NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. An estimated 49,560 new uterine cancer cases will occur in 2013, with 8190 deaths resulting from the disease.1 Uterine sarcomas (stromal/mesenchymal tumors) are uncommon malignancies, accounting for approximately 3% of all uterine cancers.2 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Uterine Neoplasms describe malignant epithelial carcinomas and uterine sarcomas; each of these major categories contains specific histologic groups that require different management (see UN-1, page 250). This excerpt of the NCCN Guidelines for Uterine Neoplasms focuses on early-stage disease (ie, disease confined to the uterus), because this occurs more frequently (http://seer.cancer.gov/statfacts/html/corp.html). Fertility-sparing and non-fertility-sparing treatment options are described for those with early-stage disease. The complete version of these guidelines is available on the NCCN Web site (NCCN.org).
Risk factors for uterine neoplasms include increased levels of estrogen (caused by obesity, diabetes, high-fat diet), early age at menarche, nulliparity, late age at menopause, Lynch syndrome, older age (≥55 years), and tamoxifen use.3-6 Thus, the incidence of endometrial cancer is increasing because of increased life expectancy and obesity.
For patients with suspected uterine neoplasms, the initial evaluation/workup includes a history and physical examination, endometrial biopsy, and other studies (see UN-1, page 250).7 An expert pathology review will determine whether a patient has either 1) a malignant epithelial tumor (ie, pure endometrioid cancer, uterine serous adenocarcinoma, clear cell adenocarcinoma, or carcinosarcoma, which is also known as malignant mixed Müllerian tumor [MMMT]); or 2) a stromal/mesenchymal tumor (ie, uterine leiomyosarcoma [uLMS], endometrial stromal sarcoma [ESS], or high-grade [undifferentiated] endometrial sarcoma). Because this excerpt of the guidelines mainly focuses on early-stage malignant epithelial carcinoma, in-depth information about uterine sarcomas is not provided. Given the typical age group at risk for uterine neoplasms (ie, ≥55 years) and the presence of comorbid illnesses in older patients, it is prudent to also measure renal and liver function in selected patients.
NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms, Version 1.2014
Version 1.2014, 11-27-13 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0025
NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms, Version 1.2014
Version 1.2014, 11-27-13 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0025
NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms, Version 1.2014
Version 1.2014, 11-27-13 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0025
NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms, Version 1.2014
Version 1.2014, 11-27-13 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0025
NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms, Version 1.2014
Version 1.2014, 11-27-13 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0025
NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms, Version 1.2014
Version 1.2014, 11-27-13 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0025
NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms, Version 1.2014
Version 1.2014, 11-27-13 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 2; 10.6004/jnccn.2014.0025
Most endometrial cancer is caused by sporadic mutations. However, genetic mutations cause endometrial cancer in approximately 5% of patients, which occurs 10 to 20 years before sporadic cancer.8 Screening for genetic mutations (eg, Lynch syndrome/hereditary nonpolyposis colorectal cancer [HNPCC]) should be considered in all patients with endometrial (and colorectal) cancer, but especially in those younger than 50 years.6,8-10 Genetic testing and counseling should be considered for patients younger than 50 years with endometrial cancer and those with a significant family history of endometrial and/or colorectal cancer.11-13 If these patients have Lynch syndrome, they are at greater risk for a second cancer (eg, colorectal cancer, ovarian cancer).4,10,14 In addition, their relatives may have Lynch syndrome.
Screening of the tumor for defective DNA mismatch repair using immunohistochemistry and/or microsatellite instability (MSI) should be considered to identify which patients should undergo mutation testing for Lynch syndrome (see “Lynch Syndrome” in the NCCN Guidelines for Colorectal Cancer Screening; to view the most recent version of these guidelines, visit NCCN.org).8,9,15,16 Immunohistochemistry and/or MSI is used to assess for defective DNA mismatch repair (eg, MLH1, MSH2, MSH6), which is associated with Lynch syndrome.8 The Society of Gynecologic Oncology (SGO) also has useful criteria for determining which patients should have mutation testing (eg, young patients diagnosed with multiple Lynch syndrome-associated cancers, family members with similar cancers).11,12 Some centers perform immunohistochemistry and/or MSI screening in all patients with colorectal and endometrial cancers to identify those at risk for Lynch syndrome, regardless of age at diagnosis or family history.15,16 However, this screening is usually performed in patients with epithelial tumors, and not those with stromal or mesenchymal endometrial tumors.
Women with Lynch syndrome are at higher risk (60%) for endometrial cancer; thus, close monitoring is recommended.9,17,18 In relatives with Lynch syndrome but without endometrial cancer, a yearly endometrial biopsy is recommended to assess for cancer.12,19 This strategy also enables select women to defer surgery (and surgical menopause) and preserve their fertility. Prophylactic hysterectomy/bilateral salpingooophorectomy (BSO) can then be performed either after childbearing is complete or sooner, depending on patient preference.20,21 In addition, interventions to decrease the risk of developing colorectal cancer may also be appropriate (eg, annual colonoscopy).
Endometrial Cancer
In approximately 75% of patients with adenocarcinoma of the endometrium, the invasive neoplasm is confined to the uterus at diagnosis.22 Many physicians believe that adenocarcinoma of the endometrium is a relatively benign disease, because the early symptoms of irregular vaginal bleeding (in this predominantly postmenopausal patient population) often prompt patients to seek care when the disease is at an early and treatable stage. Thus, endometrial cancer is often localized, yielding a generally high survival rate.23 However, data show that the mortality rate for uterine cancer has increased more rapidly than the incidence rate.24 This increased mortality may be related to an increased rate of advanced-stage cancers, high-risk histologies (eg, serous adenocarcinomas), and patients being diagnosed at an older age. To further improve on outcome for patients with this disease, physicians must identify patients at high risk and tailor treatment appropriately to provide the best long-term survival. A recent analysis of SEER data suggests that survival is increased in patients who are younger, have early-stage disease, and have lower-grade disease.25 It also recommended that gynecologic oncologists be involved in the primary management of patients with endometrial cancer.
Diagnosis and Workup
Approximately 90% of patients with endometrial carcinoma have abnormal vaginal bleeding, most commonly in the postmenopausal period. The workup was previously described (see “Overview,” page 248). Diagnosis can usually be made based on an office endometrial biopsy.26,27 The histologic information from the endometrial biopsy (with or without endocervical curettage) should be sufficient for planning definitive treatment. Office endometrial biopsies have a false-negative rate of approximately 10%. Thus, a negative endometrial biopsy in a symptomatic patient must be followed by a fractional dilation and curettage (D&C) under anesthesia.26,28 Hysteroscopy may be helpful in evaluating the endometrium for lesions, such as a polyp, if the patient has persistent or recurrent undiagnosed bleeding.29
Other ancillary tests (ie, CT, MRI, and PET) are reserved for evaluating extrauterine disease as indicated by clinical symptoms, physical findings, or abnormal laboratory findings.30-33 In patients with extrauterine disease, a serum CA125 assay may be helpful for monitoring clinical response.34,35 However, serum CA125 levels may be falsely increased in women who have peritoneal inflammation/infection or radiation injury, or normal in women with isolated vaginal metastases, and may not predict recurrence in the absence of other clinical findings.36-38 Currently, no validated screening test exists for endometrial carcinoma.39,40
Staging
The FIGO (International Federation of Gynecology and Obstetrics) system is most commonly used for staging uterine cancer. The original 1970 criteria for staging endometrial cancer only used information gained from presurgical evaluation (including physical examination, diagnostic fractional D&C). At that time, many patients were not treated with primary surgery because of obesity or various other medical problems. Thus, the 1970 staging system is rarely used today (eg, when the patient is not a surgical candidate).
However, several studies showed that clinical staging was inaccurate and did not reflect actual disease extent in 15% to 20% of patients.41-43 This reported understaging and, more importantly, the ability to identify multiple prognostic factors with a full pathologic review made possible with surgical staging, motivated a change in the staging classification. Therefore, in 1988, FIGO modified its staging system to emphasize thorough surgicopathologic assessment of data, such as histologic grade, myometrial invasion, and the extent and location of extrauterine spread (including retroperitoneal lymph node metastases).44 FIGO and the AJCC updated and refined the surgical/pathologic staging criteria for uterine neoplasms in 2010.45-49 Separate staging systems for malignant epithelial tumors and uterine sarcomas are now available (see Tables 1 and 2, respectively, in the complete version of these guidelines, available online at NCCN.org).
The 2010 staging streamlined stages I and II endometrial carcinoma. These revisions were made because the survival rates for some of the previous stages were similar.48 Stage IA is now less than 50% myometrial invasion, and stage IB is 50% or more myometrial invasion. Stage II only includes patients with cervical stromal invasion. Patients with endocervical glandular involvement without invasion are no longer upstaged.48 Stage IIIC is now subdivided into IIIC1 and IIIC2, because survival is worse with positive paraaortic nodes.48 Although most of the previously published studies discussed in these guidelines used the older 1988 FIGO staging system, these have been reinterpreted by the NCCN Uterine Neoplasms Panel to reconcile with the 2010 staging system.
An expert pathology review will determine the specific epithelial histology of the tumor (ie, various endometrioid histologies, serous adenocarcinoma, clear cell adenocarcinoma, or carcinosarcoma). These guidelines divide pure endometrioid cancer into 3 categories for delineating treatment: 1) disease limited to the uterus, 2) suspected or gross cervical involvement, and 3) suspected extrauterine disease (see UN-1, page 250). This shorter version of the NCCN Guidelines only discusses disease limited to the uterus. Pathologic assessment of the uterus and nodes is described in the algorithm; this assessment should also include the fallopian tubes and ovaries (see ENDO-A, page 258). Peritoneal cytology no longer affects the 2010 FIGO staging, because it is not viewed as an independent risk factor.49 However, FIGO and AJCC continue to recommend that peritoneal washings be obtained and results recorded, because positive cytology may add to the effect of other risk factors (see ENDO-B, page 259).50,51
Staging should be performed by a team with expertise in imaging, pathology, and surgery. The amount of surgical staging that is necessary to determine disease status depends on preoperative and intraoperative assessment of findings by experienced surgeons. For the 2014 update, the panel added a new section on surgical staging (see ENDO-B, page 259). Selected patients with apparent uterineconfined endometrial carcinoma may be considered (category 2B) for sentinel node biopsy (see “Sentinel Lymph Node Mapping” in the complete version of these guidelines, available online at NCCN.org). However, this new surgical staging section only applies to malignant epithelial tumors and not to uterine sarcomas. The Protocol for the Examination of Specimens From Patients With Carcinoma of the Endometrium published by the College of American Pathologists (CAP) is a useful guide (http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2013/Endometrium_13protocol_3200.pdf) This CAP protocol was revised in October 2013 and reflects the updated FIGO/AJCC 2010 staging (ie, AJCC staging manual, 7th edition).
Most patients with endometrial cancer have stage I disease at presentation, and surgery (with or without adjuvant therapy) is recommended for medically operable patients. For patients with surgical stage I (any grade) endometrial cancer, the 5-year overall survival rate is 88% after treatment.22
Primary Treatment and Surgical Staging
Medically Operable Patients: For the staging of patients (if medically operable) with endometrioid histologies clinically confined to the fundal portion of the uterus, the recommended surgical procedure includes total hysterectomy (TH)/BSO with selective surgical staging (see ENDO-1, ENDO-A, and ENDO-B, pages 251, 258, and 259; see also “Minimally Invasive Procedures,” page 266).52 When indicated, surgical staging is recommended to gather full pathologic and prognostic data on which to base decisions regarding adjuvant treatment for select patients who do not have medical or technical contraindications to lymph node dissection (see “Lymphadenectomy Controversy,” next column, and “Sentinel Lymph Node Mapping” in the complete version of these guidelines, available online at NCCN.org).
During surgery, the intraperitoneal structures should be carefully evaluated, and suspicious areas should be biopsied. Although it does not specifically affect staging, FIGO recommends that peritoneal cytology should be collected and results should be recorded. Enlarged or suspicious lymph nodes should be excised to confirm or rule out metastatic disease. Retroperitoneal node dissection with pathologic evaluation—in the absence of clinically apparent lymphadenectomy—is useful when using the 2010 FIGO staging criteria, but its routine use has been questioned (see “Lymphadenectomy Controversy,” next section).
Lymphadenectomy Controversy: Previously, a full standard lymphadenectomy (ie, dissection and assessment of both pelvic and paraaortic nodes) was recommended for all patients; however, a more selective and tailored lymphadenectomy approach is now recommended by the panel to avoid systematic overtreatment.53 No randomized trial data support routine full lymphadenectomy,54 although some retrospective studies suggested that it is beneficial.55-57 Two randomized clinical trials from Europe reported that routine lymph node dissection did not improve the outcome of patients with endometrial cancer, but lymphadenectomy did identify those with nodal disease.58,59 However, these findings remain a point of contention.52,60,61 To avoid overinterpretation of these results, it is important to address the limitations of these randomized studies, including selection of patients, extent of lymph node dissection, and standardization of postoperative therapy.62,63 The other concerns include the lack of central pathology review, subspecialty of surgeons, and adequacy of statistical power.
Decisions about whether to perform lymphadenectomy, and if so to what extent (eg, pelvic nodes only, or both pelvic and paraaortic nodes), can be made based on preoperative and intraoperative findings. The following criteria have been suggested as indicative of low risk for nodal metastases: 1) less than 50% myometrial invasion, 2) tumor less than 2 cm, and 3) well or moderately differentiated histology64,65; however, these may be difficult to accurately determine before final pathology results are available.
Another associated benefit of lymphadenectomy is for diagnosing nodal metastases to help guide the selection of appropriate adjuvant treatment to improve survival or decrease toxicity. However, one of the 2 European randomized trials was not designed to address this question.59 Therefore, there was no standardization of adjuvant treatment after staging surgery with lymphadenectomy. In fact, the use of lymphadenectomy did not translate into an increased use of adjuvant therapy. This may have contributed to the lack of difference in recurrence and survival between the 2 groups. Studies show that in 15% to 20% of cases, the preoperative grade (as assessed by endometrial biopsy or curettage) is upgraded on final fixed pathologic evaluation of the hysterectomy specimen.66 As the grade of the tumor increases, the accuracy of intraoperative evaluation of myometrial invasion decreases (ie, assessment based on gross examination of fresh tissue). In one study, the depth of invasion was accurately determined through gross examinations in 87.3% of grade 1 lesions, 64.9% of grade 2 lesions, and 30.8% of grade 3 lesions.67
The question of whether to add periaortic lymphadenectomy to pelvic node dissection has been debated. Prior studies have shown conflicting information regarding the risk of paraaortic nodal metastases in patients without disease in the pelvic nodes.43,64,68,69 A high rate of lymphatic metastasis was seen above the inferior mesenteric artery, suggesting a need for systematic pelvic and paraaortic lymphadenectomy. Hence, periaortic lymphadenectomy up to the renal vessels may be considered for selected high-risk situations, including patients with pelvic lymphadenectomy or high-risk histologic features. Many surgeons do not perform a full lymphadenectomy in patients with grade 1 early-stage endometrial cancer.53 Selected patients with apparent uterineconfined endometrial carcinoma may be candidates for sentinel node mapping (category 2B), which assesses the pelvic nodes and is a less morbid procedure than standard lymphadenectomy (see “Sentinel Lymph Node Mapping” in the complete version of these guidelines, available online at NCCN.org).
In summary, lymph node dissection identifies patients requiring adjuvant treatment with radiation therapy and/or chemotherapy.70 A subset of patients may not benefit from lymphadenectomy; however, these patients are difficult to identify preoperatively because of the uncontrollable variables of change in grade and depth of invasion on final pathology. At this point, pending further trials that seek to define the clinical benefit of lymphadenectomy, the panel recommends that lymphadenectomy be performed for selected patients with endometrial cancer, with paraaortic lymphadenectomy performed as indicated for high-risk patients (see ENDO-B, page 259).5 Lymphadenectomy is contraindicated for patients with uterine sarcoma. Sentinel node mapping may be considered (category 2B) for selected patients with apparent uterine-confined endometrial disease (see “Sentinel Lymph Node Mapping” in the complete version of these guidelines, available at NCCN.org).
Minimally Invasive Procedures: Laparoscopic pelvic and paraaortic lymphadenectomy in association with total laparoscopic hysterectomy is being used in many practices.53,71,72 However, patients undergoing laparoscopy should be followed long term so the outcomes can be compared with those of traditional laparotomy.73
The randomized phase III trial GOGLAP2 evaluated laparoscopy for comprehensive surgical staging in patients with clinical stage I to IIA disease (n=2616).73,74 Patients were randomly allocated 2:1 to either laparoscopy or laparotomy. Results from this trial indicated that 26% of patients required conversion to laparotomy because of poor visibility, metastatic cancer, bleeding, increased age, or increased body mass index. Detection of advanced cancer was not significantly different among the groups. However, significant differences were noted in removal of pelvic and paraaortic nodes (8% not removed with laparoscopy vs 4% with laparotomy; P<.0001).75,76 Significantly fewer postoperative adverse events and shorter hospitalization occurred with laparoscopy compared with laparotomy. Recurrence rates were 11.4% for laparoscopy versus 10.2% for laparotomy. The 5-year overall survival rate was 84.8% for both arms of GOG-LAP2.74 Another randomized trial (n=283) comparing laparoscopy versus laparotomy reported shorter hospital stays, less pain, and faster resumption of daily activities with laparoscopy.77 However, laparotomy may still be required for certain clinical situations (eg, elderly patients, patients with a very large uterus) or certain metastatic presentations.73
Robotic surgery is a minimally invasive technology that has been advocated by some as a feasible approach in the primary management of endometrial cancer.71,72,78-85 Costs for equipment and maintenance remain high.86 Given the recent introduction of robotic surgery, long-term outcomes are still pending.87-90 However, because of its potential advantages over traditional laparoscopic approaches, it is rapidly becoming the preferred technique for minimally invasive surgery in endometrial cancer, especially for obese patients.71,91 The SGO recently published a consensus statement about robotic surgery.92
Incomplete Surgical Staging: For patients with incomplete (ie, not thorough) surgical staging and high-risk intrauterine features, imaging is often recommended, especially in patients with higher-grade and more deeply invasive tumors.93,94 Surgical restaging, including lymph node dissection, can also be performed.64 Recommended adjuvant treatment options are provided in the algorithm based on the imaging and/or surgical restaging results (see ENDO-8, page 255).
FertilitySparing Therapy: Although the primary treatment of endometrial cancer is usually hysterectomy, continuous progestin-based therapy may be considered for highly selected patients with stage IA disease who wish to preserve their fertility.95-98 Likewise, it may also be selectively used for young patients with endometrial hyperplasia who desire fertility preservation. For the 2014 update, the panel added a new algorithm for fertility-sparing therapy in selected patients with biopsy-proven grade 1, stage IA endometrioid adenocarcinoma (see ENDO-2, page 252). When considering fertility-sparing therapy, all of the criteria must be met, as outlined in the algorithm (eg, no metastatic disease). Patients also need to receive counseling that fertility-sparing therapy is not the standard of care for the treatment of endometrial carcinoma. TH/BSO with surgical staging is recommended after childbearing is complete, if therapy is not effective, or if progression occurs. Fertility-sparing therapy is not recommended for high-risk patients (eg, those with high-grade endometrioid adenocarcinomas, uterine serous adenocarcinoma, clear cell adenocarcinoma, carcinosarcoma, or uLMS).
Continuous progestin-based therapy may include megestrol acetate, medroxyprogesterone, or an intrauterine device containing levonorgestrel.95,96,99 A durable complete response occurs in approximately 50% of patients.95 The use of progestin-based therapy should be carefully considered in the context of other patient-specific factors, including contraindications such as breast cancer, stroke, myocardial infarction, pulmonary embolism, deep vein thrombosis, and smoking.
In patients receiving progestin-based therapies, the panel recommends close monitoring with endometrial sampling (biopsies or D&C) every 3 to 6 months. TH/BSO with staging is recommended 1) after childbearing is complete; 2) if patients have documented progression based on biopsy results; or 3) if endometrial cancer is still present after 6 months of progestin-based therapy.100 Although some young women who had subsequent negative endometrial biopsies after hormonal therapy were able to become pregnant (35%), their ultimate recurrence rate was high (35%).95,98,101-103
In premenopausal women with stage IA to B endometrial cancer, data suggest that ovarian preservation is safe and not associated with an increased risk of cancer-related mortality; patients were followed for 16 years.104 Other studies also suggest that ovarian preservation may be safe in women with early-stage endometrial cancer.105,106
Medically Inoperable Patients: For medically inoperable patients, tumor-directed radiation therapy is a well-tolerated and effective treatment that can provide some measure of pelvic control and long-term progression-free survival (PFS) (see UN-A, page 262).107-109 Hormonal therapy may be considered in selected patients with endometrioid histology (eg, patients who are estrogen receptor-positive and progesterone receptor-positive), who are not candidates for radiation therapy or surgery, if they are closely monitored (eg, consider endometrial biopsies every 3-6 months).39,110 Progesterone-based therapy can provide some benefit with low toxicity in patients with low-grade tumors.111 Tamoxifen with alternating megestrol may be used.112 Aromatase inhibitors have also been used.113-116
Adjuvant Therapy: Thorough surgical staging provides important information to assist in the selection of adjuvant therapy for endometrial tumors (see ENDO-B, page 259). Patients with stage I endometrial cancer who undergo thorough surgical staging are stratified by adverse risk factors (ie, age, positive lymphovascular space invasion [LVSI], tumor size, and lower uterine [cervical/glandular] segment involvement). Recommended adjuvant treatment is shown in the algorithm (see ENDO-5, page 253). Note that the treatment algorithm was revised in 2010 based on the updated FIGO/AJCC staging (7th edition).46,48 However, by necessity, much of the discussion in this manuscript has been based on the older FIGO/AJCC staging system. The implications of stage migration should be taken into account when evaluating historical data (see Table 1 in the complete version of these guidelines, available online at NCCN.org).
Significant controversy centers on how much adjuvant therapy is necessary in patients with surgical stage I endometrial cancer, regardless of intrauterine features, if extrauterine disease has been clearly ruled out. In a large prospective study, the Gynecologic Oncology Group (GOG) reported that the 5year survival rate for patients with surgical stage I endometrial cancer with no adverse risk factors other than grade and myometrial invasion (ie, without extrauterine disease, isthmus/cervical involvement, or LVSI) was 92.7%.117 The practice of surgical staging has led to a decrease in the use of adjuvant therapy for stage I endometrial carcinoma, which is reflected in the option of “observation” in these guidelines (see ENDO-5, page 253).70,118-121
Adjuvant Radiation Therapy: Several phase III trials have assessed adjuvant therapy in patients with uterine-confined disease. In summary, the use of adjuvant radiation therapy improves pelvic control in patients with selected risk factors (and may improve PFS), but radiation therapy did not improve overall survival in any of the trials. However, many of these trials had limitations because most of the patients were low risk (ie, they had low-risk intrauterine pathologic risk factors). Thus, the trials were underpowered for patients with high-risk factors. It is recognized that in patients with uterine-confined disease, there is a spectrum of risk based on intrauterine pathologic findings. Adverse intrauterine pathologic risk factors include high-grade tumors, deep myometrial invasion (and consequently more advanced stage), LVSI, and serous or clear cell adenocarcinoma histologies.
The basic concept underlying the recommendations in these guidelines is the trend toward selection of more aggressive adjuvant therapy for patients as tumor grade and myometrial and/or cervical invasion worsen, because risk exists on a continuum.118 In surgical stage I and II endometrial cancer, other pathologic factors that may influence the decision regarding adjuvant therapy include patient age, tumor volume, and involvement of the lower uterine segment.
Four trials have evaluated the role of adjuvant external-beam pelvic RT in patients with endometrial carcinoma. In 2 of these trials, the patients were not formally staged (ie, Postoperative Radiation Therapy in Endometrial Carcinoma [PORTEC-1]122 and the trial by Aalders et al123). In the third trial (ASTEC/EN.5), only 50% of the patients were thoroughly staged as part of a companion surgical protocol.58,124 However, formal surgical staging was mandated for all patients in the fourth trial (GOG-99).125 Note that these trials used the older staging system (ie, before 2010).
The PORTEC-1 trial suggested that externalbeam pelvic RT provides a therapeutic benefit in selected patients with uterine-confined disease.122,126 Although radiation therapy significantly decreased locoregional recurrence, it did not increase overall survival.127 The randomized trial by Aalders et al123 found that radiation therapy reduced vaginal (ie, locoregional) recurrences but did not reduce distant metastases or improve survival. A recent pooled randomized trial (ASTEC/EN.5) suggested that adjuvant pelvic radiation therapy alone did not improve either relapse-free survival (ie, PFS) or overall survival in patients with intermediate-risk or high-risk early-stage endometrial cancer, but a small improvement in pelvic control was seen.124 However, the ASTEC/EN.5 study is very controversial; 51% of the patients in the ASTEC observation group received vaginal brachytherapy.61,128 The GOG-99 trial by Keys et al125 showed that adjuvant pelvic radiation therapy improved locoregional control and relapse-free interval (ie, PFS), without conferring an overall survival benefit. Both the GOG-99 and PORTEC-1 trials revealed that most of the initial recurrences in patients with initial uterine-confined tumors were limited to the vagina, prompting the increasing use of vaginal brachytherapy alone as adjunctive treatment.125,129,130
To help select a patient population who may benefit from adjuvant radiation therapy, the GOG-99 and PORTEC-1 trials defined risk factors for women at high-intermediate risk (HIR) for recurrence.122,125 These risk factors include age in addition to deep myometrial invasion, grade, and LVSI. In GOG-99, women younger than 50 years had to have all 3 histologic risk factors to be considered HIR.125 If they were aged 50 to 70 years, they were considered HIR if they had 2 histologic risk factors. Women aged 70 years or older were considered HIR if they also had one risk factor. In PORTEC-1, women had to have 2 of 3 risk factors (age >60 years, deep myometrial invasion, grade 3 histology) to be considered at HIR for recurrence.122,129
Because of concerns about potential toxicity of external-beam pelvic radiation therapy, the role of vaginal brachytherapy alone in uterine-confined disease has been evaluated. PORTEC-2 randomly assigned patients to either external-beam pelvic radiation therapy or vaginal brachytherapy alone in uterine-confined disease. Results of this trial showed excellent and equivalent vaginal and pelvic control rates with both adjuvant radiation approaches, and no difference in overall survival.131 Given that vaginal brachytherapy is associated with significantly less toxicity than pelvic radiation therapy, vaginal brachytherapy alone is a reasonable choice for most patients with uterine-confined endometrial cancer who are deemed candidates for adjuvant radiation therapy.129-137 The use of vaginal brachytherapy and/or whole pelvic radiation therapy should be carefully tailored to a patient’s pathologic findings. Both PORTEC-1 and PORTEC-2 specifically excluded patients with 1998 FIGO stage IC, grade 3 endometrial carcinoma (2010 FIGO stage IB, grade 3)46,48; thus, the use of adjuvant brachytherapy alone in the highest-risk subset remains undetermined.
The benefit of adjuvant external-beam radiation therapy in the highest-risk spectrum of uterine-confined disease remains controversial. Most panel members feel that patients with deeply invasive grade 3 tumors should receive adjuvant treatment. However, given the lack of consistent absolute survival benefit, observation (category 2B) may be appropriate in selected cases. Two large retrospective SEER analyses of women with endometrial cancer found that adjuvant radiation therapy improved overall survival in those with high-risk disease.138,139 In a meta-analysis of randomized trials, a subset analysis found that adjuvant pelvic radiation therapy for stage I disease was associated with a trend toward a survival advantage in the highest-risk spectrum (eg, those with 1988 FIGO stage IC, grade 3) but not in lower-risk patients; however, other reviews have shown conflicting results.133,140-143
Adjuvant Chemotherapy: Patients with 1998 FIGO stage IC, deeply invasive, grade 3, uterine-confined disease have a relatively poor prognosis (revised to 2010 FIGO stage IB, grade 3). Despite adjuvant therapy with pelvic radiation therapy, a significant number of patients continue to have an appreciable risk of distant metastases.125,126 Therefore, some clinicians suggested that adding chemotherapy to adjuvant radiation therapy may provide added therapeutic benefit (ie, decrease distant metastases).118,144 Studies have evaluated the role of chemotherapy in highest-risk uterine-confined disease.144,145 PFS is improved with adjuvant sequential chemotherapy/radiation therapy.144 However, the panel feels that adjuvant chemotherapy is a category 2B recommendation in this setting because an overall survival advantage has not been shown.144 The role of adjuvant chemotherapy in invasive high-grade, uterine-confined disease is being further studied (eg, GOG-249, PORTEC-3).
The recommended postoperative (ie, adjuvant) treatment options for patients with surgical stage II disease (using thorough surgical staging) are shown in the algorithm (see ENDO-6, page 254). The panel generally agrees on the role of adjuvant therapy for patients with an invasive cervical component if extrafascial hysterectomy is performed. However, for patients with stage II disease who have had a radical hysterectomy with negative surgical margins and no evidence of extrauterine disease, observation or vaginal brachytherapy are options.
Radiotherapy Principles
Radiation therapy has been a widely used modality in the treatment of patients with endometrial cancer; it clearly improves locoregional control. Tumor-directed radiation therapy refers to radiation therapy directed at sites of known or suspected tumor involvement and may include external-beam radiation therapy (EBRT) and/or brachytherapy. Radiation therapy is described in detail in the algorithm, including target areas and doses for pelvic radiation therapy and brachytherapy (see UN-A, page 262).
Although adjuvant radiation therapy is typically not associated with high rates of severe morbidity,146 studies have focused on its subtle effects on quality of life (eg, diarrhea, bowel symptoms) that deserve further investigation.134,136 In the PORTEC-2 trial, vaginal brachytherapy was associated with better quality of life when compared with EBRT, without a significant detriment to outcome.134 Therefore, many patients who were previously treated with adjuvant EBRT are now appropriately treated with vaginal brachytherapy, and this recommendation is reflected in these guidelines. Patients treated with radiation therapy are prone to vaginal stenosis, which can impair sexual function. Women can use vaginal dilators to prevent or treat vaginal stenosis. Dilator use can begin 2 to 4 weeks after radiation therapy is completed and can be used indefinitely (http://www.mskcc.org/patient_education/_assets/downloadsenglish/571.pdf).
Posttreatment Surveillance
The recommended posttreatment surveillance protocol for endometrial cancer is shown in the algorithm (see ENDO-9, page 256).30 These recommendations recognize that the value of intensive surveillance has not been demonstrated in this disease; therefore, ancillary testing is not recommended.147,148
Patients with clinical stage I and II endometrial cancer have a recurrence rate of approximately 15%23,148-150; 50% to 70% of patients have symptomatic recurrences. For most patients, disease recurs within 3 years of initial treatment. Because most recurrences are symptomatic, all patients should receive verbal and written information regarding the symptoms of recurrent disease.148 Patients with bleeding (vaginal, bladder, or rectal), decreased appetite, weight loss, pain (in the pelvis, abdomen, hip, or back), cough, shortness of breath, and swelling (in the abdomen or legs) should seek prompt evaluation and not wait until their next scheduled appointment.
In the absence of recurrence, posttreatment surveillance provides psychosocial reassurance and improves the quality of life for patients and their families. Health maintenance has been incorporated into the followup schedule (eg, blood pressure determination, breast examination, mammography as clinically indicated, stool guaiac test, immunizations), including lifestyle, obesity, exercise, and nutrition counseling (see the NCCN Guidelines for Survivorship [available online at NCCN.org] and http://www.cancer.org/treatment/survivorshipduringandaftertreatment/index).151-153 Other health problems that often coexist in patients with endometrial cancer can also be evaluated during follow-up. Given the lack of prospective studies regarding the optimal frequency of posttreatment follow-up, the panel believes that the algorithm represents a reasonable surveillance scheme. For the 2014 update, the use of vaginal cytology is no longer recommended for asymptomatic patients, consistent with the SGO guidelines.147,148,150,154 Patients with stage I endometrial cancer have a low risk of asymptomatic vaginal recurrence (2.6%), especially after adjuvant brachytherapy, and vaginal cytology is not independently useful for detecting recurrences in this group of patients.155
Hormone Replacement Therapy for Hypoestrogenism
After BSO, hypoestrogenism is associated with hot flashes, mood lability, vaginal dryness, pelvic soft tissue atrophy, osteoporosis, and an increased risk of cardiovascular disease. In postmenopausal women, estrogen replacement therapy was believed to reduce or reverse some of these signs and symptoms. However, women who have had BSO for endometrial adenocarcinoma have usually been denied estrogen replacement therapy for fear of inducing a higher relapse rate, because this cancer has historically been considered an estrogen-linked malignancy.156,157 However, estrogen replacement therapy for these patients remains controversial.
It has never been proven that patients with endometrial cancer who receive estrogen replacement therapy after hysterectomy have a higher relapse rate. In fact, several retrospective trials of estrogen replacement after treatment of early-stage endometrial cancer have shown no increase in tumor recurrence or cancer-related deaths.158-160 In women with stage I to II endometrial cancer who had hysterectomy, a randomized trial of estrogen replacement therapy versus placebo did not find an increased rate of recurrence or new malignancy; the median follow-up was 35.7 months.161 However, estrogen replacement trials in postmenopausal women without a history of malignancy have shown a significantly increased risk of breast cancer.162
Initially, the Women’s Health Initiative Estrogen-Alone Trial in women who had hysterectomy (n=10,739) reported that the risk of developing breast cancer and cardiovascular disease (eg, stroke) were increased and that estrogen replacement therapy was of concern; thus, the trial was stopped.163 However, recent long-term follow-up data from this trial suggest that the risk from estrogen-alone replacement therapy (without progesterone) may not be as high in younger women (age <60 years) who have had hysterectomy.164
The panel agrees that estrogen replacement therapy is a reasonable option for patients who are at low risk for tumor recurrence, but initiating this therapy should be individualized and discussed in detail with the patient.165,166 If adjuvant treatment is performed, there should be a 6- to 12-month waiting period before initiation of hormone replacement therapy, and participation in clinical trials is strongly encouraged. Selective estrogen-receptor modulators (SERMs) may prove to be attractive options for hormone replacement therapy.167,168 Long-term comparisons between conjugated estrogens and SERMs for hormone replacement therapy are needed. Nonhormonal therapy may be considered in patients who are deemed poor candidates for hormone replacement therapy (eg, smokers, history of breast cancer, history of multiple strokes).169,170
Drug Reactions
Virtually all drugs have the potential to cause adverse hypersensitivity reactions, either during or after the infusion.171 In gynecologic oncology treatment, drugs that more commonly cause adverse reactions include carboplatin, cisplatin, docetaxel, liposomal doxorubicin, and paclitaxel. Most of these responses are mild infusion reactions (ie, skin reactions, cardiovascular reactions, respiratory or throat tightness), but more severe allergic reactions (ie, life-threatening anaphylaxis) can occur.172-174 In addition, patients can have mild allergic or severe infusion reactions. Infusion reactions are more common with paclitaxel.175 Allergic reactions (ie, true drug allergies) are more common with platinum agents (ie, carboplatin, cisplatin).175,176
Management of drug reactions is discussed in the NCCN Guidelines for Ovarian Cancer (to view the most recent version of these guidelines, visit NCCN. org).175 It is important to note that patients who have had severe life-threatening reactions should not receive the implicated agent again unless under the care of an allergist or expert in managing drug reactions. If a mild allergic reaction has previously occurred and it is appropriate to administer the drug again, a desensitization regimen should be used even if the symptoms have resolved; various desensitization regimens have been published and should be followed.177-179 Patients must be desensitized with each infusion if they previously had a reaction. Almost all patients can be desensitized (≈90%).171 To maximize safety, it is prudent to desensitize patients in the intensive care unit.171
Uterine Serous Adenocarcinomas, Clear Cell Adenocarcinomas, and Carcinosarcomas
Overview
Uterine serous adenocarcinomas, clear cell adenocarcinomas, and carcinosarcomas are considered more aggressive histologic variants of malignant epithelial tumors, with a higher incidence of extrauterine disease at presentation.180-187 Carcinosarcomas are aggressive tumors that are staged as high-grade endometrial cancer (see Table 1 in the complete version of these guidelines, available online at NCCN.org).188,189 Pathologists now believe that carcinosarcomas (also known as MMMTs) are metaplastic carcinomas and not uterine sarcomas; therefore, carcinosarcomas are included in the high-risk malignant epithelial tumors section of the NCCN Guidelines (see ENDO-11, page 257).184,187,190,191 Even patients with apparent early-stage disease may have distant metastases. Thus, fertility-sparing therapy is not recommended for these aggressive tumors. If performed, sentinel lymph node mapping should proceed with particular caution (see the complete version of these guidelines).
Patients may present with pelvic masses, abnormal cervical cytology, or ascites in addition to postmenopausal bleeding. Both the NCCN Uterine Neoplasms Panel and the SGO recommend that CA-125 and MRI/CT may be useful before surgery to assess if extrauterine disease is present; PET may also be useful.180 Serous adenocarcinomas, clear cell adenocarcinomas, and carcinosarcomas are all considered high-risk tumors (ie, grade 3), although they are staged using the same FIGO/AJCC staging system (ie, 7th edition) as endometrial cancers (see Table 1 in the complete version of these guidelines, available online at NCCN.org).46 Patterns of failure often mimic those of ovarian cancer.
Treatment
Multimodality therapy is typically recommended for these histologically aggressive tumors. Primary treatment includes TH/BSO with surgical staging, peritoneal lavage for cytology, omental and peritoneal biopsies, and consideration of maximal tumor debulking for gross disease (see ENDO-B, page 259).192
Adjuvant therapy is highly individualized.193-200 For patients with stage IA without myometrial invasion, options include observation, chemotherapy, or tumor-directed radiation therapy.201 For all other patients with more advanced disease, chemotherapy with (or without) tumor-directed radiation therapy is the preferred option.182,194,198,202 Adjuvant platinum/taxane-based therapy seems to improve survival in patients with uterine serous and clear cell adenocarcinoma, whereas ifosfamide/paclitaxel (category 1) is recommended for carcinosarcomas (see ENDO-C, page 260).180-182,203-205 For the 2014 update, whole abdominopelvic radiation therapy with (or without) vaginal brachytherapy is no longer recommended as a primary treatment option for patients with advanced disease, because the panel no longer believes that routine use of whole abdominal radiation therapy is appropriate.202,206,207 Chemotherapy with (or without radiation therapy) seems to be more effective than radiation therapy alone.194 Data are conflicting regarding the rate of abdominal recurrence in these patients.202,208-212 Whole abdominal radiation therapy is not considered to be tumor-directed radiation therapy (see UN-A, page 262). As previously mentioned, tumor-directed radiation therapy refers to radiation therapy directed at sites of known or suspected tumor involvement and may include external-beam radiation therapy and/or brachytherapy. In general, tumor-directed external-beam radiation therapy is directed to the pelvis with (or without) the para-aortic region.
Ifosfamide was historically considered the most active single agent for carcinosarcoma.204,213,214 A phrase III trial for advanced carcinosarcoma showed that the combination of ifosfamide and paclitaxel increased survival and was less toxic than the previously used cisplatin/ifosfamide regimen.204,215 Overall survival was 13.5 months with ifosfamide/paclitaxel versus 8.4 months with ifosfamide alone. Therefore, ifosfamide/paclitaxel is category 1 in these guidelines (see ENDO-C, page 260).204 A phase II trial suggests that paclitaxel/carboplatin is also a useful regimen for carcinosarcoma (response rate, 54%).216 A GOG trial is currently assessing ifosfamide/paclitaxel versus carboplatin/paclitaxel.188
Data regarding carcinosarcoma suggest that adjuvant pelvic radiation therapy decreases the rate of local recurrences when compared with surgery alone.217-222 This improvement in local control reported in some series correlates with an improvement in survival, although other data show that lymphadenectomy confers greater benefit.221-224 A phase III randomized trial (GOG-150) in patients with carcinosarcoma of the uterus assessed whole abdominal radiation therapy versus cisplatin/ifosfamide, but no difference was seen in survival between the groups.207,212 A recent cohort study in women with early-stage MMMT suggests that postoperative chemotherapy improves PFS compared with radiation therapy or observation.188
Uterine Sarcomas
Uterine sarcomas are uncommon tumors (≈3% of all uterine neoplasms). Risk factors for uterine sarcomas include a history of pelvic radiation. Uterine sarcomas are stromal/mesenchymal tumors that are generally categorized into uLMS, ESS, and high-grade (undifferentiated) endometrial sarcoma (see “Uterine Sarcoma Classification” in the complete version of these guidelines, available online at NCCN.org). Most uterine sarcomas are LMS; ESS and high-grade (undifferentiated) endometrial sarcomas are rare (see UTSARC-1, page 261). Patients with stromal or mesenchymal tumors are not usually screened for Lynch syndrome. Because this guideline mainly focuses on early-stage malignant epithelial carcinoma, in-depth information about uterine sarcomas is not provided.
Pathologic definitions of the various histologies are undergoing revision.2 By definition, ESS has low-grade cytologic features; JAZF1 rearrangements are common. However, high-grade subtypes of endometrial sarcomas (undifferentiated endometrial sarcomas in the WHO classification) are still being defined (eg, those with YWHAEFAM22 rearrangements).225,226 Note that molecular subtyping is helpful, but not essential, for diagnosing undifferentiated endometrial sarcomas.
Individual Disclosures of the NCCN Uterine Neoplasms Panel
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