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New Treatments for Endometrial Cancer

Endometrial carcinoma in the United States is the most common gynecologic invasive malignancy of the female genital tract; 37,200 new cases in 2006, about 6,400 deaths in cancer of the uterus. In fact this total of 37,200 is about equal to cases of ovarian carcinoma and cervical carcinoma combined. The difference is about 1,000 cases total. So this is a very common invasive malignancy.

Pathologically, we are talking about adenocarcinomas. Over 70% of these tumors will be adenocarcinoma. There are some poor prognosis cell types you need to be aware of. These are actually subtypes of adenocarcinoma. Papillary serous tumors of the uterus are bad actors, as are clear cell carcinomas. Now no one can tell you how to approach these differently to make a difference in the outcome. It’s just like the mucinous and clear cells in ovary carcinoma.

There are a number of risk factors that have been reported. This is an attempt to summarize all of these risk factors, for those of you who are taking the Board. Obesity is clearly associated with endometrial carcinoma. We think because obesity leads to differences in the way hormonal agents are handled in the body.

The current position taken by the American College of Obstetrics and Gynecology does not suggest periodic endometrial sampling, but simply close follow-up and asking about symptomatology, such as abnormal vaginal bleeding or discharge. If that appears, then that would be a reason for a gynecologic evaluation, including sampling of the endometrium and it would be a red flag for the potential presence of endometrial carcinoma.

Endometrial hyperplasia is a lesion that is associated with the development of endometrial cancer. This is classified as simple, complex or atypical. And atypical is divided into simple atypical hyperplasia and complex atypical hyperplasia. The risk of progression to malignancy for each of these is 1% of patients with simple hyperplasia.

The disease presents in the peri and postmenopausal age groups, beginning at about age 40 and rising in incidence as you proceed into the postmenopausal years. As we’ve mentioned from the risk factor slide, associated factors are obesity, hypertension and diabetes. As a result of this, this has come to be known as a fragile patient population that does not tolerate aggressive.

The principal presenting manifestation of the disease is bleeding, and this accounts for why we are able to diagnose this disease process at an early stage in the vast majority of patients. If your patient presents with abnormal bleeding of any kind, particularly in the peri or postmenopausal years, that patient should be considered to have endometrial carcinoma until proven otherwise. That is an indication for sampling of the endometrium by your friendly gynecologist. The key prognostic factor for these patients is the extent of disease at the time of diagnosis or the stage. The staging system of endometrial carcinoma currently is a surgical/pathological staging system. This is an abbreviated version; stage I disease is disease confined to the corpus, stage II disease is disease that has extended to involve the cervix, stage III is regional spread.

The way we classify the disease for the purpose of treatment approaches is shown on this slide. We divide the cases into those cases that are associated with local or regional involvement in the pelvic area or the abdominal cavity, and those who have disease that has disseminated to more distant sites. The local regional cases are subdivided into low risk, intermediate risk and high risk groups. Now the basis for this sort of subdivision of the patient population comes mainly from studies done by the gynecologic oncology group.

For patients who are deemed to have low risk disease, that is stage Ia - that is disease confined to the endometrium - grade I or grade II. Surgical resection alone has a five year survival that exceeds 90% and in some series goes as high as 98%. So the recommended treatment for these patients is total abdominal hysterectomy plus a careful surgical staging to insure that the disease process is truly stage Ia, that it is confined to the endometrium, grade I or grade II.

Now this is based on three-year follow-up. Surgical resection alone yields an 89% three year survival. Surgery followed by pelvic radiation in this group yields a 96% three-year survival. The basis for that is this study, GOG protocol 99. It did not include any of the IIIa patients but it did include all the patients with stage I disease who had myometrial invasion. Patients with stage II disease, that is cervix involvement, all of these patients - 390 of them - were subjected.

Now for patients at high risk for recurrence, these include the patients who are stage III by virtue of the involvement of the vagina or the pelvic or periaortic lymph nodes. And also stage IVa patients. Those who are stage IV by virtue of involvement of the bladder or rectal mucosa. If you do surgery only on these patients, that is do a TAH - total abdominal hysterectomy - and bilateral salpingo-oophorectomy, a complete resection of gross disease.

Now for disseminated disease, we have the small percentage of patients who present with primary stage IVb disease, which is 3% of the total, that is disease outside the pelvis and we also have those who recur after initial treatment. The mainstay of management here has been systemic therapy, either hormonal therapy or chemotherapy - and we want to look at each of these areas since these tend to be more the province for medical oncologists. Hormonal therapy has been looked at for gestational agents, the most common agents used, the antiestrogens have also been studied. Now let’s look first at the progestational agents.

The second part of the mythology is that the duration of response as well as survival on progestins is often very low. These people do extremely well for decades. Let’s look at what the fact is here, and we are going to take a little more detailed look at this patient population’s makeup. If you look at patients who develop recurrent disease and receive progestational agents as treatment, what we find is that about 1:5 will have grade I disease, 36% will have grade II disease and roughly 43% will have grade III disease.