Study
Stage
Histology
Surgery
Residual
%
PFS (months)
OS (months)
Bristow et al. [22]
IV
UPSC
PS
<1 cm
>1 cm
52
48
Memahzadeh et al. [33]
IIIC + IV
UPSC
PS
0
Macro
57
43
22
8
40
10
Thomas et al. [23]
IIIC + IV
UPSC
PS
0
<1 cm
37
60
9
6
51
14
Lee et al. [34]
IV
UPSC
NACT + IDS
0
100
Prince et al. [35]
IIIC + IV
UPSC
NACT + IDS
0
100
11
17
Vandenput et al. [24]
IV
EEC + UPSC
NACT + IDS
<1 cm
inoperable
80
13
13
23
12
In addition, the rate of minor postoperative complications (wound infections, urinary tract infections, and deep vein thrombosis) and major life-threatening events (myocardial infarction, pulmonary embolism, small bowl obstruction) were 38 % and 13 % respectively with primary debulking surgery as compared to 13 % and 4 % respectively with interval debulking [22–24]. Thus, it can be concluded that use of NACT followed by debulking surgery is associated with a higher rate of optimal cytoreduction along with significant reduction in postoperative morbidity and better survival outcomes in advanced endometrial cancer with transperitoneal spread [24].
Adjuvant Treatment
Radiation
The outcome of patients with isolated adnexal involvement (stage IIIA) is better than patients with isolated serosal involvement (stage IIIA), with a reported 5-year DFS of 70.9 % versus 41.5 % after treatment with pelvic radiation [26]. If pelvic lymph node involvement is present (stage IIIC1), postoperative pelvic radiation can yield a 50–60 % long-term survival in these patients; however, distant failure remains a problem [26, 27]. Furthermore, stage IIIC2 patients, by virtue of para-aortic node involvement, represent a particularly high-risk group with a higher rate of distant relapses. This has prompted many investigators to evaluate the role of whole abdominal radiation (WAR) and many chemotherapeutic drugs in advanced-stage endometrial cancers [26–28].
Chemoradiation
Multiple trials have compared chemotherapy to radiation therapy as well as to other chemotherapeutic regimens for adjuvant treatment in patients with advanced endometrial cancer.
Two randomized trials have compared radiation therapy to chemotherapeutic regimes: GOG 122 compared WAR therapy to doxorubicin/cisplatin regimen and a Japanese GOG 2033 compared whole pelvic radiation (WPR) therapy to CAP (cyclophosphamide/doxorubicin/cisplatin) [28, 29]. Both trials had shown an improved PFS and OS in chemotherapy arm, largely due to reduction in abdominal and other distant site of recurrence.
Subsequently, two randomized clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE- III) were undertaken to clarify whether the sequential use of chemotherapy and radiotherapy improved PFS over radiation therapy alone in high-risk endometrial cancer patients (stage I–IIA, IIIC, any histology). The results of pooled analysis showed that the combined modality treatment was associated with 36 % reduction in the risk of relapse or death [hazard ratio (HR) 0.64, 95 % confidence interval (CI) 0.41–0.99; P = 0.04]. Cancer-specific survival was significantly different (HR 0.55, 95 % CI 0.35–0.88; P = 0.01) and favored the use of adjuvant chemotherapy in addition to radiotherapy [30].
Because of the safety and efficacy of carboplatin and paclitaxel in the management of other gynecologic malignancies, there is an interest in using this regimen as first-line treatment in patients with advanced endometrial cancer. A GOG 209, randomized trial was conducted to compare doxorubicin/cisplatin/paclitaxel (TAP) with carboplatin/paclitaxel (TC) in stage III, IV, and recurrent endometrial cancer. Interim analysis showed that TC was not inferior to TAP in terms of both PFS (13.5 vs. 13.3 months) and OS (40.3 vs. 36.5 months). Furthermore, the toxicity profile favored TC with less sensory neuropathy [31].
Management of Type II/Non-endometrioid Histology
Uterine Papillary Serous Carcinoma (UPSC) and Clear Cell Carcinoma
Uterine papillary serous carcinoma (UPSC) and clear cell carcinoma of uterus are biologically distinct entities. Although they represent around 20 % of endometrial cancers, they account for more than 50 % of relapses and death attributed to endometrial cancer. UPSC represents an aggressive histological subtype of endometrial cancer with 60–70 % of women presenting with disease extending outside the pelvis, with a poor 5-year survival of ~18–27 %. Similarly, clear cell carcinoma tends to occur in older women and in tamoxifen-treated breast cancer patients and is associated with higher rate of extrauterine spread [2–5].
Due to rarity of these high-risk histologies, treatment recommendations are largely based upon small, retrospective single and multi-institutional studies. Given their more aggressive behavior and pattern of recurrences, a multimodality treatment has been employed for these biologies. In one of the largest series of advanced-stage (IIIC-IV) UPSC, Rauh-Hain et al. showed that optimal cytoreduction, defined as <1 cm of the largest residual tumor, is associated with significant improvement in median survival (39 vs. 12 months; p = 0.0001) [32]. Similarly, Thomas et al. showed superior survival results in patients with stage III and IV clear cell carcinoma of uterus, who underwent an complete cytoreductive surgery as compared to patients with gross residual at the end of surgery [22, 23].
The role of adjuvant radiation therapy in the management of high-risk pathology, with a high propensity for distant failures or failures within the radiated field, remains elusive. Similar to endometrioid histology, platinum-based adjuvant chemotherapy in a doublet or triplet format in combination with paclitaxel and/or doxorubicin should be considered in women presenting with extrauterine disease [4, 5, 7, 22, 23].
Carcinosarcoma (CS)
Uterine carcinosarcoma (CS) is another rare but aggressive histology with 50 % patients presenting with disease extending outside uterus. Only few prospective trials have evaluated the optimal therapeutic strategy for uterine CS independently from other uterine sarcomas; therefore, disease-specific surgical management for advanced-stage uterine CS remains unclear. In a retrospective series by Tanner and Leitao [6] of 44 patients with advanced-stage CS of uterus, complete gross resection was associated with median OS of 52.3 months versus 8.6 months in patients with gross residual disease. Also, in patients who received adjuvant therapy (either chemotherapy or chemoradiation), OS was 30.1 months versus 4.7 months in patients who did not receive any adjuvant therapy. Thus, cytoreductive surgery with a goal of achieving complete gross resection, followed by adjuvant chemoradiation, can be suggested as optimal therapy for advanced-stage carcinosarcoma of uterus [2, 6].
Conclusion
Approximately 10–15 % of new cases of endometrial cancer present with extrauterine disease. Currently, there are no randomized trials for the best surgical management for advanced-stage endometrial cancers. Type II radical hysterectomy with bilateral salpingo-oopherectomy with systematic pelvic with or without para-aortic lymph node dissection has been considered the optimal surgical treatment for stage II endometrial cancer. For stage III and IVA disease, a multimodality approach with maximal effort at cytoreduction followed by adjuvant chemoradiation is recommended. Management of endometrial cancer with distant metastasis (stage IVB) should be individualized based upon the location and extent of disease and patient’s performance status. NACT followed by debulking surgery for advanced-stage endometrial cancer could be a promising approach and needs to be evaluated further in randomized controlled trials. For advanced-stage non-endometrioid/type II endometrial cancers, optimal cytoreduction with maximal effort at complete gross resection followed by adjuvant chemoradiation should become the norm.
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