Uterine Corpus Tumors

Recurrent or Metastatic Disease

Patterns of recurrence

Recurrent endometrial cancer is initially confined to the pelvis in 50% of patients. The major sites of distant metastasis are the abdominal cavity, liver, and lungs.

Following diagnosis and initial treatment, periodic evaluation, including history, physical examination, and pelvic examination, is recommended at 3- to 6-month intervals for the first 5 years and yearly thereafter. More extensive and more costly procedures, such as chest x-ray, CT imaging, and marker studies, used in asymptomatic patients are of questionable value and are unlikely to have a major impact on survival. Symptomatic patients should be evaluated as appropriate.

Radiation therapy

After hysterectomy alone for endometrial cancer, approximately 50% of recurrences are pelvic and 50% are extrapelvic. It is clear that locoregional recurrences can develop in isolation, without distant metastasis, and salvage can be accomplished with high-dose irradiation.

Pelvic recurrences. Five-year disease-specific survival rates as high as 51% have been reported in patients with isolated locoregional recurrences treated with radiation therapy. Factors that have an adverse impact on outcome are increased size of tumor at recurrence, young age, pelvic vs vaginal involvement, and treatment of recurrence with EBRT only vs the addition of vaginal brachytherapy.

The PORTEC group has published its experience with salvage of vaginal recurrence in patients who did not receive adjuvant irradiation. At 5 years, the survival rate after vaginal relapse was 65% in the control group, compared with 43% in the irradiated group.

Radiation treatment for pelvic recurrence usually consists of EBRT with the addition of a brachytherapy boost that may include colpostats, a cylinder, interstitial needles, or seeds. Treatment must be individualized based on the location and size of the recurrence and on the boost method selected. The tolerance of normal tissues must be respected, but combined doses > 60 Gy have been associated with improved local tumor control. The GOG has an ongoing trial evaluating the role of chemotherapy with radiation in this group of patients.

Extrapelvic recurrences. For patients with recurrences outside the pelvis, irradiation is effective in producing responses in localized symptomatic lesions. Therefore, irradiation may be effective for palliation of such lesions in the lymph nodes, brain, or bones. Doses and protocols vary, depending on the site of recurrence.

Pelvic exenteration for pelvic recurrences after irradiation

Isolated pelvic central recurrence after irradiation is rare. Selected patients in whom it does occur may benefit from pelvic exenterative surgery. No large series have been published, but some long-term survivors have been reported.

Although the long-term survival rate after this procedure is only 20%, it remains the only potentially curative option for the few patients with central recurrence of endometrial cancer who have not responded to standard surgery and radiation therapy.

Endocrine therapy

Progestins. These produce complete and partial response rates of 15% to 25% in patients with locoregional recurrence or distant metastases. The route, type, and dose of progestins do not appear to be related to response; hence, oral therapy is preferred.

TABLE 4Results of a phase III, dose-response trial of progestins in advanced or recurrent endometrial carcinoma

In clinical practice, oral administration of 200 mg of medroxyprogesterone(Drug information on medroxyprogesterone) or 160 mg of megestrol(Drug information on megestrol) produces blood levels similar to those achieved with parenteral therapy (400 to 1,000 mg of medroxyprogesterone IM weekly). A phase III trial conducted by the GOG comparing 200 mg and 1,000 mg of medroxyprogesterone given orally daily found no differences between the two regimens, although it is noteworthy that the trends all favored the low-dose regimen (Table 4). Doses higher than 200 mg/d of medroxyprogesterone, therefore, are clearly not warranted.

Several factors are predictive of a favorable response to progestin therapy. Patients with well-differentiated lesions are more likely to respond than those with poorly differentiated tumors. A related observation is that a much higher percentage of grade 1 tumors have significant levels of estrogen and progesterone(Drug information on progesterone) receptors; data show that lesions with higher receptor levels respond much more frequently to progestins than those with lower receptor levels. Response is almost always associated with better progression-free and overall survival.

The median time to disease progression for all patients treated with progestins is 3 to 4 months, and the median survival is 10 months.

Tamoxifen. Tamoxifen(Drug information on tamoxifen) has a 0% to 13% response rate, is not as active as progestins, and is of little value as second-line therapy in patients who do not respond to progestins.

The GOG has evaluated combined therapy with tamoxifen plus a progestin given sequentially in the hope that tamoxifen may increase progesterone receptor expression and, thus, increase the likelihood of response to progestins. Continuous tamoxifen and medroxyprogesterone given every other week was an active treatment, with a 33% response rate. A subsequent study found a 27% response rate for alternating megestrol, with several prolonged responses. As with prior hormonal studies, patients with well-differentiated cancers were more likely to respond. Nevertheless, this trial was relatively unique in that 22% of patients with poorly differentiated tumors responded.

Other hormonal agents. Drugs such as gonadotropin-releasing hormone analogs and aminoglutethimide (Cytadren) have been studied to some extent in endometrial carcinoma. These agents do not appear to have sufficient activity to warrant further study.

Chemotherapy

Single agents. Chemotherapy for advanced endometrial cancer focuses on three groups of agents with demonstrated activity: anthracyclines, platinum compounds, and taxanes.

The anthracyclines studied include doxorubicin(Drug information on doxorubicin) and epirubicin(Drug information on epirubicin). In a total of 298 patients, doxorubicin produced a 27% response rate. Epirubicin, primarily in European studies including 27 patients, yielded a 26% response rate. Two platinum compounds have activity. Cisplatin(Drug information on cisplatin), in 86 patients, elicited responses in 29%. Carboplatin(Drug information on carboplatin) produced a 31% response rate in 52 patients. Paclitaxel(Drug information on paclitaxel), in two GOG studies, yielded responses in 36% of chemotherapy-naive patients and 27% of previously treated patients.

For all of these studies, the progression-free interval ranged from 4 to 7 months, with an overall survival range of 8 to 12 months. Approximately one-third of the responses were clinical complete responses, with a substantially longer duration and better survival than partial responders.

Other single agents with modest activity in endometrial cancer include ifosfamide(Drug information on ifosfamide) and topotecan(Drug information on topotecan) and bevacizumab(Drug information on bevacizumab) (Avastin).

Combination regimens. A number of phase II trials of combination regimens have been conducted. The combination of carboplatin and paclitaxel has been demonstrated to be active in advanced endometrial cancer (50% to 60% response rate). Ultimately, the relative merits of combination chemotherapy with carboplatin and paclitaxel must be judged in the context of a randomized trial that is being performed by the GOG (GOG0209). A randomized trial of cisplatin and doxorubicin with or without paclitaxel following surgery and radiation therapy did not show any improvement in recurrence-free survival but did have more toxicity.

Following encouraging phase II results, a phase III trial of circadian-timed administration of cisplatin and doxorubicin found no significant benefit. The GOG then compared this two-drug (cisplatin [50 mg/m²]/doxorubicin [60 mg/m²]) regimen with a three-drug combination of cisplatin (50 mg/m²), doxorubicin (45 mg/m²), and paclitaxel (160 mg/m² as a 3-hour infusion), with G-CSF (granulocyte colony-stimulating factor, filgrastim(Drug information on filgrastim) [Neupogen]) support (GOG 177). The three-drug combination of the paclitaxel-containing program produced a higher response rate (57% vs 35%) and an improved progression-free survival (8.3 months vs 5.3 months). Overall survival was also modestly improved (15.3 months vs 12.3 months; P = .037) with the three-drug program but with considerably greater toxicity, particularly peripheral neuropathy (grade 3, 12% vs 1%).

There has been concern about the potential effect of "high-risk" endometrial histologies on response to chemotherapy. It has been suggested that papillary serous and clear-cell tumor adenocarcinomas should be treated differently. McMeekin et al (Gynecol Oncol 2007) correlated histology with chemotherapy outcomes in several of the above-mentioned trials and found no significant difference in response or survival based on the histologic type of endometrial cancer.

Sidebar: At the 2012 meeting of the Society of Gynecologic Oncology, Miller et al presented, on behalf of the GOG, the results of GOG0209. Patients in the trial (n = 1,381) were randomized to treatment with doxorubicin at dose of 45 mg/m² and cisplatin at 50 mg/m² (day 1), followed by paclitaxel at 160 mg/m² (day 2) with growth factor support (TAP) or to a regimen of paclitaxel at 175 mg/m² and carboplatin to AUC 6 (day 1) (TC) repeated every 21 days for 7 cycles. Overall survival in patients randomized to TAP was 40.3 months, compared with 36.5 months (HR = 1.05) for those randomized to TC. Progression-free survival was 13.5 months for patients treated with TAP vs 13.3 months (HR = 1.03) for those who received TC. Adverse events for patients treated with TAP vs TC, respectively, included a 7% vs 6% incidence of neutropenic fever and a 26% vs 19% incidence of grade > 1 sensory neuropathy (P < .01). It was concluded that TC is not inferior to TAP in terms of progression-free and overall survival. Overall, the toxicity profile favors TC. Thus, TC as prescribed in this study is an acceptable backbone for further trials in combination with "targeted" therapies (Miller D et al: Gynecol Oncol 125:771–773, 2012).

Chemotherapy plus progestins. Combinations of chemotherapy plus progestins have been studied in a number of phase II trials. The only large, randomized trial evaluating this approach (GOG29) allocated patients with advanced or recurrent disease to receive either cyclophosphamide(Drug information on cyclophosphamide), doxorubicin, cisplatin, and megestrol or melphalan(Drug information on melphalan) (Alkeran), fluorouracil(Drug information on fluorouracil) (5-FU), and megestrol. In pilot studies, these two regimens had been reported to yield response rates of 75% and 94%, respectively. The randomized trial produced response rates of 36% and 38%, respectively, with no evident advantage of either combination over single-agent doxorubicin (from prior studies) with regard to response rate, progression-free interval, or overall survival. These results do not suggest any advantage for the combined use of chemotherapy and progestins.

Treatment recommendations

Patients who have advanced or recurrent endometrial carcinoma should be considered for systemic therapy. Patients should first be offered the opportunity to participate in a clinical trial. Those who are ineligible or who choose not to participate should be treated according to current evidence.

Patients who have a grade 1 tumor and/or known progesterone receptor–positive disease clearly benefit from treatment with progestins (response rate, 40%; median progression-free interval, 9 months; overall median survival, 14 months) and should be so treated. Those with a grade 2 to 3 tumor and/or known progesterone receptor–negative disease do not do well with progestin therapy (response rate, 12%; median progression-free interval, 3 months; overall median survival, 10 months) and should be considered for initial treatment with single-agent chemotherapy (eg, paclitaxel, doxorubicin, carboplatin) or a combination regimen. Options include cisplatin/doxorubicin, cisplatin/doxorubicin/paclitaxel, and carboplatin/paclitaxel. Chemotherapy should also be considered for patients who do not respond to initial hormonal therapy.

Regimens that include both chemotherapy and hormonal therapy should not be considered outside a clinical trial because of the lack of data supporting any advantage of these combinations.