Francesco FanfaniGynecologic Oncology

Dpt. Obstetrics & GynecologyCatholic University - Rome

francesco.fanfani@rm.unicatt.it

Lymphadenectomy in early and advanced endometrial tumors:

when to do it and what is its extent?

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 >1/2Isthmus-cervix extensionExtrauterin spreadSpecial hystotypeEnlarged lymphnodes

WJ Hoskins

Modern Trends for Lymphadenectomy in Gynecologic Oncology

Early Stage StagingTherapeutic

Advanced Stage Cytoreduction

• 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.

Pelvic LFN definition

Based on the logistic regression model, the largest increasein probability of detecting at least a single positive lymphnode was observed when 21 to 25 lymph nodes were resected (P < 0.01).Removing > 25 lymph nodes did not improve the statisticalprobability (P0.13)

Based on the logistic regression model, the largest increasein probability of detecting at least a single positive lymphnode was observed when 21 to 25 lymph nodes were resected (P < 0.01).Removing > 25 lymph nodes did not improve the statisticalprobability (P0.13)

Cancer 2007

Common iliac

Superf.3/15 (20%)Deep 1/15 (7%) Presacral

1/15 (7%)

External iliac

4/15 (27%)

ObturatorSuperf.11/15 (73%)

Deep 1/15 (7%)

Distribution of pelvic node metastases in endometrial cancer

Int J Gynecol Cancer, 1998

Pre-caval

2/9 (22%)Pre-aortic

2/9 (22%)

Intercavo-aortic

7/9 (78%)

Para-caval

3/9 (33%)Para-aortic

4/9 (44%)

Retro-caval

2/9 (22%)Retro-aortic

Distribution of aortic node metastases in endometrial cancer

Int J Gynecol Cancer, 1998

ILIADE ASTEC- Pre-op evaluation - Endometrioid or adenosquamous EC FIGO stage I (clinical)- Intra-op randomizationexcluded 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

• 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).

537 patients randomly assigned

264 available for

Intention To Treat Analysis

250 available for

Intention To Treat Analysis

226 patients available for

Per-Protocol Analysis

228 patients available for

Per-Protocol Analysis

ILIADE

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

273 allocated

Lymphadenectomy

264 allocated

NO-Lymphadenectomy

38 protocol violations

(< 20 nodes resected)

22 protocol violations

(< 20 nodes resected)

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)

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.

ILIADE

Adjuvant therapy (RT, CHT, RT-CHT) did not differ between the two arms ( P = .07).

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.

CONCLUSIONS

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

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

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.

But….

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.

LANCET 04-2009

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.

Lancet Oncol 2011

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.

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.

Lancet Oncol 2011

Lymphadenectomy is associated with an improved survival in stage I grade 3 and more advanced endometrioid uterine cancer

LAPAROTOMIC

LAPAROSCOPIC

ROBOTICS

Early stage> obese

Early stage

Advanced stage

Standard-3 mm-LESS

Surgical approach

Fertility sparing

No fertility sparing

Early stage(IA, IB)

Endometrial CancerSurgery guidelines

No M involvementendometrioid G1,

ISC+MA

LPS ev LPT

LESSMini-LPSS-LPS with advanced bipolar devicesALF-X

UCSCTrials

Endometrial CancerSurgery guidelines

• 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)

Pe LFNNoYes

YesYes

YesYesYes

Ao LFNNo

Yes*

Yes*Yes*

Yes*Yes*Yes*

SNBNoYes

NoNo

NoNoNo

* Positive Pelvic nodes at FS

Advanced FIGO Stage

II-IV

LPT/LPS

Clinically operable patients

-Hysterectomy-SOB-LFN-Omentectomy-Metastases Resection

Clinically inoperable patients LPS NACT

Endometrial CancerSurgery guidelines

RT = 0

Francesco Fanfani, MDCatholic University of the Sacred Heart, Rome, Italy

Francesco Fanfani, MDCatholic University of the Sacred Heart, Rome, Italy

Thank you for your attention