Symposium on Cancer - September 2010
Tex Med. 2010;106(9):50-55.
By Todd Boren, MD, and David Miller, MD
Approximately 1 in 3 women in the United States will develop cancer during their lifetime. The leading sites are breast, lung, colon, and rectum, followed by endometrial cancer. In women, breast cancer is the most commonly diagnosed malignancy, accounting for 32 percent of all cancer diagnoses. Incidence rates increased rapidly in the 1980s because of increased use of mammography and have increased gradually since then. The incidence rate of lung cancer has declined since 1998, after a long period of increase. The incidence rate of ovarian cancer has remained relatively stable since 1985.
Endometrial cancer is the most common gynecologic malignancy. Approximately 1 in 40 women will develop endometrial cancer in their lifetime. An estimated 42,160 new cases were diagnosed in 2009, and 7,780 women died from endometrial cancer, making it the 8th leading cause of cancer death in women.
Most cases (69%) of endometrial cancer are diagnosed when the disease is confined to the uterus. Because of this, most women with endometrial cancer have an excellent prognosis. The 5-year overall survival rate for all women with endometrial cancer is 83%, while the 5-year overall survival rate for women with disease confined to the uterus is 96%. However, for women diagnosed with advanced-stage endometrial cancer, the prognosis is grim: a 5-year survival rate of less than 25% - worse than for women with advanced-stage ovarian cancer.1
This article reviews the etiology and risk factors for endometrial cancer and highlights the role genetics plays in the development of endometrial cancer, as well as the role of hormone replacement therapy in patients with endometrial cancer. We also include a discussion of the current treatment strategies used in early- and advanced-stage endometrial cancer, along with updates on novel therapeutic approaches.
Etiology and Risk Factors
In 1983, Bokham et al described two categories of endometrial cancer on the basis of microscopic appearance and epidemiology.2 The most common category, type I, displays an endometrioid histology and appears to arise via a precursor lesion of atypical endometrial hyperplasia. These type I cancers typically occur in young women with obesity, hyperlipidemia, and signs of increased estrogen levels (endogenous or exogenous), and have an excellent overall prognosis.
Type II endometrial cancers include uterine papillary serous carcinoma, uterine clear cell carcinoma, and poorly differentiated endometrioid endometrial cancers. These cancers tend to occur de novo in older women without the typical hormonal risk factors seen in type I cancers, and the prognosis for these patients is much worse than for patients with type I cancers.3-5
Overall, age appears to be the most important risk factor for the development of endometrial cancer, with 85% of cases occurring after age 50.6-7 Obesity also seems to be a significant risk factor, accounting for 17% to 46% of endometrial cancers in postmenopausal women.8 The peripheral conversion of androstenedione to estrone in adipose cells seems to account for the increase in estrogen in obese women.9 Non-insulin dependent diabetes, often associated with obesity, is associated with type I endometrial cancers.10 High levels of insulin-like growth factor I, coupled with elevated estrogen levels, are thought to have neoplastic potential, which accounts for the observed increased risk of endometrial cancer.11-14
Hormone Replacement Therapy
Exogenous estrogen exposure can also increase the risk of developing endometrial cancer depending on the regimen used. Estrogen therapy, unopposed by progestin use, can lead to the unchecked mitotic activity of endometrial cells, allowing for errors in DNA repair leading to atypical endometrial hyperplasia and endometrial carcinogenesis.15-17
Retrospective data have suggested that "ever-users" of unopposed estrogen are three times more likely to develop endometrial cancer than "never users," whereas "ever-users" of estrogen combined with progesterone (combined hormone replacement therapy [HRT]) have a risk for developing endometrial cancer equal to that of "never-users."18 In this same study, women who used sequential combined HRT had an endometrial cancer risk three times greater than "never-users," while patients who took continuous combined HRT had an 80% reduction in their risk of endometrial cancer following 5 years of use compared with "never-users."
The Nurses' Health Study followed 95,000 women with intact uteri over 28 years to ascertain the risks and benefits of HRT.19 Women who "ever used" estrogen-only HRT and those who used combined HRT for more than 5 years had an increased risk for developing endometrial cancer compared with "never-users." The risk for developing endometrial cancer was not increased in women who used continuous combined HRT compared with "never-users" (Hazard Ratio [HR]: 1.34; Confidence Interval [CI]: 0.88, 2.04), while an increased risk of endometrial cancer was observed in women who used sequential combined HRT compared with "never-users" (HR: 3.00; CI: 1.43, 6.28). The Women's Health Initiative (WHI) study randomized more than 16,000 women to placebo versus combined HRT. No difference in the risk of endometrial cancer was observed between the two groups (HR: 0.83; CI: 0.47, 1.47). Recent follow-up analyses of the WHI trial data have revealed similar conclusions regarding combined HRT and endometrial cancer risk.20
Definitive conclusions about the overall safety of HRT regarding endometrial cancer risk cannot be made at this time. Extensive patient counseling should take place before initiating HRT, with an emphasis on preexisting endometrial cancer risk factors, a quality-of-life assessment, and the other associated risks of HRT, including breast cancer and cardiac risks. For patients with intact uteri who have been counseled appropriately and desire HRT, the prescribed regimen should consist of continuous combined HRT.
Hereditary Endometrial Cancer Syndromes
Hereditary nonpolyposis colorectal cancer (HNPCC) syndrome accounts for 2% to 5% of all endometrial cancers and up to 10% of endometrial cancers in women younger than 50 years.21 This autosomal dominant cancer susceptibility syndrome also is associated with cancers of the colon, ovary, rectum, small bowel, genitourinary system, and pancreas. The lifetime risk for developing uterine cancer is 40% to 60% in patients with HNPCC and is similar to the risk for developing colon cancer.22 Several "red flags" should prompt an evaluation for HNPCC. These include any woman with a personal or family history of colon cancer at an early age of onset (usually before age 50) or endometrial cancer at an early age of onset (premenopausal or before age 50), as well as two or more HNPCC-related cancers in an individual or family.23-25 Assessing a patient's risk for hereditary cancer is an important process that begins with screening for the "red flags" of hereditary colon (and endometrial) cancer. Individuals with any of the "red flags" should enter into a discussion about the appropriateness of genetic testing. Medical management strategies can be tailored depending upon the genetic testing results and may include increased surveillance, chemoprevention, and prophylactic surgery. Risk-reducing surgery consisting of removal of the uterus and bilateral ovaries has been shown to decrease the risk of uterine and ovarian cancer in these high-risk patients.26
The generally favorable outcomes associated with endometrial cancer can be attributed to the fact that most patients present with symptoms, such as abnormal uterine bleeding, early in the disease process. These symptoms often prompt endometrial sampling with either an office endometrial biopsy (EMB) or dilation and curettage (D&C). Both of these methods have sensitivities approaching 100% for detecting cancer.27 Routine use of endometrial sampling in patients older than 40 years with abnormal uterine bleeding is recommended.
Atypical endometrial hyperplasia (AEH) is thought to be the precursor lesion for type I endometrioid endometrial cancer and is occasionally diagnosed on EMB or D&C. The Gynecologic Oncology Group (GOG) has reported on the risk of concurrent endometrial carcinoma associated with AEH.28 Their findings indicate that 42% of patients diagnosed with AEH by endometrial sampling will have an associated endometrial carcinoma in the final hysterectomy specimen. Both clinicians and patients should consider carefully the significant rate of cancer associated with AEH when formulating a treatment strategy.
While EMB and D&C appear to be equivalent in terms of diagnosing cancer, the accuracy of EMB appears to be inferior to D&C in predicting final posthysterectomy tumor grade. In a recent study, 18% of EMB specimens were upgraded on final hysterectomy specimen, while only 9% of D&C specimens were upgraded.29 Although a detailed discussion of the controversies in surgical management of early-stage endometrial cancer is beyond the scope of this article, this discrepancy is significant, as surgical management strategies will likely differ substantially for grade 1 versus grade 3 tumors clinically confined to the uterus.
Adjuvant Therapy for Early-Stage Disease
Four prospective randomized trials have examined the effect of adjuvant external beam radiation therapy on recurrence-free and overall survival in early-stage endometrial cancer.30-33 In all of these trials, the addition of adjuvant external beam radiation resulted in a decrease in the incidence of vaginal and pelvic recurrences without an increase in overall survival. This incongruity has been explained by the fact that most of the patients with isolated pelvic recurrences were salvaged with either radiation therapy or surgery and that the incidence of distant metastasis did not differ between patients who received radiation therapy and those who did not. Recently, results of a randomized prospective trial comparing adjuvant external beam radiotherapy versus vaginal brachytherapy in patients with intermediate-risk, early-stage endometrial cancer were reported.34 No differences in recurrence rate or overall survival were observed between the two treatment arms, suggesting that patients with intermediate-risk, early-stage endometrial cancer can be treated with adjuvant vaginal brachytherapy alone. These findings have led many U.S. clinicians to move away from the routine use of external beam radiation therapy in early-stage endometrial cancer.
While the overall prognosis of patients in adjuvant radiation trials was favorable (overall survival, 58% to 92%), 3% to 23% of patients experienced recurrence at distant sites and were mostly unsalvageable. This fact led many investigators to consider the role of adjuvant chemotherapy in intermediate- and high-risk early-stage endometrial cancers.
The Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) have published data on patients with high-risk, early-stage endometrial cancers treated with adjuvant radiation therapy ± adjuvant platinum-based chemotherapy.35-36 Both trials suggest that adjuvant radiation combined with adjuvant chemotherapy in high-risk, early-stage endometrial cancers is feasible and may result in better overall survival. These results have led to the development of PORTEC-3, an ongoing, randomized, phase III trial comparing chemoradiation combined with adjuvant platinum-based chemotherapy versus pelvic radiation alone.
The GOG is accruing patients for a randomized, phase III trial comparing vaginal brachytherapy plus adjuvant platinum- and taxane-based chemotherapy with pelvic radiation alone. Neither the PORTEC-3 trial nor the GOG trial (GOG 249) will require lymph node dissection as part of the inclusion criteria. However, full surgical staging is encouraged in the GOG trial. The results of these trials hopefully will elucidate the role of adjuvant chemotherapy combined with adjuvant radiation in high-risk, early-stage endometrial cancer.
Endometrial cancer is a hormone-dependent disease, and, therefore, adjuvant hormonal therapy might improve the outcome in the early stages of the disease. Nine randomized trials have compared hormonal therapy versus no adjuvant treatment in early-stage endometrial cancer.37-45 Only one of these trials reported a survival benefit, and only two trials showed an improvement in recurrence-free survival with the use of hormonal therapy versus no adjuvant therapy.42,43 However, a meta-analysis of these nine trials reported no significant improvement in progression-free survival (PFS) or overall survival (OS) associated with adjuvant hormonal therapy compared with no further therapy (Odds Ratio [OR]: 1.10, CI: 0.91, 1.34), suggesting that adjuvant hormonal therapy is not beneficial in early-stage endometrial cancer.46 That being said, for medically inoperable patients with grade I endometrioid endometrial cancers clinically confined to the uterus, progestin therapy may be a viable option combined with close clinical follow-up with frequent endometrial sampling.
Adjuvant Therapy for Advanced-Stage Disease
Over the past decade, the GOG has conducted a series of trials examining the optimal treatment regimen for patients with advanced-stage endometrial cancer. The results of GOG 122 indicated that the chemotherapy regimen of cisplatin and doxorubicin was superior to whole abdominal radiation, with respect to PFS and OS in advanced stage disease.47 The GOG then sought to determine if the addition of paclitaxel to cisplatin and doxorubicin would improve outcomes in a randomized prospective trial. The results of this trial (GOG 177) indicated that paclitaxel plus cisplatin and doxorubicin (TAP) improved PFS and OS with an associated increase in patient toxicity when compared with cisplatin and doxorubicin alone.48
The most recent GOG trial in advanced-stage endometrial cancer (GOG 184) compared surgery and adjuvant pelvic radiation plus cisplatin and doxorubicin with or without paclitaxel.49 No improvement was observed in either PFS or OS with the addition of paclitaxel to pelvic radiation plus cisplatin and doxorubicin. While the results of GOG 184 may seem to conflict with the results of GOG 177, several important observations can be made. First, the addition of pelvic radiation therapy may supplant the benefit of adding paclitaxel to the two-drug regimen seen in GOG 177. Second, this trial demonstrates the feasibility of combining multiagent cytotoxic chemotherapy with adjuvant radiation.
Given the increased toxicity of the TAP regimen and the overall favorable activity and side-effect profile of the carboplatin and paclitaxel combination in many gynecologic malignancies, the GOG instituted protocol 209, which randomized patients with advanced-stage or recurrent endometrial cancer to the TAP regimen versus carboplatin and paclitaxel. This study has finished the accrual phase; results are to come.
Over the past 30 years, numerous trials have confirmed the efficacy of progestin therapy in advanced endometrial cancer with response rates ranging from 23% to 33% in chemotherapy naive patients.50-53 Historically, no meaningful differences in response rates among various progestational agents have been observed.54-55 Several investigators have examined whether a dose-response relationship exists for progestational agents in advanced endometrial cancer. Patients receiving 800 to 1,000 mg of oral medroxyprogesterone acetate daily had response rates ranging from 15% to 24%, which did not differ from the 25% response rate seen in patients taking 200 mg of oral medroxyprogesterone acetate daily.51-52
Several phase II trials have looked at alternating tamoxifen with medroxyprogesterone acetate in patients with advanced endometrial cancer. Response rates ranged from 27% to 33% and were not significantly different from medroxyprogesterone acetate alone.50,53 In the studies cited earlier, progression-free survival ranged from 2.5 months to 3.2 months, and overall survival ranged from 7 months to 13 months. Common to all of these trials is the improved response rate seen in well-differentiated tumors and in tumors with positive estrogen and progesterone receptor status. While no phase III trials have compared the benefit of one progestin regimen with another, phase II trials have confirmed that progestational agents are active in advanced endometrial cancer and represent a viable alternative to cytotoxic chemotherapy.50-53
The GOG is conducting a trial on the molecular staging of endometrial cancer (GOG 210). Investigators are using tumor samples collected in this study from patients with endometrial cancer to develop more accurate models of risk, to identify candidate targets for therapeutic intervention, and to improve utilization of individualized treatments based on molecular characteristics of individual tumors. This ongoing research hopefully will shed light on the molecular mechanisms responsible for the development of endometrial cancer and the biologic pathways responsible for how patients respond to therapy.
Several completed and ongoing trials have examined the use of monoclonal antibodies in endometrial cancer. The HER2/neu receptor inhibitor trastuzumab did not show any major responses in advanced or persistent endometrial cancer.56 The anti-angiogenic drug bevacizumab has been tested in patients with advanced or recurrent endometrial cancer.57 A response rate of 15% was observed, making bevacizumab the most active biologic agent in endometrial cancer to date. Several trials testing tyrosine kinase inhibitors have completed accrual, and results are pending.
Endometrial cancer is a disease process that mostly affects postmenopausal women, many of whom may be candidates for HRT. While the absolute risk for endometrial cancer in patients taking HRT remains unknown, prescribing continuous combined HRT for postmenopausal patients who may derive a quality-of-life benefit from HRT and who have been counseled appropriately seems reasonable.
For patients with early-stage disease, the challenge remains in identifying those patients who will benefit ultimately from adjuvant therapy while developing adjuvant treatment strategies that decrease treatment-related morbidity. Current and future randomized trials for high-risk patients with early-stage endometrial cancer are crucial to identifying optimal treatment regimens, particularly in regards to the inclusion of adjuvant chemotherapy in the treatment of early-stage disease.
Patients with advanced-stage disease continue to have poor outcomes. For now, chemotherapy is the mainstay of treatment, and phase III trials are currently under way to determine the optimal regimen. The results of the molecular staging study GOG 210 will hopefully identify molecular markers in endometrial cancer that may inform on the criteria used to assess risk in early-stage disease, assist in the surgical decision-making process, and elucidate potential therapeutic targets that may result in improved outcomes in advanced-stage disease.
Finally, the success of biologic agents, including monoclonal antibodies and tyrosine kinase inhibitors, in other cancer sites has led to the development of trials testing these agents in endometrial cancer. While the results of many of these trials are pending, investigators remain hopeful that these drugs will improve outcomes, particularly in advanced-stage and recurrent disease.
Todd Boren, MD, is a fellow in obstetrics and gynecology at The University of Texas Southwestern Medical Center. David Miller, MD, is chief of the UT Southwestern School of Medicine Division of Gynecologic Oncology. He also is chair of the Uterine Cancer Committee for the Gynecologic Oncology Group, the women's cancer research arm of the National Cancer Institute.
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