Uterine Corpus Tumors

June 2, 2008

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. Adenocarcinoma of the endometrium, the most prevalent histologic subtype, is currently the fourth most common cancer in women, with 39,080 new cases, ranking behind breast, lung, and bowel cancers. Endometrial adenocarcinoma is the eighth leading cause of death from malignancy in women, accounting for 7,400 deaths this year.

ENDOMETRIAL CANCER

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. Adenocarcinoma of the endometrium, the most prevalent histologic subtype, is currently the fourth most common cancer in women, with 39,080 new cases, ranking behind breast, lung, and bowel cancers. Endometrial adenocarcinoma is the eighth leading cause of death from malignancy in women, accounting for 7,400 deaths this year.

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 < 40 years old.

Geography The incidence of endometrial cancer is higher 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, white women have a twofold higher incidence of endometrial cancer than 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 favorable prognosis.

In the other 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 longterm 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 in women, underscores the importance of the association among risk factors, estrogens, and cancer. In the late 1970s and early 1980s, several casecontrol studies demonstrated that the risk of endometrial cancer is increased 4–15fold in longterm estrogen users, as compared with agematched controls.

It is well established that past use of oral contraceptive pills protects against endometrial cancer. Maxwell et al presented a retrospective review of the US Cancer and Steroid Hormone (CASH) study to determine the effects of progestin potency. They evaluated 417 endometrial cases and 2,452 controls. It appeared that there may be an increased benefit in the higher potency progestins (overall response = 0.3 [95% confidence interval (CI): 0.2–0.6]) vs lower potency progestins (overall response = 0.5 [95% CI: 0.3–0.6]), although these differences were not significant. They also suggested that in women with a higher body mass index (BMI), the higher potency progestins might be more protective. Higher progestin dose has a greater effect on decreasing risk.

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 highfat 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 pounds over ideal weight have a 3fold increased risk of developing endometrial cancer, whereas those 50 pounds or more over ideal weight have a 10-fold increased risk.

Parity Nulliparous women are at 2 times greater risk of developing endometrial cancer, females 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.

Other risk factors Other known risk factors for endometrial cancer include diabetes mellitus; hypertension; endometrial hyperplasia; and a family history of endometrial, breast, and/or colon cancer. Diabetic females have a 3-fold increased risk, and hypertensive patients have a 1.5-fold greater risk of 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.

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/1,000 women and the cumulative rate of second primary breast cancers from 40.5 to 23.5 cases/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 outweigh the risks of endometrial cancer.

The current recommendations for screening women on 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. 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 asymptomatic patients for endometrial cancer.

Outpatient endometrial sampling 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 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 ACS recently concluded that there was 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. In addition, results from three HNPCC (hereditary nonpolyposis colorectal cancer) 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.

Pathology

Adenocarcinoma Endometrioid adenocarcinoma is the most common form of endometrial carcinoma, comprising 75%–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%–50% of cases.

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

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

Serous carcinoma is an aggressive form of endometrial cancer that accounts for < 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 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 due to their propensity for early intraperitoneal spread.

Secretory adenocarcinoma 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 Gynecologic Oncology Group (GOG) surgical staging trials reported in 1984 and 1987 helped define the prognostic factors for endometrial carcinoma and the current treatment approach. 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.

Peritoneal cytology The current International Federation of Gynecology and Obstetrics (FIGO) staging system would classify the presence of malignant cells in the peritoneal fluid as stage IIIA disease, implying a worse prognosis, similar to that observed with cancer spread to the adnexa or serosa.

Tebeu et al compared the outcome of patients with stages I vs IIIA endometrial cancer and reported their results to the American Society of Clinical Oncology. The outcomes of the patients with stage IIIA disease were then reanalyzed by dividing the population into those based solely on the finding of a positive peritoneal cytology, “cytologic stage IIIA,” and a group with histologic documentation of either serosal or adnexal involvement with cancer, “histologic stage IIIA.”

The 5-year disease-specific survival for the patients with cytologic stage IIIA disease was 91%, remarkably similar to that of women in the series who presented with stage I endometrial cancer (92%). However, the 5-year disease-specific survival for the patients with histologic stage IIIA disease was only 50% (P < .001). This analysis was confirmed after controlling for other potential prognostic factors. These data raise the important question of whether the current endometrial cancer staging system, where the finding of a positive peritoneal cytologic result alone is considered a poor prognostic factor, should be reconsidered.

Uterine size 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.

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 FIGO to define endometrial cancer as a surgically staged disease in 1988, incorporating many of the prognostic factors into the staging process (Table 1).

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 intraabdominal 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 intraabdominal 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 salpingooophorectomy. 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 over 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 (LASS) is feasible in a select group of patients, as reported by Homesley et al. 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 pounds. Spirtos et al recently reported a feasibility trial by GOG on laparoscopic lymphadenectomy after incomplete surgical staging. A total of 69% of the women underwent complete endoscopic staging with photographic documentation, whereas 10% were incompletely staged. In addition, 20% needed laparotomy, of whom 6% had bowel complications and 11% were found to have more advanced disease. The safety, efficacy, and cost savings of LASS are currently being evaluated by GOG in a prospective randomized trial comparing LASS vs staging laparotomy.

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 one-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% chance of node positivity.

Lymphadenectomy The extent of lymph node removal has been the subject of debate. Recently, GOG 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 by 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 is surgically staged according to the 1988 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.

Grossly involved lymph nodes can often be completely resected. Havrilesky et al reported data for 96 patients with stage IIIC endometrial cancer and pelvic and/or aortic lymph node metastasis who underwent surgery between 1973 and 2002. Of these women, 45 had microscopic lymph node involvement and 51 had grossly enlarged nodes. Forty-four of the women with grossly involved lymph nodes underwent complete resection. Analysis 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 based on prognostic factors found at the time of surgery. A pelvic recurrence rate of 7%–14% is predictable 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, lymph nodes, peritoneal fluid, 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 has been delivered primarily using external-beam irradiation directed to the pelvis, which allows for treatment of the pelvic nodes.

A trial conducted by GOG 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, had lymph-vascular 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 rate from 36% to 17%, the cancer death rate from 17% to 10%, and the distant metastatic rate from 19% to 10%. This finding suggests that pelvic irradiation may not only influence pelvic recurrence in these patients, but 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 Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) study have been reported. Eligible patients had IC grade 1 (21%), IB or IC grade 2 tumors (69%), or 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 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, grade 3 histology, and myometrial depth > 50%, the 10-year locoregional relapse rate was 4.6% in the radiotherapy group vs 23.1% in the control group.

Creutzberg et al registered patients on 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.

Straughn et al published a large retrospective study of the National Cancer Database, where there appeared to be a trend toward improved survival in patients with clinical stages IC and II disease who received adjuvant radiation therapy. However, a difference in recurrence rates or survival in patients with surgical stages IC and II disease who received adjuvant radiation therapy compared with observation was not demonstrated.

Brachytherapy A few reports have demonstrated excellent local 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 vaginal brachytherapy.

In a randomized study from the Norwegian Radium Hospital, pelvic irradiation significantly decreased the incidence of locoregional recurrences compared with vaginal irradiation alone. 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.

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. Fanning reported outcomes of 66 patients, with a follow-up of 4.4 years. These patients were treated with bilateral pelvic and para-aortic lymphadenectomy with hysterectomy and oophorectomy. Brachytherapy alone was given as adjuvant therapy. There were no pelvic recurrences. Major complications occurred in 6% of patients.

In general, vaginal irradiation alone is reserved for patients at low risk for pelvic node metastasis. Because of 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 external-beam irradiation alone. Patients with uterine-confined disease have excellent local 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 high-dose rate (HDR) or low-dose rate (LDR) equipment. Both techniques have resulted in excellent local control rates and low morbidity when administered by experienced practitioners. Each technique has its advantages. HDR treatments require multiple insertions, generally with one insertion performed every week for 3–6 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 2–3 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, grade 2 or 3 histology, or evidence of vascular space invasion (Table 2). Data support the use of vaginal irradiation alone for women with more superficial tumors and low-grade histology.

 Stage
Histologic gradeIAIBIC
G1
G2+
G3+++
Vascular space invasion+++



Radiation doses are generally 45–50 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. For these patients, 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 to the recommendation that they 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%.

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

Extensive cervical involvement

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 40–45 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 20–25 Gy to point A (defined as 2 cm caudally and 2 cm laterally to the cervical os). Hysterectomy should follow in approximately 4–6 weeks. The expected 5-year disease-free survival rate for patients with extensive disease is 70%–80%.

More favorable patients have an isolated extrauterine site (eg, adnexa or peritoneal cytology alone), low-grade histology, and/or disease confined to the pelvis. Greven et al 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.

Isolated ovarian metastasis

One subgroup found to have a relatively favorable prognosis includes women with isolated ovarian metastasis. Five-year disease-free survival rates ranging from 60%–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 45–50 Gy using standard fractionation. A vaginal boost with a cylinder or colpostats may add 30–35 Gy to the vaginal surface.

Extension to pelvic and periaortic nodes

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 70% and 35% 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 45–50 Gy to a volume encompassing the pelvic and periaortic regions.

Whole abdominal irradiation

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 disease progression-free survival rate of 35%. GOG has completed a trial of WAI compared with chemotherapy. (The outcomes from this trial are discussed in the chemotherapy section.) 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.

Combining radiation therapy with chemotherapy

Because many of these patients are at increased risk of pelvic recurrence as well as distant recurrence, there is interest in combining pelvic radiation therapy with systemic therapy. RTOG (Radiation Therapy and Oncology Group) 9708 combined pelvic radiation therapy with cisplatin and followed it with cisplatin and paclitaxel. Toxicity was predominantly hematologic. Outcomes from this phase II trial are promising. GOG currently has a phase III trial open for patients with stage III/IV cancer that includes involved-field radiation therapy for all patients with randomization to two different chemotherapy regimens.

Definitive radiation treatment

For patients who are poor operative risks, definitive treatment with irradiation has produced excellent local control and survival rates. Such treatment is considered to be justified when the operative risk exceeds the 10%–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 control rates in patients with stages I/II, III, and IV disease were 84%, 87%, and 68%, respectively.

Treatment techniques with irradiation alone for patients with early-stage disease and low-grade histology consist of uterine intracavitary insertions with Heyman or Simon capsules or an afterloading intrauterine tandem. Doses for intracavitary treatment range from 40–45 Gy prescribed to point A. 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 40–45 Gy to the pelvis, followed by intracavitary treatment that delivers 30–35 Gy to point A.

Complication rates Rates of serious complications attributable to irradiation range from 4%–5% with intracavitary treatment alone to 10%–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 To date, there are emerging data suggesting a possible role for adjuvant chemotherapy. GOG compared doxorubicin with observation in 181 patients with high-risk, early-stage, endometrial carcinoma; at 5 years, there was no difference in recurrence rates. A subsequent phase II trial suggested a better outcome for 62 high-risk patients treated with adjuvant CAP (cyclophosphamide, Adriamycin [doxorubicin], and Platinol [cisplatin]) when compared with historic controls.

A Japanese Gynecologic Oncology Group study presented at the 2005 meeting of the American Society of Clinical Oncology (ASCO) has suggested that chemotherapy may also be employed as an alternative to radiotherapy in the treatment of more localized, intermediate-risk disease (> 50% myometrial invasion). Patients (n = 425) were randomized to receive either cisplatin/doxorubicin/cyclophosphamide or whole pelvic radiotherapy. The study revealed no difference between the two regimens with respect to risk of local recurrence (15% to 16%) or survival (progression-free or overall).

Results from a GOG trial comparing adjuvant chemotherapy (doxorubicin plus cisplatin) with WAI were reported by Randall et al. The patient population included patients with stages III and IV disease (75% and 25%, respectively) with 50% endometrioid histologies. Patients treated with WAI had significantly improved progression-free (38% vs 50%, respectively) and overall (42 % vs 55%) survival at 5 years. However, serious adverse effects were also more common in the chemotherapy group than 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 may support the concept of combining chemotherapy with involved-field irradiation. A GOG trial exploring this treatment strategy has recently closed to accrual. However, the results are not yet available.

Hormone replacement therapy (HRT) Whether HRT increases the likelihood of recurrence has been studied, with several retrospective reports showing no adverse outcomes. Thus, 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. In results presented by Barakat et al at the Society of Gynecologic Oncologists, HRT was not associated with a significant incidence of recurrent disease or mortality.

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 3–6 month intervals for the first 5 years and yearly thereafter. The use in asymptomatic patients of more extensive and more costly procedures, such as chest x-ray, CT imaging, and marker studies, is of questionable value and is unlikely to have a major impact on survival. Symptomatic patients should be evaluated as is 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 external-beam irradiation only vs the addition of vaginal brachytherapy.

The PORTEC 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 external-beam irradiation 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 the boost method selected. The tolerance of normal tissues must be respected, but combined doses > 60 Gy have been associated with improved local control.

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. Selected 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.

Barakat et al reported on 44 patients who underwent pelvic exenteration for recurrent endometrial cancer at Memorial Sloan-Kettering Cancer Center between 1947 and 1994. Primary therapy usually consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy, with most patients receiving either preoperative or postoperative radiotherapy. Prior to exenteration, 10 of 44 patients (23%) had never received any form of radiotherapy. The median interval between initial surgery and exenteration was 28 months (range, 2 to 189 months).

Exenteration was total in 23 patients, anterior in 20 patients, and limited to posterior in 1 patient. One vascular injury led to the only intraoperative death. Major postoperative complications occurred in 35 patients (80%) and included intestinal/urinary tract fistulas, pelvic abscess, septicemia, pulmonary embolism, and cerebrovascular accident. Median survival for the entire group of patients was 7.36 months, with 9 patients (20%) achieving long-term survival (> 5 years). 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 produce complete and partial response rates of 15%–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.

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 (400–1,000 mg of medroxyprogesterone IM weekly). A phase III trial conducted by 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 3). Doses higher than 200 mg/d of medroxyprogesterone, therefore, are clearly not warranted.

 Oral medroxyprogesterone
Parameter200 mg/d (n =145)1,000 mg/d (n=154)
Response rate (%)2515
Complete response rate (%)179
Median disease progression-free survival (mo)3.22.5
Median survival (mo)11.17.0



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 disease progression-free and overall survival.

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

Tamoxifen

has a 0%–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.

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. Whitney reported that continuous tamoxifen and medroxyprogesterone given every other week was an active treatment, with a 33% response rate. A subsequent study by Fiorica et al 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,

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.

Active agents The anthracyclines studied include doxorubicin and epirubicin (Ellence). 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 (Paraplatin) produced a 31% response rate in 52 patients. Paclitaxel, in two GOG studies, yielded responses in 36% of chemotherapy-naive and 27% of previously treated patients.

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

Agents with limited activity Other agents studied have included alkylating agents (cyclophosphamide, ifosfamide [Ifex]), altretamine (Hexalen), fluorouracil (5-FU), methotrexate, mercaptopurine (Purinethol), vinblastine, etoposide, teniposide (Vumon), and mitoxantrone (Novantrone). All these agents exhibited insufficient activity to warrant further study.

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%–60% response rate). Further support for this approach was provided by a report from Sovak et al, who conducted a retrospective analysis of their experience with this combination chemotherapy regimen in endometrial cancer. The objective response rate in chemotherapy-naive patients was 47% (2% complete response rate), with a median progression-free survival of 4.2 months and median overall survival of 11 months. Ultimately, the relative merits of combination chemotherapy with carboplatin and paclitaxel must be judged in the context of the randomized trial that is being performed by GOG.

Following encouraging phase II results, Gallion et al reported on a phase III trial of circadian timed administration of cisplatin and doxorubicin and found no significant benefit. 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 protocol 177). The three-drug combination of the paclitaxel-containing program produced a higher response rate (57% vs 35%) and an improved disease progression-free survival (8.3 vs 5.3 months). Overall survival was also modestly improved (15.3 vs 12.3 months; P = .037) with the three-drug program but with considerably greater toxicity, particularly peripheral neuropathy (grade 3, 12% vs 1%).

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 (GOG protocol 29) allocated patients with advanced or recurrent disease to receive either cyclophosphamide, doxorubicin, cisplatin, and megestrol or melphalan (Alkeran), 5-FU, 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 prior studies of single-agent doxorubicin with regard to response rate, disease 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 disease progression-free interval, 9 months; overall median survival, 14 months) and should be so treated. Those with a grade 2–3 tumor and/or known progesterone-receptor–negative disease do not do well with progestin therapy (response rate, 12%; median disease progression-free interval, 3 months; overall median survival, 10 months) and should be considered for initial treatment with single-agent chemotherapy (eg, paclitaxel, doxorubicin, carboplatin) or a combination regimen. Options include cisplatin/doxorubicin, cisplatin/paclitaxel, and carboplatin/paclitaxel. (It is difficult to justify the routine use of the three-drug paclitaxel-containing regimen noted previously despite the modest improvement in efficacy due to substantial toxicity.) 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. Likewise, sequential use of tamoxifen and progestins is not indicated because of the absence of enhanced efficacy.

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 (LMSs) are characterized by differentiation toward one or more stromal tissues. LMSs 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 hematogeneous 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%–60% occurring with stage I disease. LMS 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 LMSs tend to fail to recur distantly. In a prospective surgical staging trial by GOG, the recurrence rate for early-stage carcinosarcoma was 53% and for LMS was 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 LMS. Retroperitoneal nodal sampling is not usually performed, because lymph node involvement is unusual. For late recurrences of LMS, surgery must be individualized. Five-year survival rates of 30%–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, as these tumors tend to have very high concentrations of estrogen and progesterone receptors and often respond to hormonal therapy. However, Li et al recently 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

Currently, there are no clear data suggesting improvement in outcome for patients with uterine sarcomas treated with adjuvant pelvic 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 clear evidence that it improves survival. Patients will often experience recurrence distantly 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.

Adjuvant radiotherapy

Uterine sarcomas represent only 2%–5% of all uterine malignancies. These patients have a high incidence of distant, as well as pelvic, recurrences. In a nonrandomized prospective GOG study, patients with stages I and II mixed mesodermal sarcomas and LMSs had fewer pelvic recurrences following irradiation than did those 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. Decreasing pelvic recurrences may improve symptom-free survival for these patients.

Currently, GOG has an open randomized study for patients with stages I–IV mixed mesodermal sarcomas. Following resection of gross disease, patients are randomized to receive WAI (30 Gy) with a pelvic boost (1,980 cGy) or chemotherapy alone with cisplatin, ifosfamide, and mesna (Mesnex).

Adjuvant chemotherapy

There is no proven role for adjuvant chemotherapy in stage I disease following complete surgical resection. A GOG study looking at adjuvant doxorubicin vs no further therapy showed no differences in recurrence rate, disease progression-free survival, or overall survival.

For patients with advanced/recurrent disease, single-agent chemotherapy can be used with a palliative intent. For carcinosarcomas, ifosfamide or paclitaxel appears to be the agent of choice. Doxorubicin has traditionally been used for LMSs. Look reported the GOG experience with gemcitabine (Gemzar) in patients previously treated for LMS, showing 20% of patients responded. Combination therapy with mitomycin (Mutamycin), doxorubicin, and cisplatin (Paraplatin; MAP) modestly increased the responses to 23% with increased toxicity. Hormonal agents, specifically progestins, are the treatment of choice for advanced/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%–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%–30%) in molar pregnancy.

Hyperthyroidism is seen clinically in approximately 7% of molar pregnancies. An elevation of triiodothyronine (T3) 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 (TSH).

Partial mole

Patients with partial mole have different clinical features than those with complete mole. Fewer than 10% of patients with partial mole have uterine enlargement. Patients with partial mole do not have prominent theca-luteal 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

GTD develops in 6%–19% of patients after molar evacuation. Metastases sometimes have an identical histology to that of molar disease, but the vast majority are choriocarcinomas. Metastatic spread is hematogeneous. Because of its extensive vascular network, metastatic GTD often produces local, spontaneous bleeding. Berkowitz et al at the New England Trophoblastic Disease Center (NETDC) 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 Glisson’s capsule. GI 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.

CNS involvement from metastatic GTD suggests widespread disease and has a poor prognosis. CNS metastases are clinically evident in 7%–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 GTD, 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 therapeutic outcome.

Radiologic studies A chest x-ray should always be performed because 70%–80% of patients with metastatic GTD have lung involvement. Although this x-ray 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%–100% of patients with CNS disease from choriocarcinoma have concomitant pulmonary metastases, a CNS work-up in asymptomatic patients with normal chest x-rays is not routinely warranted. If the chest x-ray is abnormal, or if β-hCG levels plateau or rise during treatment, a more thorough evaluation for metastatic disease is indicated. 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; 5–7, 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, as they may cause hyponatremia and fluid overload. A baseline chest x-ray and β-hCG measurement should be obtained prior to surgery. After molar evacuation, 80% of patients will need no further intervention.

Follow-up As mentioned previously, all patients with molar disease should obtain a baseline chest x-ray. Serial β-hCG levels should be obtained every 1–2 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, Lavie et al recently showed that a single undetectable human chorionic gonadotropin level after evacuation is sufficient follow-up to ensure remission in patients with partial hydatidiform moles.

Although the use of oral contraceptives 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 to 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 GTD. Likewise, methotrexate plus leucovorin induces remission in 90% of patients with low-risk metastatic disease with low toxicity. The use of dactinomycin (Cosmegen) in methotrexate-resistant patients increased the cure rate to more than 95%.

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]) by Bagshawe, who reported a survival rate of 83% in patients with high-risk choriocarcinoma.

EMA-CO is the preferred regimen for high-risk GTD. This regimen is also used for patients with middle-risk GTD, 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 of 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, utilizes 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, 1 mg/m² IV, and methotrexate, 300 mg/m² IV (day 1); bleomycin, 15 mg IV over 24 h by continuous infusion (CI), and folinic acid, 15 mg bid for four doses (day 2); bleomycin, 15 mg IV over 24 h CI (day 3); and cisplatin, 120 mg/m² IV (day 4).

A new PEBA regimen (Platinol [cisplatin], etoposide, bleomycin, Adriamycin [doxorubicin]) was reported from China and 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, ifosfamide alone and combined in the VIP regimen (VePesid [etoposide], ifosfamide, and Platinol [cisplatin]) showed promise as being an effective salvage drug in GTD. Lurain and Nejad reviewed the experience of the Brewer Trophoblastic Disease Center in patients with persistent or recurrent high-risk gestational trophoblastic neoplasia. They 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 GTD is the use of high-dose chemotherapy with autologous bone marrow transplantation.

SUGGESTED READING

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