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 © AdB 2015 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 © AdB 2015 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 © AdB 2015 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] © AdB 2015 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 © AdB 2015 Song T, et al. J Gynecol Oncol. 2013;24(1):44-51. © AdB 2015 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] © AdB 2015 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. © AdB 2015 % 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] © AdB 2015 % 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] © AdB 2015 % 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] © AdB 2015 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. © AdB 2015 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 © AdB 2015 1 1 x 3rd relapse ROBOT: PFS and OS after first relapse – invasive CA vs. BOT (n = 74 pts. with 1. relapse) © AdB 2015 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 © AdB 2015 Prognosis and FIGO stage in S-BOT in Denmark © AdB 2015 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 © AdB 2015 No evidence of efficacy! © AdB 2015 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 © AdB 2015
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