**2. The role of surgery in management of endometrial cancer:**

Despite the vast majority of patients diagnosed with endometrial cancer present to clinical attention with early stage disease limited to uterus, metastatic disease is recognized in a substantial proportion when comprehensive surgical staging is carried out [9]. In 1988, the International Federation of Gynecologists and Obstetricians (FIGO) officially suggested surgical staging as part of the primary management plan for endometrial cancer. Despite the recent amendments of the staging system in 2009, comprehensive staging (total hysterectomy, bilateral salpingooophorectomy, peritoneal cytology, intraoperative bilateral pelvic and paraaortic lymph node dissection) continue to be recommended [10-12].

The major advantages of comprehensive surgical staging are directly related to the diagnosis, prognosis, and proper categorization of patients who may benefit from adjuvant therapy. FIGO endometrial cancer staging is chiefly based on surgical pathology and comprehensive surgery permits accurate delineation of disease extent.

#### **2.1. The role of laparotomy, conventional laparoscopy and robotic-assisted laparoscopy in management of endometrial cancer**

Conventionally, laparotomy has been the primary mode for surgical staging in patients with endometrial cancer [10-12].

However, several studies examined the practicality of minimally invasive approaches such as laparoscopy for surgical staging of endometrial cancer [13,14].

Afterwards, randomized controlled trials endeavored to compare laparotomy versus conven‐ tional laparoscopic approaches. In Gynecologic Oncology Group Study (GOG) LAP2, more than 2000 patients with endometrial cancer were randomized to receive comprehensive surgical staging via conventional laparoscopy or laparotomy [15]. Conventional laparoscopic arm experienced fewer post-surgery complications (14% vs 21%, respectively; p=0.0001), shorter hospitalization rates over 2 days (52% vs 94%, respectively; p=0.0001), however, longer operating periods (204 minutes vs 130 minutes, respectively; p=0.001). The incidence of intraoperative adverse events was similar. Operative conversion from conventional laparo‐ scopy to laparotomy happened in roughly 17.5% of patients with body mass index (BMI) of 25, and 26.5% of patients with BMI of 35 and above, mainly due to poor surgical exploration. Over the 6-week recovery period, the conventional laparoscopic arm patients articulated much higher scores on multiple quality-of-life aspects (less pain, more cosmetics, faster resumption of daily and social activities) [16].

A recently published meta-analysis of survival data compiling 3 randomized controlled clinical trials did identify survival differences between the surgical approaches in patients receiving the conventional laparoscopy and laparotomy for surgical staging of endometrial cancer [17]. A secondary survival analysis showed largely comparable 5-year overall survival rate (around 90% in both groups) and 3-year recurrence rate (around 11% vs 10% in conven‐ tional laparoscopy and laparotomy groups, respectively). Based on these findings, it was concluded that conventional laparoscopic approach was not inferior to laparotomy for surgical staging of endometrial cancer [15,18]. Rather, it was concluded that conventional laparoscopic surgical management of endometrial cancer is superior to laparotomy in terms of hospital stay and short-term safety with comparable overall survival and free-recurrence rates. Hence, conventional laparoscopy ―whenever technically possible― should be considered as the recommended (primary) approach for comprehensive surgical staging in management of patients with endometrial cancer.

**2. The role of surgery in management of endometrial cancer:**

aortic lymph node dissection) continue to be recommended [10-12].

surgery permits accurate delineation of disease extent.

laparoscopy for surgical staging of endometrial cancer [13,14].

**management of endometrial cancer**

of daily and social activities) [16].

endometrial cancer [10-12].

158 Contemporary Gynecologic Practice

Despite the vast majority of patients diagnosed with endometrial cancer present to clinical attention with early stage disease limited to uterus, metastatic disease is recognized in a substantial proportion when comprehensive surgical staging is carried out [9]. In 1988, the International Federation of Gynecologists and Obstetricians (FIGO) officially suggested surgical staging as part of the primary management plan for endometrial cancer. Despite the recent amendments of the staging system in 2009, comprehensive staging (total hysterectomy, bilateral salpingooophorectomy, peritoneal cytology, intraoperative bilateral pelvic and para-

The major advantages of comprehensive surgical staging are directly related to the diagnosis, prognosis, and proper categorization of patients who may benefit from adjuvant therapy. FIGO endometrial cancer staging is chiefly based on surgical pathology and comprehensive

**2.1. The role of laparotomy, conventional laparoscopy and robotic-assisted laparoscopy in**

Conventionally, laparotomy has been the primary mode for surgical staging in patients with

However, several studies examined the practicality of minimally invasive approaches such as

Afterwards, randomized controlled trials endeavored to compare laparotomy versus conven‐ tional laparoscopic approaches. In Gynecologic Oncology Group Study (GOG) LAP2, more than 2000 patients with endometrial cancer were randomized to receive comprehensive surgical staging via conventional laparoscopy or laparotomy [15]. Conventional laparoscopic arm experienced fewer post-surgery complications (14% vs 21%, respectively; p=0.0001), shorter hospitalization rates over 2 days (52% vs 94%, respectively; p=0.0001), however, longer operating periods (204 minutes vs 130 minutes, respectively; p=0.001). The incidence of intraoperative adverse events was similar. Operative conversion from conventional laparo‐ scopy to laparotomy happened in roughly 17.5% of patients with body mass index (BMI) of 25, and 26.5% of patients with BMI of 35 and above, mainly due to poor surgical exploration. Over the 6-week recovery period, the conventional laparoscopic arm patients articulated much higher scores on multiple quality-of-life aspects (less pain, more cosmetics, faster resumption

A recently published meta-analysis of survival data compiling 3 randomized controlled clinical trials did identify survival differences between the surgical approaches in patients receiving the conventional laparoscopy and laparotomy for surgical staging of endometrial cancer [17]. A secondary survival analysis showed largely comparable 5-year overall survival rate (around 90% in both groups) and 3-year recurrence rate (around 11% vs 10% in conven‐ tional laparoscopy and laparotomy groups, respectively). Based on these findings, it was concluded that conventional laparoscopic approach was not inferior to laparotomy for surgical

The daVinci Surgical System (Intuitive Surgical, Sunnyvale, CA) is widely used by many gynecologic oncologists and designed to facilitate robotic-assisted laparoscopy. Despite the many benefits (seated and long-distance operating setting, three-dimensional image of surgical field, tremor omission, etc), one of the major disadvantages is lack of haptic feedback [2].

There are multiple published retrospective case series studies that journeyed to explore the use of robotic-assisted laparoscopy for comprehensive surgical staging of endometrial cancer [19,20]. Primary results showed that robotic-assisted laparoscopy was feasible and safe (highly governed by hands-on surgical expertise). Unfortunately, robotic-assisted laparoscopy has not been prospectively compared in randomized controlled trials to conventional laparoscopy for evaluating the efficacy of endometrial cancer surgical staging, and hence data about survival, safety, and performance differences are lacking. Nevertheless, current literature data point out that robotic-assisted laparoscopy has advantages closely comparable to conventional laparo‐ scopy. Moreover, over time, technical expertise can be simply acquired with robotic assistance as compared to conventional laparoscopy, and thus enabling the achievement of complete comprehensive staging of endometrial cancer in the obese and morbidly obese patients, as laparotomy possesses high potential adverse events in such populations [21]. For communities concerned about financial matters, cost differences between surgical approaches for staging endometrial cancer has been reported [22]. Laparotomy was the most expensive, followed by robotic-assisted laparoscopy, and followed by conventional laparoscopy.

Port-site tumor implantation taking place in patients undergoing minimally invasive laparo‐ scopic techniques for gynecologic cancers is always a major concern for many patients and surgeons [10]. Generally speaking, the incidence of port-site tumor metastatic deposits following laparoscopic procedures in patients with malignant cancer is very minimal, and mostly takes place in the setting of already locally widely spread intra-abdominal disease or distant metastatic disease [23]. Precisely, the risks of port-site tumor implantation in patients with early-stage endometrial cancer following laparoscopic procedures (conventional or robotic-assisted approaches) are very low (less than 1%) [24]. Therefore, minimally invasive laparoscopic techniques can be used safely, to a greater degree, in patient with early-stage disease.

#### **2.2. The role of lymphadenectomy in management of endometrial cancer**

The issue of bilateral pelvic and para-aortic lymphadenectomy for surgical staging of endo‐ metrial cancer remains a topic of argument [10, 25-27]. Although lymphadenectomy is required for accurate staging, lymphadenectomy should generally be considered in patients with high risk for lymph nodal involvement [28-31]. Such risk factors include: tumor grade 3 (poorly differentiated), more than 50% of myometrial invasion, lymphovascular space invasion, nonendometrioid histology (serous, clear cell, undifferentiated, small cell, anaplastic, etc), cervical stromal involvement, advanced FIGO stage (III and IV), and older age (above 60 years) [28].

Several randomized controlled clinical trials demonstrated no survival benefits from system‐ atic lymphadenectomy in patients with early-stage and low-risk endometrial cancer. Benedetti Panici and colleagues [25] explored the effect of systematic lymphadenectomy in patients with stage I endometrial cancer and documented no difference in overall survival (90% vs. 86%) and disease-free survival (80% vs. 82%) rates between lymphadenectomy and no lymphade‐ nectomy arms. Moreover, the ASTEC trial from United Kingdom [26] studied approximately 1400 patients with endometrial cancer limited to uterus, and showed no recurrence-free or overall survival benefits from pelvic lymphadenectomy in patients with early-stage endome‐ trial cancer. Another randomized clinical trial from Italy [25] reported no difference in rates of survival or recurrence between patients who underwent lymphadenectomy versus who did not undergo lymphadenectomy for early-stage endometrial cancer. Furthermore, 2 cohort studies showed that patients with low-risk endometrial cancer disease (neoplasm size ≤2 cm, less than 50% myometrial invasion, grade 1 and 2 endometrioid neoplasms) had no lympha‐ denopathy at time of surgical staging and did not gain advantage from systematic lympha‐ denectomy [30, 31]. Collectively, these data suggest no therapeutic benefit of lymphadenectomy in patients with early-stage and low-risk endometrial cancer.

Bristow and associates [32] conducted a retrospective cohort study examining 41 patients with advanced stage IIIC endometrial cancer, and found statistically significant disease-specific survival benefit of 37.5 months versus 8.8 months (p=0.006) between patients who received optimal (completely debulked) lymphadenectomy and patients who received suboptimal lymphadenectomy groups. They concluded that patients with stage IIIC endometrial carcino‐ ma, complete debulking of gross nodal disease and subsequent administration of combined adjuvant radiation therapy and chemotherapy are correlated with improved disease-specific survival.

There are continuing disputes regarding whether to perform complete bilateral para-aortic lymphadenectomy in all patients. Positive para-aortic lymph nodes can occur in the absence of pelvic lymphadenopathy [30, 33]. Abu-Rustum and colleagues [33] identified 1.6% rate of para-aortic lymphadenopathy in 734 patients with negative pelvic lymphadenopathy and lowand high-grade endometrial cancer. As such, the current practice is to perform pelvic lym‐ phadenectomy, in addition to para-aortic lymphadenectomy, or to propose sentinel lymph node mapping [34, 35]. Khoury-Collado and partners [34] evaluated a sum of 266 patients with endometrial cancer for lymph node mapping. Sentinel lymph node recognition was positive in 223 patients (84%). The utility of sentinel lymph node mapping may surface as a plausible suggestion to decide whether patients with early stage endometrial cancer will get advantage from pelvic and/or para-aortic lymph node evaluation.

Other studies recommend that para-aortic lymphadenectomy should be offered to patients with advanced stage and high-risk histopathological endometrial cancer [29-32]. Mariani and colleagues [30] explored 281 patients who had lymphadenectomy at the time of endometrial cancer staging and identified that approximately 22% of high-risk patients had lymph node invasion. Of these, roughly 33% had isolated pelvic lymphadenopathy, 16% had isolated paraaortic lymphadenopathy and 51% had both pelvic and para-aortic lymphadenopathy.

Although straightforward disease-free survival and overall survival benefits of pelvic and para-aortic lymphadenectomy have not been solidly reported, the procedure of lymphade‐ nectomy offers accurate staging of endometrial cancer, and recognizes node-positive patients who may benefit from adjuvant treatment.

## **2.3. The role of "Cytoreduction" in management of recurrent endometrial cancer**

differentiated), more than 50% of myometrial invasion, lymphovascular space invasion, nonendometrioid histology (serous, clear cell, undifferentiated, small cell, anaplastic, etc), cervical stromal involvement, advanced FIGO stage (III and IV), and older age (above 60 years) [28]. Several randomized controlled clinical trials demonstrated no survival benefits from system‐ atic lymphadenectomy in patients with early-stage and low-risk endometrial cancer. Benedetti Panici and colleagues [25] explored the effect of systematic lymphadenectomy in patients with stage I endometrial cancer and documented no difference in overall survival (90% vs. 86%) and disease-free survival (80% vs. 82%) rates between lymphadenectomy and no lymphade‐ nectomy arms. Moreover, the ASTEC trial from United Kingdom [26] studied approximately 1400 patients with endometrial cancer limited to uterus, and showed no recurrence-free or overall survival benefits from pelvic lymphadenectomy in patients with early-stage endome‐ trial cancer. Another randomized clinical trial from Italy [25] reported no difference in rates of survival or recurrence between patients who underwent lymphadenectomy versus who did not undergo lymphadenectomy for early-stage endometrial cancer. Furthermore, 2 cohort studies showed that patients with low-risk endometrial cancer disease (neoplasm size ≤2 cm, less than 50% myometrial invasion, grade 1 and 2 endometrioid neoplasms) had no lympha‐ denopathy at time of surgical staging and did not gain advantage from systematic lympha‐ denectomy [30, 31]. Collectively, these data suggest no therapeutic benefit of

lymphadenectomy in patients with early-stage and low-risk endometrial cancer.

from pelvic and/or para-aortic lymph node evaluation.

survival.

160 Contemporary Gynecologic Practice

Bristow and associates [32] conducted a retrospective cohort study examining 41 patients with advanced stage IIIC endometrial cancer, and found statistically significant disease-specific survival benefit of 37.5 months versus 8.8 months (p=0.006) between patients who received optimal (completely debulked) lymphadenectomy and patients who received suboptimal lymphadenectomy groups. They concluded that patients with stage IIIC endometrial carcino‐ ma, complete debulking of gross nodal disease and subsequent administration of combined adjuvant radiation therapy and chemotherapy are correlated with improved disease-specific

There are continuing disputes regarding whether to perform complete bilateral para-aortic lymphadenectomy in all patients. Positive para-aortic lymph nodes can occur in the absence of pelvic lymphadenopathy [30, 33]. Abu-Rustum and colleagues [33] identified 1.6% rate of para-aortic lymphadenopathy in 734 patients with negative pelvic lymphadenopathy and lowand high-grade endometrial cancer. As such, the current practice is to perform pelvic lym‐ phadenectomy, in addition to para-aortic lymphadenectomy, or to propose sentinel lymph node mapping [34, 35]. Khoury-Collado and partners [34] evaluated a sum of 266 patients with endometrial cancer for lymph node mapping. Sentinel lymph node recognition was positive in 223 patients (84%). The utility of sentinel lymph node mapping may surface as a plausible suggestion to decide whether patients with early stage endometrial cancer will get advantage

Other studies recommend that para-aortic lymphadenectomy should be offered to patients with advanced stage and high-risk histopathological endometrial cancer [29-32]. Mariani and colleagues [30] explored 281 patients who had lymphadenectomy at the time of endometrial cancer staging and identified that approximately 22% of high-risk patients had lymph node

Around 25% of endometrial cancer related mortality is primarily due to recurrent disease [6, 36, 37]. More than half of patients with endometrial cancer experience recurrence following the initial surgical treatment [38]. Recurrence rates can be as low as 15% in early-stage disease and benign pathology, and as high as 50% in late-stage disease and aggressive pathology [39-41]. Prognosis of patients with recurrent disease and peritoneal metastasis is very graving (median survival less than 12 months) [42, 43]. Optimal Surgical debulking (whenever feasible), even with multiple recurrences, is the standard of care followed with adjuvant radiotherapy, chemotherapy or hormonal therapy [43].

Bristow and associates [44] reported a cohort of 61 patients undergoing cytoreduction for recurrent endometrial cancer. Optimal cytoreduction (no gross residual disease) was achieved in 66% of patients and yielded longer median recurrence-free survival rates of 39 months as opposed to patients with suboptimal cytoreduction of only 13 months (p=0.0005).

Awtrey and partners [45] reported a cohort of 27 patients undergoing cytoreduction for recurrent endometrial cancer. Optimal cytoreduction (no gross residual disease) and subop‐ timal cytoreduction (less than 2 cm residual disease) was achieved in roughly 56% and 67% of patients, respectively, and, yielded longer median survival rates (43 months vs. 10 months, respectively; p< 0.05).

In the above-mentioned two studies, the absence of residual disease was correlated with improved disease-free survival and overall survival rates [44, 45]. Collectively, Barlin and colleagues [46] conducted a meta-analysis and showed that optimal cytoreduction to no macroscopic disease was correlated with overall survival benefits ranging from 9 to 25 months in patients with recurrent endometrial cancer.

#### **2.4. The role of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in management of recurrent endometrial cancer**

The utilization of hyperthermic intraperitoneal chemotherapy (HIPEC) has yielded signifi‐ cantly substantial improvements in disease-free survival and overall survival rates in patients with peritoneal recurrence from pseudomyxoma peritonei [47], colon cancers [48], gastric cancers [49] and ovarian cancers [50]. Its use in management of recurrent endometrial cancer is minimal and has not gained much popularity.

Bakrin and colleagues [43] studied the combination of cytoreduction and HIPEC in 5 patients with recurrent endometrial cancer. Optimal cytoreduction was achieved in all patients. HIPEC was carried out with mitomycin C and cisplatin. Intraoperative and postoperative adverse events were uneventful. Two patients developed early recurrences at 2 and 10 months and both died afterwards. The remaining three patients were alive and disease-free at 7, 23 and 39 months with fair performance status.

Abu-Zaid and colleagues [51] studied the combination of cytoreduction and HIPEC in 2 and 4 patients with primary advanced and recurrent endometrial cancer, respectively. Optimal cytoreduction was achieved in 5 patients. HIPEC was carried out with doxorubicin and cisplatin. Intraoperative and postoperative adverse events were uneventful. All patients received adjuvant chemotherapy (carboplatin and paclitaxel). Despite optimal debulking, one patient with an aggressive histology (clear cell carcinoma) relapsed within 6 months and died 5 months later because of metastatic spread to liver and pelvis. One patient with suboptimal cytoreduction (more than 2 cm residual disease) developed liver recurrence within 3 months and was still alive with disease at a follow-up of 6 months. The remaining patients were alive and disease-free without recurrence at follow-up at 35, 34, 19, and 7 months.

Another study done in France [52] included 13 patients treated with cytoreduction and HIPEC for management of endometrial cancer with peritoneal metastases. One patient was lost to follow-up. Following HIPEC, three patients died before the first year, and two patients approximately died at first year and first year and half, respectively. Three patients were alive with disease, and 4 patients were alive without disease, between approximately 2 and 125 months period.

In the above-mentioned studies, disease-free survival and overall survival rates were largely affected by degree of peritoneal cancer index, cytoreduction completeness and tumor pathol‐ ogy [43, 51, 52].

Despite promising results, almost all the existing studies are limited by their retrospective study designs, lack of randomized controlled trials, short follow-up periods and small sample sizes. This is an interesting arena for research and further studies are needed.

The logic for using HIPEC is chiefly attributed to the straightforward temperature-improved cytotoxicity of the intraperitoneal chemotherapeutic agents [53, 54]. Moreover, HIPEC aims to deeply penetrate the residual microscopic deposits [53, 54]― the primary source of surgical failure and early recurrence rates [43, 51, 52, 55, 56] in recurrent endometrial cancer. Moreover, HIPEC avoids the needless chemotherapy-related systemic toxicities while maximizing the local concentrations [57]. The most frequently used HIPEC agents include cisplatin [58] doxorubicin [59] and mitomycin C [60].

Generally, morbidity and mortality of cytoreduction and HIPEC are greatly influenced by the surgeons' expertise and learning curve [61]. A recent systematic review by Chua and collea‐ gues [62] demonstrated that the morbidity rate associated with cytoreduction and HIPEC range from approximately 12% to 52%, whereas mortality rate range from 1% to 6%.
