Current Treatment Approach of Endometrial Cancer

Introduction

The most common malignancy of the female genital tract, is endometrial cancer (EC) [1]. It mainly occurs in postmenopausal women.[1-4] Overall, 2.64% of women will develop EC during their lifetime [1]. The most common symptom in patients with EC is abnormal uterine bleeding [2].

Based on clinical and pathological characteristics, sporadic EC classified into 2 types [5,6]. Type I EC, constitutes the majority of sporadic EC cases (70-80%) [5,6]. It is well differentiated, endometrioid in histology, has less aggressive clinical course and favorable prognosis [5-7]. Type II EC, constitutes the minority of sporadic EC cases (10-20%) [5,6]. It is poorly differentiated, papillary serous or clear cell in histology, has aggressive clinical course and poor prognosis [5,6,8,9].

Surgical Treatment

Systematic surgical staging is the primary treatment, for most patients with EC [2-4], 10-15] That therapeutic approach allows a clearer decision for the appropriate postoperative adjuvant therapy [Figure 1] [11].

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Figure 1. Endometrial cancer treatment [2- 4, 11- 13, 15, 30, 33, 40, 42, 44, 51, 54].

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In patients with EC, systematic surgical staging includes: total hysterectomy, bilateral salpingo-oophorectomy, pelvic and paraaortic lymphadenectomy and complete resection of all disease [2,11,13,14] Especially in patients with type II EC, systematic surgical staging includes additional omentectomy, appendectomy and biopsy of any suspected lesion [14,16]. Although pelvic washings are no longer part of FIGO surgical staging system for EC, they should be reported separately [12].

Appropriate surgical staging has diagnostic, prognostic and therapeutic advantages for women with EC [2-4,11]. Moreover, it facilitates the implementation of targeted therapy maximizing the survival and minimizing the morbidity of overtreatment (radiation injury) and the effects of undertreatment (recurrent disease, increased mortality) [11].

Pelvic and para-aortic lymphadenectomy is very important for the surgical staging in patients with EC [3, 4, 10, 11, 13]. It identifies precisely the extent of the disease and affects the prognosis of EC patients [10, 14, 17]. Actually, it is the only way to diagnose EC patients with stage IIIc disease [11, 12,2, 18, 19]. Undoubtedly, it provides important informations for the need, type and extent of postoperative adjuvant treatment [10, 14, 17, 20].

Furthermore, pelvic and para-aortic lymphadenectomy has significant therapeutic advantages for patients with EC [21-23]. It is correlated with enhanced survival in patients with advanced stage type I EC and in all patients with type II EC [2, 21, 22, 24, 25]. However, it has no survival effect in patients with early stage type I EC [2, 13, 26, 27].

It appears that pelvic and para-aortic lymphadenectomy can be avoided safely in patients with early stage well differentiated type I EC [11, 26-29]. However pelvic and para-aortic lymphadenectomy should be performed in patients with advanced stage type I EC and in all patients with type II EC [3, 4, 24, 30, 31]. Also in any case of doubt, lymphadenectomy should be performed rather than avoided [3, 4, 30].

The extent of pelvic and para-aortic lymph node dissection (more than 14 lymph nodes) is an independent risk factor for postoperative complications [26, 29,32]. Especially in elderly patients and in patients with various comorbidities (obesity, diabetes, coronary artery disease), intraoperative and postoperative morbidity must be carefully weighed against any survival advantage [11, 32-34].

In most EC patients, systematic surgical staging performed with laparotomy [14, 35, 36]. Especially in EC patients with early stage disease, systematic surgical staging can be performed with minimally invasive techniques (laparoscopy, robotic-assisted surgery) [2, 11, 13, 14, 35-38].

Minimally invasive surgery associated with smaller incisions, improved visualization, shorter hospital stay, less need for analgesics, quicker recovery and lower risk of complications (blood loss, wound infection, herniation, ileus) [11, 13, 14, 35-38]. Especially in overweight and elderly patients, minimally invasive surgery associated with significant advantages [11, 35-39]. Compared minimally invasive surgery and laparotomy, there are relatively small differences in recurrence rates [35, 36]. However, minimally invasive surgery and laparotomy associated with similar overall and disease-free survival [13, 14, 35, 36]

Adjuvant Treatment

Especially in EC patients with increased risk for recurrence or at advanced stage disease, it is necessary a more aggressive treatment approach with postoperative adjuvant radiotherapy and/or chemotherapy [Figure 1] [2, 10, 14, 15, 30].

Radiotherapy

Postoperative adjuvant radiotherapy in EC patients includes vaginal brachytherapy and external radiotherapy [Figure 1] [14, 40].

Vaginal brachytherapy in EC patients with early stage disease is well tolerated, reduces the risk of local recurrences but has no impact on overall survival [40-43]. Furthermore, it is associated with less side effects and better quality of life [40-43]. It is the adjuvant treatment of choice for intermediate risk EC patients (stage IA grade 3 endometrioid type EC, stage IB grade 1-2 endometrioid type EC) [Figure 1] [14, 40-42, 44-46].

Especially for intermediate risk EC patients, vaginal brachytherapy is equivalent to external pelvic radiotherapy in achieving local control of disease [14, 40, 41, 44, 45]. Moreover vaginal brachytherapy in those EC patients, have significant advantages in the quality of life [14, 40, 41, 44, 45].

External pelvic radiotherapy in EC patients with early stage disease, reduces the risk of local recurrences but has no impact on overall survival [11, 40- 42, 47, 48]. Nevertheless, it is associated with significant morbidity and reduction in quality of life [41, 47]. It is the adjuvant treatment of choice only in high risk EC patients (stage IB grade 3 endometrioid type EC, stage I non-endometrioid type EC) [Figure 1] [14, 43-45].

In EC patients with advanced stage disease, although external pelvic radiotherapy reduces the risk of local recurrences it has no impact on overall survival [11, 40, 44].

Whole abdomen radiotherapy in EC patients with advanced stage disease, has tolerable toxicity and may improve survival [49]. Nevertheless, it can be used only in patients with completely resected disease [49].

Chemotherapy

Postoperative adjuvant chemotherapy has very important role for EC patients with advanced stage disease [Figure 1] [2, 10, 14, 40, 50, 51]. The most active chemotherapeutic agents for EC patients with advanced stage disease, are: taxanes, anthracyclines and platinum compounds [50, 52].

Adjuvant chemotherapy has only modest effect in progression free survival and overall survival, although it achieves high response rates [50]. Furthermore in EC patients with advanced stage disease, adjuvant chemotherapy is more effective than whole abdomen radiotherapy [30, 53].

Chemotherapy and Radiotherapy

The combination of adjuvant chemotherapy and radiotherapy is promising in high risk EC patients or in EC patients at advanced stage disease [Figure 1] [40,50, 54]. Especially in EC patients with completely resected disease, the combination of adjuvant chemotherapy and radiotherapy reduce the risk of relapse or death and increase overall survival [14, 40, 55]. Furthermore, the combination of adjuvant chemotherapy and radiotherapy is more effective than adjuvant radiotherapy alone [40, 50, 55].

Molecular Targeted Therapies

In recent years, molecular targeted therapies have only modest effect in unselected EC patients [50]. They usually target the signaling pathways of EGFR, VEGFR and PI3K/PTEN/AKT/ mTOR [56-58].

Especially the role of ErbB-targeted therapies in selected EC patients, should be further investigated in clinical trials [15, 58-68]. Perhaps ErbB-targeted therapies may be used as adjuvant treatment in type II EC patients with EGFR and ErbB-2 overexpression [15, 59, 65, 67-69]. Moreover further studies into the molecular pathways of EC, may increase our knowledge and lead to the discovery of new generation molecules with greater therapeutic efficacy [63].

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