ACR Appropriateness Criteria® Adjuvant Management of Early-Stage Endometrial Cancer

September 15, 2016

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.

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

Introduction/Background

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.[1] 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.[2] 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.[3] 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.[9]

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.[10] Once a histopathologic diagnosis is established and uterine-confined disease is suspected, blood counts, routine biochemistry, and chest radiographs are recommended to complete workup.[11] 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.

Vaginal Brachytherapy

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[15] 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).[15]

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.[16] Other investigators have reported other dose fractionation regimens with good outcomes, such as 7.0 Gy × 3 fractions prescribed to 5 mm,[17] 4 Gy × 6 fractions prescribed to the surface,[18] 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.[20] 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.[21]

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,[21] and the American Brachytherapy Society recommends treatment of the upper 3 to 5 cm of the vagina[19] (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.[17] 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.[17]

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.[26] 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).[27] 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.[28] 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.[4]

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).[29] Based on the recurrence rates seen in PORTEC-1 and -2, a nomogram was developed to estimate recurrence rates.[30] 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.[31] 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[32] (see Variant 2).

Pelvic Radiation Therapy Technique

Pelvic radiation therapy is generally associated with more side effects than vaginal brachytherapy. A long-term quality-of-life analysis of PORTEC-2 patients was carried out, with a median follow-up of 65 months. The pelvic radiation therapy group reported worse social functioning (P = .005) and higher symptom scores for diarrhea, fecal leakage, and need to stay near a toilet (P < .001) compared to vaginal brachytherapy.[33] In the acute phase of side effects, 50% to 80% of patients who received pelvic radiation therapy experienced grade 2 or higher diarrhea.[34]

Two-field or four-field treatment techniques have traditionally been used to deliver pelvic EBRT using field borders based on bony anatomy. However, using bony landmarks as the sole method of defining treatment fields can lead to a geographic miss, particularly the lateral external iliac lymph node region.[35,36] If CT imaging is obtained, contouring the at-risk nodal groups, vaginal cuff, and organs at risk permits customization of field borders. In cases where a lymphadenectomy was not performed, cross-sectional imaging can be obtained prior to radiation therapy if risk of pelvic lymph node involvement is sufficient. Intensity-modulated radiation therapy (IMRT) has been shown to reduce dose to critical structures in dosimetric studies, and retrospective reviews of IMRT for early-stage endometrial cancer have shown excellent local control rates, with low gastrointestinal toxicity rates.[37-40] It is critical to accurately define clinical target volumes using expert consensus guidelines for gynecologic IMRT. Movement of the vaginal cuff is dependent on bladder and rectal filling. Generation of an internal target volume using full and empty bladder scans can account for this movement, since nodal volumes move independently with bony landmarks. Image-guided radiation therapy may account for some degree of independent movement of the vaginal cuff and nodal volumes but is unlikely to help in moderate to extreme cases of bladder or rectal filling in which the vaginal clinical target volume is displaced. The ongoing Radiation Therapy Oncology Group (RTOG®) TIME-C trial compares the impact of IMRT vs 3-D conformal radiation therapy on patient-reported gastrointestinal toxicity.

Vaginal Cuff Brachytherapy Boost

Vaginal cuff brachytherapy combined with WPRT is associated with a low risk of vaginal and pelvic recurrences.[26,41,42] Because WPRT alone results in low recurrence rates in early-stage endometrial cancer, the addition of vaginal cuff brachytherapy to WPRT may be of marginal benefit. Two retrospective reviews revealed no improvement in local control with a vaginal cuff brachytherapy boost.[43,44] Common fractionation regimens from RTOG trials are 6 Gy × 3 fractions prescribed to the surface after 45-Gy EBRT or 6 Gy × 2 fractions prescribed to the surface after 50.4-Gy EBRT.[45,46] Although high-level evidence is lacking, vaginal cuff brachytherapy boost can be administered in grade 3 disease, presence of lymphovascular invasion, or when cervical stromal invasion is present.[47,48]

Adjuvant Chemotherapy

Adjuvant chemotherapy is not routinely used in early endometrial cancer as distant recurrence rates are low; however, high-risk endometrioid cancer with grade 3 tumors, deeply invasive tumors, or stage II disease may preferentially benefit. The largest series of patients with cervical stromal invasion who did not receive chemotherapy had a 5-year relapse-free survival rate of 77% and a disease-specific survival rate of 91%, which is similar to some stage I patients.[49] Most randomized trials comparing EBRT to sequential EBRT and chemotherapy exclude early-stage disease. The combined analysis of the Nordic Society of Gynaecological Oncology (NSGO)/European Organisation for the Research and Treatment of Cancer (EORTC) randomized clinical trials and MaNGO ILIADE-III trials consisted of FIGO stage I–III endometrial cancer patients who were randomized to EBRT or sequential EBRT and chemotherapy. The addition of chemotherapy resulted in improved cancer-specific survival (hazard ratio [HR], 0.55; P = .01) and a trend toward improved overall survival (HR, 0.69; P = .07). Seventy-one percent of patients had endometrioid histology and 79% were FIGO stage I and II.[50]

A Japanese trial compared pelvic radiation therapy to cyclophosphamide, doxorubicin, and cisplatin in FIGO stage I–IIIC endometrial cancer patients with deep myometrial invasion. Nearly 78% of patients were stage I or II. There was no difference in recurrence patterns, disease-free survival, or overall survival.[51] A similar study from Milan comparing adjuvant pelvic or extended-field radiation therapy to chemotherapy demonstrated no difference in progression-free or overall survival.[52]

GOG-249 randomized 601 patients with high-intermediate–risk stage I (see GOG-99, except greater than one-half invasion was used), stage II, or stage I–II uterine papillary serous carcinoma or clear cell carcinoma. Patients received either WPRT or vaginal cuff brachytherapy with 3 cycles of carboplatin/paclitaxel. At 2 years, overall survival and relapse-free survival were 93% and 82%, respectively, in the pelvic radiation therapy arm and 92% and 84%, respectively, in the vaginal brachytherapy/chemotherapy arm. Acute toxicity was more common in the vaginal brachytherapy/chemotherapy group[53] (see Variant 3).

Salvage Radiation Therapy

When determining whether adjuvant radiation therapy may be of benefit, one must identify who is at an appropriate level of risk of recurrence, determine if the adjuvant radiation therapy will reduce the risk of recurrence, and estimate the associated toxicity of radiation therapy. It is also critical to determine the probability of a successful salvage treatment in case of a recurrence and determine the toxicity associated with salvage treatment. Pelvic recurrences with or without prior radiation therapy have a low rate of salvage, with a 3-year survival rate of 8% in the PORTEC-1 series.[54] There are emerging data on the use of dose-escalated IMRT for isolated nonvaginal pelvic or para-aortic nodal recurrences in patients who have not previously received radiation therapy. The 2-year survival rate was 71%, with a late grade 3-4 gastrointestinal toxicity rate of 8%.[55] Isolated vaginal recurrences in the absence of previous radiation therapy can be successfully salvaged with EBRT plus brachytherapy or surgery with or without further radiation therapy. Isolated vaginal cuff recurrences treated with EBRT plus brachytherapy have local control rates of 50% to 80%, and survival rates of 40% to 65%.[54,56-58] The grade 4 toxicity rate of this approach is 9%.[56]

EBRT doses range from 45 to 50 Gy, followed by a brachytherapy boost to at least 70- to 80-Gy LDR equivalent.[19,56] Using the linear quadratic model, HDR brachytherapy doses can be converted to LDR doses for tumor and normal tissues.[59] After EBRT, the use of interstitial or intracavitary brachytherapy is dependent on the size and location of the tumor. If the thickness of the residual tumor is ≥ 5 mm or tumor involves the lower vagina, interstitial brachytherapy under laparoscopic, CT, or magnetic resonance imaging (MRI) guidance is recommended. 3-D planning is commonly used with CT or MRI. In the unusual situation in which a patient is not medically able to undergo interstitial brachytherapy, an external-beam boost can be considered. The ongoing GOG-238 trial is randomizing patients with an isolated vaginal cuff recurrence to definitive radiation therapy with or without weekly cisplatin. In this protocol, the EBRT dose is 45 Gy. If the residual tumor is < 5 mm, then intracavitary HDR brachytherapy is recommended using 7 Gy × 3 fractions prescribed to 5 mm.

Summary of Evidence

Of the 59 references cited in the ACR Appropriateness Criteria® Adjuvant Management of Early-Stage Endometrial Cancer document, 55 are categorized as therapeutic references, including 14 well-designed studies, 27 good-quality studies, and 5 quality studies that may have design limitations. Additionally, 3 references are categorized as diagnostic references, including 2 quality studies that may have design limitations. There are 10 references that may not be useful as primary evidence. There is 1 reference that is a meta-analysis study.

The 59 references cited in the ACR Appropriateness Criteria® Adjuvant Management of Early-Stage Endometrial Cancer document were published from 1965 to 2015.

While there are references that report on studies with design limitations, 41 well-designed or good-quality studies provide good evidence.

The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria® through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply individual or society endorsement of the final document.

Financial Disclosure:Dr. Small has given talks on intraoperative radiation for, and received an honorarium and travel expenses from, Zeiss. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Copyright © 2016 American College of Radiology. Reprinted with permission of the American College of Radiology.

Supporting Documents: For additional information on the Appropriateness Criteria® methodology and other supporting documents, refer to www.acr.org/ac.

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