Multidisciplinary Treatment of Early Stage Endometrial Cancer

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Abstract: Endometrial cancer is a highly curable malignancy when it presents as uterine-confined disease, but the prognosis for metastatic or recurrent ...
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Multidisciplinary Treatment of Early Stage Endometrial Cancer S.C. Cecere1, C. Pisano1, A. Bamias2, M. Di Napoli1, S. Rossetti1, G. Facchini1, R. Tambaro1 and S. Pignata1,* 1 Division of Medical Oncology, Department of Urology and Gynecology, National Cancer Institute of Naples, Italy; 2Dept of Clinical Therapeutics, Medical School, University of Athens, Athens, Greece

Abstract: Endometrial cancer is a highly curable malignancy when it presents as uterine-confined disease, but the prognosis for metastatic or recurrent endometrial cancer is poor. For those patients which are diagnosed at an early stage, surgery alone may be adequate for cure and clinical outcome is often favorable, with approximately 80 % of cases surviving at 5 years. However, after primary diagnosis and treatment, roughly 20-30% of patients are expected to recur within the following 5 years. Adjuvant treatment for endometrial cancer is not yet clearly defined. FIGO Stage I-III endometrial cancer patients, usually undergo surgery and some of them are offered adjuvant treatment based on risk assessment. Grade, age, stage are considered all independent risk factors for recurrence. Radiotherapy (RT) has been considered the adjuvant treatment of choice for decades, being able to reduce local recurrence rate and improving progression free survival, but without any impact on overall survival. In the last two decades, a shift toward the use of systemic chemotherapy (CT) in addition or instead of radiation has occurred, although few prospective studies have been performed in this field.

Keywords: Adjuvant chemotherapy, hormonal therapy, endometrial cancer, prognostic factors, radiation therapy. INTRODUCTION Endometrial cancer (EC) is the most common malignancy of the female genital tract. In the European Union its incidence is estimated to be 16 cases/100 000 women/year (range 13–24) with a mortality rate of 4–5 cases/100.000/year [1] and an overall 5-year survival rate of about 80% [2]. For those patients which are diagnosed at an early stage, surgery alone may be adequate for cure and clinical outcome is often favorable, with approximately 80 % of cases surviving at 5 years. However, after primary diagnosis and treatment, roughly 20-30% of stage I-III patients are expected to recur within the following 5 years. In particular about 16% of cases are identified with either stage III or IV disease [3] with a 5-year survival rates ranging from 30–89% to 0–10% [4] respectively. Adjuvant treatment for endometrial cancer is not yet clearly defined. FIGO Stage I-III endometrial cancer patients, usually undergo surgery and some of them are offered adjuvant treatment based on risk assessment. Grade, age, stage are considered all independent risk factor for recurrence. Radiotherapy (RT) has been considered the adjuvant treatment of choice for decades, being able to reduce local recurrence rate and to improve progression free survival, but without any impact on overall survival. In the last two decades, a shift toward the use of more systemic chemotherapy (CT) in addition or instead of radiation has occurred, although few prospective studies have been performed in this field and no clear standard guideline has been developed. This review analyzes the literature regarding treatment of early endometrial cancer, with particular focus on adjuvant treatment. Data reported are based on a PUBMED search performed in June 2012. EPIDEMIOLOGY The incidence of endometrial carcinoma increases with age, with a mean age at diagnosis of 61 years [5]. In the vast majority of cases, endometrial carcinoma is diagnosed by an endometrial biopsy, following abnormal postmenopausal vaginal bleeding. The

*Address correspondence to this author at the Division of Medical Oncology, Department of Urology and Gynecology, National Cancer Institute of Naples, Via Mariano Semmola, 80131 Naples, Italy; Tel: +39 081 5903637; Fax: +39 081 5903861; E-mail: [email protected] 1871-5206/13 $58.00+.00

frequent appearance of these early symptoms explains why most cases (about 75%) are diagnosed at an early stage, when disease is still confined to the uterus [6,7]. The risk of developing endometrial carcinoma is related to lifetime exposure to estrogens, which increase proliferative activity of endometrial glands and stroma cells. Most of the risk factors for endometrial hyperplasia and carcinoma reflect either exogenous or endogenus states of hyperestrinism that raises the likelihood for coding errors and somatic mutations [8,9]. Early onset of menses, late menopause, infertility, nulliparity, polycystic ovarian syndrome, diabetes mellitus, obesity, use of estrogen replacement therapy without concomitant use of a progestin, tamoxifen therapy, are risk factors consistent with greater lifetime estrogen exposure. In addition, up to 5% of cancers of the endometrium are associated with hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome), a cancer susceptibility syndrome inherited in autosomally dominant fashion [10]. Despite advances in defining the biology of endometrial carcinomas there has been little progress in defining markers of preinvasive endometrial progression. As in colorectal cancer, a model of multistep process of endometrial carcinogenesis by the control of cell proliferation and differentiation has also been proposed in this tumor. Overexpression of N-myc-DownstreamRegulated Gene-1 (NDRG1) and decreased expression of Phosphates and Tensin Homolog (PTEN) has been proposed as a tool for early detection of endometrial carcinoma. PTEN expression is significantly higher in normal endometrium, than in atypical hyperplasia and endometrioid carcinoma [11]. Therefore, its expression in endometrial hyperplasias could be used as an early signal of cancer risk and a potential target for preventive treatment. Complete loss of PTEN protein expression is most commonly found in endometrial carcinoma and hyperplasia with cytologicatypia. Also the negative cell regulator pRb2/p130 has been identified as one of the leading factors in the endometrial carcinogenesis; its expression progressively decreases from hyperplastic endometrium through atypical hyperplasia to poorly differentiated carcinomas. The cyclin-dependent kinase inhibitor p27 is also necessary to control the proliferation of endometrium and loss of its expression seems to play a role in some aspects of endometrial carcinogenesis. Survivins overexpression like cyclin-E might be another important mechanism

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in the development of endometrioid adenocarcinoma along with lost or decreased activity of p27 [12,13]. Regarding histology, the majority of endometrial malignancies (95%) develops in the endometrial glands and is referred as endometrial carcinomas; the remaining 5% are mesenchymal tumors, which consist of pure uterine sarcomas (endometrial stromal sarcoma and leiomyosarcomas) and mixed epithelialstromal tumors, such as carcinosarcomas and adenosarcomas. Classification of endometrial carcinomas is made according to the International Society of Gynecologic Pathologists Classification [8]. Approximately 75% of cases are classified as endometrioid adenocarcinomas and include several variants (e.g. villoglandular and adenocarcinoma with squamous differentiation); other histologies include uterine serous carcinoma (5–10%), clear cell carcinoma (5%) and a variety of relatively rare carcinomas. Endometrial carcinomas are also designated as type I or type II [14,15]. Type I tumors, consisting mostly of endometrioid adenocarcinomas, are believed to be related to estrogen stimulation, because they are associated with endometrial hyperplasia and express steroid hormone receptors. In contrast, type II tumors, consisting mostly of serous, clear cell and endometrioid high grade tumors typically arise in atrophic endometrium via a mechanism unrelated to estrogen exposure. These tumors are usually negative or weakly positive for steroid hormone receptors, are typically poorly differentiated and of high grade. In general, type II tumors are characterized by a more aggressive clinical course than type I tumors with a tendency for intraperitoneal spread [14]. TREATMENT OF EARLY ENDOMETRIAL CANCER Surgery The surgical approach is still the gold standard treatment for this cancer and it usually consists of a total hysterectomy with bilateral salpingo-oophorectomy (THA-BSO) and peritoneal washing. Surgery can be done via laparotomy or laparoscopic technique. Two extensive meta-analyses and quantitative reviews showed no significant difference in terms of recurrence and survival between these two surgical options [15-17]. A GOG trial, the LAP2 study, confirmed this data with a recently publication on Journal of Clinical Oncology. This prospective, multi-institutional randomized trial demonstrates, with a median follow up of 59 months, that laparoscopic surgical treatment and staging is non-inferior to open laparotomy in terms of time to recurrence, for the surgical staging of uterine stageI-IIendometrial cancer, with relatively small differences in recurrence rates (estimated difference at 3 years, 1.14%; 90% lower bound, 1.278; 95% upper bound, 3.996). These results, combined with previous findings from this study of improved Quality of Life (QOL) and decreased complications associated with laparoscopy, allow surgeons to reasonably suggest this method as a means to surgically treat and stage patients with presumed early-stage uterine cancers [18]. A recent population-based analysis noted that 4% of endometrial cancers occurred in women aged 40 years or younger [19]. Although prior data has been somewhat conflicting, many studies have found that young women with endometrial cancer have a more favorable prognosis than older patients. Premenopausal women with endometrial cancer often have low-grade, early-stage tumors that may, in part, explain the differential survival [19, 20]. Treatment for endometrial cancer typically involves hysterectomy and salpingo-oophorectomy. Hysterectomy results in loss of fertility and is often unacceptable to women of childbearing age. Conservative, uterine-preserving treatment with progestational agents has been proposed as an alternative for women unwilling to undergo hysterectomy [21]. Progestin treatment is associated with a reasonable success rate, particularly, in women with low-grade tumors. Oophorectomy is commonly performed in premenopausal women with endometrial cancer who undergo hysterectomy.

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However, a large unresolved question relates to the safety of ovarian preservation in young women with endometrial cancer. Conservative surgery might be complicated by an incidence of 1045% of synchronous ovarian tumors in patient with EC stage IA grade 1 (G1) and/or undetected myometrial infiltration, because of the limited sensitivity of the diagnostic procedures such as magnetic resonance [22-26]. Despite these theoretic benefits, the ooforectomy results in surgical menopause and places patients at risk for the long-term sequelae of estrogen deprivation. In a 2009 retrospective U.S. trial were extracted from the National Cancer Institute’s Surveillance, Epidemiologyand End Results (SEER) database data on 3.269 young (< 45years) women with stage IA-B endometrial cancer who underwent hysterectomy, to observe the effects of ovarian preservation on cancer specific and overall survival. In this trial, conservative surgery resulted to have no impact on either cancer-specific (hazard ratio [HR] = 0.58; 95% CI, 0.14 to 2.44) or overall (HR = 0.68; 95% CI, 0.34 to 1.35) survival [27]. The worldwide experience and data concerning hysteroscopic treatment are, however, still limited due to the small numbers of cases, potential methodological bias and the use of different therapeutic regimes. For the lack of strong evidences, conservative surgery should be applicable only in selected cases. The American College of Obstetricians and Gynecologists (ACOG) recommends full staging, including node dissection (pelvic and para-ortic lymphadenectomy), and omentectomy (in type II carcinomas) for all cases of endometrial cancer [28,29]. However, the role of pelvic and paraortic lymphadenecomy is currently the most controversial topic regarding surgical approach of endometrial carcinoma [30, 31]. In the United States, pelvic lymphadenectomy is commonly performed based on the results derived from the SEER database (of 1998-2001) comparing 39.396 patients treated by lymphadenectomy with those who did not. The results showed that lymphadenectomy is advisable for stage I grade 3 disease and more advanced endometrioid uterine cancers [32]. Several non-randomized trials suggested that the number of removed lymph nodes correlates with an increased overall survival [33,34]. These finding were the rationale for increasing the aggressiveness of the surgical approach in several cancer centers.  In this regard, the results from two major trials have been published recently [30,31]. The first one, an Italian trial, randomized 514 patients with preoperative stage I endometrial carcinoma to undergo (n= 264) or not (n= 250) to pelvic systematic lymphadenectomy. The primary endpoint of the trial was overall survival, with disease-free survival and surgical morbidity being secondary endpoints. No influence on overall survival was detected. In the lymphadenectomy arm 44 patients (16.7%) received irradiation, whereas, in the observation arm 63 patients (25.2%) were treated with radiotherapy. With a similar approach, the ASTEC/EN.5 trial randomized 1.408 women with histologically proven endometrial carcinoma confined to the corpus, to surgery (TH-BSO; n= 704) or surgery plus lymphadenectomy (n = 704). Again, the primary endpoint of the trial was overall survival. The reported absolute difference in 5-year overall survival was 1% (95% CI -4 to 6). After adjustment for baseline characteristics and pathology details, no significant differences in either overall survival or recurrence free survival were detectable. Data on acute or late toxicity were not reported. The value of systematic lymphadenectomy for adequate staging in women with stage I disease, has been the topic of a Conchrane Collaboration review [35] which pooled data from the two randomized trials [30,31] and examined, in the greater depth, the value of limphadenectomy with early desease. This analysis showed no evidence supporting a survival benefit or a reduction in the risk of disease recurrence in favour of lymphadenectomy. However, in both trials the results may be affected by the fact that a relevant part of the patients received radiotherapy (~ 25%) after surgery. Furthermore, another possible limitation of both trials is that a systematic removal of the para-

Treatment of Endometrial Cancer

aortal nodes has not been performed. Since the initial analysis by Creasman and Alders [36,37] it is known that, in parallel to the increasing risk for pelvic lymph node metastasis, the proportion of positive para-aortic lymph node increases. A recent retrospective Japanese trial analyzed the outcome (overall survival) in 671 patients with endometrial carcinoma treated with either pelvic lymphadenectomy (n = 325 patients) or pelvic and para-aortic lymphadenectomy (n = 346). Additional adjuvant treatments were offered to patients with intermediate or high risk of recurrence [38]. Overall survival was better in those patients with pelvic and paraaortic lymphadenectomy when compared to pelvic lymphadenectomy alone (HR 0.53, 95% CI 0.38-0.76; p = 0.0005). No difference was detectable between intermediate or high-risk patients, whereas overall survival was not influenced by lymphadenectomy type in low-risk patients. Also in multivariate analysis pelvic and paraaortic lymphadenectomy reduced the risk of death compared with pelvic lymphadenectomy alone in intermediate to high-risk patients (HR 0.44, 0.30-0.64; p < 0.0001). As for the ASTEC EN.5 trial and the Italian trial and also the Japanese study is limited by the bias introduced by the uncontrolled use of additional adjuvant treatment.  Thus, at present, it is believed that the choice of performing lymphadenectomy should be based on the risk for recurrence. However, since there is an up to 10% lymph node positivity in low risk and intermediate-risk cancer patients the role of lymphadenectomy should be still evaluated in these patients. The laparoscopic or robotic approach for lymphadenectomy has been proposed beneficial to reduce surgically caused morbidity even if the data from the literature are still controversial. Another outstanding issue concerns the validity of the sentinel lymph node (SLN) procedure for the assessment of nodal status in patients with endometrial cancer. Since the first sentinel node technique in endometrial cancer described by Burke in 1996 [39], a few prospective studies have been published with small numbers of patient demonstrating the reliability and applicability of using this technique, that could be especially useful in early stages endometrial cancer [40] to avoid the consequences of aggressive surgery. A recent Korean review evaluated results of 26 small studies on the topic [41]. Although SLN biopsy has shown good diagnostic performance in endometrial cancer, such data should be interpreted with caution because of significant small study effects. Current evidence is not yet sufficient to establish the true performance of SLN biopsy in endometrial cancer. A French prospective multicentre cohort study (SENTI-ENDO) has already ended the recruitment in nine centres in France in patient with early stage endometrial cancer to assess the detection rate and diagnostic accuracy of the SLN procedure in predicting the pathological pelvic-node status [42]. Five of 111 patients (5%) had an associated SLN in the para-aortic area. Considering the hemi-pelvis as the unit of analysis, negative predictive value (NPV) was 100% (95% CI 95100) and sensitivity 100% (63-100). Considering the patient as the unit of analysis, three patients had false-negative results (two had metastatic nodes in the contralateral pelvic area and one in the paraaortic area), giving an NPV of 97% (95% CI 91-99) and sensitivity of 84% (62-95). All three of these patients had type 2 endometrial cancer. SLN biopsy upstaged 10% of patients with low-risk and 15% of those with intermediate-risk endometrial cancer. SLN biopsy with cervical dual labelling could be a trade-off between systematic lymphadenectomy and no dissection at all in patients with endometrial cancer of low or intermediate risk. However, today, the sentinel concept is far from being part of routine clinical practice, but has the potential to fill the diagnostic gap in low-and intermediate risk patients in order to tailor adjuvant therapy. ADJUVANT THERAPY ACCORDING TO RISK GROUPS The choice of adjuvant treatment is commonly based on the presence of risk factors and generally consists of chemotherapy, radiotherapy, or a combination of both [43].

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Major prognostic factors for endometrial carcinoma are stage, age, histological type, grade, depth of myometrial invasion (MI) and presence of lymph-vascular space invasion (LVST); all these characteristics are independent risk factors for recurrence and are usually considered for the choice of adjuvant therapy [44]. Patients are generally staged according to the International Federation of Gynecology and Obstetrics (FIGO) that recently (2009) revised the previous classification of 1998. In the updated classification patients previously staged as IIIA due to positive cytology are staged now as IA or B, depending on myometrial and cervical stromal invasion. Furthermore, greater importance is given to the level of nodal involvement by dividing stage IIIC in 2 subgroups (C1-C2) in relation to the presence of pelvic or paraortic lymph nodes metastasis respectively [3,45,46]. Another strong prognostic factor is histologic grade, categorized as G1 (well differentiated), G2 (moderately differentiated), or G3 (poorly differentiated or undifferentiated). Histologic grade predicts the spread of disease from the uterus, with higher grade associated with deeper myometrial invasion and lymph node metastases [8]. Also elderly patients have a poorer prognosis compared to their younger counterpart. Serous papillary and clear cell are also considered at high risk, although their optimal adjuvant treatment has not been clearly established. Based on the prognostic factors, early stage endometrial cancer is classified in 3 different risk categories for recurrence. Patients with low-risk tumors are [47] those at stage IA (with no or superficial [50% myometrial invasion) of grade 3 or of non-endometrioid histology; or stage II or III. All other stage I are considered at intermediate risk; this group has further been refined with other genetic factors to define the high-intermediate risk (HIR) group. Patients belonging to the category of intermediate-risk endometrial cancers, identified as high-risk for recurrence according to a gene expression–based risk score, have a significantly increased risk for recurrence compared with those classified as low risk. Alterations in single cancer– related genes, such as the ERB-B2 oncogene and the TP53 tumor suppressor gene, have been associated with decreased progressionfree and overall. For stage I patients who overexpress ERB-B2 (HER-2/neu), there is a significant decrease in 5-year progressionfree survival from 97% to 62%. These findings suggest that gene expression profiling can potentially contribute to the clinical classification and management of intermediate-risk endometrial cancers [48,49,50,110]. According to this classification the majority of patients (85%) with EC belong to low-intermediate risk categories; only 15% have a high-risk profile. ADJUVANT RADIOTHERAPY Traditionally, external beam pelvic radiotherapy (EBRT) has been considered the adjuvant therapy of choice for decades. Adjuvant radiotherapy options include EBRT, vaginal brachytherapy (VBT) and whole-abdomen radiation (WART). Whereas radiation is recognized as a highly effective treatment modality in endometrial cancer, its exclusive role as adjuvant treatment after surgery in clinically early disease is declining. Randomized trials of both pelvic external beam radiation and vaginal vault brachytherapy have been conducted to evaluate their respective contribution. Several studies demonstrate the power of radiotherapy in reducing local recurrence rate and improving progression free survival, however, without any impact on overall survival [51]. In the last two decades, a shift toward the use of more systemic chemotherapy (CT) in addition or instead of radiation has occurred, although few prospective studies have been performed in this field. A change from external beam radiotherapy to the use of brachytherapy has also occurred in the last years, based on randomized trial showing equal efficacy and a better toxicity profile.

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For years, it has been a practice to consider the absence of lymphadenectomy as an indication for adjuvant EBRT [52, 111]. Metastasis to the pelvic and paraaortic lymph nodes is widely recognized as the most important prognostic factor for endometrial cancer. With the recognition of the importance of the status of the regional lymphatics, lymphadenectomy was incorporated into the primary surgical management of women with endometrial cancer. Proponents of the procedure argue that it provides important prognostic information and helps to guide adjuvant treatment planning. In the absence of a lymphadenectomy, decision making for adjuvant therapy remains a challenge, because of the absence of available informations from lymph node status and the poor reliability of pathologic grading. The role of surgical lymph node dissection and adjuvant radiation therapy (RT) in early stage endometrial cancer is no longer clearly defined. The increased use of surgical lymph nodes staging and the perceived “lack of survival advantage” with adjuvant pelvic RT, leads to a wide array of conclusions on who should be treated and, if so, how. A lot of trials examined the impact of lymphadenectomy on the use of adjuvant radiation treatment in women with stage I-II endometrial, suggesting that the performance of this surgical procedure effects the allocation of adjuvant treatment. The effects appear to be most pronounced for women with intermediate risk tumors and suggest that those women who undergo lymphadenectomy are less likely to receive external beam radiation. The broad consensus is that EBRT has to be performed according to risk categories. Actually, there is no role for radiotherapy in early stage low risk disease. For low-risk EC standard treatment is surgery alone, with 95% probability of 5-year recurrence free survival (RFS). In intermediate and high risk EC, four large randomized trials have explored the role of adjuvant EBRT (Table 1) [48,53]. The Norwegian trial, published in 1980, included 540 women with clinical stage I endometrial carcinoma [38]. After hysterectomy and postoperative vaginal brachytherapy (60 Gy to the mucosal surface), patients were randomly assigned to additional EBRT (40 Gy in 2 Gy fractions) or observation. After five years, significant benefit in favour of EBRT+VBT was demonstrated with regard to local relapses (7% vs 2%) without any impact on overall survival (89% vs 91% at 5 years) [54]. The subgroup with grade 3 tumors with deep (>50%) myometrial invasion showed a trend toward improved local control and survival after EBRT (18% vs 27% cancer related deaths); however, there were too few patients in this category to reach statistical significance. These results were confirmed by three other studies: PORTEC1, GOG-99 and ASTEC [49,51,55,56].

Table 1.

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The GOG-99 trial randomized patient with FIGO IA/II G3 tumors to follow–up or pelvic EBRT. This was the only study with lymphadenectomy in the primary treatment. After 2 years, the pelvic recurrence rate in the control arm was 12% and in the radiotherapy arm 3%; this difference did not influence overall survival. In the first Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial, 715 patients with stage I endometrial carcinoma, grade 1 or 2 with deep (50%) myometrial invasion (FIGO IB) or grade 2 or 3 with superficial (50% myometrial invasion [with positive cytology] ) [61]. Superiority for adjuvant chemotherapy over RT alone was not confirmed in an Italian trial [62] in which 345 women with highrisk resected endometrial cancer (IB-III, 65 % stage III) were randomly assigned to six cycles of CAP chemotherapy (cisplatin, doxorubicin and cyclophosphamide) or RT (45 to 50 Gy) following surgery. More grade 3 toxicity was reported in the CAP arm (39% hematologic, 10% nausea/vomiting) than in the EBRT arm (16%, mainly GI toxicity). There were no differences in 5-year OS (69 vs 66%), PFS or response rate. In all these trials a lower rate of distant metastasis was found in patients treated with chemotherapy thus supporting the hypothesis of the usefulness of a combined approach with chemotherapy and radiotherapy, given concurrently or sequentially. Both the last 2 trials were underpowered and there is some concern regarding the dose and schedule of chemotherapy used (low doses of antacyclines, small number of cycles). Ongoing trials are investigating if radiotherapy can be omitted in patients with node negative intermediate-high risk early stage endometrial cancer. The ENGOT en-2 trial is randomizing patients after surgery to receive 6 cycles of carboplatin/paclitaxel chemotherapy or observation [63]. ADJUVANT COMBINED TREATMENT WITH CHEMOTHERAPY AND RADIOTHERAPY Few trials have evaluated the role of chemotherapy in addition to radiotherapy in endometrial cancer. These studies have been performed in a mixed population of high risk patients including stage III; only few randomized trials have been performed and most data come from phase II or retrospective studies that suggest encouraging OS and PFS results in favor of the combined modality [64-72] (Table 2). The largest randomized phase III trial addressing this question is the NSGO-EC-9501/EORTC 55991 [72] study that randomized 372 patients with high-risk endometrial cancer (stage IB, or IB with positive cytology to stage III with positive pelvic nodes only [C1]), grade 3, deep myometrial invasion, DNA non-diploidy, serous, clear-cell, or anaplastic histology) to receive either external beam irradiation with or without vaginal brachytherapy, or radiotherapy plus sequential platinum-based chemotherapy. In the final analysis, there was a significant 36% reduction in the rate of relapse or death with the combined therapy (hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.41–0.99; P = 0.04), and the difference favoring RT– CT was significant also for Cancer Specific Survival (CSS) with HR 0.51 (95% CI 0.28–0.90, p = 0.02); on the other hand, no significant difference was identified in the OS. On the other side, the addition of chemotherapy to adjuvant RT failed to improve overall survival or recurrence free interval in a randomized Finnish

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Randomized Trial of Adjuvant Chemotherapy in Endometrial Carcinoma

Trial [Ref.] Accrual Period

N°, Patients Eligibility

Randomization

Locoregional Recurrence

Overall Survival

Sumusu et al. [61]

385 Stage I-III with > 50% MI (60% stage Ib)

Pelvic RT vs CT (3x CAP)

7% vs 7% P= ns

85% vs 8% P= ns

Maggi et al. [62]

345 stage Ib-II G3 (35%)-III(65%)

Pelvic RT vs CT (5 x CAP)

12% vs 16% P= ns

69% vs 66% P= ns

Randall et al. [60]

396 stage III; IV (28%) (residual 90% of endometrioid and 31% of papillary-serous endometrial carcinomas, whereas clear cell carcinomas typically do not express hormone receptors [81-83]. In addition, the percentage of ER/PgR positive tumors decreases among patients with higher grade disease [81]. Interestingly, ER and especially PgR expression, as well as low grade disease and long interval between initial diagnosis and relapse, predict response to these agents in advanced disease [84,85]. Progesterone’s effects are mediated through interaction with the progesterone receptor (PR), a transcription factor and a member of a large family of structurally related gene products known as the nuclear receptor superfamily [86]. Two isoforms of the progesterone receptor, PRA and PRB, are expressed in the normal endometrium, the alteration of PR isoform expression or loss of total PR leads to hyperplasia and is linked to carcinogenesis [87]. Despite the differentiating effects of progesterone, PR is often lost in advanced endometrial cancer and this phenomenon is associated to a poor prognosis [88]. Several drugs have been used in endometrial cancer, including medroxyprogesterone acetate (MPA), hydroxyl-progesterone-caproate and megestrol acetate. Based on the results obtained by oral medroxyprogesterone acetate and megestrol acetate in advanced and metastatic setting [89], adjuvant progestagen therapy has been advocated following primary surgery to reduce the risk of disease recurrence and prolong survival. In the past, for patients with malignant cytology as the only risk factor for adjuvant treatment, the use of hormonal therapy was embraced as a potential treatment strategy, but there are very few data about this topic without consistent results in favor of hormonal treatment. While patient in early stage and low risk endometrial carcinoma have better survival, an interesting setting to evaluate the effect of progestin therapy is that of patient with high risk of recurrence. A Cochrane review published in 2011 [90] summarizes the main results of seven controlled trials, randomising a total of 4.556 women with endometrial cancer to adjuvant progestagen therapy or follow up after surgery. Three trials included women with stage one disease only, whereas four included women with more advanced disease. Meta-analysis of four trials showed that there was no significant difference in the risk of death at five years between adjuvant progestagen therapy and no further treatment (RR =1.00, 95% CI 0.85 to 1.18). These trials included patients with FIGO stage I disease with all subgroup risk categories and, certainly, the inclusion of a significant proportion of low risk patients could dilute the efficacy of progestagens in more severe cases as suggested by the COSA-NZ-UK 1998 trial showing a nonsignificant benefit for high risk cases. While inclusion of patients with predominantly good prognostic factors might obscure the effects of progestagens on endometrial cancer related deaths, the effects on intercurrent deaths is much less likely to be influenced by

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the severity of the original disease. This review failed to demonstrate that adjuvant progestagen therapy has a significant beneficial effect on survival and it is commonly believed that further trials in this field are probably not justified. As regard of aromatase inhibitors, selective estrogen receptor modulators (SERMs) as tamoxifen, or combined hormonal therapy (tamoxifen with progestins) used in advanced disease [91-93] there are no data related to their efficacy in the adjuvant setting of endometrial cancer. NEW BIOLOGICAL AGENTS POTENTIALLY EFFECTIVE AS ADJUVANT THERAPY IN ENDOMETRIAL CARCINOMA Since both chemotherapy and radiotherapy failed to prolong survival of high risk patients with endometrial carcinoma, the clinical evaluation of novel drugs should be further explored. Recent advances in the understanding of the molecular and genetic basis of cancer have led to the development of targeted therapies that inhibit angiogenesis and the cellular signalling pathways involved in cell growth and proliferation. Most of clinical trials with biological agents are restricted to advanced or metastatic setting. One of the most common defects in endometrioid adenocarcinomas is mutation of the gene encoding the phosphatase and tensin homologue (PTEN), a regulator of the PI3K/AKT/ mammalian target of rapamycin (mTOR) pathway [94] that leads to constitutively activation of AKT with up-regulation of mTOR and of several transcription factors that drive cell growth and proliferation. Tumor suppressor protein PTEN has been reported to be altered in up to 83% of endometrioid carcinomas, whereas serous and clear-cell carcinomas harbor PTEN mutations in just 10% of cases [95-97], PI3KCA mutation is seen in 36% of endometrioid carcinomas and is most common in tumors that also bear the PTEN mutation [98]. Temsirolimus, everolimus, and ridaferolimus, mTOR inhibitors, have shown promising clinical activity, mainly in the form of disease stabilization in chemotherapynaïve patients with advanced, recurrent or metastatic endometrial carcinoma [98,99]. Combinations of mTOR inhibitors with hormonal therapy, chemotherapy or other targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors and antiangiogenic agents have been studied and preclinical evidence is encouraging [100]. Combined therapy with temsirolimus and bevacizumab at the time of initial recurrence of endometrial cancer has showed to be safe at the interim analysis presented at ASCO 2012 [101]. Of note, exposure of endometrial cancer cell lines to an mTOR inhibitor increases progesterone mRNA expression and inhibits ER mRNA expression suggesting a cross-talk between the mTOR pathway and hormone receptor-dependent signal transduction. Another pathway that has recently emerged as a “key” regulator of the process of tumor angiogenesis is that of the vascular endothelial growth factor (VEGF). Increased levels of VEGF in endometrial cancer have been associated with poor prognosis [102]. Preclinical models demonstrate the activity of bevacizumab, a recombinant humanized monoclonal antibody against VEGF, in combination with chemotherapy against endometrial cancer cell lines. Bevacizumab, as well as thalidomide, an older agent with documented antiangiogenic properties, are currently evaluated in early clinical trials in patients with advanced endometrial cancer [103]. Moreover, the combination of bevacizumab with chemotherapeutic agents is currently investigated in a phase II study conducted by the MITO group that randomizes patients to receive paclitaxel plus carboplatin +/bevacizumab as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer. A GOG phase II trial of VEGF-trap in metastatic endometrial cancer is closed and results should be available soon (GOG 229-F) [97]. Small molecular inhibitors of the tyrosine kinase domain of VEGFR have also been evaluated in endometrial carcinoma: A small phase II trial of sorafenib, a tyrosine kinase inhibitor with antiangiogenic activity, has been recently completed in the National Cancer Institute’s phase II network with modest results, while another phase II trial of

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a second antiangiogenic tyrosine kinase inhibitor, sunitinib, is also closed and results are awaited [104]. The epidermal growth factor receptor (EGFR) is commonly expressed in normal endometrium, and its overexpression has been associated with advanced stage and poor clinical outcome [105107]. Inhibitors of EGFR-mediated signal transduction include the monoclonal antibody against EGFR cetuximab and the small molecule tyrosine kinase inhibitors (gefitinib, erlotinib, and lapatinib). HER-2 overexpression and gene amplification have been found in 45% and 70% of serous carcinomas, respectively [108,109] and have been correlated with poor prognosis in advanced endometrial cancer [110]. Although HER-2 overexpression in endometrial carcinoma provides a theoretical rationale for the use of trastuzumab, a GOG study assessing its efficacy in women with HER-2 positive endometrial cancer did not report any activity [50,112]. Unfortunately none of these tested agent, to date, is under investigation as adjuvant treatment of endometrial cancer, although all are promising for the future. CONCLUSION Approximately 70% to 80% of patients with endometrial cancer present with localized disease that potentially can be cured with surgery alone. However, approximately 30 % of the women dying of endometrial cancer was considered to have early-stage locoregional disease at diagnosis. Adjuvant therapy of endometrial cancer is not clearly defined. The main reason for treatment failure after traditional modality-based therapy is the presence of documented or occult extrauterine systemic disease and our inability to recognize and treat it successfully. Adjuvant treatment strategies for endometrial cancer are based on risk factors categories. Patients identified to be at risk for recurrence are usually managed with adjuvant pelvic radiotherapy, brachytherapy, and chemotherapy. A shift toward the use of more chemotherapy instead of radiotherapy has occurred and many trials are exploring the role of combined treatment with both modalities, given concurrently or sequentially. We think it's worth mentioning that although endometrial cancer is one of the most common gynecological cancer, it is severely under-represented in clinical research. Also, the results of clinical trial are poorly translated in the clinical practice; an example regards the use of paclitaxel still not reimbursed in many European countries. A better understanding of the molecular aspects of endometrial cancer may either help to select the patients that can benefit from adjuvant therapy and to prompt clinical research with new targeted antineoplastic agents.

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CONFLICT OF INTEREST The author(s) confirm that this article content has no conflict of interest.



ACKNOWLEDGEMENTS Thanks to Dr Pignata for his precious support. The authors thank Dr A. Trocino, librarian of e National Cancer Institute of Naples “G. Pascale” for the bibliography assistanceand Mrs Balbina Apice and Antonietta Linardi, for editing assistance.

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Received: August 07, 2012

Revised: October 03, 2012

Accepted: October 03, 2012

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