Uterine Corpus Tumors

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Carcinoma of the epithelial lining (endometrium) of the uterine corpus is the most common female pelvic malignancy. Factors influencing its prominence are the declining incidence of cervical cancer, longer life expectancy, and earlier diagnosis.

Endometrial Cancer

Carcinoma of the epithelial lining (endometrium) of the uterine corpus is the most common female pelvic malignancy, with 54,870 new cases estimated to be diagnosed in 2015 and 10,170 deaths expected. Factors influencing its prominence are the declining incidence of cervical cancer, longer life expectancy, and earlier diagnosis.

Epidemiology

Age

Endometrial cancer is primarily a disease of postmenopausal women, although 25% of cases occur in premenopausal patients, with 5% of cases developing in patients younger than 40 years.

Geography

The incidence of endometrial cancer is high in Western nations and very low in Eastern countries.

Immigrant populations tend to assume the risks of native populations, highlighting the importance of environmental factors in the genesis of this disease. Endometrial cancers tend to be more common in urban than in rural residents. In the United States, the incidence of endometrial cancer is twice as high in white women as in black women.

Etiology and Risk Factors

Adenocarcinoma of the endometrium may arise in normal, atrophic, or hyperplastic endometrium. Two mechanisms are generally believed to be involved in the development of endometrial cancer. In approximately 75% of women, there is a history of exposure to unopposed estrogen, either endogenous or exogenous (type I). The tumors in these women begin as endometrial hyperplasia and progress to carcinomas, which usually are better differentiated and have a more favorable prognosis than tumors unrelated to estrogens.

In 25% of women, carcinomas appear spontaneously, are not clearly related to a transition from atypical hyperplasia, and rather arise in a background of atrophic or inert endometrium. These neoplasms tend to be associated with a more undifferentiated cell type and a poorer prognosis (type II).

Unopposed estrogen

It has been hypothesized that long-term estrogenic stimulation of the endometrium unmodified by progesterone has a role in the development of endometrial carcinoma. This hypothesis derives from observations that women who are infertile or obese or who have dysfunctional bleeding due to anovulation are at high risk for this disease, as are women with estrogen-secreting granulosa theca cell ovarian tumors. Also, the recognition that atypical adenomatous (complex) hyperplasia is a precursor of cancer, and that it is associated with unopposed estrogen use in women, underscores the importance of the association among risk factors, estrogens, and cancer. In the late 1970s and early 1980s, several case-control studies demonstrated that the risk of endometrial cancer is increased 4- to 15-fold in long-term estrogen users, as compared with age-matched controls.

It is well established that past use of oral contraceptives (OCs) protects against endometrial cancer. The use of OCs with either high-potency progestin or low-potency progestin is associated with a decreased risk of endometrial cancer. The potency of the progestin in most OCs appears adequate to provide a protective effect against endometrial cancer. OCs with higher progestin potency may be more protective than OCs with lower progestin potency among women with a larger body habitus.

Sidebar: The Women’s Health Initiative enrolled 16,608 postmenopausal women from 40 US clinical centers into a randomized, double-blind, placebo-controlled trial. Women aged 50 to 70 with an intact uterus and normal endometrial histology were assigned to once-daily 0.625-mg conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate or to placebo. After 6 years of the intervention and 7 years of additional follow-up, endometrial cancer was diagnosed in 66 women in the combined-hormone–therapy group and in 95 women in the placebo group, which translated to a 35% reduction in risk (P= .007) (Chlebowski RT, Anderson GL, Sarto G, et al: European Cancer Congress abstract LBA13, 2013).

Diet

The high rate of occurrence of endometrial cancer in Western societies and the very low rate in Eastern countries suggest a possible etiologic role for nutrition, especially the high content of animal fat in Western diets. There may be a relationship between high-fat diets and the higher incidence of endometrial carcinoma in women with conditions of unopposed estrogen. Endogenous estrogens rise in postmenopausal women because of increased production of androstenedione or a greater peripheral conversion of this hormone to estrone. In obese women, the extraglandular aromatization of androstenedione to estrone is increased in fatty tissue.

Obesity

Phenotypically, the majority of women who develop endometrial cancer tend to be obese. Women who are 30 lb over ideal weight have a threefold increased risk of developing endometrial cancer, whereas those 50 lb or more over ideal weight have a 10-fold increased risk.

Parity

Nulliparous women are at 2 times greater risk for developing endometrial cancer, women who undergo menopause after age 52 are at 2.5 times greater risk, and those who experience increased bleeding at the time of menopause are at 4 times greater risk.

Endometrial hyperplasia

It is believed that the majority of endometrioid neoplastic lesions of the endometrium follow a continuum of histologically distinguishable hyperplastic lesions that covers a spectrum ranging from endometrial hyperplasia without atypia to endometrial hyperplasia with atypia (AEH) to well-differentiated endometrial cancer. Whereas patients found to have simple endometrial hyperplasia have a low risk of disease progression to cancer, 29% of those with complex atypical hyperplasia, if left untreated, will develop adenocarcinoma. However, the reproducibility of these diagnoses has been questioned by many.

As recently reported, the Gynecologic Oncology Group (GOG)-0167 estimated the reproducibility of a referring institution’s pathologist’s diagnosis of AEH and determined the frequency of concomitant adenocarcinoma in the hysterectomy obtained within 12 weeks of the initial diagnosis. The referring institution’s pathologist’s diagnosis of AEH was supported by the majority of the expert panel in only 38% of cases. The majority diagnosis was adenocarcinoma in 29%, cycling endometrium in 7%, and nonatypical hyperplasia in 18% of cases. Unanimous agreement on any diagnosis was reached among the entire expert panel in only 40% of cases. This study panel found that there was a high incidence (43%) of endometrial cancer in patients who had a biopsy demonstrating AEH.

Other risk factors

Other known risk factors for endometrial cancer include diabetes mellitus; hypertension; and a family history of endometrial, breast, and colon cancer. Diabetic women have a 3-fold increased risk, and hypertensive patients have a 1.5-fold greater risk of endometrial cancer. Results from three hereditary nonpolyposis colorectal cancer (HNPCC) registries have shown a 10-fold increased risk of endometrial cancer for women who carry the HNPCC genetic abnormality, with a cumulative risk for endometrial cancer of 43% by age 70. Women with or at risk for HNPCC can be offered endometrial screening annually beginning at age 35, but informed decision making after a discussion of options, including benefits, risks, and limitations of testing, is appropriate. Additional investigation is needed to determine the appropriate monitoring for endometrial cancer in HNPCC carriers.

Tamoxifen exerts its primary effect by blocking the binding of estrogen to estrogen receptors. It also exerts mild estrogenic effects on the female genital tract. This weak estrogenic effect presumably accounts for an increased frequency of endometrial carcinoma observed in women receiving prolonged adjuvant tamoxifen therapy for breast carcinoma.

Initially reported in 1985, the increased frequency of endometrial carcinoma in patients treated with tamoxifen was characterized more fully in a study of 1,846 women recorded in the Swedish Cancer Registry. This study reported a 6.4-fold increase in the relative risk of endometrial carcinoma with a daily dose of 40 mg of tamoxifen. The greatest cumulative risk was observed after 5 years of tamoxifen use.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) subsequently reported on the incidence of other cancers in 2,843 women with node-negative, estrogen receptor–positive breast cancer treated with either tamoxifen or placebo in its B-14 randomized trial and an additional 1,220 patients treated with tamoxifen in another NSABP trial. The relative risk of endometrial carcinoma in the tamoxifen-treated patients was 7.5. The hazard rate was 0.2 per 1,000 cases with placebo and 1.6 per 1,000 cases with tamoxifen therapy. The mean duration of tamoxifen therapy for all patients was 35 months, and 36% of the cancers had developed by 2 years after the initiation of treatment. A more recent review of NSABP treatment and prevention trials revealed that the risk of uterine sarcomas was also increased with tamoxifen. The incidence of sarcomas was very low, however, with a rate of 0.17/1,000 women/year.

These data raise the question of whether tamoxifen should be used as adjuvant therapy for women at relatively low risk for breast cancer recurrence. First, it should be recognized that the endometrial cancers that develop in patients receiving tamoxifen exhibit the same stage, grade, and prognosis distribution as other endometrial cancers. There is some evidence that tamoxifen use is associated with an increased risk of uterine sarcoma; fortunately, this risk is low, and the cure rate should be high. Second, adjuvant tamoxifen reduces the cumulative rate of recurrence of breast cancer from 228 to 124 cases per 1,000 women and the cumulative rate of second primary breast cancers from 40.5 to 23.5 cases per 1,000 women.

When all of these facts are taken into account, there is an overall 38% reduction in the cumulative hazard rate for recurrence of breast cancer in tamoxifen-treated patients. Thus, the benefits of tamoxifen may outweigh the risks of endometrial cancer.

The current recommendations for screening women who are receiving tamoxifen are to educate patients about the significance of abnormal spotting, bleeding, or discharge and to investigate promptly any of these abnormalities.

Some experts have proposed that tamoxifen-treated women be screened with transvaginal ultrasonography. However, recent data suggest a high false-positive rate and a low frequency of significant findings, leading to the conclusion that endometrial screening is not warranted.

Signs and Symptoms

Postmenopausal women

Symptoms of early endometrial carcinoma are few but common. However, 90% of patients complain of abnormal vaginal discharge, and 80% of these women experience abnormal bleeding, usually after menopause. In the general population, 15% of postmenopausal women presenting with abnormal bleeding will be found to have endometrial carcinoma. Signs and symptoms of more advanced disease include pelvic pressure and other symptoms indicative of uterine enlargement or extrauterine tumor spread.

Premenopausal women

The diagnosis of endometrial cancer may be difficult to make in premenopausal patients. The physician must maintain a high index of suspicion in this group of patients and perform endometrial sampling in any women who complain of prolonged, heavy menstrual periods or intermenstrual spotting.

Screening and Diagnosis

Screening

There is no role for screening of average-risk, asymptomatic patients for endometrial cancer.

Outpatient endometrial sampling

These procedures, such as endometrial biopsy or aspiration curettage coupled with endocervical sampling, are definitive if results are positive for cancer. The results of endometrial biopsies correlate well with endometrial curettings, and these biopsy procedures have the advantage of avoiding general anesthesia. However, if sampling techniques fail to provide sufficient diagnostic information or if abnormal bleeding persists, formal dilation and curettage is required.

Dilation and curettage

This is the gold standard for assessing uterine bleeding and diagnosing endometrial carcinoma. Before dilating the cervix, the endocervix should be curetted. Next, careful sounding of the uterus is accomplished. Dilation of the cervix is then performed, followed by systematic curetting of the entire endometrial cavity. Cervical and endometrial specimens should be kept separate and forwarded for pathologic interpretation.

The American Cancer Society (ACS) has concluded that there is insufficient evidence to recommend routine screening for endometrial cancer for average-risk women. However, the ACS recommends that at the time of menopause, all women should be informed about the risks and symptoms of endometrial cancer and strongly encouraged to report any unexpected bleeding or spotting to their physicians. Women at elevated risk for endometrial cancer from tamoxifen therapy should be informed about the risk and symptoms of endometrial cancer and strongly encouraged to report any unexpected bleeding or spotting to their physicians.

Women who carry the HNPCC abnormality should be considered for a prophylactic total abdominal hysterectomy bilateral saphingo-oophorectomy, especially after childbearing and when contemplating abdominal surgery for any reason. Additional investigation is needed to determine the appropriate monitoring for endometrial cancer in HNPCC carriers.

Pathology

Adenocarcinoma

Endometrioid adenocarcinoma is the most common form of endometrial carcinoma, accounting for 75% to 80% of cases. It varies from well differentiated to undifferentiated. The former demonstrates well-preserved glands in at least 95% of the tumor, whereas in the latter, less than half of the neoplasm shows glandular differentiation. Squamous differentiation can be seen in 30% to 50% of cases.

Adenocarcinoma with benign squamous differentiation has been termed “adenoacanthoma” and generally has a good prognosis.

If the squamous component resembles squamous carcinoma, the tumor is designated an adenosquamous carcinoma. These lesions tend to have a worse prognosis because of their association with a poorly differentiated glandular component.

Serous carcinoma

This is an aggressive form of endometrial cancer that accounts for fewer than 10% of these tumors. Serous cancer of the endometrium closely resembles serous carcinoma of the ovaries and fallopian tubes and is usually found in an advanced stage in older women.

Clear-cell carcinomas

Clear-cell carcinomas of the endometrium closely resemble their counterparts in the cervix, vagina, and ovaries. As with serous cancers, these tumors generally occur in older women and have a poor prognosis because of their propensity for early intraperitoneal spread.

Secretory adenocarcinoma

This is an uncommon endometrial cancer that resembles secretory endometrium with its associated progestational changes. These cancers tend to be of low grade and have a good prognosis.

Staging and Prognosis

Two large prospective GOG surgical staging trials reported in 1984 and 1987 helped define the prognostic factors for endometrial carcinoma and the current treatment approaches. In addition to evaluating the predictive value of such factors as age, race, and endocrine status, the studies confirmed that prognosis is directly related to the presence or absence of easily determined uterine and extrauterine risk factors. Uterine prognostic factors include histologic cell type, tumor grade, depth of myometrial invasion, occult extension of disease to the cervix, and vascular space invasion. Extrauterine prognostic factors include adnexal metastases, intraperitoneal spread of disease to other extrauterine structures, positive peritoneal cytology, pelvic lymph node metastases, and aortic node involvement.

TABLE 1

2009 FIGO staging system for carcinoma of the endometrium

The revised staging system takes into account the nearly equivalent survival rates among low to intermediate grade IA and IB tumors, the lack of prognostic significance of endocervical gland involvement, and the marked survival differences of pelvic node or para-aortic node involvement. A revised staging system can be seen in Table 1.

Peritoneal cytology

Peritoneal cytology is no longer included in the staging system. It is to be reported separately without changing the stage. Several reports of patients with positive peritoneal cytology have failed to demonstrate that peritoneal cytology is a poor prognostic factor.

Uterine size

The size of the uterus was previously believed to be a risk factor and was part of the older clinical staging system. However, recent information indicates that uterine size is not an independent risk factor but rather relates to cell type, grade, and myometrial invasion.

TABLE 2

1988 FIGO surgical staging for endometrial cancer

Surgical staging

Cell type and grade can be determined before hysterectomy, although in some series, grade, as determined by dilation and curettage, has an overall inaccuracy rate of 31% compared with grade in the hysterectomy specimen, and grade 3 tumors have an inaccuracy rate of 50%. Recognition of all of the other factors requires an exploratory laparotomy, peritoneal fluid sampling, and hysterectomy with careful pathologic interpretation of all removed tissue. This primary surgical approach led the International Federation of Gynecology and Obstetrics (FIGO) to define endometrial cancer as a surgically staged disease in 1988, incorporating many of the prognostic factors into the staging process (Table 2).

Treatment

Surgery

Approximately 90% of patients with a diagnosis of endometrial cancer are medically able to undergo surgery. Preparation for this surgery should include evaluation of such concurrent medical problems as hypertension and diabetes, which are frequently found in patients with endometrial cancer.

Open surgical procedure. The operative procedure is performed through an adequate abdominal incision that allows for thorough intra-abdominal exploration and retroperitoneal lymph node removal if necessary. On entry into the peritoneal cavity, fluid samples are obtained for subsequent cytologic determination (intraperitoneal cell washings). Next, thorough intra-abdominal and pelvic exploration is undertaken, with biopsy or excision of any suspicious lesions. In particular, the uterus should be observed for tumor breakthrough of the serosal surface. The distal ends of the fallopian tubes are clipped or ligated to prevent possible tumor spillage during uterine manipulation.

These procedures should be followed by total extrafascial hysterectomy and bilateral salpingo-oophorectomy. The excised uterus is opened away from the operating table, and the depth of myometrial penetration is determined by clinical observation or microscopic frozen section. The depth of myometrial invasion can be accurately assessed in more than 90% of cases.

Laparoscopic surgery. An alternative method of surgically staging patients with clinical stage I endometrial cancer is gaining in popularity. This approach combines laparoscopically assisted vaginal hysterectomy with laparoscopic lymphadenectomy.

Laparoscopy-assisted surgical staging is feasible in a select group of patients. However, it is not yet known whether this approach is applicable to all patients with clinical stage I disease. In particular, patients who are overweight or have intra-abdominal adhesions may not be ideal candidates. Para-aortic lymphadenectomy is technically more difficult through the laparoscope. To obtain adequate exposure, it is necessary to elevate the small-bowel mesentery into the upper abdomen, which becomes increasingly difficult as the patient’s weight increases, especially when weight exceeds 180 lb.

Walker et al reported the results of GOGLAP2, which randomized patients to laparoscopy or open laparotomy surgical staging. Laparoscopy was initiated in 1,682 patients and completed without conversion in 1,248 patients (74%). Conversion from laparoscopy to laparotomy was secondary to poor visibility in 246 patients (15%), metastatic cancer in 69 patients (4%), and bleeding in 49 patients (3%). Patients randomized to undergo laparoscopy had significantly fewer moderate to severe (Common Toxicology Criteria > grade 2) postoperative complications (14% vs 21%; P < .0001) and similar rates of intraoperative complications. Length of hospital stay was significantly shorter for those randomized to undergo laparoscopy (median, 3 days vs 4 days; P < .001), but operative time was significantly longer (median, 204 minutes vs 130 minutes; P < .001). Pelvic and para-aortic nodes were removed in 92% of laparoscopy patients and 96% of laparotomy patients (P < .0001), and cytologic evaluation was performed in 96% vs 98% (P = .052). Neither treatment arm demonstrated an improved ability to detect metastatic disease (P = .841). Laparoscopic surgical staging is feasible and safe for patients with uterine cancer and results in fewer complications and a shorter hospital stay. Quality-of-life evaluation found a better body image and return to normal activities for the laparoscopy patients. A reduction in para-aortic node evaluation is a potential risk of laparoscopic staging. Walker et al reported the long-term cancer outcomes in 2012. The actual recurrence rates were substantially lower than anticipated, resulting in an estimated 3-year recurrence rate of 11% with laparoscopy and 10% with laparotomy. The estimated 5-year overall survival was almost identical in both arms, at 90%.

Lymph node evaluation. Any suspicious pelvic or para-aortic lymph nodes should be removed for pathologic evaluation. If there is no gross residual intraperitoneal tumor, pelvic and para-aortic lymph nodes should be removed for the following indications:

– Invasion of more than half of the outer myometrium

– Presence of tumor in the isthmus-cervix

– Adnexal or other extrauterine metastases

– Presence of serous, clear-cell, undifferentiated, or squamous types

– Palpably enlarged lymph nodes

Lymph nodes need not be removed in patients whose tumor is limited to the endometrium, regardless of grade, because < 1% of these patients have disease spread to pelvic or para-aortic lymph nodes. The decision of whether to perform lymph node sampling is less clear-cut for patients whose only risk factor is invasion of the inner half of the myometrium, particularly if the tumor grade is 1 or 2. This group has a 5% or less chance of node positivity.

Lymphadenectomy. The extent of lymph node removal has been the subject of debate. The GOG has defined the extent of lymphadenectomy required for entry into its studies:

• Pelvic lymphadenectomy-The skin incision may be of the surgeon’s choosing, including midline vertical, transverse, and lateral vertical. The procedure may be performed via laparoscopy or a retroperitoneal approach.

– Identify the bifurcation of the common iliac, external iliac, and hypogastric arteries; veins; and the ureters bilaterally.

– Any enlarged or suspicious nodes will be excised or biopsied if unresectable.

– Remove bilaterally all nodal tissue and skeletonization of all vessels from the mid portion of the common iliac artery superiorly, to the circumflex iliac vein inferiorly.

– Remove bilaterally all nodal tissue from the mid portion of the psoas muscle laterally to the ureters medially, including the hypogastric arteries and veins and from the obturator fossas anterior to the obturator nerves.

– An adequate dissection requires that a minimum of four lymph nodes be demonstrated pathologically from each side (right and left) of the pelvis, preferably from multiple sites.

• Para-aortic lymphadenectomy-The bifurcation of the aorta, the inferior vena cava, the ovarian vessels, the inferior mesenteric artery, the ureters, and duodenum should be identified.

– The nodal tissue over the distal vena cava from the level of the inferior mesenteric artery to the mid right common iliac artery is removed.

– The nodal tissue between the aorta and the left ureter from the inferior mesenteric artery to the left mid common iliac artery is removed.

– An adequate dissection requires that lymphatic tissue be demonstrated pathologically from each side (right and left).

Surgical staging. After these procedures, the patient should be surgically staged according to the 2009 FIGO criteria. The overall surgical complication rate after this type of staging is approximately 20%. The rate of serious complications is 6%, and they include vascular, ureteral, and bowel injuries.

Whether lymph node dissections are therapeutic or merely prognostic has been debated. A recent phase III trial comparing endometrial cancer patients who received systematic lymphadenectomy with those who had not received lymphadenectomy demonstrated improved staging but with an increased complication rate with lymphadenectomy. There was no improvement in disease-free or overall survival. In another study known as the ASTEC (Adjuvant External-Beam Radiotherapy in the Treatment of Endometrial Cancer) trial, 1,408 women were randomized to undergo a lymphadenectomy or no lymphadenectomy at the time of total abdominal hysterectomy/bilateral salpingo-oophorectomy. There was no benefit in terms of survival or recurrence-free survival for women treated with lymphadenectomy.

Grossly involved lymph nodes. These can often be completely resected. A retrospective study revealed 5-year disease-specific survival rates of 50% in the patients with grossly positive lymph nodes who underwent complete resection, compared with 63% in those with microscopic metastatic disease and 43% in the women with residual macroscopic lymph node metastasis.

Adjuvant radiation therapy

Following surgical staging, adjuvant radiation therapy is offered to patients on the basis of prognostic factors found at the time of surgery. A pelvic recurrence rate of 7% to 14% has been documented for all stage I patients after surgery alone, although certain subgroups with more risk factors may have a higher incidence of recurrence of endometrial carcinoma. Well-described prognostic factors include disease extent (cervical involvement; extrauterine involvement of the serosa, adnexa, or lymph nodes; or intra-abdominal spread) as well as histologic grade of the tumor, depth of myometrial penetration, pathologic subtype, and presence of lymphovascular space invasion.

Teletherapy. Adjuvant irradiation was delivered primarily in the past using external-beam radiotherapy (EBRT) directed to the pelvis, which allows for treatment of the pelvic nodes. There have now been four large randomized trials demonstrating that radiation can decrease local recurrence, but it has no demonstrable effect on overall survival.

One trial, GOG-0099, compared the results of pelvic irradiation with those of observation following hysterectomy and lymphadenectomy. The estimated 2-year cumulative incidence of recurrence was 12% in the observation arm and 3% in those irradiated (P = .007). The treatment difference was particularly evident among a “high-intermediate risk” subgroup defined as those (1) with moderate to poorly differentiated tumor, presence of lymphovascular invasion, and outer-third myometrial invasion; (2) age 50 or older with any two risk factors previously listed; or (3) age of at least 70 with any risk factor previously listed, where the cumulative incidence of recurrence in the observed patients was 26% vs 6% in the treated patients. Overall survival rates at 3 years did not differ significantly between the two groups.

However, one-third of patients were found to be in a high-risk group that included patients who were older and who had lymphovascular space invasion, deep myometrial penetration, and high-grade disease. When outcomes were stratified by these factors, the addition of pelvic irradiation was found to reduce the recurrence and death rates from 36% to 17%, the cancer death rate from 17% to 10%, and the distant metastatic rate from 19% to 10%. This finding suggests not only that pelvic irradiation may influence pelvic recurrence in these patients but also that there is a subgroup of patients who may benefit in terms of distant metastasis and death. A larger trial with high-risk patients is needed to validate this assumption.

Of the 18 pelvic recurrences in the no adjuvant treatment arm, 13 were in the vagina. Thirteen other sites of recurrence were outside the pelvis. It has been speculated that vaginal irradiation alone could have controlled these vaginal recurrences, leading to interest in treatment with vaginal irradiation instead of pelvic irradiation.

The findings of a multicenter trial with 754 patients from the Netherlands, called the PORTEC (Postoperative Radiation Therapy in Endometrial Carcinoma) study, have been reported. Eligible patients had stage IC grade 1 tumors (21%), stage IB or IC grade 2 tumors (69%), or stage IB grade 3 tumors (10%). After total abdominal hysterectomy without lymphadenectomy, patients were randomized to receive pelvic radiotherapy (46 Gy) or no further treatment.

Pelvic irradiation decreased the incidence of locoregional tumor recurrence but did not affect survival. Patients with grade 3 histology demonstrated the highest risk of distant metastases and death caused by endometrial cancer. Most of the locoregional relapses were located in the vagina (30 of 40 cases). It is possible that vaginal brachytherapy could have prevented the majority of these cases. When patients were subdivided into a high-risk subgroup with two or three risk factors, including age 60 and older, grade 3 histology, and myometrial depth of 50% or more, the 10-year locoregional relapse rate was 4.6% in the radiotherapy group vs 23% in the control group.

PORTEC also registered patients in a prospective trial who had deep myometrial invasion and grade 3 histology. All patients were treated with pelvic irradiation following hysterectomy. Notably, these patients had a distant recurrence rate at 5 years of 31% and a pelvic recurrence rate at 5 years of 14%. The information from this report as well as from the subgroup of patients in the GOG 99 trial suggests that there may be a role for systemic therapy as well as pelvic irradiation in this high-risk subgroup.

A third randomized trial including more than 900 patients with stage I or IIa endometrial cancer from the National Cancer Institute of Canada and the Medical Research Council randomized patients to receive pelvic radiation therapy or no pelvic radiation therapy. Notably, vaginal radiation therapy, which was optional, was delivered to 52% of patients in each arm. There was no difference in survival and only a minimal difference in local or regional tumor recurrence rates.

Sorbe et al randomized 562 patients with “medium risk” to EBRT and vaginal brachytherapy or to vaginal brachytherapy alone. The patients treated with vaginal brachytherapy alone had more overall recurrences (10.3% vs 5.7%) and more locoregional recurrences (6.8% vs 2.3%), with no difference in overall survival. The American Society of Therapeutic Radiation Oncology (ASTRO) has published consensus guidelines for adjuvant treatment of these patients.

Brachytherapy. Several reports have demonstrated excellent local tumor control with vaginal irradiation alone. A review of the world literature included 1,800 patients with low- to intermediate-risk disease. Overall, the vaginal control rate was 99.3% following adjuvant high-dose-rate (HDR) vaginal brachytherapy.

In a randomized study from the Norwegian Radium Hospital, pelvic irradiation significantly decreased the incidence of locoregional tumor recurrences compared with vaginal irradiation alone. In the initial report, patients with deeply invasive, grade 3 tumors had lower death and recurrence rates when treated with pelvic plus vaginal irradiation than patients treated with vaginal irradiation alone. Long-term follow-up of this trial was recently published by Onsrud et al. After a median of 21 (range, 0–43.4) years of follow-up, there was no significant difference in overall survival or relapse-free survival between treatment arms. Patients treated with EBRT had a significantly lower risk of developing locoregional relapse (P < .001). However, after EBRT, women younger than 60 years had a significant poorer survival (hazard ratio [HR] = 1.36; 95% CI, 1.06–1.76), which was attributed to the development of second cancers. The authors concluded that adjuvant EBRT should be used with caution, especially in women with a long life expectancy.

Many women with endometrial cancer are being treated with lymphadenectomy at the time of hysterectomy. There has been some interest in using vaginal irradiation alone to treat women who have negative nodes but deep myometrial penetration or high-grade histology. Several small retrospective reports have demonstrated excellent outcomes for such patients. However, more experience is needed to determine whether vaginal irradiation alone is adequate.

The results of a phase III randomized trial from PORTEC have been published. This trial included patients who had a high-intermediate–risk endometrial cancer: age over 60 years and stage IC grade 1/2 or stage IB grade 3; any age and stage IIA grade 1/2 or grade 3 with less than 50% invasion. They were randomized to receive pelvic radiation or vaginal brachytherapy. A total of 427 patients were randomized between 2002 and 2006. At a median follow-up of 34 months, 5-year actuarial rates of vaginal relapse were 1.8% in the vaginal brachytherapy arm and 1.6% after EBRT (P = .97), with standard error of the difference 1.4%. Five-year rates of pelvic recurrence were 5.1% and 2.1% (P = .17). There were no significant differences in 3-year overall survival (84.8% vs 79.6%; P = .57) and disease-free survival (82.7% vs 78.1%; P = .74). Because patient-reported quality of life after vaginal brachytherapy was shown to be better than after EBRT, vaginal brachytherapy should be the treatment of choice for patients with intermediate-risk endometrial carcinoma.

Vaginal irradiation alone is appropriate for patients at low risk for pelvic node metastasis. Because of the potential for increased rectal and vaginal sequelae, treatment of the entire length of the vagina is usually not recommended.

Irradiation of the pelvis and vagina has been combined for the adjuvant treatment of some patients. Patients with cervical involvement or extrauterine disease, who may have an increased incidence of local failure, may benefit from the two treatments combined, although there are no data to suggest that the addition of brachytherapy improves outcome over EBRT alone. Patients with uterine-confined disease have excellent local tumor control following treatment with either type of irradiation. Combining the two treatments has not been shown to benefit these patients.

Vaginal irradiation. Vaginal irradiation can be delivered with HDR or low-dose-rate (LDR) equipment. Both techniques have resulted in excellent local tumor control rates and low morbidity when administered by experienced practitioners. Each technique has its advantages. HDR treatments require multiple insertions, generally with one or two insertions performed every week for 3 to 6 weeks. However, hospitalization is not required, and each insertion takes only a brief amount of time. LDR treatments are delivered once but require hospitalization for 2 to 3 days.

Stage I disease. Current recommendations for the treatment of patients with pathologic stage I disease include adjuvant pelvic irradiation for women with deep myometrial penetration and grade 3 histology or evidence of vascular space invasion (Table 3). Data support the use of vaginal irradiation alone for women with more superficial tumors and low-grade histology.

TABLE 3

Recommendations for adjuvant irradiation

Radiation doses are generally 45 to 50 Gy with standard fractionation. The technique should include multiple fields treated daily, with attempts to protect the small bowel. Complications from adjuvant pelvic irradiation are related to technique and the extent of lymphadenectomy.

If full lymphadenectomy has been performed, the incidence of complications increases significantly with pelvic irradiation. Pelvic irradiation using intensity-modulated radiation therapy has been advocated by some in order to spare bowel and bone marrow. For patients at high risk for complications from pelvic irradiation, consideration should be given to adjuvant brachytherapy rather than pelvic irradiation.

Papillary serous histology. The high rate of upper abdominal, pelvic, and vaginal recurrences in patients with uterine papillary serous cancers has led some clinicians to recommend that these patients receive whole abdominal irradiation (WAI), with doses up to 30 Gy and additional treatments to bring the pelvic dose to 50 Gy. A vaginal cylinder or colpostats may be used to boost the surface dose with 40 Gy. This treatment has resulted in a 5-year survival rate of 50%.

The most common treatment for this rare cancer is combination chemotherapy and radiation therapy (either vaginal brachytherapy or EBRT). Surgical staging should be similar to that for ovarian cancer, because these patients have a high propensity of distant and abdominal tumor spread.

Stage II disease. Patients whose endometrial cancer extends to the cervix usually represent a heterogeneous group, with differing histologic grades and varying degrees of cervical involvement, myometrial penetration, and nodal involvement. Similar outcomes with preoperative and postoperative irradiation suggest that initial surgical treatment with tailored postoperative irradiation is a reasonable approach.

Current treatment recommendations frequently include adjuvant pelvic irradiation to a dose of 45 to 50 Gy, in addition to insertion of a vaginal cylinder or colpostats to raise the total dose to the vaginal surface to 80 to 90 Gy. This treatment should result in a 5-year disease-free survival rate of 80%, with a locoregional tumor control rate of 90%. Of course, outcome varies with the extent of myometrial penetration, degree of cervical involvement, and histologic grade of tumor.

Patients who have a large amount of cervical involvement that precludes initial hysterectomy are candidates for preoperative irradiation. A multiple-field technique is used to deliver a dose of 40 to 45 Gy with standard fractionation. A midline block may be inserted for the last 20 Gy to protect the rectum.

Intracavitary insertion with a standard Fletcher applicator, consisting of a uterine tandem and vaginal colpostats, delivers 20 to 25 Gy to point A (defined as 2 cm caudally and 2 cm laterally to the cervical os). Hysterectomy should follow in approximately 4 to 6 weeks. The expected 5-year disease-free survival rate for patients with extensive disease is 70% to 80%.

Stage III disease. More favorable patients have an isolated extrauterine site (eg, adnexa alone), low-grade histology, and/or disease confined to the pelvis. Greven et al (Radiat Oncol Invest 1996) reported that 17 patients with an isolated extrauterine site who had low-grade histology and received postoperative pelvic radiation therapy had a 100% disease-free survival rate. However, patients with grade 2 or 3 disease or more than one extrauterine site had progressively worse outcomes.

One subgroup found to have a relatively favorable prognosis includes women with isolated ovarian metastasis. Five-year disease-free survival rates ranging from 60% to 82% have been reported in these women after hysterectomy and pelvic irradiation, depending on the histologic grade of the tumor and the depth of myometrial penetration. Pelvic irradiation usually includes a dose of 45 to 50 Gy using standard fractionation. A vaginal boost with a cylinder or colpostats may add 30 to 35 Gy to the vaginal surface.

Patients with pelvic node involvement alone have much better outcomes than patients with extension to periaortic nodes, despite the fact that they are both considered stage IIIC patients. Morrow et al demonstrated 5-year recurrence-free survival rates of 75% and 38% for patients with pelvic nodes compared with patients with para-aortic nodes, respectively. Patients with pelvic nodes and negative para-aortic nodes are generally treated with adjuvant pelvic radiation therapy. Those with para-aortic nodes are treated with extended-field irradiation, which includes 45 to 50 Gy to a volume encompassing the pelvic and periaortic regions.

Because upper abdominal failures have been reported previously in patients with stage III disease, attention has focused on the role of WAI. Although subsets of patients have done well with WAI, it is unclear whether this more aggressive therapy has any benefit over pelvic irradiation. A GOG phase II trial of WAI demonstrated a 3-year progression-free survival rate of 35%. The GOG completed a trial of WAI compared with chemotherapy, GOG-0122. (The outcomes from this trial are discussed in the “Chemotherapy” section of this chapter.) Unfortunately, because most studies have combined patients who have favorable stage III disease with patients who have unfavorable stage IV disease, it is impossible to determine whether there are some subgroups of patients who might best be managed with a particular therapy.

Because many of these patients are at increased risk for pelvic recurrence as well as distant recurrence, there is interest in combining pelvic radiation therapy with systemic therapy. Radiation Therapy Oncology Group 9708 combined pelvic radiation therapy with cisplatin and followed it with cisplatin and paclitaxel. Toxicity was predominantly hematologic. For stage III patients, 4-year survival and disease-free survival rates were 77% and 72%, respectively. There were no recurrences for patients with stage IC, IIA, or IIB disease.

GOG-0184 was instituted following the completion of GOG-0122, based on the assumption that combined-modality therapy with radiation therapy and chemotherapy in advanced but optimally cytoreduced endometrial carcinoma may lead to a better result than either modality used alone. Patients with stages III and IV adenocarcinoma of the endometrium with less than 2 cm of residual disease were treated with radiation therapy tailored to include the volume at risk followed by randomization to cisplatin plus doxorubicin or to cisplatin, doxorubicin, and paclitaxel. As reported by Homesley et al, the addition of paclitaxel to cisplatin and doxorubicin did not improve progression-free survival.

Definitive radiation treatment

For patients who are poor operative risks, definitive treatment with irradiation has produced excellent local tumor control and survival rates. Such treatment is considered to be justified when the operative risk exceeds the 10% to 15% uterine recurrence rate expected with irradiation alone.

A more favorable outcome with definitive irradiation is related to low clinical tumor stage, less aggressive histologic variant, and use of brachytherapy for at least part of the treatment. Five-year disease-specific survival rates as high as 87%, 88%, and 49% have been reported in patients with stages I, II, and III or IV disease, respectively. Ten-year local tumor control rates in patients with stages I/II, III, and IV disease were 84%, 87%, and 68%, respectively.

For patients with early-stage disease and low-grade histology, treatment techniques with irradiation alone consist of uterine intracavitary insertions with Heyman or Simon capsules or an afterloading intrauterine tandem. Doses for intracavitary treatment range from 40 to 45 Gy prescribed to point A. One report used an HDR endometrial applicator and prescribed twice-daily fractions of 700 Gy given for five treatments to 2 cm. Patients with more advanced disease, a large uterus, or aggressive histology generally receive both an intrauterine intracavitary insertion and external pelvic irradiation. External irradiation typically delivers 40 to 45 Gy to the pelvis, followed by intracavitary treatment that delivers 30 to 35 Gy to point A.

Rates of serious complications attributable to irradiation range from 4% to 5% with intracavitary treatment alone to 10% to 15% with combined external and intracavitary irradiation.

Adjuvant systemic therapy

Only a few trials of adjuvant systemic therapy have been conducted in patients with early-stage endometrial cancer. At present, we believe that such therapy should not be recommended outside the clinical trial setting.

Endocrine therapy. Early uncontrolled trials suggested that progestin therapy might prolong the disease progression-free interval and time to recurrence in patients with stages I and II lesions treated with initial surgery and irradiation. However, at least three subsequent randomized trials failed to show any survival benefit for progestins, and a meta-analysis has demonstrated no advantage of adjuvant progestin therapy.

Chemotherapy. Three studies have evaluated the role of chemotherapy in early-stage endometrial carcinoma. The European Organisation for Research and Treatment of Cancer (EORTC) compared pelvic radiation therapy plus brachytherapy with pelvic radiation therapy and chemotherapy. The Japanese Gynecologic Oncology Group compared pelvic radiation therapy with cisplatin-based chemotherapy, and the consistent finding was a lower incidence of distant metastasis with minimal impact on survival. The EORTC trial had an overall survival benefit at 5 years of 8%; however, this trial as well as the Japanese trial included some patients with positive pelvic nodes. These trials do lead to enthusiasm for the addition of chemotherapy as adjuvant treatment for high-risk patients with early-stage disease.

Sidebar: The results of the Gynecologic Oncology Group (GOG) trial GOG0249 were presented at the 2014 meeting of the Society of Gynecologic Oncology. Eligible patients had stage I endometrioid cancer with GOG 99-based high-risk criteria (based on age, tumor grade, depth of invasion, and presence of lymphovascular space invasion), stage II, or stage I–II serous (S) or clear cell (CC) tumors. Patients were assigned to postoperative radiation therapy (PXRT) were treated with standard 4-field or intensity-modulated radiation therapy (IMRT) techniques. Additional vaginal cuff brachytherapy (VCB) was optional for patients with S/CC tumors or stage II disease. Patients assigned to VCB/C received high-dose rate or low-dose rate brachytherapy followed by paclitaxel at 175 mg/m2 (3 h) plus carboplatin to AUC 6 q 21 days for a total of 3 cycles. With a median follow-up of 24 months, the 24-month recurrence-free survival rate was 82% for PXRT vs 84% for VCB/C, and the treatment hazard ratio (HR) for VCB/C relative to PXRT was 0.97 (95% CI, 0.635–1.43). The 24-month survival rates were 93% vs 92% for PXRT and VCB/C and the treatment HR for VCB/C relative to PXRT was 1.28 (95% CI, 0.689–2.36). This study did not demonstrate a superiority of VCB/C to PXRT in women with high-risk endometrial cancer. Gynecol Oncol 134:438, 2014 [absract LBA1]).

Results from a GOG trial, GOG-0122, compared adjuvant chemotherapy (doxorubicin plus cisplatin) with WAI. The patient population included patients with stages III and IV disease (75% and 25%, respectively) with 50% endometrioid histologies. Patients treated with chemotherapy had significantly improved progression-free (38% vs 50%) and overall (42% vs 55%) survival at 5 years. However, serious adverse effects were also more common in the chemotherapy group than in the radiotherapy group, with treatment-related deaths twice as high in the former group, at 4% vs 2%. Pelvic and abdominal recurrences were the predominant pattern of recurrence for both treatment arms. Distant recurrences were slightly less frequent for patients treated with chemotherapy. This finding leads to the support of the concept of combining chemotherapy with involved-field irradiation for patients with more advanced disease.

The next GOG trial (184) randomized patients to receive involved field EBRT with doxorubicin and cisplatin or with paclitaxel, docetaxel, and cisplatin. There was a 10% locoregional recurrence at 3 years, with no difference in survival. Subset analysis suggested that paclitaxel benefited patients with gross residual disease, papillary serous histology, and grade 3 histology. The current GOG study (258) is randomizing patients to concurrent cisplatin and EBRT followed by adjuvant carboplatin with paclitaxel or carboplatin and paclitaxel alone. The ongoing PORTEC 3 trial randomizes such patients to pelvic radiation therapy and concurrent cisplatin or to radiation therapy with adjuvant carboplatin and paclitaxel.

Hormone replacement therapy (HRT). Whether HRT increases the likelihood of recurrence has been studied, with several retrospective reports showing no adverse outcomes. Thus, the GOG undertook a large randomized placebo-controlled trial of HRT after treatment for earlier-stage endometrial cancer. However, there were too few events, and it was closed after the findings of the Women’s Health Initiative were released. HRT was not associated with a significant incidence of recurrent disease, mortality, or new malignancy.

Treatment of Recurrent or Metastatic Disease

Patterns of recurrence

Recurrent endometrial cancer is initially confined to the pelvis in 50% of patients. The major sites of distant metastasis are the abdominal cavity, liver, and lungs.

Following diagnosis and initial treatment, periodic evaluation, including history, physical examination, and pelvic examination, is recommended at 3- to 6-month intervals for the first 5 years and yearly thereafter. More extensive and more costly procedures, such as chest radiography, computed tomography (CT), and marker studies, used in asymptomatic patients are of questionable value and are unlikely to have a major impact on survival. Symptomatic patients should be evaluated as appropriate.

Radiation therapy

After hysterectomy alone for endometrial cancer, approximately 50% of recurrences are pelvic and 50% are extrapelvic. It is clear that locoregional recurrences can develop in isolation, without distant metastasis, and salvage can be accomplished with high-dose irradiation.

Pelvic recurrences. Five-year disease-specific survival rates as high as 51% have been reported in patients with isolated locoregional recurrences treated with radiation therapy. Factors that have an adverse impact on outcome are increased size of tumor at recurrence, young age, pelvic vs vaginal involvement, and treatment of recurrence with EBRT only vs the addition of vaginal brachytherapy.

The PORTEC (Post Operative Radiation Therapy in Endometrial Carcinoma) group has published its experience with salvage of vaginal recurrence in patients who did not receive adjuvant irradiation. At 5 years, the survival rate after vaginal relapse was 65% in the control group, compared with 43% in the irradiated group.

Radiation treatment for pelvic recurrence usually consists of EBRT with the addition of a brachytherapy boost that may include colpostats, a cylinder, interstitial needles, or seeds. Treatment must be individualized based on the location and size of the recurrence and on the boost method selected. The tolerance of normal tissues must be respected, but combined doses greater than 60 Gy have been associated with improved local tumor control. The GOG has an ongoing trial evaluating the role of chemotherapy with radiation in this group of patients.

Extrapelvic recurrences. For patients with recurrences outside the pelvis, irradiation is effective in producing responses in localized symptomatic lesions. Therefore, irradiation may be effective for palliation of such lesions in the lymph nodes, brain, or bones. Doses and protocols vary, depending on the site of recurrence.

Pelvic exenteration for pelvic recurrences after irradiation

Isolated pelvic central recurrence after irradiation is rare. Select patients in whom it does occur may benefit from pelvic exenterative surgery. No large series have been published, but some long-term survivors have been reported.

Although the long-term survival rate after this procedure is only 20%, it remains the only potentially curative option for the few patients with central recurrence of endometrial cancer who have not responded to standard surgery and radiation therapy.

Endocrine therapy

Progestins. These produce complete and partial response rates of 15% to 25% in patients with locoregional recurrence or distant metastases. The route, type, and dose of progestins do not appear to be related to response; hence, oral therapy is preferred.

TABLE 4

Results of a phase III, dose-response trial of progestins in advanced or recurrent endometrial carcinoma

In clinical practice, oral administration of 200 mg of medroxyprogesterone or 160 mg of megestrol produces blood levels similar to those achieved with parenteral therapy (400 to 1,000 mg of medroxyprogesterone intramuscularly weekly). A phase III trial conducted by the GOG comparing 200 mg and 1,000 mg of medroxyprogesterone given orally daily found no differences between the two regimens, although it is noteworthy that the trends all favored the low-dose regimen (Table 4). Doses of medroxyprogesterone higher than 200 mg/d, therefore, are clearly not warranted.

Several factors are predictive of a favorable response to progestin therapy. Patients with well-differentiated lesions are more likely to respond than those with poorly differentiated tumors. A related observation is that a much higher percentage of grade 1 tumors have significant levels of estrogen and progesterone receptors; data show that lesions with higher receptor levels respond much more frequently to progestins than those with lower receptor levels. Response is almost always associated with better progression-free and overall survival.

The median time to disease progression for all patients treated with progestins is 3 to 4 months, and the median survival is 10 months.

Tamoxifen. Tamoxifen has a 0% to 13% response rate, is not as active as progestins, and is of little value as second-line therapy in patients who do not respond to progestins.

The GOG has evaluated combined therapy with tamoxifen plus a progestin given sequentially in the hope that tamoxifen may increase progesterone receptor expression and, thus, increase the likelihood of response to progestins. Continuous tamoxifen and medroxyprogesterone given every other week was an active treatment, with a 33% response rate. A subsequent study found a 27% response rate for alternating megestrol, with several prolonged responses. As with prior hormonal studies, patients with well-differentiated cancers were more likely to respond. Nevertheless, this trial was relatively unique in that 22% of patients with poorly differentiated tumors responded.

Other hormonal agents. Drugs such as gonadotropin-releasing hormone analogs and aminoglutethimide (Cytadren) have been studied to some extent in endometrial carcinoma. These agents do not appear to have sufficient activity to warrant further study.

Chemotherapy

Single agents. Chemotherapy for advanced endometrial cancer focuses on three groups of agents with demonstrated activity: anthracyclines, platinum compounds, and taxanes.

The anthracyclines studied include doxorubicin and epirubicin. In a total of 298 patients, doxorubicin produced a 27% response rate. Epirubicin, primarily in European studies including 27 patients, yielded a 26% response rate. Two platinum compounds have activity. Cisplatin, in 86 patients, elicited responses in 29%. Carboplatin produced a 31% response rate in 52 patients. Paclitaxel, in two GOG studies, yielded responses in 36% of chemotherapy-naive patients and 27% of previously treated patients.

For all of these studies, the progression-free interval ranged from 4 to 7 months, with an overall survival range of 8 to 12 months. Approximately one-third of the responses were clinical complete responses, with a substantially longer duration and better survival than partial responders.

Other single agents with modest activity in endometrial cancer include ifosfamide and topotecan and bevacizumab (Avastin).

Combination regimens. A number of phase II trials of combination regimens have been conducted. The combination of carboplatin and paclitaxel has been demonstrated to be active in advanced endometrial cancer (50% to 60% response rate). Ultimately, the relative merits of combination chemotherapy with carboplatin and paclitaxel must be judged in the context of a randomized trial that is being performed by the GOG (GOG-0209). A randomized trial of cisplatin and doxorubicin with or without paclitaxel following surgery and radiation therapy did not show any improvement in recurrence-free survival but did have more toxicity.

Following encouraging phase II results, a phase III trial of circadian-timed administration of cisplatin and doxorubicin found no significant benefit. The GOG then compared this two-drug (cisplatin [50 mg/m2]/doxorubicin [60 mg/m2]) regimen with a three-drug combination of cisplatin (50 mg/m2), doxorubicin (45 mg/m2), and paclitaxel (160 mg/m2 as a 3-hour infusion), with G-CSF (granulocyte colony-stimulating factor, filgrastim [Neupogen]) support (GOG 177). The three-drug combination of the paclitaxel-containing regimen produced a higher response rate (57% vs 35%) and an improved progression-free survival (8.3 months vs 5.3 months). Overall survival was also modestly improved (15.3 months vs 12.3 months; P = .037) with the three-drug regimen but with considerably greater toxicity, particularly peripheral neuropathy (grade 3, 12% vs 1%).

There has been concern about the potential effect of “high-risk” endometrial histologies on response to chemotherapy. It has been suggested that papillary serous and clear-cell tumor adenocarcinomas should be treated differently. McMeekin et al correlated histology with chemotherapy outcomes in several of the above-mentioned trials and found no significant difference in response or survival based on the histologic type of endometrial cancer.

In the GOG-0209 trial, patients (N = 1,381) were randomized to treatment with doxorubicin at dose of 45 mg/m2 and cisplatin at 50 mg/m2 (day 1), followed by paclitaxel at 160 mg/m2 (day 2) with growth factor support (TAP) or to a regimen of paclitaxel at 175 mg/m2 and carboplatin to area under the concentration-time curve 6 (day 1) (TC) repeated every 21 days for seven cycles. Overall survival in patients randomized to TAP was 40.3 months, compared with 36.5 months (HR = 1.05) for those randomized to TC. Progression-free survival was 13.5 months for patients treated with TAP vs 13.3 months (HR = 1.03) for those who received TC. Adverse events for patients treated with TAP vs TC, respectively, included a 7% vs 6% incidence of neutropenic fever and a 26% vs 19% incidence of grade 1 or higher sensory neuropathy (P < .01). It was concluded that TC is not inferior to TAP in terms of progression-free and overall survival. Overall, the toxicity profile favors TC. Thus, TC as prescribed in this study is an acceptable backbone for further trials in combination with “targeted” therapies(Miller D et al: Gynecol Oncol 125:771–773 [abstract], 2012).

Chemotherapy plus progestins. Combinations of chemotherapy plus progestins have been studied in a number of phase II trials. The only large randomized trial evaluating this approach (GOG29) allocated patients with advanced or recurrent disease to receive either cyclophosphamide, doxorubicin, cisplatin, and megestrol or melphalan (Alkeran), fluorouracil, and megestrol. In pilot studies, these two regimens had been reported to yield response rates of 75% and 94%, respectively. The randomized trial produced response rates of 36% and 38%, respectively, with no evident advantage of either combination over single-agent doxorubicin (from prior studies) with regard to response rate, progression-free interval, or overall survival. These results do not suggest any advantage for the combined use of chemotherapy and progestins.

Treatment recommendations

Patients who have advanced or recurrent endometrial carcinoma should be considered for systemic therapy. Patients should first be offered the opportunity to participate in a clinical trial. Those who are ineligible or who choose not to participate should be treated according to current evidence.

Patients who have a grade 1 tumor and/or known progesterone receptor–positive disease clearly benefit from treatment with progestins (response rate, 40%; median progression-free interval, 9 months; overall median survival, 14 months) and should be so treated. Those with a grade 2 to 3 tumor and/or known progesterone receptor–negative disease do not do well with progestin therapy (response rate, 12%; median progression-free interval, 3 months; overall median survival, 10 months) and should be considered for initial treatment with single-agent chemotherapy (eg, paclitaxel, doxorubicin, or carboplatin) or a combination regimen. Options include cisplatin/doxorubicin, cisplatin/doxorubicin/paclitaxel, and carboplatin/paclitaxel. Chemotherapy should also be considered for patients who do not respond to initial hormonal therapy.

Regimens that include both chemotherapy and hormonal therapy should not be considered outside a clinical trial because of the lack of data supporting any advantage of these combinations.

Uterine Sarcomas

Carcinosarcomas and other uterine sarcomas are uncommon tumors, accounting for less than 4% of all cancers of the uterine corpus. Carcinosarcomas, the most common histologic subtype, demonstrate both epithelial and stromal differentiation. Endometrial stromal sarcomas and leiomyosarcomas are characterized by differentiation toward one or more stromal tissues. Leiomyosarcomas occur at an earlier age than do carcinosarcomas, with a plateau observed in middle age. There is strong epidemiologic evidence that prior exposure to pelvic irradiation may increase the risk for the development of uterine sarcomas. Generally, these tumors are characterized by aggressive growth, with early lymphatic or hematogenous spread. The overall survival rate is poor, with the majority of deaths occurring within 2 years of diagnosis.

Patterns of Spread

Lymphatic metastases are a significant route of spread for carcinosarcoma, with a reported incidence of 40% to 60% occurring with stage I disease. Leiomyosarcoma has a propensity for extra-abdominal spread, often involving the lungs. For carcinosarcoma, the initial site for recurrence after surgical resection is likely to be the pelvis or abdomen, whereas leiomyosarcomas tend to fail to recur distantly. In a prospective surgical staging trial by the GOG, the recurrence rate for early-stage carcinosarcoma was 53% and for leiomyosarcoma, 71%.

Treatment

Surgery

Surgery is the mainstay of treatment for uterine sarcomas. For carcinosarcoma, this usually consists of total abdominal hysterectomy and bilateral salpingo-oophorectomy, with washings to be obtained for peritoneal cytology. The GOG prospective staging study reported a 17% incidence of nodal metastasis for this histologic subtype, so retroperitoneal nodes should be sampled as for poorly differentiated endometrial cancers. For patients with advanced/recurrent disease, aggressive surgical debulking does not appear to improve outcome.

Hysterectomy with oophorectomy is also standard therapy for uterine leiomyosarcoma. Retroperitoneal nodal sampling is not usually performed, because lymph node involvement is unusual. For late recurrences of leiomyosarcoma, surgery must be individualized. Five-year survival rates of 30% to 50% have been reported following pulmonary resection for lung metastases. Patients with unilateral metastases have a significantly better prognosis than those with bilateral disease. Local and regional recurrences may also be amenable to surgical resection of disease.

Hysterectomy with oophorectomy is the standard of care for patients with low-grade endometrial stromal sarcomas. Removal of the ovaries was thought to be critical, because these tumors tend to have very high concentrations of estrogen and progesterone receptors and often respond to hormonal therapy. However, Li et al (Obstet Gynecol 2005) reviewed a multi-institutional experience and reported that bilateral salpingo-oophorectomy did not appear to affect time to recurrence or overall survival. Retention of ovarian function may be an option for premenopausal women with low-grade endometrial stromal sarcomas. Because these tumors have a tendency to spread via the lymphatics, resection of all disease, especially extension into the parametrium, should be attempted. This approach may require radical hysterectomy.

Adjuvant irradiation

Pelvic recurrence is a pattern of failure for most uterine sarcomas; isolated pelvic recurrences are uncommon. Adjuvant irradiation can decrease local recurrence, but there is no evidence that it improves survival. Patients will often experience distant recurrence and treatment failure. Pelvic irradiation may be indicated for improvement of quality of life, however, because pelvic recurrence can be associated with pain, bleeding, and intestinal obstruction.

Radiotherapy

In a nonrandomized prospective GOG study, patients with stages I and II mixed mesodermal sarcomas and leiomyosarcomas had fewer pelvic recurrences following irradiation than did patients who did not undergo pelvic irradiation. No difference in overall or disease-free survival was noted.

Several retrospective reports have suggested improved pelvic control rates following pelvic irradiation for stages I and II uterine sarcomas. A randomized trial from the EORTC demonstrated that patients with carcinosarcoma randomized to receive pelvic radiation therapy compared with no adjuvant treatment benefited from pelvic radiation therapy, with decreased local failures but no survival improvement. Patients with leiomyosarcoma did not demonstrate any benefit with the addition of pelvic radiation therapy.

GOG-0150 was a randomized study of patients with stages I to IV carcinosarcoma of the uterus with less than 1 cm of residual disease and no extra-abdominal spread. Patients were treated with either cisplatin (20 mg/m2/d for 4 days) plus ifosfamide (1.5 g/m2/d for 4 days every 3 weeks for three cycles) or WAI to a total dose of 3,000 cGy, and the pelvis was treated to a total dose of 4,980 cGy. The abdomen received 150 cGy per fraction, with five fractions per week. The pelvis was boosted an additional 11 fractions at 180 cGy per fraction. The study tested whether patients treated with systemic treatment or locoregional treatment differ in progression-free interval, survival, and failure patterns. There were 105 patients in the WAI cohort and 101 in the chemotherapy cohort. Of 206 study patients, there were 112 total recurrences (54%), with 60 (57%) in the radiotherapy arm and 52 (51%) in the chemotherapy arm. Although patients may have had several different sites of failure, there were more vaginal failures in the chemotherapy group (10%) than in the WAI group (4%). However, there were more abdominal relapses in the WAI arm (28%) than in the chemotherapy cohort (19%). Pelvic and distant failures were essentially the same. Although acute toxicities of anemia and neuropathy were more frequent in the chemotherapy arm, there were more severe grade 3/4 gastrointestinal late effects in the WAI group, and two patients died as a direct result of radiation hepatitis. The estimated probability of surviving 5 years was 35% for WAI vs 45% for chemotherapy. After adjusting for stage and age, there was no definite survival advantage but rather a trend favoring chemotherapy. The estimated death rate was 29% lower for chemotherapy patients than for WAI patients (HR = 0.712; 95% CI, 0.484–1.048; P = .085, two-tailed test).

GOG-0150 showed that adjunctive chemotherapy has less toxic long-term adverse effects and is more likely than radiotherapy to improve survival for patients. Because chemotherapy did not reduce the risk of vaginal relapses, less toxic vaginal brachytherapy with chemotherapy would be an appropriate experimental arm for future adjuvant therapeutic trials in this group of patients.

Chemotherapy

There is no proven role for adjuvant chemotherapy in stage I disease following complete surgical resection. A GOG study assessing adjuvant treatment with doxorubicin vs no further therapy showed no differences in recurrence rate, progression-free survival, or overall survival. GOG-0117 showed that adjuvant ifosfamide and cisplatin after primary surgery for stage I or II carcinosarcoma of the uterus was tolerable. That combination was then compared with WAI in GOG-0150 (described in detail above), which showed a trend in survival favoring those treated with that chemotherapy combination.

For patients with advanced or recurrent disease, single-agent chemotherapy or combination chemotherapy can be used with a palliative intent. For carcinosarcomas, ifosfamide or paclitaxel appears to be the agent of choice. Because GOG-0108 showed that ifosfamide plus cisplatin had no greater progression-free interval or survival than ifosfamide alone, GOG-0161 randomized patients to receive ifosfamide (at 2 g/m2 for 3 days every 3 weeks for eight cycles) or ifosfamide (1.6 g/m2 for 3 days) plus paclitaxel (135 mg/m2 by 3-hour infusion on day 1 repeated every 3 weeks for eight cycles). There was a survival advantage for combination chemotherapy (13.5 months vs 5.8 months).

Doxorubicin has traditionally been used for leiomyosarcomas. Hensley et al reported that the combination of gemcitabine plus docetaxel produced a 36% response rate in leiomyosarcoma. Hormonal agents, specifically progestins, are the treatment of choice for advanced or recurrent endometrial stromal sarcomas.

Gestational Trophoblastic Diseases

Gestational trophoblastic diseases (GTDs) encompass a spectrum of neoplastic disorders that arise from placental trophoblastic tissue after abnormal fertilization. In the United States, GTDs account for less than 1% of gynecologic malignancies. Forty years ago, women with choriocarcinoma had a 95% mortality rate. Today, with the advent of effective chemotherapy and the development of a reliable tumor marker (β-subunit human chorionic gonadotropin [β-hCG]), the cure rate for choriocarcinoma is 90% to 95%.

Clinical Presentation

Complete mole

The classic signs of a molar pregnancy include the absence of fetal heart sounds, physical evidence of a uterus that is larger than expected for gestational age, and vaginal bleeding. Although an intact fetus may coexist with a partial mole, this occurs in fewer than 1 in 100,000 pregnancies.

The most common presenting symptom of molar pregnancy is vaginal bleeding, reported in up to 97% of patients. Intrauterine clots may undergo oxidation and liquefaction, producing pathognomonic prune juice–like fluid. Prolonged or recurrent bleeding may result in iron deficiency anemia. Symptoms of anemia occur in approximately 50% of patients at the time of diagnosis. Early toxemia (hypertension, proteinuria, and edema) presenting during the first or second trimester is common (20% to 30% of cases) in molar pregnancy.

Hyperthyroidism is seen clinically in approximately 7% of molar pregnancies. An elevation of triiodothyronine and thyroxine (T4) levels is observed more commonly than are the clinical manifestations of tachycardia, sweating, weight loss, and tremor. These hormonal elevations are presumed to be secondary to the structural similarity of hCG to thyroid-stimulating hormone.

Partial mole

Patients with partial mole have clinical features different from those with complete mole. Fewer than 10% of patients with partial mole have uterine enlargement. Patients with partial mole do not have prominent theca-lutein cysts, hyperthyroidism, or respiratory insufficiency. They experience toxemia only rarely. The diagnosis of partial mole is usually made after histologic review of curettage specimens.

Gestational trophoblastic neoplasia

Gestational trophoblastic neoplasia (GTN) develops in 6% to 19% of patients after molar evacuation. Metastases sometimes have a histology identical to that of molar disease, but the vast majority are choriocarcinomas. Metastatic spread is hematogenous. Because of its extensive vascular network, metastatic GTN often produces local, spontaneous bleeding. The New England Trophoblastic Disease Center reported that the common metastatic sites of GTD are the lungs (80%); vagina (30%); pelvis (20%); liver (10%); brain (10%); and bowel, kidneys, and spleen (5% each).

Pulmonary metastases are common (80% of patients with metastatic disease) and occur when trophoblastic tissue enters the circulation via uterine venous sinuses. The radiologic features may be protean or subtle and include alveolar, nodular, and miliary patterns. Pleural effusions may also be present. Pulmonary metastases can be extensive and can cause respiratory failure and death.

Right upper quadrant pain has been observed when hepatic metastases stretch the Glisson capsule. Gastrointestinal lesions may result in severe hemorrhage or in perforation with peritonitis, both of which require emergency intervention. Vaginal examination may reveal bluish metastatic deposits; these and other metastatic sites should not undergo biopsy because severe uncontrolled bleeding may occur.

Central nervous system (CNS) involvement from metastatic GTN suggests widespread disease and has a poor prognosis. CNS metastases are clinically evident in 7% to 28% of patients with metastatic choriocarcinoma. Cerebral metastases tend to respond favorably to both radiotherapy and chemotherapy.

Diagnostic studies

Although the clinical presentation may suggest a diagnosis of GTN, certain laboratory studies, particularly a determination of the patient’s β-hCG level, and radiographic studies are needed to confirm this diagnosis.

Laboratory studies. Thyroid function studies should be performed in all patients with a clinical history or physical examination suggestive of hyperthyroidism. Abnormal thyroid function, manifested as an elevated T4 level, is common in GTD. Metastatic deposits in the kidneys or GI tract may reveal themselves by hematuria or hematochezia.

Tumor markers. A well-characterized glycoprotein hormone secreted by the syncytiotrophoblast, hCG is essential to maintaining normal function of the corpus luteum during pregnancy. Because all trophoblastic tumors secrete β-hCG, this hormone serves as an excellent marker for tumor activity in the nonpregnant patient. Serial β-hCG levels should be monitored during therapy to ensure adequate treatment. The level of β-hCG is roughly proportional to the tumor burden and inversely proportional to the therapeutic outcome.

Radiologic studies. A chest radiograph should always be obtained, because 70% to 80% of patients with metastatic GTN have lung involvement. Although this radiograph usually demonstrates nodular metastases, the patterns of metastatic disease can range from atelectatic areas to subtle pleural abnormalities. A CT scan is often helpful in evaluating these nonspecific findings.

Since it has been demonstrated that 97% to 100% of patients with CNS disease from choriocarcinoma have concomitant pulmonary metastases, a CNS workup in asymptomatic patients with normal chest radiographs is not routinely warranted. If the chest radiograph is abnormal, or if β-hCG levels plateau or rise during treatment, a more thorough evaluation for metastatic disease is indicated. Magnetic resonance imaging (MRI) of the brain, brain stem, and cerebellum as well as CT scans of the abdomen and pelvis should be performed to evaluate other likely sites of metastatic spread. The presence of intrauterine or ovarian disease also may be detected by MRI of the pelvis. Ultrasonography is a reliable, safe, economical, and relatively simple method for confirming the diagnosis of intrauterine GTD. It is also useful in identifying embryonic remnants.

The proposed FIGO 2000 anatomic staging system is a straightforward system based on anatomic criteria. In GTD, stage I disease is confined to the uterus; stage II disease is outside the uterus but limited to the genital structures; stage III disease extends to the lungs with or without known genital tract involvement; and stage IV disease includes all other metastatic sites. The FIGO 2000 scoring system is based on a method (adapted from the World Health Organization [WHO]) to identify patients at high risk for treatment failure. With the FIGO 2000 scoring system, patients are classified as being in a low-, middle-, or high-risk category. A total score of up to 4 is considered low risk; 5 to 7, middle risk; and 8 or greater, high risk. (Some centers recommend a low-risk score of 6 or less, a high-risk score of 7 or greater, and no middle-risk score.)

Treatment

The treatment strategy for GTD must be individualized for each patient. The stratification of risk groups enables physicians to direct an appropriate treatment strategy. Low-risk disease responds readily to single-agent chemotherapy and is virtually 100% curable. High-risk disease is not likely to be cured with single-agent therapy and therefore requires multidrug regimens.

Molar pregnancy. For patients with complete or partial hydatidiform mole, evacuation of the mole by suction and sharp curettage should be performed. Oxytocics also are given to produce uterine involution and to control bleeding. However, these agents should be used judiciously because they may cause hyponatremia and fluid overload. A baseline chest radiograph and β-hCG measurement should be obtained before surgery. After molar evacuation, 80% of patients will need no further intervention.

Follow-up. As mentioned previously, a baseline chest radiograph should be obtained in all patients with molar disease. Serial β-hCG levels should be obtained every 1 to 2 weeks until the level is normal for three consecutive assays. Complete remission is defined by three consecutive normal β-hCG levels. Once this has occurred, β-hCG levels should be checked monthly for 12 months, every 4 months for the following year, and then yearly for 2 years. However, a single undetectable β-hCG level after evacuation is sufficient follow-up to ensure remission in patients with partial hydatidiform moles.

Although the use of OCs during the surveillance period remains controversial, strict contraception is required, because pregnancy would obviate the usefulness of β-hCG as a tumor marker. In general, once 12-month surveillance establishes a disease-free status, conception is acceptable. These women are always at high risk for future molar disease and will require close observation during future pregnancies. A pelvic ultrasonographic examination should be performed during the first trimester of all subsequent pregnancies to confirm that gestation is normal.

Chemotherapy is indicated when there is a plateau or increase in β-hCG levels on consecutive measurements, failure to reach normal levels by 16 weeks, or metastatic disease. Such patients are usually at low risk and will respond to single-agent chemotherapy. Methotrexate is the most commonly initiated single agent. Therapy is continued for one or two courses after a normal β-hCG level is achieved.

Low-risk metastatic disease

In more than 30 years of experience, single-agent chemotherapy with methotrexate has produced a high cure rate in patients with low-risk GTN. Likewise, methotrexate plus leucovorin induces remission in 90% of patients with low-risk metastatic disease with low toxicity. The GOG conducted two phase II trials; both showed that a single dose of dactinomycin every other week (GOG-0069) or weekly intramuscular methotrexate (GOG-0079) had good compliance, comparable activity, and tolerable toxicity. The use of dactinomycin in methotrexate-resistant patients increased the cure rate to more than 95%. As reported by Osborne, GOG-0174 was the first randomized, prospective, front-line chemotherapy trial in 240 patients with GTN. The primary endpoint was normalization of the β-hCG levels. Eligible patients were those with untreated, histologically confirmed low-risk GTN (WHO risk score, 0–6) defined as one of the following: less than 10% decrease in β-hCG level over 3 consecutive weeks, persistently elevated β-hCG level for more than 4 months following initial curettage, or histologically proven nonmetastatic choriocarcinoma. Among eligible patients, complete response was observed in 53% of those given methotrexate and 69% of those given dactinomycin (P = .015). Both regimens were well tolerated; only two patients experienced grade 4 toxicity, and no patient experienced grade 5 toxicity. This study demonstrates that biweekly dactinomycin (at 1.25 mg/m2) is statistically superior to weekly parenteral methotrexate (at 30 mg/m2) as initial management for low-risk GTN. The first prospective multicenter phase II trial of salvage therapy for failed low-risk GTN, GOG-0176 found that pulse actinomycin D (1.24 mg/m2 IV every 2 weeks) is an active regimen.

High-risk metastatic disease

The discovery that etoposide is an effective agent against trophoblastic disease led to the development of the EMA-CO regimen (etoposide, methotrexate, actinomycin D [dactinomycin], cyclophosphamide, Oncovin [vincristine]), with a reported survival rate of 83% in patients with high-risk choriocarcinoma.

EMA-CO is the preferred regimen for high-risk GTN. This regimen is also used for patients with middle-risk GTN, as defined by the FIGO 2000 criteria. EMA-CO is generally well tolerated, with no life-threatening toxic effects. Alopecia occurs universally, and anemia, neutropenia, and stomatitis are mild. Reproductive function is preserved in approximately 75% of patients.

Within hours of receiving chemotherapy, patients with a significant tumor burden are at risk for hemorrhage into tumors and surrounding tissues. Thus, any acute organ toxicity that begins shortly after the induction of chemotherapy should be considered as possibly related to this phenomenon. Some researchers have advocated a reduction in dosage at the beginning of therapy in patients with large-volume disease, to minimize these sequelae.

Salvage therapy

Unfortunately, about 25% of women with high-risk metastatic disease become refractory to EMA-CO and fail to achieve a complete remission. Currently, there is no standard salvage chemotherapy regimen for patients not responding to EMA-CO. However, salvage regimens that combine cisplatin, etoposide, vinca alkaloids, and bleomycin have been administered.

Early studies show cisplatin-based regimens to be an effective salvage therapy in GTD. A recent dose-intensive regimen, EMA-CE, uses cisplatin (100 mg/m2) and etoposide (200 mg/m2) combined with EMA, with favorable results.

Another alternative is to give cisplatin in the EMA-POMB regimen (Platinol [cisplatin], Oncovin [vincristine], methotrexate, bleomycin). POMB is administered as vincristine, at 1 mg/m2 IV, and methotrexate, 300 mg/m2 IV (day 1); bleomycin, at 15 mg IV over 24 hours by continuous infusion, and folinic acid, at 15 mg twice daily for four doses (day 2); bleomycin, at 15 mg IV over a 24-hour continuous infusion (day 3); and cisplatin, at 120 mg/m2 IV (day 4).

A PEBA regimen (cisplatin, etoposide, bleomycin, doxorubicin) reported from China (Chen LP et al: Gynecol Oncol 1995) was found to be effective in EMA-CO–resistant disease. A complete remission was achieved in 96% of the women, and 73% had a sustained complete remission that lasted at least 1 year. In a small study by Lurain et al, ifosfamide alone and combined in the VIP regimen (VePesid [etoposide], ifosfamide, and Platinol [cisplatin]) showed promise as an effective salvage drug in GTD. The experience of the Brewer Trophoblastic Disease Center in patients with persistent or recurrent high-risk GTN showed that those who develop resistance to methotrexate-containing treatment protocols should be treated with drug combinations employing a platinum agent and etoposide with or without bleomycin or ifosfamide.

Another consideration in the treatment of refractory GTN is the use of high-dose chemotherapy with autologous bone marrow transplant.

Suggested Reading

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On Uterine Sarcomas

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