ESGO-ESTRO-ESP Cervical Cancer Clinical Practice Guidelines Management of early stages: algorithms focusing on the histological data

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1 ESGO-ESTRO-ESP Cervical Cancer Clinical Practice Guidelines Management of early stages: algorithms focusing on the histological data David Cibula Gynecologic Oncology Centre General University Hospital in Prague Charles University David Cibula, VFN

2 Clinical staging Patients with cervical cancer should be staged according to the TNM classification!! based on a correlation of various diagnostic modalities (integrating physical examination, imaging and pathology) the method i.e. clinical (c), imaging (i) and or pathological (p) should be recorded David Cibula, VFN

3 Clinical staging Mandatory clinical and radiological diagnostic work-up Local work-up: Pelvic examination and biopsy Pelvic MRI OR endovaginal/transrectal ultrasound Nodal / distant work-up (LACC or suspicious LN): PET-CT or chest/abdomen CT David Cibula, VFN

David Cibula, VFN Tumor detection Tumor size

invasion Agreement with histology Agreement with

histology Ultrasound vs MRI Ultrasound vs MRI

93% 91 vs 88% 97 vs 90% P 0.001 P=0.10 P=0.39 P 0.

4 David Cibula, VFN Tumor detection Tumor size measurements Stromal invasion depth Parametrial invasion Agreement with histology Agreement with histology Agreement with histology Agreement with histology Ultrasound vs MRI Ultrasound vs MRI Ultrasound vs MRI Ultrasound vs MRI 96 vs 86% 95 vs 93% 91 vs 88% 97 vs 90% P P=0.10 P=0.39 P Epstein E., Fischerova D. et al. Gynecol Oncol. 2013;128(3):

5 David Cibula, VFN T1a T1a Conisation Diagnosis should be based on a conisation specimen Margins neg (except for preinvasive ectocervix) Margins pos Re-conisation Final pathology T1a1 / T1a2

6 David Cibula, VFN T1a T1a1 LVSI neg. LVSI pos. FU FU SLN LVSI neg. T1a2 Conisation or SH is an adequate treatment LVSI pos. ± SLN ± SH SLN ± SH LN staging should be performed; SLN is adequate

7 David Cibula, VFN T1b1/T2a1 Treatment strategy should aim for the avoidance of combining radical surgery and radiotherapy due to the highest morbidity after combined treatment.

8 David Cibula, VFN Radical surgery OR Fertility sparing surgery LN + Adjuvant radiotherapy

9 David Cibula, VFN Radical surgery OR Fertility sparing surgery SLN LN + Adjuvant radiotherapy Radical surgery OR Fertility sparing surgery Primary radiotherapy

10 T1b1/T2a T1b1/T2a MRI / (US) LN neg. LN pos. Surgery RT CRT ± PALND David Cibula, VFN

11 T1b1/T2a Radical surgery by a gynecologic oncologist is the preferred modality (MIS) T1b1/T2a MRI / (US) LN neg. LN pos. Surgery RT CRT ± PALND David Cibula, VFN

12 Incidence of local-regional recurrence (%) Cumulative Local/Regional Recurrence HR: 4.26 (95% CI ), p=0.009 TLRH/TRRH TARH Number at risk TARH TLRH Years from randomization

13 T1b1/T2a - Surgery LN assessment should be performed as the 1st step. SLN is strongly recommended. SLN (LN) FS (S)LN neg or not done LN pos (MAC or MIC) PLND + RH Final histology ± PALND RH abandoned No further LN dissection CRT David Cibula, VFN

14 Barranger E IB1 IIB N = 33 Detection rate Side specific detection rate False negative rate Early stages N = 23 Locally advanced N = 10 86,9 % 67,4 % 0 80 % 55 % 20 % Annals of Oncol, 2005, 16, David Cibula, VFN

15 David Cibula, VFN Long spinal needle Application into the residual stroma Gynecol Oncol, 2009, 115, 46-50

16 David Cibula, VFN SLN detection rate in large tumors Pathologic largest tumour size p Detection rate 2 cm N= cm N=138 4 cm N=72 Unilateral 91% 97% 89% Bilateral 79% 83% 76% FNR if bilateral SLN detected 1% 1% 0% Gynecol Oncol Mar;148(3):

17 T1b1/T2a - Surgery SLN (LN) FS Intraoperative assessment of LN is recommended (SLN / LN / suspicious LN) (S)LN neg or not done LN pos (MAC or MIC) PLND + RH Final histology ± PALND RH abandoned No further LN dissection CRT David Cibula, VFN

Intraoperative SLN examination N = 225; IA2 IIB FS Final: ITC MIC MAC Negative = 152 8 15 9

18 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, David Cibula, VFN

19 T1b1/T2a - Surgery SLN (LN) FS (S)LN neg or not done LN pos (MAC or MIC) PLND + RH Final histology ± PALND RH abandoned No further LN dissection CRT David Cibula, VFN

20 T1b1/T2a1 - Surgery SLN (LN) FS (S)LN neg or not done LN pos (MAC or MIC) PLND + RH Final histology ± PALND RH abandoned No further LN dissection CRT David Cibula, VFN

21 David Cibula, VFN SLN should be combined with systematic PLND (IB1) until results from prospective trials have confirmed its safety Unknown risk of LVD (small MAC) in non-sln Absence of universal protocol for SLN ultrastaging Limited prospective data available

David Cibula, VFN ENGOT-Cx 2 A prospective Phase II trial

cervical cancer ENGOT model: A Sponsor(s): CEEGOG Planned

22 David Cibula, VFN ENGOT-Cx 2 A prospective Phase II trial on sentinel lymph node biopsy in patients with early stage cervical cancer ENGOT model: A Sponsor(s): CEEGOG Planned No. of patients: 600 Countries participating: 18 Sites activated: 49 No. of already recruited patients: 300 Status: recruiting Timeline: 30/May/2016 (first patient recruited)

23 David Cibula, VFN Early stages SLN SENTICOL III Study type: RCT Leading group: GINECO Population: T1a1+LVSI T2a1 Primary objective: co-primary: DFS + Health Related QoL Description: SLN vs SLN + PLND 1:1; FS of SLN; Target group: 950 Expected completion: Q Current status: Recently opened

24 T1b1/T2a SLN (LN) FS (S)LN neg or not done LN pos (MAC or MIC) PLND + RH Final histology ± PALND RH abandoned No further LN dissection CRT David Cibula, VFN

25 David Cibula, VFN Querleu-Morrow classification (update 2017) Type of RH Lateral parametrium Ventral parametrium Dorsal parametrium Type A Halfway between cervix and ureter Minimal Type B1 At the ureteral bed Partial excision of the vesicouterine lig Minimal Partial excision of the recto-uterine/-vaginal lig Type B2 B1 + paracervical LND B1 B1 Type C1 At the iliac vessels transversally, at the uterine vein horizontally Excision of the vesicouterine lig (cranial to the ureter) Type C2 C1 + caudal part At the bladder (incl. vesico-vaginal lig) At the rectum (hypogastric nerve is spared) At the sacrum

26 David Cibula, VFN Risk groups according to prognostic factors and suggested type of radical hysterectomy Risk group Tumor size LVSI Stromal invasion Type of rad hyst LR 2 cm Neg Inner 1/3 B1 (A) IR 2 cm Neg Any B2 (C1) 2 cm Pos Any HR 2 cm Pos Any C1 (C2)

27 T1b1/T2a Final histology ` SLN pathologic ultrastaging increases staging accuracy, namely the identification of MIC and small MAC LN pos (MAC or MIC) OR Parametria pos OR Vaginal margins pos Adjuvant (C)RT David Cibula, VFN

28 Retrospective study, , stage IB1-IIA pn0 + no adjuvant treatment N=83; Recurrence rate = 18% ultrastaging of ALL LN Variable OR P value pn1 mic Stromal invasion 2/ Tumor size ( 2 cm ) LVSI Int J Gyn Obst 2016, 133, David Cibula, VFN

29 8 centres Inclusion criteria IA2 IIB Histology (S, A, AS) SLN + ultrastaging PLND FU data Gynecol Oncol, 2012, 124, N = 645 FU (median) 40 mo (1 116) Age (median) 46 y (23 93) Cell type Stage Adeno 25 % Squamo 75 % IB1 74 % IB2-IIB 17 % David Cibula, VFN

30 Proportion of surviving Overall survival 1,0 Neg 0,9 0,8 p<0.001 MIC MAC 0,7 0, Time (months) Mutual comparison of categories (p values): ITC Micro-met. Macro-met. Negative <0.001 <0.001 ITC Micro-met ITC Negative Micro-metastases Macro-metastases

31 David Cibula, VFN SLN ultrastaging Entire SLN should be analyzed Each section should be stained by both H E and cytokeratin Intervals between sections? ( m)

32 Sensitivity IA2 IIB; N = 645; 8 centers FU (median) 40 mo (1 116) SLN (ultrastaging) PLND SLN ultrastaging Pelvic non-sln N (%) Neg Neg 438 (68%) Neg Mac 18 (2.8%) ITC (4); MIC (19) MAC 23 (3.6%) = FNR Pos Neg 118 (18.3%) MAC MAC 48 (18.3%) Gynecol Oncol, 2012, 124, David Cibula, VFN

33 David Cibula, VFN N=645; at least unilateral SLN detection Pelvic LN status SLN status SLN sensitivity Positive N=41 Positive (any type) N=18 91%

34 Sensitivity IA2 IIB; N = 645; 8 centers FU (median) 40 mo (1 116) SLN (ultrastaging) PLND SLN ultrastaging Pelvic non-sln N (%) Neg Neg 438 (68%) Neg Mac 18 (2.8%) ITC (4); MIC (19) MAC 23 (3.6%) = FNR Pos Neg 118 (18.3%) MAC MAC 48 (18.3%) Gynecol Oncol, 2012, 124, David Cibula, VFN

35 David Cibula, VFN N=645; at least unilateral SLN detection Pelvic LN status SLN status SLN sensitivity Positive N=41 Positive (any type) N=18 91% Positive for MAC N=23 80%!!!

36 David Cibula, VFN Detection of LVSI from biopsy Intraoperative LN / SLN evaluation SLN ultrastaging Assessment of tumor related prognostic risk factors (LVSI, stromal invasion, tumor size)

37 3 7 David Cibula, VFN

Enterprise Interest None

Enterprise Interest None Cervical Cancer -Management of late stages ESP meeting Bilbao Spain 2018 Dr Mary McCormack PhD FRCR Consultant Clinical Oncologist University College Hospital London On behalf