Treatment and prognosis of uterine leiomyosarcoma

INTRODUCTION — Uterine leiomyosarcoma (LMS) is a rare uterine malignancy that arises from the smooth muscle of the uterine wall. Compared with other types of uterine cancers, LMS is an aggressive tumor associated with a high risk of recurrence and death, regardless of stage at presentation [1]. Tumor grade and other histologic features can influence clinical behavior of the tumors and may be important determinants of treatment recommendations. Whenever possible, patients with uterine sarcomas should be referred to specialty centers with expertise in their diagnosis and management.

This topic will cover the treatment approach to high-grade uterine LMS. The classification, clinical manifestations, diagnosis, and staging of other uterine sarcomas are covered separately. Treatment of other types of uterine sarcomas is also covered separately.

●(See "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis".)

●(See "Endometrial stromal sarcomas, related tumors, and uterine adenosarcoma".)

●(See "Clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma".)

●(See "Endometrial stromal sarcomas, related tumors, and uterine adenosarcoma".)

●(See "Overview of the initial treatment of metastatic soft tissue sarcoma".)

SURGERY — In most cases, the diagnosis of uterine LMS is made following hysterectomy or myomectomy for presumed benign uterine leiomyomas [2,3]. As an example, in one series of 106 patients with uterine sarcoma, 65 percent of those with LMS were preoperatively diagnosed with a benign leiomyoma [3]. The sequence of events leading to the diagnosis may influence the treatment approach.

The diagnosis of LMS and differentiating benign leiomyomas from LMS are discussed in detail separately. (See "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas" and "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis".)

Preoperative or intraoperative diagnosis — LMS is typically diagnosed postoperatively, but in rare cases it is diagnosed with endometrial sampling preoperatively or with frozen section intraoperatively. There is no single preoperative test that can reliably differentiate benign from malignant uterine disease. (See "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas", section on 'Diagnostic methods'.)

Disease confined to the uterus — For patients with uterine LMS that is confined to the uterus at time of surgery, we proceed with a total hysterectomy.

Several case series support the role of primary surgery [4-6]. In the largest series involving 46 patients with LMS, complete cytoreduction was significantly associated with disease-free survival (p = 0.03) [5].

There is no reliable method to distinguish uterine sarcoma from benign leiomyomas preoperatively, as discussed in detail above. Among patients planning surgery for one or more uterine masses that are presumed to be benign leiomyomata, the reported prevalence of uterine sarcoma ranges from 1 in 350 to 1 in 500. The risk of occult LMS was reported to be 0.2 percent (1 in 500) in the largest cohort study of patients undergoing surgery for presumed benign leiomyomata (n = 34,728) [7]. This should be taken into account when considering the approach to patients. Several retrospective studies show that patients with LMS diagnosed following uterine morcellation have a high risk for sarcomatosis on re-exploration and have poorer survival outcomes [8-10].

In 2014, the US Food and Drug Administration issued a safety alert recommending against the use of power morcellators in patients with suspected or known uterine cancer and recommending patients be informed about the risk of unexpected cancer, which could be spread by power morcellation and worsen the patient's prognosis [11]. On this basis, a reasonable approach is to avoid morcellation of the uterus in cases where there is clinical suspicion for uterine sarcoma.

A bilateral salpingo-oophorectomy (BSO) at the time of total hysterectomy is often performed, particularly for menopausal or perimenopausal patients. However, it is not clear if BSO influences survival in patients with newly diagnosed LMS. We do not perform BSO in premenopausal patients. A National Cancer Database study assessing the impact of BSO in patients with uterine-confined LMS reported that there was no difference in overall survival (OS) among patients who underwent a BSO compared with those who did not [12]. (See 'Premenopausal patients' below.)

Disease extending beyond the uterus — For patients with extrauterine disease, the role of surgery is controversial. Our approach depends on whether the patient is a surgical candidate and whether or not a complete resection of disease is feasible.

●For patients with disease confined to the pelvis, but with no invasion of the bladder or rectum (stage II) or the abdomen (stage III) (table 1), we perform a total hysterectomy with BSO and surgical cytoreduction of intra-abdominal and retroperitoneal disease. Although the data are limited to small patient series, an optimal cytoreduction (to no gross residual disease) is associated with improved OS compared with patients with residual disease at the end of surgery [3,6].

●For patients with disease not amenable to an optimal cytoreduction or extensive widespread disease, there is no benefit to surgery. The presence of residual disease following surgery was associated with a poor prognosis compared with a complete cytoreduction [5]. In a series of 96 patients with newly diagnosed LMS and extrauterine spread, complete surgical cytoreduction resulted in a progression-free survival (PFS) improvement of 7.4 months and an OS improvement of 11.7 months [13]. The PFS improvement remained significant on multivariable testing, but not OS. In addition, surgery may delay the start of systemic treatment, especially in patients with extensive disease. Therefore, in the absence of high-quality data showing a benefit to surgical cytoreduction, we initiate medical therapy rather than surgical cytoreduction. (See 'Metastatic disease' below.)

However, surgery may be reasonable in the following scenarios:

•Total hysterectomy may serve as palliation for patients experiencing significant pelvic symptoms (ie, pain or vaginal bleeding).

•Total hysterectomy and resection of metastatic disease may be considered for selected patients with a relatively low disease burden beyond the peritoneal cavity (eg, isolated metastatic disease in the lung or liver). Complete resection in these patients may be possible with limited morbidity. (See 'Metastatic disease' below.)

Postoperative diagnosis — For patients who are diagnosed with LMS after total hysterectomy (on final pathologic review), we do not perform a second surgical procedure for the sole purpose of staging. Instead, we perform a postoperative computed tomography of the chest, abdomen, and pelvis to help guide postoperative treatment.

For patients who underwent a hysterectomy (or myomectomy) alone and who are surgical candidates, however, a second surgical procedure is reasonable in the following situations [8]:

●If ovaries were conserved in prior surgery, we do not routinely reoperate solely to perform salpingo-oophorectomy; this is of uncertain benefit and exposes the patient to the risks of surgery.

●For patients who underwent a supracervical hysterectomy (or myomectomy), we suggest removal of the cervix or hysterectomy with resection of any visible residual disease if possible. Concomitant BSO can also be performed in perimenopausal and menopausal patients. It is not clear that BSO in premenopausal patients is beneficial.

●For patients in whom the tumor was morcellated, we suggest surgical exploration and staging to ensure any residual peritoneal disease is resected. The value of re-exploration after morcellation and the rapidity of spread were evaluated in a study in patients with no evidence of extrauterine disease at time of surgery who underwent morcellation and were subsequently diagnosed with uterine LMS. Re-exploration was performed immediately (within 50 days), and three of eight of these patients were upstaged to stage III or IV [9].

INDICATIONS FOR LYMPHADENECTOMY — We perform a pelvic lymphadenectomy for patients if the pelvic nodes are palpably enlarged intraoperatively or there is evidence of extrauterine disease [14,15]. Patients with LMS confined to the uterus have a low incidence of lymph node involvement. This was illustrated in a Gynecologic Oncology Group study of 59 patients with clinical stage I or II LMS (all of whom underwent surgical staging) in which the incidence of lymph node metastases was less than 5 percent [16]. In another series of 37 patients with LMS who underwent nodal sampling, only three patients had positive nodes, and in all cases, they were clinically suspicious at surgery [15]. Routine lymphadenectomy should not be performed in patients with uterine LMS confined to the uterus and normal-appearing lymph nodes.

ROLE OF IMAGING — Up to 33 percent of patients with newly diagnosed uterine LMS present with distant metastatic disease (stage IVB), most commonly involving the liver, lung, or upper abdomen [2,6,14,17,18]. Therefore, all patients should undergo imaging to rule out metastatic disease following pathologic confirmation of the diagnosis.

There are no data on the ideal imaging evaluation for patients with LMS. Chest radiograph, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) scans are all used to evaluate for metastatic disease for soft tissue sarcomas. We perform a CT perioperatively in all patients diagnosed with LMS. There are no data on the utility of PET in perioperative staging of LMS, and the data on PET for the detection of recurrence are limited to retrospective case series [19,20]. There is no evidence that it provides more useful information than either CT or MRI. Further discussion on the imaging evaluation of sarcomas is covered separately. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Radiographic studies'.)

STAGING — Uterine LMS is surgically staged according to the 2017 International Federation of Gynecology and Obstetrics (FIGO)/Tumor, Node, Metastasis (TNM) classification system (table 1). This is the same staging system that is used for endometrial stromal sarcoma but differs somewhat from the staging system for uterine adenosarcoma (table 1). The difference is in the definitions for stage I; for LMS stage I, substages are defined by tumor diameter (IA: ≤5 cm; IB: >5 cm). Endometrial carcinoma and carcinosarcoma use an entirely different staging system (table 2). The separate staging systems for uterine sarcomas were introduced in 2010 [21].

The FIGO staging system does not predict the prognosis for overall survival for patients with uterine LMS [22]. A nomogram that incorporates patient age, tumor size, grade, local extension, distant metastases, and mitotic rate as key variables may be prognostically more useful [22]. (See 'Prognosis' below.)

ADJUVANT TREATMENT — Observation is the standard of care following resection of a uterus-limited, intact specimen. While chemotherapy or pelvic radiation is sometimes considered following surgery for LMS, no form of adjuvant therapy has demonstrated improvement in survival outcomes compared with observation.

Early-stage disease — For patients with early-stage (stage I or II) uterine LMS, there is evidence that intervention does not improve the survival outcomes compared with postsurgical surveillance [23-26]. Therefore, for patients with surgical stage I or II LMS, we suggest observation as the standard management rather than adjuvant therapy. A prospective, randomized trial was conducted by the Gynecologic Oncology Group (GOG) in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC) and Cancer Research UK, which compared the regimen from SARC 005 with observation in patients who had undergone surgical resection of high-grade International Federation of Gynecology and Obstetrics (FIGO) stage I uterine LMS (GOG 277) [27]. This study closed after enrollment of 38 patients due to slow accrual. Nevertheless, the data showed that the same number of recurrences were seen in both arms, there was not statistical improvement in progression-free survival (PFS), and overall survival (OS) was worse in the chemotherapy-treatment arm. These data support the conclusion that observation is the standard of care for this population [27].

The data evaluating chemotherapy and radiation therapy (RT) for early-stage LMS are discussed below.

Chemotherapy — Doxorubicin, combination chemotherapy, and RT have been evaluated as adjuvant treatment for patients with early-stage disease. However, the lack of benefits of a treatment with associated morbidity must be considered.

Doxorubicin — The GOG conducted a phase III trial in 156 patients with stage I or II uterine sarcoma (all histologies) who were randomly assigned treatment with postoperative doxorubicin or no further treatment [23]. Although patients treated with doxorubicin had a lower recurrence rate compared with those not treated with chemotherapy (41 versus 53 percent), this was not statistically significant. In addition, adjuvant doxorubicin had no impact on PFS or OS.

Docetaxel and gemcitabine — Although not composed exclusively of patients with early-stage disease, fixed-dose-rate gemcitabine (900 mg/m² over 90 minutes on days 1 and 8) plus docetaxel (75 mg/m² on day 8) administered with hematopoietic growth factor support was evaluated in a trial involving 25 patients with completely resected, high-grade uterine LMS [24]. Among patients with stage I or II disease, 59 percent remained progression free at three years (median, 39 months). Of note, at a median follow-up of 49 months, the two-year PFS rate was 45 percent, and median PFS was 13 months for the entire cohort. Given the lack of a control arm and the small number of patients treated, the significance of these findings is not clear.

Gemcitabine and docetaxel therapy was not associated with a survival advantage in a retrospective study of 111 patients with stage I uterine LMS [28]. The 33 patients treated with gemcitabine-docetaxel had similar three-year disease-free survival compared with the 77 patients who did not receive adjuvant chemotherapy (three-year PFS, 45 versus 53 percent). The three-year OS rates were also similar (59 versus 66 percent). These data support surveillance/observation for patients with stage I, uterus-limited LMS rather than chemotherapy [29].

Docetaxel and gemcitabine followed by doxorubicin — A prospective, multi-institutional phase II trial (SARC 005) enrolled 47 patients with uterus-limited, high-grade LMS [30]. All patients received four cycles of fixed-dose-rate gemcitabine plus docetaxel, followed by four cycles of doxorubicin and were evaluated for disease recurrence by imaging approximately every three months. Of those enrolled, 89 percent of patients received all eight planned cycles. The median time to recurrence was 27 months, and the three-year PFS rate was 57 percent. As detailed above, the randomized trial comparing this regimen with observation did not show improvement in recurrence rates or survival outcomes. (See 'Early-stage disease' above.)

Radiation therapy — The use of adjuvant RT has no impact on survival outcomes for patients with early-stage LMS. This was demonstrated in an EORTC randomized trial (EORTC 55874), which enrolled patients with stage I and II uterine sarcomas and randomly assigned them to treatment with postoperative RT or observation [26]. Among patients with LMS (n = 103), pelvic RT resulted in:

●No significant differences in either local or distant progression rates compared with observation

●A trend toward a reduction in OS (hazard ratio for survival 0.64, 95% CI 0.36-1.14), although this did not reach statistical significance

Advanced disease — Patients with intra-abdominal involvement of disease (stage III) or distant metastases (stage IV) who have undergone complete resection of disease have a high risk of disease progression following surgery alone. Therefore, postresection chemotherapy may be offered, rather than observation, although whether treatment improves survival has not been established. Thus, surveillance is also a reasonable alternative to chemotherapy.

Docetaxel and gemcitabine — Only one prospective study evaluated chemotherapy following a complete cytoreduction for uterine LMS. As discussed above, 25 patients with stage I to IV LMS received docetaxel and gemcitabine on a GOG trial [24]. However, this study lacked a control arm, and it remains unclear whether treatment results in an improvement in survival. (See 'Docetaxel and gemcitabine' above.)

Combined-modality treatment — For patients with advanced LMS, the administration of combined-modality treatment (eg, pelvic radiation plus chemotherapy) remains investigational. One study randomly assigned 81 patients with uterine sarcoma (53 with LMS) to treatment with pelvic RT with or without combination chemotherapy using ifosfamide, cisplatin, and doxorubicin (API) [31]. Compared with pelvic RT, the addition of API was associated with the following nonstatistically significant trends:

●A lower incidence of recurrence (39 versus 62 percent)

●Higher PFS at three years (52 versus 41 percent)

●Improvement in OS at three years (80 versus 67 percent)

Treatment with API was associated with serious (grade 3/4) toxicity, including neutropenia (84 percent), febrile neutropenia (22 percent), and nausea and vomiting (24 percent). Two treatment-related deaths due to febrile neutropenia also occurred. The study was closed early due to poor accrual. Until further data become available, the administration of combined-modality treatment should be considered investigational.

POST-TREATMENT SURVEILLANCE — Uterine LMS is an aggressive tumor with a high risk of relapse, even when confined to the uterus at diagnosis [1]. Therefore, we perform a physical exam every three to four months and chest, abdomen, and pelvic imaging every three to four months for two to three years, then every 6 to 12 months for the next two years. There are no data defining the optimal frequency or duration of surveillance imaging. Although there are no data that surveillance improves survival outcomes for patients with LMS, these recommendations are consistent with surveillance guidelines of the National Comprehensive Cancer Network [32].

PROGNOSIS — Patients with LMS have a poor prognosis regardless of stage [17,33]. In a large study of 1396 patients with LMS (71 percent with stage I/II disease), the five-year disease-specific survival (DSS) was 66 percent [17]. Stratified by stage, the five-year disease-specific overall survival (OS) for stage I, II, III, and IV disease was 76, 60, 45, and 29 percent, respectively. Factors associated with worse DSS were:

●Higher tumor grade (hazard ratio [HR] 1.83, 95% CI 1.43-2.34)

●Higher disease stage (HR 1.58, 95% CI 1.47-1.71)

●African American race (HR 1.45, 95% CI 1.09-1.94)

Despite the prognostic significance of grade, there is no single, universally accepted grading system for uterine LMS. Low-grade LMS and smooth muscle neoplasms that do not meet diagnostic criteria for uterine LMS (eg, smooth muscle tumors of uncertain malignant potential) likely have a more favorable disease course. Classification and grading of uterine smooth muscle tumors can be challenging, thus specialized pathology review is recommended. (See "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis", section on 'Leiomyosarcoma'.)

Neither International Federation of Gynecology and Obstetrics (FIGO) nor American Joint Committee on Cancer (AJCC) staging performs well in terms of providing prognostic information for OS in uterine LMS [22]. A nomogram has been developed that incorporates patient age, tumor size, grade, local extension, distant metastases, and mitotic rate as key variables. This nomogram performs better than FIGO and AJCC staging in terms of predicting five-year OS [33,34].

ROLE OF MOLECULAR DIAGNOSTIC TESTING AND SOMATIC TUMOR PROFILING — While some soft tissue sarcomas are associated with diagnostic chromosomal translocations or characteristic gene mutations, this is not the case for uterine LMS. Uterine LMS commonly have multiple chromosomal abnormalities associated with chromothripsis. They frequently harbor inactivating mutations in tumor protein p53 (TP53), retinoblastoma gene (RB1), and/or have whole-genome duplication [35]. Based on available data, these genetic alterations and mutations are not considered therapeutically actionable. Microsatellite instability and/or high tumor mutational burden are distinctly uncommon in uterine LMS, perhaps explaining the lack of activity of immunotherapy agents observed in phase II trials in LMS [36,37].

While there is not an established role for routine use of next-generation sequencing of uterine LMS, in some cases the information may have implications for diagnostic precision and/or therapies. For example, somatic alterations in breast cancer susceptibility gene 2 (BRCA2) have been reported in 5 to 8 percent of uterine LMS, and responses to poly(ADP-ribose) polymerase (PARP) inhibition have been observed among patients with homozygous BRCA2-altered uterine LMS treated on clinical trials that included PARP inhibitor therapy [38]. Similarly, next-generation sequencing and/or RNA-based fusion mutation testing may provide useful diagnostic precision in uterine sarcomas with nonclassical histologic appearance (epithelioid and myxoid findings, for example), which could have import for treatment choices and clinical trial eligibility [39,40].

SPECIAL POPULATIONS

Premenopausal patients — Premenopausal patients with uterine LMS may wish to retain their ovaries for fertility preservation. In addition, oophorectomy in these patients will result in premature menopause, which may impact quality of life.

Most experts perform a bilateral salpingo-oophorectomy (BSO) as part of standard surgical treatment. However, data are limited regarding the impact of BSO on LMS survival. At least 40 percent of uterine LMS express estrogen and/or progesterone receptors [41-43]. However, in one study of 341 patients who were <50 years old and had stage I or II disease at diagnosis, there was no difference in five-year disease-free survival in those who did or did not undergo BSO [17]. This study was limited because the number of patients who had previously had both ovaries removed was not reported. As mentioned above, a larger National Cancer Database study assessing the impact of BSO in 1076 patients with uterine-confined LMS also reported that there was no difference in overall survival among patients who underwent a BSO compared with those who did not [12].

In the absence of randomized trial data addressing the impact of BSO on survival in LMS, recommendations regarding BSO must be individualized. Some may reasonably recommend BSO for patients whose International Federation of Gynecology and Obstetrics stage I uterine LMS is estrogen and/or progesterone receptor positive. However, there have not been any reports suggesting that such an approach will improve outcomes. The correlation of expression of estrogen receptor and/or progesterone receptor and performing BSO is speculative at this time.

Medically inoperable patients — The approach to patients who are not candidates for surgical resection due to comorbidity or poor performance status must be individualized. Given the poor prognosis for patients with uterine LMS regardless of stage, nonsurgical treatment is palliative, not curative. Therefore, careful consideration of the benefits (eg, control of pain or bleeding) must be weighed against the toxicities of medical treatment. The treatment approach to medically inoperable patients mirrors that of patients with metastatic disease. (See 'Metastatic disease' below.)

LOCAL RECURRENCE OR OLIGOMETASTATIC DISEASE — For patients with localized recurrences or limited metastatic disease, surgical resection may offer a survival advantage and should be offered to appropriately selected patients. However, the data supporting this approach are limited to small series [44-46]. In one series of 31 patients with pulmonary metastases, for example, metastasectomy resulted in a median overall survival (OS) of 70 months.

The best candidates for this approach are those who recur after a prolonged progression-free interval (at least 12 to 18 months) and with an isolated site of recurrence that is amenable to complete resection. (See "Surgical treatment and other localized therapy for metastatic soft tissue sarcoma".)

For patients who are not surgical candidates, radiation therapy is an alternative treatment option for locally recurrent disease. Its application in uterine sarcomas is similar to the approach in endometrial adenocarcinomas. (See "Management of locoregional recurrence of endometrial cancer", section on 'Those with no prior radiation'.)

Another approach to localized metastatic disease is radiofrequency ablation (RFA). Although no randomized trials have been performed, RFA may successfully treat individual lesions that are small (generally under 4 cm) and accessible (generally not near major blood vessels) [47]. Appropriate candidates for RFA have single-site disease that is accessible for ablation and has recurred after a prolonged disease-free interval.

Hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of complete surgical cytoreduction has gained attention in the management of multiple malignancies with intraperitoneal metastases. A small, retrospective series of 26 patients with recurrent uterine sarcoma (22 with LMS) did not find statistically significant differences in progression-free survival or OS comparing patients who underwent surgery and HIPEC and those who underwent surgery but not HIPEC [48]. The authors suggest there may be a benefit with HIPEC, but this is speculation. The use of HIPEC in patients with uterine LMS outside of a clinical trial cannot be justified at this time.

METASTATIC DISEASE — Uterine LMS most commonly metastasizes to the lungs, liver, abdomen, and pelvis [49]. Bone and brain metastases are less common sites of involvement. For patients with metastatic disease that is not amenable to complete surgical resection, treatment is given with palliative intent. Chemotherapy is a reasonable option for patients with metastatic LMS who maintain a good performance status and in whom organ function permits the use of cytotoxic chemotherapy. For other patients, we suggest palliative care. (See "Benefits, services, and models of subspecialty palliative care".)

Although there is no widely agreed upon agent or regimen, there is sufficient activity of chemotherapy to support its use in patients with unresectable, recurrent disease [50]. Of the available options, we favor fixed-dose-rate gemcitabine plus docetaxel because of the high objective response rates demonstrated in prospective clinical trials as a first- or second-line therapy and because of superiority of the gemcitabine-docetaxel combination over gemcitabine alone in a randomized trial for soft tissue sarcoma [51]. Doxorubicin is also a reasonable first-line choice. For patients who progress after first-line therapy, further treatment is based on patient preference, organ function, and performance status.

In general, management of recurrent uterine sarcoma is similar to treatment of metastatic soft tissue sarcomas arising at other sites, although some data suggest that uterine LMS may be more sensitive to some chemotherapy regimens than other non-LMS histology soft tissue sarcomas [6,32]. (See "Surgical treatment and other localized therapy for metastatic soft tissue sarcoma".)

Preferred options for first-line therapy

Gemcitabine plus docetaxel — The combination of fixed-dose-rate gemcitabine plus docetaxel has been evaluated as a first- and second-line treatment for metastatic uterine LMS and is our preferred first-line regimen. Doxorubicin is also a reasonable first-line choice. (See 'Doxorubicin' below.)

Data in support of fixed-dose-rate gemcitabine plus docetaxel are summarized below:

●In Gynecologic Oncology Group (GOG) 87L, 42 patients were treated with gemcitabine plus docetaxel until disease progression or unacceptable toxicity. The overall response rate (ORR) was 36 percent [52]. The major toxicity was myelosuppression, with grade 3 or 4 neutropenia occurring in 17 to 20 percent of patients. Other side effects included fatigue (74 percent), gastrointestinal complaints (14 percent), and pulmonary toxicity (9 percent).

●In GOG 131G, 51 patients who had disease progression after first-line treatment (90 percent had received doxorubicin) received gemcitabine plus docetaxel [53]. The ORR was 27 percent, and 52 percent were progression free at six months.

●In GOG 0250, a phase III trial of gemcitabine-docetaxel plus bevacizumab or placebo, the addition of bevacizumab failed to improve response rate, response duration, progression-free survival (PFS), or overall survival (OS). Objective response rates in both arms of this study were similar to those observed in the first-line, phase II study of gemcitabine-docetaxel. Some patients had sustained responses even after stopping active cytotoxic therapy [54].

Doxorubicin — For patients with good venous access or central venous access and normal cardiac function, doxorubicin (75 mg/m² every three weeks) is a reasonable first-line alternative to gemcitabine and docetaxel for metastatic LMS. Doxorubicin is also a reasonable second-line treatment choice for patients who received gemcitabine-docetaxel as first-line treatment.

A phase III randomized trial compared fixed-dose-rate gemcitabine plus docetaxel versus doxorubicin as first-line treatment for metastatic sarcoma (of any site or histology) [55]. Twenty-seven percent of patients had LMS, site of origin not specified. The regimens were similar in terms of response rates and PFS.

In one GOG study, 104 chemotherapy-naïve patients were randomly assigned to treatment with doxorubicin with or without cyclophosphamide (500 mg/m²) [56]. The ORR was 19 percent in both arms. OS was also similar (median, 12 months with doxorubicin versus 11 months with the combination).

The combination of doxorubicin and olaratumab showed benefit over doxorubicin alone for advanced soft tissue sarcoma in one phase II trial, but not in the confirmatory phase III trial. Olaratumab was removed from the market following the negative phase III study results. These data are discussed in detail elsewhere. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Doxorubicin'.)

In combination with trabectedin — Doxorubicin plus trabectedin followed by trabectedin regimen may be appropriate first-line treatment for patients with LMS:

●Who are fit, have excellent organ function, are likely able to sustain the high risk for clinically significant toxicities, and,

●In whom rapid objective response is clinically needed and/or in whom objective response is likely to make a subsequent complete gross resection possible.

The combination of intravenous doxorubicin (60 mg/m²) plus intravenous trabectedin (1.1 mg/m² over three hours) once every three weeks for up to six cycles followed by maintenance with trabectedin was compared with doxorubicin 75 mg/m² once every three weeks for up to six cycles followed by observation in a randomized trial [57]. The doxorubicin-trabectedin followed by trabectedin arm had longer PFS compared with six cycles of doxorubicin followed by observation, but with greater toxicity.

In a non-blinded, randomized trial including 150 patients with metastatic LMS of uterine or nonuterine soft tissue sarcoma origin, doxorubicin-trabectedin followed by trabectedin improved PFS relative to doxorubicin alone (12.2 versus 6.2 months, adjusted hazard ratio 0.41, 95% CI 0.29-0.58), as well as objective response rates (36 versus 13 percent) [57]. Among the 67 patients with uterine LMS, the trabectedin group also experienced improved PFS (10.0 versus 4.1 months, HR 0.46, 95% CI 0.27-0.78) and objective response rates (36 versus 15 percent). However, toxicities were higher with the combination. The most common grade ≥3 adverse events were neutropenia (80 percent with trabectedin plus doxorubicin versus 13 percent with doxorubicin alone), anemia (31 versus 5 percent), thrombocytopenia (47 versus 0 percent]), and febrile neutropenia (28 versus 9 percent).

Some important issues for consideration in interpretation of these data include that more patients in the doxorubicin arm had bone metastases, and fewer patients had grade 1 tumors compared with the doxorubicin-trabectedin arm. Since the study was unblinded, there is the potential for bias in the timing of imaging such that patients on observation may have been imaged sooner. More patients in the doxorubicin-trabectedin arm underwent surgery following six cycles of treatment than in the doxorubicin arm (20 versus 8 percent), a decision which may have been influenced by potential bias and/or by the presence of bone metastases, and which complicates the interpretation of the observed PFS difference in the whole cohort.

Furthermore, it is important to note that this was a first-line treatment study; there are no available data to demonstrate whether this regimen would be tolerable as a later line of therapy, nor whether it would have the same PFS advantage.

Alternatives and subsequent-line options

Doxorubicin — For patients who did not receive front-line doxorubicin-based treatment, doxorubicin may be administered in the second line. (See 'Doxorubicin' above.)

Pegylated liposomal doxorubicin — Pegylated liposomal doxorubicin (50 mg/m² intravenous therapy [IV] every four weeks) may be a reasonable choice for patients with a lower disease burden and no impending organ dysfunction, since in such patients achieving stable disease with less toxicity may be the objective. Most patients do not require central venous access, and most do not experience alopecia. Pegylated liposomal doxorubicin achieved objective response in 16 percent of patients with uterine LMS as first-line therapy in a phase II trial of 35 patients. Although this response rate is lower than what one would expect with doxorubicin, pegylated liposomal doxorubicin is better tolerated [58].

Gemcitabine — Some patients with lower disease burden and without impending organ dysfunction may achieve disease control with single-agent gemcitabine (1000 mg/m² IV over 30 minutes on a three-week on/one-week off schedule) with less toxicity than with fixed-dose-rate gemcitabine and docetaxel. A randomized trial showed higher response rates, longer PFS, and improved OS for fixed-dose-rate gemcitabine plus docetaxel compared with gemcitabine alone in patients with soft tissue sarcomas [51]; however, gemcitabine has shown an ORR of 20 percent as single-agent therapy [59]. Serious (grade 4) toxicity consists of neutropenia (16 percent), nausea and vomiting (4.5 percent), and rash (2.3 percent).

Ifosfamide — Ifosfamide (1.5 g/m² IV for five days with mesna, every three weeks) was evaluated in a GOG study of 56 patients and resulted in an ORR of 17 percent [60]. A second GOG study evaluated ifosfamide plus doxorubicin that resulted in a 30 percent ORR, although the duration of response was only four months [61].

Trabectedin (as a single agent) — Trabectedin (1.5 mg/m² IV over 24 hours every three weeks) is a rational second- or third-line treatment option for patients with LMS who have previously received anthracycline therapy [62-67]. It is approved for use in Europe, the United States, and other countries for advanced liposarcoma and LMS after progression on an anthracycline-based treatment. Trabectedin is given via central venous access, and requires a normal cardiac ejection fraction.

In a phase III trial, patients with liposarcoma or LMS whose tumors had progressed after prior anthracycline therapy were randomized 2:1 to trabectedin versus dacarbazine. PFS was 4.2 months among patients treated with trabectedin compared with 1.5 months among those treated with dacarbazine. Objective response rates were low in both arms: 9.9 percent for trabectedin versus 6.9 percent for dacarbazine [62]. In a phase II GOG study that enrolled 20 patients with metastatic uterine LMS and who were treatment naïve, only two responses were observed; however, median PFS was 5.8 months [63]. A retrospective study of 66 patients with previously treated LMS reported an ORR of 16 percent [64]. However, median PFS was only three months.

Trabectedin has also been evaluated as part of a combination therapy. For example, a single-arm phase II trial performed by the French Sarcoma Group evaluated trabectedin (administered as a three-hour infusion) in combination with doxorubicin as a first-line treatment for advanced or metastatic LMS (of uterine or soft tissue origin) [65]. Among the cohort with uterine LMS (n = 48), the ORR was 59.6 percent. Grade 3 or 4 neutropenia occurred in 78 percent of patients and grade 3 or 4 thrombocytopenia in 37 percent. Febrile neutropenia occurred in 24 percent of patients. In a subsequent, randomized, phase II trial for trabectedin plus doxorubicin versus doxorubicin alone as first-line treatment for soft tissue sarcoma, there was no difference in response rates (17 percent in each arm) or PFS (approximately 5.5 months in each arm), and toxicities were greater with the combination treatment [66].

Dacarbazine and temozolomide — Dacarbazine (1200 mg/m² every three weeks) has modest activity in soft tissue sarcomas [68]. In addition, temozolomide (50 to 75 mg/m² taken orally every day for six out of eight weeks), an oral prodrug of dacarbazine, also appears to be active, although the data are quite limited [69,70]. Prospective phase III data have shown that trabectedin is superior to dacarbazine in patients with liposarcoma or LMS who have previously received anthracycline-based therapy.

Pazopanib — Pazopanib (800 mg once daily), an oral multikinase inhibitor, may be a reasonable option for patients with good gastrointestinal function and who are not considered high risk for pulmonary hemorrhage or intestinal perforation. It is approved in the United States for the treatment of metastatic soft tissue sarcomas after disease progression on an anthracycline-based therapy. The European Organisation for Research and Treatment of Cancer conducted a phase III trial that included 372 patients who were randomly assigned to treatment with pazopanib or placebo [71]. Compared with placebo, pazopanib resulted in an improvement in median PFS (5 versus 2 months; hazard ratio [HR] 0.31, 95% CI 0.24-0.40) but no significant difference in median OS (13 versus 11 months; HR 0.86, 95% CI 0.67-1.11). The objective response rate to pazopanib was 6 percent [71].

Eribulin — Eribulin (1.4 mg/m² IV on days 1 and 8 of a 21-day cycle), a microtubulin inhibitor, may be a reasonable choice for third- or greater-line therapy in patients who have failed prior anthracycline therapy. Eribulin was compared with dacarbazine in a phase III trial for patients with LMS or adipocytic sarcoma who had received two or more lines of therapy and had also received prior anthracycline therapy. There was no statistically significant difference between the two arms in terms of PFS (2.6 months in each arm) or the percentage of patients who were progression free at 12 weeks (33 versus 29 percent). Treatment with eribulin was associated with a small increase in OS (13.5 versus 11.5 months) for the overall cohort, but OS was not superior with eribulin in the LMS subset (12.8 months with eribulin versus 12.3 months with dacarbazine). In the LMS subset, PFS was 2.2 months with eribulin and 2.6 months with dacarbazine [72].

Endocrine therapy — The aromatase inhibitors (anastrozole or letrozole) have been associated with low ORR (less than 10 percent) in patients with LMS [73-76]. However, for some patients with estrogen receptor- or progesterone receptor-positive LMS, and in whom the disease burden is low and the disease pace is indolent, treatment with hormone blockade may be reasonable [77].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine cancer".)

SUMMARY AND RECOMMENDATIONS

●Introduction – Uterine leiomyosarcoma (LMS) is a rare and aggressive uterine malignancy that arises from the smooth muscle of the uterine wall. (See 'Introduction' above.)

●Staging – LMS is surgically staged according to the 2017 International Federation of Gynecology and Obstetrics/Tumor, Node, Metastasis classification system (table 1). This is the same staging system that is used for endometrial stromal sarcoma but differs somewhat from the staging system for uterine adenosarcoma (table 1). (See 'Staging' above.)

●Surgery

•Preoperative or intraoperative diagnosis – For patients in whom the diagnosis of LMS is made preoperatively (see 'Preoperative or intraoperative diagnosis' above):

-We recommend a total hysterectomy for patients with disease confined to the uterus rather than nonoperative therapy (Grade 1B). We suggest a bilateral salpingo-oophorectomy (BSO) at the time of surgery in perimenopausal and menopausal patients (Grade 2C). There is no proven benefit of BSO in premenopausal patients. (See 'Disease confined to the uterus' above.)

-For patients with disease that has spread beyond the uterus but is confined to the peritoneal cavity, we suggest surgical cytoreduction (Grade 2C).

-We limit pelvic lymphadenectomy to patients with pelvic nodes that are palpably enlarged intraoperatively. (See 'Indications for lymphadenectomy' above.)

•Postoperative diagnosis – For patients whose hysterectomy specimen is found postoperatively to be LMS, a second surgical procedure for the sole purpose of staging is not required. Further surgical management depends upon the initial procedure and patient characteristics:

-For patients who underwent a supracervical hysterectomy (or myomectomy), we suggest removal of the cervix or hysterectomy and resection of any residual disease (Grade 2C).

-For patients in whom the tumor was morcellated at the time of surgery, we suggest surgical exploration (Grade 2C), with the goal of assessing for residual disease and resection of disease if amenable to complete resection.

●Indications for adjuvant therapy

•For patients with newly diagnosed uterine LMS that is limited to the body of the uterus, we suggest observation rather than adjuvant chemotherapy (Grade 2C). We recommend against pelvic RT in these patients (Grade 1B). Enrollment in clinical trials investigating the role of adjuvant therapy compared with observation should be encouraged. (See 'Early-stage disease' above.)

•For patients with stage III or IV LMS that is completely resected, we suggest chemotherapy rather than observation (Grade 2C). (See 'Advanced disease' above.)

●Post-treatment surveillance – For all patients with newly diagnosed LMS, surveillance examinations and imaging is recommended due to the high risk of relapse, regardless of stage. (See 'Post-treatment surveillance' above.)

●Local recurrence or metastatic disease

•Local recurrence or limited metastatic disease – For patients with localized recurrence or limited metastatic disease that is amenable to complete resection, we suggest surgical resection (Grade 2C) or consideration of local ablation techniques. (See 'Local recurrence or oligometastatic disease' above.)

•Unresectable disease – For patients with metastatic, unresectable disease, treatment is administered with palliative intent. Chemotherapy is a reasonable option for patients with metastatic LMS who maintain a good performance status and in whom organ function permits the use of cytotoxic chemotherapy. For other patients, we suggest palliative care.

-For patients with metastatic disease who are chemotherapy naïve, we suggest fixed-dose-rate gemcitabine plus docetaxel or doxorubicin (with or without trabectedin) as first-line therapy (Grade 2C). (See 'Preferred options for first-line therapy' above.)

-For patients who progress after fixed-dose-rate gemcitabine plus docetaxel and/or doxorubicin, the choice among chemotherapy options is based on patient preference, organ function, and performance status. For patients with hormone receptor-positive LMS, in whom the disease burden is low and the pace of disease is indolent, hormone-blockade therapy may be an alternative treatment option. (See 'Metastatic disease' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Nadeem R Abu-Rustum, MD, who contributed to an earlier version of this topic review.