Endometrial Cancer: Pharmacologic Management

Endometrial cancer is the most common type of gynecologic cancer in the United States, with approximately 66,000 new cases diagnosed in 2023.¹ Excess body weight has been identified as the culprit in approximately 70% of cases of endometrial cancer, in part due to its contributing to increased circulating estrogen, which is a known risk factor for endometrial cancer development.¹

Early-stage endometrial cancer can often be treated with curative surgery including total hysterectomy and bilateral salpingo-oophorectomy. When there is a low risk for recurrence, the omission of adjuvant systemic therapy may be considered.² Although localized endometrial cancer has a 96% 5-year survival rate, advanced metastatic or recurrent endometrial cancer does not have as favorable a prognosis.³ The 5-year survival for distant endometrial cancer is 20%.³ 

Adjuvant systemic drug therapy may be used to prevent recurrence in high-risk patients or used instead of surgery in patients who are too ill or wish to preserve fertility. The type of systemic therapy used to treat endometrial cancer may depend on several factors, including²:

• Tumor stage and grade 
• Risk of recurrence
• Lymph node involvement 
• Hormone receptor status 
• Molecular classification
• Patient health 

Systemic pharmacotherapy for endometrial cancer includes chemotherapy and hormone therapy, with some immunotherapy and targeted therapies recently approved by the US Food and Drug Administration (FDA).² This article will review FDA-approved treatments for endometrial cancer, as well as those commonly recommended in guidelines. 

Chemotherapy

Chemotherapy for endometrial cancer is usually reserved for patients with advanced or recurrent disease. Although there are no chemotherapy drugs currently approved by the FDA to treat endometrial cancer, chemotherapy is often used as systemic adjuvant therapy. There is a paucity of data regarding preferred chemotherapy regimens for endometrial cancer treatment because there are few phase 3 trials comparing endometrial cancer chemotherapy regimens.²

Chemotherapy may be given in combination with radiation therapy. The National Comprehensive Cancer Network (NCCN) recommends chemoradiation therapy consisting of cisplatin plus radiotherapy followed by carboplatin/paclitaxel.⁴ 

Several current guidelines agree that carboplatin plus paclitaxel every 21 days for 6 cycles is the preferred chemotherapy regimen for advanced or recurrent endometrial cancer.^2,4-6 

There is no standard of care for second-line chemotherapy regimens, but doxorubicin and docetaxel are options that may be considered for palliative therapy.⁵ 

Cisplatin 

Cisplatin inhibits DNA synthesis by interrupting DNA cross-links and denaturing the double helix. It is indicated for use in advanced testicular, ovarian, and bladder cancer.⁷ Off-label use of cisplatin for endometrial cancer is recommended by several treatment guidelines.^2,4 

Dosing and Administration

The manufacturer of cisplatin recommends pretreatment hydration to prevent nephrotoxicity. Adequate hydration and urinary output should be maintained for at least 24 hours after administration.⁷ Pretreatment with appropriate antiemetic agents is also recommended due to cisplatin’s high emetic potential.⁸

Cisplatin is administered by slow intravenous infusion at a dose of 50 mg/m² when used to treat endometrial cancer.⁷ 

If the patient is also receiving radiotherapy, cisplatin should be administered on day 1 every 3 weeks for 2 cycles.⁹ 

When given in combination with doxorubicin or paclitaxel, cisplatin should be given on day 1 every 3 weeks for 7 cycles or until disease progression or unacceptable toxicity.¹⁰

Dose reductions may be required for patients with renal impairment.⁷ 

Adverse Reactions

The most common adverse reactions associated with cisplatin administration for endometrial cancer include⁷:

• Nephrotoxicity
• Peripheral neuropathy
• Nausea and vomiting
• Myelosuppression
• Ototoxicity 

Patients with endometrial cancer undergoing treatment with cisplatin should be monitored for adverse reactions, hypersensitivity reactions, and infusion reactions.⁷

Drug-Drug Interactions

Caution should be used when administering cisplatin with other nephrotoxic or ototoxic drugs, such as vancomycin or aminoglycosides, due to an additive effect.⁷ 

Carboplatin

Carboplatin is a platinum-compound alkylating agent that produces intra-strand DNA crosslinks to disrupt DNA synthesis.¹¹ Although indicated for use in advanced ovarian cancer, carboplatin is included in many chemotherapy protocols for endometrial cancer, often along with paclitaxel.^2,4 

Dosing and Administration

Carboplatin has a moderate emetic risk, so appropriate antiemetic pretreatment may be necessary.⁸ Carboplatin should not be administered with needles or intravenous administration sets that contain aluminum. Carboplatin is administered intravenously over a time period of 15 to 60 minutes.¹¹ 

Dosing of carboplatin is based on achieving a target area under the curve (AUC). The dose of carboplatin can be calculated using the patient’s glomerular filtration rate (GFR) with the Calvert formula¹¹:

Total dose (mg) = Target AUC x (GFR + 25)

Target AUC between 2 and 6 have been used in clinical trials.^12,13 European Society for Medical Oncology (ESMO) guidelines for endometrial cancer recommend carboplatin AUC 5-6 plus paclitaxel 175 mg/m² every 21 days for 6 cycles.⁵

The Calvert formula automatically accounts for dose adjustments needed for patients with renal insufficiency and geriatric patients.¹¹ 

Adverse Reactions

Possible adverse reactions to carboplatin include¹¹:

• Gastrointestinal pain
• Myelosuppression 
• Abnormal liver function tests
• Pain
• Nephrotoxicity 

Patients with endometrial cancer undergoing treatment with carboplatin should be monitored for adverse reactions and hypersensitivity reactions during infusion.¹¹

Drug-Drug Interactions

Carboplatin may potentiate the renal effects of other nephrotoxic compounds.¹¹ 

Paclitaxel

Paclitaxel inhibits cell replication by stabilizing microtubules and distorting mitotic spindles. It is indicated for use in ovarian cancer, breast cancer, small cell lung cancer, and AIDS-related Kaposi sarcoma.¹⁴ It is used off-label to treat advanced or recurrent endometrial cancer.⁵ 

Dosing and Administration

The manufacturer of paclitaxel recommends that all patients undergo premedication to prevent hypersensitivity reactions. Premedication can include the following agents¹⁴: 

• Dexamethasone 20 mg administered orally 12 and 6 hours before treatment;
• Diphenhydramine 50 mg administered intravenously 30 to 60 minutes before treatment; and
• Cimetidine 300 mg or ranitidine 50 mg administered intravenously 30 to 60 minutes before treatment.

Paclitaxel is infused intravenously over a period of 3 to 24 hours.¹⁴ 

ESMO guidelines recommend carboplatin AUC 5-6 plus paclitaxel 175 mg/m² every 21 days for 6 cycles.⁵ 

Dosage adjustment for hepatic impairment may be necessary due to increased risk of myelosuppression with paclitaxel.¹⁴ 

Adverse Events

Possible adverse events associated with paclitaxel use include:¹⁴ 

• Myelosuppression
• Alopecia 
• Nausea and vomiting
• Stomatitis
• Diarrhea 
• Abnormal electrocardiographic (ECG) findings
• Edema
• Hypotension
• Abnormal liver function tests 
• Peripheral neuropathy
• Muscle and joint pain
• Infection
• Hypersensitivity reaction

Drug-Drug Interactions

Paclitaxel can interact with other chemotherapy agents used to treat endometrial cancer. Results of a phase 1 trial revealed that when paclitaxel was given after cisplatin, myelosuppression was greater than when paclitaxel was given before cisplatin. When doxorubicin and paclitaxel are used in combination, doxorubicin plasma levels may be increased.¹⁴ 

Additionally, paclitaxel is metabolized by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Clinicians should use caution when administering paclitaxel with known substrates, inhibitors, or inducers of these enzymes.¹⁴ 

Doxorubicin

Doxorubicin is an anthracycline that stops or slows cancer cell growth by inhibiting DNA and RNA synthesis by inhibiting topoisomerase II. Doxorubicin is indicated to treat several cancers including breast cancer, lymphoma, leukemia, ovarian cancer, and thyroid cancer.¹⁵ It is used off-label to treat advanced endometrial cancer.^16-18 

Dosage and Administration

Doxorubicin is administered by intravenous push over 3 to 10 minutes. The rate of administration should be decreased if erythematous streaking in the proximal vein or facial flushing occurs.¹⁵ 

Several doxorubicin regimens have been used in research and are documented in the literature. 

• Doxorubicin 60 mg/m² on day 1 every 21 days (in combination with cisplatin) for 8 cycles up to a maximum of 420 mg/m² cumulative dose¹⁶ 
• Doxorubicin 45 mg/m² on day 1 every 3 weeks (in combination with cisplatin) for up to 6 cycles¹⁷ 
• Doxorubicin 60 mg/m² once every 3 weeks (as a single agent) until disease progression or unacceptable toxicity¹⁸

A patient’s cumulative dose of doxorubicin must be monitored. Myocardial damage can occur at a rate of 1% to 20% in patients who have had a cumulative dose ranging from 300 mg/m² to 500 mg/m².

Doxorubicin should not be administered to patients with cardiac insufficiency, a recent myocardial infarction, hepatic impairment, or persistent drug-induced myelosuppression.¹⁵ 

Adverse Reactions

The most common adverse reactions associated with doxorubicin are alopecia, nausea, and vomiting. Extravasation and tissue necrosis can occur during infusion of doxorubicin. Patients should be monitored and the infusion stopped if signs of extravasation occur.¹⁵ 

Cardiotoxicity with doxorubicin can be acute or delayed. Acute cardiotoxicity includes atrioventricular block, arrhythmias, ECG abnormalities, and bundle branch block. Delayed cardiotoxicity includes decrease in left ventricular ejection fraction (LVEF), signs and symptoms of congestive heart failure (CHF), and myocarditis or pericarditis.¹⁵ 

Clinicians are advised to assess LVEF before treatment with doxorubicin and regularly during and after treatment.¹⁵ 

Drug Interactions

Concomitant administration of other cardiotoxic drugs, such as trastuzumab, should be avoided during doxorubicin therapy to protect against the additional risk of cardiac dysfunction.¹⁵ 

Doxorubicin is metabolized by P-glycoprotein and CYP450 isoenzymes CYP3A4 and CYP2D6. The use of inhibitors or inducers of these enzymes should be avoided while using doxorubicin.¹⁵ 

Immunotherapy

Immunotherapy has emerged as an effective second-line treatment option for recurrent endometrial cancer among patients for whom standard therapy with chemotherapy and radiation therapy is ineffective. The immune checkpoint inhibitors, in particular, have shown antitumor activity against a specific molecular subgroup of endometrial cancer.¹⁹ 

Starting in 2020, NCCN guidelines have recommended molecular analysis of endometrial carcinomas to determine the molecular subgroup to aid in prognosis and treatment selection.⁴ The four subgroups are:

• POLE mutated
• Microsatellite instability-high (MSI-H)/deficit mismatch repair (dMMR)
• Copy number low
• Copy number high 

Patients with MSI-H/dMMR subgroups have been found to be particularly sensitive to immunotherapy.²⁰ Approximately 30% of patients with endometrial cancer exhibit this molecular subgroup, making immunotherapy useful in this setting.⁵ 

Two immunotherapy drugs — pembrolizumab and dostarlimab — both of which are immune checkpoint inhibitors, are approved by the FDA for the treatment of endometrial cancer. 

Pembrolizumab

Pembrolizumab is a monoclonal antibody that inhibits the programmed death receptor-1 (PD-1). When the PD-1 pathway is blocked, T-cell suppression is reversed, inducing an antitumor response.²¹ 

Pembrolizumab is the first drug to be approved based on a common tumor biomarker instead of an anatomic location of origin.²² It is indicated for the treatment of MSI-H/dMMR endometrial cancer tumors that have progressed after conventional therapy.²

Pembrolizumab is approved by the FDA to treat endometrial cancer that is not MSI-H/dMMR when used in combination with lenvatinib. It is indicated as a second-line treatment for patients with advanced endometrial cancer who are not candidates for curative surgery or radiation therapy.²¹ 

Dosing and Administration

Pembrolizumab is administered via intravenous infusion over 30 minutes.²¹ 

The recommended dosage of pembrolizumab is 200 mg once every 3 weeks or 400 mg once every 6 weeks for up to 24 months or until disease progression or unacceptable toxicity.²¹ 

Adverse Reactions

For pembrolizumab in combination with lenvatinib, the most common adverse reactions are²¹:

• Fatigue
• Hypertension
• Musculoskeletal pain
• Diarrhea
• Decreased appetite
• Hypothyroidism
• Nausea and vomiting
• Stomatitis
• Weight loss
• Abdominal pain
• Headache
• Constipation
• Urinary tract infection
• Dysphonia
• Hemorrhagic events
• Hypomagnesemia
• Palmar-plantar erythrodysesthesia (hand-foot syndrome) 
• Dyspnea
• Cough
• Rash 
• Infusion-related reactions 

When pembrolizumab is used as a single agent, adverse reactions included fatigue, pain, decreased appetite, pruritus (itchy skin), diarrhea, nausea, rash, pyrexia (fever), cough, dyspnea (shortness of breath), and constipation.²¹ 

Severe or fatal immune-mediated adverse reactions associated with pembrolizumab can occur in any organ system. Regular monitoring is important for early identification and management. The manufacturer recommends monitoring liver enzymes, creatinine level, and thyroid function at baseline and regularly during treatment.²¹ 

Adverse reactions and complications have also been reported in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) before or after treatment with pembrolizumab.²¹ 

Drug-Drug Interactions 

The manufacturer of pembrolizumab does not list any known drug-drug interactions in its prescribing information.²¹ However, immunosuppression from systemic corticosteroids may decrease the therapeutic effect of pembrolizumab.²³ 

Dostarlimab

Dostarlimab is a PD-1-blocking monoclonal antibody. It is approved by the FDA to treat recurrent or advanced endometrial cancer with dMMR as second-line therapy for patients with prior treatment with a platinum-containing regimen or for any patient who is not a candidate for curative surgery or radiation therapy.²⁴ 

Dosing and Administration

Dostarlimab is administered via intravenous infusion over 30 minutes.²⁴ 

The recommended dosage of dostarlimab is 500 mg every 3 weeks for doses 1 through 4. Starting 3 weeks after dose 4, the dosage should change to 1000 mg every 6 weeks until disease progression or unacceptable toxicity.²⁴

Adverse Reactions

The most common adverse reactions associated with dostarlimab include²⁴:

• Fatigue
• Anemia
• Diarrhea 
• Nausea

Dostarlimab can cause severe or fatal immune-mediated adverse reactions in any organ system. Regular laboratory monitoring including liver enzymes, creatinine level, and thyroid function tests should be conducted to identify early signs of adverse reactions with dostarlimab.²⁴ 

Infusion-related reactions can also occur with dostarlimab; administration should be stopped, slowed, or permanently discontinued depending on the severity of the reaction.²⁴  

Dostarlimab can result in abnormal laboratory findings. The most common grade 3 or 4 laboratory anomalies include²⁴:

• Decreased lymphocytes
• Decreased sodium
• Increased alkaline phosphatase
• Decreased albumin 

Drug-Drug Interactions

The manufacturer of dostarlimab does not list any drug interactions in its prescribing information; however, as documented with other PD-1 inhibitors, immunosuppression from systemic corticosteroids may decrease its therapeutic effect.²³ 

Targeted Therapy

Targeted therapy for endometrial cancer focuses on different aspects of how cancer cells grow and spread. The use of targeted therapy for the treatment of endometrial cancer is relatively new and is mostly used in high-risk, metastatic, or recurrent settings.²⁵ 

Lenvatinib is currently the only targeted therapy approved by the FDA to treat endometrial cancer.²⁶ Additional targeted therapies are under investigation, with targets including the PI3K pathway, mammalian target of rapamycin (mTOR) kinase, human epidermal growth factor receptor 2 (HER2), and protein phosphatase 2 (PP2A).²⁷ 

Lenvatinib 

Lenvatinib slows cancer progression and decreases tumor growth by inhibiting several kinases implicated in pathogenic angiogenesis, tumor growth, and cancer progression. Lenvatinib targets the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4); fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha (PDGFRα); KIT; and RET.²⁶

Lenvatinib is approved to treat advanced endometrial cancer that is not MSI-H or dMMR in combination with pembrolizumab for patients who are not candidates for curative surgery or radiation therapy and who have disease progression after prior systemic treatment in any setting.²⁶

Dosing and Administration

Lenvatinib is available as a 4-mg and 20-mg oral capsule. It should be taken at the same time each day, with or without food. The recommended dosage of lenvatinib for endometrial cancer is 20 mg once daily in combination with pembrolizumab 200 mg via intravenous infusion over 30 minutes every 3 weeks.²⁶ 

Adverse reactions may necessitate dosage modifications. For the first instance of an adverse reaction, the dosage of lenvatinib should be reduced to 14 mg/d; for the second instance of an adverse reaction, the dosage of lenvatinib should be reduced to 10 mg/d; and for the third instance of an adverse reaction, the dosage of lenvatinib should be reduced to 8 mg/d.²⁶ 

Adverse Reactions 

The most common adverse reactions for lenvatinib and pembrolizumab for treating endometrial cancer include²⁶:

• Hypothyroidism
• Hypertension
• Fatigue
• Diarrhea
• Musculoskeletal disorders
• Nausea and vomiting
• Decreased appetite 
• Stomatitis (inflammation of the oral mucosa)
• Weight loss
• Abdominal pain
• Urinary tract infection
• Proteinuria
• Constipation
• Headache 
• Hemorrhagic events
• Palmar-plantar erythrodysesthesia 
• Dysphonia (change in voice quality)
• Rash 

Clinicians should closely monitor patients for adverse reactions that may require a dose reduction, interruption, or discontinuation of lenvatinib. In clinical trials of lenvatinib, dose reductions or interruptions were common and occurred in 63% and 70% of patients, respectively.²⁸ 

Adverse reactions associated with lenvatinib requiring a dose reduction or interruption include²⁶:

• Hypertension
• Cardiac dysfunction
• Arterial thromboembolic event
• Hepatotoxicity 
• Renal failure or impairment 
• Proteinuria
• Fistula formation and gastrointestinal perforation 
• QT prolongation
• Reversible posterior leukoencephalopathy syndrome 
• Severe, recurrent diarrhea
• Hypocalcemia
• Thyroid dysfunction
• Impaired wound healing
• Osteonecrosis of the jaw

Among patients undergoing treatment with lenvatinib, regular monitoring of blood electrolytes, liver and kidney function, thyroid function, cardiac function, and blood pressure is recommended. Regular dental examinations should also be performed to check for osteonecrosis of the jaw.²⁶ 

Drug-Drug Interactions

Lenvatinib should not be taken concurrently with other drugs that prolong the QT interval.²⁶ 

Trastuzumab

Trastuzumab is a monoclonal antibody that binds to HER2 and inhibits the proliferation of cells that overexpress HER2 by mediating antibody-dependent cellular cytotoxicity. Trastuzumab is indicated for use in the treatment of HER2-overexpressing breast and gastric cancer, but it is used off-label for advanced or recurrent HER2-positive endometrial cancer. ^4,29 

For HER2-positive carcinosarcomas, the NCCN guidelines recommend systemic therapy with carboplatin/paclitaxel with trastuzumab.⁴ 

Dosing and Administration

Trastuzumab is administered by intravenous infusion. The initial loading dose should be administered over a period of 90 minutes. Maintenance doses should be administered over 30 minutes if tolerated.²⁹ 

In clinical trials for endometrial cancer, trastuzumab was given in combination with carboplatin and paclitaxel with an initial dose of 8 mg/kg, followed by a maintenance dosage of 6 mg/kg every 3 weeks until disease progression or prohibitive toxicity.³⁰  

Adverse Reactions

The most common adverse reactions (more than 10%) associated with trastuzumab include²⁹:

• Infusion reactions 
• Skin rash
• Infection
• Chills 
• Dizziness
• Headache
• Insomnia
• Asthenia (weakness)
• Fever
• Abdominal pain
• Nausea and vomiting
• Pain
• Decreased LVEF 
• Neutropenia 
• Pruritus 

Serious adverse reactions requiring interruption or discontinuation of treatment with trastuzumab include²⁹:

• Cardiomyopathy
• Infusion reactions
• Exacerbation of chemotherapy-induced neutropenia
• Pulmonary toxicity

Patients should be regularly assessed for serious adverse events during and after treatment with trastuzumab. Serious and fatal infusion reactions can occur. Patients should be monitored for signs and symptoms of pulmonary toxicity during infusion and for 24 hours after trastuzumab administration. Monitoring of LVEF at baseline and regularly every 3 months during treatment with trastuzumab is recommended.²⁹ 

Drug-Drug Interactions

Serum trastuzumab concentrations may increase when the agent is given in combination with paclitaxel. Trastuzumab may potentiate the effects of other cardiotoxic or myelosuppressive drugs.²⁹

Hormone Therapy

Hormone therapy is an alternative option for patients with endometrial cancer who want to preserve fertility, as well as for the treatment of advanced, recurrent endometrial cancer. Hormone therapy is an attractive option due to its favorable safety profile and ease of administration.³¹ 

Estrogen receptor (ER) and progesterone receptor (PR) status can predict a patient’s response to hormone therapy, with ER-positive and PR-positive tumors having the best response. However, response to hormone therapy has also been seen in ER-negative and PR-negative tumors.⁵ 

Several hormonal agents have been used to treat endometrial cancer, but progestins — such as megestrol and medroxyprogesterone — are generally considered first-line hormone therapy agents. Other hormone therapy drugs that can be used to treat endometrial cancer include aromatase inhibitors, tamoxifen, and fulvestrant.^2,4,5 

Women with stage IA endometrial cancer who wish to preserve fertility can be treated with progestins or levonorgestrel intrauterine device (IUD) in combination with oral progestins plus gonadotropin-releasing hormone analogs.² 

Megestrol

Megestrol is a synthetic progestin with antiestrogenic properties.³² The exact mechanism of action of megestrol is unknown, but it may have a direct effect on the endometrium.³³ It is approved by the FDA for the palliative treatment of advanced endometrial cancer. 

Dosage and Administration

Megestrol is available as 20-mg or 40-mg tablets to be taken orally. The daily dose may be divided throughout the day.³² 

The European Society of Gynaecological Oncology (ESGO)/European Society for Radiotherapy and Oncology (ESTRO)/European Society of Pathology (ESP) guidelines recommend a dosage of 160 to 320 mg/d of megestrol for fertility preservation in women with stage IA endometrial cancer.² 

Doses between 40 and 320 mg have been used to treat advanced or recurrent endometrial cancer. The ESGO/ESTRO/ESP guidelines recommend a dosage of megestrol 160 mg/d.² 

Megestrol may be used in a regimen alternating with tamoxifen 40 mg/d every 3 weeks.^4,34 

Adverse Reactions

Common adverse reactions associated with megestrol include³²:

• Nausea
• Diarrhea
• Rash
• Flatulence
• Hypertension
• Asthenia 

It is possible that megestrol may increase the risk of thrombo-embolic events.³⁵ Patients undergoing treatment with megestrol should therefore be monitored for signs and symptoms of thrombosis.² 

Medroxyprogesterone 

Medroxyprogesterone is a synthetic progestin.³⁶ It is indicated in the treatment of abnormal uterine bleeding and is used off-label to treat endometrial cancer.^2,4,5 

Dosage and Administration

Medroxyprogesterone is available as oral tablets and a suspension for intramuscular or subcutaneous injection.³⁶ 

The ESGO/ESTRO/ESP guidelines recommend a dosage of 400 to 600 mg/d for fertility preservation in women with stage IA endometrial cancer and 200 to 300 mg/d for the treatment of advanced or recurrent endometrial cancer.^2,37  

Adverse Reactions

Common adverse reactions associated with medroxyprogesterone include³⁶:

• Breast tenderness
• Nausea
• Acne
• Weight gain or loss
• Headache 
• Edema
• Fatigue

Medroxyprogesterone may also increase the risk of thromboembolic events. Patients undergoing treatment with medroxyprogesterone should therefore be monitored for signs and symptoms of stroke, myocardial infarction (MI), deep vein thrombosis (DVT), and retinal vascular thrombosis.² 

Tamoxifen

Tamoxifen is an estrogen agonist/antagonist indicated for use in ER-positive breast cancer.³⁸ Tamoxifen is used off-label to treat recurrent or high-risk endometrial cancer.^34,39 

Dosing and Administration

Tamoxifen is available as an oral tablet to be taken with or without food.³⁸ 

When used alone, the dosage to treat endometrial cancer is 20 mg twice daily.³⁹ When used in combination with megestrol, the dosage of tamoxifen is 20 mg twice daily for 3 weeks alternating with megestrol 80 mg twice daily for 3 weeks.³⁴  

Adverse Reactions

Common adverse reactions associated with tamoxifen include³⁸:

• Hot flashes
• Mood disturbances
• Vaginal discharge
• Vaginal bleeding
• Nausea
• Fluid retention 

Serious adverse reactions associated with tamoxifen include thromboembolic events and liver toxicity. Patients with a prior history of DVT or pulmonary embolism should not take tamoxifen. Patients taking tamoxifen should undergo period liver function tests.³⁸ 

Drug-Drug Interactions

Tamoxifen should not be used in combination with anastrozole or letrozole. It should also be avoided with warfarin due to the possibility of an increased anticoagulant effect of warfarin.³⁸ 

Tamoxifen is metabolized by CYP450 isoenzymes CYP3A4 and CYP2D6 and should not be administered with strong inducers or inhibitors of these isoenzymes.³⁸ 

Other Hormone Therapies

Currently, there is no universally accepted consensus on alternatives to progestin therapy in endometrial cancer.

Other hormone therapies that may be useful in endometrial cancer include:^2,4

• Everolimus
• Letrozole
• Anastrozole
• Fulvestrant 
• Levonorgestrel IUD 

Monitoring Considerations During Systemic Treatment for Endometrial Cancer

Monitoring parameters will differ based on therapy and patient comorbidities. Clinicians should be aware of different monitoring considerations before treatment, during treatment, and after treatment. 

Before and During Treatment

Before cancer treatment begins, the American Society of Clinical Oncology (ASCO) recommends that all patients be tested for hepatitis B virus (HBV) using 3 tests: hepatitis B surface antigen (HBsAg), hepatitis B core antibody total immunoglobulin, and antibody to hepatitis B surface antigen. However, cancer treatment should not be delayed pending receipt of results of the HBV screening tests. Further treatment and follow-up are required if the screening tests reveal HBV positivity.⁴⁰ 

Clinicians should also screen for pregnancy in premenopausal women with endometrial cancer. All systemic agents used to treat endometrial cancer, other than medroxyprogesterone, can cause fetal harm; therefore, pregnancy should be avoided during treatment.^{7,11,14,15,21,24,26,29,32,36,38} 

Baseline laboratory assessment should also be performed based on the planned treatment regimen. For most treatment regimens for endometrial cancer, the following tests should be performed at baseline^{7,11,14,15,21,24,26,29,32,36,38}: 

• Complete blood count with differential
• Renal function test
• Liver function tests 
• Blood chemistry 
• Thyroid function

Measurements taken at baseline should be repeated regularly throughout therapy to identify potential adverse reactions such as nephrotoxicity, hepatic toxicity, myelosuppression, or immune-mediated reactions.^{7,11,14,15,21,24,26,29,32,36,38}   

Cardiotoxic drugs — including paclitaxel, doxorubicin, lenvatinib, and trastuzumab — require a baseline evaluation of cardiac function and LVEF. Cardiac monitoring should continue during treatment and for several years after treatment is completed.^14,15,26,29 

Patients receiving drugs associated with ocular or ototoxicity, such as cisplatin and carboplatin, should undergo audiometric and vestibular testing. Clinicians should consider repeating these tests before each dose and for several years after.^7,11 

Patients receiving oral treatments should be monitored for adherence through interviews or blood serum levels.^26,32,36,38 

During Infusion

Infusion-related reactions or hypersensitivity reactions can occur with several drugs, including chemotherapy agents, pembrolizumab, dostarlimab, and trastuzumab. Infusions should be administered under the supervision of a physician experienced in the administration of cancer agents.^21,24,29 

Pretreatment with hydration therapy, steroids, antihistamines, or antiemetics when indicated can reduce the risk of infusion reactions.^7,14 

After Treatment 

Once treatment for endometrial cancer ends, patients often need continued monitoring due to the effects of their treatment regimen. In addition to surveillance for recurrence, several therapies for endometrial cancer are known to increase the risk of developing a secondary malignancy. For example, cisplatin is associated with an increased risk for leukemia.⁶ Patients who have taken doxorubicin have a higher incidence of secondary acute myelogenous leukemia and myelodysplastic syndrome.¹⁵ 

Monitoring for the effects of delayed cardiotoxicity should continue for at least 2 years following treatment with trastuzumab.²⁹ 

Considerations for Specific Populations

Women older than 55 years make up 78.7% of new endometrial cancer cases in the United States.¹ Clinicians do not frequently have to consider pediatric, pregnant, or lactating patients when treating endometrial cancer. However, in premenopausal patients, pregnancy should be avoided as all systemic therapies used to treat endometrial cancer can cause fetal harm. Breastfeeding is either not recommended by manufacturers or the excretion into breast milk is not known for the drugs used to treat endometrial cancer.^{7,11,14,15,21,24,26,29,32,36,38}   

Considerations for the Geriatric Population

Many patients diagnosed with and treated for endometrial cancer are older than 65 years; therefore, differences in the geriatric population are of special interest for endometrial cancer.¹ Patients older than 65 years were included in many clinical trials conducted to assess outcomes for endometrial cancer treatments. Investigators found no difference between the geriatric population and younger patients in the case of pembrolizumab, dostarlimab, and tamoxifen.^21,24,38 Although clinical trials for lenvatinib in endometrial cancer found no differences in the geriatric population, trials for lenvatinib in hepatocellular carcinoma observed that patients older than 75 years had reduced tolerability to the treatment.²⁶ 

The geriatric population may be more susceptible to adverse reactions than a younger population. Additionally, the incidence of many comorbidities that can affect treatment, such as cardiovascular disease, increases with age. For example, geriatric patients taking cisplatin may be more susceptible to nephrotoxicity, myelosuppression, and infection.⁷ In clinical trials, carboplatin was more likely to cause severe thrombocytopenia in older patients.¹¹ Adverse events such as myelosuppression, neuropathy, and cardiovascular events were more common in older patients taking paclitaxel than younger ones.¹⁴ Older patients taking trastuzumab had a higher risk of developing cardiomyopathy than younger patients.²⁹ 

References

1. Cancer facts & figures 2023. American Cancer Society. Accessed April 26, 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 

2. Concin N, Matias-Guiu X, Vergote I, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer. 2021;31:12-39. doi:10.1136/ijgc-2020-002230

3. Survival rates for endometrial cancer. American Cancer Society. Updated March 1, 2023. Accessed May 2, 2023. https://www.cancer.org/cancer/endometrial-cancer/detection-diagnosis-staging/survival-rates.html

4. Abu-Rustum NR, Yashar CM, Arend R, et al. Uterine neoplasms, version 1.2023. J Natl Compr Canc Netw. 2023;21(2):181-209. doi:10.6004/jnccn.2023.0006

5. Oaknin A, Bosse TJ, Creutzberg CL, et al; the ESMO  Guidelines Committee. Endometrial cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(9):860-877. doi:10.1016/j.annonc.2022.05.009

6. Barretina-Ginesta M P, Quindós M, Alarcón JD, et al. SEOM-GEICO clinical guidelines on endometrial cancer (2021). Clin Transl Oncol. 2022;24(4):625-634. doi.org/10.1007/s12094-022-02799-7

7. Cisplatin. Prescribing information. WG Critical Care, LLC; 2019. Updated February 2019.

8. 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 

9. de Boer SM, Powell ME, Mileshkin L, et al; PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;20(9):1273-1285. doi.org/10.1016/S1470-2045(19)30395-X

10. Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2004;22(11):2159-2166. doi:10.1200/JCO.2004.07.184

11. Carboplatin [package insert]. Bristol-Myers Squibb Company; 2010. 

12. Secord AA, Havrilesky LJ, Carney ME, et al. Weekly low-dose paclitaxel and carboplatin in the treatment of advanced or recurrent cervical and endometrial cancer. Int J Clin Oncol. 2007;12(1):31-36. doi:10.1007/s10147-006-0619-9

13. Miller DS, Filiaci VL, Mannel RS, et al. Carboplatin and paclitaxel for advanced endometrial cancer: final overall survival and adverse event analysis of a phase III trial (NRG Oncology/GOG0209). J Clin Oncol. 2020;38(33):3841-3850. doi:10.1200/JCO.20.01076

14. Paclitaxel [package insert]. Bristol-Myers Squibb Company; 2011. 

15. Doxorubicin. Prescribing information. Pfizer; 2019. 

16. Randall ME, Filiaci VL, Muss H, et al. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2006;24(1):36-44. doi:10.1200/JCO.2004.00.7617

17. Homesley HD, Filiaci V, Gibbons SK, et al. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study. Gynecol Oncol. 2009;112(3):543-552. doi:10.1016/j.ygyno.2008.11.014

18. McMeekin S, Dizon D, Barter J, et al. Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer. Gynecol Oncol. 2015;138(1):18-23. doi:10.1016/j.ygyno.2015.04.026

19. Cao W, Ma X, Fischer JV, et al. Immunotherapy in endometrial cancer: rationale, practice and perspectives. Biomark Res. 2021;9:49. doi:doi.org/10.1186/s40364-021-00301-z

20. Mahdi H, Chelariu-Raicu A, Slomovitz BM. Immunotherapy in endometrial cancer. Int J Gynecol Cancer. 2023;33(3):351-357. doi:10.1136/ijgc-2022-003675

21. Pembrolizumab. Prescribing information. Merck & Co., Inc; 2014. Updated March 2021.

22. Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353-1365. doi:10.1016/S1470-2045(20)30445-9

23. Arbour KC, Mezquita L, Long N, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol. 2018;36(28):2872-2878. doi:10.1200/JCO.2018.79.0006

24. Dostarlimab. Prescribing information. GlaxoSmithKline; 2021. Updated February 2023. 

25. MacKay, HJ, Freixinos VR, Fleming GF. Therapeutic targets and opportunities in endometrial cancer: update on endocrine therapy and nonimmunotherapy targeted options. Am Soc Clin Oncol Educ Book. 2020;40:245-255. doi:10.1200/EDBK_280495

26. Lenvatinib. Prescribing information. Eisai R&D Management Co; 2015. Updated November 2022.

27. Remmerie M, Janssens V. Targeted therapies in type II endometrial cancers: too little, but not too late. Int J Mol Sci. 2018;19(8):2380. doi:10.3390/ijms19082380

28. Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38(26):2981-2992. doi.org/10.1200/JCO.19.02627

29. Trastuzumab. Prescribing information. Genentech, Inc; 1998. Updated October 2010. 

30. Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. J Clin Oncol. 2018;36(20):2044-2051. doi:10.1200/JCO.2017.76.5966

32. van Weelden WJ, Massuger LFAG, ENITEC, Pijnenborg JMA, Romano A. Anti-estrogen treatment in endometrial cancer: a systematic review. Front Oncol. 2019;9:359. doi:10.3389/fonc.2019.00359

32. Megestrol. Prescribing information.  Par Pharmaceutical; 1993. Updated May 2013. 

33. Pandya KJ, Yeap BY, Weiner LM, et al. Megestrol and tamoxifen in patients with advanced endometrial cancer: an Eastern Cooperative Oncology Group Study (E4882). Am J Clin Oncol. 2001;24(1):43-46. doi:10.1097/00000421-200102000-00007

34. Fiorica JV, Brunetto VL, Hanjani P, et al. Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2004;92(1):10-14. doi:10.1016/j.ygyno.2003.11.008

35. Oberhoff C, Hoffmann O, Winkler UH, Schindler AE. Hemostatic effects of high-dose megestrol acetate therapy in patients with advanced gynecological cancer. Gynecol Endocrinol. 2001;15(5):341-348.

36. Medroxyprogesterone [package insert]. Pfizer; 2007.

37. Thigpen JT, Brady MF, Alvarez RD, et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J Clin Oncol. 1999;17(6):1736-1744. doi:10.1200/JCO.1999.17.6.1736

38. Tamoxifen. Prescribing information. Rosemont Pharmaceuticals; 1977. Updated September 2018. 

39. Thigpen T, Brady MF, Homesley HD, et al. Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2001;19(2):364-367. doi:10.1200/JCO.2001.19.2.364

41. 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 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.