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ESGO 1-st Basic Course in Gynecological Oncology
Yerevan, State Medical University30thSeptember - 1st October 2010
The role of the Lymphadenectomy The role of the Lymphadenectomy in in
Endometrial CancerEndometrial Cancer
P. ZolaProf. Paolo Zola
Department of Gynecologic OncologyUniversity of Turin
Mauriziano “ Umberto I ” Hospital
International Federation International Federation of Gynecologic and Obstetrics (FIGO)of Gynecologic and Obstetrics (FIGO)
Clinical StagingSystem
Clinical StagingSystem
Operative StagingSystem
Operative StagingSystem
1978 1988
inaccuratea paradigm
shift
GOG Study*
Stage migration in 22% (144/621) of clinical stage I patients
after surgical staging
No definite guideline: Type & Extent of LN assessment
*Creasman - Morrow et al, Cancer 1987
FIGO STAGING 2009FIGO STAGING 2009I Tumour confined to the corpus uteri
Ia No or less than half myometrial invasion
Ib Invasion equal to or more than half of the myometrium
II Tumour invades cervical stroma, but does not extend beyond the uterus
III Local and/or regional spread of the tumour
III a Tumour invades the serosa of the corpus uteri and/or adnexae
III b Vaginal and/or parametrial involvement
III cIII c Metastases to pelvic and/or para-aortic lymph nodesMetastases to pelvic and/or para-aortic lymph nodes
III c1III c1 Positive pelvic nodesPositive pelvic nodes
III c2III c2 Positive para-aortic lymph nodes with or without positive pelvic lymphPositive para-aortic lymph nodes with or without positive pelvic lymphnodesnodes
IV Tumour invades bladder and/or bowel mucosa, and/or distant metastases
Iva Tumour invasion of bladder and/or bowel mucosa
IV b Distant
Surgical Staging: LymphadenectomySurgical Staging: Lymphadenectomy Practices around the worldPractices around the world
0
20
40
60
80
NORTH AMERICA NORTH AMERICA NORTH AMERICA NORTH AMERICA WESTERN EUROPE NETHERLANDS SLOVACK REPUBLIC JPAPANWESTERN EUROPE NETHERLANDS SLOVACK REPUBLIC JPAPAN Partride, ‘99 Roland, ‘04 Maggino, ‘95 Creutzberg, ‘00 Uharcek, ‘06 Konno, ‘00Partride, ‘99 Roland, ‘04 Maggino, ‘95 Creutzberg, ‘00 Uharcek, ‘06 Konno, ‘00
Perform it or not perform it?Perform it or not perform it?
What’s new in
Literature…
SURVIVAL BENEFITS REMOVING NODAL METASTASES AUTHOR No. PTS INCLUSION OUTCOME EXENT OF BENEFIT (year) CRITERIA BENEFIT FROM
CHAN 1221 Stages IIIc-IV More extensive lymphadenectomy 5-yrs improved with extent
2006 (1, 2-5, 6-10, 11-20, > 20 nodes) of surgery - p <0.01(51, 53, 53, 69, 72%)
BRISTOW 38 Stage IIIc Complete resection of bulky nodes 5-yrs DS
2003 Extensive surgery vs macroscopic residual nodes 40% vs 0% - p= 0.006
CORN 50 Pos Aortic Nodes Surgical resection & RT 5-yrs OS
1992 Pathology & vs RT alone 61 vs 33%Lymphography
HAVRILESKY 96 Stage IIIC Removal of gross nodal disease 5-yrs DSS
2005 Extensive surgery HR= 6.85 - p=0.009(Gross nodes not debulked)
MARIANI 137 Risk for Aortic Pos N Para-aortic lymphadenectomy 5-yrs PFS
2000 Invasion > 50% ( 5 Nodes) 62 vs 77% - p= 0.12 Palpable Pos Pelvic N 5-yrs OS Pos Adnexae 71 vs 85% - p= 0.06
51 Positive Nodes Para-aortic Lymphadenctomy 5-yrs PFS
(Pelvic or Aortic) ( 5 Nodes) 36 vs 76% - p= 0.02 5-yrs OS
42 vs 77% - p= 0.05
GOG33 GOG33 GRADE 2-3, MYOMETRIAL INVASION & NODEGRADE 2-3, MYOMETRIAL INVASION & NODE
Morrow’s rule
PELVIC NODE METASTASES ASSESSMENT:
GRADE x MYOMETRIAL INVASION x 3= % POSITIVE NODE
PELVIC NODE METASTASES ASSESSMENT:
GRADE x MYOMETRIAL INVASION x 3= % POSITIVE NODE
AORTIC NODE METASTASES ASSESSMENT:
GRADE x MYOMETRIAL INVASION x 2= % POSITIVE NODE
AORTIC NODE METASTASES ASSESSMENT:
GRADE x MYOMETRIAL INVASION x 2= % POSITIVE NODE
621pts/70 pts N+ (11%); 36(51%)P only, 22(31%) P&PA, 12(17%)PA
58/70 (83%) P pos 34/70 (49%) PA pos
Type of translationType of translation Who do not consider that surgical staging is
appropriate or necessary for any pts (GOG33)
Strong proponents of surgical staging argue
for surgical staging in all pts regardless of the implications for pts outcomes (PFS,OS, L.C.,complication, choice of subsequent therapy)
Only high risk group according P.F.
Algorithms Decision-Making 1Algorithms Decision-Making 1
N+: 0-7%
Any G no inv.,G1-2<50%
Thomas & Aalders 2007
Algorithms Decision-Making 1Algorithms Decision-Making 1
In practice: 75% at l.risk are not staged nor adj therapy 25% at h.risk received Rt (!)
Thomas & Aalders 2007
MINIMUN BENEFIT LYMPHEDENECTOMY MINIMUN BENEFIT LYMPHEDENECTOMY
IN LOW RISKIN LOW RISK
AUTHOR No. PTS INCLUSION CRITERIA OUTCOME
MARIANI 328 G1-2 Endometrioid Overall disease-specific survival 97%
2000 Invasion <50% (Post-operative Brachytherapy)< 2 cm
TRIMBLE 7052 Clinical Stage I Overall disease-specific survival >98%
1998 G1-2 Endometrioid
CAREY 227 Clinical Stage I Overall relapse-free survival 95%
1995 G1-2 Endometrioid without lymphadenectomyInvasion < 50%
ELTABBAKH 302 Stage I G1-2 Overall disease-specific survival 98.9% 1997 Invasion < 50% without lymphedenectomy
W= negative (57% received lymphadenectomy)
CHAN 5556 Stage Ia G1-3 No survival benefit associated with a 2006 Stage Ib G1-2 more extensive lymph-node resection; p= 0.23
Endometrioid extensive lymph-node resection; p= 0.23
Chan, Lancet 2007
SURVIVAL BENEFITS REMOVING BENIGN LYMPH NODES SURVIVAL BENEFITS REMOVING BENIGN LYMPH NODES
AUTHOR No. PTS INCLUSION OUTCOME EXENT OF BENEFIT (year) CRITERIA BENEFIT FROM
KILGORE 649 Clinical Stages I-II Multiple site 4 pelvic node sampling High-Risk, p= 0.0006 (OS)
1995 No sarcomas vs no node sampling Low risk, p= 0.026 (OS)
CRAGUN 509 Clinical Stage I-IIa More extensive lymphadenectomy 5-yrs OS
2005 79% vs 88% - p= 0.013( 11 vs > 11 Nodes)
CHAN 12333 FIGO Stages I-IV More extensive lymphadenectomy 5-yrs improved with extent
2006 (1, 2-5, 6-10, 11-20, > 20 nodes) of surgeryStages IbG3, Ic, II-IV G1-2 (75.3, 81.5, 84.1, 85.3, 86.8%)
MARIANI 137 High-Risk disease More extensive para-aortic 5-yrs OS
2000 No Stage IV lymphadenectomy 71% vs 85% - p=0.06(< 5 vs 5 Nodes)
LUTMAN 467 FIGO Stage I-II More extensive lymphadenectomy 5-yrs OS
2006 High-Risk Histology 64% vs 90% - p <0.001( 11 vs > 11 Nodes)
Chan, Lancet 2007
Algorithms Decision-Making 2Algorithms Decision-Making 2
Adjuvant therapy: ch/Rt / RT /Ch
Thomas & Aalders 2007
Algorithms Decision-Making Algorithms Decision-Making
Thomas & Aalders 2007
STAGE ALL
Failing to stage even low risk pts,may miss significant numbersof pts with extra uterine disease, particularly since pre surgical G &Inv is realtive inaccurate. Outcome data do not support this assumption
ONLY 4% of 922 pts low risk disease and no surgical staging oradjuvant therapy subsequently recurred.
STAGE ALL
Failing to stage even low risk pts,may miss significant numbersof pts with extra uterine disease, particularly since pre surgical G &Inv is realtive inaccurate. Outcome data do not support this assumption
ONLY 4% of 922 pts low risk disease and no surgical staging oradjuvant therapy subsequently recurred.
Algorithms Decision-MakingAlgorithms Decision-MakingFrom these data, one can estimate that the number in whomnodal/extra uterine disease was present is about 5%.The patters of failure predict that 3/5 will recur in the pelvis alone and 2/3 will be salvaged with RT at the time of relapse
Thus in low risk negligible gains come from attending accurately know the nodal status by staging
Incidence of N+ is low, morbidity rate for surgical staging is 6-7%, recurences are pelvic, and salvage therapy is significant
From these data, one can estimate that the number in whomnodal/extra uterine disease was present is about 5%.The patters of failure predict that 3/5 will recur in the pelvis alone and 2/3 will be salvaged with RT at the time of relapse
Thus in low risk negligible gains come from attending accurately know the nodal status by staging
Incidence of N+ is low, morbidity rate for surgical staging is 6-7%, recurences are pelvic, and salvage therapy is significant
Thomas & Aalders 2007Thomas & Aalders 2007
Algorithms Decision-MakingAlgorithms Decision-MakingUNSTAGED “HIGH RISK”
Thomas & Aalders 2007Thomas & Aalders 2007
No EBRT Adjuvant EBRT + IC
n 51 44
Dead of disease 28% 18%
Pelivic and vaginal recurrence
20% 5%
Distant recurrence
16% 14%
Subset analysis in “high-risk” (grade 3, > 50% myometrial tumor infiltration) clinical stage I endometrial carcinoma patients
Subset analysis in “high-risk” (grade 3, > 50% myometrial tumor infiltration) clinical stage I endometrial carcinoma patients
Algorithms Decision-Making 3Algorithms Decision-Making 3STAGING ONLY “HIGH RISK”
No information on EBRT omissionGOG: rec. from 12 to 3% but OS 86vs92
Age,G2-3, 3/3 inv,LVSI pos 1/3 high risk of recurrences in N- Thomas & Aalders
2007
Thomas & Aalders 2007Thomas & Aalders 2007
Algorithms Decision-Making 3Algorithms Decision-Making 3STAGING ONLY “HIGH RISK”
Which pts are most likely to have para-aortic nodal involvement?
In which group is systematic PA nodal dissection justified?
In how many is disease confined to lymph nodes?
What are the incremental survival results of detecting and treating PA nodal involvement?
Specific questions on PA nodesSpecific questions on PA nodes
Para Aortic nodes involvement Para Aortic nodes involvement
Overall risk: stage 1 4%-6% Gross pelvic nodes: 55% Gross adnexal disease: 43% 98% Outer-third invasion: 18% Pelvic nodes+: 47% Other sites & PA node 50% (50% node only)
With unsophisticated techniques (45-50Gy), approx 40%may achieve long term DFS (range 35-75%). Thus 1-2/100 pts are cured by virtue of surgical detection and treating involved PA.
Thomas & Aalders 2007
Percent radiation use after surgery, by surgeon & FIGO stage
Lymph Node Assessment by surgeon:General Gynecologist vs Gynecologic Oncologist
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100
GYN
GYO
No. 9954No. 9954
No. 204No. 204
Partridge, 1999Partridge, 1999 Roland, 2004Roland, 2004
ILIADE II - LINCEILIADE II - LINCE
Systematic Pelvic lymphadenectomy versus
no lymphadenectomy
Mario Negri Institute, Milan (MANGO)
Pelvic nodes involvementPelvic nodes involvement
Stage I (well differentiated tumour, superficial myometrial invasion): 3-5%
Stage I (undifferentiated tumour, deep myometrial invasion): 20%
ASTEC, Lancet 2009
537 pts. Stage I
537 pts. Stage I
Intra-operatory randomization
Intra-operatory randomization
LYMPHADENECTOMYLYMPHADENECTOMY NO LYMPHADENECTOMY NO LYMPHADENECTOMY
M1 M2
G1 X
G2 X X
G3 X X
ILIADE II - LINCEILIADE II - LINCE
LymphNo
lymph
Median age 63 61
Stage IA-C 191 195
Stage IIA & B 22 21
Stage IIIA & C 44 27
Grade 2 57% 59%
Grade 3 35% 31%
Median N° of removed nodes
Lymph(25°-75°)
No Lymph(25°-75°)
Pelvic* 26 (19-35) 0 (0-0)
Pelvici e Para-aortic* 30 (21-42) 0 (0-0)
*P< .001
Patients with at least 1 N+
Lymph No Lymph
13.3% 3.2%
P< .001
Surgery
Lymph No lymph
Median surgery time* 180’ 120’
Blood transfusion 26 19
Hospitalization (days)* 6 5
* P< .001
Adjuvant Therapies
Lymph (%)
No lymph (%)
None 69 65
Radiotherapy 17 25
Chemiotherapy 9 6
Chemio-Radiotherapy 6 4
Complications
Lymph No lymph
Total* 81 34
Lymphedema 35 4
Deep venous trombosis 2 2
Pulmonar embolism 2 0
Bladder-vaginal fistula 2 0
*P< .001
Sites of disease recurrenceLymph No lymph
Total 34 33
lung 8 8
intraperitoneal 8 7
vagina 7 6
lymph node 4 4
bone 4 3
liver 2 3
missing data 3 3
0
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40
60
80
100
0 6 12 18 24 30 36 42 48 54 60
monthsmonths
%%
χ2=0.17; P=0.68
events total
---- Lymphadenectomy 42 264
___ No lymphadenectomy 36 250
Disease Free SurvivalDisease Free Survival
81.7
81.0
Overall SurvivalOverall Survival
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60monthsmonths
%%
χ2=0.45; P=0.50
events total
---- Lymphadenectomy 30 264
___ No lymphadenectomy 23 250
90.0
85.9
ASTEC surgical trial 2009ASTEC surgical trial 2009
Iliac & para-aortic nodesMean count: 12 nodes
Iliac & para-aortic nodesMean count: 12 nodes
ASTEC, Lancet 2009
ASTEC, Lancet 2008
ASTEC, Lancet 2008
Cochrane Review 2010Cochrane Review 2010
Survival effect of para-aortic
lymphadenectomy in endometrial
cancer (SEPAL study): a retrospective cohort analysis
Todo et al 2010
• Para-aortic lymphadenectomy has survival benefits for patients at intermediate or high risk of recurrence.
• Pelvic lymphadenectomy alone might be an insufficient surgical procedure in patients at risk of lymph node metastasis
Todo et al 2010
Cox regression analysis of overall survival with pelvic and para-aortic lymphadenectomy compared with pelvic lymphadenectomy alone according to risk of recurrence
• Study over long time change in staging and management
• Are PA nodes involved at preoperative imaging?• Surgical morbidity?
Correspondence Correspondence (The Lancet, August 2010)(The Lancet, August 2010)
Latha Balasubramani, Desiree F Kolomainen, Marielle Nobbenhuis, Jane Bridges, Desmond Barton
Roy Kruitwagen, Harold Pelikan,Hans Trum
• Inguinal lymphadenectomy as part of the routine systematic pelvic lymphadenectomy: low incidence and extend the morbidity
• Include recent FIGO staging• Selection patients and surgery details • Bias: 2 different hospitals
• Retrospective review 2000-08• 352 patiens• “Our data suggest that the
number of lymph node stations sampled, and not the number of nodes removed, is a more accurate predictor of lymph node status in endometrial carcinoma.”
• The purpose of this study was to identify practice patterns among gynecologic oncologists when performing a lymphnode evaluation during staging for endometrial cancer.
• A self-administered survey was sent via email to all SGO members, the survey addressed surgical approach, algorithms used to determine staging, and anatomic landmarks defining lymphadenectomy.
• 40% members responded. • 40% prefer laparotomy, • 31% perform robotic surgery, • 29% use laparoscopy.
• 53% never/rarely use frozen section to determine whether or not to perform lymphadenectomy.
• A majority perform staging on all grade 2 and grade 3 cancers (66% and 90%, respectively).
• When performing paraaortic lymphadenectomy, 50% use the IMA as the upper border and 11% take the dissection to the renal vessels.
ConclusionsCurrent controversies in surgical staging for endometrial
cancer are reflected in the practice patterns among gynecologic oncologists. At this point it is unclear if standardizing surgical practice patterns will improve outcomes for patients with endometrial cancer.
ConclusionsConclusions• In low risk patients no evidence of benefits
perfoming systematic lymphadenectomy
• In high risk patients strong evidence against performing systematic lymphadenectomy except of one retrospective study
• Open question evaluation of nodal status (FIGO stage)
Thank you !Thank you !