Dpt. Obstetrics & Gynecology Catholic University - Rome Lymphadenectomy in early and advanced endometrial tumors: when to do it and what is its extent? First of all I’d like to thanks the organization committe for the invitation to this meeting. I will share with you about… Francesco Fanfani Gynecologic Oncology Dpt. Obstetrics & Gynecology Catholic University - Rome francesco.fanfani@rm.unicatt.it

Early Stage Endometrial Cancer “ If there is no gross residual intraperitoneal tumor, pelvic and para-aortic lymphnodes should be sampled for the following indications: Myometrial invasion >1/2 Isthmus-cervix extension Extrauterin spread Special hystotype Enlarged lymphnodes This is the old reccomandation by hoskins about the role of lfn in ec patients…. WJ Hoskins

Modern Trends for Lymphadenectomy in Gynecologic Oncology Early Stage Staging Therapeutic And te modern trends of the gyo communite suggest that …… Advanced Stage Cytoreduction

Pelvic LFN definition Sistematic: > 20 lymph nodes removed; Sampling : suspected (pre- and intra- operative) lymph nodes; Bulky: enlarged lymph nodes; Lymph-centre concept: preferential lymphnodal metastasis spread Sentinel lymph-node concept: positive sentinel lymph node. Considering the different definition of lymohadenectomy, we have to consider that sistematic ie more than 20 nodes remove is the standard

Based on the logistic regression model, the largest increase in probability of detecting at least a single positive lymph node was observed when 21 to 25 lymph nodes were resected (P < 0.01). Removing > 25 lymph nodes did not improve the statistical probability (P0.13) In fact…. Cancer 2007

Distribution of pelvic node metastases in endometrial cancer Common iliac Superf.3/15 (20%) Deep 1/15 (7%) Presacral 1/15 (7%) Obturator Superf.11/15 (73%) Deep 1/15 (7%) The pelvic retroperitoneal spread of endometrial cancer involve all the pelvic regions. Differently for those reported for cc, the common iliac and not only the external and the obturator one should be remove in order to adequately stage ec patients… External iliac 4/15 (27%) Int J Gynecol Cancer, 1998

Distribution of aortic node metastases in endometrial cancer Intercavo-aortic 7/9 (78%) Pre-caval 2/9 (22%) Pre-aortic 2/9 (22%) Para-caval 3/9 (33%) Para-aortic 4/9 (44%) As fa as lomboartic retroperitoneal node are concerned, all stations could be involved, in particular the intercavoaortic… Retro-caval 2/9 (22%) Retro-aortic Int J Gynecol Cancer, 1998

- Endometrioid or adenosquamous EC FIGO stage I (clinical) ILIADE ASTEC - Pre-op evaluation - Endometrioid or adenosquamous EC FIGO stage I (clinical) - Intra-op randomization excluded stage IA and IB (<50% miometrial invasion) G1 (intraoperative) - Nr. of Pe-LPN (> 20) - Pre-op evaluation and randomization EC FIGO stage I (clinical) No. of pts with FIGO stage IA and IB about 60% - No. of Pe-LPN < 14 in 60% of pts (median 12), with a 35% pts had < 9 In the last 5 yars two very relevant RTC trials have been published, and theyr results have contributed to change the way of think aboutrole of LFN in early stage EC. The gola of these two trial was to investigate the impact of LFN in low and intermediate risk ec patients. We will discus resulta and bias of these studies.

This prospective multicenter RCT was conducted in order to determine whether the addition of systematic pelvic lymphadenectomy to standard hysterectomy with BSO improves OS and DFS in patients with preoperative stage I EC. Between October 1996 and March 2006, 537 patients were enrolled at 35 centers (34 in Italy and 1 center from Chile).

ILIADE 537 patients randomly assigned 273 allocated Lymphadenectomy NO-Lymphadenectomy 9 patients not eligible intra-operatively Other histotype = 3 Stage IA = 2 Stage IB Grading 1 = 4 14 patients not eligible intra-operatively Other histotype = 5 Stage IA = 3 Stage IB Grading 1 = 6 264 available for Intention To Treat Analysis 250 available for Intention To Treat Analysis More than 500 patients were enrolled and quite 450 were avalible for protocol analysis. Patients with less than 20 nodes removed were non considered. 38 protocol violations (< 20 nodes resected) 22 protocol violations (< 20 nodes resected) 226 patients available for Per-Protocol Analysis 228 patients available for Per-Protocol Analysis 10

OT and hospital was significantly higher in LFN group OT and hospital was significantly higher in LFN group. About this, we have to consider that this trial was not performed in the LPS era, and a lot of operative and post-operative outcomes could be influence by the laparotomic approach. Both early and late postoperative complications occurred statistically significantly more frequently in pts. who had received pelvic systematic LFN (mainly lymphedema and lymphocysts) (p 0.001)

ILIADE PROGRESSION FREE AND OVERALL SURVIVAL After a median FU up of 49 months (interquartile range = 27 to 79 months) tumor had recurred in 67 women (13.0%): 34 (12.9%) in LFN arm and 33 (13.2%) in no-LFN arm. 53 (10.3%) pts. died: 42 (8.2%) for disease-specific cause and 11 (2.1%) without evidence of relapse. Median time to relapse was 14 months in LFN arm and 13 months in no-LFN arm.

As showe by the survival curves, no significant differences in terms of PFS and OS were observed between LFN and no-LFN group. Adjuvant therapy (RT, CHT, RT-CHT) did not differ between the two arms ( P = .07).

CONCLUSIONS Although systematic pelvic lymphadenectomy significantly improved surgical staging of women with clinical early stage endometrial carcinoma by detecting a higher rate of patients with positive nodes, it did not improve either PFS and/or OS. 10 % of overstaging (13.3% and 3.2% of stage IIIC)

MRC - ASTEC Trial 1408 pts with diagnosis of EC randomized to - TAH + BSO = 704 - TAH + BSO + LND = 704 Endpoints - Primary: Survival - Secondary: RFS, DSS, Toxicity Secondary randomization of pts with intermediate-high risk to the ASTEC-RT trial In this larger study, secondary randomization between RT and observation was performed. Lancet 2009; 373: 125-36

MRC - ASTEC Trial With a median FU up of 37 months (IQR 24–58 months), 191 (14%) women had died. The 5-year OS was 81% (95% CI 77–85) in the standard surgery group and 80% (76–84) in the lymphadenectomy group

Similarly for that reported for ilaide trial, no significant differences in terms of PFS and OS were observed. No evidence of a benefit for systematic lymphadenectomy for endometrial cancer in terms of overall, disease-specific, and recurrence-free survival. Morbidity was low overall, but we noted a substantial increase in the incidence of lymphoedema in the LFN group. 17

But…. LANCET 04-2009 The number of lymph nodes resected was insufficient in many pts. Although the median number resected overall was 12, 35% of patients in the LFN group had nine or fewer lymph nodes removed. A specific bias of this study was….

Role of SLN The main interest in the sentinel-node concept for patients with early stage endometrial cancer is to reduce the morbidity of surgical staging by lymphadenectomy, while accurately identifying patients who will benefit from adjuvant therapy. When lymph-node status is unknown, indications for adjuvant therapies are based on uterine features alone. In order to reduce the……..

Different groups have investigated th SLN role in ec Different groups have investigated th SLN role in ec. There was a alrge eterogeneity abou the way of injection of the bly-day or radio-drug: isteroscopy and cervical injection have been proposed and probably this eterogeneity negatively influence the feeling of gyo community baout this issue.

This is a prospective, multicentre cohort study to assess the detection rate and diagnostic accuracy of the SLN procedure in predicting the pathological pelvic-node status in patients with early stage endometrial cancer. From July 5, 2007, to Aug 4, 2009, 133 patients were enrolled at nine centres in France. At least one SLN was detected in 111 of the 125 eligible patient. Furthermore No isolated paraortic node was detected. Lancet Oncol 2011

SLN biopsy alone can accurately diagnose lymph-node involvement in patients with low-risk or intermediate-risk endometrial cancer, and that adjuvant therapy can be planned withoutthe need for complete pelvic lymphadenectomy By contrast, we observed a high incidence of metastases in SLNs and non-SLNs in patients with high-risk endometrial cancer (IB G3); pelvic lymphadenectomy cannot be omitted for these patients.

Lancet Oncol 2011 Conclusions SLN biopsy could be an alternative to systematic lymphadenectomy in patients with low-risk and intermediate-risk endometrial cancer. A systematic (pelvic and aortic) lymphadenectomy should be considered for patients with high-risk (IB G3) endometrial cancer.

Lymphadenectomy is associated with an improved survival in stage I grade 3 and more advanced endometrioid uterine cancer In high-risk or advanced ec patients the role of LFN is not staging but probably. These data strongly suggest the role of systematic lymphadenectomy in these patients. 24

Surgical approach LAPAROTOMIC ROBOTICS LAPAROSCOPIC Early stage Advanced stage Early stage > obese In early stage the must for do lfn should be minimally invasive surgery. Whereas lpt approach could be reserved for advance stages. LAPAROSCOPIC Standard-3 mm-LESS Early stage

This is an interesting italian study that shows how was the MIS impact for the incorporation of laparoscopy in the practice of a gyo service. Less and less procedeures performed by LPT…

To date survival data are more that encouraging about the adequacy of LPS in the management of early stage ec patients.

In addictaion QoL data strongly confirm this trend….

Endometrial Cancer Surgery guidelines No M involvement endometrioid G1, Fertility sparing ISC+MA Early stage (IA, IB) No fertility sparing LPS ev LPT This is our algorithm for early staeg ec patients. FS is reserved for < 40 years old women desiing to retain thet fertility potential with G1 endometrioid endometrial cancer withput miometrial involvement. These patienst are treated wit progesteron and followed by ISC….. After FS analysis pelvic lymphadenectomy is performed in G3 or in G1-2 with more than half of M invasion. Aortic lymphdeenctomy was performed only in patients with posotivie pelvic nodes…… LESS Mini-LPS S-LPS with advanced bipolar devices ALF-X UCSC Trials 29

Endometrial Cancer Surgery guidelines Pe LFN No Yes Ao LFN No Yes* SNB No Yes Low-risk (IA G1-2) Intermediate-risk (IA G3, IB G2) High-risk (IB G3) FIGO stage I special hystotype (CC, SP) Stage II G1-2 Stage II G3 Advanced stage (III-IV) * Positive Pelvic nodes at FS

Endometrial Cancer Surgery guidelines -Hysterectomy -SOB LFN Omentectomy Metastases Resection Clinically operable patients LPT/ LPS Advanced FIGO Stage II-IV RT = 0 Advanced ec patients are manged similarly to advanced ovarian cancer patients… Clinically inoperable patients LPS NACT 31

Catholic University of the Sacred Heart, Rome, Italy Thank you for your attention Francesco Fanfani, MD Catholic University of the Sacred Heart, Rome, Italy