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EARLY STAGE CERVICAL CANCER: IS MINIMAL INVASIVE SURGERY HARMING? GIOVANNI SCAMBIA Fondazione Policlinico Universitario A. Gemelli IRCCS Università Cattolica Sacro Cuore Roma

EARLY STAGE CERVICAL CANCER: IS MINIMAL INVASIVE SURGERY NOT HARMING?

EARLY STAGE CERVICAL CANCER: IS MINIMAL INVASIVE SURGERY HARMING? MIS vs OPEN approach in CERVICAL CANCER: Difficult to win…but it’s not over…

RADICAL HYSTERECTOMY IN CERVICAL CANCER: IS MINIMAL INVASIVE SURGERY HARMING?

RADICAL HYSTERECTOMY IN CERVICAL CANCER: IS MINIMAL INVASIVE SURGERY HARMING?

Uterus

SURGICAL TREATMENT OF CERVICAL CANCER: a long history

Ernst Wertheim and Friedrich Schauta introduced Radical Hysterectomy

RCT 1890

Japanese school introduced Nerve sparing RH

1940 Vincent Meigs added Lymphadenectomy to RH

Lymph nodes

RCT 1960

Daniel Dargent and Costantino Mangioni introduced Radical Trachelectomy and simple conization in selected cases

Camran Nezhat introduced Laparoscopic Radical Hysterectomy

1992

RCT

2000

2018

Daniel Dargent and Rene Verheijen proposed SLN concept

RCT ongoing

Cibula D, Pรถtter R, Planchamp F, et al. The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology Guidelines for the Management of Patients with Cervical Cancer. Int J Gynecol Cancer. 2018 May;28(4):641-655.

Meta-analysis 1539 cases: - LRH shows better short term outcomes compared with ARH - Oncologic outcome and 5-year survival were similar between the two groups

Wang YZ, et al. BMC Cancer. 2015;15:928

LRH: laparoscopic; ARH: open; RRH: robotic

Meta-analysis 2922 cases: - LRH is safe and has lower operative complication rates than ARH

Cao T, et al. J Laparoendosc Adv Surg Tech A. 2015;25(12):990-8

RRH (n = 259) ORH (n = 232): - RRH had improved clinical outcomes compared to ARH - Disease recurrence and survival were comparable

Sert BM, et al. Eur J Surg Oncol 2016; 42: 513-22

• • • • •

Retrospective analysis National Korean database OPEN vs LPS RH 2011-2014 6335 patients (3235 open vs 3100 LPS) LPS was associated with lower rates of complication, fewer transfusions, a shorter hospital stay, less adjuvant therapy, and reduced total medical costs (p<0.001) • Laparoscopic surgery was associated with a better overall survival than abdominal operations (HR, 0.74; 95% CI, 0.64 - 0.85)

RADICAL HYSTERECTOMY IN CERVICAL CANCER: WE SEE WHAT WE WANT TO SEE

MIS was as adequate and effective as abdominal surgery in terms of surgical and oncological outcomes in the surgical treatment of FIGO stage IB1

RADICAL HYSTERECTOMY IN CERVICAL CANCER: IS MINIMAL INVASIVE SURGERY HARMING?

Hypothesis: MI-RH was not inferior to OPEN-RH in terms of survival rate 33 centers worldwide recruited 631 patients June 2008 - June 2017

RECURRENCES LACC trial 2018: HR 4.26 (95%CI: 1.44 – 12.60) LPT: 2.2% LPS: 8.5%

LACC trial 2019: HR 3.96 (95%CI: 1.91 – 8.21) LPT: 2.9% LPS: 11.3% OVERALL SURVIVAL LACC trial 2018: HR 6.0 (95%CI: 1.77 – 20.30) LPT: 0.9% LPS: 5.9%

As the follow-up is prolonging, the survival difference is reducing

LACC trial 2019: HR 2.86 (95%CI: 1.29 – 6.38) LPT: 2.6% LPS: 7.5%

RADICAL HYSTERECTOMY IN CERVICAL CANCER: IS MINIMAL INVASIVE SURGERY HARMING?

• 400 responses • 83% of the survey respondents did not anticipate these trial results • Respondents attributed the outcomes in the MIS group to several factors, such as: 1. less radical technique than with open surgery 2. incorrect manipulation 3. spread of the tumor because of CO2 gas insufflation

• 57% of the ESGO members who responded to the survey have changed their approach to open surgery • 50% consider MIS to be appropriate only for small tumors • Almost 90% of the respondents reported that they intend to share this article with every patient • 75% consider it unethical not to discuss the trial results with surgical candidates Chiva L, Cibula D, Querleu D. Minimally Invasive or Abdominal Radical Hysterectomy for Cervical Cancer. N Engl J Med. 2019 Feb 21;380(8):793-4.

LACC trial Criticisms

Which is the pathogenic mechanism explaining survival difference?

Are different Institutional/ Country experiences consistent with LACC trial?

Is there a difference in sub-groups of patients?

Does surgeonâ&#x20AC;&#x2122;s experience impact on oncological outcomes?

Do we need a confirmatory trial and how should it be designed?

LACC trial Criticisms

Which is the pathogenic mechanism explaining survival difference?

Are different Institutional/ Country experiences consistent with LACC trial?

Is there a difference in sub-groups of patients?

Does surgeonâ&#x20AC;&#x2122;s experience impact on oncological outcomes?

Do we need a confirmatory trial and how should it be designed?

LACC trial possible criticisms High rate of parametrial involvement in MIS group (7% vs 4%) Adjuvant treatment administered according to center guidelines/no standardized adjuvant treatment No info on pathologic data/Lack of central pathology review

Number of robotic cases in LACC trial: 45

Number of patients per site

64% of recurrences in 5/33 centers

14 countries - 9,5 years recruitment Open arm: excellent result

Missing data (grade, stromal invasion, tumor diameter) Trial was not powered to evaluate difference in tumors <2cm

Uterine manipulation and colpotomy approach not stated

MIS/Robot

Trial

Open

Cibula et al.

Int J Gynecol Cancer. 2011;21(4):690-8 -

IA-IIB Cervical cancer Radical hysterectomies Median FU 55 months 120 IB1 Adjuvant treatment 6.4% Recurrences in IB1: 3/120 (2.5%)

Nie et al.

Int J Gynecol Cancer. 2017;27(9):1990-1999 -

Hockel et al.

Lancet Oncol. 2009;10(7):683-92 -

IB-IIB Cervical cancer TMMR Median FU 41 months 159 IB1 - IIA (total 212) Adjuvant treatment 3.7% (NO RT) Recurrences 3/159 (1.9%)

Robot vs Laparoscopic RH Median FU: not reported IB1: 592 Adjuvant treatment 40% robotic and 55% laparoscopic Recurrences in 32/856 (3.7%) (0 recurrences in robotic arm)

Chiantera et al.

Gynecol Oncol. 2015;139(1):47-51 -

L-TMMR Median FU 18 months IB1: 61 Adjuvant treatment 36.6% Recurrences 2/71 (2.8%)

LACC trial Criticisms

Which is the pathogenic mechanism explaining survival difference?

Are different Institutional/ Country experiences consistent with LACC trial?

Is there a difference in sub-groups of patients?

Does surgeonâ&#x20AC;&#x2122;s experience impact on oncological outcomes?

Do we need a confirmatory trial and how should it be designed?

Uterine manipulation

CO2 effect

Radicality of surgery

Lymph nodes manipulation

Cancer cell implantation could be caused by: â&#x20AC;˘ inadvertent presentation of cancerous tumor cells to the circulating pneumoperitoneum â&#x20AC;˘ disturbance of the superficial mesothelial layer caused by the high CO2 pressure

The ability of malignancy to spread in laparoscopic surgeries is mainly due to the direct implantation of cancer cells at trocar sites during extraction of the tumor specimen, with spilling of exfoliated cells, and excessive and non-standard manipulation of the tumor.

CO2 may cause peritoneal implantation

No role of CO2 in peritoneal implantation

MI-RH intracorporeal colpotomy under CO2 pneumoperitoneum may carry a risk of positive vaginal cuff margin, as well as intraperitoneal tumor spread in ECC

Exposure of cervical cancer to circulating CO2 may result in tumor spread ?

256 underwent MIS for IB1 CC

40 had no exposure to circulating CO2

19 vaginal manchette or vaginal colpotomy

216 possible exposure to circulating CO2 due to intracorporeal colpotomy

21 cervical conization (+LND) for fertility sparing surgery

Exposure of cervical cancer to circulating CO2 may result in tumor spread ?

NO cancer exposure

Intracorporeal colpotomy

40

216

Tumor Diameter < 20mm > 20 mm

26 (66.7) 13 (33,3)

128 (60,1) 85 (39.9)

0.439

LVSI Neg Pos

19 (59.4) 13 (40.6)

110 (58.8) 77 (41.2)

0.953

LN status Negative Positive

32 (97.0) 1 (3.0)

173 (86.9) 26 (13.1)

0.239

Recurrence No Yes

38 (95.0) 2 (5.0)

187 (86.6) 29 (13.4)

0.133

Distant recurrence No Yes

2 (100) -

21 (72.4) 8 (27.5)

patients

p

NO cancer exposure to CO2 Intracorporeal colpotomy

P=0.081 0.098

ď&#x192;&#x2DC; Present numbers are to low to clarify the issue. Anyway,

ď&#x192;&#x2DC;Any possible cancer spillage should be avoided!

Vaginal colpotomy or vaginal manchette

Endobag for LN removal

Gottschalk E, Lanowska M, Chiantera V, et al.

JSLS. 2011

Avoid uterine manipulation

Vaginal Closure with EndoGIA Boyraz G. et al. JMIG 2018

LACC trial Criticisms

Which is the pathogenic mechanism explaining survival difference?

Are different Institutional/ Country experiences consistent with LACC trial?

Is there a difference in sub-groups of patients?

Does surgeonâ&#x20AC;&#x2122;s experience impact on oncological outcomes?

Do we need a confirmatory trial and how should it be designed?

MIS in ECC: Gemelli experience over time 2yrs DFS

Rate of Minimally Invasive procedures performed each year

ď&#x192;źNo evidence of reduced survival related to the increase use of MIS ď&#x192;źDFS improved among the past years and will continue over the years

CONCLUSION: Patient’s selection criteria can be developed, based on the presence or absence of risk factors, that would allow safe selection of those patients who can safely be treated with minimal access surgery

• • • • • • • •

Retrospective analysis IB1 only 779 cases 8 UK centers 78% Laparoscopic/Robotic approach Median FU: 23 months 36/779 (4.6%) recurrences No mortality difference between MIS and open approach

Selection bias???

# Abs. 12539 12471

12677

Country SNUH

All

IB

LR/HR

5yr PFS 80.2 vs 84.9 5yr OS 98.0 vs 98.1

HRr 2.88 (1.71-4.86) HRd nr

HRr 2.27 (1.03-4.98) OS nr

PFS no difference in LR (IB<2); OS nr

AMC

---

---

---

PFS and OS no difference in HR (N+)

ICES

5yr PFS 87.2 vs 89.2 5yr OS 91.8 vs 92.9

PFS and OS no difference

HRr 1.97 (1.1-3.5) HRd 2.2 (1.14.1)

PFS and OS no difference in LR (IA)/HR (II)

3yr PFS 87.0 vs 90.8 3yr OS 95.2 vs 96.3

PFS and OS no difference

PFS worse OS no difference

PFS and OS no difference in LR (IA)

---

OS no difference after learning curve

---

12994

12773

All MIS vs open

NCDB

---

LACC trial Criticisms

Which is the pathogenic mechanism explaining survival difference?

Are different Institutional/ Country experiences consistent with LACC trial?

Is there a difference in sub-groups of patients?

Does surgeonâ&#x20AC;&#x2122;s experience impact on oncological outcomes?

Do we need a confirmatory trial and how should it be designed?

Authors

Year

Journal

Design

N. pts total

Median FU (months)

MIS Survival ≤2cm

OPEN Survival ≤2cm

P-value

Ramirez et al.

2018

NEJM

RCT

631

30

RR: 1.6%

RR: 0.3%

0.90

Kanao H et al.

2019

J Gynecol Oncol

Retrospective

163

30.2

PFS 2.5y: 100%

PFS 2.5y: 96.3%

0.897

Doo et al.

2019

Gynecol Oncol

Retrospective

105

25.4

HR (Recurrence): 0.72 (95%CI 0.09-5.87)

0.76

Kim et al.

2019

Gynecol Oncol

Retrospective

593

114.8

PFS 5y: 92.4%

PFS 5y: 93.5%

0.74

Melamed et al.

2018

NEJM

Retrospective

2461

45

HR (Death): 1.46 (95%CI 0.703.02)

0.99

Nam JH et al.

2012

Ann Oncol

Retrospective (matched)

526

92

PFS 5y: 94.2%

PFS 5y: 97.4%

0.166

Gemelli series

2019

Not yet published

Retrospective

421

33

PFS 3y: 93.9%

PFS 3y: 88.6%

0.372

PFS: progression-free survival HR: hazard ratio RR: recurrence rate

Authors

Year

Journal

Design

N. pts total

Median FU (months)

MIS Survival >2cm

OPEN Survival >2cm

P-value

Ramirez et al.

2018

NEJM

RCT

631

30

RR: 5.6%

RR: 1.6%

NR

Kanao H et al.

2019

J Gynecol Oncol

Retrospective

163

30.2

PFS 2.5y: 89.9%

PFS 2.5y: 87.6%

0.60

Doo et al.

2019

Gynecol Oncol

Retrospective

105

25.4

Kim et al.

2019

Gynecol Oncol

Retrospective

593

114.8

HR (Recurrence): 0.31 (95%CI 0.11-0.90)

0.04

PFS 5y: 72.1%

PFS 5y: 86.9%

0.04

OS 5y: 91.5%

OS 5y: 87.6%

0.90

Melamed et al.

2018

NEJM

Retrospective

2461

45

HR (Death): 1.66 (95% CI 1.19 â&#x20AC;&#x201C; 2.30)

Nam JH et al.

2012

Ann Oncol

Retrospective (matched)

526

92

PFS 5y: 90.6%

PFS 5y: 88.5%

0.68

Gemelli series

2019

Not yet published

Retrospective

272

25

PFS 3y: 71.4%

PFS 3y: 85.4%

0.014

PFS: progression-free survival HR: hazard ratio RR: recurrence rate

Significant

LACC trial Criticisms

Which is the pathogenic mechanism explaining survival difference?

Are different Institutional/ Country experiences consistent with LACC trial?

Is there a difference in sub-groups of patients?

Does surgeonâ&#x20AC;&#x2122;s experience impact on oncological outcomes?

Do we need a confirmatory trial and how should it be designed?

Survival results according to surgeon’s experience at Gemelli hospital

Survival %

 15 surgeons, 239 laparoscopic Radical Hysterectomy performed  Each one had performed > 50 laparoscopic procedures and > 50 oncological procedures  no difference in terms of pathological patients characteristics

Number of procedures performed

 L-RH is a complex surgical procedure that requires a dedicated training

Learning curves for MI-RH

Robotic Radical Hysterectomy during learning period resulted in higher post-operative complications and lower OS when compared to Laparoscopic Radical Hysterectomy in the experienced period Chong GO, et al. Int J Gynecol Cancer. 2018 Feb;28(2):226-232

An acceptable level of surgical proficiency in laparoscopic radical hysterectomy is reached after approximately 20 cases Kong TW, et al. Obstet Gynecol Sci. 2015 Sep;58(5):377-84

Improvement of surgical performance in robot-assisted surgery for cervical cancer can be achieved after 28 cases Yim GW, et al. J Gynecol Oncol. 2013 Oct;24(4):303-12

LACC trial Criticisms

Which is the pathogenic mechanism explaining survival difference?

Are different Institutional/ Country experiences consistent with LACC trial?

Is there a difference in sub-groups of patients?

Does surgeonâ&#x20AC;&#x2122;s experience impact on oncological outcomes?

Do we need a confirmatory trial and how should it be designed?

• Only ROBOTIC in MIS arm? Laparoscopy?

• Biology of each tumor • Standardization of surgical technique according to tumor size • Standardization of adjuvant treatment a priori • Standardization of pathology assessment • Quality of life assessment • Only high-volume/referral centers • Record video of each operation • How to integrate SLN biopsy in a new trial?

• Only ROBOTIC in MIS arm?

Robotic-assisted Approach to Cervical Cancer (RACC Trial) PRIMARY ENDPOINT • Recurrence-free survival (RFS) at 60 months SECONDARY ENDPOINTS • Overall survival (OS) at 60 months • Perioperative morbidity • Quality of life • Diagnostic accuracy of a sentinel node algorithm in cervical cancer • Health care costs

Early stage Cervical Cancer:

RANDOMIZED

- IB1-2 (IB3 excluded) and IIA1

- Type B or C radical hysterectomy - ECOG 0-2

NOT YET RECRUITING

OPEN RH + SLN + Pelvic lymphadenectomy ROBOTIC RH + SLN + Pelvic lymphadenectomy

Women should be informed of all the evidence, weighing the power of different studies No study was able to find a difference in tumors <2cm Different studies demonstrated that survival is worse in tumors >2cm No study was able to explain the reason why MIS worsen survival Many observational studies demonstrated lower complication rate in MIS

Stage > IIIB

Locally advanced/ persistence

MIS Before LACC trial

Stage IB1, >2cm, N+

Stage IB1

MIS After LACC trial

<2CM, N0

Stage IA1-IA2

N0

?

MIS IN EARLY STAGE CERVICAL CANCER: CONCLUSIONS • LACC trial reminded gynecologic oncology community that NEW TECHNOLOGIES MUST BE CONTROLLED AND TESTED WITH PROSPECTIVE TRIALS (e.g. morcellation) • LACC trial helped surgeons to re-think and reevaluate MIS in surgical oncology

• LACC trial must represent a PUSH TOWARD THE FUTURE and not a step back to the past

See you in Roma !!!

The Catholic University GYO ALLIANCE Abano Terme

Novara

Florence/Grosset o Chieti Campobasso Olbia Acquaviva delle Fonti

Palermo

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