A.Ercoli, G. Scambia

CHIRURGIA DELLA

RECIDIVA

The role of secondary cytoreductive surgery The role of secondary cytoreductive surgery in the treatment of pts. with recurrent EOCin the treatment of pts. with recurrent EOC

SurvivalSurvival determineddetermined byby useuse ofof preoperativepreoperative salvagesalvage CTCT

No preop CT

EisenkopEisenkop SM, 2000SM, 2000

No preop CT

Preop CT

Secondary cytoreductive surgery for pts. Secondary cytoreductive surgery for pts. with relapsed EOC: who benefits ?with relapsed EOC: who benefits ?

SurvivalSurvival accordingaccording to the to the sizesize of RTof RT

No RT

Zang RY, 2004Zang RY, 2004

RT ≤ 1cm

Rt > 1cm

0,5

0,6

0,7

0,8

0,9

1su

rviv

al p

rob

abil

ity

no residualsmedian OS 45.2 mos.

residuals > 10 mmmedian OS 19.7 mos.

0

0,1

0,2

0,3

0,4

0,5

0 12 24 36 48

months

surv

ival

pro

bab

ilit

y

median OS 19.7 mos.

residuals 1 - 10 mmmedian OS 19.6 mos.

Harter P, du Bois A, Hahmann M, et al. Ann Surg Oncol 2006

Secondary cytoreductive surgeryfor OC

When?

How?How?

Prognostic factors?

DESKTOPDESKTOP-- OVAR IOVAR I

who benefits ? multivariate analysis who benefits ? multivariate analysis

(survival)(survival)

Variable OR (95% CI) p-value

Residual after surgery (0 vs. > 0 mm) 2.94 (1.68-5.17) < 0.001

Ascites (cut-off 500 ml) 2.30 (1.31-4.04) 0.004

Pt-based chx after surgery (yes vs. no) 1.84 (1.13-3.01) 0.015 Pt-based chx after surgery (yes vs. no) 1.84 (1.13-3.01) 0.015

Not an independent prognostic factor for survival after surgery for recurrence are:

Localization of recurrence (pelvic vs. others)PS (ECOG 0 vs. > 0)

Residuals after 1st surgery ( 0 vs. > 0 mm)

TFI (< 6 vs. > 6-12 vs. > 12 months), but small no. of pts with TFI < 6 months

FIGO-stage at primary diagnosis (I/II vs. III/IV)

Secondary cytoreductive surgeryfor OC

When?

Only complete resection offers benefits in terms of

survival and there is no room for incomplete but so

colled “optimal debulking” in recurrent ovariancancer !!!

AGO DESKTOP OVAR II: CONCLUSIONS

The DESKTOP II trial has shown that a surgical multicentre study

within the GCIG is feasible and could answer complex questions in an

appropriate interval

44% of all patients with platinum sensitive relapse underwent surgery44% of all patients with platinum sensitive relapse underwent surgery

for ROC in specialized centres (clinical reality or assignment of pre-selected pts?)

The AGO-Score is a useful and reliable tool to predict complete

resection in at least 2 out of 3 patients

First score succesfully validated in surgery for ovarian cancer

The comorbidity is comparable to surgery in primary ovarian cancer

Prognostic and predictive value of the Arbeitsgemeinschaft GynaekologischeOnkologie (AGO) score in surgery for recurrent ovarian cancer*

AGO score

217 pts AGO score +

n. 112

AGO score -

n.105

COMPLETE SCS

p<0.001 89.3% 66.7%

OS

p=0.07 not significant57.3 months 33.5 months

AGO score- complete resection at

1st surgery (or FIGO I/II)

- ECOG 0

– ascites < 500 ml

*Harter P, Beutel B, Alesina PF, Lorenz D, Boergers A, Heitz F, Hils R, Kurzeder C, Traut A, du Bois A. Prognostic and predictive value of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) score in surgery for recurrent ovarian cancer. Gynecol Oncol. 2014 Mar;132(3):537-41

**van de Laar R, Massuger LF, Van Gorp T, IntHout J, Zusterzeel PL, Kruitwagen RF. External validation of two prediction models of complete secondary cytoreductive surgery in patients with recurrent epithelial ovarian cancer. Gynecol Oncol. 2015 May;137(2):210-5

External validation of two prediction models of complete secondary cytoreductive surgery in

patients with recurrent epithelial ovarian cancer

273 pts AGO score + AGO score -

COMPLETE SCS 82.0% 68.5%

257 pts Tian model low risk Tian model high risk

COMPLETE SCS 80.3% 55.6%

20102010

20122012

Elaboration of an objective LPS-score (PIV) to assess OC

Application of PIV at IDS after NACT

Prospective multicentric validation of PIV

20142014

Independent Prognostic role of PIV

20132013

Safety of PIV introducton into

20152015

Modified Score

Evolution of SEvolution of S--LPS scoring systemLPS scoring system

S-LPS can subjectively assess OC

20052005

20062006

20082008

20112011

Elaboration of an objective LPS-score (PIV) to assess OC (retrospective evaluation)

Retrospective validation of an objective LPS-score (PIV) to assess OC in an external centre

Reproducibility of PIV in external centers.

Safety of PIV introducton into clinical practice

COMMON STANDARD OF CARE� CHEMOTHERAPY

WHAT’S THE ROLE OF SECONDARY CYTOREDUCTIVE SURGERY?

RECURRENT OVARIAN CANCER

PLATINUM-RESISTANT PATIENTSlow survival (<10 months). Surgery might not justify the high morbidity, butif the relapse is isolated and located in the retroperitoneal tissue/lymphnodes, complete cytoreduction is a viable option

PLATINUM-SENSITIVE PATIENTSSCS can be a viable option. The most important predictive factor for OS after SCS seems to be residualtumor.tumor.

�DESKTOP III active, not recruiting

�GOG 213 active, not recruiting

�SOCceR premature stop

TRIALS

Suh DH, Kim HS, Chang SJ, Bristow RE. Surgical management of recurrent ovarian cancer. Gynecol Oncol. 2016 Aug;142(2):357-67

Strata:

Platinum-free-interval

RAN

Cytoreductivesurgery

AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)

A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer

Platinum-free-interval

6-12 vs > 12 months

1st line platinum

based chx: yes vs no

NDOM

platinum-basedchemotherapy*recommended

* Recommended platinum-based chemotherapy regimens: - carboplatin/paclitaxel- carboplatin/gemcitabine- carboplatin/pegliposomal doxorubicin -or other platinum combinations in prospective trials

no surgery

Surgery Ovarian Cancer Recurrence (SOCceR) trial*Multicenter RCT, phase III

Netherlands,2012 - PREMATURE STOP** 2015 � 27 pts. (230 patients needed)

progression-free survival in patients with recurrent platinum sensitive

epithelial ovarian cancer

SECONDARY CYTORECTIVE SURGERY + CT VS CT ALONE

POSSIBLE EXPLANATIONS OF THE PREMATURE STOP:

� Gynecological oncologists strongly believe in SCS and operated outside the trial, WHILE medical oncologistsstrongly believe in CT in case of relapse after 6 months (platinum sensitive) and offered treatment outside the trial

� CA 125 is not routinely done during FU visits (after OV05/EORTC 55955 study***)

� MIGHT cause late detection and reduced possibilities to SCS

� Tendency to perform “neo-adjuvant” CT in case of relapse

*Van deLaarR, Zusterzeel PL,VanGorpT, et al. Cytoreductive surgery followed by chemotherapy versus chemotherapy alone for recurrent platinum-sensitive epithelial ovarian cancer (SOCceR trial): a multicenter randomised controlled study. BMC Cancer. 2014;14:22.

**Van de Laar R, Kruitwagen RF, Zusterzeel PL, Van Gorp T, Massuger LF. Correspondence: Premature Stop of the SOCceR Trial, a Multicenter Randomized Controlled Trial on Secondary Cytoreductive Surgery: Netherlands Trial Register Number: NTR3337.

Int J Gynecol Cancer. 2017 Jan;27(1):2

***Rustin GJ, van der Burg ME, Griffin CL, et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet. 2010;376:1155Y1163

975 pts

SECONDARY CYTORECTIVE SURGERY + CT VS CT ALONE

Impact of secondary cytoreductive surgery on survival in patients with platinum

sensitive recurrent ovarian cancer: analysis of the CALYPSO trial

SCS

19%

CT alone

80%

Lee CK, Lord S, Grunewald T, Gebski V, Hardy-Bessard AC, Sehouli J, Woie K, Heywood M, Schauer C, Vergote I, Scambia G, Ferrero A, Harter P, Pujade-LauraineE, Friedlander M. Impact of secondary cytoreductive surgery on survival in patients with platinum sensitive recurrent ovarian cancer: analysis of the CALYPSO

trial. Gynecol Oncol. 2015 Jan;136(1):18-24.

19% 80%

18.2 PFS

P<0.001

10.8

49.9 OS

p=0.004

29.7

3 yrs OS � not measurable disease � 72%

� tumor larger than 5 cm � 28%

Prospective study, 2007-2017

QoL: SECONDARY CYTORECTIVE SURGERY + CT VS CT ALONE

Quality of Life in Platinum-Sensitive Recurrent Ovarian Cancer:

Chemotherapy Versus Surgery Plus Chemotherapy

NO DIFFERENCE

BETWEEN THE 2

Plotti F, Quality of Life in Platinum-Sensitive Recurrent Ovarian Cancer: Chemotherapy Versus Surgery Plus Chemotherapy. Ann Surg Oncol. 2015

BETWEEN THE 2

GROUPS AT

BASELINE, 3

MONTHS AND 6

MONTHS, except

for costipation and

pain at 3 months in

group A

38 pts with isolated platinum-resistant recurrent OC:

� 11 SCS + CHT

� 27 received CHT alone

20142014

� Patients treated with SCS + CHT a 24 months longer

Post-Relapse Survival compared to CHT alonePost-Relapse Survival compared to CHT alone

� The Survival benefit of SCS over CHT alone was

maintained up to 3rd line chemotherapy

TIME

SURGERY IN OVARIAN CANCERSURGERY IN OVARIAN CANCER

TIME

IDS Palliation(II look) Secondary

cytoreductionPDS

Secondary cytoreductive surgeryfor OC

How?

BULKY NODES RESECTION VS SYSTEMATIC LYMPHADENECTOMY

The addition of lymphadenectomy to secondary cytoreductive surgery in

comparison with bulky node resection in patients with recurrent ovarian cancer*Single Center, 2001-2015, 35 pts

FIGO III-IV, platinum sensitive, epithelial ovarian cancer

recurrence located in the retroperitoneal tissue only

LYMPHADENECTOMY 11 pts

BULKY NODES REMOVAL 24 pts

*Bogani G, Leone Roberti Maggiore U, Chiappa V, Ditto A, Martinelli F, Sabatucci I, Mosca L, Lorusso D, Raspagliesi F. The addition of lymphadenectomy to secondary cytoreductive surgery in comparison with bulky node resection in patients with recurrent ovarian cancer. Int J

Gynaecol Obstet. 2018 Sep 8

11 pts 24 pts

= complications =

21 months DFI-2 p=0.019 12 months

< CT lines after SCS >

36.9 months OS p=0.976 32 months

SECONDARY CYTORECTIVE SURGERY + HIPEC

Long-Term Survival for Platinum-Sensitive Recurrent Ovarian Cancer Patients Treated with

Secondary Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy (HIPEC)Retrospective analysis,2004-2015

70 pts, median FU time 73 months (48-128)

FIRST

RELAPSEDIAGNOSIS

Surgery + CT > 6 months PFI-1

SECOND

RELAPSE

PFSSCS + HIPEC PRS

: Petrillo M, Long-Term Survival for Platinum-Sensitive Recurrent Ovarian Cancer Patients Treated with Secondary Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy (HIPEC). Ann Surg Oncol. 2016

Surgery + CT > 6 months PFI-1 PFSSCS + HIPEC PRS

• Median PFS (progression free survival) 27 months (5-104)

• PFS longer than PFI-1 (primaryplatinum free interval) in 37 out of 70 pts

• PRS (post relapse survival) 62 months (10-128)

• No post-operative deaths

Transcelomatic dissemination

Ovarian cancer not “organ disease”

but “loco-regional illness”

HIPEC ROLE IN OVARIAN CANCER: Rationale

Biological basis

�A multi-step process from

detachment to implantation(Detachment: E-cadherin, Immune

evasion: Fas-ligand, Spheroid formation

Ascites formation: lymphatic flow, VEGF,

peritoneal inflammation, serum albumin;

Production of proinvasive ascitic

components: MMP, CXCL2, CD44)

Future Future PerspectivesPerspectives

HIPEC ROLE IN OVARIAN CANCER

HIPEC FOLLOWS THE EVOLUTION IN OVARIAN CANCER TREATMENT

CONVENTIONAL LPT MIS

2014

�First platinum sensitive recurrence

�Median hospital stay 4 days, median

OT 188 minutes, post-operative

complications 1/27 (pleural effusion)

25

complications 1/27 (pleural effusion)

�All women alive without recurrence

with a Median DFS 14 months

For selected patients with localized

recurrent ovarian cancer, laparoscopy is a

feasible and safe approach to achieve

optimal cytoreduction.

2017

MINIMALLY INVASIVE SECONDARY CYTOREDUCTION MINIMALLY INVASIVE SECONDARY CYTOREDUCTION

IN RECURRENT OVARIAN CANCERIN RECURRENT OVARIAN CANCER

107 women with platinum-sensitive OC relapse

successfully treated with MIS in the literature.

2014

Secondary cytoreductive surgeryfor OC

Prognostic factors?

BMI AS AN INDEPENDENT PREDICTOR OF SURVIVIAL AFTER SCS

Impact of obesity on secondary cytoreductive surgery and overall survival in women

with recurrent ovarian cancerRetrospective

104 pts

90 received complete cytoreduction � BMI did not correlate with the ability to perform it (p=0.25)

Equal comorbidities (except underweight pts, who had no comorbidities)

Tran AQ, Cohen JG, Li AJ. Impact of obesity on secondary cytoreductive surgery and overall survival in women with recurrent ovarian cancer. Gynecol Oncol. 2015 Aug;138(2):263-6. doi: 10.1016/j.ygyno.2015.05.035.

Equal comorbidities (except underweight pts, who had no comorbidities)

2 underweight pts � median survival greater than 50 months

46 ideal body weight pts � median survival 46 months

32 overweight pts � median survival 38 months

24 obese pts � median survival 34 months(p=0.02)

A: Discrete, >12mts

D: Diffuse, <12 mts

B: Discrete, <12 mts

C: Diffuse, >12 mts

328 RECURRENT OVARIAN CANCER

D: Diffuse, <12 mts

�Duration of PFI and extension of recurrent disease

influence post-relapse survival

Group A vs B: p =0.013;

Group C vs D: p =0.04;

Group B vs C: p =0.7.

� Pattern of localized relapse influences

prognosis, in particular: lymphnodal

recurrences have the best outcome, followed

by peritoneal and parenchymal Localized lymphnodal

� SCS prolongs PRS in all patients with

localized relapse compared with CHT

alone

SCS+CHT

CHT only

Localized peritoneal

Localized parenchimal

Pla

tin

um

fre

e In

terv

al(

%)

Pla

tin

um

fre

e In

terv

al(

%)

P=0.014 P=0.006

PDS

PDS

A longer PFI-1 and a more favorable pattern of presentation of

recurrence in pts with peritoneal carcinomatosis and high tumor

dissemination at diagnosis treated with complete PDS compared to

women submitted to NACT followed by IDS.

MonthsMonths

Pri

ma

ryP

lati

nu

m

Se

con

da

ryP

lati

nu

m

MonthsMonths

PDS

IDS IDS

BRCA status

wild type

BRCAmut

Post Recurrence Survival according to BRCA status.

5-years PRS of BRCAwt (78 patients) compared with BRCAmut (48 patients) :

45% vs 76%; (p = 0.08)

BRCA status

wild type/SCS-

wild type/SCS+

BRCAmut/SCS-

BRCAmut/SCS+

Post Recurrence Survival according to BRCA status and SCS

Most important predictor factors of survival:

1° complete tertiary cytoreduction

then: FIGO I-II at initial diagnosis, exclusive retroperitoneal, recurrence,

TCS performed >3 yrs after primary diagnosis

Most important predictor factors of complete cytoreduction:

TERTIARY CYTORECTIVE SURGERY

Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer:

A multicentre MITO retrospective study

Most important predictor factors of complete cytoreduction:

Single lesion and ECOG 0

Falcone F, Scambia G,. Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer: A multicentre MITO retrospective study. Gynecol Oncol. 2017 Fotopoulou C, Sehouli J. Clinical outcome of tertiary surgical cytoreduction in patients with recurrent epithelial ovarian cancer. Ann Surg Oncol. 2011

Clinical outcome of tertiary surgical cytoreduction in patients with recurrent epithelial

ovarian cancer

Most important predictor factors of survival:

1° complete tertiary cytoreduction

followed by interval to primary diagnosis > 3 yrs and serous papillary histology

Thank you for Thank you for

your kind attentionyour kind attention

Grazie perGrazie per

l’attenzionel’attenzione