Obstetrics and Gynecology

Endometrial Cancer - Molecular therapies

Endometrial Cancer or Uterine Cancer

1. What every clinician should know Are you sure your patient has Endometrial cancer? What should you expect to find?

Endometrial cancer is the fourth most common cancer among women in the United States and has been increasing in frequency because of an aging female population and changes in dietary and hormonal factors, with obesity as a major culprit. Women with early-stage disease (FIGO stage I and II) and endometrioid histology (type I) have a relatively good prognosis with surgery alone or surgery plus radiation.

However, 10% to 15% of patients are diagnosed with FIGO stage III disease (tumor extension outside the uterus but limited to the true pelvis) at the time of surgery, and have an estimated 5-year survival rate of 40% to 50%. Lastly, the remaining 10% to 15% of patients are diagnosed with FIGO Stage IV disease (tumor extension beyond the true pelvis) and have a very poor 5-year survival rate of 15% to 20%.

Those patients with advanced stage III or IV disease are unlikely to be cured by surgery, conventional chemotherapy, radiation, or a combination of these modalities. In addition, 20% of women will be diagnosed with a tumor of either serous or clear cell histology (type II), and even in the setting of early-stage disease (FIGO stage I), these women have a 5-year survival rate of 60% as compared with an 85% to 90% survival rate in those with Stage I endometrioid adenocarcinoma.

Unlike type I endometrial cancers that are associated with obesity and estrogen excess, there is no clear epidemiologic profile for type II cancers, which behave much more aggressively. In addition, African American women suffer a much higher mortality (two-fold higher) from endometrial cancer than Caucasian women, and it is unclear whether this is the result of delayed treatment, lack of access to care, or a higher likelihood of cancer with more serious prognostic characteristics such as the more lethal histologies. Interestingly, despite the discontinuation of the use of unopposed estrogen and the success of the office endometrial biopsy, the death rate from endometrial cancer has continued to steadily rise over the past 10 years.

A dualistic model for the development and progression of endometrial cancer exists that divides these tumors into type I and type II based on biologic, molecular, and clinical parameters. Type I or those tumors of endometrioid histology comprise 80% of cases and are thought to arise from persistent unopposed estrogen stimulation. Women who develop these tumors are typically perimenopausal and often have risk factors such as obesity, hyperlipidemia, nulliparity, diabetes mellitus and insulin resistance, polycystic ovarian syndrome (PCOS), hypertension, and late-onset menopause.

These tumors are preceded by an identifiable premalignant state of hyperplasia and ultimately, atypical hyperplasia, and are generally estrogen receptor (ER) and progesterone receptor (PR) positive. Genetic alterations associated with these tumors include microsatellite instability (20% to 40%), PTEN deletions or mutations (50% to 80%), PIK3CA mutations (30%) and amplification (2% to 14%), activation of K-ras (15% to 30%), and gain of function mutations in b-catenin (25% to 40%).

In contrast, type II or those tumors of atypical histologies, such as serous and clear cell carcinomas, have no association with excess endogenous or exogenous estrogen and have no recognized risk factors. These tumors generally occur in postmenopausal women in the setting of an atrophic endometrium. Type II tumors behave much more aggressively and show a propensity for deep invasion, lymphovascular permeation, and distant spread. ER and PR are generally negative or weakly positive.

A precursor lesion is not as well defined but an in situ form of this type of carcinoma has been described and is referred to as endometrial intraepithelial carcinoma (EIC). The molecular genetic profile for these tumors is distinctly different than type I tumors and is associated with aneuploidy, p53 mutations (80% to 90%), overexpression of HER-2/neu (40% to 80%), p16 inactivation (40%), PIK3CA mutations (20%) and amplification (46%), and E-cadherin alterations (60% to 90%).

The classic symptom of endometrial cancer is abnormal uterine bleeding, which is seen in 90% of cases. For postmenopausal women with abnormal uterine bleeding, 5% to 20% will be diagnosed with an endometrial cancer. Thus, even one drop of blood or even persistent abnormal vaginal discharge in a postmenopausal woman warrants further diagnostic testing.

Premenopausal and perimenopausal women with abnormal uterine bleeding may also need further workup if the following risk factors are present, including (1) obesity, (2) chronic anovulation, (3) unopposed estrogen therapy, (4) tamoxifen use, (5) prior history of endometrial hyperplasia, (6) diabetes mellitus, and (7) family or personal history of ovarian, breast, colon, or endometrial cancer. A minority of asymptomatic women with endometrial cancer may also be found during cervical cancer screening, via the workup of atypical glandular cells of uncertain significance (AGUS) on a pap smear or via the presence of atypical endometrial cells on pap testing.

Screening for endometrial cancer is not advocated in the general population. Women considered at higher risk for developing this disease (i.e., obese, chronic ovulation, diabetes, tamoxifen use) should be counseled about their increased risk, as well as symptoms that should be reported to their health care providers. Of special note, obese women should be encouraged to lose weight as a potential risk reducing strategy. Women who are on tamoxifen have a three- to seven-fold increased risk of endometrial cancer and possibly uterine sarcomas. Despite this, routine screening has not proven to be useful; and thus, women on tamoxifen should only undergo endometrial biopsy in the setting of abnormal vaginal bleeding.

For women with hereditary nonpolyposis colorectal cancer syndrome (HNPCC), the lifetime risk of developing endometrial cancer is 27% to 71%, which is higher than their risk of colon cancer. Endometrial cancer is often the first manifestation of malignancy in women with HNPCC, occurring at a younger age (46 to 54 years old) than sporadic endometrial cancer. Thus, the recommendation for women with HNPCC is to start annual endometrial cancer screening by the age of 30 to 35 years old and then a hysterectomy and bilateral salpingo-oophorectomy when childbearing is complete. These women also have a 3% to 14% increased risk of ovarian cancer; and thus should undergo screening via pelvic examination, CA-125, and transvaginal ultrasound every 6 to 12 months, starting at the age of 30 to 35 years old.

2. Diagnosis and differential diagnosis

The first step in diagnosing endometrial cancer is sampling of the endometrium. This is usually obtained by office endometrial biopsy using a standard Pipelle sampling device. The benefits to an office endometrial biopsy are that it is simple to perform, requires no anesthesia, and is well-tolerated by patients. In addition, this procedure has a high sensitivity for detecting disease, a low complication rate, and can be done at a low cost. Dilation and curettage (D&C) with or without hysteroscopy is another potential option, but this approach often requires anesthesia and is associated with increased complications such as uterine perforation.

However, if a patient has a negative endometrial biopsy but there remains concern for endometrial cancer, D&C and hysteroscopy is the next logical step for further workup. Findings worrisome for missing an underlying cancer in the setting of a negative endometrial biopsy would include persistent bleeding, necrosis on histology, and pyometra.

Transvaginal ultrasound (TVUS) can also be helpful in the evaluation of abnormal vaginal bleeding, especially if the office endometrial sampling is difficult due to cervical stenosis in postmenopausal women. TVUS is noninvasive and can often successfully discriminate between bleeding due to atrophy as opposed to anatomic lesions in the uterus. Studies have shown that the risk of endometrial cancer is minimal in women with an endometrial strip of less than 4 to 5 mm. Of course, women with a thickened stripe on TVUS or persistent vaginal bleeding will ultimately need endometrial sampling. TVUS is less useful in premenopausal or perimenopausal women where the endometrial stripe would be expected to be thickened.

The next step after tissue diagnosis of endometrial cancer is referral to a gynecologic oncologist for consideration of hysterectomy, bilateral salpingo-oophorectomy, and surgical staging. For patients with grade 1 endometrial cancer, there is no need for further imaging prior to surgery, given the low risk of extrauterine disease.

For women with grade 2 and 3 lesions or suspicion for metastases on physical examination, a CT scan of the abdomen and pelvis may be performed to determine if there is any concern for disease spread prior to surgical staging. This information may be helpful in determining the surgical approach via a minimally invasive technique (i.e., laparoscopically or robotically) versus open laparotomy, which may be preferred in the case of abdominopelvic metastases or bulky lymphadenopathy.

Other pretreatment testing would include a complete pelvic and physical examination to assess uterine size and mobility, evidence of ascites or extrauterine masses, or nodal disease (i.e., groin and supraclavicular nodes). A CA-125 may also be measured and has been shown to be a predictor of extrauterine spread of endometrial cancer, although the optimal threshold of detection is unclear. If a woman has an elevated CA-125 prior to treatment, the CA-125 may then be a marker for her disease and be useful in follow-up for recurrence after treatment. Given that most women with endometrial cancer will undergo surgical staging, other pretreatment testing would be focused on comorbidities for surgery, requiring some women to undergo medical or cardiac clearance.

3. Management

A. What therapies should you initiate immediately (i.e., emergently)?

After the diagnosis of endometrial cancer, no particular therapies need to be initiated within hours to days of the diagnosis. In the rare case of excessive uterine bleeding, a patient may need to undergo emergent hysterectomy/BSO and staging.

B. What should the initial definitive therapy for the cancer be?

Per the recommendation of the Society of Gynecologic Oncology (SGO) and the American College of Obstetricians and Gynecologists (ACOG), all women with endometrial cancer should undergo primary surgical staging including hysterectomy, BSO, washings, and pelvic and paraaortic lymph node dissection. Exceptions to this would include young women with type I, grade I endometrial cancer who desire fertility or women at increased risk of mortality from surgery related to their medical comorbidities.

Controversies surround the recommendation for complete surgical staging, including the necessity of lymph node evaluation for all endometrial cancer patients, as well as the extent of lymph node dissection. However, the reasoning behind the recommendation of comprehensive surgical staging is based on maximizing information needed for the optimal management of this disease.

Furthermore, there is the concern about endometrial tumors being undergraded by preoperative sampling procedures. In up to 30% of cases, a higher grade of endometrial cancer is ultimately found at the time of hysterectomy.

Depth of invasion is also difficult to predict based on gross inspection, as well as frozen section. Thus, given the relatively low morbidity of pelvic and paraaortic lymph node dissection by experienced surgeons, the benefits of delineating lymph node status seem to outweigh the risks. For patients with metastatic disease in the abdomen and pelvis, optimal cytoreductive surgery should be attempted and is associated with improved outcomes.

Surgical staging for early-stage endometrial cancer is generally curative, and close follow-up is all these patients will need postoperatively. For patients with high, intermediate-risk, early-stage disease, vaginal cuff brachytherapy has been shown to decrease the rate of vaginal and pelvic recurrences but has not impacted overall survival. High, intermediate-risk patients were characterized by GOG 99 as one of the following:

  • Over 70 years old, grade 2-3 OR invasion of outer one third of the myometrium OR lymphovascular space involvement

  • 50 to 69 years old, two of the above risk factors

  • Younger than 50 years old, all 3 risk factors

Vaginal cuff brachytherapy is considered the equivalent of pelvic radiation in this patient population, with fewer side effects and a shorter duration of treatment, and thus has emerged as the current standard of care. Given that vaginal cuff brachytherapy does not increase the overall survival rate, observation may also be a reasonable alternative for early-stage endometrial cancer patients. Vaginal cuff brachytherapy does prevent local recurrences; however, local recurrences are likely to be salvageable by radiation, accounting for the lack of a survival benefit. The risks and benefits of both options should be discussed with the patient.

Approximately 15% of women with early-stage endometrial cancer will recur and often have high risk factors such as increased grade, deep myometrial invasion, lymphovascular space involvement, or atypical histologies (i.e., serous and clear cell). For these patients, it is not known whether more intensive treatment such as chemotherapy would improve outcomes. The GOG is currently exploring this question via GOG 249, which is a phase II trial of pelvic radiation therapy versus vaginal cuff brachytherapy, followed by paclitaxel/carboplatin chemotherapy in patients with high-risk, early-stage endometrial cancer.

Although early-stage disease has a high survival and cure rate, women with advanced-stage disease have a much poorer prognosis. In addition, the prognosis for recurrent disease is even more dismal, with expected overall survival of only 14 to 15 months. Much needs to be learned about how to best manage patients with advanced-stage or recurrent disease.

In general, these patients are treated with chemotherapy, possibly in combination with pelvic, paraaortic, or vaginal cuff radiation for local control. Adjuvant pelvic and whole abdominal external beam radiation have been effective in decreasing the rate of pelvic recurrences, but have not significantly impacted overall survival time. Approximately 30% to 50% of patients with stage III and IV disease develop distant metastases, demonstrating the need for effective systemic therapies.

Doxorubicin and cisplatin have been shown to be effective as single agents and in combination. These are the two most frequently used chemotherapeutic drugs, with an overall response rate of 24% to 28% for doxorubicin and 21% to 25% for cisplatin as single agents. In combination, objective response rates range from 31% to 60%. The addition of paclitaxel to this regimen has also been associated with increased response rates but at the expense of higher toxicities in those patients receiving the three-drug regimen.

Furthermore, there is some evidence to suggest that substituting carboplatin for cisplatin may improve tolerability without impacting efficacy. A significant portion of the community has adopted the treatment regimen of carboplatin and paclitaxel for endometrial cancer, largely based on the familiarity of physicians with the tolerability and efficacy of this combination in ovarian cancer. Although this treatment regimen has only recently been evaluated in the phase III setting for endometrial cancer, its efficacy has been assessed in several retrospective studies and phase II trials, with overall response rates between 43% to 78%.

The majority of these studies included both type I and type II endometrial cancers. The Gynecologic Oncology Group (GOG) has completed a randomized phase II trial (GOG 209), comparing doxorubicin/cisplatin/paclitaxel versus the less toxic combination of paclitaxel/carboplatin, and results of this trial are currently pending. Other chemotherapeutic agents with a response rate of approximately 20% are topotecan, ifosfamide, cyclophosphamide, and docetaxel. Given that type I endometrial cancers are associated with a state of estrogen excess, hormonal therapy using a variety of antiestrogens, including progestins, tamoxifen, and letrozole, have been assessed in endometrial cancer management.

In the normal endometrium, progesterone antagonizes the actions of estrogen and inhibits estrogen-induced cell proliferation. Progestins, such as medroxyprogesterone acetate, have been used in the treatment of endometrial cancer in two diverse settings: (1) palliative treatment for advanced or recurrent disease or (2) primary treatment in premenopausal women with grade 1 tumors who are interested in preserving their fertility or in those women considered poor operative candidates.

The response rate for progestin therapy in the primary setting is estimated at approximately 60% and only 10% to 25% in the palliative setting. In general, women with well-differentiated tumors and a high progesterone receptor content had better response rates to progestin therapy. The obvious appeal of progestin therapy has been the ease of administration and excellent tolerability. Unfortunately, for many endometrial cancers, the activity of progestins is compromised by the eventual downregulation of the progesterone receptor in the target tissues.

The estrogen agonist/antagonist, tamoxifen, has been evaluated in a phase II trial with a minimal response rate of 10% in endometrial cancer patients. Other trials have used tamoxifen in conjunction with progestins, based on the hypothesis that tamoxifen should prevent downregulation of the progesterone receptor. Two phase II trials using tamoxifen and megestrol acetate demonstrated response rates of 27% to 33% with very little toxicity, warranting further evaluation.

Another approach to reduce estrogen stimulation is through aromatase inhibitors, such as letrozole. Letrozole has also been evaluated in women with locally recurrent or metastatic endometrial cancer with an overall response rate of 9.4%. Thus neither of these hormonal agents show promise as single agents but may have improved efficacy when used in conjunction with other hormonal or chemotherapeutic treatments.

Despite some success with cytotoxic and hormonal therapies, advanced or recurrent endometrial cancer is notoriously difficult to treat with poor response rates and dismal overall survival time. Women with high-risk histology (i.e., serous and clear cell) also have a much poorer prognosis, even in the setting of early-stage disease, and require adjuvant chemotherapy. Thus the search has been for novel agents that target specific cellular signaling pathways thought to be essential in endometrial cancer progression and metastasis. The GOG has conducted a series of phase II trials to evaluate some of these targeted therapies in advanced and recurrent endometrial cancer patients. In particular, the GOG 229 series is meant to study these novel agents in women with refractory endometrial cancer who have measurable disease.

Angiogenesis inhibitors

Angiogenesis is the formation of new blood vessels and is thought to be critical in the growth and metastasis of many malignancies, including endometrial cancer. Vascular endothelial growth factor (VEGF) induces this new blood vessel formation and thus is the target of many angiogenesis inhibitors. Not surprisingly, VEGF expression is seen in the majority of endometrial cancer specimens (56% to 100%), but it is unclear whether there is an association between VEGF expression and clinical outcomes.

Bevacizumab is a humanized mAb to VEGF-A and has been evaluated as a single agent in women with recurrent endometrial cancer (15 mg/kg IV q 3 weeks, GOG 229-E). In this trial, bevacizumab showed promising activity with a RR of 13.4% and with 40% of women remaining progression free at 6 months. Translational studies found a correlation between plasma VEGF-A levels and tumor response and survival. Immunohistochemical staining activity of VEGF-A in the tumors was also associated with overall survival time. The GOG is currently studying the combination of bevacizumab with the mTOR inhibitor, temsirolimus, in a similar patient population (GOG 229-G). Bevacizumab is also being evaluated in combination with cytotoxic agents, such as carboplatin and paclitaxel.

Thalidomide is another antiangiogenic agent whose underlying mechanism of action is unknown. Although this drug was well tolerated in women with recurrent or persistent endometrial cancer (GOG 229-B), the response rate to thalidomide was low. VEGF-TRAP acts as a decoy receptor and binds VEGF-A, subsequently neutralizing VEGF-A isoforms. A phase II trial of VEGF-TRAP (4 mg/kg IV every 14 days) is ongoing in women with recurrent endometrial cancer, and the primary endpoint is progression-free survival at 6 months (GOG 229-F). Sorafenib, sunitinib, and brivanib are oral tyrosine kinase inhibitors that target the VEGF receptors in combination with other receptor tyrosine kinases (i.e., PDGFR and FGFR), and are being actively evaluated in phase II clinical trials in endometrial cancer. GOG 229-J is currently evaluating cediranib, an oral inhibitor of VEGFR-1, -2, -3, PDGFR-B, and c-kit.

Epidermal growth factor receptor inhibitors

The epidermal growth factor receptor (EGFR) has been found to be overexpressed in 50% to 80% of women with endometrial cancer and has been correlated with increasing grade, deep myometrial invasion, and a poor survival rate. Thus, this seemed to be a logical therapeutic target for endometrial cancer treatment. Antibodies (i.e., cetuximab, matuzumab, pertuzumab, trastuzumab) and small molecule tyrosine kinase inhibitors (i.e., lapatinib, gefitinib, erlotinib) against EGFR are under investigation in women with endometrial cancer, both within and outside the GOG. The GOG has assessed both lapatinib (GOG 229-D) and gefitinib (GOG 229-C) in women with recurrent or persistent endometrial cancer.

Although the final results from these studies are pending, neither opened to the second stage of accrual suggesting that these drugs had limited activity. Erlotinib has also been evaluated in women with advanced endometrial cancer in two separate trials. A response rate of 12.5% was reported in one trial, and 52% of women had stable disease with a median duration of 3.4 months in a subsequent trial. Cetuximab has also been assessed in endometrial cancer with a 5% partial response rate and 10% stable disease rate.

HER2 amplification is rare in type I endometrial cancer but is seen in a larger majority of type II disease. Given this, the GOG explored trastuzumab as a single agent in a phase II trial (GOG-0181-B) that enrolled chemotherapy-exposed endometrial cancers. The results from this trial were disappointing in that no objective responses were found among the patients with HER2 amplification. This is dramatically different from response rates seen among HER2-amplified metastatic breast cancers, and the reason behind this discrepancy is unclear.

Among these clinical trials, EGFR overexpression has not been a strong predictive marker of response to anti-EGFR therapy. Among non-small cell lung cancer patients, response to anti-EGFR treatment has been correlated with tumors having EGFR mutations and/or amplification but not EGFR overexpression alone. The prevalence of EGFR mutations and amplification in endometrial cancer is unknown and may have a bearing on who would most benefit from this class of agents. However, in general, the activity of anti-EGFR therapy has been very limited in this disease.

Phosphoinositide 3 kinase/Akt/mammalian target of rapamycin (mTOR) inhibitors

Loss of PTEN expression is one of the most prevalent molecular abnormalities associated with endometrial cancers and occurs in an estimated 50% to 80% of type I endometrial cancers. Unlike most other tumor types, loss of PTEN expression is observed in premalignant lesions of the endometrium, suggesting that PTEN loss may be a potential initiator of endometrial cancer development. Wild-type PTEN downregulates the PI3K/Akt/mTOR signaling pathway, which transduces extracellular growth regulatory signals to intracellular mediators of growth and cell survival.

Loss of PTEN results in constitutive activation of Akt and subsequently leads to promotion of cellular proliferation and resistance to apoptosis. In addition to PTEN mutations, mutations and amplifications of the catalytic subunit of PI3K (i.e., PIK3CA) are commonly seen in both type I and II endometrial cancer. Therefore, the mTOR pathway seems like an especially logical target for endometrial cancer therapy.

Three mTOR inhibitors are currently being evaluated in endometrial cancer, either alone or in combination with cytotoxic, hormonal or other molecular targeted therapies—temsirolimus, everolimus, and deforolimus. Temsirolimus has been the most studied in endometrial cancer, and response rates up to 26% have been reported. The GOG is currently studying temsirolimus (25 mg IV weekly) in combination with megestrol acetate (80 mg orally BID) and tamoxifen (20 mg orally BID) (GOG 248) and in combination with bevacizumab (GOG 229-G). Temsirolimus has also shown good tolerability in combination with paclitaxel and carboplatin in endometrial cancer patients and will further be tested in a phase II trial.

Studies are also ongoing to evaluate temsirolimus in combination with other cytotoxic drugs such as topotecan, docetaxel, and Doxil. Similar encouraging response rates have also been found for deforolimus and everolimus. Everolimus has the added benefit of being an oral agent; however, an oral agent for deforolimus is currently in development. In addition, there is an ongoing trial of everolimus and oral topotecan in endometrial cancer patients. Of note, many times insurance companies will cover temsirolimus for the treatment of endometrial cancer, and is a viable alternative for treatment in endometrial cancer patients who have failed cytotoxic therapy.

Despite the high prevalence of PTEN and PIK3CA alterations in endometrial cancers, no biomarker has yet emerged to predict response to mTOR inhibitor treatment. PTEN status and Akt/mTOR overexpression have both been examined but have failed to emerge as biomarkers of sensitivity, although these studies have been limited by small sample size. The possibility of PIKCA mutations being predictive of sensitivity may be a possibility but has yet to be fully explored. This search to identify appropriate biomarkers of response will continue to remain an important objective of future clinical trials.

Temsirolimus, everolimus, and deforolimus are considered first generation mTOR inhibitors in that these drugs only inhibit mTOR complex 1 (mTORC1) and not mTOR complex 2 (mTORC2). It is hypothesized that the effectiveness of mTOR inhibitors may be increased by the simultaneous inhibition of both mTORC1 and mTORC2. Thus, second generation, dual mTORC1/mTORC2 inhibitors are being developed and evaluated in clinical trials (AZD8055 and OSI-027). Other targeted therapies within this pathway that are being examined include PI3K (XL147, GDC-0941, BKM120) and Akt inhibitors (GSK2141795) as well as dual inhibitors of PI3K and mTOR (XL765, PKI-587). The mTOR pathway is clearly implicated in endometrial cancer pathogenesis and should continue to be an active area of investigation for targeted therapies related to this seemingly critical pathway.

Other emerging agents

Fortunately, many other targeted agents are on the horizon as potential therapies for endometrial cancer, and this list is rapidly growing as we have come to better understand the underlying molecular basis of type I and II endometrial cancer. PARP inhibitors are one example. In addition to its effects on mTOR signaling, PTEN loss of function leads to impaired homologous recombination repair of DNA double-strand breaks and thus enhanced sensitivity to PARP (poly[ADP]-ribose polymerase) inhibition. Given this relationship between PTEN loss and PARP inhibition, plans are to evaluate the PARP inhibitor BSI-201 in endometrial cancer; one trial is already ongoing in uterine carcinosarcomas in combination with paclitaxel and carboplatin.

Obesity, diabetes, and insulin resistance are strong risk factors that drive the development of the more common type I endometrial cancers. Metformin is a biguanide drug that is widely used for the treatment of type II diabetes. It is commonly thought of as an insulin sensitizer because it enhances signaling through the insulin receptor, leading to an improvement in insulin resistance, followed by a reduction in circulating insulin levels. Recent epidemiologic evidence suggests that metformin lowers all cancer risk and reduces cancer incidence and deaths among diabetic patients.

Furthermore, a recent retrospective cohort study of diabetic patients with early-stage breast cancer found that those women receiving metformin and adjuvant chemotherapy had a higher response rate. This has led to the idea that metformin may have a role in cancer treatment and prevention, and multiple phase I-III clinical trials are ongoing, most notably in breast cancer, to further test metformin’s effects.

Metformin’s immediate downstream target is AMP-activated protein kinase (AMPK), and its activation leads to regulation of multiple signaling pathways involved in the control of cellular proliferation, including inhibition of the mammalian target of rapamycin (mTOR) pathway. Thus metformin may behave as a novel mTOR inhibitor, with important chemotherapeutic implications for treatment and prevention in a patient population that is often obese and insulin resistant. Preoperative (phase 0) trials of metformin in endometrial cancer are currently ongoing, as well as a pilot clinical trial for metformin in endometrial hyperplasia patients.

4. Complications

A. What complications could arise as a consequence of condition? Are there strategies to lower risk of complications?

The main complication that can occur as a consequence of endometrial cancer is vaginal bleeding, leading to anemia. To prevent this, patients diagnosed with endometrial cancer should be referred to a gynecologist in a timely fashion for treatment management. Women should also be educated to seek medical attention for postmenopausal vaginal spotting/bleeding or for premenopausal or perimenopausal bleeding if at high risk for this disease (i.e., obese, diabetic, polycystic ovarian syndrome).

B. What complications could arise as a consequence of the management – chemotherapy, radiation, and/or surgery?


Complications of surgery for endometrial cancer are those that are related to all surgeries such as intraoperative/postoperative hemorrhage, genitourinary or gastrointestinal injury, ileus/small bowel obstruction, deep venous thrombosis/pulmonary embolus, and infection. Lymphedema (13% to 15%) and lymphocysts (2%) can also occur related to pelvic and paraaorotic lymphadenectomy as part of surgical staging. Many endometrial cancer patients are obese and thus at a higher risk of surgical and postoperative complications, especially given their often related co-morbidities (i.e., diabetes, hypertension, coronary artery disease, sleep apnea, obesity hypoventilation syndrome).


Complications of chemotherapy depend on the drug being used but common toxicities include hematologic toxicity (i.e., neutropenia, anemia, and thrombocytopenia), gastrointestinal toxicity (i.e., nausea, vomiting, and constipation), hypersensitivity reactions (taxanes and platinum compounds are the most likely culprits), and renal toxicity with cisplatin and neurologic toxicity (i.e., peripheral neuropathy for paclitaxel and cisplatin).


Complications of radiation therapy depend on the extent of radiation (i.e., vaginal cuff brachytherapy versus pelvic and extended field radiation). Acute complications of radiation include radiation proctitis and enteritis with associated diarrhea, radiation cystitis, and bone marrow effects (i.e., anemia, neutropenia, thrombocytopenia). Late complications of radiation therapy for endometrial cancer can also occur and include chronic radiation cystitis, small bowel obstruction, and fistulas, but these are rare.

C. What other therapies are helpful for reducing complications?


To reduce complications of surgery, two measures can be undertaken. Perioperative antibiotic prophylaxis are typically used for the prevention of infections. Thromboembolic prophylaxis also is the standard of care through mechanical methods (i.e., graduated compression stockings and external pneumatic compression) and pharmacologic intervention (i.e., low-dose heparin and low molecular weight heparin). Dual prophylaxis should be considered in high-risk patients, such as those older than 60 years undergoing endometrial cancer surgery OR obese patients younger than 60 years undergoing endometrial cancer surgery).


As far as complications of chemotherapy related to endometrial cancer treatment, growth factor support (i.e., filgrastim and long-acting pegfilgrastim) can be useful to accelerate neutrophil recovery, maintain treatment doses, and prevent febrile neutropenia in regimens significantly associated with this life-threatening side toxicity. Emesis prevention is related to the emetic risk of each agent and combination of agents.

Those regimens considered to be at high or moderate emetic risk should include premedication with aprepitant or fosaprepitant plus dexamethasone plus a 5-HT3 agonist +/- lorazepam and +/- an H2 blocker or proton pump inhibitor. Many drugs used for endometrial cancer treatment are considered high or moderate emetic risk, including cisplatin, carboplatin and doxorubicin. Hypersensitivity reactions to paclitaxel can be decreased from 30% to 10% with the use of premedication via dexamethasone, diphenhydramine, and a H2 agonist.


The two most common complications from radiation therapy are radiation proctitis/enteritis with associated diarrhea and radiation cystitis. Diarrhea can be effectively managed with dietary modifications and antidiarrheal medications (i.e., Lomotil and Imodium). Management of urinary symptoms include increased oral liquid intake and urinary analgesics.

5. Prognosis and outcome

The majority (approximately 84%) of type I endometrial cancers are diagnosed at an early stage and have a good prognosis. Five-year survival for Stage I disease is 85% to 90% and 70% for Stage II. Survival time is much worse for stage III and IV disease at 40% to 50% and 15% to 20%, respectively. In contrast for type II endometrial cancers, more women present with advanced-stage disease (approximately 38%), and stage for stage, the 5-year survival rates are much poorer. Women with type II endometrial cancer and stage I and II disease have a survival rate of 50% to 60%; this drops to 5% to 20% for advanced-stage patients.

First-line chemotherapy for advanced endometrial cancer is usually combination therapy with either paclitaxel/carboplatin or doxorubicin/cisplatin/paclitaxel. Response rates to this these treatment regimens ranges from 30% to 78%. For advanced endometrial cancer patients with lymph node only disease, chemotherapy is usually combined with pelvic radiation +/- extended field radiation that is given in either a sandwich (three cycles of chemotherapy followed by radiation followed by three more cycles of chemotherapy) versus a sequential fashion. Women with the more aggressive type II cancers and early-stage disease are also usually treated with a combination of chemotherapy and radiation, although many times vaginal brachytherapy is substituted for the pelvic radiation.

If patients fail these treatment regimens, second-line chemotherapy options for endometrial cancer fair worse, with no FDA approved agents in this setting. Most patients who progress through first-line chemotherapy have little hope for disease remission. The GOG has conducted multiple phase II trials of single-agent chemotherapy in the second-line treatment setting, with response rates ranging from 7% to 27%. Unfortunately, even for patients who do respond to treatment, most responses only last for several months.

Response rates to single-agent paclitaxel on a weekly and every 3 week schedule have been the best in the second-line setting and are reported to be 26% to 27%. Clinical trials of therapies that target specific molecular abnormalities for endometrial cancer, such as mTOR inhibitors and vascular epidermal growth factor inhibitors (VEGF), have shown some promise in the second-line setting. However, based on clinical trials in other malignancies, these targeted therapies may have the greatest clinical impact when combined with cytotoxic chemotherapy and when given to patients with tumors bearing alterations in the specific molecular pathway being “targeted” by these various agents. Thus more research is needed to assess the therapeutic potential of these novel treatments.

B. "What if" scenarios

The most common pitfall in the management of patients with advanced stage endometrial cancer is progression through first-line chemotherapy. Paclitaxel/carboplatin is what I commonly use as first-line treatment in advanced or recurrent endometrial cancer patients. If patients progress through this regimen, I often next treat with doxorubicin.

Of course, patient preferences, functional status, preexisting toxicities, availability of appropriate clinical trials, and scheduling concerns all play a role in treatment decision making. Once patients fail doxorubicin, I usually will prefer a clinical trial versus other cytotoxics, including weekly Taxol, monthly Taxotere, Gemzar, topotecan or the mTOR inhibitor, and temsirolimus. Hormonal therapy is another option using either megestrol acetate or megestrol acetate in combination with tamoxifen.

6. Follow-up surveillance and therapy management of recurrences

Current endometrial cancer surveillance recommendations differ according to stage and histology. Women with low risk disease (stage 1A1 or 1A2) undergo symptom review and physical examination every 6 months for the first year and then yearly. For women with intermediate-risk disease (Stage 1B-2), these visits should be every 3 months for the first year and then every 6 months until year 5. Lastly, for women with high-risk disease (stage 3-4, type II histologies), clinic visits should occur every 3 months for follow-up years 1 and 2 and then every 6 months for follow-up years 3 to 5.

Pap smear testing at these visits is no longer recommended given the low yield of detecting early recurrences. If CA-125 is a marker for the disease (i.e., elevated prior to treatment), this may be useful in selected patients but is not recommended for routine care. Periodic radiographic imaging is also not indicated for routine use, and should be only performed in the setting of suspicion for recurrent disease.

If recurrence is suspected based on physical examination findings or symptoms, CT scan or PET imaging should be performed +/- CA-125. FNA can also be helpful for a palpable inguinal or supraclavicular node.

Recurrences can be local or distant, with the most common site of local recurrence being the vagina or pelvis. Isolated vaginal recurrences are usually treated with surgical resection (even including pelvic exenteration in some instances) versus radiation therapy. Localized pelvic recurrences can also be surgically managed if complete surgical resection is possible. Surgery in these instances is often followed by multimodality treatment, including radiation and chemotherapy. For patients with disseminated recurrences, chemotherapy is usually the only option for treatment and management is similar to what has already been described for advanced endometrial cancer.

7. What is the evidence for specific management and treatment recommendations?

Gehrig, PA, Bae-Jump, VL. "Promising novel therapies for the treatment of endometrial cancer". Gynecol Oncol. vol. 116. 2010. pp. 187-94.

(Review of novel therapies for the treatment of endometrial cancer.)

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