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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 113Endometrial Cancer

, MD, , MD, and , MD.

It has been predicted that 36,100 new cases of endometrial cancer will occur in the United States in 2000 and that the disease would result in 6,500 deaths.1 In 1991, the number of endometrial cancer deaths in the United States began to exceed the number attributable to cervical cancer, which is the most prevalent gynecologic cancer in the populous, less-developed areas of the world and the one that causes the most deaths. The incidence in the United States has diminished slightly since the first half of the last decade, when approximately 39,000 new cases of endometrial cancer a year were seen. The reasons for this are unclear, but contemporaneously, Norway, Czechoslovakia, and other northern European countries reported significant increases in the incidence of endometrial cancer. It is possible that recognition of risk factors during the last decade and their translation into an alteration of life style and menopause management may have diminished the incidence of new disease in the United States. Five-year survivals in the United States are estimated to be 84% overall for 1989 to 1994.1 However, there has been a statistically significant decline in the 5-year survival rate in comparison with the rates between 1974 to 1976 (88%) and 1980 to 1982 (82%). Survival figures published in the Annual Report on the Results of Treatment in Gynecologic Cancer (23rd volume) shown in Table 113.1 demonstrate that overall survival for patients treated between 1990 and 1992 was 73.4%. This report includes data from 117 institutions around the world.

Table 113.1. Carcinoma of the Corpus Uteri*.

Table 113.1

Carcinoma of the Corpus Uteri*.

Although the incidence of endometrial carcinoma is lower among African American women compared with Caucasian women, the mortality rates are higher in the former group of patients.2 In their review of the National Cancer Data Base, Hicks and co-workers2 observed that African American women were diagnosed with less favorable histologies, more advanced stages of disease, and with poorly differentiated tumors compared with Caucasian women. The African American women were less frequently treated surgically, and the surgically treated patients with advanced-stage disease received adjuvant radiotherapy less often and chemotherapy more often than did the Causasian patients. Most significantly, 5-year survival was poorer for African American women, even for those with stage I disease who were treated surgically.2

Risk Factors

The list of conditions thought to increase the risk for endometrial cancer has included body size, obesity, hypertension, diabetes, nulliparity, a history of colon and/or breast carcinoma, syndromes of ovulation failure, syndromes of increased endogenous estrogen exposure, and exposure to exogenous estrogen. Recently, the list was refined and focused, on the basis of an improved understanding of the underlying pathophysiology. Multivariate analysis. controlled for age and obesity, verified the association between endometrial cancer and diabetes. but not hypertension. The obesity observed in the typical phenotype associated with the endometrial cancer patient is related to a higher level of circulating estrogen than in cohorts of thinner patients. This results from peripheral aromatization in the fat of estrogen precursors. Data from a recent population-based case-control study indicate that diabetes confers no additional risk of endometrial carcinoma in women who are neither overweight body mass index (body mass index [BMI], 29.1–31.9) nor obese (BMI, > 31.9).3 However, other investigators have observed an increased risk of endometrial carcinoma in patients with normal BMIs, with higher BMI associated with increased risk of disease.4 Nulliparity as compared with multiparity of five or more births, menopause after age 53 years, and 50 pounds of excess weight are all important risk factors that can increase a woman’s probability for endometrial cancer by 5 to 10 times compared with patients without these risk factors.

There are pathologic variants that are associated with an increased risk of endometrial cancer, and these features have in common the production of increased levels of estrogen or the requirements for exogenous estrogen supplementation. It is known that patients with granulosa theca cell tumors of the ovary have clinical manifestations of increased estrogen exposure. Gusberg and Kardon5 reviewed the endometrial histology from 115 patients with these ovarian tumors and found that 21% developed endometrial carcinoma and 43% had benign changes that were thought to be precancerous, such as adenomatous hyperplasia. Others have not found the same incidence of adenocarcinoma but have identified a high incidence of atypical hyperplasias.6,7 Patients with polycystic ovary syndrome usually do not ovulate and, thus, are exposed to continuous estrogen production. When endometrial carcinoma occurs in women younger than 45 years of age, it is usually in patients with polycystic ovary syndrome8,9 and is most frequently surrounded by atypical hyperplasia histologically. These lesions are usually well-differentiated cancers, suggesting the influence of estrogen exposure. Finally, patients who were treated for ovarian dysgenesis by oophorectomy with unopposed estrogen replacement have been found to develop endometrial carcinoma in the residual uterus.10

Extrapolating from the observed association between hyperestrogen states and the development of endometrial cancer, clinicians became wary of the theoretic risk of exogenously administered estrogen highlighted by Gusberg’s suggestion that the glandular atypicalities originally described by Cullen in 1900 were related to estrogen and were, in fact, precursors of endometrial adenocarcinoma.11,12 In 1975, Smith and colleagues,13 in a retrospective case-control study of 317 women with endometrial carcinoma, noted a 4.5 relative risk among those women who had been treated with unopposed estrogen, as compared with 317 controls who had gynecologic cancers other than endometrial cancers. There followed a series of retrospective analyses14–17 describing the relative risk of endometrial cancer in estrogen users as ranging from 1.7 to 8.0, with some subsets of patients experiencing a risk as high as 14-fold. Critics found each of the many studies deficient in some feature, but there was no common deficit among the studies and a relative risk of 4 to 7 was consistently found by each investigator.

In 1993, mindful of the defects of the earlier studies, Brinton and Hoover,18 representing the Endometrial Cancer Collaborative Group, completed a hospital-based case-control study analyzing 300 menopausal women with new diagnoses of endometrial carcinoma and 207 matched population controls. These investigators identified a relative risk of 3.0 for all users, although risks were higher for recent use, thin habitus, or cigarette smoking. There was no clear dose relationship observed, but women who used low-dose preparations exclusively were found to be at lowest risk, although when low-dose use continued beyond 5 years, this advantage was lost. While only 4% of the women used progestogens simultaneously with estrogen, there seemed to be a partial protective effect, but the risk was not eliminated. Some investigators have described an immediate decline in risk after cessation of estrogen use,19 but Brinton’s study confirms the observation made by others that the excess risk can persist beyond 5 years after discontinuation, especially when there has been long-term exposure.

The Centers for Disease Control reported that oral contraceptive use for at least 12 months diminished the risk of endometrial cancer by 50% compared with that for women who had never utilized oral contraception. Nulliparous women seemed to benefit most, and the protection lasted for a decade following the discontinuation of oral contraceptive use.20 Brinton’s study observed that previous oral contraceptive use did not protect women from increased relative risk of endometrial cancer when they employed unopposed estrogen in postmenopausal hormone replacement therapy, suggesting that the role of the progestogen in the combination oral contraceptive pills is essential in protecting against endometrial carcinoma.

For more than 20 years, tamoxifen has been used to treat breast cancer, following the observation that it causes regression of metastatic tumor, diminishes the incidence of cancer in the contralateral breast, delays time to recurrence, and improves survival in subsets of patients. While tamoxifen was originally employed as an antiestrogen, the mechanisms by which it produces the observed effects and acts both as agonist and antagonist are not well understood. Once estrogens bind to their receptors, receptor activation induces transcriptional activation of the tumor angiogenic factors, TAF-1 and TAF-2. Tamoxifen, however, binds and activates the receptor but only induces TAF-1, resulting in an agonistic effect. The absence of TAF-2 activation could result in antagonistic activity. Whether a cell is affected by TAF-1 or TAF-2 will determine the agonistic or antagonistic behavior of the drug.21 Clinically, tamoxifen diminishes serum cholesterol, increases sex hormone–binding globulin,22 preserves bone density in the lumbar spine,23 thickens the vaginal epithelium in some patients,24 and is associated with the enlargement of uterine fibroids, the growth of endometrial polyps, and the development of endometrial neoplastic change. These are all estrogen-like functions.

Paradoxically, the same drug is associated with the production of vaginal atrophy, the onset of vasomotor symptoms, and the development of clinical dyspareunia. These are features of estrogen deprivation.

The action of tamoxifen may be organ specific, just as it is known to be quite species specific in its association with hepatic neoplasia in laboratory animals. When immortalized breast cancer and endometrial cancer cell lines were implanted in athymic mice, both cancers grew well in the same animal. When tamoxifen treatment was given, the breast cancers were inhibited and the endometrial cancers continued to grow.25 Several investigators have described an increase in the incidence of endometrial cancers among patients with breast cancer who were treated with tamoxifen.26–30 Killackey and co-workers30 were the first to report endometrial carcinoma occurring in three breast cancer patients receiving antiestrogens. The strongest initial data implicating tamoxifen use in the subsequent development of endometrial carcinoma were reported by Fornander and co-workers,26 who reviewed the frequency of new primary cancers in the Swedish Cancer Registry for a group of 1,846 postmenopausal women with early breast cancer. There was a 6.4-fold increase in the relative risk of endometrial cancer in the 931 tamoxifen-treated patients compared with controls. The dose of tamoxifen in this study was 40 mg/d. At doses of 20 mg/d, several investigators with small series have not observed an increased incidence of endometrial cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABBP) described observations on 3,863 patients prospectively studied.29 In the B-14 protocol, 2,843 patients with node-negative, estrogen receptor–positive breast cancer received either tamoxifen (20 mg/d) or placebo. An additional 1,020 patients taking tamoxifen were registered in this project. The average time in the study was 8 years for the randomized patients and 5 years for the registered patients. Originally, 25 endometrial cancers were reported, but upon review, 1 was found to be a sarcoma, and 2 of the cancers developed in women originally assigned to the placebo group, who were ultimately treated with tamoxifen before discovery of their endometrial cancers. None of the patients who did not receive tamoxifen developed endometrial cancer. This is surprising because the relative risk for endometrial cancer in breast cancer patients is 1.4. The relative risk calculated for the tamoxifen-treated group as compared with the placebo group was 7.5, with an annual hazard rate of 0.2 per 1,000 for the placebo group and 1.6 per 1,000 for the randomized tamoxifen-treated group. The distribution of pathologies among the 24 adenocarcinomas was the same as that reported in the Surveillance, Epidemiology, and End Results (SEER) data for the years 1983 to 1987.

More recently, in the Breast Cancer Prevention Trial (P-1) of the NSABBP, 13,388 women were randomly assigned to receive placebo (6,707) or 20 mg/d of tamoxifen (6681) for 5 years.31 Tamoxifen reduced the risk of invasive breast cancer by 49% and of noninvasive breast cancer by 50%. The rate of endometrial carcinoma was increased in the tamoxifen group (risk ratio = 2.53); this increase occurred primarily in women aged 50 years or older. All endometrial carcinomas in the tamoxifen group were stage I, and no endometrial cancer deaths have occurred in this group.

In one report of 15 patients who developed endometrial cancer while exposed to tamoxifen, two-thirds of the patients had histologically virulent tumors. The patients with these tumors were significantly older than the general endometrial cancer patient population, however, and fell into an age group where sarcomas and nonendometrioid carcinomas are likely to occur more frequently.32 In several other series of similar size, the distribution of pathology among such patients was no different from that observed in endometrial cancer patients who have not been exposed to tamoxifen.33 Similarly, Barakat and co-workers, in a retrospective review of 73 patients with a history of breast cancer who subsequently developed endometrial carcinoma, found no significant difference in stage, grade, or histologic subtype.34

Critics have expressed several reservations about the studies reporting an increased incidence of endometrial cancer. In most of the studies, the cancers occurred during the first years of study, suggesting the possibility of lead-time bias. In none of the studies were control biopsies performed prior to the administration of tamoxifen. In all the studies, the confidence intervals are so wide that reliable conclusions are difficult. There are ongoing prospective studies in the chemoprevention trials that may address this risk factor more precisely.

It is interesting to note that tamoxifen was employed as an infertility drug before its use in patients with breast cancer. There are no reported cases of endometrial cancer developing in women treated with tamoxifen who did not have breast cancer. If women at high risk for breast cancer in the chemoprevention trial receive tamoxifen and do not develop endometrial cancer, we may learn much about transcription and neoplasia in the endometrium.

More recently, studies have focused on the surveillance of breast cancer patients using tamoxifen. Runowicz and co-workers,35 in a summary analysis of the transvaginal ultrasound and endometrial biopsy data from NSABBP (P-1), observed that ultrasonography had a sensitivity of 27% and a specificity of 70%. Of 13 significant biopsies, only 1 showed invasive cancer; the other 12 revealed simple hyperplasia without atypia (9 patients) or complex hyperplasia without atypia (3 patients). The authors did not recommend the substitution of ultrasonography for endometrial biopsy for the assessment of endometrial hyperplasia or carcinoma in this group of patients. In another study, Barakat and co-workers36 evaluated 159 tamoxifen-treated patients by serial office endometrial biopsies obtained at the start of tamoxifen therapy and at 6 month intervals for 2 years, followed by three additional annual biopsies. Although the procedure was feasible, significant pathology requiring hysterectomy was observed in only 3 patients, and the authors concluded that the utility of routine endometrial biopsy for screening in tamoxifen-treated women is limited. Neither of these studies provides strong support for screening with ultrasonography or endometrial biopsy. Serial pelvic examinations and prompt evaluation of vaginal bleeding are, given the current data, the reasonable management approach for these patients.

While a large cohort of women with endometrial carcinoma is noted to have one or more risk factors, the background of hormonal aberration stemming from inappropriate estrogen exposure, either endogenous or exogenous, with all the attendant typical phenotypes, accounts for no more than 30% of endometrial cancer patients. Historically, this figure was thought to be much higher, and conventional wisdom suggested that women of high parity, lean phenotype, unremarkable family history, and who had not had estrogen replacement therapy and had little intercurrent disease were relatively immune to endometrial cancer. Unfortunately, this is not the case, and many centers are reporting increasing numbers of patients with endometrial cancer who have no recognized risk factors. Such women frequently have more virulent disease histologically with implied diminished survival than do traditional endometrial cancer patients.37,38

Pathology

Endometrial Hyperplasia

When Gusberg introduced the term “adenomatous hyperplasia” to describe the pattern of hyperplastic glands noted in association with, and often prior to, the development of endometrial adenocarcinoma, he included all the variants of precursor histology. These ranged from a mild arrangement of densely crowded glands with eosinophilic cytoplasm through the spectrum of more disordered arrangements, with intraluminal tufting, and increase in mitosis, pseudopalisading, and bizarre nuclei.11,39 Hertig40 similarly studied preinvasive changes in the endometrium and described three intensities of abnormality, which he called “adenomatous hyperplasia”, “atypical hyperplasia”, and “carcinoma in situ”. The students of these two investigators published their findings and generated official pathology reports in their clinical centers, employing these overlapping terminologies for the next three decades. Some investigators objected to the term “carcinoma in situ” because a curettage or other endometrial sampling may not be able to rule out the invasion that a hysterectomy specimen would reveal. Clinicians were confused because Hertig’s adenomatous hyperplasia implied a small risk for subsequent transition to cancer, whereas Gusberg’s adenomatous hyperplasia carried a 15 to 30% risk over time if it was not reversed by therapy. Once the malignant implications of this diagnostic feature were published, few gynecologists or patients were willing to observe the natural history, and hysterectomy frequently followed. Wentz observed a cohort of women classified by the Hertig system who had two curettage specimens at least 8 weeks apart.41 The women were followed up for 2 to 8 years and were not treated with hormonal therapy. He found that 26% of those with adenomatous hyperplasia, 82% of those with atypical hyperplasia, and 100% of those with adenocarcinoma in situ progressed to invasive adenocarcinoma.

In 1983, Ferenczy challenged the notion of the continuum from the simplest glandular aberrations through intermediate stages to invasive carcinoma.42 He reported that only lesions with cytologic atypia progressed to cancer and suggested that the innocuous lesions be termed endometrial hyperplasia and the others be considered endometrial neoplasia. Kurman, in 1985,43 followed up 170 patients with endometrial hyperplasia for a minimum of 1 year; the mean follow-up time was 13.4 years. He established criteria for distinguishing lesions on the basis of architectural abnormalities and cytologic abnormalities. Only 1.6% of patients without cytologic atypia progressed to cancer, as compared with 23% of those with atypical cytology. Architectural abnormalities were not prognostically important. The details of Kurman’s classification and observations are presented in Table 113.2. His classification of simple or complex hyperplasia, with or without atypia, is now more widely accepted for describing these lesions.

Table 113.2. Comparison of Follow-up of 170 Patients with Simple and Complex Hyperplasia and Simple and Complex Atypical Hyperplasia.

Table 113.2

Comparison of Follow-up of 170 Patients with Simple and Complex Hyperplasia and Simple and Complex Atypical Hyperplasia.

Endometrial Adenocarcinoma

Endometrioid adenocarcinoma is the most common of the endometrial cancer histologies. It is characterized by the disappearance of stroma between abnormal glands that have infoldings of their linings into the lumens, disordered nuclear chromatin distribution, nuclear enlargement and a variable degree of mitosis, necrosis, and hemorrhage. This classical variety accounts for 60 to 65% of the adenocarcinomas (Fig. 113.1 and Fig. 113.2).

Figure 113.1. Adenocarcinoma of the endometrium.

Figure 113.1

Adenocarcinoma of the endometrium. Greade 1 (well-differentiated), with preservation of glandular features. A. High power. B. Low power (Courtesy Dr. Liane Deligdisch, Mount Sinai School of Medicine).

Figure 113.2. Adenocarcinoma of the endometrium grade 2 showing solid tumor and few glands.

Figure 113.2

Adenocarcinoma of the endometrium grade 2 showing solid tumor and few glands. (Coutesy Dr. Liane Deligdisch, Mount Sinai School of Medicine).

Adenosquamous Carcinoma

Adenosquamous cancer has malignant elements from both its squamous component and its adenomatous component. It usually accounts for 7% or less of the adenocarcinomas of the endometrium. However, in 1974, Reagan44 described a rising incidence of this entity in the University Hospitals of Cleveland, with adenosquamous cancer making up 20% of the endometrial cancers; these patients had a very poor prognosis. Apparently, this change in the ratio of histologies has not been universal in the United States. The staging convention, now published in the 23rd volume of the Annual Report, requires grading of this tumor on the basis of its glandular component and not its squamous component. While data are still maturing, it is suggested that when this convention is followed, adenosquamous cancer will not behave differently from endometrioid adenocarcinomas of the same stage and grade.

Uterine Papillary Serous Carcinoma

Described by Hendrikson45 in 1982, uterine papillary serous carcinoma (UPSC) comprises 5 to 10% of stage I endometrial carcinomas and is characterized by an expansive papillary architecture with a fibrovascular matrix, marked cytologic atypia, bizarre nuclei, and widespread nuclear pleomorphism (Fig. 113.3). The features are suggestive of papillary serous cystadenocarcinoma of the ovary. The lesion is highly virulent, usually found with deep myometrial penetration at the time of diagnosis, often extrauterine in location in patients with clinical early-stage disease, and almost always incurable when the disease has spread beyond the uterus. In one series, observations on 15 patients with UPSC were compared with 76 adenocarcinomas (AC) and 26 adenocarcinomas with papillary features (PE), all treated in the same institution.46 At 3 years, 75% of the AC group were alive without disease. For the PE group, the progression-free interval was 33 months, and for the UPSC group, it was 9 months. In a study of recurrent disease, Lee and Belinson identified 28 recurrences in a series of 227 patients with clinical stage I endometrial carcinoma.47 Of the 28 patients, 7 had no invasion of the endometrium at the time of diagnosis. Five of these 7 had histologic characteristics of UPSC, and all died of the disease.

Figure 113.3. Uterine papillary serous carcinoma Broad stalks supporting papillary fronds, appearing like papillary ovarian carcinoma.

Figure 113.3

Uterine papillary serous carcinoma Broad stalks supporting papillary fronds, appearing like papillary ovarian carcinoma. (Courtesy Dr. Liane Deligdisch, Mount Sinai School of Medicine).

Endometrial Papillary Adenocarcinoma

Endometrial papillary adenocarcinomas must be distinguished from UPSC because of their different behavior. They are characterized histologically as being usually well differentiated PEs composed of very slender papillations, orderly neoplastic epithelial cells, few mitoses, and less cellular disorder than UPSC. The distinction between these two groups has been carefully detailed by Chen and colleagues.48 The endometrial carcinomas with papillary features behave identically to the endometrioid adenocarcinomas.

Clear Cell Carcinoma

Clear cell cancers have been described in detail by Kurman and Scully.49 Histologically, while there are a variety of patterns, a presentation of polygonal or flattened cells with clear cytoplasm accounts for more than half the cells. This group constitutes approximately 6% of endometrial carcinomas and occurs more frequently in older women. The 5-year survival overall is approximately 40%,50 but this may be due to the older age of the patients and the fact that clear cell carcinomas are generally found in patients with higher stages of cancer. Clear cells often appear in histologic mixtures when tumors are assigned to a different category on the basis of the prevalent cell type, and their presence usually confers a diminished prognosis.

Diagnosis

The median age for patients with adenocarcinoma of the endometrium is 61 years, with the largest number of women developing their cancers during the sixth decade. Only 5% develop adenocarcinomas before the age of 40 years, and these are usually women with the abnormal syndromes previously discussed. Eighty percent of patients have experienced menopause, and only 20% are diagnosed before they stop menstruating. Irregular or postmenopausal bleeding is the presenting symptom in at least 75% of patients, and at the time of diagnosis, 75% of patients have disease confined to the uterus. Thus, it is obvious that irregular bleeding is a critical symptom, and by explaining it histologically, one has an opportunity to identify endometrial cancer when it is highly curable by relatively uncomplicated therapy.

The traditional technique for diagnosis has been fractional dilation and curettage of the uterus, with careful sampling of both the endometrial cavity and the endocervical canal. Once a procedure for the hospital operating room, this is now performed with increasing frequency as an office procedure. There will always be patients who require general anesthesia in a hospital setting, however, either because of very low pain thresholds, cervical stenosis, or other intercurrent ailments.

Early diagnosis can be achieved by the intrauterine insertion of narrow cannulas, usually one with an outside diameter of less than 3.5 mm. The instrument can be inserted even through an undilated cervix so that suction retrieval of cytologic or histologic material can be accomplished. Several investigators51,52 have demonstrated a high sensitivity and specificity (greater than 95% accuracy) when employing these techniques.53 If specimens are inadequate or the cervix is stenotic, formal curettage under anesthesia is indicated.

Techniques for retrieving cytologic material through even smaller cannulas have been perfected, and if cytologic material is preserved in Bouin’s solution, cellular abnormalities are readily detectable.

Hysteroscopy, either by direct observation or with video-camera amplification, allows direct assessment of the topography of the endometrial cavity with the possibility for more selective sampling. Many reserve this procedure as an accompaniment to formal dilation and curettage under anesthesia. Also, hysteroscopic dissemination of malignant cells has been described in the literature.54–57

Noninvasive radiographic imaging techniques, such as magnetic resonance imaging (MRI)58,59 and ultrasonography60,61 are not cost effective for screening. However, these techniques can achieve an accuracy rate above 80%, accurately measure disease volume, and, on the basis of grade of tumor and volume of disease, predict probabilities of extrauterine spread of tumor.

Staging

Historically, endometrial cancer staging was a clinical exercise, based on physical examination, noninvasive radiographic testing, and measurement of the depth of the uterine cavity. One can see from Table 113.3 that clinical staging for those with a large uterus very likely would be inaccurate and would lead to understaging, and possibly undertreating, a significant proportion of the stage I cancers. When tumor grade was identified as an important prognostic feature, many therapists argued for a staging system that would permit consideration of the histologic prognostic variables since a biopsy or curettage was required even to make the diagnosis. In 1971, tumor grade was officially incorporated into the staging system. During this same era, the Gynecologic Oncology Group (GOG) inaugurated a pilot study to perform staging laparotomy in the course of initial surgical treatment of patients with clinical stage I endometrial carcinoma.62 This study noted that 16 of 140 patients evaluated had cancer in their lymph nodes, despite the fact that they had early-stage disease by preoperative clinical evaluation. In a subsequent expansion of this pilot study,63,64 it was noted that 9.6% of 843 patients in clinical stage I had lymph node metastasis. In addition, extensive surgical staging detects extrauterine disease in 23.2% of patients with apparent preoperative clinical stage I disease.65 These observations strengthened the impetus for more precise staging, and in 1988, the International Federation of Gynecology and Obstetrics (FIGO) introduced the requirement for surgical staging of patients with endometrial carcinoma.

Table 113.3. Definitions of the Clinical Stages in Carcinoma ofthe Corpus Uteri*.

Table 113.3

Definitions of the Clinical Stages in Carcinoma ofthe Corpus Uteri*.

The latest modifications of the surgical staging system were promulgated in 1994 to 1995 and may be seen in Tables 113.4 and 113.5. This system requires the performance of total abdominal hysterectomy, bilateral salpingo-oophorectomy, washings for cytologic examination, lymph node sampling from the pelvic and para-aortic lymph nodes for those patients whose histology and depth of myometrial penetration (determined during the operation) are other than well-differentiated tumors with minimal myometrial penetration, and biopsies of any suspicious areas. Employing the updated FIGO staging system, a recent report described disease-free survival as 90% for stage I, 83% for stage II, and 43% for stage III.66 When surgical staging has been completed, it becomes the strongest predictor of survival. Univariate analysis reveals that 5-year survival for patients in surgical stage IA is 93.8%, in stage 1B, 95.4%, and in stage 1C, 75%.67

Table 113.4. Staging for Corpus Uteri Carcinoma.

Table 113.4

Staging for Corpus Uteri Carcinoma.

Table 113.5. Histopathology: Degree of Differentiation.

Table 113.5

Histopathology: Degree of Differentiation.

The adoption of a surgical staging system has created controversy regarding what constitutes an adequate staging procedure, which patients should be surgically staged, and whether extensive staging or lymphadenectomy has therapeutic value.65 Recent studies have helped provide answers to these questions. Current data indicate that retroperitoneal palpation contributes little toward accurate retroperitoneal evaluation, particularly in obese patients.64,68 Also, selective sampling on the basis of nodal enlargement does not appear effective, given the fact that nearly half the diagnosed lymph node metastases in one study occurred in nodes that were less than 1 cm.69 Selective pelvic and para-aortic lymphadenectomy refers to removal or biopsy of some but not all lymph nodes within the external iliac, internal iliac, obturator, hypogastric, and common iliac groups, as well as the para-aortic groups.70 Adverse risk factors necessitating lymph node dissection include G2 or G3 lesions with > 50% myoinvasion; clear cell, papillary serous, and squamous and undifferentiated cell types; adnexal metastasis; lymph-vascular space invasion and/or cervical invasion; > 50% of uterine cavity involved; and suspicious nodes.71

The therapeutic benefit of node dissection has been described by several investigators.68,72–74 Most recently, Trimble and co-workers75 reported on the impact of pelvic node sampling in 10,066 women with stage I and II endometrioid adenocarcinoma from the National Cancer Institute SEER program. They found an improved 5-year relative survival only in patients with stage I, grade 3 tumors. However, data on adjuvant postsurgical treatment were not available in this population.

Prognostic Factors

In a GOG study, 1,180 patients with clinical stage I or II endometrial carcinoma were studied by surgical-pathologic staging.76 Of this group, 895 patients were evaluable not only for all the parameters derived from surgical staging but also for follow-up from postoperative treatment to recurrence, with documentation of recurrence site. From this experience and the other previously cited interim GOG reports of surgical staging outcome, one can appreciate those factors that are predictive of extrauterine spread of disease at the time of initial diagnosis and those factors that correlate with ultimate survival.

Surgical stage and age are highly significant prognostic features that maintain their significance in each of the analyses performed in the various reports.

Histologic Cell Type

Whereas 80 to 95% of endometrial cancers are classic endometrioid adenocarcinomas, the remainder constitute a series of cell types with a more unfavorable prognosis. These include serous papillary adenocarcinoma, and clear cell, undifferentiated, and squamous cancers. These cell types confer an unfavorable prognosis, independent of other known prognostic factors.77

Grade

Within classic endometrioid adenocarcinomas, tumor grade is highly significant as an independent prognostic factor. Additionally, numerous studies have demonstrated that, in general, there is a greater tendency for the less-differentiated tumors to be associated with other poor prognostic factors, including deep myometrial penetration, vascular space invasion, and increasing stage (Table 113.6).76,78–81 Recently, Salvesen and co-workers82 have shown that morphometric nuclear grade was a stronger prognostic factor than subjective histologic grade. Further studies will be needed to confirm the significance of these findings.

Table 113.6. Proportional-Hazard Modeling of Recurrence-Free Interval.

Table 113.6

Proportional-Hazard Modeling of Recurrence-Free Interval.

Myometrial Invasion

The depth of myometrial penetration is a very important independent prognostic factor for outcome in stage I disease. Deeper penetration is associated with higher probabilities of tumor recurrence and death.76,78,83,84 While increasing depth of invasion correlates with increasing grade of tumor, depth appears to be a more significant prognostic factor and predicts for the presence of extrauterine disease as detected at surgical staging procedures.64 Regardless of grade, however, only 1% of patients with disease confined to the endometrium have extrauterine disease as compared with patients with deep muscle invasion, where the incidence of pelvic node invasion rises to 17% and para-aortic nodal involvement rises to 25%.64 DiSaia and colleagues found that patients with only endometrial involvement had an 8% recurrence rate as compared with 12% if there was superficial or intermediate myometrial invasion versus 46% if there is involvement of the outer third of the myometrium.83

Both relative and absolute measures of the degree of myometrial invasion have been used. While it is clear from a number of studies that involvement of the uterine serosa is an extremely bad prognostic sign,85 some difficulties arise in attempting to compare reports with absolute distances from the serosa versus those with relative degrees of penetration into muscle, since the thickness of the myometrium varies from patient to patient. The current FIGO staging classification requires uterine thickness to be measured as less than or greater than invasion of 50% of the myometrial thickness.

Capillary–Lymphatic Space Invasion

Vascular space invasion is a significant risk factor for recurrence, but it is not as important as the grade and depth of myometrial penetration. About 15% of endometrial adenocarcinomas invade capillary-like spaces.64,86,87 There is a significantly increased probability of pelvic and para-aortic lymph node invasion when this happens. Where the capillary-like spaces are involved, pelvic and para-aortic lymph nodes are also involved in 27% and 19% of cases, respectively, representing about a five-fold increase over those without such involvement.

Positive Peritoneal Cytology

The presence of positive peritoneal cytology in washings is associated with an increased risk of relapse.76 About 15% of patients have positive peritoneal cytology, and this is often related to other poor prognostic factors, such as high grade or deep myometrial penetration. Thus, it is not surprising that it is also associated with an increased risk for metastases to pelvic and para-aortic lymph nodes. Opinions and data in the literature conflict with respect to interpreting the independent prognostic significance of peritoneal cytology. About 5% of patients with positive peritoneal cytology have no evidence of extrauterine disease,64 but about one-third of patients with extrauterine disease do have positive cytology.

Unfortunately, there has been no study correlating the sites of relapse with the presence or absence of positive peritoneal cytology. That positive cytology, independent of other bad prognostic features, conferred a worse prognosis would be more convincing if one could associate an increased risk of peritoneal and upper abdominal relapse in patients with positive cytology as compared with those without. Two large series suggest that positive peritoneal cytology may be a poor independent prognostic factor,88,89 but several small series and one review report that there are no outcome differences between those with positive peritoneal cytology and those without.90–93

Liu and colleagues recently reviewed the treatment patterns, risk factors, and survival of 219 patients treated surgically for endometrial cancer between 1990 and 1993.94 Clinicopathologic features were tabulated and the interval between the onset of abnormal uterine bleeding and therapy was noted. In this study, African American women, when compared with Caucasian women, had a higher incidence of unfavorable histology (38% versus 12%), advanced-stage disease (51% versus 19%), poor differentiation (49% versus 18%), and poor survival. There was no delay between onset of bleeding and hysterectomy in the two groups. Even when corrected for hormone use, these differences persisted. From this study, it may be concluded that African American women face a poorer prognosis for survival from endometrial cancer than do their Caucasian counterparts.

Hormone Receptor Status

The presence of cytoplasmic estrogen receptor (ER)– and progesterone receptor (PR)– binding proteins has been quantitatively associated with histologic differentiation95 and with response to therapy.96 Of the early large studies evaluating receptor status as a prognosticator in patients with endometrial cancer, 217 patients with clinical stage I and II endometrial cancer were available for analysis.88 In these patients, receptor status and histology were available, and 130 patients underwent full surgical staging so that lymph node status was known. In every analysis, the presence of ER and PR was significantly associated with better histologic differentiation and histologic subtype.

The receptor content was present and higher in well-differentiated lesions, and the receptors occurred less frequently in tumors with virulent histology, that is, the nonendometrioid carcinomas. The analysis of combined ER/PR and separated ER and PR revealed that patients with receptor-positive lesions had better disease-free survival rates than did those with no identifiable receptors. A stepwise proportional hazards regression analysis identified these predictors as independent factors.

Tumor Ploidy and Kinetics

Although tumor ploidy in endometrial cancer has been widely studied, the results are conflicting. Approximately 65% of these cancers are determined to be diploid by flow cytometry. In general, diploid patterns occur in the better-differentiated tumors. In one study, flow cytometry measurements of RNA, S-phase fraction, DNA index, and proliferative index were conducted on the tissues from 140 specimens.97 Only in 19% of patients was advanced disease predicted on the basis of clinical evaluation. However, 40% of patients with advanced disease were found to be aneuploid, 69% had high S-phase fraction, and 69% had a proliferative index greater than 14%.97

The nuclear Ki-67 antigen, which is expressed in all stages of the cell cycle except G0, may be detected by immunohistochemistry to estimate the proliferative activity in tumors. Salvesen and co-workers98 observed that Ki-67 expression was significantly higher among patients with FIGO stage III/IV disease, clear cell or serous papillary histology types, and poor histologic grade. Ki-67 expression was significantly related to survival.

Refinements of this approach may hold great promise for prognostic assessment.

Oncogene activation and Loss of Tumor Suppressor Function

The molecular events involved in the pathogenesis of endometrial carcinoma are poorly defined; however, several aspects of the molecular pathology of this disease have recently been elucidated. Mutations in the p53 tumor suppressor gene leading to overexpression of mutant p53 protein are the most common molecular alterations described in human cancers to date.99 Between 4 and 49% of endometrioid carcinomas99-113 and 71.4 and 100% of serous carcinomas103,105,107,111,114,115 overexpress p53 protein. Of note, p53 protein overexpression has been demonstrated in 10 to 15% of early-stage disease99,115,116 and 40 to 50% of advanced-stage disease,99,102 but does not occur in endometrial hyperplasia.99,107,108 This suggests that p53 mutation may be a late event in the histogenesis of endometrial carcinoma99,107,108 or that acquisition of a p53 mutation leads to the development of a virulent endometrial cancer that does not pass through a phase of hyperplasia as postulated by Berchuck and co-workers.117 Several studies have demonstrated a positive association between p53 overexpression and high nuclear grade101,104,105,110,118 and FIGO stage,102 though these have not been universal findings.104,110,113,119 In addition, overexpression of p53 is independently associated with poor survival.102,105,120,121 For example, Kohler and co-workers102 observed a median survival of 6.1 years in patients whose tumors did not overexpress p53 in comparison with a median survival of 1.4 years in patients whose tumors overexpressed p53.

The ras family of G-proteins (N, H, K-ras) play a critical role in the regulation of cellular proliferation.117 The most frequent site of mutation of the K-ras oncogene in endometrial carcinoma is codon 12. However, there does not appear to be a significant relationship between K-ras mutation and survival in endometrial cancer.122–125

The HER-2/neu gene encodes for a tyrosine kinase receptor that is activated following binding of the ligand heregulin.117 Several studies suggest that this oncogene product is overexpressed in 10 to 15% of endometrial cancers.126–132 Herzel and co-workers,128 in an immunohistochemical analysis of 247 patients with endometrial cancer, observed strong staining in 37 patients (15%), mild staining in 144 (58%), and no staining in 66 (27%) patients. The 5-year progression-free survival was 56% for the strong staining, 83% for the mild staining, and 95% for the nonstaining groups. Strong overexpression was associated with a poor (51%) overall survival. Likewise, Lukes and co-workers126 found high expression in 12% of patients. Overexpression was more common in stage III and IV patients (24%) than in stage I or II patients (6%) and was associated with poor progression-free survival in univariate analysis. However, in multivariate analysis, HER-2/neu was found to be an independent variable only if DNA ploidy was excluded from the statistical model.

PTEN (phosphate and tensin homologue deleted on chromosome ten) is a candidate tumor suppressor gene that has been isolated from the 10q23-24 region.100 Risinger and co-workers133 identified PTEN mutations in 34% of 70 endometrial carcinoma specimens. The tumors in which PTEN was mutated did not have a unique clinical phenotype. Mutations were seen in 32% of cases in which the tumor was confined to the uterus and 24% of cases with metastatic disease. The frequency of PTEN mutations described by these investigators was several-fold higher than that described for any other gene mutated in endometrial cancers, including K-ras and p53, making the PTEN mutation the most common defined genetic alteration identified to date in endometrial cancers.

Microsatellite instability is one of the major mechanisms of cancer susceptibility and has been identified in 17 to 43% of endometrial carcinomas.100,103,133–136 Microsatellite instability was initially noted in colorectal patients with hereditary nonpolyposis colorectal cancer (HNPCC). Risinger and co-workers136 observed microsatellite instability in 17% of sporadic endometrial carcinomas and in 75% of those associated with HNPCC. Of note, the sporadic endometrial carcinomas displaying microsatellite instability were all stage I adenocarcinomas with diploid or near-diploid DNA content, indicating these tumors are from clinical type 1 patients.136

Deligdisch and Holinka38 classified endometrial carcinoma into type 1, which is associated with unopposed estrogen, good differentiation, endometrioid histology, early stage, and favorable prognosis; and type 2, which is associated with older age, poor differentiation, nonendometrioid histology, advanced stage, and unfavorable prognosis. The studies discussed above suggest this clinical classification can be expanded to include molecular features associated with type 1 and type 2 endometrial carcinomas.(Berchuck A. Personal communication). These molecular features are illustrated in Table 113.7.

Table 113.7. Clinical and Molecular Features of Endometrial Carcinoma.

Table 113.7

Clinical and Molecular Features of Endometrial Carcinoma.

Treatment of Primary Disease

Surgery

The initial surgical staging procedure, outlined earlier, is the standard therapeutic procedure as well. When there is disease outside the uterus and in the retroperitoneal nodes, there is no reason to believe that aggressive cytoreductive efforts might not help in presenting a reduced tumor burden during adjunctive therapy, despite the absence of a clinical trial suggesting efficacy.

There are occasions when, at the time of staging laparotomy, cervical or parametrial invasion is detected and radical (Wertheim’s) hysterectomy with pelvic and aortic lymphadenectomy is performed in order to achieve clearance of all disease. However, the addition of tailored external beam radiation therapy following surgery has largely eliminated the routine performance of such procedures.

Surgery for recurrent disease is generally confined to those patients who have symptoms of intestinal or urinary tract obstruction, isolated regional recurrence, or isolated lung metastases that have not responded to cytotoxic or hormonal therapy. For such patients, surgery may be useful to correct functional deficits or to excise isolated recurrences or resistant metastatic deposits.

The first reports of surgical staging of endometrial carcinoma with the use of laparoscopy-assisted vaginal hysterectomy and laparoscopic lymphadenectomy were in 1992.137,138 Since that time, several reports have included laparoscopic bilateral para-aortic lymph node dissections.139,140 However, no randomized clinical trials have been performed comparing laparoscopic management of endometrial carcinoma with traditional surgical therapy. The GOG is currently conducting a prospective phase III study comparing laparoscopy-assisted surgical staging with traditional total abdominal hysterectomy and staging. In addition to assessing variables, such as completeness of surgical staging, complications, operating room time, and hospital stay, this study will also evaluate expanded outcome variables, including patient-reported measures of quality of life.

An algorithm for the surgical management of endometrial carcinoma is presented in Fig. 113.4.

Figure 113.4. Surgical management of endometrial carcinoma.

Figure 113.4

Surgical management of endometrial carcinoma. * > 50% myoinvasion, clear cell or papillary serous histology, adnexal metastasis, lymphvascular space invasion and/or cervical invasion, > 50% uterine cavity involved, suspicious nodes. Adapted (more...)

Radiation Therapy

While surgery, where possible, constitutes the definitive treatment for most patients with endometrial carcinoma, it is clear that radiation therapy is the second most effective modality in its management. The literature does not provide definitive data to elucidate the role of radiation therapy in management. However, we have been better able to rationalize the use of radiotherapy because of a growing body of observational information delineating groups at different risks of relapse after definitive primary surgery. Furthermore, an understanding of the patterns of failure following surgery alone, as well as knowing the sites of occult extrauterine disease with clinical stage I and stage II endometrial cancer, have provided a better understanding of the settings in which adjuvant treatment, such as radiotherapy, hormone therapy, or chemotherapy, should be tested in future clinical trials.

Definitive Irradiation for Inoperable Patients

Modern surgical techniques and improved postoperative care have diminished the number of patients considered inoperable. Nevertheless, since endometrial cancer is a disease of elderly, often obese, and sometimes diabetic women with intercurrent ailments, surgery is not always possible. Table 113.8 shows three relatively large series141–143 in which patients received pelvic radiation therapy as their definitive management without initial surgery.

Table 113.8. Primary Radiotherapy as Definitive Management of Inoperable Clinical Stage I Cancer of the Endometrium.

Table 113.8

Primary Radiotherapy as Definitive Management of Inoperable Clinical Stage I Cancer of the Endometrium.

The proportion surviving depends on tumor grade, just as for patients treated surgically; those with grade 1 tumors have better survivals than do those with grade 3. Significant numbers of patients die of causes unrelated to their primary carcinoma.

Some patients with small uteri may have their disease adequately irradiated by intracavitary radiation only, but usually definitive management consists of both external beam and intracavitary irradiation because of more favorable radiation dosimetry. Complication rates are acceptable (usually less than 10%). After definitive irradiation, the pattern of failure, in contrast to that following surgery, consists mainly of central failure in the uterus. This observation is important for developing treatment strategies for patients with stage II disease. Removal of the uterus at some point in treatment provides better overall central control than that achieved by radiation alone.

Recently, Kucera and co-workers144 reported their experience with high-dose iridium-192 intracavitary brachytherapy without additional external beam radiation. At 5 years, the overall survival rate was 59.7%. In clinical stage IA disease, survival was 88.6% at 5 years and 82.7% at 10 years, significantly different in comparison with 80.2% and 63.4%, respectively, in stage IB disease. Intrauterine recurrence was 17.5%, but extrauterine pelvic relapse occurred in only 0.4% of patients.

Adjuvant Radiation Therapy for Stage I Disease

For the majority of patients who are medically operable, radiation therapy plays an adjuvant role. It is important to distinguish between patients with clinical stage I disease, where decisions for postoperative adjuvant therapy are made on the probability of extrauterine diseases being present and those with FIGO stage I or surgical stage I cancer, where surgery and pathology have excluded extrauterine disease.

Adjuvant radiation therapy has been used in the past in clinical stage I disease for patients believed to be at high risk for relapse following bilateral salpingo-oophorectomy and hysterectomy. Historically, most patients with endometrial cancer received preoperative intracavitary irradiation or postoperative vault irradiation, but the use of external beam irradiation was reserved for those considered at high risk.

The present recommendation to give postoperative radiation therapy in clinical stage I is dependent on prognosis as defined by the histologic features of the primary tumor within the endometrium. Extensive staging studies have identified that several of the aforementioned factors predict for the presence of clinically occult extrauterine disease.76

While patients considered to be at high risk for recurrence (e.g., those with grade 2 or 3 disease with penetration of the outer 50% of the myometrium) have generally been treated with postoperative adjuvant radiation therapy, only one randomized trial has examined its contribution to outcome. Aalders78 reported that 540 patients with clinical stage I endometrial cancer were treated by abdominal hysterectomy and bilateral salpingo-oophorectomy and 60 Gy to the vaginal vault postoperatively. Patients were then randomized to either no further therapy or external beam pelvic radiation in a dose of 40 Gy in 20 fractions over 4 weeks. The dose to the midline was minimized with a midline block introduced at a tumor dose of 20 Gy. Approximately half the patients (261) were considered to be in the high-risk category, with greater than 50% myometrial penetration of any grade, or grade 3 tumors with any degree of invasion. The study showed no improvement in overall survival, death, or recurrence rates for the whole group. Pelvic relapse rates were reduced by approximately 60% in the high-risk group, however. A separate subset analysis of the high-risk patients suggested a survival benefit of approximately 12%.

One of the deficits of postoperative adjuvant pelvic irradiation in the high-risk group is that these patients with grade 2 and grade 3 tumors involving the outer third of the myometrium are also most likely to have para-aortic node metastases. Thus, it is likely that the only patients who are cured by adjuvant pelvic irradiation are those with disease confined to the pelvis, usually in the pelvic sidewall nodes. In most series, it is estimated that only 15 to 20% of stage I patients fall into this high-risk category of patients for whom external beam radiation therapy is recommended. The majority of patients with clinical stage I endometrial cancer have low-grade tumors with less than 50% myometrial penetration. Estimates from careful GOG clinical pathologic staging studies64 suggest that the risk of extrauterine disease in these low-risk patients is probably less than 5 to 7%, and outcome is unlikely to be improved by the addition of pelvic irradiation. Thus, there would appear to be no data to support the use of any adjuvant irradiation, be it preoperative intracavitary, postoperative vault, or external beam therapy, in patients with low-risk clinical stage I disease.

Vault Irradiation

Although it has been standard practice to use preoperative intracavitary radiation or postoperative vaginal cuff irradiation for most patients, data and opinions are mixed as to whether this is beneficial. Preoperative irradiation has been largely abandoned. Staging studies indicate that approximately 80% of patients fall into the low-risk category and have such a small probability of relapse that intracavitary irradiation is unlikely to change it. Current practice for those who use vaginal vault irradiation is to advise its use in patients with demonstrated extrauterine disease or deep myometrial penetration, or high-grade lesions without demonstrated extrauterine disease. Unfortunately, no study has documented the pathologic risk factors for isolated vaginal vault recurrence. In general, the majority of patients who are at risk for vault relapse are also at risk for recurrence throughout the pelvis. Thus, if there is a tiny subgroup of patients at risk for vaginal vault recurrence alone, they have not been identified. It is difficult to conceive of a situation where vault irradiation alone, with minimal penetration of radiation dose below the mucosa, is sufficient to prevent pelvic recurrence. Although retrospective studies have shown a decrease in vault recurrence with the use of vaginal cuff irradiation, it is unclear as to which, if any, patients should receive this treatment alone.

In a nonrandomized study by the GOG, 78 of 766 patients received postoperative vaginal irradiation.76 Only 3 of the 78 patients had subsequent recurrence of disease. We can infer that the risk of recurrence was so low that it is hard to justify the employment of cuff irradiation in this group. Of the 766 patients, 368 received external beam therapy, and in this group, 26% relapsed (95 of 368). Only 7 (2%), had a component of vaginal relapse, however. Thus, it is unlikely that vaginal vault irradiation contributes significantly to pelvic control, when added to external beam irradiation.

More recently, a study from Roswell Park145 reported on the use of vaginal brachytherapy in 303 patients with stage I endometrial carcinoma, grade 1-2 with < 50% myometrial invasion, treated with hysterectomy without formal staging and pelvic or para-aortic lymph node sampling. No vaginal recurrences occurred, and the 5-, 10-, 20- and 30-year disease-free survivals were 98.9%, 97.8%, 96.7%, and 96.7%, respectively.

Indications for Adjuvant Therapy for Surgically Staged Patients

Surgical Stage I

Within the sensitivity of the surgical staging procedure, patients with pathologically proven stage I disease have no evidence of extrauterine disease. The indications for adjuvant radiation therapy in this circumstance are not settled. While it is recognized that patients with low-grade tumors with less than 50% myometrial penetration have a very low risk of recurrence, for patients with high-grade lesions and/or deep myometrial penetration without identified extrauterine disease at surgical exploration, the magnitude of risk for recurrence is unclear. Thus, where it is known that there is no microscopic involvement of the pelvic nodes, the degree of risk for relapse is uncertain. Similarly, it is uncertain whether these patients benefit from postoperative pelvic irradiation. Patients with negative extrauterine findings but high-risk factors in the uterus have been designated by the GOG as intermediate risk.

The GOG recently completed a phase III randomized trial of no additional treatment versus 5,040 rad of pelvic radiotherapy in patients with intermediate-risk endometrial cancer.146 The median follow-up for the study was 56 months. There have been 39 recurrences and 52 deaths among these women; 56% of these deaths were the result of disease or treatment. The estimated progression-free interval rate was 88% in the no-additional-therapy arm, significantly different from the 96% observed in the whole-pelvic-radiation-therapy arm. Radiation had the most impact on local and regional (vaginal and pelvic) recurrences. There were 17 pelvic/vaginal recurrences in the no-treatment arm versus 3 in the radiation arm (2 of whom refused adjunctive radiation therapy). However, since these pelvic recurrences are often effectively treated with second-line therapy, survival was not statistically significant between the two groups.

The surgical staging study of the GOG76 has demonstrated that it is patients with clinical stage I and II disease with grade 2 and grade 3 tumors involving the outer third of the myometrium who constitute the majority of those with involved para-aortic nodes. These high-risk patients have a 17% incidence of para-aortic nodal invasion and a 22% incidence of positive pelvic cytology or adnexal involvement. Thus, while the overall risk of involvement of the para-aortic nodes in clinical stage I is only 4 to 6%, the risk for patients with outer-third myometrial involvement is 17 to 18%. Although pelvic radiation has been the standard, consideration should be given to the use of whole abdominal irradiation with para-aortic nodal boost in high-risk patients, clinical stage I or surgically staged patients with microscopic para-aortic nodal involvement (FIGO stage III). It is the involvement of the upper abdomen in a significant proportion of patients that decreases the probability that adjuvant pelvic irradiation will be of curative benefit. The opportunity thus exists for exploring the curative benefit of radiation, if predicted or known sites of microscopic disease are encompassed in the treatment volume.

Clinical Stage II

The optimal treatment for patients with clinical stage II disease is somewhat controversial. The probable sites of microscopic involvement of extrauterine structures and the relative efficacies of radiation and surgery in controlling central disease in the uterus and microscopic parametrial and pelvic nodal disease are the critical factors in developing rational treatment policies. The patient with clinical stage II disease has significant risk (just as the patient with a primary invasive cervical cancer has) for occult paracervical and parametrial disease, as well as pelvic nodal disease. In addition, these patients have an increased risk for para-aortic and upper abdominal disease.

Optimizing therapy for patients with clinical stage II disease includes exploiting the differing efficacies of radiation and surgery. Both modalities of treatment, therefore, are used. There have been no prospective studies to determine the optimal combinations of radiation and surgery. The principles of combining the two modalities are to use radiation therapy to sterilize occult parametrial and pelvic nodal disease and to treat the cervical component of disease. Given that surgery provides better control of central uterine disease, if the patient is medically operable and the disease is small enough in the cervix to be removed surgically, then hysterectomy is performed to control central disease.

Thus, common treatment schemes employ the use of preoperative external beam irradiation, which usually results in diminution of the volume of cervical disease. This may then be followed by bilateral salpingo-oophorectomy and hysterectomy. If, however, the cervical component of the tumor is very bulky and tumor shrinkage is less than optimal, consideration may be given to using intracavitary irradiation further to shrink the cervical component of the tumor. While there are no good data, there is concern that the addition of intracavitary irradiation prior to surgery may increase the risk of complications. This risk will be significantly compounded if a more radical hysterectomy is required to remove disease completely after prior treatment by both external beam and intracavitary irradiation. For the patient in whom hysterectomy can be performed, intracavitary irradiation contributes little to the control of disease in the uterine body. This is partially so because of the technical inability to irradiate the myometrium adequately. A central uterine stem with a line source of radiation does not adequately treat a relatively or markedly enlarged uterus. Surgical removal of the uterus is much more effective in controlling central disease. Thus, use of intracavitary radiation should probably be reserved for the patient with a very bulky cervix that has not responded to external beam irradiation. Intracavitary radiation may then improve the probability of more complete surgical clearance.114–117 Survival rates range between 70 and 85% for therapies combining radiation and surgery.

Given the fact that patients with lower pole disease (isthmus and cervix) have an increased risk of para-aortic and upper abdominal disease, there may be utility in exploring the para-aortic nodes at the time of surgery, or even before pelvic irradiation, to determine the need for upper abdominal and para-aortic irradiation.

For the small proportion of patients who may be medically inoperable, definitive irradiation usually with both external beam and intracavitary treatment, may be curative. Cure rates are clearly inferior when the uterus is not removed, and this is probably related to residual active disease in the uterine body. Three series,141,148,151 indicate 5-year survival rates of about 50%.

Stage III

The 1971 FIGO clinical staging for endometrial carcinoma defines stage III as disease that has extended outside the uterus but not outside the true pelvis. Since the 1988 FIGO surgical staging for endometrial cancer appeared, the IIIC classification now includes patients with metastases to pelvic and/or para-aortic lymph nodes. The current staging classification covers a broad spectrum of prognostic groups that have diverse outcomes after standard surgery plus or minus adjuvant pelvic irradiation. Unfortunately, many of the published series include patients with microscopic extension to the adnexae (IIIA), those with malignant ascites (IIIA), and those with gross pelvic side wall disease (IIIA or IIIC) without distinction, resulting in widely variable survival data. In a series reported by Grigsby and colleagues,152 the 5-year progression-free survival for 22 patients treated with radiation alone was 42%. Aalders and colleagues153 reported a 5-year survival rate of 40% for patients with surgical/pathologic stage III disease, compared with 16% for patients with clinical stage III disease. Similarly, Bruckman and colleagues154 and MacKillop and Pringle155 report 5-year survivals of 80 to 85% when only the ovary and/or fallopian tube was involved, compared with 15% when other extrauterine pelvic structures were affected. Since patients with occult adnexal involvement as the only site of extrauterine disease were often treated with pelvic irradiation, it is impossible to know whether and in what proportion patients with adnexal spread were cured with surgery alone, and whether they have a propensity for upper abdominal disease, such as primary ovarian cancers, and could benefit from wider-field irradiation.

It is impossible to conclude from the literature what the optimal therapy is for various sites of disease within stage III. Different observers have employed surgery and radiation, alone or in combination. Greven and colleagues156 reported the results of therapy for 52 patients with clinical stage III disease with protracted median survivals for those undergoing both radiation and surgery, compared with those treated with radiation alone. Survival rates of approximately 27% have been reported in small groups of patients with stage III disease.157,158

Treatment recommendations at this time for patients with stage III disease must be made on an ad hoc basis. Those in whom appropriate surgical staging has been completed without evidence of disease beyond the ovaries should be considered for adjuvant postoperative pelvic irradiation. Since the role of microscopic adnexal invasion in patients without other risk factors is unclear, it is also unclear whether such patients benefit from adjuvant therapy. It would not be unreasonable to consider the patient with additional high-risk factors, such as high-grade or deep myometrial penetration, for whole abdominopelvic irradiation. For those who have had surgical staging and have pelvic but not para-aortic nodal involvement, it may be appropriate to offer postoperative adjuvant irradiation confined to the pelvis. For those with positive peritoneal cytology and/or para-aortic nodal disease, consideration should be given to whole abdominopelvic irradiation with a para-aortic nodal boost. Table 113.9 reveals disease-free survival rates between 35 and 60% for patients receiving 45 to 50 Gy of external beam irradiation to the para-aortic nodes, usually with pelvic irradiation. In almost no case is macroscopic para-aortic nodal disease curable with radiation therapy.76,159–164

Table 113.9. Results of Para-aortic Radiotherapy in Endometrial Cancer.

Table 113.9

Results of Para-aortic Radiotherapy in Endometrial Cancer.

For patients with gross parametrial or side wall disease at presentation, cure rates are usually less than 10 to 15%.153,165 These patients are usually treated with radiotherapy alone, and if disease shrinkage is total or the residuum is only in the uterus, it may be worthwhile to attempt to complete a hysterectomy if residual disease can be removed completely. However, in a series of 101 patients with clinical stage III disease treated at the Norwegian Radium Hospital, 66 received radiation alone and 35 received combined surgery and irradiation.153 The overall 5-year survival rate was 16%, and no apparent differences were detected between those receiving irradiation and those receiving combined therapy, although the groups may have had inherently different tumor prognostic factors.

An algorithm for the postoperative management of endometrial carcinoma is presented in Fig. 113.5.

Figure 113.5. Postoperative management of endometrial carcinoma.

Figure 113.5

Postoperative management of endometrial carcinoma. Adapted from Morrow and Curin.

Treatment of Recurrent Disease

While most patients with disease recurrence after primary therapy are incurable, there is a subset of patients treated with surgery only who have recurrence confined to the pelvis that may be cured with appropriate radical pelvic irradiation. Several series have documented a substantial fraction of patients surviving disease free, when so treated. In general, the probability of long-term disease-free survival depends on the extent of pelvic disease at the time of relapse and also probably on the dose of radiation employed. In a series from Toronto,166 54 patients with recurrent endometrial carcinoma were identified from a retrospective review of charts of 304 endometrial cancer patients seen between 1983 and 1989. Forty percent of the entire recurrent population are long-term survivors. Of the 54 relapsing patients, primary therapy had been surgery alone in 32 and surgery and adjuvant radiotherapy in 22. Isolated pelvic recurrence was the predominate relapse site in those who had not received adjuvant pelvic radiation therapy as primary therapy (23 of 32, or 72%). Distant relapse predominated in those who received adjuvant radiation therapy (17 of 22, or 77%). Twenty-eight (54%) failed in the pelvis alone, and 26 (46%) had a component of distant failure. Of the 28 with isolated pelvic relapse, 16 had vaginal mucosal disease involvement only, and 12 had disease in the parametrium and/or the pelvic side wall. With a minimum follow-up of 5 years for the survivors, 21 of the 28 with isolated pelvic relapse received radical radiotherapy, and 14 (67%) had maintained pelvic control until death or last follow-up. Eleven of 14 (79%) with disease confined to the mucosa had pelvic control, whereas only 3 of 7 (43%) with extramucosal disease were controlled. No patient experienced major treatment-related toxicity. In an analysis of prognostic factors, only the anatomic extent of pelvic recurrence showed a nonstatistically significant trend as a predictor for control with p = .08. The authors concluded that a significant fraction of patients with disease recurrence confined to the pelvis can be rendered disease free in the long term with maintained pelvic control. Of interest in the overall series of 54 patients was the observed pattern of failure in the remaining patients, 30% of whom had upper abdominal or para-aortic nodal disease as the only site of failure. This pattern of failure strongly suggests that there may be a role for upper abdominal and para-aortic nodal irradiation as adjuvant therapy. This might prevent upper abdominal failure for some classes of stage I and stage II patients predicted to be at high risk for, or identified to have, occult or small-volume upper abdominal disease.

Other retrospective reviews substantiate the curability of patients with isolated vaginal recurrence. In the report from the Mallinckrodt Institute,167 the 5-year progression-free survival for patients with isolated vaginal recurrence was 40%, compared with a 20% survival for those with more extensive pelvic disease. Similarly, Poulsen and Roberts168 demonstrated a 10-year survival of 45% in those with vaginal disease only, as compared with 24% for those with more extensive pelvic disease.

In the patient who has had initial adjuvant postoperative pelvic irradiation, there may rarely be a role for interstitial therapy at relapse, if there is isolated central pelvic failure. For patients with other sites of disease or bony, cerebral, or nodal metastases, short courses of palliative irradiation may be useful in relieving symptoms of disease. Similarly, palliative irradiation may be used for the uncommon patient (approximately 3% of those at presentation) who has stage IV disease.

Unlike ovarian carcinoma, little is known regarding the role of secondary cytoreduction in recurrent endometrial carcinoma. Recently, 20 women with recurrent endometrial adenocarcinoma were treated with maximal cytoreductive surgery.169 Sixty-five percent of patients had complete resection of their tumor. Women with no residual tumor had a significantly increased progression-free and overall survival compared with women with residual tumor; however, there was a 10% perioperative death rate in this series. The role of pelvic exenteration has been examined in a four-institution retrospective review of 31 patients.170 Twenty patients underwent exenteration with curative intent, all of whom had previously received pelvic irradiation. The 5-year disease-free survival was 45%.

Cytotoxic Chemotherapy

Cytotoxic chemotherapy for patients with endometrial cancer was rarely administered before 1980. In his 1974 literature review, Donovan171 reported only 126 patients who had been treated with 16 different agents. A combination of complete and partial responses was identified in 34 of 126 patients (27%).

In 1979, Muggia and colleagues172 reported that doxorubicin (Adriamycin, 37.5 mg/m2) in combination with cyclophosphamide (500 mg/m2) intravenously (IV) every 21 days in 11 patients with recurrent endometrial cancer resulted in 5 objective responses. The GOG studied single-agent doxorubicin at a dose rate of 60 mg/m2 IV every 3 weeks and reported a 37% response rate in 43 patients.173 Performance status was an independent prognostic variable, but length of time to first recurrence, histologic tumor grade, and site of metastasis had no effect on response. Although the most frequent adverse effect was on the hematopoietic system, cardiac toxicity occurred in 12% and there was one cardiotoxic death in a patient who had received more than 500 mg/m2 of drug. This study was important because it clearly established the value of doxorubicin as a single agent in the chemotherapy of endometrial cancer. Furthermore, it suggested a wider applicability of cytotoxic agents, unrelated to locus of recurrence, and it provided a model for the evaluation of other agents. The Eastern Cooperative Oncology Group tested doxorubicin versus cyclophosphamide in patients with advanced or recurrent endometrial adenocarcinoma. The group found no activity for cyclophosphamide when administered at a dose of 660 mg/m2 IV every 3 weeks.174 The GOG then tested doxorubicin with or without cyclophosphamide and found no advantage for the combination over doxorubicin alone.175

Early investigation of combination chemotherapy included the use of doxorubicin, cyclophosphamide, 5-fluorouracil, and medroxyprogesterone acetate.176 An alternative to doxorubicin-based therapy, for those in whom it might have been a contraindication, was the combination of melphalan and 5-fluorouracil. That combination produced objective responses in 11 of 26 patients, 5 of which were complete responses.177

On the basis of these early studies, the GOG compared these two regimens in 358 patients with FIGO stages III and IV or recurrent endometrial cancer.178 The two regimens tested were (1) melphalan, 7 mg/m2 orally daily for 4 days plus 5-fluorouracil 525 mg/m2 daily IV for 4 days repeated every 28 days; and (2) the combination of doxorubicin, 40 mg/m2, cyclophosphamide, 400 mg/m2, and 5-fluorouracil, 400 mg/m2 given IV every 21 days. Since it was rare at the time of the investigation for patients with recurrent endometrial carcinoma to have been referred to therapeutic centers without their having been treated with progestational agents, both of these regimens included 180 mg of megestrol daily for 8 weeks. Early in the study, a dose reduction of 25% was required in the first arm due to adverse hematologic effects. The response rate for measurable disease was 37% in both arms. Twenty-six percent of patients progressed on treatment. Response was unaffected by the grade of tumor or performance status, site of recurrence or time to recurrence, or presence or absence of previous treatment with progestational agents or radiation therapy. The study did not demonstrate an advantage for combination therapy over the historic experience with single-agent doxorubicin therapy at a higher dose. The equivalent activity of the melphalan and fluorouracil regimen did demonstrate the availability of an alternative to doxorubicin treatment for those patients with contraindications to doxorubicin.

As these studies were being conducted, the activity of cisplatin was demonstrated in patients with advanced endometrial cancer and in those who had failed conventional surgery, radiation therapy, hormonal therapy, or other cytotoxic programs. In one study, cisplatin at a dose rate of 100 to 120 mg/m2 by 4-hour infusion induced 4 objective responses among 13 patients.179 Seski and colleagues treated 26 patients in a dose-seeking regimen of 50, 70, or 100 mg/m2 every 4 weeks and observed an objective response rate of 42%, with 10 partial responses and 1 complete response. In this study, 21 of the 26 patients had not been previously treated with cytotoxic agents.180 In the GOG experience, 23 patients were treated with cisplatin at a dose of 50 mg/m2 every 3 weeks with only one response, but 20 of these 23 had previously been treated with doxorubicin or an alkylating agent.181 Trope produced 4 responses (36%) by treating 11 chemotherapy-naive patients with cisplatin at a dose rate of 50 mg/m2.182

A combination of cisplatin and doxorubicin had been used to treat patients with advanced or recurrent ovarian cancer. Extending this approach to patients with endometrial carcinoma, the range of response to these platinum-based combinations in advanced or recurrent disease was 33 to 47%.183, 184 Thigpen and co-workers185 reported the GOG experience comparing doxorubicin with doxorubicin and cisplatin in patients with advanced or recurrent endometrial carcinoma. The combination had a higher overall response rate (45% versus 27%) and complete response rate (22% versus 8%) than did doxorubicin as a single agent.

The demonstrated utility of cytotoxic agents in the treatment of endometrial carcinoma provoked numerous phase II drug trials. Muss has reviewed the published studies that have evaluated single-agents or combinations of drugs.186 He had considered studies of 11 investigational drugs and 17 other conventionally employed drugs from the various pharmacologic groupings. If one selects only drugs that have achieved at least a 20% response rate in studies including at least 25 patients, the list is small (Table 113.10). Results with the most active combinations are presented in Table 113.11.

Table 113.10. Single-Agent Cytotoxic Chemotherapy for Endometrial Cancer.

Table 113.10

Single-Agent Cytotoxic Chemotherapy for Endometrial Cancer.

Table 113.11. Combination Chemotherapy Regimens for Endometrial Cancer.

Table 113.11

Combination Chemotherapy Regimens for Endometrial Cancer.

There are several randomized trials comparing either single agents with one or two different combinations. These are shown in Table 113.12. Of note, paclitaxel has emerged as an active drug in recurrent endometrial adenocarcinoma. The GOG studied paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium.187 Among 28 evaluable patients, 4 complete responses and 6 partial responses were observed for an overall response rate of 35.7%. Similarly, Lissoni and co-workers188 evaluated paclitaxel in 19 patients with advanced endometrial adenocarcinoma previously treated with cisplatin, doxorubicin, and cyclophosphamide. Two complete responses and 5 partial responses were achieved for an overall response rate of 37%.

Table 113.12. Randomized Trials of Combination Chemotherapy Regimens for Endometrial Cancer.

Table 113.12

Randomized Trials of Combination Chemotherapy Regimens for Endometrial Cancer.

In view of the activity of paclitaxel in endometrial adenocarcinoma, the GOG initiated a phase III study of doxorubicin plus cisplatin versus doxorubicin plus 24-hour paclitaxel in primary stage III or IV or recurrent endometrial carcinoma. This study was completed in November 1998, but the results have not yet been published.

Because of the common adjuvant use of radiation therapy for patients with FIGO stage I and stage II endometrial cancer, there has been little impetus for the administration of adjuvant cytotoxic chemotherapy, even when such prognostic features as depth of myometrial invasion and histologic grade have suggested the possibility of recurrence. Two studies are available, from which information may be drawn inferentially.

Stringer and colleagues189 studied 31 patients with stage I endometrial cancer and 2 patients with occult stage II disease who had the poor prognostic features of deep myometrial invasion, grade III tumors, nonendometrioid histology, or extrauterine disease that was completely resected. Some of these patients were entered into the trial before the introduction of the new surgical staging system. Postoperatively, the patients were treated with cisplatin, 50 mg/m2, doxorubicin, 50 mg/m2, and cyclophosphamide, 500 mg/m2, every 4 weeks for six cycles. The 2-year progression-free interval rate was 79%, and 2-year survival was 83%. The median survival time for patients with disease confined to the uterus was not reached at 45 months. These results were considered superior to those of historic controls from the same institution.

The GOG treated patients with clinical stage I and stage II disease who had poor prognostic features with postoperative whole pelvic irradiation with or without doxorubicin.190 Those patients randomized to receive doxorubicin were treated with 45 to 60 mg/m2 every 3 weeks to a cumulative dose of 500 mg/m2 after their radiotherapy was completed. No differences were noted in progression-free interval or survival. Patients with disease limited to the uterus had a 63% survival with radiation therapy only and 72% survival when doxorubicin was added. This difference was not statistically significant because the sample size (181 patients) was too small.

More recently, Burke and co-workers191 prospectively treated 62 patients at high risk for systemic failure with six courses of cisplatin, doxorubicin, and cyclophosphamide. Although this regimen did not prevent distant failures in women with extrauterine disease, it was effective in patients with disease confined to the uterus, with actuarial 3-year survivals of 82%.

Hormone Therapy

In view of the emergence during the 1950s of publications identifying the role of estrogen in the etiology of endometrial carcinoma, it is not remarkable that Kelly and Baker, in 1961, noticing a profound effect of progesterone on the normal endometrium, should have treated patients with advanced endometrial cancer with a progestational agent. Their original report192 describes six objective responses in 21 patients that lasted from 9 months to 41/2 years. Since that time, there have been numerous reports describing treatment with a variety of progestational drugs: the most commonly employed are 17-hydroxyprogesterone caproate, medroxyprogesterone, and megestrol acetate. The notion of treating a hormone-dependent tumor with a hormone antagonist without important adverse effects is very attractive when confronting a patient who may be aged, obese, suffering from imperfect cardiovascular function, and has failed surgical remedy with or without subsequent radiation therapy and possible cytotoxic chemotherapy. At the other end of the spectrum, it is also attractive to employ hormonal therapy as a painless adjuvant in patients who have disease confined to the uterus but who are at high risk for recurrence. In an effort to demonstrate efficacy, therapists first applied progestational regimens to the most advanced or recurrent disease.

Reifenstein193 analyzed 992 patients treated with hydroxyprogesterone caproate by 113 investigators. He studied the records of 314 patients in detail and found that there was little response before 7 weeks of treatment, that the longest remissions were achieved with a minimum of 12 weeks of initial therapy, and that there was no relation between clinical response and patient age when correction was made for tumor differentiation.

The optimum dose for progestational treatment has not been determined. Kohorn’s early survey of the members of the Society of Gynecologic Oncology identified 15 different dose schedules for the use of medroxyprogesterone.194

Kauppila195 reviewed 1,068 patients treated in 17 different trials with either medroxyprogesterone acetate (Provera), megestrol acetate, or hydroxyprogesterone caproate and found an overall response rate of 34%. The duration of response was approximately 20 months, and the average survival time was approximately 25 months. The GOG, employing medroxyprogesterone, 50 mg orally three times a day, in heavily pretreated patients with advanced or recurrent endometrial carcinoma noted a 14% objective response rate. Median survival was 10.4 months. The GOG completed a subsequent dose-seeking study comparing oral medroxyprogesterone at doses of 200 mg/d with 1,000 mg/d and found that the lower dose resulted in a response rate of 26% as compared with 18% with the higher dose.196 Podratz and colleagues noted an objective overall response rate of 11.2% and a 5-year survival of only 8%, when treating with progestational agents.197 This study group found no difference in response rates among megestrol, hydroxyprogesterone, and medrogestone.

The GOG198 studied high-dose megestrol acetate (800 mg/d) in advanced or recurrent endometrial carcinoma and concluded that this regimen had no advantage over lower-dose progestins. Of 54 evaluable patients, 6 complete responses and 7 partial responses were observed for an overall response rate of 24%. Three deaths secondary to cardiovascular events were possibly related to therapy.

Several investigators195, 199 have tried to compare oral and parenteral routes of administration employing a variety of progestational agents and have found no advantage for the parenteral route. Milligram equivalents of progestational agents frequently do not translate into biologic equivalence, and the dose of a particular progestogen required for tumor control may have to be empirically derived. Progestational therapy is most effective in well-differentiated cancers, and it is precisely those cancers that have the highest progesterone receptor content. Furthermore, the well-differentiated cancers are most easily treated by first-line therapy and tend to recur or metastasize less frequently.

In summary, the following generalizations can be made concerning progestational therapy: (1) The response rate for patients with advanced or recurrent endometrial carcinoma ranges from 10 to 30%, probably relating to the receptor level in the tumor. (2) Well-differentiated cancers respond best. (3) The progesterone receptor level diminishes sharply as the grade of the tumor increases. (4) Clinical responses may not occur before 7 to 12 weeks of therapy. (5) Two-thirds of patients will not respond. (6) There is no published evidence that progestational agents employed in an adjuvant mode offer any benefit.

Hormonal therapy by agents other than progestogens has been studied by many. Extrapolating from the experience with breast cancer, investigators have employed tamoxifen in doses of 20 to 40 mg daily for patients with advanced or recurrent endometrial carcinoma. In a review of eight published studies, Moore and colleagues described an overall response rate of 22%.200 As one might predict, there is a wide spectrum of reported responses, ranging from 0 to 53%.201, 202 This variation may be explained by the report of Edmonson and colleagues, who found a 21% response rate in patients naive to hormone therapy and no response in patients who had failed progesterone treatment.203 Not unlike the progestin experience, it would seem that tamoxifen is more likely to be effective in patients with low-grade tumors, receptor positivity, and either no previous hormone therapy or a prior response to progestin therapy.

Because progestins ultimately downregulate partial responses, and because tamoxifen induced partial response in target tissues, the notion of the sequential administration of hormones has been examined. Ayoub and colleagues204 studied 46 patients with metastatic endometrial cancer, randomly assigning them to receive monthly cycles of cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) or CAF plus Provera, 200 mg daily for 3 weeks, followed cyclically by tamoxifen, 20 mg daily for 3 weeks. Objective responses of 15% and 43% were seen, respectively, with CAF and CAF plus hormonal therapy (p = .05). Since progestational agents have not improved the response to chemotherapy in previously cited studies, it is reasonable to attribute this difference to the addition of tamoxifen and to explore other opportunities for exploiting its properties.

The GOG is studying the efficacy of tamoxifen citrate plus intermittent medroxyprogesterone in patients with recurrent or metastatic endometrial carcinoma. A study of alternating courses of megestrol acetate and tamoxifen citrate is also being studied by the GOG. Recently, Pinelli and co-workers205 evaluated sequential cyclical hormone therapy (megestrol acetate and tamoxifen citrate) plus the single agent carboplatin. Of 13 evaluable patients, 4 patients had complete response, and 6 had partial responses for an overall response rate of 77%. The median progression-free interval was 14 months for complete responders. The median survival for all patients was 11 months, and 33 months for complete responders.

Gonadotropin-releasing hormone analogues have been tested in small groups of patients with recurrent endometrial carcinoma.206 A response rate of 35% was observed in 17 postmenopausal patients, but the mechanism for this achievement is unknown.

Future

Efforts must continue to expand information about oncogene expression to better define risk groups. From a surgical standpoint, results of randomized studies examining the role of laparoscopy-assisted vaginal hysterectomy and staging are needed to better define the future role of these procedures. For patients with early disease and poor prognostic features, studies with extended fields for radiation therapy should be undertaken and can be tested against adjuvant cytotoxic chemotherapy. For patients with advanced or recurrent disease, better cytotoxic agents must be identified. The integration of sequential hormonal and cytotoxic therapy is rational and should be pursued. More randomized trials for chemotherapy combinations must be undertaken and measured against sequenced single-agent therapy. It is obvious that with a cure rate in the United States of approximately 80%, it will be essential that patients with poor prognostic features or recurrent/metastatic disease be entered into collaborative trials in order to maximize the opportunities for improving survival.

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