Borderline Tumors of the Ovary:
the ROBOT study (AGO-OVAR OP.5) and more
Prof. Andreas du Bois, MD, PhD
Director Dept of Gynecology & Gynecological Oncology. KEM Essen
© AdB 2015
Borderline Tumors and invasive Ovarian Carncer
FIGO World Report Vol. 16-26: 1963-2001
- relative Frequencies and 5-Year-Survival (5-YSR) 100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
63-68
69-72
73-75
Borderline Tumor (BOT)
76-78
79-81
82-86
Ovarian Cancer (OC)
87-89
90-92
5-YSR BOT
93-95
96-98
99-01
5-YSR OC
Clinical, pre-OP diagnosis in BOT
= the majority of pts. are primarily operated inadequately
(at least 25% each understaged or overtreated)
100%
Pre-OP diagnosis
Multiple answers were allowed
75%
50%
25%
0%
unclear
might be CA
Spain: Cusido et al. 2007
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probably benign
might be BOT
unknown
Germany: Coumbos et al. 2006
ROBOT AGO-OVAR OP.5
Retrospective/ prospective multicenter Outcome survey in Borderline Ovarian Tumours
Retrospective:
data collection in clinical records/registries
Inclusion of all BOT pts. 1998-2008
Exclusion, if paraffine blocks
were not available
Exclusion, if surgical reports
were not availlable
Prospective: central pathology review
Prospective: actual follow-up
Prospective analysis plan
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ROBOT
1,236 pts.
initially diagnosed
as BOT
cohort:
1,042 pts.
with
reference pathology
194 pts.
reference pathology
not possible
excluded
92 pts. BOT
not confirmed
950 pts. BOT
confirmed
11.5 % (Range: 0-43 %)*
92/803 (1042-126-77-36)*
40 x invasive malignancies
Study cohort
52 x no BOT and benign
43 % of non-BOT
57 % of non-BOT
(= 5.0 % of all with ref. path.)
*HSK Wiesbaden, Berlin Charite and UFK Halle only enrolled pts.
who already had a reference pathology confirmation of BOT
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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ROBOT: PFS pts. with reference pathology result
% PFS
median follow-up alive: 4.1 yrs. (interquartile 1.5-6.1 yrs.)
HR
95 % CI
p
N
E
-
-
-
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
BOT
Log-rank test: p < 0.0001, N = 1042, E = 126
[years]
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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
120
19
18.6
3.0
8
1
2.8
0.3
Implants
- invasive implants
* P < 0.05
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Song T, et al. J Gynecol Oncol. 2013;24(1):44-51.
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I. Surgical therapy
% PFS
ROBOT: PFS – initial surgical access:
No hint for higher risk after laparoscopy
N
364
585
Laparoscopy (incl. conversions)
Laparotomy
E
41
67
Laparoscopy vs. Laparotomy: HR = 1.183, 95 % CI: (0.799 , 1.752)
Log-rank test: p = 0.4007
[years]
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ROBOT
Surgical
therapy:
1st
surgery
n
%
All
950
100
Laparoscopy (LSC)
297
31.3
LSC -> Laparotomy
67
7.1
585
61.6
1
0.1
Incomplete
720
75.8
Complete
230
24.2
Laparotomy
Vaginal
Staging quality
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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% PFS
ROBOT: PFS and final staging quality (n = 950)
Complete
Incomplete
N
390
560
E
29
79
Incomplete vs. complete staging: HR = 1.765, 95 % CI: (1.152, 2.706)
Log-rank test: p = 0.0091
[years]
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% PFS
ROBOT: PFS and FIGO stage
FIGO
I
II vs. I
III vs. I
Total
HR
95 % CI
p
0.0010
0.0003
N
782
72
96
E
72
16
20
2.489
2.483
(1.444, 4.289)
(1.511, 4.080)
Log-rank test
< 0.0001
950
108
[years]
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% PFS
ROBOT: PFS and organ-preserving surgery
BSO
USO (Ref)
Cystectomy
HR
0.584
1
3.306
95 % CI
0.377-0.903
1.741-6.278
Log-rank test: p < 0.0001
[years]
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p
0.0129
0.0002
N
708
199
41
E
63
30
14
ROBOT: Multivariate analysis of prognostic factors
regarding progression-free survival (PFS)
* due to low numbers no OS analysis (follow up)
*
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.
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Recurrence rate in BOT- a systematic review
(92 series including 10.971 patients)
FIGO I
FIGO II-III
Localisation relapse (%)
Localisation relapse (%)
pts
Extragonadal
ovary
all
pts
Extragonadal
ovary
all
Conservative
surgery
1543
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


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: 11151124, 2010 (English
© AdB 2015language)
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
invasive disease
recurrent BOT
100%
140
90%
80%
120
70%
100
60%
80
50%
40%
60
30%
40
20%
20
10%
0%
0
0-2
2-5
5-10
> 10
0-2
2-5
5-10
> 10
Years after diagnosis
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: 11151124, 2010 © AdB 2015
ROBOT: Histology of relapse after initial BOT
30 % malignant transformation (incl. 36 % high grade OC!)
52 (70 %) BOT
7 x 2nd relapse
74 relapses
(7.8 % of 950)
22 (30 %)
invasive carcinoma
(2.3 % of 950)
8 (36 %)
high grade carcin.
10 + 1 (50 %)
low grade carcin.
3 (14 %)
no grade available
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1
1 x 3rd relapse
ROBOT: PFS and OS after first relapse – invasive CA vs. BOT
(n = 74 pts. with 1. relapse)
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World largest series of 1,042 pts. with confirmed S-BOT after central pathology review
• (invasive) implants had a significant negative
impact on prognosis (overall survival)
• = advanced FIGO stage
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Prognosis and FIGO stage in S-BOT in Denmark
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II. Systemic therapy
33 pts. received adjuvant therapy;
12 with FIGO I BOT and
21 (64 %) with FIGO stages II/III.
% PFS
ROBOT:
PFS and
adjuvant
therapy
PFS
und adjuvante
Therapie
beim
fort- in
advanced BOT
BOT(nFIGO
II/III
(n =II/III)
168)
geschrittenen
= 168 pts.
mit FIGO
keine adjuvante Therapie
mit adjuvanter Therapie
N
146
22
E
30
6
mit vs ohne adjuvante Therapie: HR=1.359 95%CI: (0.563, 3.278)
Log-Rank: p=0.4940
[Jahre]
http://www.apotheken-umschau.de
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No evidence of efficacy!
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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
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