**3. Management of endometrial cancer**

The primary treatment of endometrial cancer is surgical. Following tissue diagnosis, most patients are offered surgical staging. Routine preoperative work-up includes complete blood count, serum electrolytes/ creatinine, liver function tests, urinalysis, and a CXR. Further evaluation with CT/MRI/PET-CT (with or without CA-125) may be performed, if extrauterine disease is suspected on initial assessment. In patients with suspected cervical involvement, MRI or cervical biopsy may be helpful to confirm the diagnosis (Akin et al. 2007).

## **3.1 Surgical staging and related issues**

In 1988 the FIGO staging committee replaced the clinical staging system for endometrial cancer with a surgical staging system. This transition from clinical to surgical staging was mainly due to the seminal findings of a large gynecologic oncology group trial (GOG 33), which evaluated the surgical-pathologic patterns in apparent early stage endometrial cancer with particular emphasis on pelvic and para-aortic lymph node involvement (Creasman et al. 1987). A significant number (25%) of patients with clinical stage I in this study were found to have extrauterine disease upon comprehensive surgical staging.

The 1988 FIGO staging system was recently modified (Pecorelli et al. 2009). These two staging criteria are shown in Tables 1 and 2 respectively.


Table 1. 1988 FIGO Surgical Staging for Endometrial Cancer.


Table 2. 2009 FIGO Surgical Staging for Endometrial Cancer.

The primary treatment of endometrial cancer is surgical. Following tissue diagnosis, most patients are offered surgical staging. Routine preoperative work-up includes complete blood count, serum electrolytes/ creatinine, liver function tests, urinalysis, and a CXR. Further evaluation with CT/MRI/PET-CT (with or without CA-125) may be performed, if extrauterine disease is suspected on initial assessment. In patients with suspected cervical involvement, MRI or cervical biopsy may be helpful to confirm the diagnosis

In 1988 the FIGO staging committee replaced the clinical staging system for endometrial cancer with a surgical staging system. This transition from clinical to surgical staging was mainly due to the seminal findings of a large gynecologic oncology group trial (GOG 33), which evaluated the surgical-pathologic patterns in apparent early stage endometrial cancer with particular emphasis on pelvic and para-aortic lymph node involvement (Creasman et al. 1987). A significant number (25%) of patients with clinical stage I in this study were

The 1988 FIGO staging system was recently modified (Pecorelli et al. 2009). These two

found to have extrauterine disease upon comprehensive surgical staging.

**Stage IB G123 Invasion to less than half of the myometrium** 

**Stage IIA G123 Endocervical glandular involvement only** 

**inguinal lymph nodes** 

**Stage IA G123 Invasion to less than half of the myometrium** 

**Stage IVA G123 Tumor invasion of bladder and/or bowel mucosa** 

**inguinal lymph nodes** 

**Stage IB G123 Invasion equal to or more than half of the myometrium** 

Table 1. 1988 FIGO Surgical Staging for Endometrial Cancer.

**Stage IIIA G123 Tumor invades serosa and/or adnexa** 

**Stage IIIC1 G123 Metastasis to pelvic lymph nodes Stage IIIC2 G123 Metastasis to para-aortic lymph nodes** 

Table 2. 2009 FIGO Surgical Staging for Endometrial Cancer.

**Stage IC G123 Invasion equal to or more than half of the myometrium** 

**Stage IIIC G123 Metastasis to pelvic and/or para-aortic lymph nodes Stage IVA G123 Tumor invasion of bladder and/or bowel mucosa** 

**Stage IIIA G123 Tumor invades serosa and/or adnexa and/or positive peritoneal** 

**Stage IVB G123 Distant metastasis including intra-abdominal metastasis and/or** 

**Stage IVB G123 Distant metastasis including intra-abdominal metastasis and/or** 

staging criteria are shown in Tables 1 and 2 respectively.

**Stage IIB G123 Cervical stromal invasion** 

**Stage II G123 Cervical stromal invasion** 

**Stage IIIB G123 Vaginal metastasis** 

**Stage IIIB G123 Vaginal metastasis** 

**cytology** 

**Stage IA G123 Tumor limited to the endometrium** 

**3. Management of endometrial cancer** 

**3.1 Surgical staging and related issues** 

(Akin et al. 2007).

The current standard surgical staging procedure includes total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, peritoneal washings for cytology, and meticulous exploration of the abdomen and pelvis with biopsy of any suspicious lesions (NCCN guidelines for uterine neoplams, V.2.2011) (NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Uterine Neoplasms V.2.2011. © 2011 National Comprehensive Cancer Network). This procedure has been shown feasible by laparoscopy. In LAP-2 trial; the pelvic and para-aortic lymph nodes were obtained in 96% patients undergoing laparotomy compared to 92% of those who had laparoscopy (p<0.001). The detection rate of advanced stage was also comparable between the groups (17% vs. 17%, p=0.841) (Walker et al. 2009).

GOG 33 identified that depth of myometrial invasion, and tumor grade were predictive of lymph node metastasis (Creasman et al. 1987) and that all were predictive of recurrence. The preoperative and intra-operative evaluation of these high-risk features is often inaccurate, and surgical staging is therefore recommended in most patients diagnosed with endometrial cancer (NCCN guidelines for uterine neoplasms, V.2.2011).

The preoperative tumor grade was upgraded on final pathology in approximately 18% patients in different studies (Goudge et al. 2004) (Ben-Shachar et al. 2005). Neither imaging nor frozen section is very accurate for assessing the depth of myometrial invasion. In a recent study by Case et al, concordance between frozen and final pathology was noted only in 67% patients for depth of myometrial invasion and 58% patients for tumor grade (Case et al. 2006). The sensitivity of MRI has similarly been found to be only 54%-75% in this regard (Hricak et al. 1991; Nakao et al. 2006).

The use of imaging (CT, MRI, and PET-CT) has been evaluated for the pre-operative assessment of lymph node metastasis in endometrial cancer. Park et al showed that the sensitivity and specificity of MRI and PET-CT was only modest (46% and 88%; and 69% and 90%, respectively) (Park et al. 2008). Palpation of lymph nodes is also not reliable, with a false negative rate of over 35% in some studies (Girardi et al. 1993; Arango et al. 2000). Intra-operative frozen section evaluation was found to miss nearly 2/3rds of endometrial cancer patients with positive lymph nodes, in a recent study (Pristauz et al. 2009).

Several retrospective studies have shown an improvement in survival following pelvic and para-aortic lymphadenectomy (Kilgore et al. 1995; Mohan et al. 1998; Trimble et al. 1998; Cragun et al. 2005; Chan et al. 2006). In contrast, no survival benefit could be demonstrated in either of the two recent prospective randomized controlled trials (Kitchener et al. 2009; Panici et al. 2008). The ASTEC trial recruited 1,408 women with early stage endometrial cancer from 85 centers across four countries (U.K., Poland, New Zealand, and South Africa) (Kitchener et al. 2009). These women were randomized to undergo surgery either with or without lymphadenectomy. To control for postsurgical treatment, women with intermediate or high risk of recurrence were randomized into the ASTEC radiotherapy trial. No survival benefit was observed from pelvic lymphadenectomy in this trial. The 5-year overall survival was 81% in the surgery only group and 80% in the surgery plus lymphadenectomy group (HR: 1.04, CI: 0.74-1.45, p=0.83). The corresponding 5-year recurrence free survival was 79% and 73%, respectively (HR: 1.25, CI: 0.93-1.66, p=0.14). In another randomized study from Italy, 514 patients with preoperative FIGO stage I endometrial carcinoma were evaluated (Panici et al. 2008). At a median follow-up of 49 months, the rates of disease free survival (81.0% vs. 81.7%, HR: 1.20, CI: 0.75-1.91) and overall survival (85.9% vs. 90.0%; HR: 1.16, CI: 0.67-2.02) were not significantly different between the lymphadenectomy and the nolymphadenectomy arms. Although, these trials have been criticized for various shortcomings (Amant et al. 2009; Uccella et al. 2009; Uccella et al. 2009); they constitute level one evidence and indicate that lymphadenectomy by itself does not provide survival advantage in endometrial cancer.

The morbidity associated with surgical staging has been reported in several studies (Moore et al. 1989; Larson and Johnson 1993; Franchi et al. 2001). In a study of 168 patients with endometrial cancer; the short term complications after complete surgical staging included fever (31.5%), surgical site infection (4.7%), embolic events (1.3%), and death (0.7%). The late complications in this series were leg edema (0.7%), intestinal obstruction (0.7%), and lymphocysts (1.3%) (Larson et al. 1993). In another study by Cragun et al, adverse events were noted in 18% patients. The most common complications were illeus (2.6%), deep venous thrombosis (2.6%), lymphocysts (2.4%), and small bowel obstruction (1.8%) (Cragun et al. 2005). The postoperative morbidity after surgical staging was significantly less in patients undergoing laparoscopy compared to those who had the procedure performed via laparotomy (14% vs. 21%, p<0.001) in the LAP-2 trial (Walker et al. 2009). To further limit the morbidity associated with complete lymph node dissection; sentinel lymph node detection is being evaluated in endometrial cancer (Gien et al. 2005; Delaloye et al. 2007; Frumovitz et al. 2007). Though controversial worldwide, FIGO staging remains the standard at this time as it allows for more accurate post surgical treatment.
