125Uterine Cancer

CHARACTERISTICS

•   Uterine corpus cancer is the most common female gynecologic cancer in the United States with an estimated 61,380 cases and 10,920 deaths in the United States in 2017. Currently, endometrial adenocarcinoma is the most common malignancy of the female genital tract and ranks as the fourth most common cancer in females.

•   Risk factors for endometrial cancer include the triad of obesity, diabetes, and hypertension. Other risk factors are a prolonged exposure to estrogens, nulliparity, early menarche, late menopause, and unopposed estrogen hormone therapy.

•   Most women present with abnormal uterine bleeding. Of those postmenopausal women who do present with bleeding, 10% result in a diagnosis of uterine cancer.

•   Other presenting signs and symptoms can be menorrhagia, intermenstrual bleeding, pain, pyometria, hematometria, and an abnormal Pap smear.

•   Hyperplasia and cellular atypia, alone or combined, have known rates for progression to uterine cancer (Table 2.16) (1).

        According to one collaborative study, a diagnosis of complex atypical hyperplasia was associated with a 43% chance of concurrent endometrial cancer. Of these specimens, 31% had myometrial invasion and 10% had greater than 50% myometrial invasion (2).

126PROGNOSTIC FACTORS

Stage is the most important prognostic factor. Other factors include depth of myometrial invasion (DOI), LVSI, grade, histology, tumor size, patient age, and hormone receptor status.

PRE-TREATMENT WORKUP

•   Workup for abnormal bleeding begins with a history and physical examination. Evaluation involves endometrial biopsy (EMB) with endocervical curettage or D&C. Pelvic ultrasound and Pap smear may also be performed, but are insufficient modalities used alone for persistent abnormal bleeding.

•   An endometrial stripe thickness that is 5 mm or greater in a postmenopausal patient is abnormal and biopsy should be performed. The accuracy of EMB and D&C are relatively the same, between 91% and 99%, when compared with final pathology (2).

•   Women with the following should be ruled out for cancer via endometrial biopsy: postmenopausal women with bleeding; postmenopausal patients with pyometria; asymptomatic postmenopausal women with endometrial cells on Pap smear (especially if atypical); perimenopausal patients with intermenstrual bleeding or increasingly heavy periods; and premenopausal patients with abnormal uterine bleeding, particularly if there is a history of anovulation.

•   In women over the age of 35 years with abnormal bleeding, an EMB should be performed. 25% of cancers occur in premenopausal women and 5% occur in women less than 40 years of age.

•   The pre-treatment workup for uterine cancer includes a CXR and abdominal-pelvic imaging. This can be with a pelvic ultrasound, CT, or MRI. Lab tests include a CBC, comprehensive metabolic panel (CMP), and CA-125 (which can predict LN metastasis) (Figure 2.8).

127CATEGORICAL DIVISIONS

•   Histologic grouping: epidemiological and clinical studies suggest that endometrial cancers be separated by histologic appearance and behavior into two groups: type I and II tumors. Genetic evaluation is moving toward categorizing tumors outside standard histological status into four separate categories.

        Type I tumors are the most common. The main risk factor in type I carcinomas is hyperestrogenism. These tend to be hormonally responsive and have an 83% all stage 5Y survival. These cancers typically have a favorable prognosis with appropriate therapy (Figure 2.9).

             The most common type I cancer is endometrioid adenocarcinoma, which occurs in 75% of cases.

             Adenosquamous carcinoma is diagnosed in 18% to 25% of uterine cancers. The behavior is similar to that of endometrioid cancer.

             Villoglandular carcinoma occurs in 6% of uterine cancers. This subtype is distinguished by delicate fibrovascular cores. It is usually of low grade and is more differentiated than endometrioid adenocarcinoma.

             Secretory carcinoma occurs in 2% of uterine cancers and appears as a well-differentiated glandular pattern with intracytoplasmic vacuoles containing glycogen, similar to secretory endometrium. It is usually grade 1.

             Mucinous carcinoma is diagnosed in 5% of cases and mucin is present as the major cellular component. There are columnar cells that are basally oriented or pseudostratified. It is necessary to rule out other cancers such as colon, mucinous ovarian, and primary endocervical cancers. It has the same prognosis as endometrioid cancer.

             Squamous carcinoma is associated with cervical stenosis, pyometria, and chronic inflammation. It is important to rule out a primary cervical cancer origin. It has a poorer prognosis.

             IHC to differentiate type I tumors from type II includes: estrogen receptor (ER)/progesterone receptor (PR)+, p53–, and WT-1 negative.

         Type II cancers are poorly differentiated tumors, and are histologically represented by the serous, clear cell (CC) and malignant mixed Müllerian tumors (MMMT) histologies. Type II tumors are more biologically aggressive and have a 53% 5 YS for all stages. Type II tumors account for 15% of uterine carcinomas, but represent 50% of all relapses. These type II tumors are classified as high risk, high grade, and are unresponsive to hormonal therapy.

             Serous uterine carcinoma is diagnosed in 10% to 15% of endometrial cancers. If there is 10% or less serous component, it is called a mixed tumor. This subtype resembles serous carcinoma of the ovary. It is often found at an advanced stage. The depth of invasion is often not predictive of LN metastasis, and extrauterine disease is found in 60% of tumors. If the cancer is identified in a polyp without other evidence of uterine disease, 38% of patients will be found to have extrauterine spread. Intraperitoneal spread is common even when myometrial invasion is minimal. When comprehensively staged, 70% of patients are found to have advanced-stage disease: 25% of apparent stage I cancers (3) have omental metastasis and 25% of patients have upper abdominal disease (4). Microscopically, there are fibrous papillary fronds, picket fencing of the terminal cells, LVSI is common, and psammoma bodies are often present. It is high grade by definition. There is a 2% rate of BRCA1 mutations in uterine serous cancer patients. Nine percent of women with a history of breast cancer followed by uterine serous cancer have a BRCA 1/2 mutation (5).

             IHC for serous cancers: ER/PR variable, WT-1 negative, p53+.

             Clear cell carcinoma is diagnosed in 5% of uterine cancers. It also is an aggressive tumor. The cells contain a large amount of glycogen and when processed for histology, the glycogen in the cells gives an appearance of cellular clearing and nuclear hobnailing.

             Mixed Müllerian mesodermal tumors (MMMT; carcinosarcoma) are now thought to be metaplastic epithelial (or carcinomatous) cancers. These tumors tend to occur in older women with a median age of 65 to 75 years. Other characteristics include obesity, nulliparity, and diabetes. Tumor can be seen via speculum examination in 50% of women. Pathologically, there is a mixture of carcinomatous and sarcomatous tissues. The carcinomatous component is most commonly endometrioid, but can be of serous or CC histology. Prognosis is mainly dependent on the epithelioid histology. The sarcomatous/nonepithelial component is commonly an endometrial stromal sarcoma (ESS), but can be leiomyosarcoma (LMS), rhabdosarcoma, or chondrosarcoma. The presence or absence of heterologous elements is not predictive of outcome. Studies have shown similar allelic losses present in both the carcinomatous and sarcomatous areas of MMMTs in multiple patients. This suggests a late divergence in phenotype and a common abnormal clone for the entire cancer. Prior tamoxifen use has been implicated in this tumor’s development. The median time of exposure to diagnosis of MMMT was 9 years and ranges to a relative risk (RR) of 15.9 (6). Prior pelvic XRT has also been noted to have a causal effect: in 23 patients with prior pelvic XRT, 35% had an MMMT uterine cancer. Surgical management is critical for staging and optimization of treatment. 20% of patients with clinical stage I and II are upstaged by LND. Cytoreduction in advanced stage disease (III and IV) with optimal resection was associated with improved survival of 52.3 months versus 8.6 months (p < 0.0001), with another study showing similar results in debulking to no residual versus optimal (less than 1 cm) and suboptimal disease with a PFS of 0.8 versus 8.6 versus 13 months and OS of 4.5 versus 12.7 versus 29.6 months, respectively (Figure 2.10) (7).

•   Genetic groupings: adjuvant recommendations may be determined by genetic grouping in the future (8).

        POL-E: ultramutated

        Copy number high: serous/CC/some G3 adenocarcinomas

        Copy number low: commonly G1/2 endometrioid adenocarcinomas

        Microsatellite instability (MSI): genomic, somatic, and epigenetic (hypermethlyated)

STAGING

•   Staging is surgical. In 1988, the staging was changed from clinical to surgical. Surgical staging was further revised in 2009 (Table 2.17A–D).

•   Grade is specified as a three-tiered system: grade 1 tumors are highly differentiated, with less than 5% of the tumor containing solid areas; grade 2 tumors are moderately differentiated with 6% to 50% solid areas; grade 3 tumors are poorly differentiated carcinomas with greater than 50% of the tumor containing solid components. If nuclear atypia is present at a higher degree than the stated histological grade, the overall grade is increased by one grade.

TREATMENT

•   Treatment is primarily surgical staging to include: pelvic washings, hysterectomy, bilateral salpingo-oophorectomy, LND, omentectomy and peritoneal biopsies (especially for the type II tumors), and surgical debulking of extrauterine/metastatic disease.

        Treatment approaches:

             Laparotomy

             Minimally invasive (preferred)

                  Laparoscopic assisted vaginal

                  Robotic assisted

        Treatment modifications:

             Conversion to laparotomy from laparoscopy: in one study this occurred in 17.5% of patients with body mass index (BMI) of 25, 26.5% with a BMI 34 to 35, and 57% of patients with BMI greater than 40. Port site metastasis occurred in 1% (9).

             The ability of infrarenal/PA-LND was 81% in one study when the BMI was greater than 35 kg/m², compared to 95% when the BMI was less than 35 (10).

             Ovarian conservation in young women with uterine cancer: only 18% of women less than 45 years old have stage IAG1 disease. The risk of a synchronous ovarian malignancy can be as high as 19%–25% in younger women. Bilateral salpingo-oophorectomy (BSO) should be considered for all women with uterine cancer per Society of Gynecologic Oncology (SGO) guidelines. If ovarian conservation is desired, patients should be stage IA and G1-2. A retrospective review showed that conservation was not independently associated with survival (HR 0.94; 95% CI: 0.65–1.37) (11). Younger women have a higher risk of genetic mutations. The risk of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome and ovarian malignancy is up to 10% if women harbor this genetic mutation. MRI is the best mode to evaluate for DOI and cervical involvement when considering preoperative radiologic staging for possible ovarian preservation (12).

             Morcellation: the risk of a fibroid harboring a LMS is 0.3% to 0.49%. Regardless, morcellation is not recommended for uterine cancer cases to avoid tumor spill and spread, or alter pathologic evaluation. Alternatives to morcellation for laparoscopic approaches to surgery are minilaparotomy or morcellation within an endoscopic bag after vaginal delivery of the specimen (13).

             Sentinel LND: this strategy remains under investigation (category 3) and careful consideration should be given to not performing this procedure with type II tumors. If it is considered, surgeon experience, adherence to an sentinel LND algorithm or clinical study, and the use of pathologic “ultrastaging” are key factors for successful SLN mapping. Serous/CC/MMMT histologies should not undergo this type of LN assessment.

•   Lymph node dissection

        The boundaries for pelvic LND (P-LND) are the following: the distal half of the common iliac vessels, the anterior and medial aspect of the external iliac vessels, the ureter or (superior vesicle artery below the common iliacs) medially, the circumflex iliac vein distally, and the obturator nerve inferiorly. The PA-LN boundaries are the following: the fat pads over and lateral to the great vessels, the inferior mesenteric artery superiorly, and the mid common iliac vessels inferiorly. For a high PA dissection, the LNs up to the renal vessels are removed medial to the ureters and anterior to the great vessels.

        There is much controversy to the benefit and/or extent of an LND. LND has been shown not to increase the duration of surgery significantly. Some practitioners perform an LND based on tumor risk factors. Others recommend a comprehensive LND for all surgical candidates. Others have provided data that show that a LND is not therapeutic but can provide staging information to guide adjuvant therapies.

        For those providers who choose a selective LND, the Mayo criteria is often employed to determine if a patient is low risk for LN metastasis. The Mayo criteria are: grade 1 or 2 disease; necessarily tumor size that is 2 cm or less; and ≤50% myometrial invasion. If all these criteria are met, patients have a less than 5% chance of positive LNs (14). Frozen section should be employed for this decision analysis. The accuracy of frozen section decreases with grade: 87% accurate with grade 1, 65% with grade 2, only 31% with grade 3 (15). Doering et al correlated visual inspection for DOI with frozen section and found 91% accuracy (16), and Franchi et al supported this data with 85% accuracy and 72% sensitivity (17).

        For those who perform comprehensive LND, the following benefits are cited: there may be a therapeutic benefit with removal of micrometastasis; there is a 22% chance of extrauterine disease found with surgical staging; and 20% of tumors are upgraded at final pathology. Data have shown that removing nodes provides a survival benefit (18,19). An improvement in survival from 72% to 88% has been reported for patients undergoing lymphadenectomy with more than 11 LNs removed (20). Using Surveillance, Epidemiology, and End Results (SEER) data, Chan et al showed that in patients staged IB grade 3 and above, more than 20 LNs removed was found to provide the best OS (21). In low-risk patients, there was no association with LN count and survival. The PORTEC 1 trial subset of stage IC grade 3 (unstaged) patients who were treated with pelvic XRT had a 5 YS of only 58%. Most recurrences were distant (22). In contrast, stage IIIC patients staged and treated have a 5 YS of 57% to 72% (23,24).

        In some instances, LND is not performed. This can occur when cancer is found incidentally after hysterectomy. Postoperative pathological review can risk stratify patients for possible post hoc staging. There can be intraoperative complications that prevent full staging, or the patient may be medically intolerant of the procedure. Body habitus may also prohibit adequate staging: in the Lap-2 data, 50% of patients with a BMI greater than 40 were not able to have a para-aortic (PA-LND) performed (9). For those who support no LND, data from the following two randomized studies are commonly used.

             The Bendetti Panici study evaluated 514 eligible clinical stage I uterine cancer patients. Patients were randomly assigned to systematic P-LND versus no LND. Researchers found that early and late postoperative complications were higher in the systematic LND group. LND improved staging as more patients were found to have advanced stage disease with LN involvement. (13.3% vs. 3.2%). However, the 5 Y DFS and OS were similar (81% vs. 85.9% in the lymphadenectomy arm and 81.7% vs. 90% in the nonlymphadenectomy arm) (25).

             The ASTEC A Study in the Treatment of Endometrial Cancer, study (26, 27) evaluated 1,408 women with clinical stage I endometrial cancer and randomized them to standard surgery (hysterectomy, BSO, washings with PA LN palpation) or standard surgery plus lymphadenectomy. The primary outcome for this study was OS. The HR for death was higher in those who underwent comprehensive staging with LND, 1.16 (p = 0.3; 95% CI: 0.87–1.54). The absolute difference in 5Y OS was 1%.

             Based on a surgical/pathological review, in patients thought to have disease confined to the uterus, extrauterine disease has been found in 22% of patients, LN metastasis has been found to occur in 9% to 13% of patients, and isolated para-aortic LNs have been found in 2% of patients. The rate of positive PA LNs is approximately half the rate of positive pelvic LNs (Figure 2.11). For those who were identified with positive PA LNs, 47 of 48 patients had one or more of the following: grossly positive pelvic LN; grossly positive adnexal metastasis; or outer one-third myometrial invasion (28). Omental metastasis has been found in up to 8% of patients (Table 2.18).

             If gross cervical involvement is seen at diagnosis: cervical biopsy and pelvic MRI should be performed for confirmation. If negative, TH-BSO and staging can be considered. If cervical biopsy is positive, a radical hysterectomy with BSO and surgical staging as primary treatment should be performed. Preoperative XRT consisting of external beam radiation therapy (EBXRT) and brachytherapy to a total dose of 75 to 80 Gy to point A can be alternative management. An adjuvant simple hysterectomy can then be considered. If not a surgical candidate, EBXRT and brachytherapy with consideration of systemic chemotherapy should be implemented. Reevaluation at a later date for surgical therapy should be performed. Systemic chemotherapy can also be an option alone for surgically inoperable patients.

             There are data to suggest that performing a radical hysterectomy, based on a positive endocervical curettage only, commonly shows no evidence of cancer on final pathology and may be overtreatment (29).

             If gross parametrial involvement is identified by physical examination or preoperative imaging, primary XRT with dosing analogous to that for cervical cancer (75–80 Gy) can be considered, followed by a simple hysterectomy, with or without chemotherapy.

             There are data to suggest that the incidence of omental metastasis is 6% to 8% and is associated with: grade of disease, extrauterine involvement, LN metastasis, deep myometrial invasion, and positive cytology.

             If there is extrauterine disease confirmed at presentation, neoadjuvant chemotherapy can be considered but most patients should proceed with total hysterectomy, BSO, and surgical staging and debulking. If tumor appears to be surgically unresectable at presentation, EBXRT with/without brachytherapy and consideration of chemotherapy should be offered. Systemic therapy alone is another option. If liver metastasis is present and biopsy confirmed, systemic therapy with or without EBXRT and/or hormonal therapy can be considered. Palliative TH-BSO can be considered.

•   If cancer is found incidentally on post hysterectomy specimen and:

        Stage IA G1-2, less than 50% DOI, no LVSI, and the tumor size is less than 2 cm, observation is recommended.

        If stage IA G3, greater than 1/2 DOI, LVSI, or the tumor size is greater than 2 cm, stage 1B, or stage II, surgical staging should be considered. Imaging can also be considered and if negative, with other low risk features, protocols for adjuvant XRT can be considered.

•   Adjuvant treatment is commonly recommended in patients with endometrial cancer. Treatment is based on stage and pathologic risk factors. Early stage disease is defined as stages I and II. Advanced stage is defined as stages III and IV.

        High intermediate risk (HIR) early stage disease is often treated with adjuvant XRT. HIR is classified by two different studies.

             PORTEC 1: stratified patients into an intermediate high-risk subgroup for which treatment was recommended: patient age older than 60 years, DOI greater than half myometrial thickness, or grade 2 or 3 tumor.

             GOG 99 stratified patients by age and risk factors. If a patient fell into any of the following groups, they were considered HIR: patients age ≥70 years with one risk factor, age 50 to 69 years with two risk factors, and any age with all three. The risk factors are: outer one-third myometrial invasion, grade 2 or 3 tumor, and LVSI.

             Absent RF:

                  Stage IA G1,2,3: can be observed or vaginal brachytherapy can be recommended

                  Stage IB G1,2,3: can be observed but more commonly vaginal brachytherapy with/without whole pelvic (WP) EBXRT (especially for G3) is recommended

             RF present:

                  Stage IA G1-2: observation or brachytherapy can be offered

                  Stage IAG3: brachytherapy, WP EBXRT, or observation can be offered

                  Stage IBG1-2: brachytherapy, WP EBXRT, or observation can be offered

                  Stage IBG3: brachytherapy with/without WP EBXRT with/without chemotherapy can be recommended

        High-risk early stage disease is defined variably. Stage I serous, CC, MMMT, and variably grade 3 endometrioid cancers put patients into the high-risk early stage disease category. There are data to show that (FIGO 1988) stage 1CG3 type I tumors had a 58% 5 YS. Some clinicians recommend chemotherapy and XRT for these high-risk patients. Stage IA type II tumors are recommended to have adjuvant therapy: preferably a combination of XRT and chemotherapy (three cycles of chemotherapy with brachytherapy). Stage IB cancers are recommended to have chemotherapy (three to six cycles) with/without vaginal XRT and/or EBXRT.

        Stage II disease: adjuvant XRT is recommended and cumulative data supports both WP EBXRT and brachytherapy treatment. Chemotherapy should be considered if a type II cancer is present and variably for G3 endometrioid cancer.

        Advanced-stage endometrial cancer. For advanced-stage disease (stages III/IV) treatment is primarily surgical with comprehensive staging and cytoreduction to microscopic status if possible. Adjuvant therapy is commonly multimodal including both XRT and chemotherapy, and can include hormonal therapies.

             Stage IIIA: chemotherapy, EBXRT and/or brachytherapy, or both is recommended.

             Stage IIIB: chemotherapy and/or EBXRT, and brachytherapy.

             Stage IIIC: chemotherapy and/or EBXRT and/or brachytherapy

             Stage IV: chemotherapy with/without EBXRT and/or brachytherapy.

             There is literature to support cytoreduction in advanced metastatic uterine cancer.

                  Greer treated 31 patients with stage IVB disease with whole abdominal XRT. Those with residual disease less than 2 cm had a corrected 5 YS of 80% and an absolute 5 YS of 63%, whereas there were no survivors in the group with residual greater than 2 cm (30).

                      Goff evaluated patients with stage IV disease. Those who were cytoreduced had a longer median survival of 18 months compared to an 8-month survival in those who were not able to be cytoreduced (31).

                  Bristow reviewed 65 patients with stage IVB endometrial cancer who underwent cytoreduction. Optimal cytoreduction (residual tumor ≤1 cm in maximal diameter) was accomplished in 55%. The median survival rate of patients who underwent optimal surgery was 34 months versus 11 months for patients with greater than 1 cm residual disease. Furthermore, patients with microscopic residual tumor survived significantly longer (median survival 46 months) compared to patients optimally cytoreduced but with macroscopic disease (32).

                  Shih also suggested optimal cytoreduction for stage IV uterine cancer patients. Median survival: the median PFS was 40.3 months for patients with microscopic disease, 11 months for patients with any residual disease, and 2.2 months for patients who did not have attempted cytoreduction. The median OS was 42.2 months for patients with microscopic disease, 19 months for patients with any residual disease, and 2.2 months for patients that did not have attempted cytoreduction (33).

                  There are data to support that most stage IIIA patients (adnexal spread of primary uterine disease) are clonally related metastatic tumors from one primary uterine tumor demonstrated on genetic analysis (34).

        Type II cancers

             Early stage type II cancers (serous or CC histology): there are data to support platinum-based chemotherapy in addition to XRT for patients staged IA or above. Stage IA patients with no residual cancer in the hysterectomy specimen had no recurrences whether they received adjuvant therapy or not. 77% of stage IB patients not treated with adjuvant chemotherapy recurred versus no recurrences in the treated group; 20% of stage (FIGO 1988) IC patients who received chemotherapy recurred versus 80% who did not. Recurrences tended to occur at the vaginal cuff in patients not treated with brachytherapy, thus brachytherapy in combination with chemotherapy was recommended for all patients staged IA (with residual) or higher (35).

             Maximal cytoreduction for stage IV serous uterine cancer can offer an improvement in survival. Bristow showed that patients with optimal cytoreduction had a median survival of 26.2 months versus 9.6 months in patients with suboptimal surgery. Patients with microscopic residual tumor had a significantly longer median survival of 30.4 months versus those with 0.1 to 1 cm residual disease who had a median survival of 20.5 months. A 41-month versus a 34-month versus an 11-month OS was observed for those patients who were microscopically cytoreduced, optimally cytoreduced to less than 1 cm, or suboptimally cytoreduced, respectively (32).

             MMMT (carcinosarcoma) used to be classified as a uterine sarcoma. Recent data have suggested an improvement in survival with surgical cytoreduction (36). An adjuvant XRT trial from the EORTC evaluated a subset of carcinosarcoma patients and found a trend toward improvement in local control with whole-pelvic radiation therapy (WP-XRT), but there was no improvement in survival (37). Chemotherapy in combination with XRT has been shown to be effective in treatment of MMMTs. Ifosfamide and paclitaxel have been shown to produce a RR of 45% (38).

RECURRENCE

Recurrent disease can be broken into local recurrence or distant recurrence. Local recurrence is divided into vaginal and pelvic. A full metastatic workup should be performed with a physical examination; imaging of the chest, abdomen, and pelvis; lab tests for baseline organ function; and possibly PET imaging. Patients who were previously radiated in the pelvis tend to fail distantly at 70%, only 16% recur vaginally, and 14% recur in the pelvis. Patients without prior pelvic XRT tend to fail vaginally at 50%, 21% fail in the pelvis, and 30% distantly.

•   If the recurrence is vaginal, XRT can be administered. Prior XRT does affect response. In the PORTEC 1 trial, data on relapsed patients showed a 5 YS of 65% if patients had no prior adjuvant XRT versus 19% if they had prior XRT. The treatment of recurrence is WP-XRT in combination with brachytherapy dosed to 75 to 80 Gy if no prior XRT. There are data to support surgical cytoreduction of vaginal lesions to less than 2 cm. This is associated with an improvement in OS to 43 months versus 10 months (39).

        If no prior XRT to the site of recurrence, then surgical cytoreduction to < 2 cm should occur if possible with/without intraoperative radiation therapy (IOXRT), or EBXRT and brachytherapy dosed at 75 to 80 Gy.

        If prior XRT given:

             And prior brachytherapy only, then EBXRT or surgical resection with/without IOXRT can be provided.

             If prior EBXRT, surgical resection with/without IOXRT or hormonal therapy, or chemotherapy can be offered.

•   For pelvic recurrence including pelvic LN involvement:

        Surgical resection can be considered followed by tumor directed EBXRT with/without chemotherapy

        EBXRT with/without chemotherapy

•   For extrapelvic recurrences:

        For isolated recurrence: surgical resection with/without XRT or ablative therapy can be considered.

        If upper abdominal recurrence is resectable it should be surgically reduced, chemotherapy should follow, and consideration of EBXRT can be offered.

        If not resectable and low grade, asymptomatic, or ER/PR positive, hormone therapy can be attempted and if progression, then systemic chemotherapy provided. If symptomatic, grade 2-3, or large volume disease, then chemotherapy with/without palliative XRT should be provided.

        For widely metastatic disease: if low grade, asymptomatic, or ER/PR positive: hormone therapy can be attempted and if progression, then systemic chemotherapy. If symptomatic, grade 2/3, or large volume disease, then chemotherapy with/without palliative XRT should be provided.

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