1 of 64

Role of sentinel lymph node (SLN) mapping in cervical cancer

Mario M. Leitao, Jr., MD

Member & Attending Surgeon, Gynecology Service

Director, Gynecologic Oncology Fellowship Program

Director, Minimal Access and Robotic Surgery (MARS) Program

Department of Surgery

Professor, Weill Cornell Medical College

@leitaomd

2 of 64

Disclosures��Ad hoc consulting and lab proctoring: Intuitive Surgical�Consulting: Medtronic�Ad Board: JnJ/Ethicon�Ad Board: Immunogen

3 of 64

WHERE ARE THE RANDOMIZED TRIALS ESTABLISHING LYMPHADENECTOMY IN THE CARE OF UTERINE OR CERVICAL CANCER??

4 of 64

Therapeutic LND?? (microscopic disease)�No “gate” at the renal vessels or anywhere to scalenes

5 of 64

Cervical cancer�Scalene node mets if PAN (+)

Series	PAN mets (N)	Scalene mets N (%)
Brandt 1981 Vasilev 1990 Boran 2003	25 17 28	7 (28%) 4 (24%) 3 (11%)

6 of 64

LND �Therapeutic?

Landoni F, et al. Lancet 1997;350:535-540.

RCT of surgery vs RT for 2009 stage IB-IIA

So, is LND really therapeutic or diagnostic?

7 of 64

LND �Prognostic not therapeutic?

Chen Y, et al. Int J Gynecol Cancer 2013;23:157-163.

Retrospective review of 120 LN+ cervical cancers

RLN = total number of resected LNs

8 of 64

Need for PA node dissection�NCDB (2009 stage IA2-IB2)

del Carmen MG, et al. Gynecol Oncol 2018;406-411.

9 of 64

Need for PA node dissection�NCDB (2009 stage IA2-IB2)

del Carmen MG, et al. Gynecol Oncol 2018;406-411.

3-yr OS: 93% for both

10 of 64

Need for PA node dissection�NCDB (2009 stage IA2-IB2)

del Carmen MG, et al. Gynecol Oncol 2018;406-411.

NPV of PLN for PA node mets = 99.9%

19% with PLN mets with PA mets

11 of 64

Lymphadenectomy Concerns�Lower extremity lymphedema – endo ca

Yost KJ, et al. Obstet Gynecol 2014;124:307-315.

Attributable risk = 23%

Hysterectomy alone = 36%

LND = 52%

12 of 64

Lower extremity lymphedema (PRO)�SLN vs LND – endo ca

Group	N	PRO LEL N (%)	95%CI	P-value
SLN	180	27.2%	20.7-33.7%	0.002* 0.039**
LND	352	40.9%	35.8-46.1%	0.002* 0.039**

*Chi-square test

**Interval censoring method

Leitao Jr MM, et al. Gynecol Oncol 2020;156:147-153.

13 of 64

Lower extremity lymphedema (PRO)�SLN vs LND – endo ca

Multivariable analysis

Variable	OR	95% CI	P-value
LND vs SLN	1.81	1.22 – 2.69	0.003
BMI (one unit increase)	1.04	1.02 – 1.06	<0.001
EBRT (Yes vs No)	1.85	0.99 – 3.46	0.05

Leitao Jr MM, et al. Gynecol Oncol 2020;156:147-153.

14 of 64

Lower extremity lymphedema (PRO)�SLN vs LND – endo ca

¹Leitao Jr MM, et al. Gynecol Oncol 2020;156:147-153.

²Yost KJ, et al. Obstet Gynecol 2014;124:307-315.

LND¹

MSKCC

Med LN=19

LND²

MAYO

Mean LN=32

Comparing our findings with those published by our colleagues at the Mayo Clinic using the same 13-item questionnaire, we note that the rate of patient-reported lower extremity lymphedema was lowest in the cohort of women that underwent sentinel node mapping alone. It is important to recognize that patients will develop lymphedema over time even after hysterectomy alone as seen in 37% of patients in the Mayo Clinic study. This may be secondary to the surgery but more likely is a reflection of a natural aging process. Both studies are also consistent in that BMI and the use of external beam radiotherapy were associated with lower extremity lymphedema in both. There are of course differences between the 2 studies which need to be considered in greater detail and further analyses would be needed. However, our findings suggest that sentinel lymph node mapping alone in patients with endometrial carcinoma does not increase the rate of lower extremity lymphedema over hysterectomy alone.

15 of 64

SLN mapping

Is it the answer?

IS THE ANSWER!

16 of 64

SLN mapping in uterine/cervix cancer�History

1996

MDACC
First report in laparotomy

2001

Czech Republic
First report in laparoscopy

2003

MSKCC
Pilot study initiated

17 of 64

Cervical Injection Under Anesthesia�Isosulfan Blue 1%, Methylene Blue or Indocyanine Green (ICG)

Courtesy of N. Abu-Rustum

18 of 64

FILM RCT�ICG vs blue dye

Frumovitz M, et al. Lancet Oncol 2018;19:1394-1403.

P<0.0001

19 of 64

SLN via laparotomy

Can use blue dye
Can use ICG

NIR laparoscope
NIR handheld

https://www.stryker.com/us/en/endoscopy/products/spy-phi.html#:~:text=SPY%20Portable%20Handheld%20Imager%20(SPY,microsurgical%2C%20reconstructive%20and%20gastrointestinal%20procedures. (accessed 8/26/22)

20 of 64

SLN is for normal appearing nodes

Any suspicious nodes or extra uterine disease takes priority over mapping

21 of 64

SLN mapping �Early study (?first)

Prospective
2009 FIGO IB-IIA
4cc isosulfan blue in 4-6 sites on cervix
No ultrastaging
N=20

12 (60%) mapped
5 (25%) bilateral mapped
3 (25%) of 12 mapped (+)SLN
No false negatives

O’Boyle JD, et al. Gynecol Oncol 2000;79:238-243. (UT-Southwestern)

22 of 64

SLN mapping detection in cervix ca�Early prospective trials

Series	Year	N	Technique	Mapped		NPV	FNPV	Ultrastaging
				Any	Bilateral
O’Boyle	2000	20	Blue	12 (60%)	5 (25%)	9/9 (100%)	0%	N
Levenback	2002	39	Blue+Tc99	39 (100%)	37 (95%)	31/32 (96.9%)	3.1%	Y
Marchiole	2004	29	Blue (27) Blue+Tc99 (2)	29 (100%)	26 (90%)	21/24 (87.5%)	12.5%	Y
Devaja	2012	86	Blue+Tc99	84 (98%)	63 (73%)	67/67 (100%)	0%	Y
Altgassen (AGO)	2008	507	Tc99 (45) Blue (159) Blue+TC99 (303)	529 (90%)	?	398/422 (94.3%)	5.7%	N
TOTAL						526/554 (94.9%)	5.1%

Early learning curves

Ultrastaging not standard

Just looking for blue or hot nodes

23 of 64

SLN mapping cervical cancer�MSK algorithm

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

122 patients

All nodal disease identified using algorithm

Paraaortic LND – at attending discretion

If there is no mapping on a hemi-pelvis, a side-specific LND is performed

Retroperitoneal evaluation

Any suspicious nodes must be removed regardless of mapping

Peritoneal & serosal evaluation & washings

Excision of all mapped SLN w/ ultrastaging

24 of 64

SENTICOL study

Prospective single-arm
7 centers in France
2009 FIGo IA1(LVSI) – IB1
SCC, adeno, adenosquamous
Tc99+blue
SLN + LND
Ultrastaging done

Lecuru F, et al. J Clin Oncol 2011;13:1686-1691.

25 of 64

SLN mapping�SENTICOL study

Lecuru F, et al. J Clin Oncol 2011;13:1686-1691.

104 patients with bilateral SLN

NO false negatives

26 of 64

SENTICOL-2 study

RCT
SLN alone vs SLN+PLND
Randomized intraop if bilateral SLNs identified
28 centers in France
2009 FIGo IA1(LVSI) – IB1 and IIA1
SCC, adeno, adenosquamous
Tc99+blue
Ultrastaging done

Mathevet P, et al. Eur J Cancer 2021;148:307-315.

27 of 64

SENTICOL-2 study

Primary endpoint – lymphatic morbidity at 6 months

Circumference measured at various levels
Patient and surgeon questionnaires

Secondary endpoints – QOL, SLN detection, oncologic outcomes up to 3 years, false negative in SLN+LND group
Sample size

17% lymphatic morbidity in SLN+PLND
5.6% in SLN alone
Type I error=5%, Power=80%
124/arm required

Mathevet P, et al. Eur J Cancer 2021;148:307-315.

28 of 64

SENTICOL-2 study

Mathevet P, et al. Eur J Cancer 2021;148:307-315.

29 of 64

SENTICOL-2�SLN metastases

Mathevet P, et al. Eur J Cancer 2021;148:307-315.

NO false negatives in the SLN+PLND arm

30 of 64

SENTICOL-2�Lymphatic morbidity

Mathevet P, et al. Eur J Cancer 2021;148:307-315.

P=0.004

P=0.06

P=0.007

31 of 64

Lower extremity lymphedema (PRO)�SLN vs LND – endo ca

¹Leitao Jr MM, et al. Gynecol Oncol 2020;156:147-153.

²Yost KJ, et al. Obstet Gynecol 2014;124:307-315.

LND¹

MSKCC

Med LN=19

LND²

MAYO

Mean LN=32

SENTICOL-2

Comparing our findings with those published by our colleagues at the Mayo Clinic using the same 13-item questionnaire, we note that the rate of patient-reported lower extremity lymphedema was lowest in the cohort of women that underwent sentinel node mapping alone. It is important to recognize that patients will develop lymphedema over time even after hysterectomy alone as seen in 37% of patients in the Mayo Clinic study. This may be secondary to the surgery but more likely is a reflection of a natural aging process. Both studies are also consistent in that BMI and the use of external beam radiotherapy were associated with lower extremity lymphedema in both. There are of course differences between the 2 studies which need to be considered in greater detail and further analyses would be needed. However, our findings suggest that sentinel lymph node mapping alone in patients with endometrial carcinoma does not increase the rate of lower extremity lymphedema over hysterectomy alone.

32 of 64

SENTICOL-2�Survival

Favre G, et al. Front Oncol. 10:621518. doi: 10.3389/fonc.202.621518.

Median f/u =51 mo

4-yr DFS

89.5% (SLN)

93.1% (SLN+PLND)

4-yr OS

95.2% (SLN)

96% (SLN+PLND)

P=0.97

33 of 64

SENTICOL I&II �Survival (post-hoc analysis)

Balaya V, et al. Gynecol Oncol 2022;164:53-61.

Median f/u

53m SLN v 46m SLN+PLND (P=0.09)

7-yr DFS

85.1% (SLN)

80.4% (SLN+PLND)

aHR 1.78 (95%CI: 0.71-3.94)

OPEN vs MIS

HR 1.60 (95%CI:0.37-6.90)

“trend” worse for OPEN

34 of 64

SENTICOL I&II �Survival (post-hoc analysis)

Balaya V, et al. Gynecol Oncol 2022;164:53-61.

Median f/u

53m SLN v 46m SLN+PLND (P=0.09)

7-yr DSS

90.8% (SLN)

97.2% (SLN+PLND)

aHR 3.02 (95%CI: 0.69-13.18)

OPEN vs MIS

HR 3.90 (95%CI:0.8-19.02)

35 of 64

Lecuru F, et al. Int J Gynecol Cancer 2019;29:829-234.

36 of 64

SENTICOL III study

RCT
SLN alone vs SLN+PLND in SLN negative cases on frozen section and bilateral mapping
Randomized intraop
Tc99 alone, Tc99+blue, Tc99+ICG, ICG alone
Blue alone not allowed

Lecuru F, et al. Int J Gynecol Cancer 2019;29:829-234.

37 of 64

SENTICOL III study

Co-primary endpoints

DFS (non-inferiority)
Health related QOL (superiority)

Multiple secondary endpoints
5% non-inferiority margin for DFS
One-sided alpha = 5%
Power = 80%
Interim analysis planned after 132 events
900 patients total needed
For HR-QOL, need 950 patients

Lecuru F, et al. Int J Gynecol Cancer 2019;29:829-234.

38 of 64

As of 9/16/22

39 of 64

Cibula D, et al. Int J Gynecol Cancer 2019;29:212-215.

Blue, Tc99, ICG

(alone or in combo)

24 months follow-up

40 of 64

SENTIX

Non-inferiority, single arm prospective
Primary endpoint is recurrence at 24 months
Secondary endpoints

LEL
Symptomatic lymphocele

Historical “reference” recurrence rate 7%
Non-inferiority margin 5%
Power 90%
300 “per-protocol” cases needed

Cibula D, et al. Int J Gynecol Cancer 2019;29:212-215.

41 of 64

SENTIX�Secondary endpoints