Uterine Cancer Treatment & Management

After diagnosis of endometrial cancer or uterine sarcoma is made, preoperative workup should include complete blood cell count, electrolytes, CA-125 (if indicated by atypical presentation or histology), chest radiographs, and EKG, coagulation studies, as indicated. Also, the patient should be in compliance with routine health maintenance screening (ie, mammography, Papanicolaou test, sigmoidoscopy/colonoscopy as indicated by the patient’s age or symptoms).

If the patient has specific symptoms such as neurologic abnormalities, bone pain, or respiratory symptoms, a directed metastatic workup should be performed preoperatively (eg, head CT scan/MRI, bone scan). 

Other tests that are occasionally used are CT, MRI, PET/CT, proctosigmoidoscopy, and cystoscopy. A CT of chest, abdomen, pelvis would be reasonable in all high risk histology or symptoms of advanced disease patients. Nonsurgical treatment can then be individualized for these patients. An early referral to a gynecologic oncologist should be made for complete preoperative workup and discussion of extensive staging and cytoreductive surgery or nonsurgical management options.

Endometrial cancer risk factors associated with higher recurrence risk include lymph node metastases, high histologic grade, deep myometrial invasion, lymphovascular space invasion, cervical involvement, positive cytology, and adnexal or serosal involvement. ^[19]

For cancers confined to the uterus, surgical pathologic findings create categories of low risk, moderate risk, and high risk for recurrence.  These categories help define prognosis and treatment recommendations.

Low risk

Low risk is defined as grade 1 or 2 endometrioid tumors with only inner one half myometrial invasion, no cervical extension, no lymphovascular space involvement, and negative findings on cytology and grade 3 endometrioid tumors with no myometrial invasion. These patients need no adjuvant therapy, although some gynecologic oncologists administer adjuvant therapy to all patients with grade 3 tumors.  Low risk patients randomized to vaginal brachytherapy versus observation found no significant difference in vaginal recurrence (1.2% vs 3.1%) and no difference in 5 yr OS 96%.  ^[20]     UPSC, clear cell, and carcinosarcoma are considered high risk for recurrence even with only endometrial involvement. 

Moderate risk

Much controversy and research surrounds post-operative management of intermediate risk for recurrence patients with endometrial cancer, which includes low grade (1 or 2) with deep myometrial invasion or cervical involvement. Guidelines suggest consideration of adjuvant external beam or vaginal brachytherapy or both. Prospective trials have shown a decrease in local recurrence but no change in overall survival. ^{[21, 22, 23]}

This category is further divided into low-intermediate risk with recommendation for observation only.  The subset of patients with high-intermediate risk has a significant decrease in local recurrence and would benefit from adjuvant radiation. This category includes patients who have any 2 of the following 3 risk factors: grade 3 histology, age older than 60 years, or deep invasion to outer one half of the myometrium. ^{[21, 23]}   PORTEC-2 compared vaginal brachytherapy verus pelvic exernal beam radiation for high-intermediate risk patients and found no difference in vaginal recurrence, DFS, or OS at 5 years, with significantly less bowel toxicity and better quality of life. ^{[24]   [25, 26]}  

High risk

High risk for recurrence includes patients with grade 3 disease with any myometrium invasion, stage II or greater, have lymphovascular or low uterine segment involvement, or clear cell and papillary serous histologies. These patients need adjuvant radiation, chemotherapy, or both. While some recommend whole-pelvic radiation therapy, others advocate only vaginal brachytherapy if the tumor is fully staged without evidence of extracorporeal spread. The results of a recent Gynecologic Oncology Group (GOG) study demonstrated that, while adjuvant whole-pelvic radiation therapy for patients with high-risk early-stage disease reduced the risk of pelvic recurrence by 50%, overall survival was not improved. GOG 249 randomized patients with high risk and stage I and II patients to pelvic radiation versus carboplatin and taxol chemo with cuff brachytherapy.  We are awaiting mature data to compare local and distant control and 5 year OS.

There will be a subset of unstaged patients who after hysterectomy did not undergo lymph node staging, either because of falsely reassuring frozen section or because cancer was not diagnosed preoperatively. Management will need to be individualized depending on grade, histology, and depth of invasion. Management may include close follow-up, returning to the operating room for full staging, vaginal radiation, or pelvic radiation.

A shift toward the use of more systemic chemotherapy over radiation for the treatment of extra-uterine metastatic endometrial cancer has occurred. A Gynecologic Oncology Group (GOG) prospective trial found a survival benefit for patients with stage III or IV disease with the use of systemic chemotherapy with doxorubicin and cisplatin (AP) when compared to whole-abdominal pelvic radiation (WART). ^[27] Another GOG trial found a survival advantage with the addition of paclitaxel to cisplatin and doxorubicin (TAP), and was the standard for those patients who can tolerate the treatment. ^[28]

An increasingly popular alternative regimen is carboplatin and paclitaxel, which has shown efficacy in retrospective trials, and was found in randomized trial (GOG 209)  to be noninferior to TAP for PFS or OS . ^{[29, 30, 31]}    Due to a higher pelvic recurrence rate seen in the subgroups receiving chemotherapy instead of radiation, ongoing trials are studying the efficacy and tolerability of chemotherapy and radiation together as dual modality treatment. GOG 258 is an ongoing phase 3 trial to determine if treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel (4 cycles) improves DFS and OS compared to carboplatin and paclitaxel (6 cycles) alone in stage III and IVA patients.

After tumor reductive surgery for extrapelvic/advanced disease at the time of laparotomy, adjuvant/adjunctive therapy is individualized. Localized radiation therapy is administered for CNS and symptomatic bone metastases. Otherwise, these patients are treated with chemotherapy and/or progestin or antiestrogen therapy. Medroxyprogesterone acetate and megestrol therapy is efficacious for those low-grade tumors that are estrogen and/or progesterone receptor–positive.

Tamoxifen is another alternative when progestin therapy is contraindicated or has failed. A 75-80% objective response occurs with estrogen and/or progesterone receptor–positive tumors compared to less than 5% in the absence of estrogen and/or progesterone receptor–positive tumors. Unfortunately, the tumors that tend to have intra-abdominal metastases are high grade and are less likely to be estrogen and/or progesterone receptor–positive tumors (15-41%). In cases of advanced disease, sending tissue, specifically from metastatic sites, for receptor analysis is useful. Metastases are receptor positive in 25% of metastatic tumors compared to 60% of primary tumors.

The major curative treatment of uterine sarcomas is TAH/BSO with or without surgical staging. However, a significant number of these tumors are diagnosed intraoperatively and postoperatively. Subsequently, postoperative therapy usually is necessary, although disagreement generally exists regarding its efficacy in terms of survival. At times, reoperation for removal of remaining gynecologic organs with surgical staging may be necessary. In terms of adjuvant therapy, whole-pelvic radiation or progestin therapy can be offered depending on surgical and pathologic findings.  stage I low grade ESS can be observed after surgery.  NCCN guidelines recommend that stage II or higher patients receive hormonal treatment given high ER/PPR positivity.  Megestrol acetate or medroxyprogesterone can improve DFS but not OS.  Pelvic radiation can also be offered for advanced stage disease.  Whole-pelvic radiation also improves local control for HGESS, especially stage I disease.

However, if advanced disease is present, progestin therapy and doxorubicin-based chemotherapy have a role. Undifferentiated ESS and leiomyosarcoma have a poor prognosis with tendency for hematogenously spread and recur at distant/extrapelvic sites, thus whole-pelvic radiotherapy is relatively ineffective. Chemotherapy with doxorubicin, ifosfamide, etoposide, and/or cisplatin may be used with LMS. Recently, gemcitabine and docetaxel (Taxotere) combination therapy has shown promise in unresectable LMSs of different sites. Patients with MMT that is limited to the pelvis benefit from whole-pelvic radiation with respect to local control.

Those patients with evidence of extrapelvic disease may respond to additional postoperative therapy with doxorubicin, cisplatin, and/or ifosfamide. These cytotoxic therapies have demonstrated up to a 20% complete response rate in patients with advanced or recurrent disease. A review by Galaal et al pooled data from 2 randomized controlled trials and concluded that treatment of advanced stage or recurrent carcinosarcoma with combination chemotherapy (Ifosfamide plus paclitaxel or cisplatin) is associated with improved overall survival and progression-free survival. Paclitaxel and carboplatin have also shown comparable efficacy and is better tolerated.

In conclusion, radiation therapy provides local tumor control but no consistent improvement in survival rates. Chemotherapy and hormonal therapy are better suited for evidence of extrapelvic spread but yield somewhat inconsistent results. For these reasons, postoperative therapy for uterine sarcomas is variable.

Routine surveillance intervals for endometrial cancers are typically every 3-4 months for the first 2 years, since 85% of recurrences occur in the first 2 years after diagnosis. Intervals are every 6 months for the next 3 years and annually after 5 years. Each visit should include a pelvic examination and and a lymph node survey. Pap smears have been found to not be effective or cost effective in detecting recurrence. Chest radiographs may be taken annually. CT scan is recommended only if symptoms arise or examination suggests a new finding. CA-125 levels are helpful if they were elevated preoperatively in advanced-stage cancers. Most recurrences are discovered during evaluation of symptomatic patients. Most recurrences in early-stage disease are at the vaginal cuff and pelvis.

NCCN guidelines recommend similar follow up for uterine sarcomas; however, for aggressive sarcomas, consider CT of chest, abdomen, and pelvis every 6-12 months for up to 5 years.

For excellent patient education resources, visit eMedicineHealth's Cancer Center and Women's Health Center. Also, see eMedicineHealth's patient education articles Cervical Cancer and Vaginal Bleeding.

The treatment of endometrial cancer needs to be individualized depending on patient factors and disease stage. Although surgical therapy and surgicopathologic staging is the mainstay of therapy for most endometrial cancers and uterine sarcomas, nonsurgical therapies such as radiation therapy, chemotherapy and hormonal therapy play a role in the treatment of uterine cancers. However, most of these therapies are used as adjuvant/adjunctive therapy or in the treatment of recurrences or metastatic disease.

The other instance in which primary radiation is recommended is with stage III disease based on vaginal and/or parametrial extension, where complete resection of the tumor with primary surgery is unlikely. Even in this case, adjuvant hysterectomy and adnexectomy are performed 6 weeks after radiation is completed, when feasible. Treatment of clinical stage IV disease is individualized based on the disease sites. In addition to surgical therapy to control bleeding, radiation therapy is usually administered for symptomatic bone and CNS metastases, as well as for local tumor control if the tumor extends to the bladder or rectum. Primary hormone therapy and chemotherapy may be indicated with distant disease. Primary radiation for uterine sarcomas is usually limited to those patients who are medically inoperable.

Women with significant comorbidities who are not surgical candidates and have clinical stage I endometrial cancer can be managed by primary radiation or hormonal treatment. Primary radiotherapy (total dose to tumor of up to 80 Gy) may be offered to those patients who are poor surgical candidates. Although the survival rate with primary radiation alone is 15-20% less than with surgery, the morbidity and mortality from surgical therapy in some patients may outweigh the benefits gained in terms of survival and recurrence. Many of these women will die due to other comorbid conditions. ^[32]

For most patients, the recommended primary treatment is surgical excision and staging. Surgical staging involves abdominal exploration, obtaining pelvic washings, total hysterectomy, bilateral salpingo-oophorectomy, biopsy of any suspicious lesions, and pelvic +/- para-aortic lymphadenectomy. If papillary serous or clear cell carcinoma is present, omental biopsy is also required for full staging. Lymph node dissection of nonbulky lymph nodes in leiomyosarcomas is prognostic but does not improve outcome.  Bilateral salpingo oophorectomy is of unproven benefit in sarcomas but is is recommended unless fertility is a concern.  Low grade ESS can have a higher recurrence rate due to ER/PR positivity.  Surgical staging and cytoreduction in sarcomas do offer survival benefit just as in endometrial cancer.  The International Federation of Gynecology and Obstetrics (FIGO) and AJCC stage classifications are based on surgical-pathological findings.

Many gynecologic oncologists use the grade and intraoperative frozen analysis of the uterine specimen to determine the extent of lymph node staging performed. Some oncologists treat patients with well-differentiated endometrioid adenocarcinomas of the endometrium without adverse risk factors (eg, no deep myometrial invasion and tumor size < 2 cm) by simple total abdominal hysterectomy (TAH), and bilateral salpingo-oophorectomy (BSO). However, many will perform a full bilateral pelvic and para-aortic lymphadenectomy for every endometrial cancer patient. The rationale for this more aggressive approach is frozen analysis of the grade and depth of endometrial cancer is notoriously unreliable, with upgrading from grade 1 or less in 61% and upstaging in 28% of specimens on final pathology. ^[33] A complete lymph node dissection would prevent the need to return to the operating room (OR) for lymph node staging or use of unnecessary radiation therapy.

One recent study found that almost 20% of patients with grade 1 disease who underwent routine staging, avoided whole-pelvic radiation based on pathologic findings. Also, a small percentage of patients with grade 1 disease required whole-pelvic radiation that they would not have received based on uterine and adnexal pathology. In addition, controversy exists as to whether lymph node sampling is adequate or if more extensive full lymphadenectomy might offer a survival advantage. ^[34]   If a lymph node dissection was not performed due to presumed benign or noninvasive disease, one can consider returning to the OR for staging only if poor histology or deep invasion and she is a good surgical candidate.  Otherwise it is reasonable to offer pelvic radiation based on uterine risk factors.

Laparoscopic or robot-assisted staging is becoming increasingly common. Laparoscopy offers less intraoperative blood loss, less complications, shorter hospital stay, and faster recovery with comparable lymph node yield. Significantly longer operative times were reported with robotic technology. Comparable disease-free and over-all survival is seen thus far. ^[35] Concerns have been raised regarding seeding of laparoscopic port sites, tubal spillage of tumor, or vaginal cuff metastases due to uterine manipulation. No data are available to support an increase in these complications, but care should be used to decrease possible seeding by decreasing uterine manipulation, fulguration of tubes upon entry, and removal of large lymph nodes and specimens using endo-pouches.

Morbidity with extended staging when performed by surgeons trained in these techniques is not dramatically increased. Most gynecologic oncologists suggest performing at least limited staging for all patients with endometrial cancer because a significant upgrade or deeper microscopic myoinvasion (15% in some series) may be missed on frozen section and gross examination. However, some patients, specifically elderly patients or those with significant comorbidities, are better served by extrafascial hysterectomy and bilateral adnexectomy alone, followed by radiation as indicated by histologic factors, even in light of adverse risk factors. Vaginal hysterectomy may be used in the morbidly obese or medically infirm patient who may tolerate the vaginal approach better than the abdominal or laparoscopic approach. Recent studies demonstrate similar survival rates for clinical stage I disease.

In cases of gross cervical involvement, the traditional procedure had been Wertheim radical hysterectomy; however, TAH/BSO and lymphadenectomy followed by postoperative radiation have been found to be adequate for clinical stage II disease.

The significance and management of positive cytology in the absence of other peritoneal or retroperitoneal disease is controversial. Some evidence suggests the endometrial cancer cell in the washings without other high-risk factors, such as high grade, or other extra-uterine disease may not lead to worse outcome and may not need aggressive intervention. This may be caused by uterine manipulation or tubal spillage after hysteroscopy. Others found it to be an independent predictor of worse survival, similar to those patients with positive adnexal or serosal disease. ^[36]

If bulky disease is found at laparotomy, optimal cytoreduction is recommended to improve patient outcome. ^[37] All patients with advanced stages III and IV disease should be offered adjuvant treatment after surgery.

The role of surgery in stage IVB disease may involve tumor reduction or palliative chemotherapy or radiation. Tumor reductive surgery is typically followed with adjuvant/adjunctive chemotherapy, hormonal therapy, with or without radiation therapy.

Surgery with staging is also the primary treatment of choice for uterine sarcomas. Patients with leiomyosarcoma (LMS), mixed müllerian tumors (MMT), or high-grade endometrial stromal sarcoma (HGESS) benefit from total abdominal hysterectomy and bilateral salpingo-oophorectomy through a vertical midline incision, with pelvic washings, omental biopsy, and selective pelvic and para-aortic lymphadenectomy. Lymphadenectomy for low-grade endometrial stromal sarcoma (LGESS) is of limited value because the incidence of lymph node metastases is low. 

Because of the typical early clinical presentation, most cases of endometrioid endometrial cancer are treated at stage I disease. Overall 5-year survival rates for all grades and histologic subtypes are approximately 85-95%, 75%, 50%, and 20% for surgical stage I, II, III, and IV disease, respectively. The nuclear grade is an important determinant of prognosis. For surgical stage I disease, 5-year survival rates for grade 1, 2, and 3 endometrial carcinoma is 92%, 87%, and 74%, respectively.

In terms of histologic subtype, clear cell and papillary serous carcinomas have the lowest overall 5-year survival rates. When considering all stages together, the 5-year survival rates for clear cell and papillary serous carcinomas are 51% and 46%, respectively. Endometrioid adenocarcinoma has an overall 5-year survival rate of approximately 76%. Adenosquamous carcinoma has an overall 5-year survival rate of approximately 68%.

Increasing nuclear grade is associated with deeper myometrial invasion. Deeper myometrial invasion is, in turn, associated with pelvic and para-aortic lymph node metastases. These are all adverse prognostic factors. Recurrence rates up to 46% are observed with deep myometrial invasion (greater than one-half) as compared to 8-13% with superficial or no invasion.

Most recurrences of endometrial cancer are diagnosed within 2 years. Recurrences in patients treated with surgery alone tend to be more localized to the pelvis (40%), particularly at the vaginal cuff. Most recurrences (70%) are associated with symptoms of vaginal bleeding, pain, or weight loss. Asymptomatic recurrences are found by physical examination, abdominal/pelvic imaging, or chest radiography. Rarely is a recurrence found by abnormal vaginal cytology. These recurrences are usually salvageable with radiation therapy, surgical excision, occasionally pelvic exenteration, or a combination of surgical excision and radiation. The prognosis for these patients is better if the original diagnosis was more than 2 years before the recurrence.

Endometrial cancer treated with surgery and radiation that does recur is less often localized and, as such, is less amenable to localized therapy such as surgical excision and radiation. The most common extrapelvic sites for recurrences include the lungs, abdomen, para-aortic lymph nodes, brain, bones, and liver. Distant recurrences also present in the anterior scalene, supraclavicular, and inguinal lymph nodes. If the tumor is hormone receptor–rich, it may be amenable to progestin or antiestrogen therapy. Otherwise, the same chemotherapy that is used for advanced endometrial cancer has been studied for recurrent disease, with the same results.

 Uterine sarcomas have a high recurrence rate. Stage I uterine sarcomas recur in up to 50% of cases. The overall 5-year survival rate for leiomyosarcoma (LMS) is 15-25%. Stage I LMS has a 58% and 70% 5-year survival after surgery without and with radiation therapy, respectively. Recurrences are rarely localized and tend to reappear in the lungs most often. Stage I low-grade endometrial stromal sarcomas (LGESS) and high-grade endometrial stromal sarcomas (HGESS) have 5-year survival rates of 80% and 50%, respectively.

As expected, advanced disease has a much worse prognosis, with a 5-year survival rate of 0-33% for stages II-IV. Early-stage mixed müllerian tumor (MMT) has a 5-year survival rate of approximately 50%, whereas stages II-IV have a 5-year survival rate of 5-15%.

Localized disease, pelvic or extrapelvic, may be responsive to surgical excision or radiation therapy. Although doxorubicin, ifosfamide, and cisplatin have been studied and used in treatment of distant multifocal recurrent disease, no definitive choice of chemotherapeutic has been recommended for the treatment of recurrent uterine sarcomas. Evaluation of imatinib mesylate (Gleevec) in advanced and recurrent MMTs is in progress.

Malignant cytology

Debate still continues regarding the management of surgical stage III endometrial cancer as determined by positive findings on peritoneal cytology with disease otherwise limited to the uterine corpus. Several multivariate studies have demonstrated that positive findings on peritoneal cytology are an adverse risk factor for recurrence. A recent retrospective study found that patients with stage IIIA disease identified by cytology alone had survival similar to that of patients with early-stage disease compared to patients with stage IIIA disease identified by adnexal and uterine spread. Therapy is very controversial.

Options include observation, progestin therapy, chemotherapy, or whole-abdominal radiation. However, review the cytopathology carefully before initiating any of these treatments.

Estrogen replacement therapy

The use of estrogen replacement therapy (ERT) in women with a history of endometrial cancer is controversial in stage I, grade 1 endometrioid adenocarcinoma. The results of the recent Women's Health Initiative (WHI) have only clouded this issue. Although data are limited, patients who are in complete remission or who have surgical stage I disease and have undergone optimal treatment may be candidates for ERT. The Gynecologic Oncology Group study designed to evaluate ERT in early-stage endometrial cancer patients was closed prematurely because of the fallout from the WHI results. As a result, it is hard to draw any conclusions from the limited data.

Therapy should be individualized and extensive counseling regarding risks, benefits, and alternatives must be completed prior to initiating estrogen replacement therapy. An alternative for relief of vasomotor symptoms is clonidine. Raloxifene is a selective estrogen receptor modulator, has bone protective benefits without increased risk of endometrial or breast cancer, and may be used as an alternative. However, vasomotor symptoms may worsen with raloxifene.

While the majority of endometrial cancer patients are post-menopausal, an increasing number of young women at risk due to our obesity epidemic.  If a woman of childbearing age wishes fertility preservation, she may be a candidate for medical management with high dose progesterone therapy.  Patients require careful counselling and screening for candidacy if she is low risk stage I, grade 1, and has a realistic fertility possibility.  She will need to be counselled that a unstaged, unresected tumor may have occult mets despite negative imaging for metastatic disease.  A patient can be a candidate if she has grade 1/2, endometrioid disease with only superficial myometrial invasion.  She would undergo dilation and curettage with hysteroscopy to rule out higher grade disease and to debulk tumor.  An ultrasound or MRI is needed to rule out extrauterine disease or deep myometrial invasion.  Candidates can be treated with a levonorgestrel IUD or high dose oral progestins or both.  Oral progestin dose can vary from 80 mg up to 800 mg.  At our institution we treat with an IUD in addition to oral progestin 160 mg.  Progestin dose can be increased if there is inadequate response.   Prospective and retrospective series report initial response rates of 50-75%, but many will recur. One study reports 25% have achieved pregnancies after conservative management. ^{[38, 39]} Recommendation is for definitive total hysterectomy, bilateral salpingo-oophorectomy (BSO), and possible staging with disease persistence, recurrence, or at completion of childbearing.

Some have suggested ovarian preservation after hysterectomy in young women wishing to preserve hormonal function and future childbearing through egg retrieval. ^[40] This should be cautioned against due to risk of adnexal metastases or synchronous tumors, which occur in up to 25% of young women. ^[9]