Post on 09-Jul-2020
Who needs surgery in relapsed ovarian
cancer
J. Sehouli
Director of the Department of Gynecology and Center for Oncological Surgery
ESGO Ovarian Cancer Center of ExcellenceCharité Comprehensive Cancer Center
Charité/ Campus Virchow-Klinikum
University of Berlin; Europe
©Sehouli 2019 Charité Berlin
=?
What factors influence the treatment decision making process
(„the Charité-algorhytm“)
➢ Current syptoms?, tumor pattern?
➢ Therapie free and progression free interval? (platinumresistance yes/no, relative or platinumsensitive?)
➢ General and functional status
➢ Relevant comorbidities? comedication?
➢ Side effects and complications of previous therapies?
➢ Ressources to overcome complications?
➢ Quality and results of the surgical and medical therapies?
➢ Previous therapy with bevacizumab?
➢ Tumorbiology (BRCA-Test?)
➢ Surgery vs. Surgery + medical therapy vs medical therapy vsbest supportive care
➢ Motivation of the patients (preference, attitude)
➢ Treatment options?
➢ Study participation?
Treatment decision
Personalized Strategies in Relapsed Ovarian Cancer
Symptoms?
Bowel obtruction? (Subileus/Ileus), Pleural effusion?/Ascites?
Symptomatic
Therapy required?
Operation?
(ggf.
PEG?,
pleura-
drainage?
ascites-
drainage?)
no
Bevacizumab-
Prior therapy or
contraindications
?
yes negativunknown
Carboplatin+ Gemcitabine
yes
Surgery with the chance
of complete resection?
yes no
yes no
Carboplatin + peg. lip.
Doxorubicin
Carboplatin +
Paclitaxel
In case of platinum
allergy,
desensibilization
/Trabectidin + peg.
lip. Doxorubicin
* based on country
specific aproval
status
Olaparib*
Bevacizumab*
Fast track
BRCA-testing
BRCA-Status ?
©Sehouli/2019
Niraparib*
Rucaparib*
Who needs sugery in relapsed ovarian
cancer?
What are the realistic goals?
Improving
QoL
Increasing
PFS
Increasing
OAS
©Sehouli 2019 Charité Berlin
Palliative surgical and non-surgical
interventions in relapsed ovarian cancerIndication, technique, objective, outcome parameter, evidence?
Pain management
Conservative (medical) therapies of symptoms
Chemotherapy
Irradiation
PEG (endoscopic, open)
Stents
Ascites punctions(drainage) (alpha-pump)
Pleural effusion punction bzw. -drainage (Denver-
drainage)
Nephrostomata
PORT-implantation
Surgery Jalid Sehouli, 2019
©Sehouli 2015
Jalid Sehouli, 2015
Jalid Sehouli, 2015
Jalid Sehouli, 2015
Jalid Sehouli, 2015
Jalid Sehouli, 2015
Salvage Surgery due to mechanical bowel
obstruction in relapsed ovarian cancer -
clinical and surgical results of an
observational studyArmbrust Robert, Fotopoulou Chrisiina, Sehouli Jalid (unpublished)
- Retrospective analysis, N=87 (Charité: 67, Imperial: n= 10)
- Relapsed OC patients between 2013 and 2017 with acute
mechanical bowel obstruction
- salvage extraperitoneal “enbloc” intestinal resection
- Surgical time: 270 min (range,126-678 min)
- CDG>III: 73%
- 30 mortality: 8%
- 53% received another cycle of chemotherapy median
44days after surgery
The evolution of surgery in ovarian cancer
• Indication/contraindication
• Modified sugrical techniques, with higher bowel resection
rates and enbloc-resections
• Improved intraoperative management
• Introduction of ERAS concept
• Better possibilities to plan compex surgery at the best time at
the best center
©Sehouli 2019
The formulation has improved, this true for (targeted)
drugs and surgery!
© AGO e.V.in der DGGG e.V.
sowie
in der DKG e.V.
© Sehouli/2017
J Surg Oncol. 2010
Role of secondary cytoreductive surgery in ovarian cancer relapse: Who
will benefit? A systematic analysis of 240 consecutive patients.
Sehouli J, Richter R, Braicu EI, Bühling KJ, Bahra M, Neuhaus P, Lichtenegger
W, Fotopoulou C.
©Sehouli 2015
What is the target population for a sallvage
surgery study?
How to select the patients preoperatively?
AGO DESKTOP OVAR I/IIwhat is the surgical endpoint and who are the best candidates?
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 12 24 36 48
months
su
rviv
al
pro
bab
ilit
y
0 vs. 1-10 mm:
HR: 4.17 (CI 2,42 - 7,16); p < 0.001
0 vs. 10+ mm:
HR: 3.31 (CI 1,86 - 5,88); p < 0.001
no residuals
median OS 45.2 mos.
residuals > 10 mm
median OS 19.7 mos.
residuals 1 - 10 mm
median OS 19.6 mos.
DESKTOP OVAR I
Harter P, du Bois A, Hahmann M, et al. Ann Surg Oncol 2006
Anticancer Res. 2015 Jun;35(6):3423-9.
AGO Score As a Predictor of Surgical Outcome at Secondary Cytoreduction in
Patients with Ovarian Cancer.
Muallem MZ, Gasimli K, Richter R, Almuheimid J, Nasser, Braicu, Sehouli J.
CONCLUSION:
AGO score is a useful predictor for
operability in patients with a first
recurrence of ovarian cancer. Patients with
negative scores may still have a 50%
chance of achieving optimal tumor
resection after secondary cytoreductive
surgery. This will be a pivotal factor when
counseling patients with recurrent disease
regarding further management options.
Abstr. 5501: Randomized controlled phase III study
evaluating the impact of secondary cytoreductive surgery in
recurrent ovarian cancer: the interim analysis of
AGO DESKTOP III / ENGOT ov20
Andreas du Bois1, I. Vergote2, G. Ferron3, A Reuss4, W. Meier1, S. Greggi5,
P. Jensen6, F. Selle3, F. Guyon3, C. Pomel3, F. Lecuru3, R. Zang7,
E. Avall-Lunqvist6, JW Kim8, J. Ponce9, F. Raspagliesi5,
S. Ghaem-Maghami10, A. Reinthaller11, P. Harter (PI)1 , and J. Sehouli1
1 AGO & Essen, Düsseldorf, Essen, Berlin, Germany; 2 BGOG & Leuven, Belgium; 3 GINECO & Toulouse, Paris, Bordeaux, Clermont-Ferrand, Paris France; 4 KKS Marburg, Germany; 5 MITO & Naples, Milan, Italy; 6 NSGO & Odense, Stockholm, Denmark & Sweden; 7 SGOG & Shanghai, China; 8 KGOG & Seoul, Korea; 9 GEICO & Barcelona, Spain; 10 NCRI & London, UK; 11 AGO-Austria & Wien, Austria
AGO Study Group
AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)
A randomized trial evaluating cytoreductive surgery
in patients with platinum-sensitive recurrent ovarian cancer
Strata:
Platinum-free-interval
6-12 vs > 12 months
1st line platinum
based chx: yes vs no
R
A
N
D
O
M
Cytoreductive
surgeryplatinum-based
chemotherapy*
recommended
* Recommended platinum-based chemotherapy regimens:
- carboplatin/paclitaxel
- carboplatin/gemcitabine
- carboplatin/pegliposomal doxorubicin
-or other platinum combinations in prospective trials
no surgery
AGO DESKTOP III: Surgery arm(AGO–OVAR OP.4; ENGOT-ov20; NCT01166737)
Duration of surgery (minutes; median /
quartiles)
220 (150 – 300)
Bowel resection 33.2%
Stoma diversion temporary / permanent 3.5% / 3.5%
Blood loss (ml; median / quartiles) 250 (50 – 500)
RBC transfusion 20.3%
Fever > 38°C 4.8%
Antibiotic treatment (mainly for urinary tract
infections)
19.0%
Peri-OP thrombosis 1.1%
Re-laparotomy rate 3.2%
Macroscopic complete resection
rate
72.5%
AGO DESKTOP III: Outcome 2 (PFS, ITT population)(AGO–OVAR OP.4; ENGOT-ov20; NCT01166737)
Surger
y
No
surgery
Median
PFS
19.6
mos
14.0 mos
Δ median
PFS
5.6 mos
HR (95%
CI)
0.66 (0.52 – 0.83)
P-value < 0.001
AGO DESKTOP III: Outcome 3 (PFS by surgical outcome)
(AGO–OVAR OP.4; ENGOT-ov20; NCT01166737)
Median
PFS
[mos]
Δ PFS
[mos]
HR
(95% CI)
P-value
Wald-
test
No surgery 14.0 - 1 -
Surgery but with
residual tumor13.7 - 0.3
0.98
(0.71 –
1.35)
0.8952
Surgery with
complete
resection
21.2 + 7.2
0.56
(0.43 –
0.72)
< 0.0001
AGO DESKTOP III: Outcome 5 (TFST = time to 3rd line)(AGO–OVAR OP.4; ENGOT-ov20; NCT01166737)
Surger
y
No
surgery
Median
TFST
21.0
mos
13.9 mos
Δ median
TFST
7.1 mos
HR (95%
CI)
0.61 (0.48 – 0.77)
P-value < 0.001
A Phase III Randomized Controlled Trial of Secondary Surgical Cytoreduction followed by
Platinum-Based Combination Chemotherapy, With or Without Bevacizumab in Platinum-Sensitive,
Recurrent Ovarian Cancer: A NRG Oncology/Gynecologic Oncology Group Study
Robert L. Coleman, Nick Spirtos, Danielle
Enserro, Thomas J. Herzog, Paul Sabbatini,
Deborah Kay Armstrong, Byoung Kim, Keiichi
Fujiwara, Joan L. Walker, Patrick J. Flynn,
Angeles Alvarez Secord, David E. Cohn, Mark
F. Brady, Robert S. Mannel
ROBERT L. COLEMAN, MD
Primary Endpoint OS: Surgery vs. No Surgery
by Randomized Surgical Treatment
Overall Survival
240 180 122 78 47 23 16
245 188 143 91 52 32 19
1
2
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion S
urv
ivin
g
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion S
urv
ivin
g
2: No Surgery
1: Cytoreductive Surgery
Treatment Group
65.724569
53.624078
Median(mos)TotalEvents
HRITT: 1.28 (0.92-1.78)HRNon-USA: 1.28 (0.6-2.75)
Number at-risk (Number censored)0
months12
months24
months36
months48
months60
months72
monthsSurgery 240 (0) 180 (52) 122 (84) 78 (110) 47 (130) 23 (146) 16 (150)No surgery
245 (0) 188 (50) 143 (83) 91 (111) 52 (138) 32 (153) 19 (162)
by Randomized Surgical Treatment
Overall Survival
240 180 122 78 47 23 16
245 188 143 91 52 32 19
1
2
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Proportion S
urviv
ing
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Proportion S
urviv
ing
2: No Surgery
1: Cytoreductive Surgery
Treatment Group
65.724569
53.624078
Median(mos)TotalEvents
Surgery
No Surgery
ROBERT L. COLEMAN, MD
by Randomized Surgical Treatment
Progression-Free Survival
240 128 52 31 17 8 6
245 132 57 27 11 6 3
1
2
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion S
urv
ivin
g P
rogre
ssio
n-F
ree
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion S
urv
ivin
g P
rogre
ssio
n-F
ree
2: No Surgery
1: Cytoreductive Surgery
Treatment Group
16.5245161
18.2240142
Median(mos)TotalEvents
Secondary Endpoint PFS: Surgery vs. Chemo
Surgery
No Surgery
HR: 0.88 (0.70-1.11)
Number at-risk (Number censored)0
months12
months24
months36
months48
months60
months72
monthsSurgery 240 (0) 128 (48) 52 (68) 31 (78) 17 (86) 8 (90) 6 (92)No surgery
245 (0) 132 (45) 57 (61) 27 (69) 11 (78) 6 (78) 3 (81)
ROBERT L. COLEMAN, MD
by Surgery Outcome
Progression-Free Survival
84 38 10 5 2 1 1
146 90 42 26 15 7 5
Other
R0
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion S
urv
ivin
g P
rogre
ssio
n-F
ree
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion S
urv
ivin
g P
rogre
ssio
n-F
ree
R0
Other
Surgery Outcome
21.414678
13.18464
Median(mos)TotalEvents
Exploratory Endpoint: Surgery Outcome (ITT) CGR (R0) vs. Non-CRS
R0
Non-R0
by Surgery Outcome
Overall Survival
84 65 43 24 12 8 4
146 115 79 54 35 15 12
Other
R0
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion S
urv
ivin
g
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion S
urv
ivin
g
R0
Other
Surgery Outcome
55.214641
38.68437
Median(mos)TotalEvents
R0
Non-R0
HR: 0.67 (0.41-1.08)HR: 0.51 (0.36-0.72)
ROBERT L. COLEMAN, MD
R0 vs No Surgery
Progression-Free Survival
245 132 57 27 11 6 3
146 90 42 26 15 7 5
No Surgery
R0
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion S
urv
ivin
g P
rogre
ssio
n-F
ree
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion S
urv
ivin
g P
rogre
ssio
n-F
ree
R0
No Surgery
21.414678
16.5245161
Median(mos)TotalEvents
Exploratory Endpoint: Surgical CGR (R0) vs. No Surgery
HR: 0.68 (0.51-0.90)
R0No Surgery
R0 vs No Surgery
Overall Survival
245 188 143 91 52 32 19
146 115 79 54 35 15 12
No Surgery
R0
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion S
urv
ivin
g
0 12 24 36 48 60 72
Months on Study
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion S
urv
ivin
g
R0
No Surgery
55.214641
65.724569
Median(mos)TotalEvents
HR: 1.11 (0.74-1.66)
R0
No Surgery
ROBERT L. COLEMAN, MD
What are the differences?
Study
Primary endpoint
Status OS
Study periode
Race
Defined
Selection criteria
Complete
resection rate
Bev in 2nd-line
Rand. phase III
OS, 244 events
200 events,
still blinded
2010-2015
2% East Asian
AGO-Score
72.5%
20%
Rand. phase III
(„2 in 1“, 16% only
for the surgery trial)
OS, 250 events
147 events, ASCO
2018
2007-2017
49.5% East Asian
no
64%
84%
DESKTOP III GOG 213+
Steps for surgery in relapsed ovarian cancer
➢ Discussion of therapeutic options
➢ Definition of therapeutic aim of surgery (Improvement of
symptoms vs. Improvement of PFS)
➢ Definition of therapeutic concept after surgery
➢ Best preoperative organization and preparation (less maybe be
more!)
➢ Best intraoperative assistance ( more is allways better)
➢ Evaluation of abdominal situation, preparation of all relevant
(retroperitoneal) structures without damage
➢ Re-Evaluation and if acquired adaption of therapeutic goal and
alternative and/or following therapy
➢ Identification of emergency exit
➢ Priorization of operative procedures (starting with resection of
main tumor burden, preferably en-bloc-resections, restriction to
small amount of anastomoses)
➢ Postoperative: fast-track
➢ Re-Evaluation and if acquired adaption of therapeutic goal and
alternative and/or following therapy
Pre-OP
OP
Post-OP
©Sehouli 2018
➢Gynonc-Surgeons are able to
perform trials!
➢Post progression survivorship
longer than expected!
➢Surgery in a „real center“ followed
by chemotherapy and (targeted
theapy) is one option!