1. Management of early stage cervical cancer
David Cibula
Gynecologic Oncology Centre
General University Hospital in Prague
Charles University

2. Stage IB1 Sentinel lymph node Avoidance of parametrectomy Adjuvant radiotherapy

3. Sensitivity SENTICOL IA1 – IB1; N=139 Ultrastaging protocol (200 μm)
FNR Sensitivity 95% CI
All % % (74%, 99%)
Bilateral 0 % %
JCO, 2011, 29,

4. Sensitivity IA2 – IIB; N = 645 FU (median) 40 mo (1 – 116)
Age (median) 46 y (23 – 93)
Ultrastaging protocol
FNR Sensitivity 95% CI
All % % (86%,95%) Bilateral % % (91%,99%)
Gynecol Oncol, 2012, 124,

5. Sensitivity IA2 – IIB; N = 645 FU (median) 40 mo (1 – 116)
Age (median) 46 y (23 – 93)
FNR Sensitivity 95% CI
All % % (86%,95%) Bilateral % % (91%,99%)
No impact of stage on sensitivity.
Gynecol Oncol, 2012, 124,

6. Detection of „key nodes“ in atypical localization

7. SLN mapping Roy M, Plante M IA – IB1; N = 211 Localization
interiliac 86 %
common iliac 17 %
paraaortic % (incl. 2 positive)
Gynecol Oncol, 2011, 122,

8. SLN mapping SENTICOL study IA – IB1; N = 139 Localization
interiliac or external 81 %
„unexpected“ region 38 %
only „unexpected region 5 %
Ann Surg Oncol, 2012, 22

9. Detection of „key nodes“ in atypical localization
Triaging of patients

10. Fertility sparing surgery
Radical surgery OR
Fertility sparing surgery
LN +
Adjuvant radiotherapy
SLN
Radical surgery Primary radiotherapy OR
Fertility sparing surgery

11. Intraoperative SLN examination
N = 225; IA2 – IIB FS Final: ITC MIC MAC Negative = Positive = Sensitivity of FS: 0.56 (0.44;0.68)
Gynecol Oncol, 2013,

12. Detection of „key nodes“ in atypical localization
Triaging of patients
Detection of micrometastasis

13. SLN ultrastaging ; N=645 Negative 70 % Macromets 15 % Micromets 10 %
ITC %
=================================================
FIGO stage IA IB1 IB2 IIAB
Macromets 9 % 20 % 24 % 44 % <0.001
Micromets 4 % 6 % 12 % 13 %
ITC 4 % 4 % 5 % 5 %
Would not have been
Gynecol Oncol, 2012, 124,

14. Overall survival N = 645 Stage IA - IIB ITC Neg MIC MAC
Proportion of surviving
MAC
p<0.001
Time (months)
ITC
Negative
Micro-metastases
Macro-metastases

15. Detection of „key nodes“ in atypical localization
Triaging of patients
Detection of micrometastasis
Systematic PLND  SLN removal ?

16. Remaining task Level A evidence !
excellent prognosis after standard treatment
poor outcome of recurrences

17. SENTIX
A prospective observational trial on sentinel lymph node biopsy in patients with early stage cervical cancer
ClinicalTrials.gov: NCT
ENGOT CX2

20. SENTIX trial office: ivana.nohova@vfn.cz sentix@ceegog.eu

21. Stage IB1 Sentinel lymph node Avoidance of parametrectomy Adjuvant radiotherapy

22. Study
No of cases
LVSI (%)
LN+
Adjuv treat
FU (mo) median
Recurr
DOD
Rob 34 42 6 47 1
Pluta 57 32 5
Maneo 36 14 66
Fagotti 13 23 2 16
Palaia - 38
Raju 15 96
Biliatis 62 22 56
Plante 25 27
Total
247 7
Adopted from: Ramirez et al: Gynecol Oncol 2014, 132,

23. RCT – power analysis
Sample size estimates for non-inferiority trial (HR<1.4)
Recurrence rate
Arm A
Arm B
Total sample size estimate
5 %
4369
10 %
2185
15 %
1457
20 %
1093

24. Parametrial involvement
Multicenter trial, Israel
Stage I – IIA; N=530
All radical hysterectomy + PLDN
Parametrial involvement 58 (11%)
≤ 2 cm + no LVSI 2
≤ 2 cm + no LVSI + LN neg
M.D. Anderson
Stage IA2 – IB1; N=350
All radical hysterectomy
Parametrial involvement 27 (8%)
≤ 2 cm + no LVSI + LN neg 0
EJSO 2013, 39, 76-80
The parametria are never processed completely
Obstet Gynecol 2009, 114, 93-9

25. Unanswered questions Limited histological performance
Radicality of parametrectomy
Technique of pelvic lymph node dissection

26. Parametrial involvement
A) Parametria separated intraoperativelly
B) and completely histologically processed; N=69
Parametrial LN were detected in 93% of cases!!
Parametrial involvement
FIGO No
Type of parametrium
Ventral
Dorzal
Lateral
IB1 49 5 1 16
IB2 8 - 4
IIA 12 2 6
Total 69
8 (12%)
1 (1%)
26 (38%)
Cancer 2000, 88,

27. Parametrial involvement
Type of parametrial involvement
FIGO
Positive parametria(%)
Type of involvement
Continuous
LVSI
Parametrial LN+
IB1 31 4 10 9
IB2 63 3 1
IIA 58 6
Total
10 (15%)
12 (17%)
16 (23%)
All patients with pelvic LN+ had parametrial involvement
Two patients with pelvic LN negative had parametrial involvement!!
Cancer 2000, 88,

28. All patients with SLN negativity had all pelvic LN negative
573 LN (43 SLN non-SLN)
5762 sections! (2881 HE IHC)
No of cases
SLN
Non SLN 9
Neg 3
ITC 2
MIC 1
MAC
All patients with SLN negativity had all pelvic LN negative
for all types of metastases!
Gynecol Oncol Oct;143(1):83-6. 

29. SHAPE
A Randomized Phase III Trial Comparing Radical Hysterectomy and Pelvic Node Dissection vs Simple Hysterectomy and Pelvic Node Dissection in Patients With Low-Risk Early Stage Cervical Cancer  End point: Pelvic PFS
GOG 278
Studying the Physical Function and Quality of Life Before and After Surgery in Patients With Stage I Cervical Cancer
End points: physical functions (bladder, bowel, sectual), lymphedema
Concerv
Conservative Surgery for Women With Low-risk, Early Stage Cervical Cancer
End point: Immediate failure rate (residual disease in hyst specimen)

30. Stage IB1 Sentinel lymph node Avoidance of parametrectomy Adjuvant radiotherapy

32. RT (RH + PLDN  adjuvant radiotherapy) N=137 OBS (RH + PLDN) N=140
RCT; GOG 92
Stage IB, LN neg. + 2 of: >1/3 stromal invasion OR LVSI OR large tumor
RT (RH + PLDN  adjuvant radiotherapy) N=137
OBS (RH + PLDN) N=140
1988 – 1995 !!
RR for recurrence = p=.008
Gynecol oncol 1999,73,

33. RT (RH + PLDN  adjuvant radiotherapy) N=137 OBS (RH + PLDN) N=140
RCT; GOG 92
Stage I, LN neg. + 2 of: >1/3 stromal invasion OR LVSI OR large tumor
RT (RH + PLDN  adjuvant radiotherapy) N=137
OBS (RH + PLDN) N=140
HR for recurrence = p=.007
Int J Radiation Oncology Biol Phys 2006, 65,

34. Site of recurrence 30% recurrence rate in the OBS group!! OBS RT Local
21%
14%
Distal 9% 3%
30% recurrence rate in the OBS group!!
P=.074
Int J Radiation Oncology Biol Phys 2006, 65,

35. Site of recurrence 30% recurrence rate in the OBS group!! OBS RT Local
21%
14%
Distal 9% 3%
30% recurrence rate in the OBS group!!
„Radical hysterectomy required
removal of the uterus, parametrial
and paravaginal tissues, and the 25%
of the vagina along the uterosacral
ligaments.“
P=.074
Int J Radiation Oncology Biol Phys 2006, 65,

36. GUH, Prague 2003 - 2007 Number N=192 Follow-up 55 mo Age (mean) 46 y Stage IB1 62,5 % IB2-IIB 32 %
LN + 18 % Adjuvant th 22 %
Gynecol Oncol Mar;124(3):

37. OS and EFS as main end-points of the study (N = 192)
Cumulative proportion of survivors
RR in LN neg = 3 %
5-y EFS = 95,4 %
OS = 93,1 %
Overall survival (OS)
Event free survival (EFS)
Survival (months)
Gynecol Oncol Mar;124(3):

38. Surgery below current standards is a significant negative prognostic factor
Even in LN negative patients
There is an urgent need for trials on adjuvant treatment (radiotherapy / chemotherapy) with the emphasis on quality of the surgery!

39. Fertility sparing surgery
Radical surgery OR
Fertility sparing surgery
LN +
Adjuvant radiotherapy
SLN
Radical surgery Primary radiotherapy OR
Fertility sparing surgery