These consensus guidelines on adjuvant radiotherapy for early-stage endometrial cancer were developed from an expert panel convened by the American College of Radiology. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method; and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. After a review of the published literature, the panel voted on three variants to establish best practices for the utilization of imaging, radiotherapy, and chemotherapy after primary surgery for early-stage endometrial cancer.
Summary of Literature Review
Endometrial cancer is the most common gynecologic malignancy diagnosed in the United States and is second to ovarian cancer in annual mortality for gynecologic cancers, with 10,170 deaths. With the decline in hormone replacement therapy utilization, there was a corresponding decline in the incidence of endometrial cancer. However, more recently this trend has reversed as obesity rates have increased. The majority of new endometrial cancers will be International Federation of Gynecology and Obstetrics (FIGO) stage I–II disease, at approximately 85% of new cases. Recurrence rates of early endometrial cancers vary within a specific stage and thus treatment options differ across the early endometrial cancers.[4,5] Endometrial cancer is less likely to lead to death than other medical comorbidities.[6-8] A Surveillance, Epidemiology, and End Results (SEER) study of early-stage, low-grade endometrial carcinoma showed that 7% of patients diagnosed died of malignancy, whereas 42% died of cardiovascular disease.
The most common presenting symptom of uterine carcinoma is vaginal bleeding, typically after menopause. Workup of a suspected endometrial cancer includes history and physical examination with an endometrial biopsy. A false-negative result can occur in 10% of cases, so a negative biopsy is typically followed by dilation and curettage. Once a histopathologic diagnosis is established and uterine-confined disease is suspected, blood counts, routine biochemistry, and chest radiographs are recommended to complete workup. Surgery consists of total hysterectomy and bilateral salpingo-oophorectomy with or without lymph node dissection. Visual inspection of the peritoneal, serosal, and diaphragmatic surfaces with biopsy of suspicious lesions is required to evaluate for extrauterine disease. FIGO recommends obtaining peritoneal washings even though a positive finding was removed from the most recent staging system.
The recommendations for adjuvant radiation therapy in early-stage endometrial cancer depend on the presence or absence of several risk factors, such as older age, deep myometrial invasion, high grade, large tumor size, and lymphovascular space invasion (LVSI).[12-14] Classification into low-risk, intermediate-risk, and high-risk early-stage uterine cancer is based on a combination of these risk factors, but investigators and studies often differ in their definitions. In early-stage endometrial cancer, the most common site of recurrence in the absence of adjuvant radiation therapy is the vaginal cuff. Vaginal brachytherapy reduces the risk of a vaginal recurrence and has a low side-effect profile.
Sorbe et al published a randomized trial comparing adjuvant vaginal brachytherapy to observation in grade 1 or 2, stage IA endometrioid carcinoma in 645 patients. After a median follow-up of 68 months, there was no difference in vaginal recurrence rates (1.2% in the brachytherapy group vs 3.1% in the observation group; P = .114). The impact of adjuvant brachytherapy appears to be limited in low-risk patients. The toxicity of vaginal brachytherapy is mild and limited to urinary (2.8% in the brachytherapy group vs 0.6% in the observation group; P = .063) and vaginal side effects (8.8% in the brachytherapy group vs 1.5% in the observation group; P < .01).
Fluoroscopic- or computed tomography (CT)-based treatment planning for vaginal brachytherapy is generally used. Confirmation of appropriate placement of the cylinder at the top of the vagina is generally accomplished utilizing fiducials placed at the top of the vagina or review of CT images. The dose fractionation regimens for high-dose-rate (HDR) vaginal brachytherapy have generally been developed to approximate a 60-Gy low-dose-rate (LDR) equivalent to the surface of the vagina. Lower-dose HDR regimens may provide an equivalent outcome with lower toxicity rates. A prospective randomized trial of two dose fractionation regimens, 2.5 Gy × 6 fractions vs 5.0 Gy × 6 fractions, was carried out in 230 patients. The dose was prescribed to 5 mm in both groups. There was no difference in local control between the two doses but vaginal foreshortening was more pronounced in the 5.0-Gy fraction group. Other investigators have reported other dose fractionation regimens with good outcomes, such as 7.0 Gy × 3 fractions prescribed to 5 mm, 4 Gy × 6 fractions prescribed to the surface, and 6 Gy × 5 fractions prescribed to the surface.[16,19] Clearly, multiple dose fractionation regimens exist, and future trials, such as Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC)–4, may help establish care. Ninety-five percent of the vaginal lymphatics lie within 3 mm of the vaginal surface, so ensuring an adequate dose to at least this depth may be important. In a recent survey of US radiation oncologists, 57% prescribe to 5 mm and 27% prescribe to the vaginal surface. Of those who prescribe to 5 mm, 64% use 7 Gy × 3 fractions, and of those who prescribe to the vaginal surface, 45% use 6 Gy × 5 fractions.
There is also variation in the appropriate length of vagina to treat with vaginal brachytherapy. It is important to establish the length of the vagina during physical examination prior to treatment in order to prescribe the dose to the correct length. The upper one-half of the vagina was treated in PORTEC-2 and the upper two-thirds of the vagina was treated in studies by Sorbe et al.[15-17] The most common prescription length in the United States was either the upper one-half or upper 4 cm of the vagina, and the American Brachytherapy Society recommends treatment of the upper 3 to 5 cm of the vagina (see Variant 1).
Pelvic Radiation Therapy
Patients with intermediate-risk endometrial cancer have higher risks of recurrence than low-risk patients and are thus more likely to benefit from adjuvant radiation therapy. There are differing definitions of intermediate-risk and high-intermediate–risk disease, which makes comparisons of randomized trials challenging. Typically, intermediate-risk disease consists of early-stage patients with risk factors such as high grade, deep myometrial invasion, LVSI, and/or older age. Numerous retrospective studies of vaginal brachytherapy alone for intermediate-risk endometrial cancer have been published, with good outcomes.[22-25]
PORTEC-2 was a randomized trial of vaginal brachytherapy vs whole-pelvic radiation therapy (WPRT) in high-intermediate–risk uterine cancer. Inclusion criteria were age > 60 years, > 50% myometrial invasion, and grade 1/2; age > 60 years, < 50% myometrial invasion, and grade 3; or cervical glandular involvement at any age. Staging lymphadenectomy could not be performed. There was no difference in vaginal recurrence rate between vaginal brachytherapy and WPRT (1.8% vs 1.6%, respectively; P = .74). WPRT resulted in a lower risk of pelvic recurrence (3.8% compared with 0.5%; P < .02). After randomization, a central pathology review was conducted and the most frequent tumor grade change was from grade 2 to 1, resulting in 79% of the patients having grade 1 disease. Fourteen percent of the enrolled patients would have ultimately been ineligible and considered as low-intermediate–risk disease.
Two randomized trials of vaginal brachytherapy vs vaginal brachytherapy plus WPRT have been conducted. The most recent study included intermediate-risk patients, defined as nuclear grade 1 or 2, stage I endometrioid carcinoma with 1 of the following: deep myometrial invasion, DNA aneuploidy, or FIGO grade 3. Locoregional relapse rates were higher in the vaginal brachytherapy–alone arm (5.0% vs 1.5%; P = .013), with no corresponding difference in overall survival between arms. An earlier randomized trial from Norway included 537 stage I endometrial cancer patients. Vaginal brachytherapy was compared to vaginal brachytherapy plus WPRT. WPRT resulted in a lower local recurrence rate (2% vs 7%, respectively; P < .01). Although the results of these two trials were similar, the lack of well-defined risk groups in the Norwegian trial makes a comparison to modern trials challenging.
The Medical Research Council ASTEC (A Study in the Treatment of Endometrial Cancer) trial was a randomized trial of standard surgery of hysterectomy, bilateral salpingo-oophorectomy, washings, and palpation of suspicious lymph nodes with or without lymphadenectomy. In women with intermediate-risk or high-intermediate–risk disease, there was a second randomization of pelvic radiation therapy vs observation. Vaginal brachytherapy could be given in a nonrandomized fashion on study, and 52% of participants in the observation arm received vaginal brachytherapy. Pelvic recurrence rate was 3.2% in the pelvic radiation therapy group vs 6.1% in the observation arm, with no difference in overall survival. There was no difference in the effectiveness of pelvic radiation therapy between the surgical arms.
Only two randomized trials, Gynecologic Oncology Group (GOG)-99 and PORTEC-1, compared adjuvant pelvic radiation therapy to no adjuvant radiation therapy in early-stage, intermediate-risk endometrial carcinoma. GOG-99 defined intermediate risk as stage I or occult stage II disease, and all patients had pelvic and para-aortic lymphadenectomy. External-beam radiation therapy (EBRT) reduced the recurrence rate (12% in observation group and 3% in radiation therapy group). As a result of a lower-than-expected local failure rate, the investigators identified a high-intermediate–risk subgroup on post hoc analysis, with the risk factors of grade 2–3, outer one-third invasion, or LVSI. If a patient’s age was > 70 years, 1 risk factor was necessary; if the age was > 50, 2 risk factors were necessary; and if the age was < 50, 3 risk factors were necessary. The recurrence rate in the high-intermediate–risk group was 27% with observation and 13% with EBRT. At 4 years, the incidence of death was 12% and 26% in the EBRT group and observation group, respectively.
In PORTEC-1, patients had grade 1 disease with more than one-half myometrial invasion, grade 2 disease with any invasion, or grade 3 disease with less than one-half myometrial invasion. Surgical staging was not performed. A statistically significant reduction in local failures was noted with the addition of adjuvant pelvic radiation therapy (12% vs 4%; P < .001). Based on the recurrence rates seen in PORTEC-1 and -2, a nomogram was developed to estimate recurrence rates. No improvement in overall survival was noted with the addition of adjuvant WPRT in either GOG-99 or PORTEC-1. Creutzberg et al reported a 58% overall survival rate and a 14% locoregional relapse rate in patients with grade 3 disease, outer one-half myometrial invasion, and treated with pelvic radiation therapy. A SEER study of 21,249 patients demonstrated an improved overall survival with the addition of pelvic radiation therapy in patients with invasion of the outer one-half of the myometrium (see Variant 2).
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