Gary S. Leiserowitz
Sarcomas comprise approximately 3% to 7% of uterine corpus malignancies. Although they represent a small proportion of uterine cancers, they disproportionately contribute to mortality. Their biologic behaviors are highly variable, ranging from a locally invasive process with minimal metastatic risk to highly aggressive tumors that are characterized by intra-abdominal or disseminated hematogenous spread. This reflects the complex origin of the malignant tissue components: endometrium, endometrial stroma, and smooth muscle, plus supportive elements of the uterine corpus.
EPIDEMIOLOGY
Key Points
1. Uterine sarcomas represent only 3% to 7% of all uterine malignancies.
2. The median age for patients with uterine sarcomas is 57 years, but patients with carcinosarcoma are approximately 10 years older.
3. African American women have a higher incidence of both leiomyosarcomas and carcinosarcomas.
4. Carcinosarcomas have been associated with a history of previous pelvic radiation and previous tamoxifen use.
Using Surveillance, Epidemiology, and End Results (SEER) data from the National Cancer Institute from 1988 to 2001, there were 48,642 uterine malignancies, of which 3742 were uterine sarcomas (7.7%).1The relative proportions of the 4 major uterine sarcoma categories are noted in Table 7-1.2 Carcinosarcomas are now considered to be an aggressive, dedifferentiated, or metaplastic form of endometrial cancer, and some authors therefore exclude them from the uterine sarcoma classification list.3 However, the vast majority of previous clinical studies have included carcinosarcomas with other uterine sarcomas, and that convention is followed in this chapter. The World Health Organization (WHO) classification scheme for uterine sarcomas is noted in Table 7-2,4 and uterine sarcomas are divided into 2 large pathologic categories: mesenchymal and mixed epithelial and mesenchymal tumors. Table 7-2includes common and uncommon variants, as well as benign tumors (eg, leiomyomas, adenofibromas), malignant tumors (eg, leiomyosarcomas, carcinosarcomas), and those of uncertain malignant behavior (eg, smooth muscle tumor of uncertain malignant potential [STUMP]).
Table 7-1 Percentage of Histologic Categories of Uterine Sarcomas
Table 7-2 World Health Organization Classification System of Uterine Sarcomas4
The median age for patients with uterine sarcomas (excluding carcinosarcoma) is 56.6 years, with a range of 20 to 90 years, based on Cancer Registry data from Norway.5 The median ages for the various histologies are as follows: leiomyosarcoma, 56.6 years; endome-trial stromal sarcoma, 50.7 years; adenosarcomas, 65.7 years; and undifferentiated sarcoma, 58.6 years. Only 41% of women with leiomyosarcoma are post-menopausal.6 The average age of patients with carcinosarcoma tends to be approximately 10 years older than for other sarcomas, with a mean of 65 years.7 The incidence of carcinosarcoma increases with age.8
The incidence of uterine malignancies (endome-trial adenocarcinoma and uterine sarcomas) varies significantly by race.9 Taken from SEER data, Table 7-3 shows that both carcinosarcomas and leiomyosarcomas are quite infrequent as compared with endometrial adenocarcinomas in all ethnicities. Endometrial adenocarcinomas are approximately half as frequent in Hispanics and blacks. Hispanics have approximately the same incidence of leiomyosarcomas, and a slightly decreased incidence of carcinosarcoma, as compared with whites. Blacks have a significantly higher risk of carcinosarcomas and leiomyosarcomas as compared with whites. Brooks also used SEER data and showed that the age-adjusted incidence of uterine sarcomas in blacks was twice that of whites and other races.8 They found that even with a racial difference in sarcoma incidence, the survivals of white and black women who received comparable treatment were equivalent.
Table 7-3 Incidence of Malignant Uterine Corpus Tumors by Histopathologic Category, Race, and Ethnicity: SEER Data (1992-1998)
Several factors may increase the risk of uterine sarcomas. Radiation therapy is commonly noted to be associated with development of carcinosarcomas. Up to 37% of carcinosarcoma patients have a precedent history of pelvic radiation.2,3 The radiation is more frequently administered for a nongynecologic indication (eg, colon cancer) than for a previous gynecologic malignancy. In contrast, previous radiation is rarely reported with leiomyosarcomas. Giuntoli et al6 reported only 1 of 208 uterine leiomyosarcoma patients who had previous radiation.
Tamoxifen, a selective estrogen receptor modulator, is associated with an increased risk of endometrial cancer because of its agonistic effects on the genital tract, including the uterus. Several case studies also report a higher than expected rate of high-grade uterine cancers, including sarcomas. An early report from the Yale Tumor Registry appeared to show that tamoxifen-associated endometrial cancers behaved more aggressively and had a worse prognosis.10 Recent case reports also suggested higher rates of uterine carcinosarcoma.11,12 Barakat13 performed a literature review of tamoxifen-related uterine malignancies and concluded that the rate of high-risk uterine malignancies, including carcinosarcoma, was not different from that of non–tamoxifen-related cancers. Clinicians should recognize that some patients with tamoxifen-related cancers may be at risk for uterine carcinosarcoma.
DIAGNOSIS
Key Points
1. Common symptoms include abnormal uterine bleeding, vaginal discharge, pelvic mass, abdominal/pelvic pain, and occasionally constitutional symptoms.
2. Endometrial sampling (with or without hysteros-copy) is typically diagnostic, although leiomyosarcomas may be missed.
3. Imaging tests typically demonstrate a uterine mass, either involving the endometrial cavity of uterine wall. Magnetic resonance imaging may distinguish between benign and malignant tumors, but the diagnostic accuracy is limited.
4. Preoperative imaging tests (eg, chest x-ray, computed tomography or positron emission tomography/computed tomography scans) are valuable to identify patients with uterine sarcomas who have distant metastases, which may influence surgical management.
Patients with uterine sarcomas present with various symptoms depending on the location of the sarcoma. When the endometrium is involved (carcinosarcoma or endometrial stromal sarcoma), abnormal uterine bleeding is usually the first symptom. Even leiomyosarcomas cause abnormal bleeding in 40% of patients. Vaginal discharge (watery or mucous) is commonly seen as well. The malignant tumors can fill the endometrial cavity and the polypoid tumor can protrude through the cervix into the vagina. The uterus is often enlarged, resulting in a palpable pelvic mass. Pain is associated with either an enlarged uterine mass or advanced-stage disease. Locally extensive disease can involve the vagina or parametria or invade the bladder or rectum, resulting in symptoms. Parametrial extension can cause ureteral obstruction, leading to hydronephrosis and flank pain. Advanced-stage disease is often accompanied by constitutional symptoms (fatigue, weight loss, anorexia) and/or medical complications such as venous thromboembolism.
The diagnostic evaluation usually follows from the presenting symptoms. Vaginal bleeding from an endometrial tumor is an indication for endometrial sampling either with an endometrial biopsy or with hysteroscopically directed endometrial sampling. An endometrial biopsy is more than 90% sensitive to detect malignancy when it is present (especially because the lesions often fill the uterine cavity), but sampling error can result in a false-negative result. Persistent abnormal uterine bleeding should always be further investigated, and hysteros-copy is quite effective.
Pelvic ultrasounds are commonly used as an initial diagnostic evaluation for uterine bleeding instead of endometrial sampling because it is very reassuring if normal (ie, it has a high negative predictive value). If a mass is detected in the endometrium on ultrasound, then endometrial sampling is the next step. If a mass is noted in the uterine wall, then the differential diagnosis will include a benign leiomyoma versus a leiomyosarcoma. The evaluation of a uterine wall mass can be problematic. Endometrial sampling may not be effective for diagnosis. Ultrasonic criteria to distinguish between a benign or malignant tumor include a diffuse irregular border, invasion, and a mixed echogenicity (indicative of hemorrhage or necrosis). Color flow Doppler may show irregular vessels with low impedance and high systolic velocities.14The detection of a rapidly growing uterine mass is considered a classic presentation for a leiomyosarcoma, but the actual risk is very low, and none of 198 such patients had a sarcoma.15 The incidence of leiomyosarcoma contained within a leiomyoma is less than 1%, although the rate increases with age.16
Magnetic resonance imaging (MRI) is well-suited to delineating tissue planes and has some value in distinguishing between benign and malignant masses.17 In uterine leiomyosarcoma, the tumors have intermediate-signal intensity on T1- and T2-weighted images, with scattered foci of high-signal intensity on T2 weighting. Classically, leiomyosarcomas have an ill-defined irregular margin and intensely enhance after use of gadolinium contrast. Depending on the location within the uterine wall, it can cause distortion of the endometrial cavity. Endometrial stromal sarcomas usually invade the myometrium and are noted to have an irregular border. They have high-signal intensity on T2 weighting and variable signals on T1 weighting. Diffuse infiltration into adjacent tissues such as the parametrium and fallopian tube walls can be a distinguishing feature and indicates invasion of blood vessels and lymphatics. Contrast enhancement is commonly seen with endometrial stromal sarcomas. They can be confused with leiomyomas, but the latter are notable for well-defined margins. Carcinosarcomas have a mixed-signal intensity, corresponding to areas of necrosis and hemorrhage. Depending on the degree of invasion, there is a loss of the junctional zone between the endometrium and myometrium. Myometrial invasion can be assessed. Carcinosarcomas usually enhance in the early phase and persist in the delayed phase after use of contrast, which is unusual for endometrial cancers.
In patients with a known uterine sarcoma, various imaging tests can be used for preoperative staging, including a chest x-ray, computed tomography (CT) scan of chest/abdomen/pelvis, and even positron emission tomography (PET) scan. A high proportion of sarcoma patients do have advanced-stage disease, but it is unclear whether imaging tests contribute significantly to the clinical management. In a recent study, imaging tests altered therapy in only 9% of patients and had no effect on survival (when compared with histology, stage, and surgical resection).18 In the patient who appears to have clinical stage I disease, an imaging test that demonstrate metastases can lead the clinician to avoid unnecessary surgical staging (eg, a patient with lung metastases does not benefit from staging lymphadenectomy) and focus the clinician to consider best palliative care instead of curative intent. There does not appear to be any advantage to the use of a PET scan over a CT scan. Other tests such as bone scans and CT scans of the head should be limited to specific circumstances when bone or brain metastases are clinically suspected.
The gynecologist who sees a patient with abnormal uterine bleeding or a symptomatic uterine mass should consider uterine sarcomas in the differential diagnosis, but endometrial carcinoma and benign leiomyomas will be much more common. Simple diagnostic maneuvers such as an endometrial sampling and/or ultrasound will triage the majority of patients into low- and high-risk categories. If a uterine sarcoma is diagnosed, then the patient will be best managed by those with specialized expertise. However, a certain number of sarcoma patients will not be diagnosed until after hysterectomy, because preoperative testing is never completely predictive.
PATHOLOGY
Key Points
1. Uterine sarcomas can be either mesenchymal or mixed epithelial and mesenchymal tumors.
2. Leiomyosarcomas are characterized by a high mitotic index, hypercellularity, nuclear atypia, and coagulative necrosis.
3. Endometrial stromal sarcomas are typically low-grade, indolent tumors with infiltrating tumor borders, a low mitotic count and mild nuclear atypia. They must be distinguished from endome-trial stromal nodules, cellular leiomyomas, and undifferentiated endometrial sarcomas.
4. Carcinosarcomas likely represent undifferentiated metaplastic endometrial carcinomas. These meta-plastic tumors have both malignant epithelial and mesenchymal components (the latter of which can be homologous or heterologous). The malignant epithelial component is usually responsible for metastases.
5. International Federation of Gynecology and Obstetrics staging was modified in 2009. Carcinosarcomas are staged as endometrial cancers. Leiomyosarcomas, endometrial stromal sarcomas, and adenosarcomas have new staging criteria derived from the knowledge of soft tissue sarcomas.
Uterine sarcomas are named based on their tissue origin (refer to Table 7-2 for the WHO classification system)—either mesenchymal or mixed epithelial and mesenchymal tumors.
They derive from the endometrium, endometrial stroma, and uterine smooth muscle, plus rare variants derived from other supportive tissue elements such as blood vessels. Several of the sarcomas may have extra-uterine sites as the origin for tumors, such as carcinosarcoma from the ovary or pelvic endometriosis or a leiomyosarcoma of the fallopian tube. The pathologic diagnosis may be problematic at times, with several variants having confusing and subtle tumor characteristics that make distinguishing among the entities challenging. In these cases, review of the pathology slides by an expert gynecologic pathologist will be the key to establishing an accurate diagnosis, because the treatment and prognosis can be dramatically different.
Leiomyosarcoma
These are sarcomas derived from the smooth muscle of the uterus. Leiomyosarcomas typically arise de novo and rarely transition from a benign leiomyomas. Grossly, they are large, solitary, fleshy masses that are greater than 10 cm in diameter and are poorly circumscribed.19 Intratumoral hemorrhage and necrosis are commonly seen. The mass can be confined to the uterine wall or burst into the abdominal cavity associated with hemoperitoneum. Characteristic pathologic features include a mitotic index > 15 mitoses/10 high-power field (hpf), hypercellularity, nuclear atypia, and coagulative tumor cell necrosis.3Examples of a high-grade leiomyosarcoma are seen in Figures 7-1A and 7-1B. The pathologic diagnosis for most leiomyosarcomas is straightforward, because most tumors contain most of these features. There are a number of tumors, though, that do not contain all of these features, and their biologic behavior can be more difficult to predict.20 Other features that support the diagnosis of leiomyosarcoma include age > 51 years, extrauterine disease, tumor size > 10 cm, and an infiltrating border.3 Expression of receptors for estrogen, progesterone, and androgens can be seen in 30% to 40% of leiomyosarcomas, but their presence does not necessarily imply hormonal responsiveness.
FIGURE 7-1. High-grade leiomyosarcoma. A. There is a sharp demarcation between an area of coagulative necrosis (bottom) and a proliferation of atypical spindle cells (top). ×100 magnification. B.Spindle cell proliferation with marked nuclear atypia. An atypical mitotic figure (arrow) is present. ×200 magnification.
Some smooth muscle tumors appear atypical and have some worrisome features; these should be classified as leiomyomas (eg, mitotically active leiomyoma, cellular leiomyoma, leiomyomas with bizarre nuclei; see Table 7-2 for other examples). Smooth muscle tumors of uncertain malignant potential (STUMP) can also be mistaken for leiomyosarcomas. The pathologic criteria for STUMP include (1) tumor cell necrosis in a typical leiomyoma, (2) necrosis of uncertain type with ≥ 10 mitoses/10 hpf or marked diffuse atypia, (3) marked diffuse or focal atypia with borderline mitotic counts, and/or (4) necrosis difficult to classify.3 These tumors can be mistaken for low-grade leiomyosarcomas, but their behavior is actually bland with few documented recurrences.
The metastatic spread pattern includes local extension, intra-abdominal dissemination, lymphatic, and hematogenous. The lungs are a common source of distant metastases. Lymphatic involvement is variable, ranging from 3.5% to 11%.6,21 Surgical staging is not considered valuable, because nodal involvement is commonly associated with other extrapelvic metastatic disease6 and even patients with apparent stage I tumors have a very high relapse rate.
Endometrial Stromal Sarcoma
This is the second most common sarcoma of pure mesenchymal origin, deriving from the endometrial stroma. Endometrial stromal sarcoma is by definition a low-grade malignancy and must be distinguished from an endometrial stromal nodule and an undifferentiated sarcoma (previously referred to as a high-grade endometrial stromal sarcoma). Endometrial stromal sarcoma is an irregularly shaped nodular growth emanating from the endometrium to infiltrate into the myometrium. The mass may include worm-like plugs that may fill the myometrial veins and extend into the broad ligament, pelvic vessels, and even to the right side of the heart.22 Microscopically, the mitotic count is usually < 5 mitoses/hpf, and there is mild nuclear atypia (Figures 7-2A and 7-2B). The cells are round or spindle-shaped and resemble endometrial stroma. There is an infiltrating border of endometrial stromal sarcoma into the myometrium, and vascular invasion is common. Necrosis is unusual.3 Estrogen receptor (ER) and progesterone receptor (PR) can be identified with immunohistochemistry and may reflect hormonal response to progestational agents.
FIGURE 7-2. Endometrial stromal sarcoma. A. Proliferation of endometrial stromal cells. Note the irregular, infiltrating margin. ×100 magnification. B. The neoplastic cells resemble endometrial stromal cells with bland, uniform, round to ovoid nuclei and scant cytoplasm. ×200 magnification.
The pattern of metastatic spread includes local extension, vessel permeation, and nodal spread. Up to 33% of endometrial stromal sarcoma patients have nodal spread. Late recurrences are occasionally seen and are most common in the pelvis and abdomen, but sometimes in the lungs. The indolent nature of endome-trial stromal sarcoma, even when recurrent, allows for various salvage treatments, including surgical resection, regional radiation, and use of hormonal agents such as progestins or aromatase inhibitors. Endometrial stromal sarcoma can also occur in extrauterine locations in the pelvis (ovary, fallopian tube, parametrium, and retroperitoneum). The distribution may reflect an association with extrauterine endometriosis.22
Endometrial Stromal Nodule
This is a rare, benign tumor that superficially resembles endometrial stromal sarcoma. On gross appearance, there is also a tumor mass from the endometrium pushing into the myometrium, with a size ranging from a few centimeters to 22 cm. Endometrial stromal nodules are fleshy and tan-yellow in color. They are circumscribed, but non-encapsulated. Microscopically, they have uniform, small, bland cells that resemble endometrial stromal cells. The distinguishing features of an endometrial stromal nodule are that there are “pushing” borders (instead of infiltrating borders seen with endometrial stromal sarcoma) and no vascular invasion.23 There may be tongues of tumor extending between muscle fascicles. The diagnosis can be suspected with endometrial curettage, but the distinction between endometrial stromal sarcoma and a stromal nodule is best determined after examining the hysterectomy specimen because the prognosis is quite different between the two. Endometrial stromal nodule can be confused with a cellular leiomyoma, but there are histologic and immunohistochemical differences that will assist with the differential diagnosis.23
Undifferentiated Endometrial Sarcoma
These tumors were previously called high-grade endometrial stromal sarcomas, but current classification limits endometrial stromal sarcoma to low-grade tumors. Undifferentiated endometrial sarcomas are very aggressive malignancies with a high propensity for hematogenous spread, resulting in distant metastases. In contrast to endometrial stromal sarcoma, undifferentiated endometrial sarcoma tumors are often noted to have necrosis and hemorrhage. Microscopically, the cells show marked cellular pleomorphism, nuclear atypia, and a brisk mitotic rate greater than 10 mitoses/10 hpf.3,23 There is destructive infiltration into the myometrium.
Necrosis is present. Undifferentiated endometrial sarcomas can be confused with some carcinosarcomas, adenosarcomas with sarcomatous overgrowth, or muscle differentiation indicative of a leiomyosarcoma or rhabdomyosarcoma. The differential diagnosis is dependent on extensive tumor sampling and use of immunohistochemistry stains.
The pattern of spread for undifferentiated endometrial sarcomas includes local extension, regional nodal metastases, and distant metastases. In 2 series, 50% to 61% of high-grade endometrial stromal sarcomas were noted to be stage III or IV at presentation in contrast to 23% to 31% for low-grade endometrial stromal sarcoma.24,25 Involvement of the pelvic and/or para-aortic nodes was noted to range between 12% and 18%.25,26 Relapse has been documented in the pelvis, abdomen, lymph nodes, and lungs.24
Carcinosarcoma
Also known as malignant mixed mullerian tumors (MMMT), carcinosarcomas are biphasic with both malignant epithelial and mesenchymal elements. A number of potential etiologic hypotheses have been proposed for the pathogenesis of carcinosarcomas, including the possibility of a collision tumor, but most authors have now coalesced around the theory that they are metaplastic cancers derived from a monoclonal population of dedifferentiated stem cells.27 The biologic aggressiveness is driven largely by the carcinomatous component. The behavior and pattern of spread is most similar to that of high-grade endome-trial adenocarcinoma and therefore is considered with this group of tumors.
Carcinosarcomas are usually bulky, polypoid masses arising from the endometrium and often prolapsing through the cervical os.3 Necrosis, hemorrhage, and cystic changes are noted when the uterine specimen is cut open. Gross myometrial invasion is typically seen. The tumors can be confined to an endometrial polyp or involve the entire endometrial cavity, with a size ranging up to 20 cm. Microscopically, the carcinomatous component is usually high grade, with two-thirds being serous and one-third being endometrioid, although other histologies such as clear cell can be seen.28 The mesenchymal elements can be either homologous (usually spindle cell or pleomorphic, but occasionally leiomyosarcoma) or heterologous (including rhabdomyosarcoma, chondrosarcoma, and osteosarcoma). See Figures 7-3A and 7-3B.
FIGURE 7-3. Carcinosarcoma (malignant mixed mullerian tumor). A. Malignant glands and stroma. Note the stromal mitotic figure (arrow). ×200 magnification. B. Heterologous elements are present; malignant cells with abundant eosinophilic cytoplasm show rhabdoid differentiation. ×400 magnification.
Metastatic spread to the pelvic and para-aortic lymph nodes is the predominant pattern, occurring in 32% of surgically staged patients in one series.29 Other sites include ovaries, fallopian tubes, omentum, and other intra-abdominal organs.30 This pattern of spread is similar to what is seen with high-grade endometrial cancers, although with a higher frequency. The risk of metastasis is related to depth of myometrial invasion, but even if the tumor appears confined to an endometrial polyp, there is still significant risk. The metastatic component is usually epithelial, although sarcomatous and mixed components are also seen.3,22 In a study from MD Anderson Cancer Center, recurrences were noted in 56% of carcinosarcomas seen from 1955 to 1981. The pattern of relapse was locoregional alone (pelvis and vagina) in 10% and distant (abdomen, lungs, supraclavicular nodes) in 49%. The distant recurrences were responsive for 84% of first recurrences and likely reflects that almost all patients received adjuvant whole-pelvic radiation therapy.31
Adenosarcoma
This is an unusual tumor of mixed epithelial and mesenchymal histologies. In contrast to carcinosarcomas, adenosarcomas are usually low-grade, indolent tumors. The tumor mass usually emanates from the uterine cavity, but the cervix can also be the origin.23 A polypoid lesion often fills the cavity and protrudes through the cervix. The tumor margin is usually clear. On microscopic examination, a benign gland is associated with a low-grade sarcomatous element that is typically of the endometrial stromal type. Modest mitotic activity and mild to moderate nuclear atypia are present.3 The sarcoma is typically homologous, but can be heterologous in uncommon cases. A high percentage of cases express both ER and PR positivity. Adenosarcomas usually act in an indolent fashion and remain confined to the uterine corpus. Relapses can be seen in the vagina, pelvis, and abdomen and can be late occurrences.
An unusual variant is adenosarcomas with sarcomatous overgrowth. In contrast to adenosarcomas, the sarcoma is high grade, and the tumor behavior is aggressive. In a retrospective case series, adenosarcomas with sarcomatous overgrowth were noted to have a higher risk of metastasis to the regional lymph nodes and worse prognosis even when compared with carcinosarcomas from the same period.32
FIGO Staging
FIGO made changes in the staging system of uterine sarcomas in 2009. New staging systems were developed for leiomyosarcomas and endometrial stromal sarcomas with adenosarcomas (Table 7-4).33Because carcinosarcoma are considered to be an aggressive form of endometrial cancer, the staging classification is the same [refer to FIGO staging system in Chapter 6]. FIGO noted that the behavior of the uterine sarcomas, other than CS, is qualitatively different from that of endometrial cancer. Somewhat arbitrarily, it was decided that the staging system for soft tissue sarcomas was a better model for these entities, and therefore further refinements in the current system will await the collection of further data. The American Joint Commission on Cancer (AJCC), which uses the TNM system, has adopted the FIGO 2009 modifications in its most recent edition, which maintains concurrence between the two.
Table 7-4 Staging for Uterine Sarcomas (Leiomyosarcomas, Endometrial Stromal Sarcomas, Adenosarcomas, and Carcinosarcomas)33
TREATMENT
Key Points
1. Standard primary surgical treatment for most uterine sarcomas includes a total hysterectomy and bilateral salpingo-oophorectomy. Surgical staging of the pelvic and para-aortic nodes may be helpful for carcinosarcomas and has less or uncertain value when managing the other uterine sarcoma types. Aggressive tumor debulking may be valuable when there is extrauterine spread.
2. Chemotherapy provides a high response rate in patients of advanced-stage uterine sarcomas, but duration of response is often limited.
3. Most uterine sarcomas are radiosensitive, and therefore, whole pelvic radiation improves pelvic control in the majority of patients. However, improved pelvic regional control does not usually improve overall survival.
4. Hormonal therapies (eg, progestins and aromatase inhibitors) may be effective for metastatic or recurrent uterine sarcomas that express ER and PR (eg, low-grade endometrial stromal sarcomas).
The treatment plans for the various uterine sarcomas are often mired in controversy because (1) these are rare tumors with limited clinical data; (2) the classification of the tumor types has been inconsistent, confusing, and/or lumped together, making assessments of therapeutic response challenging; (3) several of the malignancies are highly aggressive, and many current therapies are ineffective; and (4) there have been few randomized controlled clinical trials, so most of the therapeutic information is derived from case series. The best treatment plans are based on understanding the biologic behavior of the malignancy, the typical pattern of spread and/or relapse, a determination of therapeutic intent (eg, curative, adjuvant, palliative), and assessment of therapeutic efficacy versus treatment toxicity. Assessment of the cancer stage is important to make rational decisions about treatment options. Multimodality treatments are common for uterine sarcomas, but an honest appraisal of benefits and risks should be discussed with the patient and her family when aggressive therapies are offered. A summary of treatment options is noted in Figure 7-4 and includes many aspects from the uterine sarcoma practice guidelines from the National Comprehensive Cancer Network.34
FIGURE 7-4. Treatment summary by stage. Please see the Treatment section for details. Clinical trials should be considered for all patients, when available. Supportive care should be considered for advanced or recurrent disease that is incurable. BSO, bilateral salpingo-oophorectomy; chemo, chemotherapy; CS, carcinosarcoma; ESS, endometrial stromal sarcoma; LS, leiomyosarcoma; RT, radiation therapy. (Adapted from National Comprehensive Cancer Network Guidelines, 2010).34
Surgery
Primary surgery has several important goals, including primary treatment of the malignancy, surgical staging, and relief of symptoms (eg, uterine bleeding, pelvic pain, bowel obstruction). The components for surgical treatment of uterine sarcomas generally include (1) total hysterectomy, (2) bilateral salpingo-oophorectomy, (3) staging of the pelvic and para-aortic lymph nodes, and (4) cytoreduction of intra-abdominal disease. The therapeutic intent should be thoroughly considered before the patient goes to the operating room, because operations on patients with advanced-stage uterine sarcoma can be fraught with a high risk of morbidity (and occasionally perioperative death). When advanced-stage disease is suspected before surgery, then preoperative imaging is valuable to help with decision making about the roles of surgical staging, tumor debulking, and symptom relief.
Leiomyosarcoma
Evidence supports a hysterectomy, with or without oophorectomy, and possible cytoreduction to no gross residual disease. There is no evidence that lymphadenectomy is beneficial. Fewer than 50% of patients with leiomyosarcoma have a preoperative biopsy showing leiomyosarcoma, which means that the pathologic diagnosis is usually made after hysterectomy. Lymph node metastases occur infrequently (3.5%-11%)6,21,35 and usually in the setting of other extrauterine disease.6,35 Identification of lymph node metastases probably has only prognostic value, because survival with positive nodes is rare, even with adjuvant treatment. Also, lymphadenectomy by itself does not appear to affect survival.35 Consequently, surgical staging, either at the time of hysterectomy or after hysterectomy, is not justified. There may be some survival advantages to tumor debulking at the time of primary surgery, but only if all gross tumor is resected.36 Attempts at aggressive cytoreduction should be balanced with the understanding that the morbidity can be high, and current adjuvant chemotherapy has limited efficacy. In rare circumstances with a long disease-free interval, complete resection of recurrent leiomyosarcoma may be beneficial.37
Endometrial Stromal Sarcoma
Standard recommendations include a hysterectomy and possibly bilateral salpingo-oophorectomy. Although one-third of endometrial stromal sarcoma patients may have nodal metastases, the value of surgical staging is unclear because the pattern of relapse is often in the abdomen or lungs.38 Patients who have systematic lymphadenectomy do not experience recurrence in the retroperitoneal nodes,39 suggesting that there may be benefit to debulking enlarged nodes. Nonetheless, lymphadenectomy itself does not appear to improve survival.26 Patients with extrauterine disease, whether intra-abdominal or retroperitoneal, do appear to benefit from cytoreduction.14,39 In the study by Leath et al,25 optimal cytoreduction appeared to benefit only patients with high-grade endometrial stromal sarcoma.
Low-grade endometrial stromal sarcoma have a high rate of ER and PR positivity, and relapses are typically hormonally responsive. Therefore, conservation of the ovaries is controversial. Still, recurrence and survival are not adversely affected when the ovaries are left in situ,26,38,40,41 which suggests that ovarian conservation is a reasonable option in young, premenopausal women.
Endometrial Stromal Nodules
Endometrial stromal nodules are best treated by hysterectomy, primarily to endometrial stromal sarcomas, because the final pathologic diagnosis is based on thorough sectioning of the uterine specimen. Because these are not malignancies, neither an oophorectomy nor lymphadenectomy contribute to surgical treatment. In rare cases, where the stromal nodule is diagnosed by endometrial curettings and the tumor is well-defined on a pelvic MRI, then hysterotomy with resection to clear margins would be a consideration for a fertility-sparing procedure.
Carcinosarcoma
Because these are considered a high-grade, metaplastic, biphasic endometrial cancer, then the surgical treatment paradigm is parallel to what is recommended for high-grade endometrial cancers. This includes a hysterectomy, bilateral salpingo-oophorectomy, and staging of pelvic and para-aortic lymph nodes. Surgical staging clearly results in upstaging of patients with clinical stage I and II disease because the risk of nodal involvement is approximately 35%. There is some evidence suggesting that lymphadenectomy improves survival in early-stage carcinosarcoma.29,42,43 There is limited circumstantial evidence that optimal cytoreduction of intra-abdominal disease is beneficial,44,45 although it is sometimes performed after the same paradigm of ovarian cancer treatment. A major factor that impedes demonstrating the value of aggressive cytoreduction is the limited response rate to adjuvant chemotherapy and/or radiation therapy. Enthusiasm for aggressive surgery should be tempered with the understanding that many patients with carcinosarcoma are elderly and have a compromised performance status, which limits treatment tolerability.
Adenosarcoma
These tumors act in a similar manner to endometrial stromal sarcomas. Consequently, the recommendations for surgical treatment are comparable.14 Patients with adenosarcoma with sarcomatous overgrowth have an extremely poor prognosis, with a limited response to adjuvant treatment. Surgery should be guided by symptom relief and should include a hysterectomy to control vaginal bleeding. Consideration of any other surgical maneuvers should be tempered, weighing the limited benefits against potential morbidity.
Chemotherapy
There are a limited number of clinical trials available to assess the efficacy of chemotherapy for uterine sarcomas. Problems in interpreting these data result from a paucity of phase 3 comparative studies, failure to separate the different uterine sarcoma types, use of chemotherapy in patients who have also received radiation therapy, and limited numbers of trial participants. There are 3 indications for use of chemotherapy in the treatment of uterine sarcomas: as adjuvant treatment (after surgery), after recurrence, and for palliation. The majority of the data comes from studies of advanced-stage and recurrent disease, so evidence is lacking that demonstrates the efficacy of adjuvant use in early-stage disease to prevent recurrence. Because the risk of recurrence with leiomyosarcoma, carcinosarcoma, and undifferentiated endometrial stromal sarcoma is at least 50%, even with stage I disease, clinicians may feel compelled to offer adjuvant chemotherapy even in the absence of documented efficacy.
Early clinical trials of chemotherapy did not separate out the different uterine sarcoma categories. One classic study randomized patients with uterine sarcomas (leiomyosarcoma and carcinosarcoma) to use of doxorubicin versus placebo in stages I and II disease.46 Radiation therapy was given in a nonrandomized fashion. Overall progression-free survival and overall survival were not improved when the groups were combined. Recurrences appeared to be less frequent in the leiomyosarcoma patients who received doxorubicin versus no chemotherapy (44% vs. 61%), but no statistical evaluation was done. Use of radiation therapy did not improve survival, but there were fewer vaginal recurrences in carcinosarcoma patients who received radiation, suggesting some local benefit.
Leiomyosarcoma
Responses to various single and combination chemo-therapeutic agents for advanced-stage and recurrent leiomyosarcoma are limited and primarily used for palliation. The response rates (complete plus partial) for the following single agents appear to be the best: doxorubicin (25%),47 ifosfamide (17%),48 paclitaxel (9%),49 gemcitabine (20.5%),50 and liposomal doxorubicin (16.1%).51 The current best combination chemotherapy for leiomyosarcoma is gemcitabine and docetaxel. In a phase II Gynecologic Oncology Group (GOG) study evaluating its use as a second-line therapy, gemcitabine and docetaxel provided a 27% response rate; an additional 50% of patients had stable disease.52 Median survival was greater than 5.6 months. In another phase II GOG study, this time using gemcitabine and docetaxel as first-line agents, the overall response rate was 35.8%, and another 26.2% of patients had stable disease. Median progression-free survival was 4.4 months, and overall survival was greater than 16 months. In both studies, myelosuppression was the most common toxicity, and the rate of grade 3 or 4 toxicity was moderate, with good tolerability. Other chemotherapy combinations show less activity and/or are more toxic.14
There are no separate studies that have tested the efficacy of adjuvant chemotherapy for early-stage leiomyosarcoma. The study by Omura, noted earlier, suggested that recurrences were decreased in leiomyosarcoma after adjuvant doxorubicin, but no separate survival data were available.46 Use of hormonal agents for low-grade leiomyosarcomas that are ER/PR positive is anecdotal and suggests some effectiveness. Several ongoing clinical trials are using targeted agents, such as trabectedin. One anti-angiogenesis agent, sunitinib, has been tested in advanced, recurrent leiomyosarcoma, but was found to be ineffective.53 A current phase III trial (GOG-250) is investigating whether bevacizumab (an anti-angiogenesis agent) with the current standard of docetaxel and gemcitabine adds additional benefit.
Carcinosarcoma
Response rates to single-agent chemotherapy for advanced-stage and recurrent carcinosarcoma are better than for leiomyosarcomas. The best ones include cisplatin (19%-42%),54,55 doxorubicin (19%),56ifosfamide (18%-36%),57,58and paclitaxel (18%).59 Combination chemotherapy regimens have been shown to have higher response rates in 2 phase 3 GOG trials. Cisplatin plus ifosfamide was better than ifosfamide alone (response rates, 54% vs. 36%), with improved progression-free survival (6 vs. 4 months), but overall survival was not statistically different.57 Another combination, ifosfamide plus paclitaxel, was compared with ifosfamide alone in advanced and recurrent carcinosarcoma in a phase 3 trial (GOG-161).60 The response rates favored the ifosfamide combination (45% vs. 29%). The progression-free survival and overall survival were both statistically better in the combination arm (5.8 vs. 3.6 and 13.5 vs. 8.4 months, respectively). The hazard of death was decreased 31% by the combination arm. The authors noted that the toxicities were predictable and manageable. Thus the GOG considered the combination of ifosfamide and paclitaxel to be the new standard treatment.
Several studies have recently evaluated carboplatin plus paclitaxel for treatment of advanced and recurrent carcinosarcoma. Hoskins et al61 reported that carboplatin plus paclitaxel showed a response rate of 60% for adjuvant treatment and 55% for recurrent carcinosarcoma, with minimal toxicity. The progression-free survival durations were 16 and 12 months, respectively. A recently reported study, GOG-232, was a phase 2 study of carboplatin and paclitaxel in patients with advanced, persistent, or recurrent carcinosarcoma.62 The response rate was 54% (13% complete responses, 41% partial responses), and 24% of patients had stable disease. The progression-free survival was 7.6 months, and overall survival was 14.7 months. Toxicity was very manageable, and 59% of patients completed ≥ 6 cycles, with no deaths attributable to chemotherapy. These results compare very favorably with ifosfamide and paclitaxel. Consequently, GOG has initiated another phase 3 trial to compare ifosfamide plus paclitaxel with carboplatin plus paclitaxel to assess survival and toxicity in carcinosarcoma.
Endometrial Stromal Sarcoma
Adjuvant treatment of endometrial stromal sarcoma is dependent on whether it is low grade or high grade (also known as undifferentiated endometrial sarcoma). Because low-grade endometrial stromal sarcoma often expresses ER and PR, the recommended initial treatment is hormonal.38 Choices include either a progestational agent such as megestrol or aromatase inhibitors. There are limited data supporting this recommendation, which is based largely on retrospective case series. In a review of uterine sarcomas, Amant et al14 noted that the reports on endometrial stromal sarcoma showed an overall response rate of 76% for progestational agents and that letrozole (an aromatase inhibitor) provided an 88% response rate. Undifferentiated endometrial sarcoma is typically not responsive to hormones. Some studies suggest that doxorubicin and ifosfamide are active agents with advanced and recurrent endometrial stromal sarcoma.63,64 A recommended chemotherapy combination is ifosfamide and doxorubicin.14
Adenosarcoma
Adenosarcomas typically have a low-grade stromal sarcoma in association with benign epithelium. Their behavior is similar to that endometrial stromal sarcoma, and so the paradigm for treatment is similar. Interestingly, adenosarcomas have a high rate of ER and PR positivity (90% in one immunohistochemistry study).65 Thus hormonal treatment of advanced and recurrent adenosarcomas should be considered. However, patients with adenosarcoma with sarcomatous overgrowth have far more aggressive disease that is unlikely to respond to hormonal manipulation. Two case reports noted an excellent response to liposomal doxorubicin, 66,67 and in one case, the tumor apparently did not respond to ifosfamide and cisplatin.
Radiation Therapy
Radiation therapy is most commonly used as adjuvant therapy after surgery for uterine sarcomas. There are limited cases in which radiation is used for palliation of local problematic recurrences or as primary therapy when surgery is deemed undesirable (eg, to control bleeding in a patient either with extensive locoregional spread into the pelvis or vagina or a patient with stage IV disease). Uterine sarcomas are radiosensitive as a group, and so radiation therapy is a valuable (and probably underused) tool for palliation of symptoms due to pain or bleeding. However, for the remainder of this discussion, we will limit consideration only to use of adjuvant radiation therapy.
The literature evaluating the efficacy of radiation therapy in the treatment of uterine sarcomas is difficult to interpret. In many cases, radiation therapy is not given alone, but rather is combined with chemotherapy, making it challenging to separate out the relative benefits of this modality. Similar to chemotherapy, studies have commonly combined the results of several categories of uterine sarcomas, so that the responses of the specific sarcoma types are hard to gauge. The vast majority of the studies are retrospective case series, and the limited number of cases diminishes the statistical power to find a difference in benefit. Nonetheless, there are several larger studies from which conclusions can be drawn.
Radiation is a locoregional treatment modality, meaning that cancer control is expected only within the radiation field. Those malignancies that have a significant risk of distant metastases (ie, hematogenous spread) would be unlikely to have an overall benefit with adjuvant radiation. The literature on use of adjuvant radiation therapy for uterine sarcomas consistently reflects this concept. Most studies fail to show an improvement in overall survival when adjuvant radiation is used alone. Studies that do show an improvement in pelvic control and overall survival are an exception.68,69
The largest phase 3 randomized controlled trial of adjuvant pelvic radiation versus no further treatment after surgery for stage I or II uterine sarcomas was completed by the European Organisation for Research and Treatment of Cancer.70 Thirteen years were required to accrue 224 patients, with 219 evaluable patients. Uterine sarcoma subtypes were included, with data on 99 leiomyosarcoma, 92 carcinosarcoma, and 30 endometrial stromal sarcoma patients. Neither disease-free nor overall survival was improved by use of adjuvant radiation. Locoregional control was improved for patients with carcinosarcoma, but not for patients with leiomyosarcoma.
Sampath reported on a nonrandomized, retrospective population-based study of 3650 uterine sarcoma patients, derived from 130 hospital tumor registries in the United States.71 They evaluated the use of adjuvant radiation using external-beam whole-pelvis radiation (with or without vaginal vault brachytherapy) after surgical treatment for uterine sarcomas. Uterine sarcoma subtypes were separated by type: 1877 carcinosarcomas, 920 leiomyosarcomas, 544 endometrial stromal sarcomas, 130 adenosarcomas, and 179 others. Some patients received chemotherapy, but the report did not note how many received it adjuvantly or for recurrences. Overall survival was not improved with use of radiation or chemotherapy. However, locoregional control was clearly improved for all uterine sarcomas (compared with no adjuvant radiation), and benefit was seen for carcinosarcoma, leiomyosarcoma, and endometrial stromal sarcoma. The benefit was even seen in sarcoma patients with negative lymph nodes (96% vs. 88%).
Several notable earlier GOG studies have also shown decreased rates of pelvic failures associated with adjuvant radiation to the pelvis.21,46,72 Thus adjuvant radiation does appear to provide improved locoregional control. The benefits of this are difficult to gauge, because recurrences are common outside of the radiation field, and overall survival is not improved.
The issue of multimodality therapy (adjuvant radiation plus chemotherapy) remains unsettled, especially for carcinosarcoma, where there seems to be more support. GOG-150 compared whole abdominal radiation (with a pelvic boost) versus 3 cycles of ifosfamide and cisplatin in patients with stages I to IV carcinosarcoma who were optimally debulked to less than 1 cm.73 Overall survival was better in the chemotherapy group, but the rate of vaginal failures was higher compared with the radiation therapy group. This suggests that adding radiation to chemotherapy might provide overall benefit. Menczer et al74evaluated the outcomes of 49 carcinosarcoma patients who were treated at 3 different hospitals where adjuvant treatment preferences varied (chemotherapy alone, whole pelvic radiation therapy alone, or sequential chemotherapy followed by whole pelvic radiation). This nonrandomized case series found that sequential therapy had superior 5-year survival as compared with chemotherapy alone (75% vs. 22%; P < .05), but was not statistically significant when compared with whole pelvic radiation (75% vs. 50.5%; P = .4). Cox proportion hazard modeling for survival favored sequential treatment versus either chemotherapy or radiation. A study from the Mayo Clinic reviewed their retrospective experience with 121 patients with stages I to IV carcinosarcoma and compared cancer characteristics and several treatment strategies (surgery alone, chemotherapy alone, pelvic radiation therapy alone, and combined adjuvant radiation and chemotherapy).75 They found that pelvic adjuvant radiation alone decreased the risk of vaginal recurrences, but had no effect on survival. However, both disease-free and disease-specific survivals were improved with multimodality treatment; however, the number of patients receiving both was small. In combination, these studies suggest that patients with optimally debulked carcinosarcoma may derive the most benefit from combined adjuvant chemotherapy and radiation, although the evidence is very limited.
SURVIVAL AND PROGNOSIS
Key Points
1. Tumor type and stage are the most important prognostic factors in uterine sarcomas.
2. The recurrence rate is greater than 50% in patients with high-grade, stage I uterine sarcomas, making long-term survival very challenging.
Survival in uterine sarcoma patients is highly dependent on the tumor type, and then stage. As noted previously, the various uterine sarcomas have biologic behaviors that range from indolent to highly aggressive with poor survival, even when the tumor is stage I. Figure 7-5 shows the crude survivals of patients with uterine sarcomas (with carcinosarcomas excluded) based on a Norwegian Cancer Registry from 1970 through 2000, which is highly accurate as all cancer cases are reportable by law.5 Similar data are available in the United States from SEER data from 1988 through 2001 and is stratified by AJCC stage as well as tumor type (carcinosarcoma and mullerian mixed tumors were reported separately; Figure 7-6 and Table 7-5).1
Table 7-5 Number, Distribution of Cases, and 5-year Relative Survival Rate by Tumor Types, AJCC Stage, Ages > 20 Years, SEER Data, 1988-2001
FIGURE 7-5. Crude survival by type of uterine sarcoma. AS, adenosarcoma; ESS, endometrial stromal sarcoma; LMS, leiomyosarcoma; UUS, undifferentiated endometrial or uterine sarcoma. (Reproduced with permission from Abeler et al.5)
FIGURE 7-6. Survival of patients with uterine sarcomas by American Joint Committee on Cancer stage. Age > 20 years, 1988-2001. (Reproduced with permission from Korsary.1)
The prognostic factors, other than tumor type and stage, are noted in Table 7-6. Not all studies confirm all of the prognostic factors, so various sources are cited.
Table 7-6 Adverse Prognostic Factors Associated With Uterine Sarcomas (Other Than Stage)
MANAGEMENT OF RECURRENT DISEASE
Key Points
1. Surveillance for patients with uterine sarcomas is comparable to that of patients with endometrial cancer and includes symptom history, examination, and consideration for serial imaging tests. The efficacy of surveillance is limited by the relatively poor response to salvage therapies, except for patients who have low-grade tumors.
2. Because most patients with recurrent uterine sarcoma have a limited-duration response to salvage treatment, palliation of symptoms is the primary therapeutic goal in most patients.
3. Some patients with low-grade, indolent sarcomas (eg, endometrial stromal sarcomas) can be successfully treated with salvage therapy using a combination of surgery, radiation, and/or hormonal treatments.
Surveillance of patients treated for a uterine sarcoma should follow the same approach as for endometrial cancer. Generally, surveillance includes an interval history, focused physical examination including a pelvic examination, and imaging tests based on symptoms. There is limited value to performing routine imaging tests for surveillance for most asymptomatic patients, although some clinicians recommend annual chest radiographs.
Recurrences are common with all of the uterine sarcomas, with the patterns of relapse noted in the preceding Pathology section. Most recurrences are fatal, unless the patient has an indolent tumor (eg, low-grade endometrial stromal sarcoma). Treatment of recurrent disease is highly dependent on the goals of treatment, the presence of symptoms, and the performance status of the patient. Many of the uterine sarcoma patients are older with a compromised medical status, which limits the options for treatment. In these patients, a frank discussion is appropriate, because responses to chemotherapy are less than 50%, and duration is limited to months. Thus consideration should be given to best supportive care for symptom palliation (which can include targeted radiation therapy) instead of aggressive chemotherapy.
There are several categories of patients who will benefit from treatment of recurrent disease. Patients with a long disease-free interval who experience recurrence with limited-volume disease are the best candidates for aggressive treatment. Classically, these patients have low-grade, indolent sarcomas (eg, endometrial stromal sarcomas). Isolated recurrences, even in the lungs, may be amenable to surgical resection followed by adjuvant treatment including radiation, hormones, and chemotherapy. The majority of patients with recurrent disease are not candidates for repeat surgery, and therefore treatment options include chemotherapy, hormones, and/or radiation. Patients with a good performance status should be offered chemotherapy. Several chemotherapy doublets for carcinosarcoma and leiomyosarcoma are active with very manageable toxicity. The potential agents are listed in the preceding Treatment section by sarcoma type. Patients with recurrent disease should be offered participation in clinical trials.
SPECIAL MANAGEMENT SITUATIONS
Ovarian Conservation
Low-grade leiomyosarcoma often is ER/PR positive (see preceding Pathology section). Therefore, concern has been raised about the deleterious effects of conserving the ovaries when a hysterectomy is done for leiomyosarcoma. Available literature does not show an adverse effect from ovarian conservation.6,35,36 Also, the risk of ovarian metastases is only approximately 4%, and typically the ovaries are grossly involved.35 Similarly, ovarian preservation does not appear to adversely affect recurrence or survival in low-grade endometrial stromal sarcoma.26,40 Consequently, in premenopausal women with leiomyosarcoma or endometrial stromal sarcoma, it is reasonable to conserve normal-appearing ovaries.
Rapidly Enlarging Leiomyomata
It is rare to find leiomyosarcoma in a myomectomy specimen performed as a fertility-sparing procedure.
In their review of 39 studies encompassing 6815 myomectomy patients from 1950 to 1993, Parker et al15 calculated the risk to be 0.29%. None of their 198 patients with rapidly enlarging fibroids had leiomyosarcoma. Lissoni et al78reported on 8 patients who were found to have leiomyosarcoma after a myomectomy who did not have a subsequent hysterectomy. Six of 8 patients had “pushing” tumor borders, and 2 patients had infiltrating borders. None had involvement of the endometrium. Three subsequent pregnancies were reported. One patient was noted to have recurrent leiomyosarcoma in the uterus at the time of cesarean section and later died of disseminated disease. Van Dinh and Woodruff79 reported on 9 patients found to have leiomyosarcoma associated with a myomectomy. Six patients were managed without hysterectomy, and 1 patient experienced disease recurrence. All appeared to have low-risk leiomyosarcoma (low mitotic count, no necrosis). There were 3 subsequent pregnancies. This suggests that uterine preservation may be an option in young women found to have leiomyosarcoma at myomectomy if given appropriate counseling about their risks.
FUTURE DIRECTIONS
The GOG has coordinated multiple previous cooperative group studies on uterine sarcomas, as noted in the preceding Treatment section. Two phase e studies are ongoing to investigate the best options for leiomyosarcoma and carcinosarcoma. In GOG-250, investigators are evaluating whether the addition of an anti-angiogenesis agent, bevacizumab, to the current standard combination chemotherapy (docetaxel and gemcitabine) improves progression-free survival in patients with recurrent or advanced uterine leiomyosarcoma. GOG-261 is designed to compare the current standard chemotherapy doublet (ifosfamide and paclitaxel, which showed superior results compared with ifosfamide alone in GOG-16160) with a commonly used regimen doublet (carboplatin and paclitaxel, which was shown to be effective and well-tolerated in GOG-232B and in a study by Hoskins et al61). Both studies will assess the effectiveness and tolerability of the treatment combinations to help clinicians in their choice of chemotherapy for the most common uterine sarcomas.
Investigators are also evaluating the feasibility of molecular targeted agents in the treatment of uterine sarcomas. Leiomyosarcomas express ER and PR in approximately 40% to 80% of patients, especially when tumors are low grade. Objective responses to either progestins or aromatase inhibitors have been noted in case reports. In a retrospective case series, 40 patients with advanced/recurrent leiomyosarcomas were treated with aromatase inhibitors.80The 1-year progression-free survival rate was 28% in ER/PR-positive leiomyosarcoma patients, versus 9% for all leiomyosarcoma patients. It is unknown whether the relatively prolonged survival reflected a therapeutic response or simply indolent tumor progression. Other trials using aromatase inhibitors are ongoing.
Use of anti-angiogenesis agents in leiomyosarcomas are also under investigation, examples of which have included thalidomide, sunitinib, and bevacizumab.53,81,82 The response rates to use of single-agent anti-angiogenesis agents have been limited, despite evidence that the vascular endothelial growth factor pathway activity is associated with poorer outcomes in uterine leiomyosarcoma. The combined use of an anti-angiogenesis agent along with conventional chemotherapy has proven to be more effective than either separately in several other solid tumors, including colon, lung, and breast cancers, and therefore is being tested with other gynecologic cancers such as ovarian cancer. This has been extended to include uterine leiomyosarcoma in GOG-250, as described earlier.
Anti-angiogenesis agents have been investigated in advanced and recurrent endometrial cancer. Bevacizumab has been used as a single agent in recurrent endometrial cancer (GOG-229E) and had 13.5% response rate, and 40.4% of patients were progression-free at 6 months of treatment, suggesting that it acts as a cytostatic agent. Other anti-angiogenesis agents under investigation include: vascular endothelial growth factor-trap, sorafenib, and sunitinib.83These agents appear to be candidates to be used in carcinosarcoma as well, given the current belief that carcinosarcoma is a form of poorly differentiated endometrial cancer.
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