1. 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

2. 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

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

4. 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

5. 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

6. 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

7. 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

8. - 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.

9. 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).

10. 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

11. 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)

12. 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.

13. 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).

14. 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)

15. 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:

16. 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

17. 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

18. But….
LANCET
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….

19. 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……..

20. 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.

21. 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

22. 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.

23. 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.

24. 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

25. 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

26. 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…

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

28. In addictaion QoL data strongly confirm this trend….

29. 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

30. 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

31. 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

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