Kaled M. Alektiar
ANATOMY
The uterus is a hollow, muscular organ located in the true pelvis between the bladder and the rectum. The average adult uterus is about 8 cm long, 5 cm wide, and 2.5 cm thick. It is divided into the fundus, body (corpus), and cervix. The junction between the body and cervix is called the isthmus. The fundus is pierced at each cornu by the fallopian tubes. The uterine surface is partially covered by peritoneum. The uterine cavity is lined by endometrium, made up of columnar cells forming many tubular glands. The thickness of the endometrium varies during the menstrual cycle, but by the end of menstruation it should be 2 to 3 mm in thickness. The wall of the uterus is composed of myometrium, consisting of smooth muscle fibers. The major supports of the uterus are the broad, round, uterosacral and cardinal ligaments. The major blood supply to the uterus is the uterine artery, which enters the uterus at the isthmus after it crosses over the ureter. The lymphatic drainage for the body of the uterus is mainly to the obturator and internal and external iliac lymph nodes. The lymphatics from the fundus accompany the ovarian artery and drain into the para-aortic lymph nodes.
EPIDEMIOLOGY AND RISK FACTORS
Endometrial cancer is the most common gynecologic cancer and the fourth most frequently diagnosed cancer in women in the United States. According to 2011 cancer statistics, the estimated number of newly diagnosed cases is 46,470, with a probability of 1 of every 39 women (2.58%) developing it during her lifetime.1 Although it is a cancer that affects predominantly postmenopausal women, 5% to 30% of women are <50 years of age at the time of diagnosis.2,3 The expected number of deaths from endometrial cancer in 2011 was 8,120, making it the eighth-leading cause of death from cancer in women. Prior estimates on the death rate from endometrial cancer seemed to indicate that the rate was on the rise, but the most recent data show that the death rate of 4.18 per 100,000 women did not change from the year 1990 to 2007.1
The age-standardized rate per 100,000 for endometrial cancer in more developed areas of the world is 12.9, with a cumulative risk of 1.6% (age 0 to 74 years), compared to 5.9 and 0.7%, respectively, in less developed areas, indicating a possible influence of environmental factors on the incidence of this disease.4 The exact etiology of endometrial cancer remains unknown, but several risk factors have been associated with it, chiefly unopposed estrogen. It is well established that endometrial cancer risk is increased among women who have high circulating levels of bioavailable estrogens and low levels of progesterone, so that the mitogenic effect of estrogens is insufficiently counterbalanced by the opposing effect of progesterone.5–7 The source of unopposed estrogen could be endogenous or exogenous. In a case–control study, the association between endogenous estrogen and endometrial cancer was demonstrated. In that study there was correlation between high blood concentrations of estrogens and increased risk of endometrial cancer.7 Lifetime cumulative number of menstrual cycles, that is, menstruation span, is associated with increased risk of developing endometrial cancer. This is due to the fact that endometrial cell proliferation increases during the follicular phase, which is the longest in the menstrual cycle. Thus, early age at menarche (estimated relative risk [RR], 1.5 to 2) and late age at menopause (RR, 2 to 3), examples of increased menstruation span, are risk factors for endometrial cancer.8,9 Nulliparity (RR, 3) is also associated with increased risk of endometrial cancer8due in part to anovulatory menstrual cycles. Obesity increases endometrial cancer risk (RR, 5) mainly through changes in endogenous hormone metabolism. After menopause, when ovarian production of both estrogen and progesterone ceases, the major source of estrogen is via peripheral conversion, mostly within adipose tissue, of androgens that continue being produced by the adrenal glands and ovaries. Thus with obesity there is an increase in the amount of bioavailable estrogens in the circulation and the endometrial tissue.7,10,11 Obesity may also influence endometrial cancer risk via chronic hyperinsulinemia, which appears to be a key factor for the development of ovarian hyperandrogenism, associated with anovulation and progesterone deficiency, especially for premenopausal women.10 Non–insulin-dependent diabetes mellitus and hypertension (RR, 1–3) also increases the risk of endometrial cancer. This is often believed to be secondary to obesity, but there are data showing that these risk factors could be independent of obesity.12,13,14 With regard to exogenous estrogen, it is well established that the use of estrogen-only hormone-replacement therapy and sequential oral contraceptives greatly increases endometrial cancer risk (RR, 10 to 20), whereas combined preparations, that is, those that contain a progestogen as well as estrogen throughout the treatment period, have a protective effect (RR, 0.3 to 0.5).15–16,17 The use of tamoxifen in patients with breast cancer has been associated with increased risk (RR, 3 to 7) of endometrial cancer.18,19–20 The mechanism of action of tamoxifen is in competition with that of endogenous estrogen for estrogen receptors. In premenopausal women, tamoxifen has an antiestrogenic effect, but in postmenopausal women it has a weak estrogenic effect because of the upregulation of estrogen receptors. In a recent meta-analysis on adjuvant tamoxifen and endometrial cancer, for patients who were <55 years of age there was little absolute risk compared to patients in of 55 to 69 years of age, for whom the 15-year incidence was 3.8% in the tamoxifen group versus 1.1% in the control group (absolute increase 2.6% [standard error 0.6], 95% confidence interval [CI] = 1.4 to 3.8), highlighting the influence of age on the risk of endometrial cancer from tamoxifen use.21 Initial data seemed to indicate that the majority of endometrial cancers associated with tamoxifen use were of early stage with favorable features.22 More recent data, however, show a change in the profile of these endometrial cancers, with a rise in the rate of serous, clear-cell, carcinosarcoma, and sarcoma types.23,24 Inherited genetic predisposition, especially in the setting of hereditary nonpolyposis colorectal cancer (HNPCC), probably accounts for <5% of all endometrial cancer cases. Mutations in one of the four mismatch repair genes hMLH1, hMSH2, hMSH6, or hPMS2 have been identified in patients with Lynch syndrome. Although HNPCC is thought of primarily in terms of risk of developing colorectal cancer, it is important to note that lifetime cumulative risk of endometrial cancer for women with HNPCC is 40% to 60%, which equals or exceeds their risk of colorectal cancer.25 There seems to be a high rate of lower uterine segment involvement in patients with HNPCC-associated endometrial cancer.26
CLINICAL PRESENTATION AND NATURAL HISTORY
The most common presentation for endometrial cancer is postmenopausal vaginal bleeding, which is reported by 80% to 90% of patients. The incidence of endometrial cancer in women presenting with postmenopausal bleeding is only 10% to 15%. This incidence, however, could range from 1% up to 25%, depending on patient age and the presence of other risk factors. In a recent repot of a total of 3,548 women presenting with postmenopausal vaginal bleeding, 201 (6%) had a diagnosis of endometrial carcinoma. Use of a multiple logistic regression model showed that recurrent episodes of bleeding (odds ratio [OR], 3.64), a history of diabetes (OR, 1.48), older age (1.06), and high body-mass index (OR, 1.07) increased the risk of endometrial malignancy when corrected for other characteristics.27 Other patterns of presentations include vaginal discharge, abnormal Papanicolaou smear, or thickened endometrium on routine transvaginal ultrasound. For patients with advanced disease, they may present with urinary or rectal bleeding, constipation, pain, lower-extremity lymphedema, abdominal distension due to ascites, and cough and/or or hemoptysis.
The International Federation of Gynecology and Obstetrics (FIGO) annual report28 showed that the 5-year survival rate for 8,110 patients with endometrial cancer treated between 1999 and 2001 was 80%. Such excellent outcome is a reflection of the fact that the majority of patients are diagnosed with early-stage disease. The tumor was limited to the corpus uteri in 71% of cases, involved the cervix in 12%, and extended beyond the uterus, but short of distant spread, in 13%. For patients with disease limited to the endometrium or with <50% myometrial invasion, the 5-year survival rate was 91%. However, the rate dropped to 66% when disease extended to adnexa/serosa/positive peritoneal cytology, to 57% with regional lymph node involvement, to 25.5% with bladder or rectal involvement, and to 20% with distant spread. For clinically staged patients, the 5-year survival rate ranged from 67% for early-stage disease down to 15% for advanced disease. Mass screening for endometrial cancer in women at average risk or increased risk due to a history of unopposed estrogen therapy, tamoxifen therapy, late menopause, nulliparity, infertility or failure to ovulate, obesity, diabetes, or hypertension is not recommended. American Cancer Society (ACS) recommends that women at average and increased risk should be informed about risks and symptoms (in particular, unexpected bleeding and spotting) of endometrial cancer at the onset of menopause and should be strongly encouraged to immediately report these symptoms to their physician. However, screening has been recommended by the ACS for women who carry, or are related to carriers of, the HNPCC mutation, starting at age 35 years, including annual transvaginal ultrasound and endometrial biopsy.29 Prophylactic hysterectomy and bilateral salpingo-oophorectomy once childbearing is completed have been shown to effectively reduce the risk of endometrial cancer in patients with HNPCC and should be strongly considered.30
FIGURE 70.1. Sagittal view of the uterus on transvaginal ultrasound. A: Normal thin endometrium (arrow). B: Thickened endometrium (arrow).
DIAGNOSTIC WORKUP
Endometrial tissue sampling remains the gold standard by which the diagnosis of endometrial cancer is established. This is achieved via biopsy or dilatation and curettage (D&C). Endometrial biopsy, which can be easily performed in the office with a Pipelle or similar device, is the preferred approach. Its sensitivity in detecting endometrial cancer in postmenopausal women is 99.6% compared to 91% in premenopausal women. Its specificity is >98% for both groups.31 If the patient is undergoing hysterectomy, routine D&C is not necessary after an office Pipelle sampling has documented malignancy. However, if symptoms persist, the office sampling is inadequate, or the patient is being considered for conservative fertility-sparing approaches, a D&C should be performed. In addition, D&C provides more reliable assessments of final pathologic findings in hysterectomy specimens, mainly with regard to tumor grade.32 Given that the incidence of endometrial cancer in women with postmenopausal bleeding is only 10% to 15%, it is unclear how feasible it is to perform endometrial sampling on every patient. Transvaginal ultrasonography(TVU) may be considered as a useful tool to assess patient’s vaginal bleeding.33 Normal endometrium looks thin and homogeneously hyperechoic, but it is thickened and heterogeneous, with hyperplasia, polyps, and cancer,34 as shown in Figure 70.1. The consensus statement from the Society of Radiologists in Ultrasound defines an endometrial thickness of 5 mm or greater as being abnormal.35 If the thickness of the endometrium is <5 mm, the risk of endometrial cancer is minimal; the false-negative rate is about 4%. Under such circumstances, endometrial sampling may be foregone if no further episodes of vaginal bleeding occur.33 Recent meta-analysis seems to indicate that perhaps a cut-off of 3-mm thickness rather than <5 mm provides even better diagnostic accuracy.36 If the TVU is abnormal but the biopsy is negative/nondiagnostic or the uterine cavity is inaccessible, then saline-infusion sonography or hysteroscopy should be considered to help exclude intracavitary lesions, especially polyps that might contain cancer.37,38 In addition, these methods are also helpful in premenopausal women, for whom the accuracy of TVU is limited because the endometrial thickness fluctuates, depending on the level of female hormones. The potential downside to saline infusion or hysteroscopy is that there have been reports that the insufflation of the distending medium into the canal has been associated with an increase in positive peritoneal cytology, although the prognostic implications are unclear of such positive cytology “induced” by sampling.39 Several imaging studies are available to define the extent of disease preoperatively. Good-quality pelvic computed tomography(CT) scans obtained with oral and intravenous contrast can demonstrate the extent of the endometrial tumor. The endometrial carcinoma is a hypodense mass relative to the normal myometrium and may be seen as a diffuse, circumscribed vegetative or polypoidal mass within the uterine cavity. If myometrial invasion is seen, it usually implies involvement of greater than one-third to one-half of the myometrial thickness. Involvement of the cervix is seen on CT as cervical enlargement >3.5 cm in diameter with heterogeneous low-attenuation areas within the fibromuscular stroma. Parametrial or sidewall extension is seen by the loss of periureteral fat in the former and <3 mm of intervening fat between the soft tissue mass and the pelvic sidewall in the latter. Involvement of the fallopian tubes and ovaries is detected in the usual fashion, and for lymph nodes is >1 cm in diameter in the short axis.40,41 Magnetic resonance imaging (MRI) is considered the most accurate imaging study to assess tumor extension in endometrial cancer, especially myometrial invasion. Dynamic contrast-enhanced MRI is the optimal MRI method for detecting myometrial invasion,42 with an accuracy of 85% to 93%. A clear junctional zone or preservation of a sharp delineation between the tumor and the myometrium implies disease limited to the endometrium. Disease characterized by disruption of the junctional zone, increased–signal-intensity tumor in the inner half of the myometrium with preservation of the outer myometrium, or both correlate with superficial myometrial invasion. If there is extension of the high–signal-intensity tumor into the outer myometrium with preservation of a peripheral rim of normal, intact myometrium, then that is considered deep myometrial invasion (Fig. 70.2). MRI also helps to delineate tumor extension into the cervix. The normal cervical stroma is hypointense on T2-weighted images and is replaced by intermediate–signal-intensity tumor in cases of invasion.34 The reported sensitivity of MRI in detecting lymph node metastasis is 27% to 66% and the specificity is 73% to 94% in surgically staged patients.43 Positron emission tomography/computed tomography(PET/CT) is also being used in endometrial cancer. There seems to be little benefit in assessing the primary tumor extension. With regard to regional lymph node metastasis, the reported sensitivity is 50% to 100%, the specificity is 87% to 100%, and the accuracy is 78% to 100%. The main limitation of PET/CT is its inability to detect metastasis in lymph nodes ≤5 mm in size.43 The FIGO staging for endometrial cancer is a surgical staging, and thus preoperative imaging studies (except chest x-rays) are not part of the staging. Cancer antigen 125 (CA 125) serum levels could be elevated in patients with endometrial cancer. Kim et al.,44 in a review of 413 patients, found that 23.9% of patients had >35 U/mL serum CA 125 levels. Hsieh et al.45 found that preoperative levels of >40 U/mL correlated significantly with regional lymph nodes metastasis and suggested that such levels could be used as an indication for full pelvic and periaortic lymphadenectomy at the time of surgical staging in the absence of metastatic disease.
FIGURE 70.2. Sagittal magnetic resonance imaging view of the uterus. A: Normal uterus. B: Deep myometrial invasion (arrows).
Pathologic Classification
Endometrial Hyperplasia
The diagnostic criterion for hyperplasia is an increase in the number and size of proliferating glands. The International Society of Gynecologic Pathologists standardized the subclassification of endometrial hyperplasia. In simple hyperplasia, there is only glandular proliferation and enlargement with increased stromal cellularity. This rarely progresses to carcinoma (<1%). Complex hyperplasia is characterized by back-to-back proliferation of glands with intraluminal papillae, epithelial pseudostratification, and few mitotic figures. If there is no cytologic atypia, the risk of malignant degeneration is again quite low, on the order of 3%. Any proliferation demonstrating cytologic abnormalities (in cellular or nuclear morphology) is classified as atypical hyperplasia. Atypical hyperplasia has a much higher risk of progression to an invasive carcinoma—8% for simple atypical hyperplasia, increasing to 29% for complex hyperplasia associated with atypia.46 The GOG conducted a prospective trial in which all patients with atypical hyperplasia of the uterus underwent an immediate hysterectomy. The rate of underlying concurrent carcinoma in the uterus was 42.6% in these patients.47 The standard recommended treatment for atypical hyperplasia of the uterus is hysterectomy if childbearing is complete and the patient has no other contraindications to surgery. In patients who desire future fertility or have an absolute contraindication to surgery, progestational therapies may be used with caution.48
TABLE 70.1 PATHOLOGIC CLASSIFICATON OF ENDOMETRIAL CANCERS
FIGURE 70.3. Different histologic types of endometrial cancer. A: Endometrioid. B: Papillary serous. C: Clear cell.
Carcinoma of the Endometrium
Endometrioid Carcinoma
Endometrioid adenocarcinoma is the most common endometrial carcinoma, constituting 75% to 80% of all cases (Table 70.1). The classic histologic appearance is that of marked glandular proliferation with back-to-back proliferation of glands and little intervening stroma (Fig. 70.3A). The name endometrioid is derived from resemblance to proliferative-phase endometrium. Architectural grading is determined by the amount of solid mass of tumor cells compared to well-defined glands. Grade 1 is an endometrioid cancer in which <5% of the tumor growth is in solid sheets. Grade 2 is an adenocarcinoma in which 6% to 50% of the tumor is composed of solid sheets of cells. Grade 3 occurs when >50% of the tumor is made up of solid sheets. Nuclear grading is determined by the nuclear shape, size, chromatin distribution, and size of the nucleoli. The grading is primarily driven by the architectural grading, but if there is marked nuclear atypia in an otherwise grade 2 architectural grading, it should be increased to grade 3. Within endometrioid adenocarcinoma, the subtypes are endometrioid carcinoma not otherwise specified (NOS), endometrioid carcinoma with squamous differentiation, villoglandular endometrioid carcinoma, secretory carcinoma, and a ciliated cell variant.49 Most of the endometrioid adenocarcinomas are designated NOS. Foci of squamous differentiation are often found with endometrioid adenocarcinoma. The squamous component could be benign, with the designation of adenoacanthoma, or malignant, in which case it is called adenosquamous carcinoma. Such designations have not been very useful, however, because the degree of differentiation of the squamous component parallels that of the glandular architectural grading. Therefore, most gynecologic pathologists use the term adenocarcinoma with squamous differentiation. Other subtypes of endometrioid adenocarcinoma include the relatively common villoglandular carcinoma, which grows in a papillary fashion. The prognosis of this subtype is similar to that of low-grade endometrioid cancer, and it must not be confused with serous carcinoma because of its papillary features. Secretory carcinoma, which represents <2% of all endometrial carcinomas, is characterized by a very well differentiated glandular pattern with much intracellular glycogen, thus resembling early secretory endometrium. Although the cells have clear cytoplasm, their histologic and cytologic features are different from those of clear-cell carcinoma. Ciliated carcinoma is a very rare subtype, characterized by the presence of ciliated cells comprising >75% of the tumor specimen. It is usually associated with a history of prior estrogen use, and the prognosis is quite good, since most are well differentiated.
Mucinous Carcinoma
This designation requires >50% of the tumor cells to be mucinous. These cells are carcinoembryonic antigen positive and are laden with mucin, which stains positively with mucicarmine and periodic acid–Schiff stains but is diastase resistant. Because of the resemblance to endocervical adenocarcinoma, it is essential to exclude it by endocervical curettage. Mucinous carcinomas are usually well differentiated and have the same prognosis as ordinary endometrioid carcinomas.
Serous Carcinoma
Serous carcinomas, also known as papillary serous cancers, resemble ovary cancer in terms of histology and to some extent in terms of behavior. The mere presence of papillary structure is not diagnostic because other histologic types may have papilla as well. However, the presence of marked cellular atypia in addition to papilla distinguishes serous carcinoma from others (Fig. 70.3B). Psammoma bodies are found in up to 33% of cases. The incidence of serous endometrial cancer is about 10% that of endometrial carcinomas. This is a very aggressive subtype, with a high propensity for early lymphatic and intraperitoneal dissemination, often despite little myometrial penetration.50 In the FIGO annual report, the 5-year survival rate was 52.6% compared to 83.2% for endometrioid carcinoma.28
Clear-Cell Carcinoma
Clear-cell carcinoma of the endometrium resembles renal carcinoma, but its origin from Müllerian structures is now well established. Unlike vaginal and cervical clear-cell carcinoma, it is not related to intrauterine diethylstilbestrol exposure. The microscopic structure may vary from solid patterns to glandular differentiation (Fig. 70.3C). In the latter pattern, small cells resembling “hobnail” cells line spaces and glands. These are cells that extruded their cytoplasm, leaving bare nuclei that protrude into the glandular lumens. The prognosis of this cancer is somewhat similar to that of serous cancer. In the FIGO annual report, the 5-year survival rate was 62.5% compared to 83.2% for endometrioid carcinoma and 52.6% for serous carcinoma.28
Squamous Carcinoma
This type of cancer is extremely rare, and the diagnosis has to be made after the exclusion of cervical origin. The 5-year survival rate based on the FOGO report is 68.9% overall, but the prognosis is poor for patients with extrauterine disease or distant spread.28
Undifferentiated Carcinoma
The World Health Organization classification describes endometrial undifferentiated carcinomas as “malignant poorly differentiated endometrial carcinomas, lacking any evidence of differentiation” without any further characterization.51 Undifferentiated carcinomas can also be associated with an endometrioid carcinoma component, and such tumors have been referred to as “dedifferentiated carcinomas,” which is being recognized with increased frequency. Some of these tumors may belong to the spectrum of gynecologic neoplasms seen in the setting of microsatellite instability and possibly Lynch syndrome.52
Mixed Histology
Mixed-cell-type endometrial cancer composed of two or more pure types is not uncommon. By convention, in order to be designated as mixed, the other cell-type component has to comprise at least 10% of the tumor. Except for mixed endometrioid and serous or clear-cell carcinoma, the clinical significance of mixed cell type is questionable.
Simultaneous Tumors
Cancers of identical type may be discovered in the ovary and endometrium simultaneously. Usually, the site of the largest tumor is assigned the primary origin, but occasionally true primary endometrial and ovarian malignancies may coexist. This field effect of the Müllerian system may occur in as much as 15% to 20% of ovarian endometrioid tumors.53 If the endometrial tumor is <5 cm in diameter, well differentiated, with no vascular invasion, limited to less than the middle one-third of the myometrium, and the ovarian lesions are bilateral, it is more likely that there are two concomitant primary tumors. Genetic profiling may represent a powerful tool in clinical practice for distinguishing between metastatic and dual primaries in patients with simultaneous ovarian/endometrial cancer and for predicting disease outcome.54
Molecular Biology
Several investigators pointed out that there are two distinct types of endometrial cancer.55,56 In type I endometrial cancer there is strong correlation with prior estrogen stimulation. The cancers in this category are often indolent in nature, with minimal myometrial invasion and low-grade histology. They affect premenopausal and perimenopausal women. Type II endometrial cancer often affects postmenopausal women with no prior history of estrogen stimulation. The histology of the tumors is often high grade, such as serous or clear-cell cancers with deep invasion, and at a more advanced stage at the time of presentation. What is intriguing is the fact that at the molecular level, the existence of two distinct types of endometrial cancer seems to be validated. In a recent review by Dedes et al.,57 the compiled data from the literature show that the most frequently altered molecular pathway in type I endometrial carcinomas is the PI3 K/PTEN/AKT pathway, which is dysregulated by oncogenic mutations, PTEN loss of function, and/or overexpression of upstream tyrosine kinase growth factor receptors, leading to uncontrolled cell proliferation and survival. On the other hand, the main pathway alterations in type II endometrial cancers involve the tumor suppressors p53 and/or p16, which cause cell cycle dysregulation and genetic instability. Other features frequently observed in type II cancer are loss of E-cadherin expression and the amplification and overexpression of HER2. Inactivation of the p53 tumor suppressor gene is seen in almost 90% of cases of serous carcinoma.58,59Mutation in the p53 gene, however, is encountered in only 10% of endometrioid adenocarcinoma, with most occurring in grade 3 tumors. Inactivation of the cell cycle regulator p16 is also more frequent in type II (40%) than in type I (10%). The underlying mechanism is not clear but probably involves deletion and promoter hypermethylation.60 Reduction in the levels of the adhesion molecule E-cadherin is more frequent in type II (62% to 87%) than in type I (5% to 53%) tumors.61,62 HER2 overexpression or amplification is seen in 17% to 32% of type II compared to 3% to 10% in type I tumors.63–64,65 In contrast, mutation in the PTEN tumor suppressor gene is found in 30% to 50% of type I endometrial cancer. PTEN mutations have been detected in endometrial hyperplasia with and without atypia (19% and 21%, respectively), which suggests that PTEN mutations are early events in the development of endometrial cancer.60 Mutations in PIK3CA occur in 36% of type I endometrial cancer and coexist frequently with PTEN mutations.60 Mutation in K-ras proto-oncogene is seen in 10% to 30% of endometrial cancer patients.59Microsatellite instability (MSI), which is found in patients with HNPCC, is also seen in approximately 20% of “sporadic” endometrial cancers.66,67 MSI, mutations in PTEN/PIK3CA, and mutations in K-ras frequently coexist within the same tumor.68 B-Catenin is important for cell differentiation, maintenance of normal tissue architecture, and signal transduction. B-Catenin mutations are seen in 25% to 40% of type I endometrial cancer. Of interest, the mutations do not usually coexist with MSI and mutations in PTEN/PIK3CA and K-ras. This suggests that type I endometrial cancers with B-catenin mutations may develop via a unique pathway.68 Microarray analysis has further revealed distinct gene expression profiles among different histologic types of endometrial cancer.69,70
TABLE 70.2 ENDOMETRIAL CANCER SURGICAL STAGING SYSTEM: INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS 1988
TABLE 70.3 REVISED ENDOMETRIAL CANCER SURGICAL STAGING SYSTEM: INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS 2009
STAGING
Before 1988, the staging system for endometrial cancer was clinical. Stage I was tumor limited to the uterus, with IA designation if the length was ≤8 cm and IB if it was >8 cm. Stage II was for when cervix was involved, stage III when disease extension beyond uterus/cervix was limited to the true pelvis, and stage IV when it extended beyond the true pelvis or involved bladder or rectum (IVA) or distant spread (IVB). This system is applicable to the few patients who cannot have surgery and are treated with definitive radiation. Creasman et al.71 reported a Gynecologic Oncology Group (GOG) study on 621 patients with clinically stage I endometrial cancer, that is, confined to the corpus, who underwent total abdominal hysterectomy/bilateral salpingo-oophorectomy, peritoneal cytology, and selective pelvic and para-aortic lymphadenectomy. Of the 621 patients, 144 (22%) were found to have disease outside the uterus. The rate of positive peritoneal cytology was 12%, that of adnexal involvement was 5%, and that of regional lymph node involvement was 11%. Pelvic node metastases were found in <3% of patients with grade 1 endometrium-confined disease but in >30% when grade 3 disease penetrated the outer one-third of the myometrium. Aortic nodal disease, although rare in grade 1 disease or in the absence of pelvic node metastasis, was seen in 14% and 23% of patients with deeply invasive grade 2 or 3 disease, respectively. This highlighted some of the shortcomings of the clinical staging system and led to the adoption of a surgical staging system by FIGO in 1988 in order to better estimate 5-year prognoses for patients and to better tailor adjuvant therapy to those patients most likely to benefit from it (Table 70.2).
In 2009 the FIGO staging system was modified again.72 Patients who formerly were staged as IB, that is, <50% myometrial invasion, are now considered IA. Patients with >50% myometrial invasion are designated as stage IB. Endocervical glandular involvement no longer affects staging; only patients with cervical stromal invasion are considered stage II. Having positive peritoneal cytology no longer affects staging. Parametrial extension is now considered IIIB. Patients with stage IIIC are now subdivided into IIIC1 if pelvic nodes are involved and IIIC2 if para-aortic nodes are involved (Table 70.3). The discriminating power of the new FIGO staging system is being debated. Page et al.73 evaluated 10,839 cases from 1998 to 2006 using the Surveillance, Epidemiology, and End Results (SEER) Program. The analysis demonstrated the usefulness of two divisions rather than three for stage I in the new FIGO staging system. In contrast, a study from Memorial Sloan-Kettering Cancer Center (MSKCC) of 1,307 patients with FIGO 1988 stage I disease showed that the revised system for stage I did not improve its predictive ability over the 1988 system.74
Prognostic Factors
Several clinicopathologic factors have been identified in patients with endometrial carcinoma to help predict the prognosis and individualize the treatment plan. At MSKCC, a nomogram was developed for predicting overall survival of women with endometrial cancer (n = 1,735) after primary therapy.75 Use of five prognostic factors—age, grade, histologic type, number of lymph nodes removed, and FIGO 1988 surgical stage—predicted OS with high concordance probability (Fig. 70.4).
Age
The influence of older age on worse outcome has been well established. The adverse impact of older age is often explained by pointing out that older patients tend to present with aggressive histology and more-advanced disease and are generally treated less aggressively. What is intriguing, however, is that the strongest correlation between older age and poor outcome is seen in patients with favorable characteristics. Age ≥60 years has been shown to be predictive of local-regional recurrence (hazard ratio [HR], 3.9; p = .0017) and death (HR, 2.66; p = .01) in a randomized trial limited to stage I and in which patients with deep myometrial invasion grade 3 were excluded.76 The adverse impact of advanced age on outcome persists even when elderly patients are treated as aggressively as their younger counterparts.77
FIGURE 70.4. Nomogram for predicting overall survival in patients with endometrial cancer.
Race
White women tend to fare better than African Americans, independent of other prognostic factors.78 It is important to note that although the prevalence of endometrial cancer is lower in African American women, the incidence of high-risk tumors in this group is higher.79
Histologic Subtype
According to the FIGO annual report, the 5-year survival rate was 83.2% for endometrioid adenocarcinoma, compared to 52.6% for serous cancer and 62.5% for clear-cell cancer in 8,033 surgically staged patients. Patients with endometrioid histology have surgical stage III to IV disease only in 13.8% of patients, compared to 41.7% with serous and 33% with clear-cell carcinoma, which could explain the worse outcome. However, the influence of histology was seen even in patients with surgical stage I disease (n= 5,285), for whom 5-year survival dropped from 90% for endometrioid histology to 79.9% with serous and 85.1% with clear-cell carcinoma.28
Grade
Tumor grade is one of the most sensitive indicators of prognosis. Grade directly affects the depth of myometrial penetration and the frequency of lymph node involvement. Most grade 1 tumors are limited to the endometrium or have superficial myometrial penetration, and the overall risk of pelvic and para-aortic lymph nodal metastases is 3% and 1.5%, respectively. Only 10% of grade 1 tumors have deep myometrial invasion, and pelvic and para-aortic lymph nodal involvement in these is 12% and 6%, respectively. Conversely, >50% of grade 3 tumors have >50% myometrial invasion, and these have pelvic and para-aortic nodal involvement on the order of 30% and 20%, respectively.71In the FIGO annual report,28 grade 3 was an independent predictor of poor survival on multivariate analysis within each stage—stage I (HR, 2.45), II (HR, 2.14), III (HR, 2.44), and IV (HR, 2.55).
Myometrial Invasion
Regardless of grade, only 1% of tumors limited to the endometrium had lymph nodal involvement, as compared with 25% pelvic and 17% para-aortic involvement with deep penetration.71 Before the 1988 FIGO staging system, the depth of invasion had been reported as none or inner, middle, or outer one-third of the myometrium. The 1988 FIGO staging system subdivided myometrial invasion into none or inner or outer half. Under that staging system, for patients with <50% myometrial invasion, it seems that invasion to less than versus greater than one-third is not a significant predictor of outcome.80 In the current 2009 FIGO staging system, depth of invasion in stage I is divided into two categories: A (no or <50% myometrial invasion) and B (>50% invasion).
Lymphovascular Invasion
This is seen in about 15% of the cases of endometrial cancer. The GOG study found that lymphovascular invasion (LVI)–positive tumors were associated with a 27%, or fourfold, increase in the pelvic lymph nodal metastases, and a 19%, or sixfold, increase in para-aortic nodal metastases.71 This translates into more frequent relapses, including vaginal recurrences,81 and a poorer outcome.82
Lower Uterine Segment Involvement
The GOG study of surgical-pathologic spread patterns found a doubling of the incidence of pelvic nodal involvement from 8% to 16% and an increase in para-aortic nodal involvement from 4% to 14% when the tumor arose from or involved the isthmus.71 There seems to be a high rate of lower uterine segment involvement in patients with HNPCC-associated endometrial cancer.26
Cervical Involvement
In the 1988 FIGO staging system, cervical involvement was divided into IIA when limited to endocervical glandular involvement and IIB when it involves the cervical stroma. According to the FIGO report, the 5-year survival for stage IIA was very good (89.9% for grade 1 and 83.7% for grade 2). In contrast, the corresponding figures for stage IIB were 81.2% and 76.9%, respectively.28 This led to a change in the 2009 FIGO staging system, in which only cervical stromal invasion is considered stage II. Although the prognosis of the old stage IIA grades 1 and 2 approximated stage I rather than stage IIB, it is important to note that in the same FIGO annual report, patients with stage IIA grade 3 did not fare as well; their 5-year survival was 68.3%, which was worse than that for IC grade 3 (74.9%) and similar to that for IIB grade 3 (64.9%).
Peritoneal Cytology
Peritoneal fluid positive for malignant cells is found in 12% to 15% of all patients undergoing surgical staging. This is associated with 25% pelvic lymph node involvement and 19% para-aortic node involvement.71 The data suggest a higher rate of positive cytology for patients undergoing laparoscopic-vaginal hysterectomy, in which there is manipulation of the uterine cavity, compared to total abdominal hysterectomy, in which there is no such manipulation.84The literature regarding the true impact of positive peritoneal cytology is mixed. One confounding factor, mainly in patients with no other risk factors, is whether all endometrial cancer cells that gained access to the peritoneal cavity are capable of independent growth. In a review of the literature, Wethington et al.85 found that the overall incidence of positive washings is approximately 11%. Patients with grade 1 or 2 disease, no evidence of cervical involvement, <50% myometrial invasion, and no LVI were considered low risk. In patients with positive peritoneal cytology, the rate of recurrence for low-risk patients was 4.1% compared to 32% for those considered high risk (p < .001). This indicates the association of malignant cytology with other adverse prognostic factors. In the recent FIGO staging (2009), having positive peritoneal cytology is no longer considered stage IIIA.
Adnexal/Serosal Involvement
About 5% of patients with stage I and occult stage II disease have adnexal involvement.71 This is associated with a fourfold increase in lymph node metastases; thus, pelvic lymph nodal positivity rises to 32% (as compared with 8% without adnexal spread), and para-aortic nodal involvement is seen in 20% (as opposed to only 5% in patients with no adnexal spread). The incidence of serosal involvement is less common. Jobsen et al.86 reported on 46 patients with isolated adnexal involvement and 21 with isolated serosal involvement. There was no statistically significant difference in outcome between adnexal and serosal involvement. The 5-year disease-free survival was 76.4% versus 59.6% (p = ns), and the disease-specific survival was 76.3 % and 75.4%, respectively.
Pelvic and Para-Aortic Lymph Node Involvement
The pattern of lymphatic spread in endometrial cancer is different than that in cervical cancer. In endometrial cancer, a simultaneous spread to both pelvic and para-aortic nodes could occur, whereas in cervical cancer the spread to para-aortic nodes is almost always secondary to pelvic lymph node involvement. Overall, about 11% of patients with stage I and occult stage II endometrial cancer have pelvic nodal involvement. This increases to 25%, 30%, and 50% with deep myometrial invasion, adnexal involvement, and extrauterine spread, respectively.71 Lymph node involvement is a major predictor of outcome; the 5-year disease-free survival rates drop to 65% to 70% in patients with pelvic lymph node involvement as their only risk factor.87 The rate of para-aortic nodal metastases is about 5% of all patients with stage I and occult stage II disease. The biggest risk factor for para-aortic node involvement is the presence of pelvic nodal metastases; more than 30% of patients with pelvic nodal involvement have para-aortic disease. The 5-year disease-free survival rates drop to about 30% in this subpopulation.87
Molecular Prognostic Factors
The application of molecular biology tools to endometrial cancer has provided insights into the pathogenesis of the disease and may lead to early detection, as well as to development of novel therapeutic strategies.88 Mutations of the tumor suppressor gene p53have been most extensively studied. There is a consistent observation linking the overexpression of p53 with advanced stage and poorer outcome.89,90 Overexpression of HER-2 is also associated with more advanced disease and poor outcome.65 PTEN mutation is associated with early-stage, nonmetastatic disease and more favorable survival outlook.91 Data in the literature suggest a favorable survival outlook associated with microsatellite instability in endometrioid endometrial cancers.92 As our knowledge regarding the molecular biology of endometrial cancer matures, risk stratification may soon be based on molecular alterations rather than pathologic variables.
SURGICAL MANAGEMENT
Surgery is the main treatment for endometrial cancer. It consists of simple hysterectomy, bilateral salpingo-oophorectomy (BSO), and inspection of the pelvic and abdominal cavities, with biopsy of any suspicious extrauterine lesions, accompanied in most cases by peritoneal washings. Surgical assessment of lymph nodes ranges from palpation, biopsy of suspicious nodes, to pelvic and para-aortic lymphadenectomy.
Hysterectomy
There are several approaches to simple hysterectomy, also known as extrafascial hysterectomy, but in the main it consists of removal of the entire uterine corpus and cervix without contiguous parametrial tissue. The pubocervical fascia is entered, and the ureters are not unroofed. Total abdominal hysterectomy/BSO (TAH/BSO) is the most prevalent and time-tested form of simple hysterectomy in endometrial cancer. It is an abdominal approach, usually via a vertical midline incision that allows thorough exploration of intra-abdominal and pelvic cavities. The main drawback of TAH/BSO is, that it is a laparotomy-based approach, in a group of patients with pre-existing comorbidities such as obesity, hypertension, and diabetes. Therefore, it is not surprising that minimally invasive surgery, whether laparoscopically or robotically, has gained a great deal of acceptance in the surgical management of endometrial cancer. In laparoscopic vaginal hysterectomy/BSO (LAVH/BSO) the uterus is removed vaginally rather than abdominally. The benefit of using the laparoscope is to enable the surgeon to have a thorough intra-abdominal exploration and to perform BSO, which is difficult to accomplish with just a vaginal hysterectomy. The GOG completed a trial in which patients with clinical stage I to occult IIA uterine cancer were randomly assigned to laparoscopy (n = 1,696) or open laparotomy (n = 920), including hysterectomy, salpingo-oophorectomy, pelvic cytology, and pelvic and para-aortic lymphadenectomy. The main study endpoints were 6-week morbidity and mortality, hospital length of stay, conversion from laparoscopy to laparotomy, recurrence-free survival, site of recurrence, and patient-reported quality-of-life outcomes.93 Laparoscopy had fewer moderate to severe postoperative adverse events than laparotomy (14% vs. 21%, respectively; p < .0001). Hospitalization of >2 days was significantly lower in laparoscopy than in laparotomy patients (52% vs. 94%, respectively; p < .0001). The conversion rate to laparotomy was 25.8%. With a median follow-up time of 59 months for 2,181 patients still alive, there were 309 recurrences (laparoscopy, 210, laparotomy, 99) and 350 deaths (laparoscopy, 229; laparotomy, 121). The estimated 5-year recurrence rate was 11.61% in the laparotomy arm and 13.68% for laparoscopy. The estimated 5-year overall survival rate was 89.8% for laparoscopy and 89.8% for laparotomy. The study demonstrated that surgical treatment of endometrial cancer can be performed laparoscopically with relatively small differences in recurrence rates (estimated difference at 3 years, 1.14%). These results, combined with improved quality of life and decreased complications associated with laparoscopy, are reassuring to patients and allow surgeons to reasonably suggest this method as a means to surgically treat and stage patients with presumed early-stage uterine cancers.94 In recent years, robotic-assisted hysterectomy/BSO has emerged as an alternative minimally invasive surgery in endometrial cancer. It affords many advantages, including three-dimensional visualization, increased freedom of instrument movement, and enhanced ergonomics and surgeon comfort. The question of difference in cost is under debate debatable.95 Radical hysterectomy is not routinely performed in endometrial cancer due to low incidence of parametrial involvement. There is no evidence to show that the cure rates are any better with such radical operations. The possible exception to this might be in patients with gross cervical involvement.96
FIGURE 70.5. Sentinel lymph node. Solid arrow points to the blue dye in an external iliac node. Dashed arrow points to a lymphatic channel draining to the sentinel node.
Lymphadenectomy
The question of which patients need routine surgical lymph nodal staging and, if so, to what extent is a matter of great debate. The uncertainty about lymphadenectomy relates to whether the benefit from it is prognostic rather than therapeutic. Those who advocate for no lymphadenectomy and limit nodal assessment to inspection and removal of any enlarged/suspicious pelvic or para-aortic nodes cite the lack of documented survival advantages to lymphadenectomy. Furthermore, patients who have adverse pathologic features that increase the risk of microscopic lymph node metastasis are generally offered adjuvant pelvic radiation. Advocates for full pelvic and para-aortic lymph node sampling reason that surgical staging is the most accurate method to assess the extent of disease and that the sensitivity and specificity of palpation of lymph nodes are only 72% and 81%, respectively.97Lymphadenectomy in endometrial cancer includes removal of the fat pads surrounding the major vessels in the abdomen and pelvis without skeletonizing them. According to the GOG surgical guidelines, pelvic lymph nodes are to be removed from the distal one-half of the common iliac artery down to the circumflex iliac vein, and nodal tissue is to be removed anterior to the obturator nerve and surrounding the iliac arteries and vein. The para-aortic nodes include those overlying the vena cava, between the vena cava and aorta, and to the left of the aorta. The cephalad boundary of the para-aortic specimen is generally, but not limited to, the inferior mesenteric artery, and the distal boundary is the midpoint of the common iliac artery.93 For the sampling to be adequate, five lymphatic stations need to be removed—para-aortic, common iliac, internal iliac, external iliac, and obturator—or total of 10 nodes. Optional lymphadenectomy is another approach, in which preoperative tumor grading with intraoperative assessment of depth of myometrial invasion, as well as histologic subtype, is frequently used to decide whether lymph node dissection is necessary at the time of hysterectomy. With such a policy, patients with grade 3 disease or serous or clear-cell histology and those with deep myometrial invasion on frozen section will undergo lymphadenectomy. Opponents of selective lymphadenectomy point out that depth of invasion on frozen section correlated with final pathology in only 67% of cases.98 With regard to grade, preoperative FIGO grade 1 diagnosis correlates with final grade diagnosis in only 85% of cases of endometrial cancer.32
Despite the misgivings about optional or no lymphadenectomy, many surgeons have not embraced full lymphadenectomy. In a study of 27,063 women with unstaged endometrioid uterine cancer, lymphadenectomy was performed in only 30% of patients.99 Two trials addressed the role of lymphadenectomy. The first was an Italian study100 in which 514 eligible patients with preoperative FIGO stage I endometrial carcinoma were randomly assigned to undergo pelvic lymphadenectomy (n = 264) or no lymphadenectomy (n = 250). The median number of lymph nodes removed was 30 in the pelvic lymphadenectomy arm. Both early and late postoperative complications occurred more frequently in patients who had received pelvic systematic lymphadenectomy (81 patients in the lymphadenectomy arm and 34 patients in the no-lymphadenectomy arm; p = .001). Lymphadenectomy improved surgical staging, as statistically significantly more patients with lymph node metastases were found in the lymphadenectomy arm than in the no-lymphadenectomy arm (13.3% vs. 3.2%; p < .001). At a median follow-up of 49 months, the 5-year disease-free and overall survival rates in an intention-to-treat analysis were similar between arms (81.0% and 85.9% in the lymphadenectomy arm and 81.7% and 90.0% in the no-lymphadenectomy arm, respectively). In the second trial (Medical Research Council [MRC]/A Study in the Treatment of Endometrial Cancer [ASTEC]) patients with endometrial cancer believed preoperatively to be confined to the uterine corpus were first randomized to standard surgery consisting of hysterectomy-BSO, pelvic washing, and palpation of para-aortic nodes (n = 704) or to lymphadenectomy (n = 704). In the lymphadenectomy group patients underwent standard surgery plus systematic dissection of iliac and obturator nodes.101 If the nodes could not be dissected, sampling of suspect nodes was recommended. Whether to dissect the para-aortic nodes was left to the discretion of the surgeon. After a median follow-up of 37 months, 191 women (88 standard surgery group, 103 lymphadenectomy group) had died, with an absolute difference in 5-year overall survival of 1% (95% CI = 4 to 6) and an absolute difference in 5-year recurrence-free survival of 6%. The conclusion from both trials was that pelvic lymphadenectomy significantly improved surgical staging, that is, it is a good prognosticator, but it did not improve disease-free or overall survival. As a trade-off between lymphadenectomy and no surgical assessment at all in patients with endometrial cancer, there has interest in adopting a sentinel lymph node approach similar to that in breast cancer (Fig. 70.5). In a recent report from MSKCC, 266 patients with endometrial cancer underwent sentinel lymph node (SLN) mapping. At least one sentinel node was identified in 223 (84%) cases. Location of SLN was in the pelvis in 94% of cases, in the pelvis and para-aortic in 5%, and in the para-aortic in 1%. Positive nodes were diagnosed in 32 of 266 (12%) patients.102 In a prospective trial from France, at least one SLN was detected in 111 of the 125 eligible patients. Of the 111 patients, 19 (17%) had pelvic-lymph-node metastases. Three patients had false-negative results (two had metastatic nodes in the contralateral pelvic area and one in the para-aortic area), giving a negative predictive value of 97% (95% CI = 91 to 99) and sensitivity of 84% (95% CI 62 to 95). SLN biopsy up-staged 10% of patients with low-risk and 15% of those with intermediate-risk endometrial cancer.103 The results from these two studies suggest that SLN mapping is feasible and that adding SLN mapping to surgical staging procedures seems to increase the likelihood of detecting metastatic cancer cells in regional lymph nodes. Whether sentinel lymph node mapping will replace lymphadenectomy needs to be determined.
ROLE OF RADIATION
Radiation therapy plays a significant role in the management of endometrial cancer. It is often used as an adjuvant treatment after surgery (which will be discussed here) or as definitive treatment for patients who are medically inoperable or with local recurrence (which will be discussed later). In the past, most patients were treated with preoperative intracavitary brachytherapy with or without external-beam radiotherapy, followed by hysterectomy. This approach is not without its merit, especially in patients with gross cervical involvement. However, most patients nowadays undergo surgery first; then, depending on the prognostic features obtained from the pathology review, the need for radiotherapy is determined. In recent years there has been a plethora of data from prospective, randomized trials addressing several aspects of the management of endometrial cancer. However, unlike in cervical cancer, for which the data from the majority of the randomized trials pointed in the same direction, that is, chemoradiation is better than radiotherapy (RT) alone, the data in endometrial cancer are less conclusive. Therefore, it is important for radiation oncologists to be familiar with the methodology of these studies so that objections to the use of any form of adjuvant RT can be addressed with facts.
Role of RT in Stages I and II
Treatment options for patients with early-stage endometrial cancer after hysterectomy include observation, intravaginal RT, or pelvic RT. At MSKCC, intravaginal RT is the preferred approach for most patients because it provides the best therapeutic ratio. As the discussion will demonstrate, observation may have the best morbidity profile, but it does not provide the best therapeutic ratio because of the increased risk of local recurrence. Pelvic RT, on the other hand, although very effective in reducing recurrence, has a higher morbidity profile than intravaginal RT. The results of prospective, randomized trials will be discussed first, and then treatment recommendations based on risk factors will follow.
Results of RT Randomized Trials
There are six randomized trials regarding the role of adjuvant RT in early-stage endometrial cancer, mainly pertaining to endometrioid histology and conducted in the “modern” era.
Observation Versus Pelvic RT
Three randomized trials compared pelvic RT to observation in early-stage endometrial cancer. The first trial was the Postoperative Radiation Therapy in Endometrial Cancer (PORTEC) trial, which randomized 715 patients after total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) to observation or pelvic RT.104 Patients included were those with stage (FIGO 1988) IB grades 2 and 3 and those with IC grades 1 and 2. Those with IB grade 1 and those with IC grade 3 were excluded because it was felt that adjuvant RT was not indicated for the former and most physicians would not omit it for the latter. No lymph node sampling was done, and the dose of pelvic RT was 46 Gy at 2 Gy per fraction. At 5 years there was a statistically significant difference in the rates of vaginal/pelvic recurrence in favor of adjuvant pelvic RT (14% vs. 4%; p < .001). Overall survival, however, was not different between the two groups (81% RT vs. 85% surgery; p = .31), and the complications with pelvic RT were significantly higher (25% vs. 6%; p < .0001). In addition, many of the patients who relapsed locally after surgery alone were successfully salvaged with subsequent definitive RT. The second randomized trial was GOG 99. There were 190 patients with stage (FIGO 1988) IB to IIB (grades 1 to 3), who all underwent TAH/BSO, pelvic washing, and pelvic/para-aortic lymph node sampling and then were randomized to observation versus pelvic RT to a dose of 50.4 Gy at 1.8 Gy per fraction.105 At 2 years there was a statistically significant difference in the rates of relapse in favor of the adjuvant pelvic RT arm (3% vs. 12%; p = .007). The 2-year estimated incidence of isolated vaginal/pelvic recurrence was 1.6% in the RT group and 7.4% in the surgery-alone group. There was, however, no significant difference in 4-year overall survival (92% RT vs. 86% with surgery alone; p = .557), but there were more complications with pelvic RT. The third trial consisted of two trials with separate randomizations consolidated into one intergroup trial. One trial was conducted by the MRC and the other by the National Cancer Institute of Canada (NCIC). Furthermore, the MRC ASTEC trial in itself consisted of two trials with separate randomizations designed to answer a surgical as well as a radiation question.106 The surgical question was discussed earlier and regarded the need for lymphadenectomy in clinical localized endometrial cancer.101 The radiation question was whether pelvic RT is needed. Intermediate- or high-risk early-stage patients were then randomized to observation or pelvic RT. Intermediate risk included stage (FIGO 1988) IA grade 3, IB grade 3, IC grades 1 and 2, and IIA grades 1 and 2. High risk included IC grade 3, IIA grade 3, and IA to IIA serous and clear-cell tumors. Patients who had positive pelvic nodes (stage IIIC) were allowed but not those with cervical stromal invasion (IIB). The pelvic RT was given to a total dose of 40 to 46 Gy in 20 to 25 fractions over 4- to 5 weeks. Intravaginal RT was permitted regardless of the pelvic RT randomization as long as it was the stated policy for the treating center to do so. The recommended dose was 4 Gy in two fractions prescribed to a depth of 0.5 cm treating the upper one-third of the vagina when using high dose rate and 15 Gy when using low dose rate. The NCIC had a similar design but with a few exceptions. Patients with stage IIA serous or clear-cell carcinoma were excluded, as were those with positive nodes. The dose of pelvic RT was 45 Gy in 25 fractions, and intravaginal brachytherapy was permitted in accordance with local practice.
Of the 905 patients (789 MRC and 116 NCIC) in the trial, 453 were randomized to observation and 452 to pelvic RT. The two arms were balanced except for more high-risk patients (113; 25%) in the observation arm than in the pelvic RT arm (89; 20%). There were 137 (32%) patients in the observation arm in whom nodes were removed, and 5 (4%) had positive nodes. In the pelvic RT arm, 159 (38%) had nodes removed, and 6 (4%) were positive. In the observation arm, 228 (51%) patients received intravaginal RT, 7 (2%) received pelvic and intravaginal RT, 3 (1%) received pelvic RT, and 3 (1%) were unknown. Only 212 (47%) received no form of adjuvant RT. Conversely, in the pelvic RT arm, 24 (5%) did not receive any adjuvant RT, 10 (2%) received intravaginal RT, and 2 (0.4%) were unknown. Combined intravaginal and pelvic RT was given to 232 (52%) patients, and only 184 (41%) received pelvic RT alone. The primary endpoint of this study was overall survival. With a median follow-up of 58 months, the 5-year overall survival was 84% in both arms (p = .77). The 5-year cumulative incidence for isolated vaginal or pelvic recurrence was 6.1% in the observation group and 3.2% in the pelvic RT group. This difference was statistically significant (p = .2) with a HR of 0.46 (95% CI = 0.24 to 0.89). The rate of any acute toxicity was 27% in the observation arm compared to 57% for pelvic RT. Similarly, late toxicity was more prevalent in the pelvic RT compared to observation (61% vs. 45%, respectively).
The triad of lack of overall survival advantage, increased toxicity, and high salvage rate of local recurrence for patients who are observed have led many to conclude that all forms of adjuvant RT, not simply pelvic RT, should be abandoned. The morbidity of pelvic RT and the validity of omitting adjuvant RT in favor of RT for salvage policy will discussed later in the chapter. With regard to overall survival it is considered the gold standard for primary endpoint in many randomized trials in oncology, but for early-stage endometrial cancer it is perhaps unattainable with adjuvant RT for two reasons. First, many of the patients have other, competing causes of death such as hypertension, diabetes, and obesity. In the PORTEC trial the 8-year actuarial rates of intercurrent death were 19.7% in the RT arm and 15.6% in the surgery-alone arm.107 Endometrial cancer–related deaths in comparison were only 9.6% and 7.5%, respectively. Similarly, in the GOG 99 trial,105 approximately half of the deaths were due to causes other than endometrial cancer or treatment (surgery alone, 19 of 36; RT, 15 of 30). This led the authors of GOG 99 to write, “With this number of intercurrent deaths in both arms, even if RT reduces the risk of endometrial cancer-related deaths, the size of this trial is not adequate to reliably detect an overall survival difference.” That is why overall survival was not the primary endpoint in GOG99 but rather the disease-free interval, which was significantly different in favor of adjuvant pelvic RT over surgery alone.105 Therefore, it is not unreasonable to conclude that neither PORTEC nor GOG 99 was large enough to conclusively show whether adjuvant pelvic RT affected overall survival. The second difficult hurdle for adjuvant RT to overcome when discussing overall survival has to do with its localized nature. In the MRC/NCIC trial, the rate of first vaginal/pelvic recurrence was reduced from 11.4% (n = 37 of 453) in the observation arm to 2.8% (n = 13 of 452) with pelvic RT. Adjuvant pelvic RT, however, did not affect distant spread; the rate of first distant spread was 8.1% (n = 37 of 453) in the observation compared to 9% (n = 41 of 452) in the pelvic RT arm.106 One would expect adjuvant RT to make a difference in overall survival only when systemic therapy makes has an effect on the rate of distant spread. This is exactly the story learned from postoperative chest wall irradiation in breast cancer. Because pelvic RT significantly improved local control, albeit with increased toxicity, why not replace it with intravaginal RT rather than advocating observation for all early-stage endometrial cancer?
Observation Versus Intravaginal RT
In a trial reported by Sorbe et al.,108 645 patients with stage (FIGO 1988) IA to IB grades 1 and 2 endometrioid adenocarcinoma were randomized after surgery to observation (n = 326) or intravaginal RT (n = 319). Surgery consisted of TAH/BSO (laparoscopic surgery was allowed), pelvic washing, and removal of enlarged nodes. The dose and type of intravaginal RT varied among the six centers participating in this trial, but 347 of 645 patients were treated with high dose rate (HDR) to 18 Gy in six fractions. The proximal upper two-thirds of the vagina was treated with the dose prescribed to 0.5 cm from the surface of the cylinder. The rate of vaginal recurrence was 3.1% in the observation arm compared to 1.2% for the intravaginal RT arm (p = .114). The rate of pelvic recurrence was 0.9% in the observation arm and 0.3% in the treatment arm (p = .326). No significance difference was seen between the two arms in terms of overall survival. There was significantly more grade 1 vaginal toxicity with intravaginal RT (8.8% vs. 1.5%; p = .00004). There was no significant difference in gastrointestinal (GI) or genitourinary toxicity.
Pelvic RT Versus Intravaginal RT
In the PORTEC-2 trial, 427 patients were randomized to pelvic RT (n = 214) or intravaginal RT (n = 213). Patients enrolled were those with stage (FIGO 1988) IB grade 3 and >60 years old, IC grades 1 and 2 and >60 years old, and IIA grades 1 and 2 of all ages but with <50% myometrial invasion. During surgery patients underwent TAH/BSO, pelvic washing, and removal of suspicious pelvic or para-aortic lymph nodes. Routine lymphadenectomy was not performed. The dose of pelvic RT was 46 Gy given in 23 fractions. Intravaginal RT was delivered using a cylinder to treat the upper half of the vagina. The dose was prescribed to 0.5 cm from the surface of the cylinder. Three types of brachytherapy were used: HDR to 21 Gy in three fractions, low dose rate to 30 Gy at 0.5 to 0.7 Gy/hr, and medium dose rate to 28 Gy at 1 Gy/hr. With a median follow-up of 36 months, the 3-year vaginal recurrence rates were 0.9% in the intravaginal RT arm and 1.9% in the pelvic RT arm (p = .97). The pelvic recurrence was significantly different; the 3-year rate was 3.5% in the intravaginal RT arm compared to 0.6% in the pelvic RT arm (p = .03). The corresponding rates of isolated pelvic recurrence, however, were not significant: 0.6% versus 1.2%, respectively (p = .54). There was no significant difference in disease-free or overall survival between the two arms. The rate of grades 1 and 2 acute GI toxicity was 53% versus 12% in favor of intravaginal RT (p < .001). This trial showed that intravaginal RT alone is sufficient to control vaginal recurrence even in patients with intermediate- to high-risk features.109
In a more recent Swedish trial reported by Sorbe et al.110 patients with stage (FIGO 1988) I endometrioid adenocarcinoma with at least one of the risk factors grade 3, ≥50% myometrial invasion, or DNA aneuploidy were randomized to adjuvant intravaginal RT (IVRT; n = 263) or pelvic and IVRT (n = 264). Lymphadenectomy was required. There was no difference in vaginal recurrence, which was 2.7% (7 of 263) in the IVRT-alone arm compared to 1.9% (5 of 264) in the combined arm (p = .555). Pelvic recurrence rate, however, was different: 5.3% in the IVRT arm compared to 0.4% in the pelvic plus IVRT arm (p = .0006). There was no significant difference in overall survival between the two arms (90% vs. 89%, respectively). The toxicity was significantly higher in the combined arm compared to IVRT alone.
Radiation Treatment Recommendations for Early-Stage Disease Based on Risk Factors
Based on the results of these trials in early-stage endometrial cancer, it is clear that pelvic RT is an excessive treatment for most of those patients. Therefore the treatment recommendations should be individualized based on risk factors. When deciding on whether to recommend observation, intravaginal RT, or pelvic RT, the risk of vaginal recurrence and pelvic recurrence should be assessed separately. With respect to vaginal recurrence, the data from randomized trials indicate that adjuvant intravaginal RT alone is sufficient to control potential microscopic disease in the vagina. The PORTEC-2 trial showed that intravaginal RT is as good as pelvic RT in controlling vaginal recurrence (0.9% vs. 1.9%, respectively; p = .97) despite the fact that patients included in this trial were at high risk for vaginal recurrence based on age ≥60 years old, deep myometrial invasion, or endocervical gland involvement.109The data from a recent Swedish randomized trial further confirmed that when it comes to vaginal control, IVRT alone is sufficient.110 The vaginal recurrence was 2.9% in the IVRT arm compared to 1.9% (p = .555) in the pelvic plus intravaginal RT arm. How best to reduce pelvic recurrence is more controversial. For patients at low risk of having pelvic lymph node involvement, that is, endometrioid grade 1 or 2 with no or minimal myometrial invasion, neither lymphadenectomy nor pelvic RT is likely to be of significant benefit.111 Those who are at higher risk of having lymph node involvement may need to have their lymph nodes surgically assessed to ensure that they are pathologically negative or receive pelvic RT to control potential microscopic disease. However, the two PORTEC trials, as well as the Swedish trial, showed that the risk of pelvic recurrence was only 2% to 6% even in the absence of lymphadenectomy.104,109,110 This low rate of pelvic recurrence, coupled with the lack of survival advantage to lymphadenectomy and pelvic RT, raises the question of whether either approach is needed for the majority of patients with early-stage endometrial cancer. In the eyes of many, having LVI is almost indicative of nodal involvement. Cohn et al.112 correlated LVI and the risk of positive pelvic nodes in 366 surgically staged patients. The rate of LVI was 25%, and the rate of positive pelvic nodes was 13%. Patients with LVI were significantly more likely to have nodal metastasis (35 of 92 vs. 11 of 274; p < .001). However, the influence of LVI on pelvic nodal metastasis was the strongest in patients with deep myometrial invasion and high grade. Data from MSKCC on 126 patients with endometrioid FIGO (1988) stages IB to IIB and LVI also showed that the mere presence of LVI should not be a trigger for giving pelvic RT, especially when patients had lymphadenectomy. Patients were divided into two groups: those from the old era, when treatment was often pelvic RT, and those from the modern era, when patients were more often treated with lymphadenectomy and intravaginal RT.113 The rate of pelvic relapse for patients with LVI was 7% in the old era compared to 3% (p = .3) in the modern era.
No Myometrial Invasion, Grades 1 and 2
The risk of vaginal recurrence is almost negligible. Straughn et al.114 reported no vaginal recurrence in 103 such patients treated with surgery alone. Pelvic lymph nodal positivity was ≤3%. The 5-year progression-free survival rate in this group was on the order of 95% to 98%. It is unlikely that postoperative pelvic or intravaginal RT would add anything to the final outcome, and therefore radiation is not routinely recommended to this group of patients.
No Myometrial Invasion, Grade 3
In GOG study 33, there were only eight patients with stage IA grade 3 disease, making it difficult to draw any meaningful conclusion.87 There were no relapses in the three patients receiving postoperative radiation as compared with one failure in the five patients who received no postoperative therapy. Straughn et al.114 reported on eight patients with stage IA grade 3 disease treated with surgery alone, with two of patients developing isolated vaginal recurrence. The risk of lymph node metastasis in this group of patients is not very high. At MSKCC, these patients are offered either intravaginal RT alone or observation.
Less Than 50% Myometrial Invasion, Grades 1 and 2
This group of patients constitutes the most common stage subgroup of all endometrial cancers. Straughn et al.114 reported a 3% (9 of 296) risk of vaginal recurrence when surgery alone was done. In the surgery alone arm of the PORTEC-1 trial115 the 5-year vaginal recurrence rate for patients with <50% myometrial invasion grade 2 was 5%. In a randomized trial reported by Sorbe et al.108 the vaginal recurrence rate was 3.1% for those in the observation arm compared to 1.2% for those in the intravaginal RT arm (p= .114). The trial was designed to detect a difference of 1% versus 5% in the vaginal recurrence rate in the two groups. The data were not reported separately based on whether myometrial invasion was present or not, making it difficult to determine the true impact of intravaginal RT on the rate of vaginal recurrence in patients with myometrial invasion. Data from MSKCC on 233 patients with <50% myometrial invasion grade 1 or 2 showed a vaginal recurrence rate of only 1% using intravaginal RT alone.116 In addition, Sorbe et al.117 reported on 110 patients with IB grade 1 or 2 who were part of a prospective, randomized trial evaluating two different intravaginal RT doses; the rate of vaginal recurrence was 0.9%. The risk of pelvic recurrence was only 1.8%, even though lymphadenectomy was not required. This low rate of pelvic recurrence is similar to those reported by Straughn et al.114 of 0.3% (1 of 296) and by Horowitz et al.118 of 0% (0 of 62) in the setting of lymphadenectomy. This indicates that pelvic RT is of limited use, and therefore it seems reasonable to suggest that either observation or intravaginal RT is a reasonable option for patients with grade 1 or 2 and <50% myometrial invasion.
However, when deciding on whether adjuvant RT is needed, it is important to address two issues. First, older patients tend to have higher rates of relapse. In the study by Straughn et al.114 8 of the 10 vaginal/pelvic recurrences were in patients ≥60 years old. In the randomized trial by Sorbe et al.108 comparing adjuvant intravaginal RT to observation, patients with vaginal recurrences were significantly (p = .018) older (mean age, 68.6 years) than patients without vaginal recurrences (mean, 62.6 years). Second, patients with LVI have a higher chance of vaginal recurrence, as demonstrated by Mariani et al.,81 who reported on 508 patients with endometrial cancer limited to the corpus treated with surgery alone. The presence of LVI significantly increased the vaginal relapse rate from 3% to 7% (p = .02). The rate of vaginal relapse would have been even higher if patients without myometrial invasion (152 of 508) had been excluded because LVI is exceedingly rare in patients without myometrial invasion. At MSKCC, patients who are ≥60 years old or have LVI are recommended to have intravaginal RT.
Greater Than 50% Myometrial Invasion, Grade 3
Some advocate observation for patients with <50% myometrial invasion grade 3, yet the 5-year vaginal recurrence rate in PORTEC-1 was 14% for such patients treated with surgery alone compared to 0% for those treated with pelvic RT.115 Perhaps a better choice for those patients is intravaginal RT. The incidence of positive pelvic lymph nodes at time of surgery in this subset of patients is not negligible. In the GOG 33 study the rate was 9% (5 of 54 of patients with inner one-third myometrial invasion), and in the study by Chi et al.119 the rate was 7% (3 of 42) based on <50% myometrial invasion.71 Yet the rate of pelvic recurrence, when the pelvic nodes are not surgically assessed, does not reflect these incidences. In the PORTEC-1 trial, none of the 37 patients with grade 3 disease and <50% myometrial invasion who were treated with TAH/BSO alone relapsed in the pelvis.115 Horowitz et al.118 (n = 31) and Fanning120 (n = 21) reported no vaginal or pelvic recurrence in their series of patients with <50% myometrial invasion grade 3 treated with hysterectomy and lymphadenectomy followed by intravaginal RT. At MSKCC, intravaginal RT is recommended for this subset of patients irrespective of whether lymphadenectomy was performed.
TABLE 70.4 OUTCOME FOR ENDOMETRIAL CANCER WITH ≥50% MYOMETRIAL INVASION (GRADES 1 AND 2) AFTER LYMPHADENECTOMY AND INTRAVAGINAL RADIOTHERAPY ALONE
TABLE 70.5 TREATMENT RECOMMENDATIONS AT MEMORIAL SLOAN-KETTERING CANCER CENTER FOR STAGE I AND II PATIENTS WITH ENDOMETRIOID ADENOCARCINOMA
Fifty Percent or Greater Myometrial Invasion, Grades 1 and 2
The risk of vaginal recurrence with surgery alone in this group of patients is not minimal. In the PORTEC-1 trial, the 5-year vaginal recurrence for patients with ≥50% myometrial invasion treated with surgery alone was 10% for those with grade 1 and 13% for grade 2. The corresponding 5-year vaginal recurrence rates for patients treated with pelvic RT were 1% and 2%, respectively.115 Vaginal control with intravaginal RT alone in this group of patients is about 1.8% based on several series.118,121–122,123 This highlights the fact with regard to vaginal control, pelvic RT is not superior to IVRT in patients with ≥50% myometrial invasion grade 1 or 2. With regard to pelvic control, in the PORTEC-1 trial115 the 5-year pelvic recurrence for patients with ≥50% myometrial invasion treated with surgery alone was 2% for grade 1 and 6% for grade 2. The data from the PORTEC-2 trial109 and the Swedish trial,110 in which patients with ≥50% myometrial invasion grade 1 or 2 were included, indicate that the omission of pelvic RT increased the risk of pelvic recurrence. In PORTEC-2 trial109 the 3-year rate was 3.5% in the intravaginal RT arm compared to 0.6% in the pelvic RT arm (p = .03). In the Swedish trial110 the pelvic recurrence rate was 5.3% in the IVRT arm compared to 0.4% in the pelvic plus intravaginal RT arm (p = .0006). The risk of pelvic recurrence for this subset of patients with lymphadenectomy is about 1.8% on average118,121–122,123 from data in the literature (Table 70.4). At MSKCC, most of these patients undergo lymphadenectomy or SLN mapping, and if the nodes are pathologically negative, they undergo intravaginal RT alone.
Fifty Percent or Greater Myometrial Invasion and Grade 3
In the study by Chi et al.119 the risk of finding positive lymph nodes in this group of patients was 28% (8 of 29). Such patients were not enrolled in the PORTEC trials because it was felt that omitting pelvic RT when lymphadenectomy was not performed could not be justified. In the registry study reported by Creutzberg et al.115 99 patients with ≥50% myometrial invasion grade 3 were treated with postoperative pelvic RT. The 5-year rate of vaginal recurrence was 5%, that of pelvic recurrence was 8%, and that of distant relapse was 31%. Very few investigators would recommend surgery alone for these patients. In fact an argument could be made that pelvic RT might be needed even after a negative lymphadenectomy, especially for older patients and those with LVI. In GOG 99 trial, factors associated with an increased recurrence rate (25% at 5 years) were identified using proportional hazards regression modeling of historical data from GOG 33.105 These factors were (a) increasing age, (b) moderate to poorly differentiated tumor grade, (c) presence of lymphovascular invasion, and (d) outer one-third myometrial invasion. From the results of that analysis a subgroup of patients with high intermediate risk (HIR) was defined as follows: (a) at least 70 years of age with only one of the other risk factors, (b) at least 50 years of age with any two of the other risk factors, or (c) any age with all three of the other risk factors. Those on the RT arm demonstrated a somewhat lower overall death rate when compared to those on the observation arm (relative hazard [RH] = 0.73, 90% CI = 0.43 to 1.26) in the HIR subgroup. AT MSKCC, patients with deep myometrial invasion grade 3 who are high to intermediate risk per GOG 99 would be offered postoperative pelvic RT even in the setting of negative lymphadenectomy. If they are not HIR, then intravaginal RT could be considered, but only in the setting of adequate lymphadenectomy, that is, sampling the obturator, external iliacs, internal iliacs, common iliacs, and para-aortic lymph node stations and a minimum of 10 nodes.
Cervical Involvement
It is important to recognize the distinction between gross and occult cervical involvement. Gross involvement increases the risk of parametrial extension as well as spread to pelvic lymph nodes in a fashion similar to primary cervical cancer. Patients with gross cervical involvement from endometrial cancer could undergo radical hysterectomy and pelvic lymph node dissection or preoperative radiation including pelvic radiation and intracavitary brachytherapy followed by simple hysterectomy. For occult cervical involvement, the treatment often consists of simple hysterectomy with or without lymphadenectomy and adjuvant radiation. The type of radiation most often used is pelvic RT and intravaginal RT. Pitson et al124 reported on 120 patients treated with such a combination. The 5-year disease-free survival rate was 68% and the rate of pelvic relapse was 5.8% (7 of 120).
There are also emerging data on the role of intravaginal RT alone in some patients with occult cervical involvement who also had surgical lymph node staging. The average rate of vaginal recurrence was 1.47% (1 of 68), and pelvic recurrence was also 1.47%. It is important to note that in these series patients treated with intravaginal RT alone were highly selected.118,125–126,127 Patients with endocervical glandular involvement are no longer considered stage II in the new FIGO staging system. In PORTEC-2 trial patients with glandular cervical involvement were randomized to pelvic RT or intravaginal RT.109 At MSKCC patients with endocervical glandular involvement are treated with IVRT alone, especially if there are no other adverse features or if they had lymphadenectomy. For patients with cervical stromal invasion grade 1 and 2 and the depth of cervical stromal invasion is <50%, intravaginal RT could be offered if they underwent adequate lymphadenectomy. For those with grade 3 or deep cervical stromal invasion, pelvic RT is recommended irrespective of lymphadenectomy. Table 70.5 shows overall treatment recommendations for early-stage endometrioid adenocarcinoma at MSKCC.
Role of RT in Stage III
The outcome of patients with isolated adnexal involvement treated with pelvic RT is reasonably good. Connell et al.128 reported on 12 patients treated with postoperative pelvic radiation with a 5-year disease-free survival of 70.9%. The weighted average of 5-year disease-free and overall survival rates from literature review in that study was 78.6% and 67.1%, respectively. Jabson et al.86 reported 5-year disease-free and disease specific survival of 76.4% and 76.3%, respectively, in 46 patients with isolated adnexal involvement treated with postoperative RT. The rate of local/regional recurrence was 2.2% (1 of 46) and that of distant relapse was 26.1% (12 of 46). In the same report, the outcome of patients with isolated serosal involvement (n = 21) was somewhat similar: the 5-year disease-free and disease-specific survival rates were 59.6% and 75.4.3%, respectively. The rate of local/regional recurrence was 14.3% (3 of 21) and that of distant relapse was 33.3% (7 of 21). If pelvic node involvement (IIIC) is the only major risk factor, treatment with postoperative pelvic radiotherapy can yield a 60% to 72% long-term survival rate in these patients.87 Patients with stage IIIC disease, by virtue of para-aortic node involvement, represent a particularly high-risk group. After surgery, these patients are generally treated with extended-field radiation to encompass the pelvis and the para-aortic regions. With this aggressive approach, several investigators reported 30% to 40% survival rates in small patient populations.87 The question of whether it is safe to omit radiation even after adequate surgical lymph node staging in patients with stage IIIC endometrial cancer was addressed in a study from the Mayo Clinic. Mariani et al.129 reported on 122 patients with node-positive disease; at 5 years the risk of pelvic recurrence was 57% after inadequate lymph node dissection and/or no RT compared to 10% with adequate lymph node dissection (>10 pelvic nodes and ≥5 para-aortic nodes) and RT. This difference was statistically significant on univariate (p < .001) and multivariate analysis (p = .03) indicating the need for postoperative radiation even after adequate surgical staging.
The recognition that a significant number of patients with stage III disease fail in the abdomen has prompted a number of investigators to evaluate whole-abdomen irradiation (WAI) in these patients. The GOG did a pilot study (GOG study 94) on patients with maximally debulked stages III and IV disease using whole-abdomen radiotherapy to a total dose of 30 Gy at 1.5 Gy per fraction followed by a pelvic boost for an additional 19.8 Gy at 1.8 Gy per fraction.130 The 3-year disease-free and overall survival rates for the 58 patients with stage III typical adenocarcinoma were both 34.5%, and for stage IV the corresponding rates were 10.4% and 21.1%, respectively.
ROLE OF SYSTEMIC THERAPY
Hormonal therapy has been used in the treatment of recurrent/advanced endometrial cancer for many years. Agents used include megestrol acetate (Megace), medroxyprogesterone acetate (Provera), and to a lesser extent tamoxifen.131–133 The response rate rages from 9% to 33%, with an overall survival of 6 to 14 months. In GOG 107, doxorubicin was compared to doxorubicin and cisplatin.134 The response rate was 42% vs. 25% (p = .004), and the progression-free interval was 5.7 versus 3.8 months (p = .014) in favor of combination chemotherapy. However, this did not translate into overall survival advantage (9 vs. 9.2 months). In GOG 177 trial135 doxorubicin/cisplatin was compared doxorubicin/cisplatin/paclitaxel. The three-drug regimen was superior in terms of response rate (57% vs. 34%, p < .01), progression-free interval (8.3 vs. 5.3 months, p < .01), and survival (15.3 vs. 12.3 months, p = .037).
With the widespread use of chemotherapy in the recurrent/advanced setting, its use in the adjuvant setting has also started to increase and to challenge the role of adjuvant RT. There are several randomized trials addressing the role of adjuvant chemotherapy in advanced endometrial cancer.
Chemotherapy Versus RT Trials
There are three randomized trials comparing adjuvant chemotherapy to radiation. The Japanese Gynecology Oncology Group (JGOG) trial randomized 385 patients with stage (FIGO 1988) IC to III (25% with stage III) endometrial cancer to pelvic radiation (193 patients) or to chemotherapy (192 patients).136 The surgery was hysterectomy with optional lymphadenectomy. The dose of pelvic RT was 45 to 50 Gy using open anteroposterior/posteroanterior (AP/PA) fields. Chemotherapy consisted of cyclophosphamide (333 mg/m2), cisplatin (50 mg/m2), and doxorubicin (40 mg/m2) every 4 weeks for three cycles or more. There was no significant difference in progression-free (p = .726) or overall survival rate (p = .462) between the two groups. A trial from Italy had a similar design, in which 340 patients with stage (FIGO 1988) IC grade 3, stage II grade 3, and stage III (two-thirds of patients) were randomized to radiation or to chemotherapy.137 With a median follow-up of 95.5 months, the 5-year disease-free survival rate was 63% in both arms (p = .44) and the 5-year overall survival rate was 69% in the radiation arm and 66% in the chemotherapy arm (p = .77). Again there was no significant difference in outcome despite using five cycles of Cytoxan, cisplatin, and doxorubicin. In GOG 122, 396 patients with stage (FIGO 1988) III to IV disease were randomized to whole-abdomen radiation (n = 202) versus doxorubicin/cisplatin (n = 194) for eight cycles. Progression-free survival was the primary endpoint of this study. With a median follow-up of 74 months, there was significant improvement in both progression-free (50% vs. 38%; p = .007) and overall survival rate (55% vs. 42%; p = .004), respectively, in favor of chemotherapy. However, before concluding that chemotherapy alone is the answer, a closer examination of the data is warranted. The overall absolute rate of relapse was 54% in the radiation arm compared to 50% in the chemotherapy arm, a small difference, if any, and yet the corresponding 5-year progression-free survival rates were 38% and 50% (p = .007), respectively. The reason for the discrepancy is that in this study, there was stage imbalance, in which there were more stage IIIA patients in the RT arm (28.2%) than in the chemotherapy arm (18%). Conversely, there were more patients with stage IIIC disease in the chemotherapy arm (51.5%) than in the RT arm (44.6%). Therefore, the 5-year disease-free survival rate for the chemotherapy arm was increased from 42% to 50%, which became significantly different than the RT arm (50 vs. 38%, p = .007) rather than 42% versus 38%, which is not likely to be significant. The 5-year overall survival rate in the chemotherapy arm was 55% compared to 42% for the RT arm (p = .004). What are we to make of the significant difference in overall survival? There were 15 deaths unrelated to endometrial cancer or protocol treatment in the radiation arm compared to only to 6 in the chemotherapy arm, raising a question about whether the two arms of the study were truly balanced, especially since no stratification was performed in that trial.138 The results of GOG 122 have led to the adoption of adjuvant chemotherapy as the preferred treatment for stage III endometrial cancer. It is important to note, however, that GOG 122, JGOG, and the Italian study all showed no significant difference in the patterns of relapse between RT and chemotherapy. If one were to use the unadjusted progression-free survival from GOG 122, then all three randomized trials failed to show that adjuvant chemotherapy is superior to adjuvant RT.
Chemoradiation Versus RT Trials
In a trial from Finland,139 156 patients with stage (FIGO 1988) IA or IB grade 3 (n = 28) or stage IC to IIIA grade 1 to 3 (n = 128) were postoperatively randomized to receive radiotherapy (56 Gy) only (n = 72) or radiotherapy combined with three cycles of cisplatin (50 mg/m2), epirubicin (60 mg/m2), and cyclophosphamide (500 mg/m2) chemotherapy (n = 84). The disease-specific overall 5-year survival was 84.7% in the RT arm versus 82.1% in the chemoradiation arm (p = 0.148). Hogberg et al.140 reported on two trials (Mario Negri Gynecologic Oncology Group [MaNGO] and Nordic Society of Gynecological Oncology [NSGO]/European Organisation for Research and Treatment of Cancer [EORTC]) combined in one report. In the MaNGO trial there were 157 patients (two-thirds were stage III); 76 were randomized to postoperative pelvic RT (45 Gy) and 80 to chemotherapy followed by pelvic RT. The chemotherapy consisted of three cycles of doxorubicin (60 mg/m2) and cisplatin (50 mg/m2). The 5-year progression-free survival (PFS) was 61% in the RT group compared to 74% for the chemoradiation group, but that difference was not significant (p = .1). The 5-year overall survival (OS) was also not significant (73% vs. 78%, respectively; p = .41). In the NSGO/EORTC trial 383 patients were randomized to RT (n = 191) versus RT and chemotherapy (n = 187). The type of chemotherapy varied, and only a handful of patients were stage III. The 5-year PFS was better for the chemoradiation arm (79% vs. 72% for RT; p = .04), but OS was not significantly better (83% vs. 76%, respectively; p = .1). Greven et al.141 reported the results of RTOG 9708 phase II study on 44 patients with stages (FIGO 1988) I to III endometrial cancer who were treated with pelvic radiation and intravaginal RT given concurrently with cisplatin 50 mg/m2 on days 1 and 28 of radiation followed by four cycles of cisplatin (50 mg/m2) and Taxol (175 mg/m2). The 4-year disease-free and overall survival rates for those with stage III disease (66% of patients) were 72% and 77%, respectively.
It is clear from the foregoing discussion that the role of adjuvant chemotherapy is gaining ground and that at least the results are equivalent to those with adjuvant RT (Table 70.6). However, adjuvant chemotherapy should not be promoted at the expense of RT, because the rate of relapse is still high even with chemotherapy.142,143 The GOG is comparing chemoradiation (similar to RTOG 9708) to six cycles of carboplatin/paclitaxel in patients with stage III disease. PORTEC 3 is a randomized trial comparing chemoradiation to RT alone. Until the results of these trials are available, the decision on whether to give chemoradiation or chemotherapy alone should be based on risk factors.
TABLE 70.6 EFFECT OF ADJUVANT CHEMOTHERAPY ON OUTCOME IN HIGH-RISK ENDOMETRIAL CANCER
Systemic Therapy Recommendations Based on Risk Factors
Isolated Positive Peritoneal Cytology
In the 2009 FIGO staging system, having positive peritoneal cytology is no longer considered stage IIIA. The true benefits of treatment when adverse features such as high grade or deep invasion are lacking are debatable. Eltabbakh et al.144 reported on 29 patients with FIGO grade 1 or 2 and <50% myometrial invasion who were treated with intravaginal brachytherapy and megestrol acetate (Megace). None of the patients relapsed or died from their disease. Megace was given for 1 year, and at the end of therapy, 24 patients underwent second-look laparoscopy and peritoneal cytology. In 23 patients, the cytology was negative, and the remaining patient, with persistent positive cytology, received an additional year of Megace, after which cytology was confirmed to be negative. At MSKCC, we generally recommend intravaginal RT and Megace for such patients.
Early-Stage Serous and Clear-Cell Cancer
Serous cancer and to a lesser extent clear-cell cancer tend to spread in a fashion similar to ovarian cancer, with a high propensity for upper abdominal relapse. Therefore, it is important to perform comprehensive surgical staging because of the high rate of surgical up-staging. With such pattern of spread, it is not surprising that whole-abdomen radiation has been extensively studied in this group of patients. Lim et al.145 reported on 78 patients with stages I to IIIA papillary serous carcinoma: 58 were treated with whole-abdomen radiation and 20 were not. The corresponding 5-year disease-specific survival rates were 74.9% and 41.3%, respectively (p = .04). The data from GOG 94 were less impressive.146 The 5-year progression-free survival for stages (FIGO 1988) I and II papillary serous cancer was 38.1% and for clear-cell carcinomas was 53.9%. Alektiar et al.147 reported on 25 patients with stages I and II serous endometrial cancer who underwent surgical staging, intravaginal RT, and six cycles of carboplatin/paclitaxel. With a median follow-up of 30 months, the 5-year progression-free and overall survival rates were 88%. None of the patients developed vaginal recurrence. In a recent update on a larger number of patients (n = 41) with a median follow-up time of 58 months, the 5-year disease-free and overall survival rates were 85% and 90%, respectively.148 The 5-year actuarial recurrence rates were 9% in the pelvis, 5% in the para-aortic nodes, and 10% at distant sites. None of the patients developed vaginal recurrence. At MSKCC patients with early-stage disease who are surgically staged are being treated with intravaginal RT with concurrent carboplatin/paclitaxel.
Early-Stage High-Risk Endometrioid Adenocarcinoma
The 5-year rate of distant metastasis from the PORTEC registry study of patients with grade 3 and deep invasion was 31% despite the use of postoperative pelvic RT.115 The rate of relapse was also 28.9% (90% distant) in a study from MSKCC despite an aggressive surgical and adjuvant RT approach.123 Thus it is not surprising that there is an inclination toward recommending adjuvant chemotherapy in addition to RT in this group of patients. The GOG is conducting a randomized trial for patients with high to intermediate risk, as well as serous and clear-cell carcinoma, in which patients are randomized to pelvic RT versus intravaginal RT and three cycles of carboplatin/paclitaxel.
Stage IIIA
The results of postoperative external-beam RT in patients with isolated adnexal or serosal involvement are generally good. However, the rate of distant relapse is still 26% to 33%, indicating the need for adjuvant systemic therapy.86At MSKCC, we recommend concurrent chemoradiation followed by carboplatin/Taxol in a similar fashion to the RTOG 9708. Although the results of isolated involvement with postoperative RT are good, patients with more than one site of involvement do worse. Jobson et al.149 reported on 141 patients with IIIA endometrioid adenocarcinoma (patients with isolated positive peritoneal cytology were excluded) treated with postoperative RT. The risk of abdominal relapse was 12.4% (11 of 89) for patients with one site of involvement compared to 36.5% (19 of 52) for more than one site (p < .001). Distant metastasis rate was 23.9% (21 of 89) compared to 34.6% (18 of 52), respectively. The 5-year disease-specific survival (DSS) was 70.4% for one involved site compared to 43.3% for more than one (p = .001). On multivariate analysis, grade 3 (HR, 2.5; p = .045) and more than one site involvement (HR, 2.2; p = .012) were independent predictors of poor DSS. In the ongoing debate on whether chemotherapy alone is better than chemoradiation in patients with stage III, it is in this group of patients with multiple sites of involvement and grade 3/aggressive histology in which chemotherapy alone might be a better choice.
Stage IIIC
The outcome of patients with isolated lymph node involvement (especially pelvic nodes), treated with postoperative pelvic RT is relatively good. At MSKCC, we recommend chemoradiation followed by carboplatin/paclitaxel to try to reduce the risk of recurrence even further. Similar to patients with IIIA, having more than one site of involvement has been shown to be a predictor of poor outcome.150 In a recent SEER review, Garg et al.151 showed that for patients with stage IIIC disease (n = 2,559), the 5-year disease-specific survival was 67%, which dropped to ~43% when extranodal involvement (i.e., positive washing, adnexa/serosal, and vaginal/parametrial involvement) was present (p < .001). Again, perhaps in this subset of patients with stage IIIC chemotherapy alone might be better.
RADIATION THERAPY TECHNIQUES
Intravaginal Radiation
The purpose of this treatment modality is to deliver the highest dose of radiation to the vaginal mucosa while limiting the dose to the surrounding normal structures such as the bladder, rectum, and small intestines. HDR brachytherapy using 192Ir sources is the preferred method of delivering intravaginal RT. The type of applicator used is generally a cylinder. The treatment is given on an outpatient basis without the need for anesthesia and without the radiation exposure to medical personnel. At MSKCC, patients start their treatment 4 to 6 weeks postoperatively, depending on the vaginal cuff healing. It takes longer for the vaginal cuff to heal after LAVH/BSO and robotic hysterectomy than after TAH/BSO. The treatment is given in three fractions of 7 Gy to a total dose of 21 Gy. The interval between each fraction is 1 to 2 weeks. The dose is prescribed to 0.5-cm depth from the mucosal surface (Fig. 70.6). The treatment is usually delivered using a 3-cm-diameter cylinder to treat a 4- to 7-cm length of the vagina, depending on depth of invasion and tumor grade. For patients with grade 3, serous or clear-cell carcinoma, the length of vagina treated is generally 7 cm (assuming an average length of vagina after simple hysterectomy of about 10 cm). This is done to account for potential submucosal extension that may lead to relapse in the distal periurethral region with these aggressive histologies. For patients with grade 1 or 2 endometrioid adenocarcinoma, the treated vaginal length increases from 4 cm if myometrial invasion is <50%, to 5 cm for >50% myometrial invasion, and to 6 cm for cervical involvement. Occasionally, the dose per fraction is lowered to 6 Gy instead of 7 Gy if the diameter of the cylinder is <3 cm. This is usually done to avoid a very high dose of radiation to the vaginal mucosa. The dose per fraction is also lowered to 4 to 5 Gy when pelvic radiation is added. Intravaginal RT could be delivered with low–dose-rate 137Cs sources, which requires admission to the hospital for a few days. The dose is usually 60 Gy prescribed to the vaginal mucosa or 30 to 35 Gy prescribed to a 0.5-cm depth from the vaginal mucosa.
External-Beam Radiation
Pelvic Radiation
Conventional Pelvic RT
At the time of simulation, the small bowel is opacified using oral contrast, a vaginal marker is used to define the vaginal cuff, and the rectum is opacified with barium or CT-compatible contrasts. Patients are usually placed in the prone position to displace the small intestines from the radiation field. The target volume consists of the pelvic lymph nodes, including obturator, external, internal, and lower common iliac groups, and the proximal two-thirds of the vagina. The presacral nodes are not included unless patients have gross cervical involvement. High-energy linear accelerators (15 MV) are preferred because of their sparing of the skin and subcutaneous tissue. The ideal beam arrangement with conventional radiation is the four-field pelvic-box technique to reduce the dose to the small intestines and to some extent the bladder and rectum. For AP/PA fields, the superior border is L5-S1, the inferior border is the bottom of the obturator foramina, and the lateral border is 2 cm beyond the widest point of the inlet of the true bony pelvis. For lateral fields, the anterior border is in front of the pubis symphysis and the posterior border at least at S2-3. The superior and inferior borders are the same for the AP/PA fields. All fields are treated daily to a dose of 1.8 Gy. A total dose of 50.4 Gy is generally used when pelvic radiation is used alone or 45 Gy when combined with intravaginal brachytherapy.
Intensity-Modulated RT
At MSKCC, postoperative intensity-modulated RT (IMRT) is used for most patients with endometrial cancer who need pelvic RT (Fig. 70.7). At the time of simulation patients are placed in the supine position and immobilized using Aquaplast. Oral and rectal contrasts are used to better visualize the small and large intestines. In addition, contrast is inserted in the vaginal cuff to better visualize the upper vagina. Because pelvic lymph nodes are poorly visualized by CT when normal, they should be defined by encompassing the contrast-enhanced blood vessels. Taylor et al.152 found that a modified 7-mm margin around contrast-enhanced vessels offers a good surrogate target for pelvic lymph nodes. Small et al.153 reported on consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy in postoperative treatment of endometrial and cervical cancer. A modified 7-mm margin (excluding bowel and muscles) is recommended around the iliac vessels to create nodal clinical target volume (CTV). To create nodal planning target volume (PTV), an additional expansion of 7 mm all around nodal CTV is generally recommended. At MSKCC vaginal PTV is created by outlining the contrast enhanced vaginal cuff and adding a 3-cm margin to account for the impact of bladder and rectal filling, as well as of vaginal motion.154
FIGURE 70.6. Dose distribution with intravaginal radiation therapy (prescription dose 7 Gy in solid yellow). A: Sagittal view. B: Axial view.
FIGURE 70.7. Pelvic intensity-modulated radiation therapy dose distribution. Outlined iliac vessels are shown in pink and nodal planning target volume in yellow.
Extended Field
This technique is mainly used for patients with documented positive para-aortic nodes. CT simulation is crucial when treating extended fields for accurate delineation of the kidneys, small bowel, and liver in addition to nodal target. The latter should include, in addition to the pelvic nodes, the pericaval, interaortocaval and para-aortic areas, defined by contrast-enhanced blood vessels. The preferred approach is the four-field box technique rather than AP/PA in order to lower the dose to the small intestines. However, attention should be paid to the dose that the kidneys might receive with the four-field arrangement. The lower border is the same as in pelvic radiation, but the upper border is extended usually to the T12-L1 interspace. The typical dose is 45.0 Gy at 1.8 Gy or 1.5 Gy if patients develop acute gastrointestinal toxicity. At MSKCC, IMRT is also the preferred choice for extended-field radiation.
Whole-Abdomen Radiation
The target is the whole peritoneal cavity, which requires adequate coverage of the diaphragm with adequate margin during all phases of normal respiration with minimal to no liver shielding. The standard approach is AP/PA open fields with five half value layer kidney blocks placed over the PA field only (if the patient is lying supine) from the start of the treatment. The dose is usually 30.0 Gy at 1.5 Gy per fraction, followed by 19.8-Gy boost to the pelvis at 1.8 Gy per fraction. The upper border is usually placed 1 cm above the diaphragm, and the lateral borders should extend beyond the peritoneal reflections. The lower border is usually at the bottom of the obturator foramen. The para-aortic region generally receives a cone down to a total dose of 45 Gy and the pelvis to 50 Gy. IMRT may allow higher and more uniform doses to be delivered with potentially less toxicity.155,156
COMPLICATIONS OF TREATMENT
Surgery
In PORTEC-1 trial104 the rate of complications in the surgery-alone arm was very low (6%). Surgical toxicity data were generally collected within 30 days of surgery, that is, before patients were enrolled in the trial. Therefore it is important to assess surgical toxicity from trials addressing a surgical question. In the GOG LAP2 trial comparing laparotomy to laproscopy93 the rate of intraoperative complications was 8% versus 10%, respectively (p = .106). More important, the rate of postoperative (within 6 weeks of surgery) grade 2 or greater complications was 21% for laparotomy versus 14% for laparoscopy (p < .001). In the Italian randomized trial comparing hysterectomy to hysterectomy and lymphadenectomy, both early and late postoperative complications occurred significantly more frequently in the lymphadenectomy patients (81 of 264; 30.6%) than for hysterectomy alone (34 of 250, 13.6%; p = .001). Most of the difference in morbidity was due to lymphocysts and lymphedema, which occurred in 35 patients in the lymphadenectomy arm and 4 patients in the no-lymphadenectomy arm.100
Radiation
Pelvic Radiation
In the PORTEC-1 randomized trial157 the overall (grades 1 to 4) rate of late complications was 26% in the RT group compared to 4% in the observation group (p < .0001). Most of the late complications in the RT group, however, were grades 1 and 2 (22%), and only 3% were grades 3 and 4. It is also important to note that many patients in this trial were treated with AP/PA fields, for which the overall rate of complications was 30%, compared to 21% for those treated with the four-field box (p = .06). Noute et al.158 reported on the quality of life for patients enrolled in PORTEC-1. Patients treated with pelvic RT reported significant (p < .01) and clinically relevant higher rates of urinary incontinence, diarrhea, and fecal leakage, leading to more limitations in daily activities. Increased symptoms were reflected by the frequent use of incontinence materials after pelvic RT (day and night use, 42.9% vs. 15.2% for surgery alone; p < .001). Patients treated with pelvic RT reported lower scores on “physical functioning” (p = .004) and “role-physical” (p = .003). In GOG 99 when lymphadenectomy was performed, chronic lymphedema was seen in 2.5% of the patients randomized to surgery alone compared to 5% with postoperative pelvic RT.105 There is an increased awareness of sacral insufficiency fractures (SIFs) as a potential complication of pelvic RT in gynecologic cancers. In a recent report from MSKCC, 13 of 223 (5.8%) patients treated with postoperative pelvic RT developed SIF (median time, 11 months after completing pelvic RT). Eight patients (62%) presented with pain, and 5 patients (38%) were diagnosed on incidental imaging. Treatment of SIF included observation in 7 patients (53%), bisphosphonate therapy in 5 patients (38%), and surgery in 1 patient (8%). On multivariate analysis, only osteoporosis was independently associated with SIF (p = .04), with a relative risk of 4.0 (95% CI 1.1 = 15.4). The rate of SIF was 5.5% (8 of 145) for the subset of patients with endometrial cancer.159
The morbidity of rate conventional pelvic radiation could be reduced by using IMRT. Mundt et al.160,161 demonstrated significant reduction in acute and chronic gastrointestinal toxicity when IMRT was compared to conventional radiation. In a recent study from MSKCC,162 the use of IMRT was associated with less bowel obstruction (BO) than with conventional RT. There were 223 patients; 145 (65%) had endometrial cancer. With a median follow-up of 48 months, the overall 5-year actuarial rate of BO was 7.2%. The rate in the IMRT group was 1.2%, compared to 9.6% for conventional RT (p = .025). This was seen despite the fact that more patients in the IMRT group had prior laparotomy (37% vs. 28%; p = .03), had more nodes removed (22 vs. 13 median lymph nodes; p= .001), and received more adjuvant chemotherapy (79% vs. 64%; p = .016). On multivariate analysis the use of IMRT (relative risk, 0.12, 95% CI = 0.015 to 0.987) and body mass index of >30 (relative risk, 0.12, 95% CI = 0.014 to 0.96) were associated with less bowel obstruction.
RTOG 0418 is a recently completed a phase II study on the feasibility of postoperative pelvic IMRT in cervical and endometrial cancers.163 In the subset of evaluable patients with stages I to IIIC endometrial cancer (n = 43), with a median follow-up of 3.5 years, the 3-year DFS and OS rates were 92% and 95%, respectively. Intestinal complications were the most common; 10 patients (23%) had grade 1, 3 (7%) had grade 2, and 1 (2%) had grade 3.
Whole-Abdomen Radiation
The toxicity of whole-abdomen radiation is more pronounced than that of pelvic radiation but not as high as expected. In the radiation arm of GOG study 122, the GI toxicity did not exceed 2% for grade 4 and 11% for grade 3, whereas in the chemotherapy arm the corresponding figures were 7% and 13%. Grade 4 liver toxicity was seen in 1% of patients in the radiation arm, and the grade 4 cardiac grade toxicity was 4% in the chemotherapy arm.138
Intravaginal RT
The main advantage of intravaginal brachytherapy is its ability to deliver a relatively high dose of radiation to the vagina while limiting the dose to the surrounding normal structures, such as the bowels and bladder. This advantage is manifested with the low rate of severe late toxicity seen with this treatment technique, ranging from 0% to 1% in several series.116,118,122 In the intravaginal RT arm of the Swedish trial110 the rate of late intestinal toxicity was 2.3% for grade 1 and 0.4% for grade 2. Urinary tract toxicity was as follows: 20.2% grade 1, 2.7% grade 2, and 0.8% grade 3. Vaginal toxicity rate was 4.1% grade 1, 0.8% grade 2, and 0.8% grade 3. However, such a low rate of severe complications cannot be taken for granted because special attention needs to be paid to the depth of prescription, the dose per fraction, the length of vagina treated, and the diameter of the cylinder used. Sorbe and Smeds164 reported a 15% late complication rate and a very high incidence of vaginal stenosis after postoperative high–dose-rate intravaginal irradiation. This was attributed to the high dose per fraction of 6 to 9 Gy; moreover, this dose was prescribed at a depth of 10 mm from the surface of the cylinder, resulting in very high vaginal mucosal, bladder, and rectal doses.
In PORTEC-2, intravaginal RT patients reported better social functioning (p = .005) and lower symptom scores for diarrhea, fecal leakage, need to stay close to a toilet, and limitation in daily activities due to bowel symptoms (p = .001) compared to pelvic RT. There were no differences in sexual functioning or symptoms between the treatment groups; however, sexual functioning was lower and sexual symptoms more frequent in both treatment groups compared to the norm population.165
Definitive Radiation for Inoperable Disease
Patients with medically inoperable stage I or II uterine cancer are usually treated in a fashion similar to those with cervical cancer by using intracavitary applicators with or without pelvic radiation. For patients with clinical stage I grade 1 or 2 and no evidence of myometrial invasion or lymph node metastasis on MRI, intracavitary brachytherapy alone is sufficient. Usually a Fletcher-Suit or Henschke applicator with one or two tandems (depending on uterus size) and ovoids is used to deliver 70 to 75 Gy to point A. The loading of the tandems is usually different than that in cervical cancer. This is done in order to provide wider coverage of the uterus laterally and superiorly. When pelvic radiation is added, the dose is usually 45 to 50 Gy supplemented with 30 to 35 Gy from intracavitary brachytherapy to bring the total dose to point A to 80 to 85 Gy. Rouanet et al.166 treated 250 patients with endometrial cancer according to this approach, which yielded a 5-year disease-specific survival of 76.5%. HDR intracavitary brachytherapy is being used with increased frequency.167,168 The American Brachytherapy Society established general guideline recommendations regarding HDR alone or in combination with external-beam RT in terms of prescription point (2 cm from the central axis at the midpoint along the intrauterine sources), number of fractions, dose per fraction, combination with EBRT, and optimization.169 Patients with stage IIIB disease (vaginal involvement), an uncommon presentation, are usually not surgical candidates and are also treated with definitive radiation, including a combination of external-beam and intracavitary/interstitial radiotherapy tailored to the extent of their disease.
Radiation Therapy for Local Recurrence
Radiation therapy can be curative in a select group of patients with small vaginal recurrences who have not received prior radiation.170–172 The 5-year local control rate ranges from 42% to 65% and the 5-year overall survival rate from 31% to 53%. Creutzberg et al. reported on survival after relapse based on the PORTEC-1 randomized trial.107 In patients who were initially randomized to surgery alone (n = 46 of 360), the 5-year survival after vaginal relapse was 65%. However, before adopting salvage radiation as a treatment policy for all early-stage endometrial cancer, a few aspects of this trial need to be addressed. First, the 5-year survival rate from the PORTEC trial is much higher than what is reported in the literature. Most likely, the vaginal recurrences in this trial were detected very early, unlike the situation for patients in the community. The extent and size of local recurrence in endometrial cancer are very significant predictors of outcome.173 Second, this high rate of salvage pertains only to isolated vaginal recurrence. The rate of survival at 3 years for pelvic recurrence in the PORTEC-1 trial107 was 0%. Third, although the trial does not mention any data on complications, it is not unrealistic to expect a higher complication rate than what is normally seen with adjuvant radiation. With salvage radiation, external-beam RT and brachytherapy are often combined, and the doses of radiation required are much higher than those used with adjuvant radiation. The study from MD Anderson Cancer Center by Jhingran et al.170 clearly highlights these issues. They reported on 91 patients who were treated with definitive radiation for isolated vaginal recurrence. The 5-year local control and overall survival rates were 75% and 43%, respectively. The median dose of radiation was 75 Gy, which often included external radiation and brachytherapy. The rate of grade 4 complications (requiring surgery) was 9%. Thus, when talking with a patient about adjuvant radiation versus radiation reserved for salvage, these issues need to be addressed and compared to the excellent local control and low morbidity obtained with adjuvant intravaginal brachytherapy.
UTERINE SARCOMA
Uterine sarcomas are uncommon, representing about 3% to 7% of all uterine cancers.174 The World Health Organization (WHO) classification includes endometrial stromal tumors, smooth muscle tumors, and miscellaneous mesenchymal tumors. In the mixed epithelial and mesenchymal tumors category, the WHO classification includes adenosarcoma and malignant mixed Müllerian tumors or carcinosarcoma.51 Age-related incidences vary among the histologic types. The mean age at diagnosis for endometrial stromal sarcoma is 41 years, for leiomyosarcoma 53.5 years, for adenosarcoma 57.4 years, and for carcinosarcoma 65 years. Little is known about the risk factors for uterine sarcomas, except for history of prior radiation and carcinosarcoma.175 Most uterine sarcomas present with vaginal bleeding, especially carcinosarcomas. Leiomyosarcomas are more commonly discovered incidentally after simple hysterectomy for presumed uterine leiomyomata.
Nodal metastases are seen in approximately 14% of carcinosarcomas at the time of surgical staging but are rarely (<5%) seen in leiomyosarcoma unless there is obvious extrauterine disease. For stromal sarcomas, dos Santos et al.176 reported a 19% (7 of 36) rate of nodal metastasis. The rate of occult metastasis was only 10%. The corresponding rates from the literature review were 10.1% and 8.1%, respectively.
Pathology and Staging
Endometrial stromal sarcomas are generally divided into endometrial stromal sarcomas, which are low grade by definition, and undifferentiated endometrial sarcoma, which are high grade. Tumor cells in endometrial stromal sarcoma resemble those found in the stroma of proliferative endometrial lining. In contrast, tumor cells in undifferentiated endometrial stromal sarcoma do not resemble endometrial stroma. Leiomyosarcomas of the uterus have a fleshy appearance, often with areas of necrosis. They display nuclear atypia, high mitotic rates, and areas of coagulative tumor necrosis. Adenosarcomas have two components—a benign epithelial tumor and a malignant mesenchymal component (generally low-grade sarcoma that resembles endometrial stroma). Sarcomatous overgrowth, defined as the presence of pure sarcoma, usually of high grade and without a glandular component, occupying at least 25% of the tumor, has been reported in 8% to 54% of uterine adenosarcomas.174 Tumors containing both malignant epithelium, that is, carcinoma, and malignant soft-tissue tumors, that is, sarcomas, are called carcinosarcomasor malignant mixed Müllerian tumors. These neoplasms are often bulky, necrotic, and deeply invasive. The epithelial component is generally serous carcinoma. Homologous tumors have stroma that contains cell types normally seen in the uterus, in contrast to heterologous tumors, which may contain striated muscle cells (rhabdomyosarcoma) cartilage (chondrosarcoma), and bone (osteogenic sarcoma). Whether carcinosarcomas are epithelial tumors or sarcomas continues to be debated. Gene profiling may shed some light on that intriguing question.177 The 2009 FIGO staging recognizes the uniqueness of each uterine sarcoma. For leiomyosarcomas and endometrial stromal sarcomas, the staging system recognizes the importance of tumor size on outcome. For adenosarcomas, the new staging system recognizes the importance of depth of myometrial invasion. For carcinosarcomas, the 2009 staging system for carcinomas of the endometrium is used, recognizing the similarity in patterns of spread.174
Management
The main treatment for uterine sarcoma is surgery in a similar fashion to endometrial adenocarcinoma. The extent of surgical staging varies, depending on the risk of lymph node involvement. Patients with carcinosarcoma should undergo comprehensive surgical staging similar to that with serous cancer. Patients with endometrial stromal sarcomas and adenosarcomas might benefit from lymph node sampling. On the other hand, for patients with leiomyosarcomas the rate of nodal involvement is too low to justify routine lymphadenectomy.178
A GOG clinicopathologic study of 453 patients with uterine sarcomas reported a 53% recurrence rate in carcinosarcoma and 71% in leiomyosarcoma, with the site of first recurrence being the pelvis in 21% of carcinosarcomas (19% in homologous and 24% in heterologous types) and 14% of leiomyosarcomas, respectively. Distant failure, as the first site, occurred in 14% of carcinosarcoma and 41% of leiomyosarcoma patients, respectively. Forty percent of patients with carcinosarcoma received adjuvant pelvic RT compared with 22% of leiomyosarcoma patients. The pelvic failure was 17% in patients receiving RT compared with 24% for those who did not.179
With regard to the role of adjuvant radiation, the EORTC performed a prospective, randomized trial addressing the role of postoperative pelvic RT in stages I to II uterine sarcomas. There were a total of 224 patients in the trial who underwent TAH/BSO, and 166 who had peritoneal washings. Lymphadenectomy was optional. There were 103 leiomyosarcomas (LMSs), 91 carcinosarcomas, and 28 endometrial stromal sarcomas. The 5-year cumulative incidence of locoregional recurrence was 18.8% in the pelvic RT arm compared to 35.9% in the surgery-alone arm. That difference was statistically significant (p = .0013). The 5-year cumulative incidence of distant relapse was 45.3% for the pelvic RT and 33.6% for surgery alone, but the difference was not statistically significant (p = .2569). There was no significant difference in progression-free (p = .3254) or overall survival (p = .923) between the two arms. For patients with carcinosarcoma, the rate of pelvic recurrence only was 4% in the pelvic RT arm compared to 24% for the surgery-alone arm. The corresponding rates for any local recurrence were 24% and 47%, respectively. For LMS patients, the rate of pelvic recurrence only was 2% in the pelvic RT compared to 14% in patients treated with surgery alone, and for any local recurrence it was 20% versus 24%. This seems to indicate that the pelvic control benefit is mainly seen in carcinosarcoma.180 It is important to note that the primary endpoint of this trial was pelvic control, which it met (p = .0013). The study was not powered to detect a significant difference in PFS or OS. Sampath et al.181 performed a retrospective review of uterine sarcoma patients using the National Oncology Database. The impact of adjuvant radiation was assessed in patients who presented with nonmetastatic disease and underwent definitive surgery (n = 2,206). In patients with carcinosarcoma, the 5-year local-regional failure-free survival was 90% for those who received adjuvant RT (n = 490) compared to 80% for those who received surgery alone (n = 638; p<.001). For endometrial stromal sarcoma, the rate was 97% with RT (109) versus 93% for surgery alone (n = 252; p < .05). For LMS it was 98% for RT (n = 131) compared to 84% with surgery alone (n = 398; p < .01).
The role of adjuvant chemotherapy has been evaluated mainly in carcinosarcoma. Sutton et al.182 reported on 65 patients with completely resected stage I or II carcinosarcoma of the uterus treated with adjuvant ifosfamide and cisplatin. Overall 5-year survival was 62%. None of the patients received adjuvant RT in this GOG trial. Initial site of relapse was vaginal apex in 6 of 65 and pelvis in 4 of 64, suggesting that a combined chemoradiation approach might be ideal. GOG-150 is a phase III randomized study of WAI versus three cycles of cisplatin, ifosfamide, and Mesna (CIM). Eligible patients (n = 206) included those with stages I to IV uterine carcinosarcoma, no greater than 1-cm postsurgical residuum, and/or no extra-abdominal spread. Stage distribution was as follows: I, 64 (31%); II, 26 (13%); III, 92 (45%); IV, 24 (12%). The estimated crude probability of recurring within 5 years was 58% for WAI and 52% for CIM. Adjusting for stage and age, the recurrence rate was 21% lower for CIM patients than for WAI patients (RH, 0.789, 95% CI = 0.530 to 1.176; p = .245, two-tailed test). The estimated death rate was 29% lower in the CIM group (RH, 0.712, 95% CI = 0.484 to 1.048; p = .085, two-tailed test). The conclusion was that there was not a statistically significant advantage in recurrence rate or survival for adjuvant chemotherapy over WAI in patients with uterine carcinosarcoma. However, the observed differences favor the use of combination chemotherapy in future trials. The rate of vaginal recurrence was 4 of 105 (3.8%) in the WAI compared to 10 of 101 (9.9%). The corresponding abdominal relapse rates were 27.6% (29 of 105) and 18.8% (19 of 101). There was no difference in pelvic recurrence between the two arms. The rates of lung metastasis (14 of 105 vs. 14 of 101, respectively) or other distant sites (13 of 101 vs. 10 of 101, respectively) were similar. Analysis of the patterns of relapse from this trial also indicates the need for chemoradiation in patients with stages I to III carcinosarcoma.183 At MSKCC, patients with surgical stages I or II carcinosarcoma are treated with intravaginal RT and chemotherapy. Stage III patients are treated with concurrent pelvic RT/cisplatin followed by carboplatin/paclitaxel.
For patients with leiomyosarcomas the main treatment is surgery, and the role of adjuvant treatment, whether RT or chemotherapy, is not well defined. The high rate of distant relapse in these patients overshadows any local control benefit attained with adjuvant RT. These patients should be encouraged to participate in trials assessing the role of chemotherapy and/or targeted therapy. For patients with endometrial stromal sarcomas (low grade) observation is feasible. For those with undifferentiated endometrial sarcomas adjuvant pelvic RT is reasonable. For patients with adenosarcomas, especially with sarcomatous overgrowth, adjuvant pelvic RT is also reasonable. Carcinosarcomasshould be treated in a similar fashion to other high-risk endometrial cancers. For early-stage comprehensively staged patients, intravaginal RT and chemotherapy is recommended. Patients with stage III could be treated with concurrent pelvic RT and cisplatin followed by carboplatin/paclitaxel.
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