ESGO 1-st Basic Course in Gynecological Oncology

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

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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:


AORTIC NODE METASTASES ASSESSMENT:


AORTIC NODE METASTASES ASSESSMENT:


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


In practice: 75% at l.risk are not staged nor adj therapy 25% at h.risk received Rt (!)


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


Adjuvant therapy: ch/Rt / RT /Ch


Algorithms Decision-Making Algorithms Decision-Making


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”


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


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.


Percent radiation use after surgery, by surgeon & FIGO stage

Lymph Node Assessment by surgeon:General Gynecologist vs Gynecologic Oncologist

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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

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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

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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

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 !

ESGO 1-st Basic Course in Gynecological Oncology

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