic assessed PFS (14.6 versus 17.7 weeks; HR: 0.72, p = 0.0001). However 52% experienced stomatitis as side effect of ridaforolimus [Chawla et al. 2011]. The final publication including mature data for OS is awaited to discuss the role of ridaforolimus in the treatment of sarcoma.

A nonrandomized multicentre phase II clinical trial with eribulin in patients with advanced or metastatic of high and intermediate grade soft tissue sarcoma has achieved the endpoint of the trial (12 weeks PFS). Patients with adipocytic sarcoma and LMS had the best responses [Schöffski et al. 2011].

The combination of carbopatin and pegylated liposomal doxorubicin seems to be favourable in terms of toxicity and safety with a good efficacy even in advanced and recurrent situations. The median PFS was 8.6 months (95% CI: 6.4–10.4). The median OS was 29.5 months and 77% of the patients had reached 12 months OS [Harter et al. 2011].

Another phase II trial (total 113 patients including 32 LMS) demonstrated the superiority of the combination therapy with dacarbacine and gemcitabine compared with gemcitabine alone in patients with previously treated soft tissue sarcoma. The median PFS was 4.2 months versus 2 months (HR: 0.58; 95%CI: 0.39–0.86; p = 0.005). The median OS was 16.8 months versus 8.2 months (HR: 0.56; 95%CI: 0.36–0.90; p = 0.014) [Garcia del Muro et al. 2011]. Table 1 summarizes the most clinical trial to this topic.

Table 1.

Overview of clinical trials with sarcoma.

Reference Entities Stage Trial-phase Design Progression-free survival Overall survival
Omura et al. [1985] Uterine sarcoma I, II II n = 156 adriamycin 60 mg/m2 q 21 versus observation no significant difference 73 months versus 55 months; p = ns
Pautier et al. [2012] Uterine leiomyosarcoma I, II IIn = 81 doxorubicin 50 mg/m2 d1, ifosfamide 3 g/m2/day d1–2 and cisplatin 75 mg/m2 d3,q 21 -> RT versus RT 3 year PFS: 51% versus 40%; p = 0.0048 3-year OS: 81% versus 69%; p = 0.41
Hensley et al. [2013] Uterine leiomyosarcoma I, II IIn = 47 gemcitabine 900 mg/m2 days 1 and 8 plus docetaxel 75 mg/m2 d8 -> doxorubicin 60 mg/m2 q21 2-year PFS: 78%
Harter et al. [2011] Uterine/ ovarian sarcoma I–IV and relapse IIn = 40 Pegylated liposomal doxorubicin 40 mg/m2 plus carboplatin AUC 6 q28 8.6 months 29.5 months
Demetri et al. [2009] Lipo-/leiomyo-sarcoma relapsed II n = 270 trabectidin 1,5 mg/m2(q21, 24 h) versus trabectidin 0.58 mg/m2 (q1W, 3 h) 3.3 months versus 2.3 months; p = 0.0418 13.9 months versus 11.8 months, p = 0.1920
Maki et al. [2007] Soft tissue sarcoma metastatic II n = 122 gemcitabine 900 mg/m2 days 1, 8 plus docetaxel 75 mg/m2 d8, q21 versus gemcitabine 1,200 mg/m2 (1+8,q3w) 6.2 months versus 3.0 months; p = 0.02 17.9 months versus 11.5 months; p = 0.03
Garcia del Muro et al. [2010] Soft tissue sarcoma advanced II n = 113 dacarbacine 500 mg/m2, gemcitabine 1,800 mg/m2(q2w) versus dacarbacine 1,200 mg/m2 (q21 16.8 months versus 8.2 months; p = 0.014. 4.2 months versus 2 months; p = 0.005
Van der Graaf et al. [2012] Soft tissue sarcoma metastatic III n = 362 pazopanib 800 mg once daily versus placebo 4.6 months versus 1.6 months; p < 0.0001 12.5 months versus 10.7 months; p = 0.25
Chawla et al. [2011] Soft tissue + bone sarcoma relapsed, maintenance III n = 711 ridaforolimus 12.5 mg (d1-d5,q2w) versus placebo 14.6 versus 17.7 weeks; p = 0.0001 21.4 months versus 19.2 months; p = ns
Schöffski et al. [2011] Soft tissue sarcoma metastatic II n = 128 eribulin 1.4 mg/m2 (d1-d8,q21) 2.1–2.6 months (depending on histologic subtype) 6 months OS: 52.9–86.8% months (see above)
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ns, not significant; OS, overall survival; PFS, progression-free survival.

ESS

This form of uterine sarcoma is a rare uterine tumour accounting for 0.2–1% of all uterine malignancies and 6–20% of all uterine sarcomas [Koss et al. 1965; Harlow et al. 1986]. Due to the rarity of this type of sarcoma, there are limited data regarding this tumour entity. Most of available data are retrospective analysis based on small number of patients. ESS affects younger women with a mean age of between 42 and 58 years [Tavassoli and Deville, 2003]. ESS is an indolent tumour with local recurrences and distant metastasis can occur even 20 years after first diagnosis [Gadducci et al. 2008].

The traditional classification of ESS into low-grade and high-grade categories is obsolete. It is necessary to distinguish between endometrial stromal sarcoma and undifferentiated uterine sarcoma. The usual clinical presentation of ESS is abnormal uterine bleeding that occurs in about 90% of women and 70% of cases show uterine enlargement. They can present with pelvic pain and dysmenorrhea, and about 30–50% of the ESS have extra uterine spread at the time of the diagnosis [Tavassoli and Deville, 2003]. Although the main tumour mass is almost intramyometrial, most ESS involve the endometrium and uterine curettage may be helpful in preoperative diagnosis [Ganjoei et al. 2006; Jin et al. 2010]. Due to the great similarity of ESS with normal endometrium, it can be difficult to diagnose ESS on curettage fragments and the definitive diagnosis can be made only on a hysterectomy specimen.

Surgical treatment

Surgical treatment of ESS includes an exploratory laparotomy, total abdominal hysterectomy and bilatreal salpingo-oophorectomy, omental biopsy and aspiration of abdominal fluid for cytologic evaluation [Berchuck et al. 1990; Ramondetta, 2006; Gadducci et al. 2008; Li et al. 2008; Weitmann et al. 2001, 2002]. Immunohistochemical studies showed a rich expression of oestrogen and progesterone receptors (ER and PgR), as they are also hormonally responsive. Therefore a hormone substitution after surgery might be contraindicated [Leath et al. 2007; Grimer R et al. 2010].

However, several studies failed to show that bilateral salpingo-oophorectomy affects time for recurrence or OS in stage I disease [Li et al. 2005; Amant et al. 2007; Gadducci et al. 1996b; Chu et al. 2003; Chan et al. 2008]. Regarding the adverse effects of early surgical menopause, preservation of the ovarian function may be an option for premenopausal women with stage I disease [Li et al. 2005].

There are various rates of lymph node involvement reported in ESS showing up to 10% nodal metastases. Whilst removal of obviously affected or enlarged lymph nodes is a widely accepted procedure, systematic pelvic and para-aortic lymphadenectomy in clinically negative nodes as routine staging procedure in a disease with mainly hematologic metastases is still under discussion and not recommended by many authors [Chan et al. 2008; Reich et al. 2005; Riopel 2005]

Adjuvant therapy

So far, adjuvant radiotherapy is ineffective in endometrial stromal sarcoma stage I/II [Reed, 2008]. Standard of care in patients with stage I or II is careful follow up. In advanced stages, endocrine treatment might be an option in patients with steroid-positive tumours [Amant et al. 2005]. Until today, the role of adjuvant chemotherapy is undefined. Pure ESS studies are lacking and ESS are mostly included in other series as a subentity. Most results from those trials, as explained above in the LMS section. might be an option for such tumours. However, if there is an indication for systemic treatment, first choice is always endocrine therapy. Medroxyprogesterone (MPA) and aromatase (AI) inhibitors showed good efficacy and led to sustained disease control in some advanced and metastatic cases [Pink et al. 2006; Lehrner et al. 1979].

Treatment of recurrent ESS

ESS recurs most commonly in the abdomen/pelvis (40–50%) followed by lung (in approximately 25% of cases) [Cheng et al. 2011; Beck et al. 2012]. Late recurrences are common even with early stage disease. Treatment for recurrent ESS depends on prior endocrine therapy. In recurrent patients without any prior endocrine therapy, endocrine agents such as MPA and AI are the primary treatment.

In patients who recur after or during endocrine therapy, cytotoxic chemotherapy is the first choice. Patients who progress following prior treatment (including endocrine therapy in the adjuvant or firstline metastatic setting) are candidates for cytotoxic chemotherapy. The approach to these patients is similar to those patients with metastatic or recurrent LMS; available treatment combinations include gemcitabine plus docetaxel and doxorubicin-based regimens

UUS

This entity of uterine sarcoma is high grade epithelioid or spindle cell sarcoma. It represents an independent uterine tumour entity. It accounts less than 5% of all uterine sarcomas [Ramondetta, 2006; Abeler et al. 2009; Nordal et al. 1997]. This type of tumour grows quickly and has high malignancy characteristics which result in a poor prognosis. The 5-year OS rate has reached 25–55% [Gadducci et al. 1996b, 2008; Berchuck et al. 1990; Koivisto-Korander et al. 2008].

Surgical treatment

Despite limited evidence, recommended surgical treatment for UUS is total abdominal hysterectomy and bilateral salpingo-oophorectomy [Ramondetta, 2006; Gadducci et al. 2008; Vrzic-Petronijevic et al. 2006; Kanjeekal et al. 2005; Kokawa et al. 2006]. The value of lymphaden ectomy remains controversial, similar to the surgical treatment of ESS [Gadducci et al. 1996b; Ramondetta, 2006; Goff et al. 1993; Shah et al. 2008]

Adjuvant therapy

So far, conclusive data are missing. The main risk is haematogenous spread and chemotherapy might be an option. Doxorubicin and/or Ifosfamid are under discussion, analogous to other sarcomas [Tierney JF et al. 1995; Hyman et al. 1985]. USS might be treated with the same drugs as soft tissue sarcoma at other sites

Treatment of recurrent UUS

No randomized trials have dealt only with this type of uterus sarcomas. The therapy of recurrence is similar to soft tissue sarcomas.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The authors declare no conflict of interest in preparing this article.

Contributor Information

Khalid El-Khalfaoui, Department of Gynecology & Gynecologic Oncology, Kliniken Essen Mitte (KEM), Evang. Huyssens-Stiftung/Knappschaft GmbH, Henricistr. 92, 45136 Essen, Germany.

Andreas du Bois, Department of Gynecology & Gynecologic Oncology, Kliniken Essen-Mitte, Essen Germany.

Florian Heitz, Department of Gynecology & Gynecologic Oncology, Kliniken Essen-Mitte, Essen Germany.

Christian Kurzeder, Department of Gynecology & Gynecologic Oncology, Kliniken Essen-Mitte, Essen Germany.

Jalid Sehouli, Department of Gynecology, Charité Medical University of Berlin, Berlin, Germany.

Philipp Harter, Department of Gynecology & Gynecologic Oncology, Kliniken Essen-Mitte, Essen Germany.

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