Uterine Corpus Tumors

Treatment

Surgery

Approximately 90% of patients with a diagnosis of endometrial cancer are medically able to undergo surgery. Preparation for this surgery should include evaluation of such concurrent medical problems as hypertension and diabetes, which are frequently found in patients with endometrial cancer.

Open surgical procedure. The operative procedure is performed through an adequate abdominal incision that allows for thorough intra-abdominal exploration and retroperitoneal lymph node removal if necessary. On entry into the peritoneal cavity, fluid samples are obtained for subsequent cytologic determination (intraperitoneal cell washings). Next, thorough intra-abdominal and pelvic exploration is undertaken, with biopsy or excision of any suspicious lesions. In particular, the uterus should be observed for tumor breakthrough of the serosal surface. The distal ends of the fallopian tubes are clipped or ligated to prevent possible tumor spillage during uterine manipulation.

These procedures should be followed by total extrafascial hysterectomy and bilateral salpingo-oophorectomy. The excised uterus is opened away from the operating table, and the depth of myometrial penetration is determined by clinical observation or microscopic frozen section. The depth of myometrial invasion can be accurately assessed in over 90% of cases.

Laparoscopic surgery. An alternative method of surgically staging patients with clinical stage I endometrial cancer is gaining in popularity. This approach combines laparoscopically assisted vaginal hysterectomy with laparoscopic lymphadenectomy.

Laparoscopy-assisted surgical staging (LASS) is feasible in a select group of patients. However, it is not yet known whether this approach is applicable to all patients with clinical stage I disease. In particular, patients who are overweight or have intra-abdominal adhesions may not be ideal candidates. Para-aortic lymphadenectomy is technically more difficult through the laparoscope. To obtain adequate exposure, it is necessary to elevate the small bowel mesentery into the upper abdomen, which becomes increasingly difficult as the patient's weight increases, especially when weight exceeds 180 lb.

Walker et al reported the results of GOGLAP2, which randomized patients between laparoscopic vs open laparotomy surgical staging. Laparoscopy was initiated in 1,682 women and completed without conversion in 1,248 cases (74%). Conversion from laparoscopy to laparotomy was secondary to poor visibility in 246 patients (15%), metastatic cancer in 69 patients (4%), and bleeding in 49 patients (3%). Patients randomized to undergo laparoscopy had significantly fewer moderate to severe (Common Toxicology Criteria > grade 2) postoperative complications (14% vs 21%; P < .0001) and similar rates of intraoperative complications. Length of hospital stay was significantly shorter for those randomized to undergo laparoscopy (median, 3 days vs 4 days; P < .001), but operative time was significantly longer (median, 204 minutes vs 130 minutes; P < .001). Pelvic and para-aortic nodes were removed in 92% of laparoscopy patients and 96% of laparotomy patients (P < .0001), and cytology was performed in 96% vs 98% (P = .052). Neither treatment arm demonstrated an improved ability to detect metastatic disease (P = .841). Laparoscopic surgical staging is feasible and safe for patients with uterine cancer and results in fewer complications and a shorter hospital stay. Quality-of-life evaluation found a better body image and return to normal activities for the laparoscopy patients. A reduction in para-aortic node evaluation is a potential risk of laparoscopic staging. Walker et al reported the long-term cancer outcomes in 2012. The actual recurrence rates were substantially lower than anticipated, resulting in an estimated 3-year recurrence rate of 11% with laparoscopy and 10% with laparotomy. The estimated 5-year overall survival was almost identical in both arms at 90%.

Lymph node evaluation. Any suspicious pelvic or para-aortic lymph nodes should be removed for pathologic evaluation. If there is no gross residual intraperitoneal tumor, pelvic and para-aortic lymph nodes should be removed for the following indications:

- invasion of more than one-half of the outer myometrium

- presence of tumor in the isthmus-cervix

- adnexal or other extrauterine metastases

- presence of serous, clear-cell, undifferentiated, or squamous types

- palpably enlarged lymph nodes.

Lymph nodes need not be removed in patients whose tumor is limited to the endometrium, regardless of grade, because < 1% of these patients have disease spread to pelvic or para-aortic lymph nodes. The decision of whether to perform lymph node sampling is less clear-cut for patients whose only risk factor is invasion of the inner half of the myometrium, particularly if the tumor grade is 1 or 2. This group has a ≤ 5% chance of node positivity.

Lymphadenectomy. The extent of lymph node removal has been the subject of debate. The GOG has defined the extent of lymphadenectomy required for entry into its studies:

• Pelvic lymphadenectomy—The skin incision may be of the surgeon's choosing, including midline vertical, transverse, and lateral vertical. The procedure may be performed via laparoscopy or a retroperitoneal approach.

- Identify the bifurcation of the common iliac, external iliac, and hypogastric arteries; veins; and the ureters bilaterally.

- Any enlarged or suspicious nodes will be excised or biopsied if unresectable.

- Remove bilaterally all nodal tissue and skeletonization of all vessels from the mid portion of the common iliac artery superiorly, to the circumflex iliac vein inferiorly.

- Remove bilaterally all nodal tissue from the mid portion of the psoas muscle laterally to the ureters medially, including the hypogastric arteries and veins and from the obturator fossas anterior to the obturator nerves.

- An adequate dissection requires that a minimum of four lymph nodes be demonstrated pathologically from each side (right and left) of the pelvis, preferably from multiple sites.

• Para-aortic lymphadenectomy—The bifurcation of the aorta, the inferior vena cava, the ovarian vessels, the inferior mesenteric artery, the ureters, and duodenum should be identified.

- The nodal tissue over the distal vena cava from the level of the inferior mesenteric artery to the mid right common iliac artery is removed.

- The nodal tissue between the aorta and the left ureter from the inferior mesenteric artery to the left mid common iliac artery is removed.

- An adequate dissection requires that lymphatic tissue be demonstrated pathologically from each side (right and left).

Surgical staging. After these procedures, the patient should be surgically staged according to the 2009 FIGO criteria. The overall surgical complication rate after this type of staging is approximately 20%. The rate of serious complications is 6%, and they include vascular, ureteral, and bowel injuries.

Whether lymph node dissections are therapeutic or merely prognostic has been debated. A recent phase III trial comparing endometrial cancer patients who received systematic lymphadenectomy with those without lymphadenectomy demonstrated improved staging but with an increased complication rate with lymphadenectomy. There was no improvement in disease-free or overall survival. In another study known as the ASTEC (Adjuvant External-Beam Radiotherapy in the Treatment of Endometrial Cancer) trial, 1,408 women were randomized to undergo a lymphadenectomy or no lymphadenectomy at the time of total abdominal hysterectomy/bilateral salpingo-oophorectomy. There was no benefit in terms of survival or recurrence-free survival for women treated with lymphadenectomy.

Grossly involved lymph nodes. These can often be completely resected. A retrospective study revealed 5-year disease-specific survival rates of 50% in the patients with grossly positive lymph nodes who underwent complete resection, compared with 63% in those with microscopic metastatic disease and 43% in the women with residual macroscopic lymph node metastasis.

Adjuvant radiation therapy

Following surgical staging, adjuvant radiation therapy is offered to patients based on prognostic factors found at the time of surgery. A pelvic recurrence rate of 7% to 14% is predictable for all stage I patients after surgery alone, although certain subgroups with more risk factors may have a higher incidence of recurrence of endometrial carcinoma. Well-described prognostic factors include disease extent (cervical involvement, extrauterine involvement of the serosa, adnexa, or lymph nodes, or intra-abdominal spread), as well as histologic grade of the tumor, depth of myometrial penetration, pathologic subtype, and presence of lymphovascular space invasion.

Teletherapy. Adjuvant irradiation was delivered primarily in the past using external-beam radiotherapy (EBRT) directed to the pelvis, which allows for treatment of the pelvic nodes. There have now been three large randomized trials demonstrating that radiation can decrease local recurrence but has no demonstrable effect on overall survival.

One trial, GOG0099, compared the results of pelvic irradiation with those of observation following hysterectomy and lymphadenectomy. The estimated 2-year cumulative incidence of recurrence was 12% in the observation arm and 3% in those irradiated (P = .007). The treatment difference was particularly evident among a "high-intermediate risk" subgroup defined as those (1) with moderate to poorly differentiated tumor, presence of lymphovascular invasion, and outer-third myometrial invasion; (2) age 50 or older with any two risk factors previously listed; or (3) age of at least 70 with any risk factor previously listed, where the cumulative incidence of recurrence in the observed patients was 26% vs 6% in the treated patients. Overall survival rates at 3 years did not differ significantly between the two groups.

However, one-third of patients were found to be in a high-risk group that included patients who were older, had lymphovascular space invasion, deep myometrial penetration, and high-grade disease. When outcomes were stratified by these factors, the addition of pelvic irradiation was found to reduce the recurrence and death rate from 36% to 17%, the cancer death rate from 17% to 10%, and the distant metastatic rate from 19% to 10%. This finding suggests not only that pelvic irradiation may influence pelvic recurrence in these patients but also that there is a subgroup of patients who may benefit in terms of distant metastasis and death. A larger trial with high-risk patients is needed to validate this assumption.

Of the 18 pelvic recurrences in the no adjuvant treatment arm, 13 were in the vagina. Thirteen other sites of recurrence were outside the pelvis. It has been speculated that vaginal irradiation alone could have controlled these vaginal recurrences, leading to interest in treatment with vaginal irradiation instead of pelvic irradiation.

The findings of a multicenter trial with 754 patients from the Netherlands, called the PORTEC (Postoperative Radiation Therapy in Endometrial Carcinoma) study, have been reported. Eligible patients had stage IC grade 1 tumors (21%), stage IB or IC grade 2 tumors (69%), or stage IB grade 3 tumors (10%). After total abdominal hysterectomy without lymphadenectomy, patients were randomized to receive pelvic radiotherapy (46 Gy) or no further treatment.

Pelvic irradiation decreased the incidence of locoregional tumor recurrence but did not affect survival. Patients with grade 3 histology demonstrated the highest risk of distant metastases and death caused by endometrial cancer. Most of the locoregional relapses were located in the vagina (30 of 40 cases). It is possible that vaginal brachytherapy could have prevented the majority of these cases. When patients were subdivided into a high-risk subgroup with two or three risk factors, including age ≥ 60, grade 3 histology, and myometrial depth ≥ 50%, the 10-year locoregional relapse rate was 4.6% in the radiotherapy group vs 23% in the control group.

PORTEC also registered patients on a prospective trial who had deep myometrial invasion and grade 3 histology. All patients were treated with pelvic irradiation following hysterectomy. Notably, these patients had a distant recurrence rate at 5 years of 31%, and a pelvic recurrence rate at 5 years of 14%. The information from this report as well as from the subgroup of patients in the GOG 99 trial suggests that there may be a role for systemic therapy as well as pelvic irradiation in this high-risk subgroup..

A third randomized trial was recently published. More than 900 patients with stage I or IIa endometrial cancer from the National Cancer Institute of Cancer (NCIC) and the Medical Research Council (MRC) were randomized to receive pelvic radiation therapy or no pelvic radiation therapy. Notably, vaginal radiation therapy, which was optional, was delivered to 52% of patients in each arm. There was no difference in survival and only a minimal difference in local or regional tumor recurrence rates.

Brachytherapy. Several reports have demonstrated excellent local tumor control with vaginal irradiation alone. A review of the world literature included 1,800 patients with low- to intermediate-risk disease. Overall, the vaginal control rate was 99.3% following adjuvant high-dose-rate (HDR) vaginal brachytherapy.

In a randomized study from the Norwegian Radium Hospital, pelvic irradiation significantly decreased the incidence of locoregional tumor recurrences compared with vaginal irradiation alone. In the initial report patients with deeply invasive, grade 3 tumors had lower death and recurrence rates when treated with pelvic plus vaginal irradiation than patients treated with vaginal irradiation alone. Long term follow-up of this trial was presented at the 2012 American Society of Clinical Oncology (ASCO) meeting. After a median of 21 (range, 0–43.4) years of follow-up, there was no significant difference in overall survival or relapse-free survival between treatment arms, with a HR of 1.12 (95% confidence interval [CI], 0.95–1.33) and a HR of 0.88 (95% CI, 0.55–1.40), respectively. Patients treated with external radiation had a significantly lower risk of developing locoregional relapse (P < .001). However, after external radiation, women younger than 60 years had a significant poorer survival (HR = 1.36; 95% CI, 1.06–1.76), which was attributed to the development of second cancers.

Many women with endometrial cancer are being treated with lymphadenectomy at the time of hysterectomy. There has been some interest in using vaginal irradiation alone to treat women who have negative nodes but deep myometrial penetration or high-grade histology. Several small retrospective reports have demonstrated excellent outcomes for such patients. However, more experience is needed to determine whether vaginal irradiation alone is adequate.

The results of a phase III randomized trial from PORTEC have been published. This trial included patients who had a high-intermediate–risk endometrial cancer: age > 60 and stage IC grade 1/2 or stage IB grade 3; any age and stage IIA grade 1/2 or grade 3 with < 50% invasion. They were randomized to receive pelvic radiation or vaginal brachytherapy. A total of 427 patients were randomized between 2002 and 2006. At a median follow-up of 34 months, 5-year actuarial rates of vaginal relapse were 1.8% in the vaginal brachytherapy arm and 1.6% after EBRT (P = .97), with standard error of the difference 1.4%. Five-year rates of pelvic recurrence were 5.1% and 2.1% (P = .17). There were no significant differences in 3-year overall survival (84.8% vs 79.6%; P = .57) and disease-free survival (82.7% vs 78.1%; P = .74). As patient-reported quality of life after vaginal brachytherapy was shown to be better than after EBRT, vaginal brachytherapy should be the treatment of choice for patients with intermediate-risk endometrial carcinoma.

Vaginal irradiation alone is appropriate for patients at low risk for pelvic node metastasis. Because of the potential for increased rectal and vaginal sequelae, treatment of the entire length of the vagina is usually not recommended.

Irradiation of the pelvis and vagina has been combined for the adjuvant treatment of some patients. Patients with cervical involvement or extrauterine disease, who may have an increased incidence of local failure, may benefit from the two treatments combined, although there are no data to suggest that the addition of brachytherapy improves outcome over EBRT alone. Patients with uterine-confined disease have excellent local tumor control following treatment with either type of irradiation. Combining the two treatments has not been shown to benefit these patients.

Vaginal irradiation. Vaginal irradiation can be delivered with HDR or low-dose-rate (LDR) equipment. Both techniques have resulted in excellent local tumor control rates and low morbidity when administered by experienced practitioners. Each technique has its advantages. HDR treatments require multiple insertions, generally with one or two insertions performed every week for 3 to 6 weeks. However, hospitalization is not required, and each insertion takes only a brief amount of time. LDR treatments are delivered once but require hospitalization for 2 to 3 days.

Stage I disease. Current recommendations for the treatment of patients with pathologic stage I disease include adjuvant pelvic irradiation for women with deep myometrial penetration and grade 3 histology or evidence of vascular space invasion (Table 3). Data support the use of vaginal irradiation alone for women with more superficial tumors and low-grade histology.

TABLE 3Recommendations for adjuvant irradiation

Radiation doses are generally 45 to 50 Gy with standard fractionation. The technique should include multiple fields treated daily, with attempts to protect the small bowel. Complications from adjuvant pelvic irradiation are related to technique and the extent of lymphadenectomy.

If full lymphadenectomy has been performed, the incidence of complications increases significantly with pelvic irradiation. Pelvic radiation using intensity-modulated radiation therapy (IMRT) has been advocated by some in order to spare bowel and bone marrow. For patients at high risk of complications from pelvic radiation, consideration should be given to adjuvant brachytherapy rather than pelvic irradiation.

Papillary serous histology. The high rate of upper abdominal, pelvic, and vaginal recurrences in patients with uterine papillary serous cancers has led some clinicians to recommend that these patients receive whole abdominal irradiation (WAI, with doses up to 30 Gy) and additional treatments to bring the pelvic dose to 50 Gy. A vaginal cylinder or colpostats may be used to boost the surface dose with 40 Gy. This treatment has resulted in a 5-year survival rate of 50%.

The most common treatment for this rare cancer is combination chemotherapy and radiation therapy (either vaginal brachytherapy or EBRT). Surgical staging should be similar to that for ovarian cancer, as these patients have a high propensity of distant and abdominal tumor spread.

Stage II disease. Patients whose endometrial cancer extends to the cervix usually represent a heterogeneous group, with differing histologic grades and varying degrees of cervical involvement, myometrial penetration, and nodal involvement. Similar outcomes with preoperative and postoperative irradiation suggest that initial surgical treatment with tailored postoperative irradiation is a reasonable approach.

Current treatment recommendations frequently include adjuvant pelvic irradiation to a dose of 45 to 50 Gy, in addition to insertion of a vaginal cylinder or colpostats to raise the total dose to the vaginal surface to 80 to 90 Gy. This treatment should result in a 5-year disease-free survival rate of 80%, with a locoregional tumor control rate of 90%. Of course, outcome varies with the extent of myometrial penetration, degree of cervical involvement, and histologic grade of tumor.

Patients who have a large amount of cervical involvement that precludes initial hysterectomy are candidates for preoperative irradiation. A multiple-field technique is used to deliver a dose of 40 to 45 Gy with standard fractionation. A midline block may be inserted for the last 20 Gy to protect the rectum.

Intracavitary insertion with a standard Fletcher applicator, consisting of a uterine tandem and vaginal colpostats, delivers 20 to 25 Gy to point A (defined as 2 cm caudally and 2 cm laterally to the cervical os). Hysterectomy should follow in approximately 4 to 6 weeks. The expected 5-year disease-free survival rate for patients with extensive disease is 70% to 80%.

Stage III disease. More favorable patients have an isolated extrauterine site (eg, adnexa alone), low-grade histology, and/or disease confined to the pelvis. Greven et al reported that 17 patients with an isolated extrauterine site who had low-grade histology and received postoperative pelvic radiation therapy had a 100% disease-free survival rate. However, patients with grade 2 or 3 disease or more than one extrauterine site had progressively worse outcomes.

One subgroup found to have a relatively favorable prognosis includes women with isolated ovarian metastasis. Five-year disease-free survival rates ranging from 60% to 82% have been reported in these women after hysterectomy and pelvic irradiation, depending on the histologic grade of the tumor and the depth of myometrial penetration. Pelvic irradiation usually includes a dose of 45 to 50 Gy using standard fractionation. A vaginal boost with a cylinder or colpostats may add 30 to 35 Gy to the vaginal surface.

Patients with pelvic node involvement alone have much better outcomes than patients with extension to periaortic nodes, despite the fact that they are both considered stage IIIC patients. Morrow et al demonstrated 5-year recurrence-free survival rates of 75% and 38% for patients with pelvic nodes compared with patients with para-aortic nodes, respectively. Patients with pelvic nodes and negative para-aortic nodes are generally treated with adjuvant pelvic radiation therapy. Those with para-aortic nodes are treated with extended-field irradiation, which includes 45 to 50 Gy to a volume encompassing the pelvic and periaortic regions.

Because upper abdominal failures have been reported previously in patients with stage III disease, attention has focused on the role of WAI. Although subsets of patients have done well with WAI, it is unclear whether this more aggressive therapy has any benefit over pelvic irradiation. A GOG phase II trial of WAI demonstrated a 3-year progression-free survival rate of 35%. The GOG completed a trial of WAI compared with chemotherapy, GOG0122. (The outcomes from this trial are discussed in the "Chemotherapy" section of this chapter.) Unfortunately, because most studies have combined patients who have favorable stage III disease with patients who have unfavorable stage IV disease, it is impossible to determine whether there are some subgroups of patients who might best be managed with a particular therapy.

Because many of these patients are at increased risk of pelvic recurrence as well as distant recurrence, there is interest in combining pelvic radiation therapy with systemic therapy. Radiation Therapy Oncology Group (RTOG) 9708 combined pelvic radiation therapy with cisplatin(Drug information on cisplatin) and followed it with cisplatin and paclitaxel(Drug information on paclitaxel). Toxicity was predominantly hematologic. For stage III patients, 4-year survival and disease-free survival rates were 77% and 72%, respectively. There were no recurrences for patients with stage IC, IIA, or IIB disease.

GOG0184 was instituted following the completion of GOG0122, based on the assumption that combined-modality therapy with radiation therapy and chemotherapy in advanced but optimally cytoreduced endometrial carcinoma may lead to a better result than either modality used alone. Patients with stages III and IV adenocarcinoma of the endometrium with less than 2 cm of residual disease were treated with radiation therapy tailored to include the volume at risk followed by randomization to cisplatin plus doxorubicin(Drug information on doxorubicin) or to cisplatin, doxorubicin, and paclitaxel. As reported by Homesley et al, the addition of paclitaxel to cisplatin and doxorubicin did not improve progression-free survival.

Definitive radiation treatment

For patients who are poor operative risks, definitive treatment with irradiation has produced excellent local tumor control and survival rates. Such treatment is considered to be justified when the operative risk exceeds the 10% to 15% uterine recurrence rate expected with irradiation alone.

A more favorable outcome with definitive irradiation is related to low clinical tumor stage, less aggressive histologic variant, and use of brachytherapy for at least part of the treatment. Five-year disease-specific survival rates as high as 87%, 88%, and 49% have been reported in patients with stages I, II, and III or IV disease, respectively. Ten-year local tumor control rates in patients with stages I/II, III, and IV disease were 84%, 87%, and 68%, respectively.

For patients with early-stage disease and low-grade histology, treatment techniques with irradiation alone consist of uterine intracavitary insertions with Heyman or Simon capsules or an afterloading intrauterine tandem. Doses for intracavitary treatment range from 40 to 45 Gy prescribed to point A. One report used an HDR endometrial applicator and prescribed twice-daily fractions of 700 Gy given for five treatments to 2 cm. Patients with more advanced disease, a large uterus, or aggressive histology generally receive both an intrauterine intracavitary insertion and external pelvic irradiation. External irradiation typically delivers 40 to 45 Gy to the pelvis, followed by intracavitary treatment that delivers 30 to 35 Gy to point A.

Rates of serious complications attributable to irradiation range from 4% to 5% with intracavitary treatment alone to 10% to 15% with combined external and intracavitary irradiation.

Adjuvant systemic therapy

Only a few trials of adjuvant systemic therapy have been conducted in patients with early-stage endometrial cancer. At present, we believe that such therapy should not be recommended outside the clinical trial setting.

Endocrine therapy. Early uncontrolled trials suggested that progestin therapy might prolong the disease progression-free interval and time to recurrence in patients with stages I and II lesions treated with initial surgery and irradiation. However, at least three subsequent randomized trials failed to show any survival benefit for progestins, and a meta-analysis has demonstrated no advantage of adjuvant progestin therapy.

Chemotherapy. Three studies have evaluated the role of chemotherapy in early-stage endometrial carcinoma. The European Organisation for Research and Treatment of Cancer (EORTC) compared pelvic radiation plus brachytherapy vs pelvic radiation and chemotherapy. The Japanese gynecologic oncology group compared pelvic radiation vs cisplatin-based chemotherapy, and the consistent finding was a lower incidence of distant metastasis with minimal impact on survival. The EORTC trial had an overall survival benefit at 5 years of 8%; however, this trial as well as the Japanese trial included some patients with positive pelvic nodes. These trials do lead to enthusiasm for the addition of chemotherapy as adjuvant treatment for high-risk patients with early-stage disease.

The current GOG trial is randomizing patients with high-risk stage I and II disease between pelvic radiation and no chemotherapy or vaginal brachytherapy with three cycles of carboplatin(Drug information on carboplatin) and paclitaxel.

Results from a GOG trial, GOG0122, compared adjuvant chemotherapy (doxorubicin plus cisplatin) with WAI. The patient population included patients with stages III and IV disease (75% and 25%, respectively) with 50% endometrioid histologies. Patients treated with chemotherapy had significantly improved progression-free (38% vs 50%) and overall (42% vs 55%) survival at 5 years. However, serious adverse effects were also more common in the chemotherapy group than in the radiotherapy group, with treatment-related deaths twice as high in the former group, at 4% vs 2%. Pelvic and abdominal recurrences were the predominant pattern of recurrence for both treatment arms. Distant recurrences were slightly less frequent for patients treated with chemotherapy. This finding leads to the support of the concept of combining chemotherapy with involved-field irradiation for patients with more advanced disease.

The next GOG trial (184) randomized patients to receive involved field EBRT with doxorubicin and cisplatin or with paclitaxel, docetaxel(Drug information on docetaxel), and cisplatin. There was a 10% locoregional recurrence at 3 years, with no difference in survival. Subset analysis suggested that paclitaxel benefited patients with gross residual disease, papillary serous histology, and grade 3 histology. The current GOG study (258) is randomizing patients to concurrent cisplatin and EBRT followed by adjuvant carboplatin with paclitaxel or carboplatin and paclitaxel alone. The ongoing PORTEC 3 trial randomizes such patients to pelvic radiation and concurrent cisplatin or to radiation therapy with adjuvant carboplatin and paclitaxel.

Hormone replacement therapy (HRT). Whether HRT increases the likelihood of recurrence has been studied, with several retrospective reports showing no adverse outcomes. Thus, GOG undertook a large randomized placebo-controlled trial of HRT after treatment for earlier stage endometrial cancer. However, there were too few events, and it was closed after the findings of the Women's Health Initiative were released. HRT was not associated with a significant incidence of recurrent disease, mortality, or new malignancy.