The role of Surgical and Chemotherapeutic Treatment in Ovarian … · 2019-04-07 · The GYN...

Current approaches to diagnosis and treatment of ovarian cancer

Poznań 24-11-2011

ESGO Workshop

The role of Surgical and Chemotherapeutic

Treatment in Ovarian Carcinoma

P. Zola

Department of Gynaecologic Oncology

University of Turin

Ovarian Cancer: clinic and biological aspects

advanced disease at diagnosis (65-75% stage III and IV)

Intraperitoneal dissemination with ascites (55-60%)

low risk of ematogenous spread (2-3%)

chemosensitivity (60-90% of PR, 20-40% of CR)

Gynecology Oncology 2008

OVARIAN CANCER SURVIVAL FIGO Annual Report: Carcinoma of the Ovary: 5-yr Survival Rates

Annual Report: stage and survival distribution

Annual Report 2008

STAGE N° of PATIENTS 5 YEARS SURVIVAL

St. I

St. II

St. III

St. IV

3073 79.3 %

1469 57.0 %

2342 24.9 %

1740 11.1 %

aggressive primary cytoreductive surgery

platinum and taxane combination chemotherapy

Ovarian Cancer: standard management

PRIMARY CYTOREDUCTION

maximal cytoreduction and primary surgery: standard initial

treatment for the management of epithelial ovarian cancer

the amount of residual disease at the end of a

cytoreductive surgery is directly correlated with survival

practice of cytoreduction surgery after a maximal primary surgical attempt has

been unsuccessful in decreasing tumor burden to an optimal status after

chemotherapy in unresectable ovarian cancer at first surgery

controversal role

Interval debulking

Neoadjuvant chemotherapy

Administrating of chemotherapy for two or three cycles and at time up to six

cycles, prior to cytoreductive surgery

Chemotherapy in biopsy-proven stage IIIc or IV invasive epithelial ovarian

carcinoma

Ovarian Cancer: management controverses

NEOADJUVANT

CHEMOTHERAPY

EXTENSIVE

SURGERY

The survival benefit of cytoreductive surgery is well estabilished by almost

every retrospective and prospective study performed to date. The amount of

residual disease after cytoreductive surgery is among the most important

prognostic factors when predicting survival in women advanced ovarian cancer.

1992 – GICOC: 529 patients RESIDUAL DISEASE RR p value (cm)

< 2 1 n.s.

2-5 1.96 < 0.001

5-10 2.03 < 0.001

> 10 3.00 < 0.001

1993 – Markman et al. RESIDUAL DISEASE SURVIVAL (cm) (months)

0 39

0 – 0.5 29

0.6 -1.5 18

> 1.5 11

1994 – Baker et al.: 136 patients

RESIDUAL DISEASE PROGRESSION FREE SURVIVAL

(cm) 5-year (%) 8-year (%)

< 1 40.3 36.2

1-2 17.1 12.8

> 2 4.3 4.3

1995 – GONO: 512 patients RESIDUAL DISEASE RR p value

(cm)

mycroscopic 1

< 2 1.77

2-5 2.64

> 5 4.29 < 0.0001

1994 – G.O.G Hoskins et al.: 637 patients

Percent Maximum Cytoreductive Surgery

20

22

24

26

28

30

32

34

36

38

40

0 10 20 30 40 50 60 70 80 90 100

%MaxCyto

Weig

hte

d M

edia

n S

urv

ival (

mo

nth

s)

Maximum Cytoreductive Surgery - Multiple Regression Model

Bristow et.al. JCO March 2002

Access to Care

Experienced

Ovarian Cancer Surgeon

Suspected

Ovarian Cancer

The GYN oncologist

“ The outcome of ovarian cancer treatment are better

when provided by gynecologic oncologists

and in specialized hospitals: a systematic review ”

Vernooij F., Heintz P., Witteven E., Van der Graaf Y.

Gynecology Oncology Jun;105 (3):801-121 2007

Metanalysis on 37 studies (01/1991- 01/2006): relationship between CARE SETTINGS

(GYN vs GYN Oncologist; General hospital vs Referral Centre)

and CARE OUTCOMES

Gyn Oncologist: stadiation

ARTICOLO OUTOCOME GIN. ONCOLOGI GIN. GENERALI p value

Grossi et al. % adequate staging 47 % 15 % < 0.001

Engelen et al. % adequate staging 43 % 22 % < 0.001

Earle et al. % lymph node dissection 60 % 36 % < 0.001

Kumplainen et al. % pelvic lymph node dissection 78 % 33 % < 0.001

Kumplainen et al. % paraortic lymph node dissection 61 % 26 % < 0.001

Gyn Oncologist: optimal cytoreduction

OPTIMAL DEBULKING = T.R. < 2 cm OPTIMAL DEBULKING = T.R. microscopic

Optimal cytoreduction: what it means?

1978: OPTIMAL Debulking: < 1.5 cm Griffit, Fuller et al.

1986 – 1992: OPTIMAL Debulking: < 0.5 cm Heinz, Hoskins et al.

1998: OPTIMAL Debulking: microscopic Vergote et al.

2002: OPTIMAL Debulking: microscopic Bristow et al.

Optimal cytoreduction: controverses

2001: optimal debulking

OPTIMAL Debulking = T.R. microcopic 12 % U.S. GYN

OPTIMAL Debulking = T.R. < 0. 5 cm 13.7 %

OPTIMAL Debulking = T.R. ≤ 1 cm 60.8 %

OPTIMAL Debulking = T.R. ≤ 1.5 - 2 cm 12.3 %

Eisenkop et al. 82; 489-97 Gynecology Oncology 2001

EARLY STAGE: lymphnodal involvement

PAPER Stage 1 (ovary)

Wu et al. (1986)

Pickel et al. (1989)

Burghardt et al. (1991)

Di Re et al. (1989)

7

28

37

128

Stage 2 (pelvic involvement)

1 (14%)

7 (29%)

9 (24%)

16 (17%)

8

14

14

26

3 (37%)

4 (29%)

7 (50%)

6 (23%)

N N + (%) N N + (%)

Benedetti et al. (1997)

TOTAL

73

273

1 (16%)

44 (16%)

10

72

2 (20%)

22 (31%)

“ Randomised study of systematic

lymphadenctomy in patients with epithelial

ovarian cancer macroscopically confined to

the pelvis”

Maggioni A., Benedetti Panici P et al

95,699-704 British Journal of Cancer 2006

EARLY STAGE: lymphonodal involvement

EARLY STAGE and LYMPHADENECTOMY: Results

Lymphnodal involvement:

OVERALL

STAGE 1

STAGE 2

9 % 22 % P < 0.007

ARM 1: sampling ARM 2: lynphadenectomy

VS

4 % 18 % VS

20 % 31 % VS

P.F.S.: 73.4% vs 78.3% p = 0.166

Overall Survival: 81.6% vs 84% p = 0.513

21% pelvic lfn

54% aortic lfn

25% both

ADVANCED STAGE: lymphnodal involvement

PAPER Stage 3 (abdomen)

Wu et al. (1986)

Pickel et al. (1989)

Burghardt et al. (1991)

Di Re et al. (1989)

59

98

114

82

Stage 4 (methastasys)

38 (64%)

69 (70%)

84 (74%)

46 (56%)

3

13

15

17

3 (100%)

8 (61%)

11 (73%)

11 (65%)

N N + (%) N N + (%)

Benedetti et al. (1997)

TOTAL

73

426

52 (72%)

289 (68%)

- -

48

- -

33 (69%)

“ Systematic aortic and pelvic

lymphadenectomy versus resection of bulky

nodes only in optimally debulked advanced

ovarian cancer: a randomized clinical trial”

Benedetti Panici P, Maggioni A. et al

97(8): 560-566 Journal of National Cancer Institute 2005

ADVANCED STAGE: lymphnodal involvement

Benedetti Panici et al 97(8): 560-566 Journal of National Cancer Institute 2005

P.F.S. medio: 22.4 m vs 27.4 m p = 0.022

O.S.. medio: 56.3 m vs 62.1 m p = 0.768

ADVANCED STAGE: lymphnodal involvement

ADVANCED STAGES: CYTOREDUCTION

Morbidity

Fader et al. Jul 10 ;25 (20):2873-83 Journal of Clinical Oncology, 2007

Citoriduzione primaria nei tumori maligni epiteliali dell’ovaio

ADVANCED STAGE: predictive criteria of sub-optimal surgery

“ rate of optimal debulking after

sub-optimal prediction”

Bristow et al. 104 (2007) 480 – 490 Gynecology Oncology 2007

ADVANCED STAGE: neoadjuvant chemotherapy

Background

increase of optimal debulking rate

less aggressive surgical approach

intra-operative complicances decrease

mortality and morbidity decrease

QOL improvement

Rose PG et al. 21 201a Abstract 802 Proc ASCO 2002

Neoadiuvant chemotherapy of primary surgery: are

there similar results? YES

P. Zola Dipartimento Discipline Ginecologiche e Ostetriche

Università degli Studi di Torino

Ospedale Mauriziano “ Umberto I ”, Torino

50% full members SGO Chen et al. Int J Gynecol Cancer 2004

ADVANCED STAGE: neoadjuvant chemotherapy

Retrospective studies

Donadio et al 24 NACT increase the chances of optimal debulking

Surwit et al 29 Median survival = 22 months (= primary debulking)

Swartz et al 59 Similar survival with treated with primary debulking

Ansquer et al 54 Better survival with NACT vs nondebulked tumors

Kaicgoglu et al 45 NACT followed by IDS does not woersen prognosis

Shibata et al. 29 Long term NACT outcome wasn’t statiscally different

Morice et al 34 IDS offers same survival as PDS but better tolerated

Mazzeo et al 45 NACT + IDS is safe treatment in unresectable cancer

Chan et al 17 Overall quality of life improves after NACT

Hegazy et al. 27 NACT + IDS is safe and does not worsen prognosis

Lee et al. 18 NACT provides equivalent survival with less morbidity

AUTHOR n MAIN CONCLUSION

ADVANCED STAGE: sub-optimal surgery

Trial EORTC 1995

CR, PR, NC PD

randomization Out of study

3 cycles CP

278 Patients stage IIb-IV (T.R. >1 cm)

3 cycles CP

evaluation

Cytoreductive surgery NO

P.F.S. 56% (C.C. arm) vs 46% p < 0,05

O.S. 38% (C.C. arm) vs 26% p < 0,05

Van der Burg, N Engl J Med, 322, 1995

Trial G.O.G. 152

CR, PR, NC PD

randomization Out of study

3 cyclesTP

3 cycles TP

evaluation

Cytoreductive surgery NO

425 Patients stage III-IV (T.R. >1 cm)

P.F.S. medio 10.5 m (C.C. arm) vs 10.8 m N.S.

O.S. medio 33 m (C.C. arm) vs 32 m N.S.

Rose PG et al. 21 201a Abstract 802 Proc ASCO 2002

ADVANCED STAGE: sub-optimal surgery

EORTC vs G.O.G. 152

EORTC GOG152

Chemotherapy

Stage IV

Performance status 2

CP TP

21% 6 %

17 % 7 %

T.R. (cm) after primary surgery

- 1 - 2

- 2 - 5

- 5 -10

- > 10

6 %

30%

38 %

26 %

12 %

56 %

23 %

9 %

Vergote et al. 18 (Suppl.1); 11-19 Int J Gynecol Cancer 2008

Carcinoma Ovarico: trattamento neoadiuvante?

The role of surgical outcome as

prognostic factor in advanced

epithelial ovarian cancer

A combined analysis of 3 prospectively

randomized phase III multicenter trials

Andreas du Bois (AGO-ovar and GINECO)

IGCS Meeting 2008

Population:

• 3 randomized studies in FIGO IIB-IV ovarian cancer pts. receiving

6 courses platinum-paclitaxel +/- third drug after initial surgery:

• AGO-OVAR 3 (Cisplatin/Paclitaxel vs. Carbolatin/Paclitaxel) - A du Bois et al. JNCI 2003

• AGO-OVAR 5 / GINECO (Carboplatin/Paclitaxel +/- Epirubicine) – A du Bois et al JCO 2006

• AGO-OVAR 7 / GINECO (Carboplatin/Paclitaxel +/- Topotecan) - J Pfisterer et al. JNCI 2006

• 3,126 of 3,388 randomized pts. (92.3%) included of whom 1,837

(58.8%) had died within a median observation period of 53.9 months.

• pts. characteristics:

surgical outcome:

1,105 pts.

975 pts.

1,046 pts.

no post-OP residuals

residuals 1-10mm

residuals >10mm

Age [median; range] 58.9 (19.6-83.6) yrs

PS ECOG 0 1,190 38.1

ECOG 1 1,592 50.9

ECOG 2 326 10.4

Stage FIGO IIB-IIIA 448 14.4

FIGO IIIB 366 11.7

FIGO IIIC 1,779 56.9

FIGO IV 530 17.0

Grading G1 244 7.8

G2 998 31.9

G3 1,702 54.4

Histology Serous 2,296 73.4

Endometrioid 272 8.7

Mucinous 147 4.7

0%

25%

50%

75%

100%

0 12 24 36 48 60 72 84 96 108 120 132 144

% p

rog

res

sio

n-f

ree

su

rviv

al

0 mm

1-10 mm

> 10 mm

HR (95%CI)

1-10 mm vs. 0 mm: 2.52 (2.26;2.81)

>10 mm vs. 1-10 mm: 1.36 (1.24;1.50)

log-rank: p < 0.0001

0%

25%

50%

75%

100%

0 12 24 36 48 60 72 84 96 108 120 132 144

% o

ve

rall

su

rviv

al

0 mm

1-10 mm

> 10 mm

HR (95%CI)

1-10 mm vs. 0 mm: 2.70 (2.37; 3.07)

>10 mm vs. 1-10 mm: 1.34 (1.21; 1.49)

log-rank: p < 0.0001

The impact of residual tumor: What is optimal debulking?

Initial

FIGO stage

No macroscopic residual

tumor

Any residual

tumor

HR

(95% CI)

No residual

tumor

Any

residual

tumor

HR

(95% CI)

Pts. (n) PFS (mos) Pts (n) PFS

(mos)

Median OS (mos)

FIGO IIB-IIIB 497 91.7 317 19.1 0.37 (0.31; 0.45) 108.6 48.3 0.37 (0.30; 0.47)

FIGO IIIC 486 35.0 1293 14.5 0.39 (0.35; 0.45) 81.1 34.2 0.36 (0.31; 0.42)

FIGO IV 63 19.2 467 12.1 0.53 (0.39; 0.72) 54.6 24.6 0.49 (0.34; 0.70)

HR = Hazard Ratio, reference class for HR is “Any residual tumor”

Initial FIGO

stage

residual tumor

1-10 mm

residual tumor

> 10 mm

HR

(95% CI)

residuals

1-10 mm

residuals

> 10 mm

HR

(95% CI)

FIGO IIB-IIIB 205 22.2 112 16.7 0.73 (0.56; 0.95) 52.3 41.0 0.75 (0.55; 1.01)

FIGO IIIC 613 15.9 680 13.7 0.78 (0.70; 0.88) 35.6 30.7 0.80 (0.70; 0.91)

FIGO IV 156 13.5 311 11.5 0.84 (0.69; 1.03) 26.2 23.9 0.86 (0.69; 1.07)

HR = Hazard Ratio, reference class for HR is “residual tumor > 10 mm”

Which surgical outcome does improve prognosis in which FIGO stage?

Can surgical resection

correct for inital tumor burden?

0%

25%

50%

75%

100%

0 12 24 36 48 60 72 84 96 108 120 132 144

0%

25%

50%

75%

100%

0 12 24 36 48 60 72 84 96 108 120 132 144

res. tum. =0, FIGO IIB-IIIB

res. tum. =0, FIGO IIIC

res. tum. =0, FIGO IV res. tum. >0, FIGO IIB-IIIB

res. tum. >0, FIGO IIIC

res. tum. >0, FIGO IV

… only partially…

both initial and post-op tumor

burden have a prognostic impact

PFS

OS

PFS analysis No residual

post-OP tumor

Residual tumor

1-10 mm

Residual tumor

> 10 mm

Parameter HR 95%-CI p-value HR 95%-CI p-value HR 95%-CI p-value

Age [10yrs] 1.17 (1.08, 1.27) 0.0002 1.02 (0.95, 1.09) 0.5969 1.06 (0.99, 1.13) 0.0912

ECOG 2 vs. 0-1 1.53 (1.11, 2.11) 0.0091 1.14 (0.91, 1.42) 0.2567 1.09 (0.91, 1.30) 0.3486

FIGO IIIC-IV vs. IIB-IIIB 1.52 (1.28, 1.81) <.0001 1.47 (1.22, 1.77) <.0001 1.41 (1.13, 1.75) 0.0022

grading G2/3 vs. G1 2.13 (1.56, 2.91) <.0001 1.26 (0.89, 1.79) 0.1910 1.38 (0.97, 1.96) 0.0693

Mucinous vs. serous 1.53 (1.05, 2.25) 0.0282 2.17 (1.52, 3.11) <.0001 2.16 (1.62, 2.87) <.0001

Ascites yes vs. no 1.70 (1.39, 2.07) <.0001 1.19 (1.00, 1.43) 0.0515 1.19 (1.02, 1.40) 0.0273

Does residual tumor overrule other prognostic factors?

Significant loss of prognostic factors with increasing tumor residuals

Post-operative residual tumor overrules patient characteristics‘ and

tumor biology associated factors (except mucinous histo type)

AIM: to validate the performance of a laparoscopy-based model to

predict optimal cytoreduction in advanced ovarian cancer

patients. STUDY DESIGN: 113 advanced ovarian cancer patients

INCLUSION CRITERIA: presence of omental cake, peritoneal and

diaphragmatic extensive carcinosis, mesenteric retraction,

bowel and stomach infiltration, spleen and/or liver superficial

Metastasis. By summing the scores relative to all parameters, a

laparoscopic assessment for each patient (total predictive index

value PIV) has been calculated.

Prospective validation of a laparoscopic

predictive model for optimal cytoreduction in

advanced ovarian carcinoma. Fagotti Am J Obstet Gynecol 2008

RESULTS:

Accuracy rate of the laparoscopic procedure: (77.3% infiltrazione intestinale, 100% carcinosi peritoneale)

NPV: 17 FN bowel involvement

PPV: 2FP gastric infiltration

RESULTS: At a PIV 8 the probability of optimally

resecting the disease at laparotomy is equal to 0, and the rate of

unnecessary exploratory laparotomy is 40.5%.

CONCLUSIONS: The proposed laparoscopic model

appears a reliable and flexible tool to predict optimal

cytoreduction in advanced ovarian cancer

:

“ Neoadjuvant Chemotherapy or Primary Surgery in

stage IIIc or IV ovarian cancer”

Vergote et al. N Engl J Med, september 2, 2010

ADVANCED STAGE: neoadjuvant chemotherapy

3 cycles CP PD

Interval debulking Out of study

Second look*

718 Patients Stage IIIC-IV (biopsy-proven epithelial ovarian carcinoma

PRIMARY

SURGERY

3cyclesCP

evaluation

NACT3cyclesCP

RANDOM

Randomised EORTC-GCG/NCIC-CTG

trial on NACT + IDS versus PDS

Baseline Characteristics (ITT)

PDS NACT -> IDS

FIGO Stage

IIIc

IV

77%

23%

81.4%

24.3%

Serous 65.5% 58%

Age 62 (25-86) 62 (33-81)

CA125 > 30 KU/L 98% 99%

Largest metastasis (mm) 80 (0-400) 80 (0-389)

Randomised EORTC-GCG/NCIC-CTG

trial on NACT + IDS versus PDS Protocol Compliance (PP1)

PDS

(n = 336)

NACT -> IDS

(n = 334)

Primary debulking 100 % 0%

Interval debulking 19% 90%

Second look surgery 5% 4%

At least 6 courses CT 83% 86%

Randomised EORTC-GCG/NCIC-CTG trial

on NACT + IDS versus PDS

Surgical findings and results (PP1)

PDS

(n = 336)

NACT -> IDS

(n = 334)*

Metastases before > 2 cm 95% 68%

Metastases before > 10 cm 62% 27%

No residual after surgery 21% 53%

≤ 1 cm after surgery 46% 82%

* % calculated on the 306 patients who underwent IDS.

Randomised EORTC-GCG/NCIC-CTG

trial on NACT + IDS versus PDS

<= 1cm residual per country (PP1)

Total PDS

(n = 336)

NACT -> IDS

(n = 334)*

Belgium (n=133) 83% 72% 94%

Argentina (n=48) 71% 68% 74%

The Netherlands(n=104) 59% 40% 77%

Sweden (n=23) 59% 40% 75%

Norway (n=82) 55% 35% 73%

Italy (n=38) 52% 40% 64%

Spain (n=62) 49% 44% 58%

UK (n=101) 47% 37% 63%

Canada (n=84) 44% 29% 59%

Randomised EORTC-GCG/NCIC-CTG

trial on NACT + IDS versus PDS

Surgical characteristics (PP1)

PDS

(n = 336)

NACT -> IDS

(n = 334)*

Postoperative mortality

(< 28 days)

2,7% 0,6%

Postoperative fever Gr 3-4 8% 2%

Fistula (bowel/GU) 1,2% / 0,3% 0,3% / 0,6%

Operative time (minutes) 180 180

Red blood cell transfusion 51% 53%

Hemorhage Grade 3/4 7% 1%

Venous Gr 3/4 2,4% 0,3%

NACT + IDS versus PDS: ITT

Median PFS

PDS: 12 months

IDS: 12 months

HR for IDS:0.99 (0.87, 1.13)

(years)

0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment

320 360 168 60 39 26 17 7 2

320 357 177 60 36 20 13 3 1

Upfront debulking surgery

Neoadjuvant chemotherapy

Progression-free survival

NACT + IDS versus PDS: ITT

(years)

0 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment

259 361 183 68 16 2

251 357 191 56 11 1

Upfront debulking surgery

Neoadjuvant chemotherapy

Overall survival

Median survial

PDS: 29 months

IDS: 30 months

HR for IDS:0.98 (0.85, 1.14)

NACT + IDS versus PDS: Per Protocol

Median survial

PDS: 30 months

IDS: 31 months

HR for IDS:1.00 (0.86, 1.16)

(years)

0 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment

235 329 175 66 16 2

239 339 186 56 11 1

Upfront debulking surgery

Neoadjuvant chemotherapy

Overall survivalPP1

NACT + IDS versus PDS: ITT

EORTC 55971Events / Patients

Upfront debulking Neo-adj. ChemoStatistics

(O-E) Var.HR & CI*

:(Upfront debulking Neo-adj. Chemo)|1-HR|

% ± SD

Surv ival time: Figo stageSurv ival time: Figo stage

*90% CI everywhere

Treatment effect: p>0.1

better betterChi-square=0.5, df=1: p>0.1

Upfront debulking Neo-adj. ChemoTest for heterogeneity

0.25 0.5 1.0 2.0 4.0

IV 68 /81 59 /83 4 31.4

Total 258/357 250/356 2.2 126.1

(72.3 %) (70.2 %)

2% ±9

increase

III 190 /276 191 /273 -1.8 94.7

NACT + IDS versus PDS: ITT

EORTC 55971Events / Patients

Upfront debulking Neo-adj. ChemoStatistics

(O-E) Var.HR & CI*

:(Upfront debulking Neo-adj. Chemo)|1-HR|

% ± SD

Surv iv al time: AgeSurv iv al time: AgeSurv iv al time: Age

*90% CI everywhere

Treatment effect: p>0.1

better betterChi-square=2.59, df=2: p>0.1

Upfront debulking Neo-adj. ChemoTest for heterogeneity

0.25 0.5 1.0 2.0 4.00.8

>70 53 /71 59 / 80 -2.6 26.9

Total 259/361 251/357 3.5 125.1

(71.7 %) (70.3 %)

3% ±9

increase

50-70 172 /244 161 / 221 0 82.7

<50 34 /46 31 / 56 6.1 15.5

NACT + IDS versus PDS: ITT

EORTC 55971Events / Patients

Upfront debulking Neo-adj. ChemoStatistics

(O-E) Var.HR & CI*

:(Upfront debulking Neo-adj. Chemo)|1-HR|

% ± SD

Surv iv al time: WHO PSSurv iv al time: WHO PSSurv iv al time: WHO PS

*90% CI everywhere

Treatment effect: p>0.1

better betterChi-square=0.09, df=2: p>0.1

Upfront debulking Neo-adj. ChemoTest for heterogeneity

0.25 0.5 1.0 2.0 4.00.8

2 33 /41 33 /45 1.3 16.4

Total 259/358 250/356 4.3 125.9

(72.3 %) (70.2 %)

4% ±9

increase

1 109 /151 112 /156 0.3 54.4

0 117 /166 105 /155 2.8 55.1

NACT + IDS versus PDS: ITT

EORTC 55971

Events / PatientsUpfront debulking Neo-adj. Chemo

Statistics (O-E) Var.

HR & CI*:(Upfront debulking Neo-adj. Chemo)

|1-HR|% ± SD

Survival time: HistologySurvival time: HistologySurvival time: HistologySurvival time: HistologySurvival time: HistologySurvival time: HistologySurvival time: HistologySurvival time: HistologySurvival time: Histology

*90% CI everywhere

Treatment effect: p>0.1

better betterChi-square=5.08, df=8: p>0.1

Upfront debulking Neo-adj. ChemoTest for heterogeneity

0.25 0.5 1.0 2.0 4.00.8

unknown 12 /17 23 /27 -3.1 8.5

Total 259/361 251/357 10.1 123.3

(71.7 %) (70.3 %)

9% ±9

increase

other 1 /2 7 /7 -0.5 1.1

mixed 4 /6 0 /2 0.9 0.6

unclassifiable 22 /26 25 /31 1.9 11.4

undifferentiated 29 /45 40 /58 -2 16.7

endometroid 8 /16 3 /7 0.9 2

clear cell 6 /7 3 /4 0.6 2.1

mucinous 10 /11 9 /13 2 4.5

serous 167 /231 141 /208 9.4 76.4

NACT + IDS versus PDS: ITT

EORTC 55971

Events / Patients Upfront debulking Neo-adj. Chemo

Statistics (O-E) Var.

HR & CI* : (Upfront debulking Neo-adj. Chemo)

|1-HR| % ± SD

Survival time: Country Survival time: Country Survival time: Country Survival time: Country Survival time: Country Survival time: Country Survival time: Country Survival time: Country Survival time: Country

*90% CI everywhere

Treatment effect: p>0.1 better better Chi-square=20.96, df=8: p<0.01

Upfront debulking Neo-adj. Chemo Test for heterogeneity 0.25 0.5 1.0 2.0 4.0 0.8

Canada (44%) 26 / 41 37 / 43 -9.4 15.2

Total 245 / 341 234 / 334 0.8 116.1 (71.8 %) (70.1 %)

1% ±9 increase

UK (47%) 38 / 53 38 / 48 -2.1 18.7

Spain (49%) 20 / 32 24 / 30 -4.4 10.6

Italy (52%) 15 / 20 15 / 18 -2.1 6.9

Norway (55%) 26 / 40 26 / 42 0 12.9

Sweden (59%) 9 / 11 4 / 12 3 3.2

The Netherlands (59%) 42 / 55 28 / 49 12.2 16.7

Argentina (71%) 19 / 25 14 / 23 2 7.9

Belgium (83%) 50 / 64 48 / 69 1.6 24.1

Multivariate analysis for OS(PP1)

P values

Optimal debulking 0.0001

Histological type (9 categories) 0.0003

Largest tumor size at

randomisation

0.0008

Figo Stage (IIIc vs IV) 0.0008

Country (14 categories) 0.0014

Age 0.0020

WHO PS NS

Differentiation Grade NS

Treatment arm NS

Conclusions (1) 1. In Stage IIIc-IV OVCA, NACT followed IDS produces

similar OS and PFS outcomes compared to standard

primary debulking followed by chemotherapy in FIGO

Stage IIIc-IV ovarian carcinoma.

2. There does not seem to be a subgroup based on

1. Stage IIIc or IV

2. Age

3. WHO performance

4. Histological type ovarian cancer

5. Countries with high or low optimal debulking rate

for which PDS or NACT -> IDS result in better

survival.

Conclusions (2) 3. Optimal debulking surgery is the

strongest independent prognostic factor for overall survival. Hence, optimal debulking (to no residual tumor) should

remain the goal of every surgical effort. The

timing of this procedure (PDS or IDS) does not seem to play a role.

4. Due to the lower morbidity of IDS compared

with PDS and the similar survival, NACT can be considered as the preferred treatment in patients, as included in this study, with Stage IIIc-IV ovarian, peritoneal and fallopian tube carcinoma.

Thank you