Update on Radiation Therapy for Endometrial Cancer

ABSTRACT: The best clinical outcomes for patients with endometrial cancer seem to be achieved with either surgery alone or a combination of surgery and radiation therapy. Although once administered preoperatively, irradiation is now rarely given prior to surgery in this population. After surgical staging, most patients receive postoperative adjuvant therapy based on their pathologic risk factors. Although prospective randomized trials in these patients are limited, recent studies have attempted to determine the best management strategies for the disease. Based on these investigations, treatment recommendations are outlined for patients who are surgically staged and for those with incomplete surgical staging. Also described is the use of irradiation in recurrent endometrial cancer after surgery alone, as well as palliative radiation. In addition, ongoing prospective randomized trials are described. [ONCOLOGY 16:777-795, 2002] Carcinoma of the endometrium is the most common invasive gynecologic neoplasm in women in the United States. Over 30,000 new cases will be diagnosed this year. The hallmark of the therapeutic management of patients with endometrial carcinoma is hysterectomy. Appropriate determination of stage or extent of disease at the time of diagnosis is of critical importance because both extent of treatment and prognosis are strongly dependent on stage. Adjuvant irradiation has been used in many settings over the past century. Overview of Treatment Strategies TABLE 1 Treatment Guidelines for Surgically Staged Endometrial Cancer Patients TABLE 2 Treatment Guidelines for Incompletely Surgically Staged Endometrial Cancer Patients In contradistinction to research in carcinoma of the uterine cervix, empiric studies in patients with endometrial carcinoma indicated that irradiation alone was not optimal therapy. The best clinical outcomes for patients with endometrial carcinoma seem to be achieved with either surgery alone or a combination of surgery and irradiation. In the past, irradiation was often administered in the preoperative setting. At present, irradiation alone is rarely administered; preoperative irradiation is given only in selected cases, with postoperative irradiation administered most commonly. Following a preoperative work-up that usually includes a physical examination, routine blood work, chest x-ray, and ECG, the patient with endometrial cancer undergoes an exploratory laparotomy with hysterectomy, lymph node sampling, and peritoneal cytology. Omental biopsies should be performed if any areas seem suspicious for tumor. These data provide the basis for administering adjuvant therapy. After surgery, further treatment with radiation may be indicated based on the surgical/pathologic staging information. Radiotherapy may be administered locally in the vagina, to the pelvis, or to the whole abdomen. Local irradiation to the vagina may be delivered in the inpatient setting using low-dose-rate brachytherapy or in the outpatient setting using high-dose-rate brachytherapy. Pelvic irradiation is administered as external irradiation alone or with the addition of vaginal brachytherapy. Radiation to the abdomen can be given as external irradiation or with intraperitoneal P-32. Postoperative chemotherapy is being evaluated in clinical trials. For some patients with serious medical conditions, radiation therapy is used as an alternative to surgery. Severe cardiopulmonary disease and morbid obesity are the primary reasons for a patient with endometrial carcinoma to forgo surgery. Patients who do not undergo surgery are clinically staged and may receive internal, external, or combination radiotherapy, depending on patient and tumor characteristics. Preoperative intracavitary brachytherapy, external irradiation, or both are administered to patients with high-grade lesions or advanced-stage disease. Radiation therapy is also used in patients with recurrent disease after surgery, and palliative radiation is administered to relieve symptoms. Approaches to Staging The International Federation of Gynecology and Obstetrics (FIGO) defined a clinical staging system for endometrial carcinoma in 1971.[1] It was revised in 1989,[2] and is now a surgical, rather than a clinical, staging system. Under the guidelines of the clinical staging system, it was implied that all patients should undergo a dilatation and fractional curettage. The uterus was sounded and an examination was performed with the patient under anesthesia. About 75% to 80% of patients were described as having clinical stage I disease, and about 10% to 15% were found to have tumor spread beyond the uterus after pathologic evaluation of the surgical specimen. The current surgical staging procedure requires that a peritoneal cytology specimen be obtained and that pelvic and para-aortic lymph node sampling be performed. Previously, these specimens were not routinely obtained. With the advent of surgical staging, more patients are now found to have disease outside the uterus. Hence, a smaller percentage have true stage I disease. It is, therefore, difficult to compare the results of therapy for patients with endometrial cancer from one report to another, because there is no consistent definition of patient populations. Despite the current recommendations for surgical staging, not all of the required specimens are obtained for all patients. Moreover, adjuvant postoperative therapy must be individualized and based on information that pertains to a specific patient. Reviewing the Data Few prospective randomized studies have been conducted in patients with endometrial carcinoma. However, in recent years, randomized studies have attempted to answer questions regarding the best management of these patients. Outlined below are treatment recommendations for patients who are surgically staged and for those who undergo incomplete surgical staging. These recommendations are based on the results of prospective randomized studies, to the extent that they exist, and on the results of retrospective studies. Also described is the use of irradiation alone in medically inoperable patients and the use of irradiation in recurrent endometrial cancer after surgery alone, as well as palliative irradiation. Current prospective randomized studies will also be described. Surgically Staged Patients Patients who have undergone complete surgical staging receive postoperative adjuvant therapy based on pathologic risk factors identified by examination of the surgical specimen. Numerous risk factors have been identified for patients with endometrial carcinoma. In general, patients can be divided into one of three categories of risk for developing locally recurrent and metastatic disease: low risk, intermediate risk, and high risk. When the patient’s tumor is confined to the uterus, the primary risk factors for recurrent disease are tumor histology and grade, depth of myometrial invasion, lymphovascular space involvement, and patient age. Depending on the individual patient risk factors, patients with tumor confined to the uterus can be classified as being either at low or intermediate risk for recurrent disease. Low Risk of Recurrence Patients with surgical stage IA, grade 1/2 endometrial adenocarcinoma are at low risk of developing recurrent disease if no adjuvant postoperative therapy is administered. This treatment issue has not been evaluated in a prospective randomized study, because the risk of recurrence in this population is less than 10% and a phase III study would require the enrollment of a prohibitively large number of patients. However, it is evident from the results of numerous retrospective studies and pathologic models of survival[3] that postoperative adjuvant irradiation should not be routinely administered to most patients in this category. Intermediate Risk of Recurrence Patients with surgical stages IB, IC, and IIA disease, grades 1, 2, and 3, can be considered at intermediate risk for developing recurrent disease postoperatively if no adjuvant therapy is administered. • GOG-99 Trial-Only one prospective randomized study has specifically addressed the issue of postoperative adjuvant radiotherapy in this population-a phase III study by the Gynecologic Oncology Group (GOG-99).[4] Patients entered into the study were randomized to receive surgery alone or surgery and adjuvant postoperative pelvic irradiation. The surgery consisted of a total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO), pelvic and para-aortic lymph node sampling, and peritoneal cytology in all patients. Study patients had surgical stage I or IIA disease and negative lymph nodes. Postoperative irradiation consisted of 50.4 Gy to the pelvis via a four-field box technique delivered at 1.8-Gy fractions per day. Vaginal cuff brachytherapy was not administered. A total of 392 patients were entered into the study; 58% had stage IB disease, 32% had stage IC, and 9% had stage IIA. Tumors were grade 1 or 2 in 82% and grade 3 in 18%. The median follow-up of patients at the time of data analysis was 56 months. Overall survival was 94% for irradiated patients and 89% for patients who underwent surgery only (P = .09). However, there was a statistically significant difference in recurrence-free survival-96% for irradiated patients vs 88% for unirradiated patients (P = .004). The failure rate in the pelvis was 2% for irradiated patients vs 12% for unirradiated patients (P = .001). Death from endometrial carcinoma occurred in 5% of irradiated patients compared to 7% of unirradiated patients (not a significant difference [NS]). However, the rate of severe complications (grade 3/4) was greater among patients receiving irradiation. The complication rate was 15% for patients receiving pelvic irradiation vs 6% for surgery-only patients (P = .007). Most patients who had been entered into GOG-99 had either stage IB disease or grade 1/2 tumors. These patients are at a rather low risk of developing recurrent disease. A subanalysis of GOG-99 indicated that the most significant risk factors for recurrent disease were advancing age, grade 2/3 histology, greater than one-third myometrial invasion, and the presence of lymphovascular space involvement. When patient survival was analyzed by prognostic factors (grade 2/3, greater than one-third myometrial invasion, and lymphovascular space invasion) and stratified by patient age, significant differences in recurrence-free survival were observed. Among patients who were more than 70 years old with one of the prognostic factors, more than 50 years old with two prognostic factors, or any age with all three prognostic factors, recurrence-free survival was 87% for irradiated patients compared to 73% for unirradiated patients (P < .01). • NCIC Trial-An ongoing trial being conducted by the National Cancer Institute of Canada (NCIC) Clinical Trials Group is similar to the GOG-99 trial. In the NCIC study, patients undergo a laparoscopically assisted vaginal hysterectomy or TAH/BSO. Patients cannot have pathologically involved lymph nodes if this surgical staging procedure is performed. Eligibility criteria include grade 3 disease with any degree of myometrial invasion (or none) and grade 2 tumors with greater than 50% myometrial invasion. Those with more (grade 1/2) or less (grade 3) than 50% myometrial invasion but with positive peritoneal cytology (stage IIIA) are also eligible. Patients are randomized postoperatively to pelvic irradiation or observation. All patients randomized to the treatment arm receive external pelvic irradiation. Vaginal brachytherapy is allowed. The accrual goal is approximately 400 patients. The results of this study and the GOG-99 study will help clinicians make appropriate therapeutic decisions for this patient population. • RTOG 99-05 Trial-The Radiation Therapy Oncology Group (RTOG) is conducting a randomized clinical trial (RTOG 99-05) to evaluate therapeutic strategies for patients at slightly higher risk of recurrence than the above-mentioned patients. In RTOG 99-05, patients undergo a total abdominal hysterectomy, vaginal hysterectomy, or laparoscopy-assisted vaginal hysterectomy and bilateral salpingo-oophorectomy, with or without additional surgical staging. Eligibility requirements include grade 2/3 adenocarcinoma with greater than 50% myometrial invasion, cervical glandular involvement, or cervical stromal invasion and no known disease outside the uterus. Following surgery, patients are randomized to one of two study arms. In arm 1, patients receive 50.4 Gy of pelvic irradiation given at 1.8 Gy/d. In arm 2, patients receive the same irradiation as in arm 1 plus concurrent cisplatin (50 mg/m2) on days 1 and 28, followed by cisplatin (50 mg/m2) and paclitaxel (160 mg/m2) on days 56, 84, 112, and 140 from the start of irradiation. This study recently opened for accrual. High Risk of Recurrence Patients with surgical stages IIB, III, and IV disease are at high risk of developing recurrent disease after surgery if no adjuvant therapy is administered. Pathologic factors associated with a high risk of recurrence are cervical involvement, tumor spread beyond the uterus, or both. This includes patients with involvement of the uterine serosa, adnexa, fallopian tubes, ovaries, pelvic and para-aortic lymph nodes, a positive peritoneal cytology, and upper abdominal metastasis. • Italian Cooperative Group Trial-Prospective studies evaluating adjuvant therapy in patients at high risk for recurrence are limited. The Italian Cooperative Group[5] randomized 340 patients with stage IC, IIA, IIB (grade 3) and IIIA, IIIB, and IIIC (grade 1-3) disease to receive postoperative irradiation or chemotherapy. All patients initially underwent TAH/BSO and selective lymph node sampling. Patients in the irradiation arm received 45 Gy to the pelvis without brachytherapy. Patients in the chemotherapy arm received five cycles (every 4 weeks) of cisplatin, 50 mg/m2; doxorubicin, 45 mg/m2; and cyclophosphamide (Cytoxan, Neosar), 600 mg/m2. The irradiation arm comprised 165 patients, and the chemotherapy arm, 175 patients. The pelvic plus distant failure rate was 27% for irradiated patients and 29% for those receiving chemotherapy (NS). Although the overall failure rate did not differ, there was a difference in the rate of failures localized to the pelvis alone. Pelvic-only failures occurred in 5% of those treated with pelvic irradiation compared to 10% of those treated with chemotherapy (P = .09). Overall and progression-free survivals were not reported. The authors performed a subgroup analysis, which indicated that the most significant prognostic factors for the development of recurrent disease were patient age, grade 3 tumor histology, and the depth of myometrial invasion. Lymphovascular space involvement was not evaluated. • GOG-94 Trial-Another group of patients at high risk for recurrent disease are those with papillary serous and clear cell histology. Traditionally, patients with this tumor histology have a poor outcome irrespective of the surgical stage of the disease. Therefore, the GOG evaluated these patients in a prospective, single-arm, phase II study (GOG-94).[6] In this trial, 165 patients with stage I-IV papillary serous and clear cell carcinoma of the endometrium and stage III/IV endometrioid endometrial carcinoma received whole-abdominal irradiation. The total dose to the abdomen (with no liver shielding, 5 half-value layer [HVL] posteroanterior kidney blocks) was 30 Gy (1.5 Gy/d). The para-aortic lymph nodes received 45 Gy of irradiation only if they were pathologically positive. The total dose to the pelvis was 50 Gy. Brachytherapy was not administered. The 5-year survival rate was 65% for patients with stage I/II papillary serous and clear cell carcinoma; 33% for those with stage III/IV papillary serous and clear cell carcinoma, and 31% for those with stage III/IV endometrial adenocarcinoma. Whole-abdominal irradiation led to chronic bowel toxicity in 7% of patients. Other investigators have reported similar results.[7] • NSGO 9501 Trial-The Nordic Society for Gynecologic Oncology (NSGO) is currently conducting a phase III study (NSGO 9501) in patients with surgical stage I endometrial cancer of the following histologic types: papillary serous carcinoma, clear cell carcinoma, undifferentiated carcinoma, and poorly differentiated (grade 3) adenocarcinoma. The objectives of NSGO 9501 are to evaluate the survival, toxicity, and relapse patterns among patients treated with adjuvant irradiation alone or adjuvant sequential irradiation and chemotherapy. All patients receive pelvic irradiation to 50.4 Gy (1.8 Gy fractions). Those randomized to receive chemotherapy are prescribed four courses of cisplatin plus doxorubicin (or epirubicin [Ellence]) every 3 weeks. This study is currently open to accrual. • GOG-122 Trial-Following completion of GOG-94, the GOG initiated a prospective randomized phase III two-arm study (GOG-122). GOG-122 has completed accrual with about 150 patients entered into each arm. Eligible patients had surgical stage III/IV endometrial carcinoma of any histology, including papillary serous and clear cell carcinoma. Patients were randomized to receive whole-abdominal irradiation (same schedule as in GOG-94) or postoperative chemotherapy consisting of eight cycles of doxorubicin and cisplatin, at 3-week intervals. The doxorubicin dose was 60 mg/m2, and the cisplatin dose, 50 mg/m2. Results of this study are pending maturation of data. • GOG-184 Trial-The GOG has opened a subsequent two-arm study, GOG-184, to evaluate the same patient population as in GOG-122. All patients undergo TAH/BSO, lymph node sampling, and debulking of abdominal disease (to < 2 cm). Postoperatively, patients receive pelvic irradiation to 50.4 Gy and, if the para-aortic lymph nodes are pathologically positive, patients receive para-aortic irradiation to 45 Gy. For those with cervical involvement, deep invasion, or lower uterine segment involvement, intracavitary vaginal cuff brachytherapy is also utilized. After completion of irradiation, patients are randomized to one of two chemotherapy regimens. In arm 1, chemotherapy consists of six cycles of doxorubicin, 45 mg/m2, and cisplatin, 50 mg/m2, at 3-week intervals. In the second arm, patients receive six cycles, at 3-week intervals, of doxorubicin, 45 mg/m2; cisplatin, 50 mg/m2; paclitaxel, 160 mg/m2; and granulocyte colony-stimulating factor (G-CSF, Neupogen), 5 µg/kg on days 3 to 12. This study recently opened to accrual. Additional clinical trials being conducted in patients with stage III/IV disease are GOG-9907 and GOG-9908. Both are phase I studies opened at a limited number of institutions. The objective of GOG-9907 is to determine the safety and maximum tolerated doses of paclitaxel and cisplatin with concurrent whole-abdominal irradiation. The objectives of GOG-9908 are to determine the feasibility as well as the acute and chronic toxicity of doxorubicin and cisplatin followed by whole-abdominal irradiation. Intraperitoneal P-32 Intraperitoneal P-32 has been advocated for patients at low risk of failure in the pelvis but who are found to have a positive peritoneal cytology at the time of hysterectomy. Limitations of the use of P-32 include inhomogeneous distribution throughout the peritoneal cavity and an unacceptably high bowel complication rate, especially in patients who receive simultaneous or immediate sequential external irradiation to the pelvis. Intraperitoneal P-32 has fallen out of favor as a therapeutic modality for patients with endometrial cancer because of these limitations and the use of adjuvant chemotherapy. Incomplete Surgical Staging TABLE 3 Preoperative Irradiation in Endometrial Cancer Patients Before FIGO adopted its surgical staging system for patients with endometrial carcinoma, routine lymph node sampling was rarely performed. The majority of published retrospective studies report results in patients who did not undergo lymph node sampling. The value of lymph node staging is currently being evaluated in a clinical trial conducted by the Medical Research Council (MRC-UK). The study objective is to compare the effects of conventional surgery alone and conventional surgery plus lymphadenectomy in patients with stage I endometrial cancer thought preoperatively to be confined to the uterine corpus. A recent survey performed by the American College of Surgeons indicated that 70% of patients who undergo surgery for endometrial carcinoma in the United States do not undergo pathologic lymph node evaluation (P. Taylor, personal communication, 2001). Therefore, the decision to initiate postoperative adjuvant therapy in the majority of patients is based on incomplete information (compared to complete surgical staging). Patients without a lymph node sampling can be categorized as being at low, intermediate, or high risk of developing recurrent disease, based on tumor grade, depth of myometrial invasion, presence of lymphovascular space invasion, lower uterine segment involvement, cervical involvement, upper abdominal involvement, and a positive peritoneal cytology. Patients with grade 1/2 endometrial adenocarcinoma and no or less than 50% myometrial invasion have a greater than 90% 5-year survival if the disease is confined to the uterus.[8] These survival results correlate with the incidence of lymph node metastasis found by Creasman and colleagues in a GOG surgical staging study.[9] The results of the latter study revealed that patients with grade 1/2 disease and no or less than 50% myometrial invasion had less than a 10% chance of having positive pelvic or para-aortic lymph nodes. Such patients usually require no postoperative adjuvant therapy. Patients at intermediate risk of developing recurrent disease following surgery are those with grade 3 disease and no or less than 50% myometrial invasion, and those with grade 1/2 disease with greater than 50% myometrial invasion. These patients have 5-year survivals ranging from 70% to 85%.[8] • Dutch PORTEC Trial-A recent, prospective randomized phase III study performed by the Dutch Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) Study Group addressed postoperative adjuvant therapy in the group of patients described above.[10] In this study, patients underwent TAH/BSO and no lymph node sampling or dissection. Postoperatively, eligible patients included those with grade 1 disease and more than 50% myometrial invasion; those with grade 2 disease and any degree of myometrial invasion; and those with grade 3 disease and less than 50% myometrial invasion. Patients with grade 3 disease and deep myometrial invasion were not eligible for the study. The 715 patients enrolled in the study were randomized to receive postoperative pelvic irradiation to 46 Gy or no further therapy after surgery. Median follow-up was 52 months. The 5-year actuarial pelvic failure rates were 4% in the radiotherapy arm and 14% in the control arm (P < .001). The actuarial 5-year overall survival rates were 81% in the radiotherapy arm and 85% in the control arm (P =.31). Deaths due to endometrial cancer occurred in 9% of patients treated with irradiation and in 6% of patients in the control group (P = .37). Complications of any severity were reported to occur in 25% of those receiving irradiation and 6% of those in the control group (P < .001). Grade 3/4 complications occurred in only seven patients (7/715), with six of the complications occurring in irradiated patients. The authors performed a Cox multivariate regression analysis and found that three significant prognostic factors for pelvic recurrence or death were age greater than 60 years, more than 50% myometrial invasion, and grade 3 histology. Lymphovascular space invasion was not evaluated. The investigators found that patients with grade 3 histology and less than 50% myometrial invasion had a risk of locoregional recurrence similar to that of patients with grade 1/2 tumors and greater than 50% myometrial invasion. The risk of death was greatest among those with grade 3 tumors. • Grigsby et al Trial-The results of the above study are similar to the findings of Grigsby and colleagues in their retrospective study of 858 patients with clinical stage I endometrial adenocarcinoma.[11] Among patients with grade 1/2 tumor and no or less than 50% myometrial invasion, 5-year survival was greater than 90%. Patients with grade 3 disease and no or less than 50% myometrial invasion, and those with grade 1/2 disease with greater than 50% myometrial invasion had 5-year survivals ranging from 69% to 85%. In addition, patients with deep myometrial invasion and grade 3 histology had a 5-year survival of only 42%. Preoperative Irradiation Primary surgery is the most commonly employed initial therapy for patients with endometrial carcinoma. However, some physicians prefer preoperative irradiation as the primary approach to the management of these patients. The rationale for this approach includes tumor shrinkage before surgery and a decrease in the incidence of subsequent distant metastasis. Preoperative irradiation can be delivered with external irradiation, intracavitary brachytherapy, or a combination of the two. Preoperative intracavitary brachytherapy was first described by Heyman and has subsequently been performed at several institutions, with reported results suggesting that preoperative irradiation is superior to postoperative irradiation in terms of survival and complications.[12] Clinical Stage I Sause and colleagues reported a survival advantage for preoperative irradiation in patients with deep myometrial invasion or grade 3 disease.[13] A retrospective analysis from the Mallinckrodt Institute of Radiology demonstrated a dose-response relationship for patients undergoing preoperative brachytherapy.[8] Patients had a 5-year progression-free survival rate of about 90%, regardless of tumor grade, if the preoperative implant delivered an irradiation dose (ie, exposure) greater than 3,500 milligram-hours (mgh) to the uterine fundus. However, patients with grade 1/2 tumors did not exhibit a dose-response relationship. Preoperative external irradiation has also been studied. Weigensberg[14] reported the results of a prospective phase III clinical trial in which patients were randomized to receive preoperative external-beam irradiation vs preoperative brachytherapy. The study demonstrated an improved survival and fewer local recurrences among patients receiving a preoperative intracavitary implant, compared to those who received preoperative external pelvic irradiation. The complication rate associated with the preoperative implant in the Weigensberg study was 3%, compared to 11% for those receiving preoperative external pelvic irradiation. Grigsby and colleagues reported no complications associated with a preoperative implant performed in 334 patients.[8] Clinical Stage II TABLE 4 Irradiation Alone in Medically Inoperable Endometrial Cancer Patients TABLE 5 Treatment of Recurrent Endometrial Cancer Preoperative irradiation (with an intracavitary implant, external irradiation, or a combination of both) is often used in patients with clinical stage II endometrial cancer at many treatment centers. This may be the best approach for patients with gross cervical involvement.[15] However, no prospective randomized studies have been conducted in patients with clinical stage II disease. Survival rates in this group of patients after preoperative irradiation range from 70% to 85%.[16] It has been advocated that a radical hysterectomy be performed in patients with clinical stage II disease in lieu of preoperative irradiation.[17] Irradiation Alone Some patients with clinical stage I endometrial cancer present with advanced age and severe comorbidities that preclude surgical staging or hysterectomy. Nevertheless, these patients may have an expected survival of several years despite their severe illnesses. Most should be treated with radiation therapy alone, with a curative intent. Brachytherapy alone or the combination of external irradiation and brachytherapy can be administered based on tumor grade, depth of myometrial invasion, and lymph node status. Grigsby and associates[18] demonstrated that the 5-year progression-free survival rate for clinical stage I disease was 94% for patients with grade 1 tumors, 92% for grade 2, and 78% for grade 3, if patients received both external irradiation and intracavitary brachytherapy. Overall survivals ranged from 70% to 80% among this elderly, medically inoperable population. Current treatment strategies utilize both tumor grade and magnetic resonance imaging (MRI) of the pelvis to determine depth of myometrial invasion and to estimate the probability of lymph node metastasis.[19] It is reasonable to anticipate that the complication rate associated with a low-dose-rate intracavitary implant in severely ill, medically inoperable patients might be excessive. However, in an evaluation of brachytherapy-related complications in medically inoperable stage I endometrial carcinoma patients, Chao and colleagues[20] demonstrated a mortality rate of 2.1% (2 of 96 died-1 from myocardial infarction, 1 from pulmonary embolus) and a life-threatening complication rate of 4.2% (4 of 96 patients). These complication rates do not appear to be excessive for this population. Similar complication rates for high-dose-rate (outpatient) brachytherapy in medically inoperable patients have been reported.[21-23] Patients with clinical stage II endometrial carcinoma who are medically inoperable are usually treated with combined external irradiation and intracavitary brachytherapy. The 5-year survival rates for these patients range from 50% to 60%.[16,24,25] Compared to the results of combined preoperative irradiation and surgery, the results of therapy with irradiation alone for clinical stage II disease are inferior.[16] Clinical stage III endometrial carcinoma occurs in 5% to 10% of patients. Patients with this stage of disease are treated with irradiation alone or with the combination of irradiation and surgery. This treatment group consists of patients with clinical findings of tumor involvement of the vagina or parametria and should not be confused with patients with surgical stage III endometrial carcinoma. The 5-year survival rates for patients with clinical stage III disease treated with external-beam irradiation and intracavitary brachytherapy range from 16% to 42%.[26-29] Because survival with irradiation alone is poor, recent clinical practice has leaned toward initial surgical debulking (when possible) followed by postoperative irradiation. However, no significant body of published data supports this approach. Stage IV endometrial carcinoma is uncommon and occurs in less than 5% of patients. When the disease is confined to the pelvis (bladder or rectum), irradiation alone may be used, but long-term survivors are uncommon among stage IV patients, regardless of treatment. Goff and colleagues evaluated the use of cytoreductive surgery in patients with stage IV disease.[30] They reported a median survival of 18 months for those who underwent cytoreductive surgery, compared to 8 months for those who did not undergo surgery. Irradiation has been shown to be effective in palliating symptoms of locally advanced unresectable disease in the pelvis. Recurrent Disease After Surgery Alone Patients with recurrent endometrial cancer after surgery should be fully evaluated to determine all sites of recurrent and metastatic disease. Patients who are found to have recurrent disease only in the pelvis (without evidence of distant metastatic disease) should be treated with radiation, with curative intent. The role of combined irradiation and chemotherapy in this patient population is undefined. Pelvic recurrence may present as a vaginal cuff recurrence, pelvic nodal disease, or a combination of both. Isolated distal suburethral recurrences are very rare (< 0.5%).[8] Kuten and associates[31] reported the prognostic significance of the site of pelvic recurrence. In their retrospective study of 51 patients with locoregional recurrent endometrial carcinoma, the 5-year disease-free survival rate was 40% for patients with an isolated vaginal cuff recurrence, but no patients with pelvic lymph node recurrences survived beyond 1.5 years. Survival results at 5 years are reported to range between 20% and 50% for patients with isolated vaginal cuff recurrences.[32-35] Irradiation for pelvic recurrences is best performed with combined external-beam irradiation and intracavitary or interstitial brachytherapy. Irradiation doses delivered to the tumor should total about 75 to 85 Gy, depending on tumor size. Palliative Irradiation Patients with locally advanced or metastatic endometrial cancer who have symptoms of pain and bleeding may receive external irradiation to the pelvis to relieve these symptoms. When palliation is the goal of therapy, it is important to fully evaluate the patient’s medical status. Patients requiring palliation who have an expected survival of greater than 1 year are treated with external radiation therapy to the pelvis, to a total of 50 Gy delivered in 1.8- to 2.0-Gy daily fractions. Spanos and colleagues have reported a safe and effective accelerated, hyperfractionated pelvic irradiation schedule for patients with advanced and recurrent endometrial carcinoma.[36] Those with a life expectancy of less than 1 year and those with other severe medical conditions causing disability receive 370 cGy of radiation twice daily for 2 consecutive days, followed by a 2-week break. They then receive twice-daily radiotherapy for 2 more days, followed by another 2-week break and then 2 more days of radiotherapy. The total dose to the pelvis following this regimen is 44.4 Gy. Palliative irradiation may also be administered with an intracavitary implant. Patients with a large volume of disease in the pelvis usually have bleeding and pain. In this patient population, external-beam radiotherapy is the treatment of choice. If the patient has a small volume of disease and bleeding is the primary symptom, an intracavitary implant with Simon-Heyman capsules, Fletcher-Suit tandem, and ovoids is performed. If the bleeding does not resolve, a second intracavitary implant is performed in 2 to 3 weeks. A second implant could also be performed if the bleeding resolves but recurs. Low- or high-dose-rate intracavitary brachytherapy can be performed as palliative therapy. Common sites of symptomatic metastasis outside the pelvis that may be treated with palliative irradiation are the bone, lung, brain, and lymph nodes. Treatment Recommendations The treatment of patients with endometrial carcinoma has evolved over the past several years. Most patients with early-stage disease undergo extrafascial hysterectomy. Complete surgical staging is performed in a minority of patients in the United States. Recommendations for adjuvant irradiation are based on the patient’s risk factors, which must be taken into account whether or not she has undergone complete surgical staging. Retrospective studies suggest that patients at high risk of recurrence may best be treated with adjuvant postoperative irradiation and chemotherapy.[37,38] Surgically Staged Patients Among patients with complete surgical staging, postoperative adjuvant irradiation is not recommended for those with stage IA/B, grade 1/2 disease. Postoperative vaginal cuff brachytherapy is recommended for those with stage IA/B, grade 3; stage IC, grade 1/2; and stage IIA, all grades and less than 50% myometrial invasion. Vaginal cuff brachytherapy should be considered for those with stage IA/B, grade 2, and lower uterine segment involvement. Postoperative external pelvic irradiation and vaginal cuff brachytherapy are recommended for patients with stage IC, grade 3; stage IIA, grade 1-3 with greater than 50% myometrial invasion; and most patients with stage IIB disease. Patients with stage IIB, grade 1/2 disease with less than 50% myometrial invasion may be considered for vaginal cuff brachytherapy alone. Those with stage IIIA disease with a positive serosa or adnexa should receive postoperative adjuvant external pelvic irradiation and vaginal cuff brachytherapy. Patients with stage IIIA disease with a positive peritoneal cytology should receive postoperative whole-abdominal irradiation and vaginal cuff brachytherapy. Intraperitoneal P-32 is rarely used in patients with a positive peritoneal cytology. Patients with stage IIIB disease (ie, vaginal involvement) should receive postoperative external pelvic irradiation and vaginal cuff brachytherapy. Groin lymph nodes should also be treated if the disease involves the distal one-third of the vagina. All patients with stage IIIC disease should receive postoperative external pelvic irradiation and vaginal cuff brachytherapy. If positive para-aortic lymph nodes are present, additional external irradiation should be administered to the para-aortic region. Prophylactic para-aortic irradiation is not recommended. Patients with stage IVA disease should receive postoperative vaginal cuff brachytherapy and external pelvic irradiation. In the presence of intra-abdominal metastasis, patients should receive postoperative whole-abdominal irradiation and vaginal cuff brachytherapy. Patients With Incomplete Surgical Staging Treatment policies for patients who undergo incomplete surgical staging (ie, unknown lymph node status) would include no further therapy for stage I, grade 1/2 tumors with less than 50% myometrial invasion. Patients with grade 3 disease but no myometrial invasion should receive postoperative vaginal cuff brachytherapy. Patients with less than 50% myometrial invasion and grade 3 tumors, and those with greater than 50% myometrial invasion with tumor of any grade, should receive postoperative external pelvic irradiation and vaginal cuff brachytherapy. All patients with stage II disease (ie, cervical involvement) should receive postoperative vaginal cuff brachytherapy and external pelvic irradiation. All stage III patients with serosal, adnexal, or vaginal involvement should also receive postoperative external pelvic irradiation and vaginal cuff brachytherapy. All patients with papillary serous or clear cell histology, regardless of stage, should receive postoperative whole-abdominal irradiation and vaginal cuff brachytherapy. Patients with a positive peritoneal cytology should receive whole-abdominal irradiation and vaginal cuff brachytherapy. Prophylactic para-aortic irradiation is not recommended. Stage IVA/B disease should be treated as outlined previously. Preoperative intracavitary brachytherapy has fallen into disfavor but is recommended for patients with clinical stage I, grade 3 tumors and those with clinical stage II, grade 1-3 tumors with microscopic cervical involvement. Combined external pelvic irradiation and intracavitary brachytherapy may be used for those with stage II, grade 1-3 disease with gross cervical involvement. Inoperable Patients Irradiation alone is the recommended therapy for clinical stage I patients who are medically inoperable. Patients with negative lymph nodes by radiographic evaluation, less than 50% myometrial invasion as determined by pelvic MRI, and grade 1/2 tumors can be treated with intracavitary brachytherapy alone. Patients with greater than 50% myometrial invasion (on MRI) by any grade tumor and all patients with grade 3 disease should receive external pelvic irradiation and intracavitary brachytherapy. All patients with clinical stage II (medically inoperable), III, and IV (confined to the pelvis) disease should receive external pelvic irradiation and intracavitary brachytherapy. Consideration for surgical debulking should be given to patients with clinical stage III/IV disease. Patients with recurrent endometrial cancer confined to the pelvis should be treated with external pelvic irradiation and intracavitary or interstitial brachytherapy. Palliative irradiation can be administered in patients with advanced and recurrent pelvic and metastatic disease. Conclusions These treatment guidelines-which may be revised after current and future prospective randomized studies are completed-are recommendations for the general population of patients with endometrial cancer. 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