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!

© AGO e.V.in der DGGG e.V.

sowie

in der DKG e.V.