Management of locoregional recurrence of endometrial cancer

INTRODUCTION — Adenocarcinomas of the endometrium are the most common gynecologic malignancy in developed countries and the second most common in resource-limited countries. While the majority of patients present with localized disease with an excellent prognosis, a subset develop recurrence after initial treatment of the primary. In the subset of patients with locoregional recurrence only, durable remissions may be achieved. However, for those in whom endometrial cancer recurs or progresses to distant sites, the goals of treatment are palliative rather than curative.

This topic will review the approach to and treatment options for women with locoregional recurrence of endometrial cancer. The approach to the initial treatment of low-risk, intermediate-risk, and high-risk endometrial cancers; to metastatic endometrial cancer; and to uterine carcinosarcoma is covered separately. In addition, chemotherapy protocols used in the treatment of endometrial cancer are available separately.

●(See "Initial treatment of metastatic endometrial cancer".)

●(See "Overview of resectable endometrial carcinoma", section on 'Role of adjuvant therapy'.)

●(See "Treatment of low-risk endometrial cancer".)

●(See "Adjuvant treatment of intermediate-risk endometrial cancer".)

●(See "Adjuvant treatment of high-risk endometrial cancers".)

●(See "Treatment protocols for gynecologic malignancies".)

●(See "Clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma".)

CLINICAL PRESENTATION — Most women who relapse will do so within three years of the initial diagnosis. Recurrent endometrial cancer presents variably, including disease localized to the vagina, limited to the pelvis, or as metastatic disease involving the abdominal cavity or other organs. For those with locoregional (vaginal and/or pelvic) relapse, symptoms may include bleeding (which emanates from the vagina, bladder, or rectum), anorexia, weight loss, pelvic pain, lower abdominal or extremity swelling, and a sciatic distribution of pain, weakness, or sensory deficits [1].

EVALUATION — For women suspected of having recurrent endometrial cancer, the diagnostic work-up should include the following, in addition to pelvic and physical exam:

Imaging and laboratory assessment

●Whole-body imaging to evaluate for metastatic disease – Imaging of the chest, abdomen, and pelvis can be performed using computed tomography (CT), magnetic resonance imaging (MRI), positron emissions tomography (PET) scan, or a combined PET-CT scan. In general, CT is usually the initial study. If CT results are equivocal, further evaluation using PET scan or a combined PET-CT scan may be indicated, particularly if surgical resection is being considered. Ultimately, the choice between these imaging modalities is dependent on institutional practice.

●Measurement of cancer antigen (CA) 125 – Measurement of serum CA 125 may be useful in the diagnostic work-up of a suspected recurrence, particularly in women that had an associated elevation in their CA 125 at the initial diagnosis. However, the level of CA 125 alone should not influence treatment decisions.

Pathologic assessments — For patients with suspected recurrence, pathologic confirmation of the diagnosis with a repeat biopsy is necessary. This provides diagnostic confirmation as well as insight into molecular features of the tumor that inform prognosis and treatment decisions. We assess both the histologic subtype and perform receptor testing for estrogen (ER) and progesterone (PR). Other assessments, including immunohistochemistry for mismatch repair proteins or microsatellite instability, tumor mutational burden, or human epidermal growth factor receptor 2 (HER2) testing for serous-histology tumors, may also be performed and are discussed in detail elsewhere. (See "Initial treatment of metastatic endometrial cancer", section on 'Clinical presentation and evaluation'.)

THOSE WITH NO PRIOR RADIATION — For women with a locoregional recurrence of endometrial cancer who were not previously treated with radiation therapy (RT), we suggest RT rather than surgery. However, surgery alone can be a curative and reasonable alternative to RT in carefully selected patients, including those women who decline RT or are not candidates for RT. (See 'Surgical candidates' below.)

Most relapses that occur among patients without prior radiation therapy are vaginal recurrences. Data regarding treatment of isolated vaginal relapse are limited, but outcomes appear favorable based on observational studies with RT and the few studies of surgical treatment for this patient population. In the PORTEC-1 trial, among 30 women without prior RT who experienced an isolated vaginal recurrence, the complete response rate to curative-intent treatment was 87 percent [2]. For most women (28 patients), curative-intent treatment consisted of whole-pelvic RT, with or without brachytherapy, although one of these patients also received surgery, and two were also treated with endocrine therapy.

However, for patients with extravaginal extension or pelvic lymph node involvement, the prognosis is worse. In PORTEC-1, only 4 of 10 patients who were treated for pelvic relapse with curative intent (typically radiation) reached a complete remission.

The role of concurrent chemotherapy with RT is investigational and, in our practice, we do not offer combined-modality treatment. The results of GOG 238, which is exploring the role of adding sensitizing cisplatin to radiation therapy, are pending.

THOSE WITH PRIOR RADIATION — Although locoregional recurrences are less common in women treated with prior radiation therapy (RT), they are associated with a poor prognosis [2]. Treatment options among women with locoregional recurrence depend on whether or not they are candidates for pelvic exenteration.

Surgical candidates

Selection of candidates and benefits of surgery — For women with a locoregional recurrence who have been previously treated with RT and who are operative candidates, we suggest surgical resection rather than additional RT or medical therapy. For those who are not surgical candidates, medical therapy is appropriate. (See 'Nonsurgical candidates' below.)

Operative candidates should meet all of the following criteria:

●Distant metastases have been ruled out by imaging. (See 'Imaging and laboratory assessment' above.)

●A complete resection is technically feasible.

●The patient can tolerate surgery.

●The patient is willing to accept the functional postoperative changes associated with radical surgery.

Pelvic exenteration is the mainstay of surgical therapy for a locoregional recurrence. Although a radical resection of locally recurrent disease (eg, vaginectomy) may be a less morbid alternative to a pelvic exenteration, it should only be offered to carefully selected patients in whom the chances of cure will not be compromised. Tailoring the extent of the exenteration based upon tumor location is sometimes possible with use of an anterior or posterior exenteration, but total exenteration is more often required. Pelvic exenteration is an extensive procedure with a substantial risk of short- and long-term morbidity, including urinary and bowel dysfunction and sexual dysfunction. Urinary and/or colonic diversions are typically required. Patients who are candidates for surgery should be thoroughly counseled about the details of the procedure, risks, recovery, and future changes in functioning. (See "Exenteration for gynecologic cancer", section on 'Patient selection'.)

Details of the procedure of pelvic exenteration for gynecologic cancer are discussed in detail separately. (See "Exenteration for gynecologic cancer".)

Data on the outcomes of women following pelvic exenteration for recurrent endometrial cancer are limited. No studies have compared surgery with additional RT or chemotherapy, although use of these options in this patient population has not been well-studied and these are regarded as options of last resort. In many case series, women with pelvic sidewall disease and/or positive pelvic or para-aortic lymph nodes were included [3-6]. As a result, the reported five-year overall survival (OS) rates range from 14 to 50 percent. The largest series included 44 women with recurrent endometrial cancer; the median OS after pelvic exenteration was 10.2 months, and five-year OS was 20 percent [4].

Option of intraoperative radiation — Some contributors also incorporate intraoperative RT (IORT) for those with microscopic or small-volume pelvic sidewall disease, though this is not standard practice in many centers. Small observational studies suggest IORT may be of benefit in locoregionally recurrent endometrial cancer in select patients, resulting in five-year OS rates of 50 to 70 percent [7,8].

For example, in one retrospective study of 25 patients with recurrent endometrial cancer, radical resection of the pelvic sidewall with negative margins and IORT was associated with a five-year OS of 71 percent [9]. In a separate retrospective study in 27 patients with recurrent endometrial cancer, the addition of IORT to cytoreductive surgery was associated with a two-year disease-free survival rate of 78 versus 67 percent among patients treated with surgery alone, although this difference did not achieve statistical significance [8].

Systemic treatment post-surgical resection — For patients with high-risk features, we offer adjuvant treatment following surgery. High-risk features include pelvic recurrences (versus isolated vaginal recurrence), incomplete resection, lymphovascular space invasion, or high tumor grade.

Options for adjuvant therapy include chemotherapy, endocrine therapy, immunotherapy (pembrolizumab or dostarlimab), or pembrolizumab with lenvatinib, with a choice between them driven by patient performance status, previous adjuvant treatment, and the histologic and molecular features of the tumor, as in the metastatic setting. For those receiving adjuvant chemotherapy, we typically administer six cycles, or until a maximal response to therapy is achieved. Further details on treatment selection are found elsewhere. (See "Initial treatment of metastatic endometrial cancer", section on 'Initial therapy' and "Subsequent line systemic therapy for metastatic endometrial cancer".)

Nonsurgical candidates — For patients with an isolated vaginal recurrence who are not candidates for surgery or radiation for whatever reason, medical treatment is usually the only treatment option. We offer medical treatment using a similar approach to women who develop metastatic disease. For women who maintain a good performance status, we also encourage participation in clinical trials. (See "Initial treatment of metastatic endometrial cancer", section on 'Initial therapy' and "Subsequent line systemic therapy for metastatic endometrial cancer".)

In general, reirradiation is not an option for women with a vaginal recurrence, particularly after pelvic RT, given the risks to the normal surrounding tissue. However, if the technical skills are available, the administration of tailored RT into a previously irradiated area may be reasonable [10]. This approach should take into account the increased complexity associated with designing the field of treatment and the possible risks to surrounding normal tissue [10-14]. In a case series of 27 patients treated with stereotactic RT after conventional RT, there were no serious (grade 3, 4, or 5) toxicities associated with retreatment, and a 96 percent symptomatic response (measured by reduced tumor size, decrease in pain, or decrease in bleeding) was reported [10]. Unfortunately, the experience with tailored RT approaches is limited, and expertise may not be available in many places to allow consideration of this approach.

POST-TREATMENT SURVEILLANCE — For patients treated with curative intent for locoregional recurrence, surveillance is necessary after treatment. Specifically, in accordance with the National Cancer Center Network guidelines [15], we perform computed tomography of the chest/abdomen/pelvis every six months for the first three years and then every 6 to 12 months for the following two years. Alternatively, it is also acceptable to image only for new or concerning signs or symptoms of recurrence.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine cancer".)

SUMMARY AND RECOMMENDATIONS

●Recurrent endometrial cancer presents variably, including disease localized to the vagina or pelvis, or as metastatic disease. Although the prognosis for the vast majority is poor, carefully selected patients with locoregional recurrence can be cured with an aggressive locoregional approach. (See 'Introduction' above.)

●For women with a locoregional recurrence who were not previously treated with radiation therapy (RT), we suggest RT rather than surgery (Grade 2C). For women who decline RT or who are not candidates for RT, surgical resection is a reasonable alternative. (See 'Those with no prior radiation' above.)

●For women with locoregional recurrence who have been previously treated with RT and who are operative candidates, we suggest surgical resection rather than additional RT or medical therapy (Grade 2C). Operative candidates are those in whom complete resection is technically feasible and those who are able to tolerate surgery. Pelvic exenteration is the mainstay of surgical therapy for a vaginal recurrence.

•Following surgery, for those with high-risk features, we suggest systemic therapy rather than observation (Grade 2C). High-risk features include pelvic recurrences (versus isolated vaginal recurrence), incomplete resection, lymphovascular space invasion, or high tumor grade. Chemotherapy or endocrine therapy are options for adjuvant treatment, with a choice between them driven by molecular features of the tumor, as in the metastatic setting. (See "Initial treatment of metastatic endometrial cancer", section on 'Initial therapy' and "Subsequent line systemic therapy for metastatic endometrial cancer".)

●For most women who are not candidates for either surgical resection or RT, we offer medical treatment. The approach mirrors that for women who develop metastatic disease. (See "Initial treatment of metastatic endometrial cancer", section on 'Initial therapy' and "Subsequent line systemic therapy for metastatic endometrial cancer".)

●Following completion of local treatment, surveillance is necessary.

●Women who have been previously treated with RT and who are not surgical candidates should be offered medical treatment. The treatment approach mirrors that for women with metastatic disease. (See "Initial treatment of metastatic endometrial cancer".)