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.
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.
The International Federation of Gynecology and Obstetrics (FIGO) defined a clinical staging system for endometrial carcinoma in 1971. It was revised in 1989, 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.
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.
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 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). 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(Drug information on cisplatin) (50 mg/m2) on days 1 and 28, followed by cisplatin (50 mg/m2) and paclitaxel(Drug information on paclitaxel) (160 mg/m2) on days 56, 84, 112, and 140 from the start of irradiation. This study recently opened for accrual.