Cancer is an ancient disease that has also frequently been described as the defining plague of our generation.1 Among women in the United States, 1 in 3 will develop cancer during her lifetime.1 With regard to genital cancer in women, five main sites are affected: the vulva, the vagina, the cervix, the uterus, and the ovary. The American Cancer Society estimates that in 2014 in the United States, approximately 52,630 new cases of cancer of the uterus will be diagnosed and about 8,590 women will die from cancers of the uterus.2 Overall, in the U.S., endometrial cancer (EC; cancer of the endometrial lining of the uterus) is the most common cancer of the female reproductive organs, and its incidence is increasing.2-4 EC is rare in women <45 years, with most cases (about 3 out of 4) diagnosed in women >55 years.2 EC is the most common gynecologic malignancy in the elderly.3,5 There has been close association of endometrial cancer with obesity, diabetes, and hypertension.6,7 Further, as prevalence of the metabolic syndrome increases (see Resources), so may EC become more common as well.
Major risk factors for EC are obesity, diabetes, and hypertension.8 TABLE 1 addresses other risk factors as well, including unopposed estrogen and tamoxifen use for >5 years. The risk of unopposed estrogen (high circulating levels of estrogen with no or low levels of progesterone) is potentially associated with obesity, polycystic ovary syndrome (PCOS), nulliparity, late menopause, estrogen-producing tumors, anovulation, and estrogen monotherapy.8 Heredity contributes to EC in as many as 10% of cases, with approximately half of these cases occurring in families with hereditary nonpolyposis colorectal cancer (Lynch syndrome).8
Pathologic Basis for Disease
Through the years, it has been observed that ECs vary in histologic appearance and clinical features; epidemiologic, clinicopathologic, and molecular support for these observations has been provided through systematic studies.9,10 Endometrial hyperplasia usually precedes EC; more than 80% of ECs are adenocarcinomas.3,8 The most common type of endometrial carcinoma is endometrioid adenocarcinoma.
Endometrial carcinogenesis is understood as a dualistic model incorporating a classic estrogen-driven pathway as well as an alternative pathway seemingly unrelated to hormones (TABLE 2).10 Most carcinomas arising from the uterus are estrogen-dependent and are associated with obesity and hypertension.5 They are designated type I ECs, diagnosed in younger or perimenopausal women, and typically, owing to their early diagnosis secondary to postmenopausal bleeding, have more benign histologic features and a good prognosis.5,8 By contrast, type II ECs develop in older patients, are not hormone-dependent, and are responsible for most of the recurrences and deaths associated with EC.5 Uterine serous cancer constitutes up to 10% of all endometrial tumors, and represents the most biologically aggressive variant of type II EC.5 Furthermore, there are suggested genetic distinctions as well, some of which are outlined in TABLE 2. Of note, the higher (more undifferentiated) the grade of the tumor, the greater the probability of deep myometrial invasion, pelvic or para-aortic lymph node metastases, or extrauterine spread.8
Clinical Manifestations, Diagnosis, and Staging
Postmenopausal bleeding, generally defined as vaginal bleeding that occurs 6 months or more following cessation of menstrual function, is the typical symptom of endometrial cancer.8,11 Bleeding is usually painless and may be a single episode of spotting or profuse bleeding for days or months.11 When unexplained vaginal bleeding occurs, malignancy should be ruled out; persistent postmenopausal vaginal bleeding should be investigated aggressively.12 Age and menstrual status influence the cause of abnormal vaginal bleeding; in postmenopausal women, structural disorders are common underlying causes (TABLE 3).12 Although postmenopausal vaginal bleeding remains a cardinal symptom of endometrial cancer, case reports have shown it may be an unusual presenting sign of other diseases, as well, including non-Hodgkin's lymphoma and pancreatic adenocarcinoma.13,14
Sampling by endometrial curettage or aspiration to rule out EC is recommended, particularly forwomen >40 years of age.8,11 The diagnosis of EC is based on endometrial biopsy, histologic tissue examination, and surgical staging (see resources).8,15 While cervical cancer may be detected by the evaluation of cervical cells (Pap test), there is no routine screening test available for endometrial cancer (nor for ovarian, vaginal, and vulvar cancers).15 At the time of menopause, women at average risk should be informed about the risks and symptoms of endometrial cancer and strongly encouraged to report any unexpected bleeding or spotting to their physician.
Treatment and Prognosis
Treatment is typically total hysterectomy and bilateral salpingo-oophorectomy; depending on staging, in some cases recommended treatment also includes lymph node dissection, pelvic radiation therapy, and/or chemotherapy (particularly carboplatin plus paclitaxel, or doxorubicin plus cisplatin as an alternative). Reference 8 discusses more specific treatment of stages I-IV.8,11
The average 5-year survival rates range from 70% to 95% for stage I or II and 10% to 60% for stage III or IV; overall, 63% of EC patients are cancer-free 5 years or more after treatment.8 Prognosis is better with type I tumors, which tend to be diagnosed in younger or perimenopausal women, are commonly estrogen-responsive, and have more benign histologic features.8 Prognosis is worse for older patients, those with higher-grade tumors, and individuals with more extensive spread.8
Metformin Studied for Endometrial Cancer Patients
As indicated above, impaired glucose tolerance and diabetes are risk factors for the development of endometrial cancer.7 Insulin sensitizers, especially the biguanide metformin, are broadly used for managing patients with PCOS; metformin ameliorates insulin resistance and hyperinsulinemia in these women, but also improves ovulation and menstrual cycle regularity with long-term use.16 Metformin not only suppresses glucose production in the liver, but also has demonstrated beneficial effects in other types of tissues, including adipose tissue, skeletal muscle, and the vascular endothelium; the drug has more recently been shown to inhibit the growth of breast cancer cells.
Tan et al sought to study the effects of metformin treatment on human endometrial adenocarcinoma cells; they studied the effects of metformin on in vitro invasion and metastasis in human endometrial adenocarcinoma cells.16 In vitro invasion in human endometrial cells was significantly attenuated by sera from PCOS women after 6 months of metformin treatment (850 mg twice daily) compared to matched controls (P <0.01). On the basis of their evaluations of the sera with various assays, the researchers indicated that the effects appear to be associated with signaling pathways that are known to be important regulators of inflammation, tumor invasion, and metastasis.16 While the researchers concluded that potentially, metformin may serve as adjuvant treatment in the management of patients with endometrial cancer, they emphasized that the findings of this study need to be investigated further with randomized, controlled trials.16
Results of the Preoperative Window Study of Metformin for the Treatment of Endometrial Cancer, a small, open-label, interventional study with a single-group assignment study design, were presented in March 2014 at the 45th Annual Meeting on Women’s Cancer, in Tampa, Florida.17 Participants in the study were obese women (BMI 30) with endometrioid EC who received short-term treatment with metformin (850 mg once daily for 1-4 weeks) that continued until the day prior to surgical staging.17 Schuler et al concluded that in this study to evaluate the antiproliferative and molecular effects of metformin in obese EC patients, metformin significantly reduced proliferation with parallel effects on inhibition of the mTOR pathway. Differences were found in the metabolic effects of metformin in “responders” versus “nonresponders” to treatment. The researchers further concluded that the study provides support for therapeutic clinical trials of metformin in this obesity-driven disease.17
Nevadunsky et al noticed that a greater progression-free survival had been reported among diabetic patients using metformin who had ovarian and breast cancers, while no studies had assessed the association of metformin use with survival in women with EC.7 In their retrospective cohort study, conducted in a single institution, they found that greater overall survival was observed in diabetic women with nonendometrioid EC who used metformin than in diabetic patients not using metformin as well as in nonendometrioid EC cases in people who didn’t have diabetes; this association remained significant after adjusting for age, clinical stage, grade, chemotherapy treatment, radiation treatment, and the presence of hyperlipidemia in multivariate analysis.7 There was no association found between metformin use and overall survival in diabetic patients with endometrioid histology. Nevadunsky et al concluded that diabetic EC patients with nonendometrioid tumors who used metformin had a lower risk of death than women with EC who did not use metformin, suggesting that metformin might be useful as adjuvant therapy for nonendometrioid EC.7
Helping patients and caregivers understand the risk factors of EC, particularly as related to medication therapy, should be incorporated in the pharmacotherapy counseling process. Pharmacists are encouraged to develop pharmacotherapy plans that:
• Appropriately address and aim to improve health outcomes related to obesity, hypertension, and diabetes
• Address other metabolic disturbances such as recent weight gain and lipid abnormalities
• Minimize or eliminate the risk of drug-associated metabolic syndrome (as from second-generation atypical antipsychotic agents [SGAs])
Further, risk minimization and appropriate management strategies should be identified; for example, including recommendations for physical activity and nutrition counseling when appropriate for patients initiated on those SGAs associated with significant weight gain; and overweight or obese patients prior to the initiation of SGA therapy.18-20 Pharmacists can also address the dramatic rise in the prescribing of antipsychotic drugs, which in the elderly relates to their controversial use for the control of behavioral symptoms of dementia. Among older patients with diabetes, the initiation of typical and atypical antipsychotic agents has been associated with a significantly increased risk of hospitalization for hyperglycemia. In one study, almost 70% of hyperglycemic events among new antipsychotic users occurred within 2 weeks of initiation of treatment.21
The pharmacist’s role in addressing adverse metabolic status, through risk minimization and appropriate management strategies, may help reduce the risks associated with the development of endometrial cancer, a condition with an incidence that is on the rise.
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