Endometrial Cancer

Don Dizon, MD, Brown University, discusses the paradigm shift in the treatment of endometrial cancer with the use of medical therapy, including chemotherapy with biologics, mTOR inhibitors combined with chemotherapy, and targeted therapies.

The European Society of Gynaecological Oncology (ESGO) biennial meeting is taking place in Milan, Italy, and will run from September 11-14, 2011.

Physicians must engage and educate patients about significant risk for cardiovascular disease.

A modified radical hysterectomy (class II) did not improve locoregional control and survival compared with simple extrafascial abdominal hysterectomy (class I). Investigators from University of Milano-Bicocca in Monza, Italy, randomized 520 patients with stage I endometrial cancer to class I or class II surgery. They found that the median length of parametria and vagina removed were 15 mm and 5 mm respectively for class I hysterectomy vs 20 mm and 15 mm for class II hysterectomy (P > .001). Operating time and blood loss were statistically significantly higher for class II hysterectomy. Five-year disease-free survival and overall survival was 87.7% and 88.9% respectively in the class I arm, and 89.7% and 92.2% in the class II arm (Ann Surg Oncol online, October 16, 2009).

Comparative uptake of two radiotracers allows characterization of tumor.

Endometrial cancer is the most common gynecologic malignancy, with an estimated 40,100 cases and 7,470 deaths in 2008. This malignancy represents 6% of all cancers, and 3% of cancer deaths in women. Endometrial cancer is more prevalent in older women, with an incidence of 1 in 142 for women 40 to 59 years old, increasing to 1 in 81 women over 70 years old.[1] Median age at diagnosis is 62.[2] The mortality of endometrial cancer has decreased from 4.18 to 4.12 per 100,000 from 1991 to 2004.

Published analyses combining groups of patients with different risk profiles have created confusion surrounding patient selection for adjuvant treatment after surgery for endometrial cancer. As a result, no randomized trial has demonstrated a survival benefit with the addition of adjuvant radiation

In this issue of ONCOLOGY, Diavolitsis et al have provided an excellent overview of the literature and state of our understanding of the role of adjuvant therapy in the treatment of endometrial cancer.

Patients with endometrial cancer who have minimally invasive robotic-assisted hysterectomies tend to have quicker surgeries and shorter hospital stays compared with patients who have similar laparoscopic surgical procedures, according to new research from The Ohio State University Comprehensive Cancer–James Cancer Hospital and Solove Research Institute.

The first phase III study of its kind has found that vaginal brachytherapy—in which a radioactive cylinder is inserted into the vagina—is as effective at preventing the recurrence of higher-risk endometrial cancer as external-beam radiation therapy, has fewer side effects, and results in a better quality of life for patients (abstract LBA5503).

For women with a gynecologic cancer, reproductive concerns may vary not only by site of disease but also by the presentation and manifestation of the disease. Gynecologic cancer can present before childbearing has been started or completed, during pregnancy, or can even arise out of pregnancy.

Carcinoma of the endometrium is the most common female pelvic malignancy and the fourth most common cancer in females, after breast, bowel, and lung carcinomas. In 1995, an estimated 32,800 new cases of endometrial carcinoma and 5,900 related deaths will occur in the United States [1]. The relatively low mortality for this cancer is probably due to the fact that in 80% of cases, the disease is diagnosed when it is confined to the uterus.

Results from Oncolytics Biotech's phase I trial of Reolysin, its oncolytic reovirus, show stable disease in 7 of 32 patients with advanced or metastatic solid tumors refractory to standard therapy or for which no curative standard therapy exists. Dr. Timothy Yap of The Institute of Cancer Research, Sutton, UK, presented the study at the 18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics

Hospitalized oncology patients are at particular risk for acute venous thromboembolism (VTE); however, more often than not, a standard for VTE prophylaxis does not exist, according to Jerelyn Osoria, RN, OCN, of Memorial Sloan-Kettering Cancer Center. Ms. Osoria reported at the Oncology Nursing Society 31st Annual Congress (abstract 113) that an electronic medical orders system and better nursing documentation have helped improve this situation at her institution's Gynecology (GYN) oncology inpatient nursing unit.

The review of the histology slides revealed predominantly decidual tissue with exaggerated placental site and a small focus of trophoblastic tissue composed of cytotrophoblast and syncytiotrophoblast with mild atypia (Figure 1). However, no necrosis or tissue invasion was identified. No villi were seen.

Endometrial cancer is the mostcommon gynecologic malignancyaffecting women in theUnited States. In 1988, the InternationalFederation of Gynecology andObstetrics shifted from a clinical stagingprotocol to one based on surgicalfactors, making surgical staging theaccepted treatment approach to endometrialcancers, with excellentsurvival compared to other gynecologicmalignancies. The manuscript byKirby et al brings to light the controversiessurrounding the surgical evaluationof endometrial cancers. Althoughsurgical staging has been shown to haveboth prognostic and therapeutic benefit,major problems in the United Statescontinue to result in suboptimal treatmentof patients with endometrial cancer.These problems include the lack ofan accepted surgical protocol (in termsof adequacy of lymph node sampling)and incomplete surgical staging secondaryto patient factors or the lack ofreferral to specialty-trained gynecologiconcologists.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomaldominant cancer susceptibility syndrome associated with inheriteddefects in the DNA mismatch repair system. HNPCC family membersare at high risk for developing colorectal, endometrial, and ovariancancers. Studies of HNPCC families have helped define the importantrole that mismatch repair genes play in the molecular pathogenesis ofendometrial and ovarian cancers. This review will describe some of theimportant clinical and molecular features of HNPCC-related endometrialand ovarian cancer and describe how genetic susceptibility can beidentified in patients with sporadic endometrial and ovarian cancers. Itis important to identify patients with HNPCC, as families of mutationcarriers may benefit from genetic counseling, testing, and intensifiedcancer surveillance.

Kirby et al are correct in theirstatement that continued controversysurrounds the comprehensivesurgical staging of all patientswith clinical stage I endometrialadenocarcinoma. Such is the case becauselymph node metastasis is foundin only 10% of these patients. Theproportion of patients found to havelymph node metastasis is even loweramong those with grade 1 and 2 tumorswith minimal or no invasion. Ahigh proportion of patients with endometrialadenocarcinoma fall intothis group.

Early presentation of endometrial cancer permits effective managementwith excellent clinical outcome. The addition of hysteroscopy todilatation and curettage (D&C) in the evaluation of postmenopausalbleeding adds little to the detection of malignancy. Imaging studies suchas computed tomography, magnetic resonance imaging, and positronemissiontomography may be of use in determining the presence ofextrauterine disease in patients medically unfit for surgical staging.However, these studies are not sufficiently sensitive to replace surgicalstaging and have little role in routine preoperative evaluation. Clinicalstaging alone is clearly inadequate, as 23% of preoperative clinicalstage I/II patients are upstaged with comprehensive surgical staging.Preoperative tumor grade from D&C or office biopsy may be inaccurateand lead to an underestimate of tumor progression if used to determinewhich patients should be surgically staged. Clinical estimationof depth of invasion, with or without frozen section, is inaccurate andmay lead to underestimation of disease status when surgical staging isnot performed. The practice of resecting only clinically suspicious nodesshould be discouraged as it is no substitute for comprehensive surgicalstaging. Comprehensive surgical staging provides proper guidance forpostoperative adjuvant therapy, avoiding needless radiation in 85% ofclinical stage I/II patients. Finally, resection of occult metastasis withsurgical staging may improve survival.

Granulocyte-macrophage colony-stimulating factor (GM-CSF,sargramostim [Leukine]) is a powerful cytokine that is able to stimulatethe generation of dendritic cells. Adjuvant treatment with continuous lowdoseGM-CSF has been shown to prolong survival of stage III/IV melanomapatients. Data on continuous low-dose GM-CSF therapy in tumorsother than prostate cancer are still lacking.

The Lynch syndrome (hereditary nonpolyposis colorectal cancer[HNPCC]), is the most common form of hereditary colorectal cancer(CRC), accounting for 2% to 7% of all CRC cases. The next most commonhereditary CRC syndrome is familial adenomatous polyposis (FAP),which accounts for less than 1% of all CRC. Lynch syndrome is ofcrucial clinical importance due to the fact that it predicts the lifetimerisk for CRC and a litany of extra-CRC cancers (of the endometrium,ovary, stomach, small bowel, hepatobiliary tract, upper uroepithelialtract, and brain) through assessment of a well-orchestrated family history.A Lynch syndrome diagnosis is almost certain when a mutation ina mismatch repair gene-most commonly MSH2, MLH1, or, to a lesserdegree, MSH6-is identified. Once diagnosed, the potential for significantreduction in cancer-related morbidity and mortality through highlytargeted surveillance may be profound. Particularly important iscolonoscopy initiated at an early age (ie, 25 years) and repeated annuallydue to accelerated carcinogenesis. In women, endometrial aspirationbiopsy and transvaginal ultrasound are important given the extraordinarilyhigh risk for endometrial and ovarian carcinoma. Thesecancer control strategies have a major impact on at-risk family membersonce they have been counseled and educated thoroughly aboutLynch syndrome’s natural history and their own hereditary cancer risk.

BETHESDA, Maryland-Convincing evidence indicates that physical activity can significantly reduce the risk of colon and breast cancer, according to a newly released National Cancer Institute (NCI) fact sheet. Moreover, studies also suggest a link between exercise and a reduced risk of cancers of the prostate, lung, and endometrium. However, despite the documented cancer and other health benefits of exercise, "recent studies have shown that more than 60% of Americans do not engage in enough regular physical activity," NCI said. The new publication summarizes the evidence supporting the role of exercise in cancer risk reduction and the possible underlying biological mechanisms

SAN DIEGO-In a cohort of endometrial cancer patients at M.D. Anderson Cancer Center, those who had previously developed breast cancer and used tamoxifen did not have a higher incidence of high-risk histologic subtypes, compared with breast cancer patients not receiving tamoxifen, reported Brian M. Slomovitz, MD, at the Society of Gynecologic Oncologists 35th Annual Meeting (SGO abstract 24).

Four randomized prospective trials have evaluated tamoxifen forchemoprevention of breast cancer. The National Surgical AdjuvantBreast and Bowel Project P-1 trial reported that tamoxifen reduced therisk of invasive breast cancer by 49%. Two smaller European trials, theRoyal Marsden Hospital Chemoprevention Trial and the Italian TamoxifenPrevention Study, demonstrated no decrease in the incidence ofbreast cancer among women using tamoxifen. The International BreastCancer Intervention Study confirmed that tamoxifen can reduce therisk of breast cancer in healthy women. The Multiple Outcomes ofRaloxifene Evaluation trial, which evaluated the use of raloxifene(Evista) to prevent osteoporosis, found that the risk of invasive breastcancer decreased by 76%. A uniform theme in these trials is thattamoxifen reduces the risk of breast cancer among women at high riskfor the disease. Tamoxifen is currently approved for breast cancer riskreduction. However, because of the side effects associated with its use(ie, endometrial cancer and thromboembolism), other agents are beinginvestigated. The Study of Tamoxifen and Raloxifene is designed tocompare the efficacy of tamoxifen and raloxifene in reducing breastcancer risk. Aromatase inhibitors will also be studied in the setting ofchemoprevention for breast cancer.

Published literature indicates that the selective estrogen-receptormodulators (SERMs) tamoxifen and raloxifene (Evista) have favorableeffects on bone density, lipid profiles, and the incidence of secondbreast cancers, and unfavorable effects on the incidence of venousthrombosis and hot flushes. Tamoxifen increases the risk of endometrialcancer, but raloxifene does not. The effects of SERMs on sexualfunction and cognition are unclear. Because the selective antiaromataseagents are relatively new, the long-term effects of these agentson normal tissues are less well established. It appears that the nonsteroidalagents (anastrozole [Arimidex], letrozole [Femara]) and steroidal(exemestane [Aromasin]) antiaromatase agents may have differenteffects on normal tissues. Preliminary data demonstrate that anastrozoleincreases the risk of arthralgias and produces a decrease in bonedensity. In contrast, exemestane appears to favorably affect bonedensity and lipid profile, similar to tamoxifen and raloxifene. Theincidence of contralateral breast cancer is decreased in women onadjuvant anastrozole, but data for the other antiaromatase agents arenot yet available. Hot flushes have been reported with the use ofselective aromatase inhibitors, but their incidence seems to be comparableto what is reported with SERMs. Antiaromatase agents do notappear to cause venous thrombosis. More information about the effectsof the antiaromatase agents on normal tissue will become available asdata from ongoing adjuvant and chemoprevention trials are reported.Clinically, we should be conscious of the differences between antiaromataseagents and SERMs and their impact on women’s health.

In their excellent summary of randomized trials examining the management of cancers of the uterus and ovary, Kim and coauthors highlight a significant and worrisome difference that has developed between the two gynecologic malignancies over the past decade, with regard to the direction of clinical research involving chemotherapy. Although it is recognized that cytotoxic chemotherapy is employed in the majority of women with ovarian cancer at initial diagnosis, whereas such treatment is fortunately only required in a minority of individuals with endometrial cancer, it is unclear why there has been such a major divergence in the drugs and combination regimens currently being evaluated in clinical trials.

Over the past few decades, we have gained a better understanding of the risk factors associated with the recurrence of endometrial cancer. Adjuvant postoperative radiotherapy in an intermediate-risk group of

Flavopiridol [2-(2-chlorophenyl 5 ,7-dihydroxy-8-[cis-(3-hydroxy-1-methyl-4-piperidinyl)-4H-1-benzopyran-4-one, hydrochloride] is a semisynthetic flavone with a novel structure compared with that of polyhydroxylated flavones, such as quercetin and genistein.[1] It is derived from rohitukine, an alkaloid isolated from the stem bark of Dysoxylum binectariferum, a plant indigenous to India.[2] Originally synthesized and supplied by Hoechst India Limited, flavopiridol is provided to the Division of Cancer Treatment and Diagnosis of the National Cancer Institute (NCI) by Aventis Pharmaceuticals, Inc.

Handbook of Gynecologic Oncology, edited by Drs. Barakat, Bevers, Gershenson, and Hoskins, is a first-edition clinical handbook formulated primarily for fellows in gynecologic oncology as well as for interested fellows in medical oncology and radiation oncology. The textbook presents concise summaries of the critical issues in the care of gynecologic cancer patients and would also be of interest to residents preparing for their gynecologic oncology rotations, obstetrician/gynecologists, other physicians who care for gynecologic cancer patients, and practicing gynecologic oncologists.

CHICAGO-Adding paclitaxel (Taxol) and G-CSF support to the standard regimen of doxorubicin and cisplatin (Platinol) improved response rates and increased survival by about 3 months for patients with advanced or recurrent endometrial cancer in a randomized controlled phase III trial conducted by the Gynecologic Oncology Group (GOG) (ASCO abstract 807).