Staging & Management for Uterine Cancer
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
The American Cancer Society (ACS) estimates that uterine cancer caused 7,000 deaths with an estimated 40,000 cases in the United States for 2008 (1). However, 75% of uterine cancers are diagnosed at an early stage and cured by surgery alone. In the past 50 years, the treatment of this cancer has evolved from a regimen of preoperative intracavitary radium packing or external radiation therapy, followed in 6 weeks by hysterectomy, to a single application of intrauterine tandem and vaginal ovoids, followed immediately or in 6 weeks by hysterectomy, to a customized treatment program that uses hysterectomy and surgical staging as primary therapy and employs additional treatment depending on various risk factors. In the past 30 years, a number of chemotherapeutic regimens have been tested as adjuvant treatment in the primary setting or for recurrent disease. In the past 10 years, helpful criteria have been adopted to permit differentiation of the two conditions into a benign lesion (atypical hyperplasia) and a neoplasm that is progressive (well-differentiated carcinoma).
The purpose of this document is to understand the staging and management of uterine cancer (endometrial cancer). The carcinoma of the endometrium is easily diagnosed, but the well-differentiated cancers may be difficult to separate from advanced atypical hyperplasia. This document also outlines the rationale for the use of chemotherapy in selected patients with endometrial cancer. In a disease long regarded as the province of the surgeon and radiation oncologist, a new look at chemotherapy is producing promising results.
Pretreatment and Staging Studies:
After the diagnosis of endometrial carcinoma has been histologically confirmed, the patient should undergo a thorough evaluation. A complete physical examination can discover suspicious lymph nodes and areas of spread within the pelvis. These patients often have other medical problems that must be evaluated for their effect on treatment choices for the cancer. Routine preoperative investigation for early-stage endometrial carcinoma are: full blood count; serum creatinine and electrolytes; liver function tests; blood sugar; urinalysis and x-ray chest.
In more advanced cases, cystoscopy and sigmoidoscopy are necessary, if bladder or rectal involvement is suspected clinically. A colonoscopy should be performed if there is occult blood in the stool or a recent change in bowel habits because concomitant colon cancer occasionally occurs, particularly if there is a family history of bowel cancer. A pelvic and abdominal computed tomographic (CT) scan may be helpful to determine the extent of metastatic disease in the following circumstances: abnormal liver function tests; clinical hepatomegaly; palpable upper abdominal mass; palpable extrauterine pelvic disease and clinical ascites. Magnetic resonance imaging (MRI) has limited usefulness in determining the depth of myometrial invasion or the presence of nodal disease. MRI was evaluated as a tool for preoperative staging in a National Cancer Institute cooperative study; until image quality and techniques improve significantly, MRI is not a cost effective method for the preoperative evaluation of patients with endometrial cancer (2).
Endometrial carcinoma spreads by the following routes:
- Direct Extension - it is the most common route of spread, and it results in penetration of the myometrium and eventually the serosa of the uterus. The cervix and fallopian tubes and ultimately the vagina and parametrium may be invaded.
- Trans-tubal Dissemination - the presence of malignant cells in peritoneal washings and the development of widespread intra-abdominal metastases in some patients with early stage endometrial cancer strongly suggest that cells may be exfoliated from the primary tumor and transported to the peritoneal cavity by retrograde flow along the fallopian tubes.
- Lymphatic Dissemination - it is clearly responsible for spread to pelvic and para-aortic lymph nodes. Although lymphatic channels pass directly from the fundus to the para-aortic nodes through the infundibulo-pelvic ligament, it is rare to find positive para-aortic nodes in the absence of positive pelvic nodes. It seems likely that vaginal metastases also result from lymph-vascular spread. They commonly occur in the absence of cervical involvement, excluding direct spread as the mechanism, and may occur despite pre-operative sterilization of the uterus with intracavitary radiation, excluding implantation of cells at the time of surgery as the mechanism.
- Hematogenous Dissemination - it most commonly results in lung metastases, but liver, brain, bone and other sites are involved less commonly.
Endometrial cancer is a surgically staged disease. To appropriately stage by International Federation of Gynecology and Obstetrics (FIGO) criteria, the surgical procedure should minimally include an adequate abdominal incision (usually vertical), sampling of peritoneal fluid for cytologic evaluation (intraperitoneal cell washings), and abdominal and pelvic exploration with biopsy or excision of any extrauterine lesions suspicious for tumor. These procedures should be followed by total extrafascial hysterectomy and bilateral salpingo-oopherectomy. Any suspicious pelvic or para-aortic lymph nodes should be removed for pathologic evaluation. If certain high-risk factors are found, routine sampling is indicated if there are no suspicious retroperitoneal nodes. All surgical specimens should be evaluated. Optimally, the surgical pathologist, who can grossly estimate the depth of invasion, assesses involvement of the cervix, and later sample the tumor for histologic assessment, should open the unfixed uterus. Invasion of the myometrium may be more extensive microscopically than is evident visibly, because of the characteristic infiltrative growth pattern of the tumor, although gross visual examination by the operating team of the cut uterine surface at the tumor site can accurately determine the depth of myometrial invasion in 91% of the patients.
Laparoscopic approach has been used increasingly over the past 5 years. A radical hysterectomy may be performed to allow removal of the parametria, cervix, and proximal vagina when cervical extension is suspected. In 1987, a large surgical-pathologic study conducted by the Gynecologic Oncology Group (GOG) found that extrauterine spread in patients with apparent Stage I disease was common. As a result of this and other studies, complete surgical staging with lymphadenectomy has been incorporated increasingly into the surgical treatment of endometrial cancer. Many experts have suggested that the primary role of surgical staging is to identify more patients who do not require adjuvant therapy, or who require less extensive adjuvant treatments such as vaginal-cuff brachytherapy (localized radiation treatment to the vaginal vault that confers minimal toxicity) (3).
International Federation of Gynecology and Obstetrics (FIGO) Staging System for Endometrial Cancer (4):
Stage IA - Tumor limited to the endometrium
Stage IB - Invasion <50% of the myometrium
Stage IC - Invasion >50% of the myometrium
Stage IIA - Endocervical glandular involvement only
Stage IIB - Cervical stromal invasion
Stage IIIA - Tumor invades uterine serosa and/or adnexa, and/or positive peritoneal cytology
Stage IIIB - Vaginal metastases
Stage IIIC - Metastases to pelvic and/or para-aortic lymph nodes
Stage IVA - Tumor invasion of bladder and/or bowel mucosa
Stage IVB - Distant metastases including intra-abdominal and/or inguinal lymph nodes < h3>Prognostic Factors:
Although stage of disease is the most significant prognostic variable, a number of factors have been shown to correlate with outcome in patients with the same stage of disease. Age appears to be an independent prognostic variable. Using proportional hazards modeling of relative survival time, and taking 45 years of age as the arbitrary reference point, the relative risks for death according to The Gynecologic Oncology Group (GOG) were as follows: 2.0 at 55 years, 3.4 at 65 years, and 4.7 at 75 years of age. Papillary serous carcinomas have a poor prognosis even in the absence of deep myometrial invasion or lymph node metastasis. They disseminate widely, with a particular predilection for recurrence in the upper abdomen. At the time of surgical staging, 62% of the patients with an unfavorable histologic subtype can have extrauterine spread of disease. Clear cell carcinomas represent fewer than 5% of endometrial carcinomas, although clear cell elements are commonly present in papillary serous tumors. Vascular space invasion is more common in these lesions. Squamous cell carcinomas of the endometrium are rare. The survival rate for patients with clinical stage I disease in this category is only 36%.
There is a strong correlation between histologic grade, myometrial invasion, and prognosis. Increasing tumor grade and myometrial penetration are associated with an increasing risk of pelvic and para-aortic lymph node metastases, adnexal metastases, positive peritoneal cytologic washings, local vault recurrence, and hematogenous spread. Vascular space invasion appears to be an independent risk factor for recurrence and for death from endometrial carcinoma of all histologic types. The overall incidence of lymph-vascular invasion in stage I endometrial carcinoma is approximately 15%, although it increases with increasing myometrial invasion and decreasing tumor differentiation. In general, mean estrogen receptor (ER) and progesterone receptor (PR) levels are inversely proportional to histologic grade. However, ER and PR content have been shown to be independent prognostic indicators for endometrial cancer; that is, patients whose tumors are positive for one or both receptors have longer survival than patients whose carcinoma lacks the corresponding receptors (5).
Treatment of Uterine Cancer
The cornerstone of treatment for endometrial cancer is total abdominal hysterectomy and bilateral salpingo-oopherectomy plus peritoneal cytology, and this operation should be performed in all cases whenever feasible. Removal of vaginal cuff is not necessary. In addition, many patients require some type of adjuvant radiation therapy to help prevent vaginal vault recurrence and to sterilize occult disease in lymph nodes. Microscopic cervical involvement (positive endocervical curettage) is often designated stage II occult disease. For practical purposes, such patients can be managed in the same way as patients with stage I disease. When the carcinomatous tissue obtained at endocervical curettage is completely separate from the endocervical tissue, it presumably represents contamination from the corpus, because the prognosis in such circumstances is similar to that of stage I disease. False-positive rates of 40% to 50% have been reported for endocervical curettage. A false-negative endocervical curettage may also occur, so if the cervix is firm and expanded and the endocervical curettage is negative, a wedge biopsy to include the underlying stroma may be necessary to determine cervical involvement.
Pelvic lymphadenectomy, with or without para-aortic lymphadenectomy, plays an important role in the surgical staging of endometrial cancer, and thus provides more accurate prognostic information. The therapeutic role of lymphadenectomy and its ability to modify adjuvant therapy are less well understood, although several reports are provocative. If there is a therapeutic benefit, it must surely be related to the resection of bulky, positive nodes, which are unlikely to be sterilized with external-beam radiation therapy. The feasibility of using the results of pelvic lymphadenectomy to modify adjuvant radiation therapy has been addressed in several non-randomized trials. All reports would suggest that if the lymph nodes are negative, it may be reasonable to omit external therapy and rely on brachytherapy to prevent vault recurrence, thereby saving both treatment time and money (6).
For those patients who require adjuvant radiation, the therapy can be better tailored to the needs of the individual patient. The options for post-operative management are as follow:
- Vault brachytherapy
- External pelvic irradiation
- Extended-filed irradiation
- Whole abdominal irradiation
- Intraperitoneal 32P
Patients with stage IA or IB, grade 1 or 2 tumors have an excellent prognosis, and no adjuvant radiation is necessary for this group. If patients are treated without adjuvant therapy, they must be followed carefully so that vault recurrences can be diagnosed early, when they are eminently curable. Vaginal brachytherapy significantly reduces the incidence of vault recurrence. With high dose-rate therapy, treatment can be accomplished as an outpatient, and the morbidity is low. When performed on patients who have negative lymph nodes after surgical staging, it is cost-effective method of treatment (7). If patients are treated without adjuvant therapy, they must be followed carefully so that vault recurrences can be diagnosed early, when they are eminently curable.
Vaginal brachytherapy significantly reduces the incidence of vault recurrence. With high dose-rate therapy, treatment can be accomplished as an outpatient, and the morbidity is low. When performed on patients who have negative lymph nodes after surgical staging, it is a cost-effective method of treatment. The available evidence would support vault brachytherapy without teletherapy for patients with negative nodes after at least a complete pelvic lymphadenectomy. With an increasing number of patients in cancer centers having pelvic lymphadenectomy as part of their primary surgery, the indications for external pelvic irradiation are decreasing. Patients with positive pelvic nodes are candidates for external pelvic radiation, if necessary combined with para-aortic radiation. It is also a reasonable option for high-risk patients who have not undergone surgical staging but have a negative chest radiograph, a negative pelvic and abdominal CT scan, and normal CA 125 level. According to GOG report the 2-year progression-free survival rate was significantly higher in the group receiving adjuvant radiation; however, overall survival rates were not significantly different (8). External irradiation appears to be as effective as vaginal brachytherapy for sterilizing micro-metastases at the vaginal; thus, there seems to be no reason to give both external and vault irradiation after surgery because morbidity will be significantly increased.
The current indications for extended-field radiation, in the most cancer centers, are patients with: biopsy-proven para-aortic nodal metastasis; positive common iliac nodes; grossly positive pelvic nodes or multiple positive pelvic nodes. The current indications for whole abdominal radiation, in the most cancer centers, are: patients with endometroid carcinomas and omental, adnexal, or peritoneal metastases that have been completely excised and patients with serous papillary or clear cell carcinomas with positive peritoneal washings.
Most patients with malignant washings are also at risk of vaginal vault and pelvic sidewall recurrences and thus require external pelvic irradiation. When the later combined with intraperitoneal 32P, 29% had chronic intestinal morbidity necessitating surgical intervention. Other problems associated with 32P include the uneven distribution of fluid commonly present and the potential for bowel injury from "hot spots". Routine adjuvant therapy for patients with malignant cytologic findings is not justified (9).
Hormonal and Chemotherapy Treatments:
Although the role of progestins in the management of patients with advanced and recurrent endometrial cancer has been established, they have not been shown to be of value in an adjuvant setting. Patients receiving MPA (medroxyprogesterone acetate) 200 mg twice daily for at least 3 years, or until recurrence in high-risk disease has been shown no difference in survival. Most tumors that recur are of higher grade and do not have progestin receptors, thus limiting the effectiveness of hormonal therapies. Improvements in chemotherapy have also paved the way for its use in the initial management of patients with endometrial cancers. Chemotherapy has the potential to address local or distant sites of disease. Combining active agents, including adriamycin/cisplatin (AP), paclitaxel/adriamycin, paclitaxel/carboplatin, and paclitaxel/adriamycin/cisplatin (TAP); has been the most common strategy to try to improve response and survival (10).
Perhaps one of the most important recent developments in cancer therapy has been the identification of specific molecular targets in tumors that respond to novel, highly selective agents. These non-cytotoxic agents, or "biologics", result in decreased proliferation of cancer cells and can activate apoptotic pathways (ie, programmed cell death). Identification of the most important molecular targets in endometrial cancer and the activity of biologics in tumors with varying characteristics (histology, grade, stage) remain to be defined. Biologic agents will likely require combination with cytotoxic agents for best activity, or may be used in adjuvant settings for patients who have completed treatment but remain at risk for recurrence.
Stage II Endometrial Cancer Management:
Stage II endometrial cancer is characterized by either cervical glandular (stage IIA) or cervical stromal (stage IIB) involvement. Cervical involvement by endometrial adenocarcinoma represents a negative prognostic factor and increases the risk of lymph node metastases. At the time of diagnosis, stage II tumors are noted in approximately 10% of women with endometrial cancer. Survival in patients with stage II tumors has been reported to range from 72% to 93%. The management of stage II neoplasms remains controversial. To date, few prospective data have been reported, and treatment strategies rely on observational studies. Initial management of stage II tumors is usually surgical: either extrafascial or radical hysterectomy. Radical hysterectomy has been advocated for women with stage II tumors, given that 13% of patients with endometrial cancer have parametrial metastases. Surgical therapy is often followed by adjuvant radiotherapy. Whether radiation improves survival in this cohort and whether external beam therapy is required remain poorly defined (12). The ideal management for stage II endometrial cancer remains a subject of active debate. Most findings suggest that adjuvant radiation improves survival for women with stage II disease, but that the type of hysterectomy performed has little influence on outcome. In this study (12) women who did not receive radiation were 48% more likely to die from their tumors.
The benefit of adjuvant radiation is most pronounced in women with high-risk pathologic features who underwent radical hysterectomy. The role of radiation in the treatment of stage II endometrial cancer is uncertain. Whereas the majority of retrospective data have not demonstrated a benefit for radiation, it has been suggested that women who undergo simple hysterectomy and are found to have cervical disease may benefit from radiotherapy. Clearly further prospective work to define treatment algorithms for subclasses of women of stage II endometrial cancer is warranted.
Clinical implications of the study are:
- Radical hysterectomy does not need to be routinely performed in all women with stage II endometrial cancer;
- Radical hysterectomy in combination with radiation may improve survival for women with high-risk stage II endometrial cancer.
- Finally, it is impossible to determine both physician and patient preferences that influence the selection of the surgical procedure and the decision to administer adjuvant radiotherapy.
Treatment of Advanced and Recurrent Disease:
Treatment of recurrent disease depends upon the original stage, the location of the recurrence and prior treatments. The most common site for recurrence of stage I disease is the vagina. Isolated vaginal recurrences in non-radiated women are generally treated with whole pelvic radiation therapy and vaginal brachytherapy. Survival after relapse is significantly better in women without previous radiation therapy. In this study treatment for vaginal relapse is effective, with 89% complete response and 65% 5-year survival in the control group (11). There was no difference in survival between patients with pelvic relapse and those with distant metastases. If the recurrence is limited to the vagina, survival is better than if the disease involves the pelvic sidewall. The majority of isolated vaginal recurrences in women with surgical stage I endometrial cancer can be successfully salvaged with radiation therapy.
For system disease, hormonal therapy with progestins has been a favored therapeutic option because of its minimal toxicity. The response rates have been reported in 10% to 25% of women. Recent studies have tried to improve this response rate by combined therapy with tamoxifen to increase the progesterone acetate. The response was 33%. The median progression-free survival was 3 months and median overall survival was 13 months (10). The combination of daily tamoxifen and intermittent weekly medroxyprogesterone acetate is an active treatment for advanced or recurrent endometrial carcinoma. Chemotherapy can be initial therapy for advanced disease or with recurrence after hormonal therapy. The combination of cisplatin, doxorubicin, and paclitaxel is the most active chemotherapeutic regimen reported in advanced or recurrent endometrial cancer. The GOG did a randomized prospective study with cisplatin and doxorubicin. Cisplatin, doxorubicin, and paclitaxel significantly improved progression-free survival and overall survival compared with cisplatin and doxorubicin. Although cisplatin, doxorubicin, and paclitaxel are the most active regimen, the toxicity has led many physicians to treat women with carboplatin and paclitaxel. A phase III study to evaluate the effectiveness of these two regimens as well to evaluate differences in quality of life is in progress.
The decision to undertake surgical staging is usually based on the histopathology from the uterine curettings, the gross findings on opening the uterus on the operating table, and possibly a frozen section of the resected uterus. Most of the cancer centers in USA follow these guidelines in the management of endometrial cancer: stage I and occult stage II require total abdominal hysterectomy; bilateral salpingo-oopherectomy. Adjuvant radiation depends on the grade of the endometrial cancer, nodal involvement and extent of myometrial invasion. Clinical stage II radical hysterectomy seems to be associated with better survival when compared with simple hysterectomy for FIGO stage II corpus adenocarcinoma. Treatment for clinical stage III must be individualized but should aim to include total abdominal hysterectomy and bilateral salpingo-oopherectomy. In the presence of an adnexal mass, surgery usually should be performed initially to determine the nature of the mass and to remove the bulk of the disease tissue. Stage IV disease must be individualized but usually involves a combination of surgery, radiation therapy, and/or chemotherapy. A major objective of therapy should be to try to achieve local disease control in the pelvis and to palliate bleeding, discharge, pain, and fistula formation. Pelvic exenteration may be considered in the occasional patient in whom disease extension is limited to bladder and/or rectum.
The Project is funded by the WHEC Initiative for Global Health.
- American Cancer Society home page website. Cancer statistics 2008. Available at: www.cancer.org/docroot/home/index.asp. Accessed June 15, 2009
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- von Gruenign VE, Tian C, Frasure H et al. Treatment effects, disease recurrence, and survival in obese women with early endometrial carcinoma: a Gynecologic Oncology Group study. Cancer 2006;107:2786-2791
- Keys HM, Roberts JA, Brunetto VL et al. A phase III randomized trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncologic Group study. Gynecol Oncol 2004;92:744-751
- Havrilesky LJ, Cragun JM, Calingaert B et al. The prognostic significance of positive peritoneal cytology and adnexal/serosal metastasis in stage IIIA endometrial cancer. Gynecol Oncol 2007;104:401-405
- Fleming GF, Brunette VL, Cella D et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2004;22:2159-2166
- Sorosky JI. Endometrial cancer. Obstet Gynecol 2008;111:436-437
- Wright JD, Fiorelli J, Kansler AL et al. Optimizing the management of stage II endometrial cancer: the role of radical hysterectomy and radiation. Am J Obstet Gynecol 2009;200:419-421
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