is there enough evidence to shift to sentinel lymph node...

Is there enough evidence to shift to

Sentinel Lymph Node Concept

in Cervical Cancer?

Mustafa Erkan Sarı, MDAnkara Training and Research HospitalDepartment of Gynecologic Oncology

November 2018

2013 NCCN Guidelines

2014 NCCN Guidelines

Approximately 50% of cervical cancers are limited to cervix

For most cases standard treatment is radical hysterectomy / trachelectomy and bilateral pelvic LND

however, usually lymphatic metastasis will not be seen(15% LN METASTASIS IN STAGE 1A2-1B1 PATIENTS)

CERVICAL CANCER

Can we determine if there is lymphatic spread without a complete lymphadenectomy?Sentinel Lymph Node Concept

Risks of Lymphadenectomy-Morbidity

•Vessel and nerve injuries (%3.9)

•Venous trombosis (%5)

•Pulmoner emboli (%2.8)

•Lymphosel (%13.5)

•Lymphedema•Pelvic LND ( % 5-38)•Bad QOL•Sellulitis

Advantages of Sentinel Lymph Node Mapping

✓ Reduction of morbidity

✓ Direction of intraoperative surgery

✓ Detection of micrometasis and isolated tumor cells

✓ Detection of lymph nodes in atypical localization

• Blue Dyes

• Metilen Blue, Patent Blue, Isosulfan Blue

• Radioactive tracer: Technetium-99(Tc-99)

• Long

• Short

• Ultrashort

• Fluorescence-guided imaging• Indocyanine green (ICG)

Indicators

Why is ICG in the foreground?

• SLN selectable brightness

• SLN can be detected even in the case of bleeding

• ICG application is easy and does not require preop preparation like Tc99

• ICG success is higher than blue dye alone

• Equal to blue dye and Tc99 combination

Ann Nucl Med (2008) 22:487–494

Conclusions

• Bilateral SLNsmapping using ICG issuperior to othermodalities

Ann Surg Oncol (2016) 23:2183–2191

Nodal staging with an intracervicalinjection of ICG is accurate, safe, andreproducible in patients with cervicalcancer

Ann Surg Oncol (2016) 23:2959–2965

Rates of Bilateral Mapping

Tc99+MM MM ICG

Number of Patients 77 38 48

SLN detection rate (%) 97 89 100

Bilateral SLN detection rate(%) 58 54 85

Sensitivity ve NPV(%) 100 100 100

Buda et al. Ann Surg Oncol 2016

p=0.001

Tecrübe önemli> 30 vaka

Laparoscopic identification of the sentinel node after injection of Patent Blue Violet (PBV)

around early tumors of the cervix

If the sensitivity of the assessment of the BDLN is confirmed to be 100%, this laparoscopic approach

could transform the management of early cervical cancer

Gynecologic Oncology 79, 411–415 (2000)

SLN procedure performs well diagnostically for the assessment of nodalmetastases in patients with early stage cervical cancer

MedOncol (2015) 32:385

%88

Gynecologic Oncology 116 (2010) 28–32

SENTICOL

•139 early stage cervix ca (1A1-1B1)

•Tc99 and blue dye combination

•SLN complete pelvic lymph node dissection

•Detection Rate %97.8

•Sensitivity %92

•2/139 False Negative

• SLN biopsy was fully reliable only when SLNs were detected bilaterally

104 patients (76.5%) Lecuru F. J Clin Oncol 2011

SLN Detects Unexpected Drainage Pathways:Insights From the SENTICOL Study

• 5% had SLNs only in unexpected areas

• Positive SLNs were located inunexpected areas in 17% of patients

Mapping scheme of expected (areas 3 and 4) and unexpected (others)

Bats AS, et al. Ann Surg Oncol. 2013;20(2):413-422.

MSKCC SLN Algorithm

• 122 patients were included. Median SLN count was 3 and median total LN count was 20

• At least one SLN was identified in 93%

• Optimal (bilateral) mapping was achieved in 75% of cases

• SLN correctly diagnosed 21 of 25 patients with nodal spread

• When the algorithm was applied, all patients with LN metastasis were detected

• With optimal bilateral mapping, pelvic LND could have been avoided in 75% of cases

Cormier B, et al. Gynecol Oncol. 2011;122(2):275-280.

Gynecologic Oncology 122 (2011) 275–280Cormier B, et al. Gynecol Oncol. 2011;122(2):275-280.

Gynecologic Oncology 122 (2011) 275–280

†Cormier B, et al. Gynecol Oncol. 2011;122(2):275-280.††Intracervcal injection with dye, 99m technetium, or both.†††Including interiliac/subaortic nodes.††††Exceptions made for select case (see CERV-A 1 of 7).

Note: all recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology (NCCN Guidelines): Cervical cancer. V1.2014.

• 188 patients, 35 (19%) LN metastases

• SLN identified in 90%, bilateral in 62%

• The false-negative rate was 3.6% (1 case)– Sensitivity of 96%, NPV of 99%

• Applying the NCCN algorithm identified 100% of patients who had (+) LN

• CONCLUSIONS: We believe it is time to change the standard of care for women with early-stage cervical cancer to SLN biopsy only

Salvo G, et al. Gynecol Oncol. 2017;145(1):96-101.

G. Salvo & P. Ramirez (MDACC) Gyn Onc 2017

47 çalışma, n=4130

Gynecologic Oncology 139 (2015) 559–567

Gynecologic Oncology 139 (2015) 559–567

Routine H&E (1st cut)

Additional H&E & IHC stains (Ultrastaging)

Additional H&E & IHC stains (Ultrastaging)

50 mm

50 mm

Ultrastaging is for Negative SLN on Initial H&E Evaluation

Kim CH, et al. Int J Gynecol Cancer. 2013;23(5):964-970.

• Macrometastasis (> 2mm)

• Micrometastasis (0.2-2 mm)

• Isolated tumor cell (<0.2 mm)

Variable N (%)

Ultrastaging (96 of 114 who mapped)

No disease

Isolated cytokeratin-staining cells

Positive on H&E

Macrometastasis

Micrometastasis

Positive on ultrastaging only

Macrometastasis

Micrometastasis

Isolated tumor cells

77 (63.1)

8 (6.6)

6 (4.9)

1 (0.8)

1 (0.8)

2 (1.6) 41 (0.8)

Ultrastaging not performed (N = 26)

Failed mapping, no disease

SLN positive on H&EReason not specified, no disease

7 (5.7)14 (11.5)5 (4.1)

D. Cibula et al. / Gynecologic Oncology 124 (2012) 496–501

• Adjuvant Rx given to:– 85% of Macromets

– 83% of Micromets

– 52% of ITC

– 10% of node negative

• OS reduced in micro & macrometastasis, but not ITC

Significance of Low-Volume SLN Metastasis (N = 645)

ITC

LN(-)

MM & Macro

Overa

ll S

urv

ival

Cormier B, et al. Gynecol Oncol. 2011;122(2):275-280.

D. Cibula et al. / Gynecologic Oncology 124 (2012) 496–501

D. Cibula et al. / Gynecologic Oncology 124 (2012) 496–501

Risk of Micrometastases in Nonsentinel Pelvic Lymph Nodes

• 17 cases Stage IB1-IIA all >3cm

• Mean 30 pelvic nodes

• After processing all pelvic LNs by pathologic ultrastaging, there were no false-negative cases

Cibula D, et al. Gynecol Oncol. 2016

BMC Cancer 11, 2011

99mTc phytate

radical abdominal trachelectomy (RAT)

n=18, conization + vs. n=32, conization -

Int J Gynecol Cancer 2011;21: 1491Y1494

Does tm size effect rate of mapping?

2 cm-cut off

•<2 cm detection rate %95 ve sensitivity %100

•>2 cm detection rate %80 ve sensitivity %89

Lukas R. Exp Rev Anticancer Ther 2013

•Tumor size is not significant <2 cm vs 2-4 cm vs >4 cm

Cibula D. Gynecol Oncol 2018

•Tumor size >2 cm ICG is more effective

Di Martino G. JMIG 2017

Tm Size and Detection Rate

SLN Biyopsi - Survival

Lennox GK. Gynecol Oncol 2017

2Y-RFS: %97 vs 955Y-RFS: %93 vs 92

Ongoing Research: SENTICOL III Accepted by the French National Cancer Institute (Fabrice Lécuru)

• A prospective multicenter international randomizedstudy

• Compare the outcome of patients with negative bilateral SLN (SLN Algorithm) vs. patients with negative SLN + pelvic lymph node dissection

SENTIX Protocol

• A prospective observational trial on sentinel lymph

node biopsy in patients with early-stage cervical cancer

• The null hypothesis is that the recurrence rate after SLN

biopsy is noninferior to the reference recurrence rate of

7% (at the 24th month of follow-up) in patients after

systematic pelvic lymphadenectomy, but that the less

radical surgery is associated with significantly lower

postoperative morbidity

There are many studies reporting high sensitivity from multiple centers

According to these results the number of patients calculated for randomized study is 1400

Frumovitz M. Gynecol Oncol 2017

Summary

• SLN algorithm is a standard of care in many practices

• Its a reasonable strategy for

Stage IA1 with LVI, IA2, and IB1 tumors

THANK YOU…