**6.1 Definitions**

For a systematic PLND, all lymph nodes and fatty tissue between the external and internal iliac arteries, from the bifurcation of the common iliac artery up to the circumflex vein and above the obturator nerve, should be removed. A systematic PaLND includes resection of all lymph nodes and fatty tissue overlying the common iliac artery, vena cava and aorta anteriorly up to the renal vessels and extending laterally to the edge of the psoas major muscle.

#### **6.2 The randomized controlled trials on lymphadenectomy**

To date, two randomized controlled trials (Benedetti Panici et al. in 2008 and the MRC ASTEC trial 2009) have investigated whether the addition of PLND to standard hysterectomy with bilateral salpingo-oophorectomy improved overall survival and diseasefree survival in patients with preoperative Stage I endometrial cancer.

#### **6.2.1 Benedetti Panici et al., 2008**

In this Italian RCT, the role of systemic PLND or no PLND in early-stage endometrioid or adenosquamous endometrial cancer (FIGO 1988) was examined. Patients with Stages IA and IB Grade I, were excluded; 514 patients were randomized to undergo PLND (n=264) or not (n=250). A minimum of 22 PLNs were removed; median was 30. PaLND and adjuvant radiotherapy were left to the discretion of the treating physician; 26% in the PLND group had PaLND compared to 2% in the no-PLND group; the median number of PaLN's removed in the LND group was four. The proportion of patients who received adjuvant radiotherapy was similar in both groups: ±31-35%. At a median follow-up time of 49 months, no difference in the disease-free or overall survival rates was seen between the two groups. The estimated blood loss and the number of intra-operative complications were similar in both arms, but operating time and hospital stay were longer in the PLND group. Furthermore, more post-operative complications were noted in the PLND group, predominantly due to the formation of lymphocysts and lymphedema (35 versus 4). The PLND group was diagnosed with 13% metastatic LN versus only 3% in the no-PLND group. The authors concluded that although disease-free or overall survival is not improved, a systemic PLND significantly improved surgical staging.

#### **6.2.2 ASTEC Trial, 2009**

Eighty-five centers in four countries participated in the ASTEC Trial, randomizing 1,408 women with histologically proven endometrial cancer that was pre-operatively (clinically) thought to be confined to the uterus (despite PLN enlargement on CT or MRI), to standard surgery with or without systemic PLND. At a median follow-up time of 37 months there was no difference in disease-free or overall survival in both groups. According to the authors, PLND cannot be recommended as a routine procedure for therapeutic purposes outside of clinical trials.

However, the ASTEC Trial had several serious shortcomings:


#### **6.3 Observational studies on the effect of lymphadenectomy on survival 6.3.1 Cragun et al., 2005**

In a retrospective analysis of 509 patients, Cragun et al. (2005) noted that patients with poorly differentiated cancers having more than 11 pelvic nodes removed had improved overall survival (hazard ratio [HR] 0.25; P < .0001) and progression-free survival (HR 0.26; P < .0001) compared with patients having poorly differentiated cancers with 11 or fewer nodes removed. Among patients with cancers of Grades 1 to 2, the number of nodes removed was not predictive of survival. In multivariate analysis, a more extensive node resection remained a significant prognostic factor for improved survival in intermediate-/high-risk patients after adjusting for other factors including age, year of diagnosis, stage, grade, adjuvant radiotherapy and the presence of positive nodes (P < .001). Performance of *selective* PaLND was not associated with survival.

#### **6.3.2 Chan et al., 2006**

106 Cancer of the Uterine Endometrium – Advances and Controversies

As discussed in the previous section, it is clear that surgical staging and knowledge of lymph node status plays a very important role in the management of patients with endometrial cancer. What is not clear is what constitutes an adequate LND. The practice varies from selective sampling of accessible nodes to systematic LND. Is the latter necessary? Is a PLND adequate or is a PaLND required in addition to a PLND? If a PaLND is required, what are the limits of dissection? What are the additional risks of a LND? When are these additional risks justified? Does LND have a therapeutic effect? Below, we discuss the studies that have tried to

For a systematic PLND, all lymph nodes and fatty tissue between the external and internal iliac arteries, from the bifurcation of the common iliac artery up to the circumflex vein and above the obturator nerve, should be removed. A systematic PaLND includes resection of all lymph nodes and fatty tissue overlying the common iliac artery, vena cava and aorta anteriorly up to the renal vessels and extending laterally to the edge of the psoas major

To date, two randomized controlled trials (Benedetti Panici et al. in 2008 and the MRC ASTEC trial 2009) have investigated whether the addition of PLND to standard hysterectomy with bilateral salpingo-oophorectomy improved overall survival and disease-

In this Italian RCT, the role of systemic PLND or no PLND in early-stage endometrioid or adenosquamous endometrial cancer (FIGO 1988) was examined. Patients with Stages IA and IB Grade I, were excluded; 514 patients were randomized to undergo PLND (n=264) or not (n=250). A minimum of 22 PLNs were removed; median was 30. PaLND and adjuvant radiotherapy were left to the discretion of the treating physician; 26% in the PLND group had PaLND compared to 2% in the no-PLND group; the median number of PaLN's removed in the LND group was four. The proportion of patients who received adjuvant radiotherapy was similar in both groups: ±31-35%. At a median follow-up time of 49 months, no difference in the disease-free or overall survival rates was seen between the two groups. The estimated blood loss and the number of intra-operative complications were similar in both arms, but operating time and hospital stay were longer in the PLND group. Furthermore, more post-operative complications were noted in the PLND group, predominantly due to the formation of lymphocysts and lymphedema (35 versus 4). The PLND group was diagnosed with 13% metastatic LN versus only 3% in the no-PLND group. The authors concluded that although disease-free or overall survival is not improved, a

Eighty-five centers in four countries participated in the ASTEC Trial, randomizing 1,408 women with histologically proven endometrial cancer that was pre-operatively (clinically) thought to be confined to the uterus (despite PLN enlargement on CT or MRI), to standard

**6.2 The randomized controlled trials on lymphadenectomy** 

systemic PLND significantly improved surgical staging.

free survival in patients with preoperative Stage I endometrial cancer.

**6. Surgical staging** 

address these questions.

**6.2.1 Benedetti Panici et al., 2008** 

**6.2.2 ASTEC Trial, 2009** 

**6.1 Definitions** 

muscle.

Further evidence for the prognostic and therapeutic benefits for a thorough LND came from Chan et al., who used the United States National Cancer Institute's Surveillance, Epidemiology and End Results Program dataset of 39,396 women with endometrioid uterine cancer. They compared 12,333 patients who underwent surgical-staging procedures, including LND, with 27,063 patients who did not receive a LND to determine the potential therapeutic role of LND in women with endometrioid corpus cancer. They found that the five-year disease-specific survival was significantly improved by lymphadenectomy, and that with increasingly high-risk disease, the survival advantage conferred by LND was progressively greater. The five-year disease-specific survival for Stages I, II, III and IV patients who underwent LND was 95.5%, 90.4%, 73.8% and 53.3%, respectively, compared with 96.6%, 82.2%, 63.1% and 26.9% for those who did not (P > 0.05 for Stage I, P < 0.001 for Stages II to IV). In the subset of patients with Stage I, Grade 3 disease, those who underwent LND, had a better disease-specific survival than those who did not (90% versus 85%; P 14 0.0001). However, no benefit for LND was identified for patients with Stage I, Grade 1 (P 14 0.26) and Grade 2 (P 14 0.14) disease.

The group also used the data from the 12,333 patients who underwent LND to determine whether the node count or extent of the LND had a therapeutic benefit, and they found that it did in women with intermediate-/high-risk endometrioid cancer but not those with lowrisk endometrial cancer. In the intermediate-/high-risk patients (Stage IB, Grade 3; Stages IC and II to IV, all grades), a more extensive lymph node resection (1, 2-5, 6-10, 11-20, and >20) was associated with improved five-year disease-specific survivals across all five groups at 75.3%, 81.5%, 84.1%, 85.3% and 86.8%, respectively (P < .001). For Stage IIIC to IV patients with nodal disease, the extent of node resection significantly improved survival from 51.0%, 53.0%, 53.0% and 60.0%, to 72.0%, (P <.001). However, no significant benefit of lymph node resection in low-risk patients could be demonstrated (Stage IA, all grades; Stage IB, Grade 1 and 2 disease; P ¼ 0.23). In multivariate analysis, a more extensive node resection remained a significant prognostic factor for improved survival in intermediate-/high-risk patients after adjusting for other factors, including age, year of diagnosis, stage, grade, adjuvant radiotherapy and the presence of positive nodes (P <.001). In a follow-through study on 11,443 patients, Chan et al. (2007) investigated the association between the number of lymph nodes examined and the probability of detecting at least a single lymph node involved by metastatic disease in patients with endometrioid corpus cancer to define what constitutes an adequate LND. Their results suggest that the ideal node count is 21 to 25 lymph nodes. Although these are retrospective analyses, the strength of the data lies in the size of the sample and the fact that the study population reflects real-life practices across a range of units from community hospitals to tertiary-care academic centers. The limitations include the lack of detail regarding the location and size of the lymph nodes resected, specifically on what the contribution of PaLND is to the sample.

#### **6.3.3 Para-aortic lymphadenectomy**

There is evidence that patients with high-intermediate and high-risk endometrial cancer have 10% to 25% risk of metastatic PaLN (Kadar et al., 1992; Keys et al., 2004; Morrow et al., 1991). About 50% of patients with metastatic PLN have metastasis in the PaLN (Mariani et al., 2008; Watari et al., 2005). Sixteen percent of patients with high-risk endometrial cancer have metastasis only to the PaLN and not to the PLN (Mariani et al., 2008) and 77% of patients with para-aortic metastases harbor disease above the inferior mesenteric artery. It would appear that PaLND, when indicated, should be systematic and extend to the renal vessels. Although Abu-Rustum et al. (2009) reported that in their patients only 1% had isolated para-arotic metastasis (with negative pelvic nodes), they used a count of eight pelvic nodes as indicating a satisfactory pelvic lymphadenectomy and the retrieval of one para-arotic lymph node below the inferior mesenteric artery as evidence of a PaLND. Most gynecologic oncologists consider these LN counts inadequate to make firm conclusions.

#### **6.3.4 SEPAL study 2010**

Given the discordance between the findings of the large observational studies (Cragun 2005, Chan 2006, 2007a, 2007b) indicating a significant advantage in survival conferred by an extensive lymphadenectomy, and the RCTs indicating otherwise, Yukiharu Todo and colleagues investigated whether it was the addition of PaLND that improved survival in endometrial cancer (SEPAL). They studied cohorts from two tertiary-care gynecologic oncology units in the city of Sapporo, Japan. Although their study is retrospective, bias was kept to a minimum as the centers differed in the use of PaLND, which was practiced as a routine standard of care in one center and not in the other. The cohorts from both centers had systematic PLND; median pelvic lymph node count 34 (21 to 42) in the PLND group (325 patients) versus 59 (46 to 73) in the PLND and PaLND group (n=346). The number of PaLN counts in the two groups were 0 versus 23 (16 to 30). Patients at intermediate or high risk of recurrence were offered adjuvant radiotherapy or chemotherapy. Overall survival was significantly longer in the PLND and PaLND group than in the PLND group (HR 0.53, 95% CI 0.38 to 0.76; p=0.0005). This association was noted in 407 patients at intermediate or high risk (p=0.0009), but not in low-risk patients. Multivariate analysis of prognostic factors showed that in patients with intermediate or high risk of recurrence, PLND and PaLND reduced the risk of death compared with PLND (0.44, 0.30 to 0.64; p<0.0001). Analysis of 328 patients with intermediate or high risk who were treated with adjuvant radiotherapy or chemotherapy showed that patient survival improved with PLND and PaLND (0.48, 0.29 to 0.83; p=0.0049) and with adjuvant chemotherapy (0.59, 0.37 to 1.00; p=0.0465) independently of one another. The authors concluded that combined PLND and PaLND is recommended as treatment for patients with endometrial carcinoma of intermediate or high risk of recurrence.

#### **6.4 Caveat with lymph node counts**

Although there is much debate on constitutes the optimum pathological sampling of pelvic lymph nodes in endometrial cancer, the importance of counting the number of lymph nodes detectable in the pathologic specimens is incontrovertible (Berney et al., 2010). Weingärtner et al. (1996) reported on the average number of PLNs found at the time of autopsy. In 30 human cadavers (19 males and 11 females, mean age of death 64 years), it was found that there were 22.7±10.2 lymph nodes (ranging from 8 to 56) in the pelvis. It has been clearly established that lymph nodes undergo fatty involution that increases with age (>72 years), BMI (>27.8), diabetes, hypothyroidism and previous chemotherapy. A recent study confirmed this phenomenon for superficial lymph nodes in the cervical, axillary and inguinal regions. The fatty degeneration of lymph nodes makes their identification unreliable with either imaging or palpation at the time of surgery or during gross pathologic examination (Arango et al., 2000; Giovagnorio et al., 2005). Consequently, the value of lymph node counts in the elderly and in obese women with endometrial cancer is highly dependent on the thoroughness of the pathology technician.

#### **6.5 Conclusion**

108 Cancer of the Uterine Endometrium – Advances and Controversies

it did in women with intermediate-/high-risk endometrioid cancer but not those with lowrisk endometrial cancer. In the intermediate-/high-risk patients (Stage IB, Grade 3; Stages IC and II to IV, all grades), a more extensive lymph node resection (1, 2-5, 6-10, 11-20, and >20) was associated with improved five-year disease-specific survivals across all five groups at 75.3%, 81.5%, 84.1%, 85.3% and 86.8%, respectively (P < .001). For Stage IIIC to IV patients with nodal disease, the extent of node resection significantly improved survival from 51.0%, 53.0%, 53.0% and 60.0%, to 72.0%, (P <.001). However, no significant benefit of lymph node resection in low-risk patients could be demonstrated (Stage IA, all grades; Stage IB, Grade 1 and 2 disease; P ¼ 0.23). In multivariate analysis, a more extensive node resection remained a significant prognostic factor for improved survival in intermediate-/high-risk patients after adjusting for other factors, including age, year of diagnosis, stage, grade, adjuvant radiotherapy and the presence of positive nodes (P <.001). In a follow-through study on 11,443 patients, Chan et al. (2007) investigated the association between the number of lymph nodes examined and the probability of detecting at least a single lymph node involved by metastatic disease in patients with endometrioid corpus cancer to define what constitutes an adequate LND. Their results suggest that the ideal node count is 21 to 25 lymph nodes. Although these are retrospective analyses, the strength of the data lies in the size of the sample and the fact that the study population reflects real-life practices across a range of units from community hospitals to tertiary-care academic centers. The limitations include the lack of detail regarding the location and size of the lymph nodes resected, specifically on

There is evidence that patients with high-intermediate and high-risk endometrial cancer have 10% to 25% risk of metastatic PaLN (Kadar et al., 1992; Keys et al., 2004; Morrow et al., 1991). About 50% of patients with metastatic PLN have metastasis in the PaLN (Mariani et al., 2008; Watari et al., 2005). Sixteen percent of patients with high-risk endometrial cancer have metastasis only to the PaLN and not to the PLN (Mariani et al., 2008) and 77% of patients with para-aortic metastases harbor disease above the inferior mesenteric artery. It would appear that PaLND, when indicated, should be systematic and extend to the renal vessels. Although Abu-Rustum et al. (2009) reported that in their patients only 1% had isolated para-arotic metastasis (with negative pelvic nodes), they used a count of eight pelvic nodes as indicating a satisfactory pelvic lymphadenectomy and the retrieval of one para-arotic lymph node below the inferior mesenteric artery as evidence of a PaLND. Most gynecologic oncologists consider these LN counts inadequate

Given the discordance between the findings of the large observational studies (Cragun 2005, Chan 2006, 2007a, 2007b) indicating a significant advantage in survival conferred by an extensive lymphadenectomy, and the RCTs indicating otherwise, Yukiharu Todo and colleagues investigated whether it was the addition of PaLND that improved survival in endometrial cancer (SEPAL). They studied cohorts from two tertiary-care gynecologic oncology units in the city of Sapporo, Japan. Although their study is retrospective, bias was kept to a minimum as the centers differed in the use of PaLND, which was practiced as a routine standard of care in one center and not in the other. The cohorts from both centers

what the contribution of PaLND is to the sample.

**6.3.3 Para-aortic lymphadenectomy** 

to make firm conclusions.

**6.3.4 SEPAL study 2010** 

In summary, it is clear that patients who have low-grade endometrioid adenocarcinoma with minimal myometrial invasion have very low risk of lymph node metastasis and do not benefit from a LND. Patients at risk of lymph node metastasis require a systematic PLND as well as PaLND. The latter should extend up to the renal vessels.

#### **7. Morbidity of lymphadenectomy and benefits of minimally invasive approach**

One of the factors that precludes LND in patients with endometrial cancer is the morbidity associated with an LND. Given that the risk factors for endometrial cancer are old age, diabetes, hypertension and obesity, it follows that a substantial number of women diagnosed with endometrial cancer have these co-morbidities, thus making them high risk for prolonged and technically complicated surgery. Several studies have tried to assess the additional risks posed by a systematic LND and the benefits of performing the surgery by laparoscopy or robotic surgery.

In a large retrospective study, Cragun et al. (2005) summarized the morbidities of LND by laparotomy. Two to three percent of patients had small bowel obstruction or ileus, deep vein thrombosis and lymphocysts requiring drainage. Patients undergoing PLND and PaLND required longer anesthesia time and hospital stay and had greater blood loss compared to those who had PLND alone. Up to 8% of patients had a wound infection. Chronic lymphedema of the lower limbs was observed in 2.5% (Abu-Rustum et al., 2006).

Querleu et al. (2006) audited 1,000 patients who had a *laparoscopic LND*. Only 1.3% were converted to laparotomy. Intra- and early post-operative complication and lymphocyst formation rates were 2.0%(bowel complication 0.7%; urinary tract complications 0.5%; nerve injuries 0.5%), 2.9% and 7.1%, respectively.

#### **7.1 RCTs comparing laparotomy to minimally invasive surgery for endometrial cancer**

In the LAP-2 study, an RCT carried out by the Gynecologic Oncology Group (GOG), 2,616 patients with endometrial carcinoma confined to the uterus were randomly assigned to laparoscopy or laparotomy (Walker, 2009). All patients had complete surgical staging including PLND and PaLND. Laparoscopic-assisted vaginal hysterectomy, total laparoscopic hysterectomy or robotic-assisted total laparoscopic hysterectomy was allowed. They found that laparoscopy resulted in similar intra-operative complications, fewer post-operative moderate or severe adverse events (14% versus 21% by laparotomy, p<0.0001), shorter hospital stay, less use of pain medication and quicker resumption of daily activities but required longer operating time. Twenty five percent of patients randomized to laparoscopy were converted to laparotomy. Patients at higher risk for a conversion to laparotomy were elderly (>63 years) and those with metastatic disease and a high BMI (17% in patients with a BMI of 25kg/m2, 26% with a BMI of 35kg/m2, 57% with a BMI >40kg/m2).

In an Australian RCT (n=361), which also compared total laparoscopic hysterectomy with abdominal hysterectomy in early endometrial carcinoma, 52% of the patients had a pelvic or para-aortic lymphadenectomy. Only 2.4% of patients assigned to laparoscopy were converted to laparotomy. Patients who had laparoscopic surgery reported significantly greater improvement in QoL from baseline compared with those who had laparotomy, this difference persisted for up to 6 months after surgery. Operating time was significantly longer in the laparoscopy group (138 minutes [SD 43]) versus 109 minutes [SD 34]; p=0.001). Intra-operative adverse events were similar between groups (laparotomy 5.6% versus laparoscopy 7.4%]; p=0.53), but postoperatively, twice as many patients in the laparotomy group experienced adverse events of Grade 3 or higher (23.2% versus 11.6%; p=0.004). The authors concluded that QoL improvements from baseline during early and later phases of recovery, and the adverse event profile, favor laparoscopy over laparotomy for the treatment of Stage I endometrial cancer.

Other studies that investigated the feasibility of minimally invasive surgery (laparoscopy and robot-assisted surgery) in elderly and obese patients concluded that neither age nor BMI is a contraindication to minimally invasive procedures, as it is these patients who benefit the most (Boggess et al., 2008; Gehrig et al., 2008; Janda et al., 2010; Obermair et al., 2005; Scribner et al., 2001).
