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Borderline Tumors of the Ovary:

the ROBOT study (AGO-OVAR OP.5) and more

Prof. Andreas du Bois, MD, PhDDirector Dept of Gynecology & Gynecological Oncology. KEM Essen

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

63-68 69-72 73-75 76-78 79-81 82-86 87-89 90-92 93-95 96-98 99-01

Borderline Tumor (BOT) Ovarian Cancer (OC) 5-YSR BOT 5-YSR OC

Borderline Tumors and invasive Ovarian Carncer

FIGO World Report Vol. 16-26: 1963-2001

- relative Frequencies and 5-Year-Survival (5-YSR) -

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Clinical, pre-OP diagnosis in BOT= the majority of pts. are primarily operated inadequately

(at least 25% each understaged or overtreated)

0%

25%

50%

75%

100%

unclear might be CA probably benign might be BOT unknown

Spain: Cusido et al. 2007 Germany: Coumbos et al. 2006

Pre-OP diagnosisMultiple answers were allowed

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ROBOT AGO-OVAR OP.5

Retrospective:

data collection in clinical records/registries

Inclusion of all BOT pts. 1998-2008

Prospective: central pathology review

Prospective: actual follow-up

Exclusion, if paraffine blocks

were not available

Exclusion, if surgical reports

were not availlable

Prospective analysis plan

Retrospective/ prospective multicenter Outcome survey in Borderline Ovarian Tumours

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ROBOTcohort:

1,236 pts.

initially diagnosed

as BOT

1,042 pts.

with

reference pathology

194 pts.

reference pathology

not possible

950 pts. BOT

confirmed

92 pts. BOT

not confirmed

11.5 %11.5 % (Range: 0-43 %)*

92/803 (1042-126-77-36)*

52 x no BOT and benign

57 % of non-BOT

40 x invasive malignancies

43 % of non-BOT

(= 5.0 % of all with ref. path.)

StudyStudy cohortcohort

1,236 pts.

initially diagnosed

as BOT

1,042 pts.

with

reference pathology

194 pts.

reference pathology

not possible

950 pts. BOT

confirmed

92 pts. BOT

not confirmed

11.5 %11.5 % (Range: 0-43 %)*

92/803 (1042-126-77-36)*

52 x no BOT and benign

57 % of non-BOT

40 x invasive malignancies

43 % of non-BOT

(= 5.0 % of all with ref. path.)

StudyStudy cohortcohort

*HSK Wiesbaden, Berlin Charite and UFK Halle only enrolled pts.

who already had a reference pathology confirmation of BOT

excluded

Another trial from Denmark (CG Hannibal et al, Gynecol Oncol 2014):

265 / 1,259 (21%) pts. with presumed S-BOT re-classified by central pathology review

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HR 95 % CI p N E

BOT - - - 950 108

Malignant vs. BOT 3.60 2.09-6.19 < 0.0001 40 15

Benign vs. BOT 0.42 0.13-1.31 0.13 52 3

Log-rank test: p < 0.0001, N = 1042, E = 126

ROBOT: PFS pts. with reference pathology resultmedian follow-up alive: 4.1 yrs. (interquartile 1.5-6.1 yrs.)

[years]

% P

FS

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ROBOT S-BOT

644 pts.

M-BOT

290 pts.

Age median 48 y. median 50 y.

FIGO

I

II

III

489

68

87

75.9

10.6

13.5

279

3

8

96.2

1.0

2.8

Microinvasion 32 5.0 17 5.9

Micro-papillary type 97 15.1 - -

Intraepithelial carcinoma - - 23 7.9

Implants

- invasive implants

120

19

18.6

3.0

8

1

2.8

0.3

* P < 0.05

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Song T, et al. J Gynecol Oncol. 2013;24(1):44-51.

I. Surgical therapy

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ROBOT: PFS – initial surgical access:

No hint for higher risk after laparoscopy

[years]

% P

FS

Laparoscopy vs. Laparotomy: HR = 1.183, 95 % CI: (0.799 , 1.752)

Log-rank test: p = 0.4007

N E

Laparoscopy (incl. conversions) 364 41

Laparotomy 585 67

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ROBOT n %

All 950 100

Laparoscopy (LSC) 297 31.3

LSC -> Laparotomy 67 7.1

Laparotomy 585 61.6

Vaginal 1 0.1

Staging quality

Incomplete 720 75.8

Complete 230 24.2

Surgical

therapy:

1st

surgery

319 of 720 pts. (44.3 %) with initial incomplete staging

received a re-staging operation.

Re-staging led to up-staging in 10.2 % and finally

390 pts. (41 %) had a complete staging.

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ROBOT: PFS and final staging quality (n = 950)

Incomplete vs. complete staging: HR = 1.765, 95 % CI: (1.152, 2.706)

Log-rank test: p = 0.0091

N E

Complete 390 29

Incomplete 560 79

[years]

% P

FS

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ROBOT: PFS and FIGO stage

FIGO HR 95 % CI p N E

I 782 72

II vs. I 2.489 (1.444, 4.289) 0.0010 72 16

III vs. I 2.483 (1.511, 4.080) 0.0003 96 20

Total Log-rank test < 0.0001 950 108

[years]

% P

FS

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ROBOT: PFS and organ-preserving surgery

[years]

% P

FS

HR 95 % CI p N E

BSO 0.584 0.377-0.903 0.0129 708 63

USO (Ref) 1 - - 199 30

Cystectomy 3.306 1.741-6.278 0.0002 41 14

Log-rank test: p < 0.0001

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F Trillsch,…, A du Bois: Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: results from

a sub-analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study. Ann Oncol. 2014;25(7):1320-1327.

ROBOT: Multivariate analysis of prognostic factors

regarding progression-free survival (PFS)

* due to low numbers no OS analysis (follow up)

*

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du Bois A, Ewald-Riegler N, du Bois O, Harter P . Borderline-Tumoren des Ovars – eine systematische Übersicht, Geburtsh Frauenheilk, 6. 807-833, 2009 [German language]

Trillsch F, Mahner S, Ruetzel JD, Harter P, Jaenicke F, du Bois A . Clinical management of borderline ovarian tumors (BOT), Expert Review of Anticancer Therapy, 10: 1115-

1124, 2010 (English language)

Recurrence rate in BOT- a systematic review

(92 series including 10.971 patients)

FIGO I FIGO II-III

Localisation relapse (%) Localisation relapse (%)

ptsExtra-

gonadalovary all pts

Extra-

gonadalovary all

Conservative

surgery1543 2,0 10,6 12,6 210 19,7 25,1 44.8

Radical surgery 2162 2,4 - 2,4 366 13,7 - 13,7

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0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0-2 2-5 5-10 > 10

Years after diagnosis

invasive disease recurrent BOT

Fig. 3: Time course of invasive and non-invasive relapse after ürimary

diagnosis of a borderline tumour of the ovary – data from a systematic review

including 381 patients with known interval between diagnosis and relapse

0

20

40

60

80

100

120

140

0-2 2-5 5-10 > 10

du Bois A, Ewald-Riegler N, du Bois O, Harter P . Borderline-Tumoren des Ovars – eine systematische Übersicht, Geburtsh Frauenheilk, 6. 807-833, 2009 [German language]

Trillsch F, Mahner S, Ruetzel JD, Harter P, Jaenicke F, du Bois A . Clinical management of borderline ovarian tumors (BOT), Expert Review of Anticancer Therapy, 10: 1115-

1124, 2010

© AdB 2015

74 relapses

(7.8 % of 950)

52 (70 %) BOT

22 (30 %) invasive carcinoma

(2.3 % of 950)

8 (36 %)

high grade carcin.

10 + 1 (50 %)

low grade carcin.

3 (14 %) no grade available

7 x 2nd relapse 1 x 3rd relapse

ROBOT: Histology of relapse after initial BOT30 % malignant transformation (incl. 36 % high grade OC!)

1

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ROBOT: PFS and OS after first relapse – invasive CA vs. BOT(n = 74 pts. with 1. relapse)

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• (invasive) implants had a significant negative

impact on prognosis (overall survival)

• = advanced FIGO stage

World largest series of 1,042 pts. with confirmed S-BOT after central pathology review

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Prognosis and FIGO stage in S-BOT in Denmark

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II. Systemic therapy

http://www.apotheken-umschau.de

33 pts. received adjuvant therapy;

12 with FIGO I BOT and

21 (64 %) with FIGO stages II/III.

No evidence of efficacy!

PFS und adjuvante Therapie beim fort-

geschrittenen BOT (n = 168 pts. mit FIGO II/III)

N E

keine adjuvante Therapie 146 30

mit adjuvanter Therapie 22 6

N E

keine adjuvante Therapie 146 30

mit adjuvanter Therapie 22 6

mit vs ohne adjuvante Therapie: HR=1.359 95%CI: (0.563, 3.278)

Log-Rank: p=0.4940

% P

FS

[Jahre]

ROBOT: PFS and adjuvant therapy in

advanced BOT FIGO II/III (n = 168)

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Summary

• BOT has a good overall prognosis

• 5-year PFS 87.3 %

• malignant transformation in 2.3 %

• mainly in the 20-30 % of extragonadal relapses

• 5-year OS 95%, disease-specific survival: 98.1 %

• Prognostic factors

• Not modifiable: FIGO stage, histological features

• modifiable by therapy:

• Staging quality (mainly for PFS, minor impact on OS ?)

• Residual tumour

• Organ preservation (only for PFS, not for OS)

• mostly intra gonadal relapse, w/o impact on prognosis in FIGO I (?)

• completion surgery for „high risk“ / advanced stages only

• No evidence for efficacy of adjuvant chemotherapy