Uterine sarcoma is a rare type of uterine cancer that makes up less than 1% of all gynecologic malignancies and only 2% to 5% of uterine malignancies. In the United States, uterine carcinoma has an annual incidence of 0.36 to 0.64 cases per 100,000 women.1

Uterine sarcomas are tumors in the myometrium or connective tissue of the uterus.1

There are 3 main subtypes of uterine sarcoma1,2:

  • Leiomyosarcoma, which is a tumor that originates from myometrial smooth muscle and accounts for approximately 30% of all uterine sarcoma;
  • Endometrial stromal sarcoma, which is a malignant tumor arising from the endometrium that accounts for up to 15% of all uterine sarcomas and has a high-grade component that is generally aggressive and a low-grade component  that typically demonstrates indolent behavior; and 
  • Undifferentiated uterine sarcoma, which is a malignant mesenchymal tumor without evidence of specific lines of differentiation that accounts for 40% to 50% of uterine sarcomas.

Other rare forms of uterine sarcoma include1,3:

  • Adenosarcoma, with benign epithelial elements within a malignancy mesenchymal background;
  • Rhabdomyosarcomas, which are diagnosed almost exclusively in infants;
  • Perivascular epithelioid cell neoplasm (PEComa), which is a perivascular epithelial-cell tumor; and
  • Mixed endometrial stromal and smooth muscle tumors. 

Symptoms of uterine sarcoma are usually nonspecific and may present in the following ways1,3:

  • Abnormal vaginal bleeding that is not part of a menstrual period
  • Vaginal bleeding after menopause 
  • Pelvic or abdominal pain
  • Abdominal mass 
  • Frequent urination
Axial T2-weighted magnetic resonance imaging (MRI) of the pelvis demonstrating uterine sarcoma.
Figure. Axial T2-weighted magnetic resonance imaging (MRI) of the pelvis demonstrating uterine sarcoma. Credit: Getty Images.

No specific serum tumor markers exist that are useful for diagnosis of uterine sarcoma. Therefore, the diagnosis should include ultrasound and magnetic resonance imaging (MRI) to differentiate between uterine sarcoma vs fibroid.1 As the sensitivity of endometrial or transvaginal biopsy is low, diagnosis is often made after analysis is performed of the surgically removed specimen.1 

The most commonly used staging system for uterine sarcoma is the International Federation of Gynecology and Obstetrics (FIGO) and the American Joint Committee on Cancer. Staging ranges from stage I to stage IV.1 

Overall, patients with uterine cancer have a 5-year survival rate of 81%,4 with the survival rate depending on the subtype and disease stage at diagnosis.1 Uterine sarcomas are typically more aggressive than other uterine cancers and have a high rate of recurrence and metastasis.1 The 5-year survival rate for patients with uterine sarcoma ranges from 31% to 64%.1,5 

Treatment for Uterine Sarcoma

Expert recommendations for the treatment of uterine sarcoma are not well defined due to the rarity and diversity of the disease as well as a lack of quality evidence. Treatment can be complicated because of a lack of well-designed clinical trials. The available evidence is often based on case series or clinical trials that combine uterine sarcoma with other soft tissue sarcomas.1  Guidelines established by the National Comprehensive Cancer Network (NCCN) strongly recommend that patients with uterine sarcoma enroll in a clinical trial for the best treatment.6 

Surgical management is the standard of care, regardless of the stage. The standard surgical procedure is a total hysterectomy with or without bilateral salpingo-oophorectomy.1 

Adjuvant radiation therapy is not considered standard of care for high-grade or low-grade uterine sarcoma. Radiation therapy may be considered in patients with certain risk factors such as serosal involvement or incomplete resection, or due to patient preference.1  

This article will summarize available systemic treatment options for uterine sarcoma, with a focus on the NCCN first-line treatment options. 


Several chemotherapy regimens are recommended as first-line treatment by NCCN (Table 1). Chemotherapy may be recommended for patients with the following subtypes of uterine sarcoma6:

  • High-grade endometrial stromal sarcoma
  • Undifferentiated uterine sarcoma
  • Leiomyosarcoma
  • PEComa

Chemotherapy is not recommended for patients with low-grade endometrial stromal sarcoma or adenosarcoma without sarcomatous overgrowth. Chemotherapy may be considered for patients with stages II, III, or IV adenosarcoma with sarcomatous overgrowth.6 

NCCN guidelines strongly recommend that patients enroll in a clinical trial.6 

Table 1. NCCN Preferred Chemotherapy Regimens for Uterine Sarcoma 

Chemotherapy RegimenDoseFrequency
DoxorubicinDoxorubicin 75 mg/m2Every 3 weeks 
Doxorubicin + ifosfamide Doxorubicin 50 mg/m2, ifosfamide 5 g/m2/24 h, and mesna 6 g/m2/36 h
Doxorubicin 75 mg/m2 via IV bolus or 72-hour continuous infusion and ifosfamide 10 g/m2 over 4 days 
Every 3 weeks 
Doxorubicin + trabectedinDoxorubicin 60 mg/m2 and trabectedin 1.1 mg/m2, followed by maintenance with trabectedin alone Every 3 weeks 
Gemcitabine + docetaxelGemcitabine 675 mg/m2 on days 1 and 8 and docetaxel 75 mg/m2 on day 8Every 3 weeks 
Doxorubicin + dacarbazineDoxorubicin 60 mg/m2 and dacarbazine 750 mg/m2 as a bolus or continuous infusion over 96 hoursEvery 3 weeks 

IV = intravenous.

From NCCN guidelines,6 Seddon et al,7 Sutton et al,8 Judson et al,9 Pautier et al,10 and Zalupski et al.11

First-line agents can be used as second-line agents if they were not previously used.6 

Second-line chemotherapy agents that may be used to treat uterine sarcoma include6:

  • Gemcitabine/dacarbazine
  • Gemcitabine/vinorelbine
  • Dacarbazine
  • Gemcitabine
  • Epirubicin
  • Ifosfamide
  • Liposomal doxorubicin
  • Temozolomide
  • Eribulin 

A review of first-line chemotherapy agents follows. 


Doxorubicin is an anthracycline topoisomerase inhibitor. Single-agent doxorubicin is considered the standard of care for uterine sarcoma. It can also be combined with other chemotherapy agents.1,6,12

Dosage and Administration

Doxorubicin is typically administered via intravenous (IV) push over 3 to 10 minutes but may be administered as a continuous infusion, based on the protocol (Table 1).9,12 

Doxorubicin has a moderate emetic potential and may require the administration of antiemetics before treatment.13 

Patients should be monitored for infusion reactions and extravasation during administration. The patient’s cumulative dose of doxorubicin should also be monitored. Between 1% and 20% of patients may experience cardiomyopathy with cumulative doses of 300 mg/m2 to 500 mg/m2.12

Dose adjustments may be necessary for patients with elevated total bilirubin concentrations and hepatic impairment.12 

Adverse Reactions

The most common adverse events associated with doxorubicin include12:

  • Alopecia
  • Nausea
  • Vomiting 

Serious warnings associated with doxorubicin include12:

  • Cardiotoxicity
  • Severe myelosuppression 

Drug Interactions

Doxorubicin is metabolized by cytochrome P450 (CYP) isoenzymes CYP3A4, CYP2D6, and P-glycoprotein (P-gp) and may have an interaction with inhibitors and inducers of these enzymes.12 

Doxorubicin should not be administered with other cardiotoxic drugs, such as trastuzumab.12 

Doxorubicin may increase the severity of radiation-induced toxicity.12


Ifosfamide is an alkylating agent that has been used in combination with doxorubicin to treat uterine sarcoma.6,14 

Dosage and Administration

Ifosfamide should be administered over a slow infusion of at least 30 minutes. Protocols for uterine sarcoma have used an ifosfamide infusion over several days (Table 1).8,9,14 

Mesna and extensive hydration (≥2 L/d of oral or IV fluid) should be administered in combination with ifosfamide to prevent hemorrhagic cystitis and bladder toxicity.14

Dose adjustments are necessary for patients with renal impairment or concomitant therapy with a CYP3A4 inducer.14 

Adverse Reactions 

The most common adverse reactions associated with ifosfamide include14:

  • Alopecia
  • Nausea and vomiting
  • Leukopenia
  • Anemia
  • Central nervous system toxicity
  • Hematuria
  • Infection 

Warnings and precautions for ifosfamide include14:

  • Myelosuppression
  • Neurotoxicity 
  • Urotoxicity
  • Cardiotoxicity 
  • Pulmonary toxicity
  • Anaphylactic reactions 

Drug Interactions

When ifosfamide is used concomitantly with CYP3A4 inducers, there may be increased ifosfamide-related toxicity. Dose adjustments may be necessary.14 

Concomitant use of ifosfamide and CYP3A4 inhibitors may decrease the efficacy of ifosfamide.14 


Trabectedin is an alkylating agent approved for use in patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have undergone prior treatment with an anthracycline-containing regimen.15 It can be used in combination with doxorubicin as a first-line therapy for leiomyosarcoma.6 

As a single agent, trabectedin is considered the preferred second-line regimen according to NCCN guidelines.6 

Dosage and Administration

As a single agent, the recommended dosage of trabectedin is 1.5 mg/m2 IV as a 24-hour infusion every 3 weeks through a central venous line. See Table 1 for dosing in combination with doxorubicin.15 

Patients should receive premedication with dexamethasone 20 mg IV, 30 minutes before trabectedin infusion.15 Due to its moderate emetic potential, antiemetics are also recommended.13 

Dose adjustments are necessary for patients with hepatic impairment.15 

Adverse Reactions

The most common adverse reactions associated with trabectedin include15:

  • Gastrointestinal (GI) effects (eg, including nausea, vomiting, constipation, diarrhea, and decreased appetite)
  • Fatigue
  • Peripheral edema
  • Dyspnea
  • Headache
  • Hematologic abnormalities (eg, neutropenia, thrombocytopenia, and anemia)
  • Increased alanine transaminase (ALT) and aspartate transaminase (AST) levels
  • Increase creatine phosphokinase level

Warnings and precautions for serious reactions associated with trabectedin include15:

  • Neutropenic sepsis
  • Rhabdomyolysis 
  • Hepatotoxicity
  • Cardiomyopathy 
  • Capillary leak syndrome 

Drug Interactions 

Trabectedin is metabolized by CYP3A isoenzymes; therefore, concomitant administration with strong CYP3A inducers or inhibitors should be avoided.15 


Gemcitabine is a pyrimidine antimetabolite that can be used in combination with docetaxel to treat uterine sarcoma.6,16 

Dosage and Administration

The manufacturer recommends that gemcitabine be infused via IV over 30 minutes.16 However, soft tissue sarcoma clinical trials used an infusion time of 90 minutes.7 There may be increased toxicity associated with infusion times longer than 60 minutes.16 

Dose adjustments may be necessary for toxicity. 

Adverse Reactions

The most common adverse reactions associated with gemcitabine are16:

  • Nausea and vomiting
  • Fever
  • Rash
  • Dyspnea
  • Hematologic effects (eg, neutropenia, leukopenia, and thrombocytopenia)
  • ALT and AST abnormalities
  • Alkaline phosphatase abnormalities
  • Proteinuria
  • Hematuria

Warnings and precautions for gemcitabine include16:

  • Myelosuppression
  • Pulmonary toxicity
  • Renal failure and hemolytic uremic syndrome
  • Hepatic impairment

Drug Interactions

No specific drug interaction studies have been conducted with gemcitabine. Although radiation is not a drug, it is worth noting that gemcitabine may increase radiation-induced toxicity.16 


Docetaxel is a microtubule inhibitor that can be used in combination with gemcitabine to treat uterine sarcoma.6,17 

Dosage and Administration

Docetaxel is administered via IV infusion over 60 minutes.17 

To prevent severe hypersensitivity, all patients should receive premedication with oral corticosteroids for 3 days starting 1 day before docetaxel administration.17 

Dose adjustments may be necessary for hepatic impairment or toxicities. Treatment-related mortality is increased in patients with abnormal liver function. Liver function tests should be performed before each treatment cycle, and docetaxel should not be given if bilirubin is greater than the upper limit of normal (ULN) or if AST and/or ALT are more than 1.5 times ULN with alkaline phosphatase more than 2.5 times ULN.17 

Docetaxel should also be held if the neutrophil count is fewer than 1500 cells/mm3. Frequent complete blood counts (CBCs) are necessary for close monitoring.17 

Adverse Reactions

The most commonly reported adverse reactions associated with docetaxel include17:

  • GI effects (eg, dysgeusia, constipation, anorexia, diarrhea, nausea, vomiting, and mucositis)
  • Hematologic effects (eg, neutropenia, anemia, and thrombocytopenia)
  • Skin effects (eg, nail disorders, alopecia, and skin reactions)
  • Febrile neutropenia
  • Hypersensitivity
  • Dyspnea
  • Myalgia 
  • Fluid retention

Serious reactions such as hypersensitivity and fluid retention may occur with docetaxel treatment despite corticosteroid pretreatment.17 

Warnings and precautions for docetaxel include:17

  • Acute myeloid leukemia
  • Cutaneous reactions
  • Neurologic reactions
  • Asthenia

Drug Interactions

Concomitant administration with CYP3A4 inducers, inhibitors, and substrates should be avoided.17 


Dacarbazine is an alkylating agent that can be used in combination with doxorubicin to treat uterine sarcoma.6,18 

Dosage and Administration

Dacarbazine can be administered via IV infusion over 15 to 60 minutes or via a continuous infusion over several days.11,18 Patients should be monitored for extravasation and anaphylaxis during infusion.18 

As dacarbazine has a high emetic potential, antiemetics are recommended.13 

Dose adjustments for toxicity may be necessary with dacarbazine.18

Adverse Reactions

The most commonly reported adverse events associated with dacarbazine include18:

  • GI effects (eg, nausea, vomiting, anorexia, and diarrhea)
  • Skin effects (eg, alopecia, facial flushing, photosensitivity, and rashes) 
  • Hematopoietic depression
  • Hepatic toxicity 
  • Abnormalities on kidney function tests

Drug Interactions

Dacarbazine is a minor substrate of CYP1A2 and CYP2E1; however, no clinically relevant drug interactions have been studied.18 

Hormone Therapy

Hormonal therapy can inhibit tumor growth, decrease the recurrence rate, and improve survival in some patients with uterine sarcoma. Hormone therapy can be considered in some cases for use as adjuvant therapy, fertility-sparing treatment, or palliative treatment. This treatment seems to be the most effective when treating low-grade endometrial stromal sarcoma because of a higher rate of hormone-receptor expression.19 Estrogen receptor (ER) and progesterone receptor (PR) testing is recommended by NCCN guidelines for patients with leiomyosarcoma, endometrial stromal sarcoma, and adenocarcinoma.6 

Hormonal therapy may be considered in patients with uterine sarcomas that are ER-positive or PR-positive, preferably with a small tumor volume or indolent growth.6 ER and PR expression are variable in uterine sarcoma and are most commonly expressed in low-grade endometrial stromal sarcoma. In contrast, ER and PR expression is rare in high-grade endometrial stromal sarcoma and undifferentiated uterine sarcoma.19  

According to NCCN guidelines, aromatase inhibitors are the preferred hormone therapy regimen for low-grade endometrial stromal sarcoma or adenocarcinoma. Aromatase inhibitors may also be used in other uterine sarcoma subtypes that are ER-positive or PR-positive.6 

Alternative hormone therapy options include fulvestrant and gonadotropin hormone-releasing hormone (GnRH) analogs. Selective estrogen receptor modulators, such as tamoxifen, are not recommended.6,19 

Aromatase Inhibitors 

Aromatase inhibitors decrease estrogen production by blocking the enzyme aromatase.19 

Dosage and Administration

Aromatase inhibitors are administered orally. Anastrozole and letrozole may be taken with or without food, while exemestane should be taken after a meal.20-22

Table 2. Aromatase Inhibitors: Dose and Drug Interactions for Uterine Sarcoma6,19

DrugDosage and AdministrationDrug Interactions
Anastrozole1 mg orally once dailyTamoxifen, estrogen-containing products
Exemestane25 mg orally once dailyStrong CYP3A4 inducers
Letrozole 2.5 mg orally once dailyTamoxifen

From FDA-approved prescribing information.20-22

Adverse Reactions

Common adverse reactions associated with anastrozole, exemestane, and letrozole include20-22:

  • Joint or muscle pain
  • Decreased bone density and osteoporosis
  • Menopausal symptoms such as hot flashes and vaginal dryness 
  • Increased cholesterol
  • Fatigue 

Aromatase inhibitors can also increase the risk of ischemic cardiovascular events. Meta-analysis evidence suggests that anastrozole may be the least cardiotoxic aromatase inhibitor agent compared with exemestane and letrozole.23  


Progestins like megestrol acetate and medroxyprogesterone acetate can be used in ER-positive and PR-positive uterine sarcomas.6

Progestins can be used in patients with early-stage low-grade endometrial stromal sarcoma who wish to preserve fertility. Progestins have also been found to reduce the rate of recurrence in patients with stages II to IV low-grade endometrial stromal sarcoma.24 

Dosage and Administration

Medroxyprogesterone acetate and megestrol acetate are administered orally. Food has been found to increase the bioavailability of both agents.25,26 

Table 3. Progestin Therapy: Dose and Drug Interactions for Uterine Sarcoma

DrugDoseDrug Interactions
Medroxyprogesterone acetate250 mg to 600 mg orally once dailyStrong CYP3A4 inhibitors and inducers 
Megestrol acetate 160 mg to 320 mg orally once dailyIndinavir 

From FDA-approved prescribing information.25-27

Adverse Reactions

Common adverse events associated with medroxyprogesterone acetate and megestrol acetate include25,26:

  • Nausea
  • Diarrhea
  • Hypertension 
  • Skin rash 
  • Insomnia 

Serious adverse events associated with high-dose progesterone therapy can include27:

  • Thrombotic complications
  • Weight gain
  • Depression 
  • Cardiovascular events 
  • Malignant neoplasms and breast cancer 

Megestrol acetate may also cause additional adverse events, including adrenal insufficiency and new onset or worsening diabetes.26 

Patients should undergo regular monitoring for serious adverse events. One study found that 69% of patients with stage I low-grade endometrial stromal sarcoma stopped taking progestins due to adverse events.28 

Targeted Therapy

The understanding of uterine sarcoma biomarkers is growing, allowing for more personalized treatment recommendations. Several targets in uterine sarcomas have been identified, including6,29:

  • Neurotrophic tropomyosin receptor kinase (NTRK)
  • Multiple tyrosine kinases (TKs) 
  • Anaplastic lymphoma kinase (ALK) 
  • Breast cancer gene 2 (BRCA2)

NTRK Inhibitors

Patients with the NTRK gene fusion may benefit from therapy with NTRK inhibitors.6,29 NCCN recommends biomarker-directed therapy with an NTRK inhibitor as first-line therapy for patients with NTRK gene fusion.6 

Table 4. NCCN First-Line NTRK Inhibitors for Uterine Sarcoma

DrugDosage and AdministrationAdverse ReactionsDrug Interactions
Larotrectinib 100 mg orally twice dailyCommon: Fatigue, nausea and vomiting, cough, dizziness, increased AST and ALT, constipation, diarrhea 
Warnings: Neurotoxicity, hepatotoxicity  
Strong CYP3A4 inducers, inhibitors, and substrates  
Entrectinib 600 mg orally once dailyCommon: Fatigue, nausea and vomiting, constipation, diarrhea, dysgeusia, edema, dizziness, dysesthesia, dyspnea, cough, myalgia, arthralgia, cognitive impairment, weight gain, pyrexia, vision problems 
Warnings: Congestive heart failure, central nervous system effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT interval prolongation, vision disorders
Moderate and strong CYP3A4 inducers and inhibitors 

ALT = alanine transaminase; AST = aspartate transaminase.

From FDA-approved prescribing information.30,31

ALK Inhibitors

The NCCN recommends first-line treatment with ALK inhibitors for patients who have an inflammatory myofibroblastic tumor with an ALK translocation. An FDA-approved test should be used to evaluate tumors for ALK status.6,29 

Table 5. ALK Inhibitors for Uterine Sarcoma 

DrugDosage and AdministrationAdverse ReactionsDrug Interactions
Crizotinib250 mg orally twice dailyCommon: Vision disorders, nausea and vomiting, diarrhea, constipation, edema, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, neuropathy
Warnings: Hepatotoxicity, ILD/pneumonitis, QT interval prolongation, bradycardia, severe vision loss
CYP3A inducers, inhibitors, and substrates 
Ceritinib750 mg orally once dailyCommon: Diarrhea, nausea, vomiting, fatigue, abdominal pain, decreased appetite, weight loss
Warnings: Severe or persistent GI toxicity, hepatotoxicity, ILD/pneumonitis, QT interval prolongation, hyperglycemia, bradycardia, pancreatitis
CYP3A inducers, inhibitors, and substrates
CYP2C9 substrates with a narrow therapeutic index 
Brigatinib90 mg orally once daily for 7 days, then increase to 180 mg orally once dailyCommon: Diarrhea, nausea, vomiting, fatigue, rash, cough, dyspnea, headache, myalgia, hypertension
Warnings: ILD/pneumonitis, hypertension, bradycardia, visual disturbance, CPK elevation, pancreatic enzyme elevation, hyperglycemia
CYP3A inducers and inhibitors 
Lorlatinib100 mg orally once dailyCommon: Edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, diarrhea 
Warnings: CNS effects, hyperlipidemia, AV block, ILD/pneumonitis 
CYP3A inducers, inhibitors, and substrates
Warning for serious hepatotoxicity with concomitant use of strong CYP3A inducers; discontinue CYP3A inducers and wait 3 half-lives before initiating lorlatinib 
Alectinib600 mg orally twice dailyCommon: Fatigue, constipation, edema, myalgia, anemia 
Warnings: Hepatotoxicity, ILD/pneumonitis, renal impairment, bradycardia, CPK elevation, severe myalgia 
None identified 

AV = atrioventricular; CNS = central nervous system; CPK = creatine phosphokinase; GI = gastrointestinal; ILD = interstitial lung disease.

From FDA-approved prescribing information.32-36

PARP Inhibitors

Poly-ADP ribose polymerase (PARP) inhibitors are recommended as second-line or subsequent therapy for patients with BRCA2-altered leiomyosarcoma.6 

Table 6. PARP Inhibitors for Uterine Sarcoma

DrugDosage and AdministrationAdverse ReactionsDrug Interactions 
Olaparib300 mg orally twice dailyCommon: Anemia, nausea, vomiting, diarrhea, constipation, stomatitis, dysgeusia, dyspepsia, decreased appetite, fatigue, neutropenia, leukopenia, respiratory infection, myalgia, arthralgia, headache, serum creatinine elevation
Warnings: MDS/AML, pneumonitis
CYP3A inducers and inhibitors 
Rucaparib600 mg orally twice dailyCommon: Nausea, vomiting, fatigue, dysgeusia, constipation, diarrhea, decreased appetite, stomatitis, anemia, thrombocytopenia, neutropenia, upper respiratory infection, abdominal pain, dyspnea, increased ALT/AST
Warnings: MDS/AML
CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates 
Niraparib 300 mg orally once dailyCommon: Nausea, vomiting, constipation, diarrhea, abdominal pain, decreased appetite, thrombocytopenia, anemia, neutropenia, leukopenia, fatigue, musculoskeletal pain, insomnia, headache, dyspnea, cough, rash, hypertension, dizziness, acute kidney injury, urinary tract infection, hypomagnesemia 
Warnings: MDS/AML, bone marrow suppression, cardiovascular events
No clinical drug interaction studies have been performed 

AML = acute myeloid leukemia; MDS = myelodysplastic syndrome.

From FDA-approved prescribing information.37-39


Pazopanib is a kinase inhibitor recommended as a second-line or subsequent therapy for uterine sarcoma.6,40 

Table 7. Pazopanib for Uterine Sarcoma

DrugDosage and AdministrationAdverse ReactionsDrug Interactions 
Pazopanib 800 mg orally once dailyCommon: Diarrhea, nausea, vomiting, anorexia, hypertension, hair depigmentation
Warnings: Hepatotoxicity, prolonged QT interval, fatal hemorrhagic events, arterial thrombotic events, GI perforation, hypothyroidism, proteinuria
CYP3A4 inhibitors, inducers, and substrates 

GI = gastrointestinal.

From FDA-approved prescribing information.40


Immunotherapy may be helpful for patients with a high tumor mutational burden and patients with the PEComa subtype of uterine sarcoma.6 


Pembrolizumab is an immune checkpoint inhibitor that targets programmed cell death-1 (PD-1) to slow tumor growth.41 Pembrolizumab is recommended as a second-line therapy for patients with unresectable or metastatic disease with high tumor mutational burden and progression following prior treatment and no satisfactory alternatives.6 Data for the use of pembrolizumab are limited to case reports and small studies.42 

Table 8. Pembrolizumab for Uterine Sarcoma

DrugDosage and AdministrationAdverse ReactionsDrug Interactions 
Pembrolizumab 2-10 mg/kg IV infusion over 30 minutes every 2 weeks until disease progressionCommon: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, abdominal pain
Warnings: Immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic HSCT
None known

HSCT = hematopoietic stem cell transplantation; IV = intravenous.

From FDA-approved prescribing information.41

mTOR Kinase Inhibitors 

NCCN guidelines recommend mTOR kinase inhibitors to treat patients with PEComa.6 Approximately 10% of patients with PEComas have genetic alterations of the tuberous sclerosis complex that activates a protein kinase called the mammalian target of rapamycin (mTOR). High mTOR activity can increase tumor cell growth. Inhibiting this kinase can slow tumor growth in patients with high mTOR activity.43

Table 9. mTOR Kinase Inhibitors for Uterine Sarcoma 

DrugDosage and AdministrationAdverse ReactionsDrug Interactions 
Sirolimus 2-6 mg orally once dailyCommon: Stomatitis, respiratory infections, hyperlipidemia
Warnings: Hypersensitivity reactions, angioedema, impaired renal function, ILD/pneumonitis, impaired wound healing
Strong CYP3A4/P-gp inducers or inhibitors 
Everolimus10 mg orally once dailyCommon: Stomatitis, infections, asthenia, fatigue, cough, diarrhea 
Warnings: Pneumonitis; infections; elevated serum creatinine, blood glucose, and lipids; decreased hemoglobin, neutrophils, and platelets
Strong and moderate CYP3A4 inhibitors, strong CYP3A4 inducers, moderate P-gp inhibitors 
Temsirolimus 25 mg IV infused over 30 to 60 minutes once weeklyCommon: Rash, asthenia, mucositis, nausea, edema, anorexia, anemia, hyperglycemia, hyperlipidemia, elevated alkaline phosphatase, elevated AST, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, leukopenia
Warnings: Infusion reactions, immunosuppression, ILD, renal failure, hepatic impairment, bowel perforation, abnormal wound healing
Strong inducers of CYP3A4 and CYP3A5, strong inhibitors of CYP3A4

AST = aspartate transaminase; ILD = interstitial lung disease; IV = intravenous; P-gp = P-glycoprotein.

From FDA-approved prescribing information,44,46,48 Świtaj et al,45 Gennatas et al,47 and Benson et al.49

Monitoring Considerations 

Monitoring parameters for patients with uterine sarcoma depend on several factors, including the tumor subtype and stage, as well as the treatment and patient comorbidities. 

Baseline tests for most treatment regimens should include the following12,14-18,20-22,25,26,30-41,44,46,48,50:

  • Hepatitis B virus
  • Physical examination including blood pressure 
  • CBC with differential
  • Renal function test
  • Liver function tests 
  • Blood chemistry 
  • Thyroid function
  • Left ventricular ejection fraction
  • Neurologic testing 
  • Vision testing 

Some systemic treatments require special monitoring considerations, including:

  • Chemotherapy for infusion-related reactions, extravasation, infection, and secondary malignancies12,14-18,41,48
  • Aromatase inhibitors for bone mineral density, cholesterol, and cardiovascular events20-22
  • High-dose progestins for thrombosis events, weight gain, depression, and cardiovascular events25,26 
  • NTRK inhibitors for liver function, cardiac function, bone mineral density, neurologic status, and vision30,31
  • ALK inhibitors for cardiac function, respiratory function, vision, blood glucose, and cholesterol32-36
  • PARP inhibitors for lung function, infections, myelodysplastic syndrome/acute myeloid leukemia, cardiac function, blood pressure, and liver function37-39
  • Pazopanib for liver function, cardiac function, thrombotic events, thyroid function, and kidney function40
  • Pembrolizumab for infusion-related reactions41
  • mTOR kinases for hypersensitivity reactions, infections, liver function, lung function, kidney function, blood glucose, and cholesterol44,46,48

In patients taking oral therapy, adherence to treatment should also be monitored with patient interviews or serum levels. 20-22,25,26,30-40,44,46

Considerations for Specific Populations  

Nearly 80% of women are older than 55 years when diagnosed with uterine cancer. As such, clinicians do not typically have to take into account considerations for pediatric patients or pregnant or lactating women when treating uterine sarcoma.4 Pregnancy and breastfeeding should be avoided, as all systemic therapies can cause fetal harm.12,14-18,20-22,25,26,30-41,44,46,48


Approximately 45% of patients diagnosed with uterine cancer are older than 65 years; therefore, clinicians must consider how uterine sarcoma treatment may affect this population, as they are more likely to experience comorbidities — such as renal, hepatic, and cardiac impairment — that may affect the choice of therapy.4  

In general, clinicians should be cautious when determining the treatment dose for elderly patients because of their increased risk of toxicity. Some drugs may not have included a significant geriatric population in clinical trials to determine if they respond differently.14,15,17,18,25,26,30,31,36,46,48 

Although no data exist specifically for the response to treatment in elderly patients with uterine sarcoma, no differences in efficacy or safety have been reported when certain agents were used for other conditions in patients older than 65 years, including12,16,20-22,32-35,37-41,44:

  • Doxorubicin 
  • Gemcitabine 
  • Aromatase inhibitors
  • Crizotinib 
  • Ceritinib 
  • Brigatinib 
  • Lorlatinib 
  • Olaparib 
  • Rucaparib 
  • Niraparib 
  • Pazopanib
  • Pembrolizumab 
  • Everolimus 

Renal Impairment

The following agents may require dose adjustments or close monitoring in patients with uterine sarcoma and renal impairment14,16,17,34: 

  • Ifosfamide 
  • Gemcitabine 
  • Docetaxel 
  • Brigatinib 

Hepatic Impairment

The following uterine sarcoma treatments may require dose adjustments or close monitoring in patients with hepatic impairment12,15,16,30-34,40,44,46,48:

  • Doxorubicin 
  • Trabectedin 
  • Gemcitabine 
  • Larotrectinib 
  • Crizotinib 
  • Ceritinib 
  • Brigatinib 
  • Pazopanib 
  • Sirolimus 
  • Everolimus 
  • Temsirolimus 

Uterine Sarcoma Treatment Guidelines 

The following updated guidelines are available to assist clinicians in decision-making when managing patients with uterine sarcoma:

  • NCCN Clinical Practice Guideline in Oncology for Uterine Neoplasms, available here (updated April 28, 2023).
  • Uterine Sarcomas: Clinical Practice Guidelines for Diagnosis, Treatment, and Follow-up, by the Spanish Group for Research on Sarcomas (GEIS), available here (published 2023). 


1. Pérez-Fidalgo JA, Ortega E, Ponce J, et al. Uterine sarcomas: clinical practice guidelines for diagnosis, treatment, and follow-up, by Spanish group for research on sarcomas (GEIS). Ther Adv Med Oncol. 2023;15:17588359231157645. doi:10.1177/17588359231157645

2. Uterine Sarcoma Treatment (PDQ®) – Health Professional Version. National Cancer Institute. Updated September 23, 2022. Accessed June 19, 2023. https://www.cancer.gov/types/uterine/hp/uterine-sarcoma-treatment-pdq#

3. Uterine Sarcoma Treatment (PDQ®) – Patient Version. National Cancer Institute. Updated October 7, 2022. Accessed June 19, 2023. https://www.cancer.gov/types/uterine/patient/uterine-sarcoma-treatment-pdq 

4. Cancer Facts & Figures 2023. American Cancer Society. Published 2023. Accessed June 18, 2023. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf 

5. Yu T, Kim HJ, Wu H-G, et al. Outcome analysis in patients with uterine sarcoma. Radiat Oncol J. 2015;33(1):29-35. doi:10.3857/roj.2015.33.1.29

6. Abu-Rustum NR, Yashar CM, Arend R, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Uterine Neoplasms. National Comprehensive Cancer Network. Published April 28, 2023. Accessed June 18, 2023. https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf

7. Seddon B, Strauss SJ, Whelan J, et al. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol. 2017;18(10):1397-1410. doi:10.1016/S1470-2045(17)30622-8

8. Sutton G, Blessing JA, Malfetano JH. Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol. 1996;62(2):226-229. doi:10.1006/gyno.1996.0220

9. Judson I, Verweij J, Gelderblom H, et al; European Organisation and Treatment of Cancer Soft tissue and Bone Sarcoma Group. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15(4):415-423. doi:10.1016/S1470-2045(14)70063-4

10. Pautier P, Italiano A, Piperno-Neumann S, et al. Doxorubicin alone versus doxorubicin with trabectedin followed by trabectedin alone as first-line therapy for metastatic or unresectable leiomyosarcoma (LMS-04): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2022;23(8):1044-1054. doi:10.1016/S1470-2045(22)00380-1

11. Zalupski M, Metch B, Balcerzak S, et al. Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study. J Natl Cancer Inst. 1991;83(13):926-932. doi:10.1093/jnci/83.13.926

12. Doxorubicin hydrochloride. Prescribing Information. Pfizer Inc; 1974. Updated March 2020. Accessed June 18, 2023.

13. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline update. J Clin Oncol. 2020;38(24):2782-2797. doi:10.1200/JCO.20.01296

14. Ifex. Prescribing Information. Baxter Healthcare Corporation; 1988.  Updated March 2012. Accessed June 20, 2023.

15. Yondelis. Prescribing Information. Janssen Pharmaceutical Companies; 2015. Updated June 2020.  Accessed June 20, 2023.

16. Gemzar. Prescribing Information. Eli Lilly and Company; 1996. Accessed June 20, 2023.

17. Docetaxel. Prescribing Information. Sandoz; 1996. Updated March 2012. Accessed June 20, 2023. 

18. Dacarbazine. Prescribing Information. DailyMed. Updated October 20, 2022. Accessed June 20, 2023. 

19. Zang Y, Dong M, Zhang K, et al.  Hormonal therapy in uterine sarcomas. Cancer Med. 2019;8(4):1339-1349. doi:10.1002/cam4.2044

20. Arimidex®. Prescribing Information. AstraZeneca; 1995. Updated October 20, 2010. Accessed June 20, 2023.

21. Aromasin®. Prescribing Information. Pfizer Inc; 1999. Updated May 2018. Accessed June 20, 2023.

22. Femara. Prescribing Information. Novartis Pharmaceuticals Corporation; 1997. Updated January 2014. Accessed June 20, 2023.

23. Zhao X, Liu L, Li K, Li W, Zhao L, Zou H. Comparative study on individual aromatase inhibitors on cardiovascular safety profile: a network meta-analysis. Onco Targets Ther. 2015;8:2721-2730. doi:org/10.2147/OTT.S88179

24. Huang X, Peng P. Hormone therapy reduces recurrence in stage II-IV uterine low-grade endometrial stromal sarcomas: a retrospective cohort study. Front Onc. 2022;12:922757. doi:10.3389/fonc.2022.922757

25. Provera®. Prescribing Information. Pfizer Inc; 2007. Accessed June 20, 2023.

26. Megace®. Prescribing Information. Bristol-Myers Squibb Company; 1993.  Updated May 2013. Accessed June 20, 2023.

27. Yamazaki H, Todo Y, Mitsube K, et al. Long-term survival of patients with recurrent endometrial stromal sarcoma: a multicenter, observational study. J Gynecol Oncol. 2015;26(3):214-221. doi:10.3802%2Fjgo.2015.26.3.214

28. Deshmukh U, Black J, Perez-Irizarry J, et al. Adjuvant hormonal therapy for low-grade endometrial stromal sarcoma. Reprod Sci. 2019;26(5):600-608. doi:10.1177/1933719118778801

29. Bose S, Schwartz GK, Ingham M. Novel therapeutics in the treatment of uterine sarcoma. Am Soc Clin Oncol Educ Book. 2022;42:900-909. doi:10.1200/EDBK_350541

30. Vitrakvi®. Prescribing Information. Loxo Oncology; 2018. Accessed June 20, 2023.

31. Rozlytrek. Prescribing Information. Genentech, Inc.; 2019.  Accessed June 20, 2023.

32. Xalkori®. Prescribing Information. Pfizer Inc; 2011. Updated July 2017. Accessed June 20, 2023. 

33. Zykadia®. Prescribing Information. Novartis Pharmaceuticals Corporation; 2014. Updated May 2017. Accessed June 20, 2023. 

34. Alunbrig®. Prescribing Information. Takeda Pharmaceutical Company Limited; 2017. Updated May 2020. Accessed June 20, 2023.

35. Lorbrena®. Prescribing Information. Pfizer Inc; 2018. Accessed June 20, 2023.

36. Alecensa®. Prescribing Information. Genentech, Inc.; 2015. Updated November 2017. Accessed June 20, 2023.

37. Lynparza®. Prescribing Information. AstraZeneca Pharmaceuticals LP; 2014. Updated January 2018. Accessed June 20, 2023.

38. Rubraca®. Prescribing Information. Clovis Oncology, Inc.; 2016. Updated June 2022. Accessed June 20, 2023.

39. Zejula. Prescribing Information. GlaxoSmithKline; 2017. Updated April 2020. Accessed June 20, 2023.

40. Votrient. Prescribing Information. GlaxoSmithKline; 2009. Accessed June 20, 2023.

41. Keytruda®. Prescribing Information. Merck Sharp & Dohme Corp.; 2014. Updated March 2021.  Accessed June 20, 2023. 

42. Wang YJ, Williams HR, Brzezinska BN, et al. Use of pembrolizumab in MSI-high uterine leiomyosarcoma; a case report and review of the literature. Gynecol Oncol Rep. 2021;35:100701. doi:10.1016/j.gore.2021.100701

43. Flechter E, Zohar Y, Guralnik L, Passhak M, Bar Sela G. Long-lasting stable disease with mTOR inhibitor treatment in a patient with a perivascular epithelioid cell tumor: a case report and literature review. Oncol Lett. 2016;12(6):4739-4743. doi:10.3892/ol.2016.5231

44. Rapamune. Prescribing Information. Pfizer Inc; 1999. Updated April 2017.  Accessed June 20, 2023.

45. Świtaj T, Sobiborowicz A, Teterycz P, et al. Efficacy of sirolimus treatment in PEComa – 10 years of practice perspective. J Clin Med. 2021;10(16):3705. doi:10.3390/jcm1016/3705

46. Afinitor. Prescribing Information. Novartis Pharmaceuticals Corporation; 2009. Updated October 2010.  Accessed June 20, 2023. 

47. Gennatas C, Michalaki V, Kairi PV, Kondi-Paphiti A, Voros D. Successful treatment with the mTOR inhibitor everolimus in a patient with perivascular epithelioid cell tumor. World J Surg Oncol. 2012;10:181. doi:10.1186/1477-7819-10-181

48. Torisel. Prescribing Information. Pfizer Inc; 2007. Updated February 2015. Accessed June 20, 2023. 

49. Benson C, Vitfell-Rasmussen J, Maruzzo M, et al. A retrospective study of patients with malignant PEComa receiving treatment with sirolimus or temsirolimus: the Royal Marsden Hospital experience. Anticancer Res. 2014;34(7):3663-3668.

50. Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757

Author Bio

Amanda Jacot, PharmD, earned a Bachelor of Science degree in biology from the University of Texas at Austin in 2009 and a Doctor of Pharmacy degree from the University of Texas College of Pharmacy in 2014. She has worked as a community pharmacist for 8 years and is a member of the American Society of Consultant Pharmacists. Amanda is passionate about empowering people to take charge of their health and improving health literacy.