The Sentinel Node Concept in Patients with Cervical Cancer -A Multicenter Validation Study- of the German SUBMITTED Hermann Hertel, Christopher Altgassen,

The Sentinel Node Concept in Patients with Cervical Cancer

-A Multicenter Validation Study- of the German

SUBMITTED

Hermann Hertel, Christopher Altgassen, Antje Brandstädt, Christhardt Köhler, Matthias Dürst and Achim Schneider

for the AGO-study group

Introduction

-sentinel concept in the surgical treatment of breast cancer

-minimize morbidity

-sensitivity 88.6 – 91.2%

-negative predictive value (NPV) 91.1 – 95.7%*

-without compromizing oncological safety

Today this technique has become method of choice in the surgical treatment of breast cancer.

*Veronesi et al.: N Engl Med 2003;349:546-553, Krag et al.: N Engl Med 1998;339:991-995

advantage of sentinel technique

-reduction of negative lymph node dissection

-sentinel lymph nodes predict accurately the negative status of the remaining regional lymph nodes

Introduction

Gynecol Oncol update Leuven

5. May

-cervical cancer metastasize mainly lymphatic

-lymph node status is the most important prognostic factor

-lymphadenectomy - gold standard

If lymph node metastases are present at the time of primary surgery

5-year survival drops from 85% to 50%.

Introduction


5. May

Removal of lymph nodes can lead to:

-serocele formation-lymphedema-paraaesthesia -voiding disorders

More than 90% of the removed lymph nodes are free of metastatic disease. Patients could be preserved from potential morbidity.

Sentinel concept might be applicable in cervical cancer.

Introduction


5. May

prospective studies

Author Tc/Blue Patients Detection (n) (%)

Hauspy et al. 2007 Tc + blue 39 98

Seong et al. 2007 blue 89 57,3%

Schwedinger et al. 2006 blue 47 83

Vieira et al. 2004 blue 51 62,7

Yuan et al. 2004 blue 41 75,6Niikura et al. 2004 Tc + blue 20 90

Li et al. 2004 Tc 75 96,4

Rob et al. 2004 blue 100 60-90,5

Plante et al. 2003 blue +/- Tc 70 87-93

Wuppertal 2004

-evaluation of detection rate and diagnostic accuracy of sentinel lymph nodes

-patients with cervical cancer

-all stages

-to predict the histopathologic pelvic nodal status

Aim


5. May

1998-2006

-prospective multi-center cohort study

-Technetium, Patent Blue®, or both to identify sentinel lymph nodes

-pelvic (and para-aortic) node dissection

-sentinel nodes and non-sentinel nodes were histopathologically examined

The study


5. May

inclusion criteria

-histological proven cervical cancer (all stages), -signed informed consent,

-intension to surgical staging of the patient, -complete pelvic lymphadenectomy,

exclusion criteria

-preoperative detected metastatic disease, -previous pelvic or para-aortic lymphdenectomies,

-concurrent adnexal carcinoma, -cervical extension which made injection in normal

cervical tissue impossible, -neoadjuvant therapyGynecol Oncol update

Leuven 5. May

primary objective:-sentinel lymph node detection rate-accuracy (sensitivity, negative predictive value)

Hypothesis

sensitivity: 96,5% should be achieved/ 90% clinically accepted

100 sentinel positive patients necessary

total sample size depended on prevalence of positive sentinel nodes and detection rate

Statistics


5. May

Tracer application

Tc-albumines

60 MBq the day prior (1ml)

Blue dye (Patent Blue®)

4 ml after anesthesia

subepithelially


5. May

surgical procedure

laparoscopic pelvic lymphadenectomy (left)

surgical procedure

N. obturatorius

N. genito-femoralis

Vasa iliacaexterna

M. psoas

laparoscopic paraaortic lymphadenectomy

A. mesenterica inferior

V. renalis

positive pelvic lymphnode left side


5. May

Results

December 1998-October 2006

603 patients enrolled in 18 centers-excluded 96 patients-

(in 64 patients no pelvic sentinel node was detected)

507 patients for analysis of accuracy


5. May

Patients fulfilling inclusion but not

exclusion criteria n = 603

Excluded patients (n = 83)Reasons: Neo-adjuvant therapy (n = 12)Pelvic SLN not detected (n = 64)Pelvic nodal status (reference) inconclusive or unknown (n = 7)

Positiven = 82

Negativen = 422

Pelvic nodal status (Reference)

Positiven = 82

Positiven = 24

Negative (impos. by definition)

Neg.n = 398

Positiven = 3

Negative (impos. by definition)

Inconclusive 2

n = 3



Pelvic SLN nodal status (Index test)

Excluded patients:(n =13) Reasons: No marker applied (n = 1)No searching for SLN (n = 12)

Population for analysis of detection rate n = 590

Population for analysis of diagnostic accuracy n= 507

n=590

n=507

n=603

n=82 n=422

n=24!!

-flowchart-

disposition of patients eligiblefor analysis

median age 41 years (range 16-79 years)

squamous cell carcinoma 383 patients (75.5%) adenocarcinoma 97 patients (19.1%)

(5,4% others)

FIGO stage -IA1 in 38 patients (7.5%), -IA2 in 42 patients (8.3%),

-IB1 in 265 patients (52.3%), -IB2 in 55 patients (10.8%),

-IIA or IIB in 91 patients (17.9%), -IIIA to IVB in 15 patients (3%)


5. May

Results

cervical cancer were removed vaginally and lymph nodes were harvested endocopically in 283 patients (56%),

open approach was chosen in 224 Patients (44%)


5. May

Results

over all detection rate: 89,7% (CI95 86.9-92%)

pelvic: 88,6% (CI95 85,8-91,1%)

Tc alone (n=55) 82% detection ratePatent Blue® alone (n=195) 82% detection rateTc+Patent Blue® (n=340) 94% detection rate (p<0,001)


5. May

Resultsindentification of sentinel lymph nodes

median number of sentinel lymph nodespelvic: 2 (2-24)

paraaortic: 1 (1-9)

>5 sentinel nodes identified in 103 patients (20,3%)

median number of all lymph nodespelvic: 24 (2-70); n=507 patients

paraaortic: 13 (1-47); n=190 patientsGynecol Oncol update Leuven

5. May


pelvic lymph node metastasis n=106 patients

sentinel lymph nodes correctly predict metastatic disease n=82 patients

Sensitivity 77,4% (CI 68,2-85%) (<90% of clinically acceptability)

NPV 94,3% (CI 83-99,4%)


5. May

Resultsaccuracy of diagnostic test

tumor size

lower or equal 20mm in 249 patients (45.8%) larger than 20mm in 305 patients (47.7%)

(6,5% no data)

overall detection rate

94% in cancers smaller than 21mm

84% in cancers larger than 20mm (p<0.001). Gynecol Oncol update Leuven

5. May


sensitivity in subgroups of women with tumors

<21mm =90.9%(70,8-98,9%),

>21mm =72,7% (61,3-82,3%)

(p=0.091)


5. May


tumors < 21mm NPV=99.1 (CI95 96.6 – 100%)

tumors >20mm NPV=88.5% (CI95 82.9 – 92.8%),

(p<0.001)


5. May



5. May

Probability of diagnostic outcome in all patients –flowchart-

SLN not detected

0.114

SLN detected

0.886

Reference positive1.000


Reference negative0.943

SLN positive

0.163

SLN negative0.837

True positive0.144

False negative0.042

True negative0.700

0.114

Probability of diagnostic outcome

SLN: Pelvic SLN (Index test)Reference: Pelvic nodal status

SLN not detected

0.114

SLN detected

0.886




SLN positive

0.163

SLN negative0.837

True positive0.144

False negative0.042

True negative0.700

0.114

Probability of diagnostic outcome


4 patients!100


5. May

Probability of diagnostic outcome in patients with cervival cancer ≤20mm -flowchart-




True positive0.081

False negative0.008

True negative0.851

0.060

Probability of diagnostic outcome in patients with tumor size 20 mm





True positive0.081

False negative0.008

True negative0.851

0.060

Probability of diagnostic outcome in patients with tumor size 20 mm


100 1 patient!

Our data suggest that the sentinel concept is NOT applicable in patients with cervical cancer.

Sensitivity is to low.


5. May

Conclusion

Using the currently available concept, systematic lymphadenectomy CAN NOT be omitted!

Ultrastaging of sentinel lymph nodes may have a future role in addition to systematic lymphadenctomy.

HPV-associated markers have the highest potential of accurate identification of viable tumor cells.


5. May

Conclusion

Documents

The Sentinel Node Concept in Patients with Cervical Cancer -A Multicenter Validation Study- of the German SUBMITTED Hermann Hertel, Christopher Altgassen,