Panoramic view of Ovarian Cancer Baskent University School of
Medicine Department of Obstetrics and Gynecology, Division of
Gynecologic Oncology Ayhan Ali, MD TJOD 2014 TJOD 2014 1
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Ovarian Cancer GLOBOCAN WorldTurkey
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OVARIAN CANCER The sd most common 238 000 pts worldwide every
year 75% advanced stage Most lethal Currently OAS up to 50%
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advanced ovarian cancer survival showed a 29% improvement
(hazard ratio of 0.71) improvement in the optimal debulking rate
from 43% to 66% van Altena AM et al. Gynecol Oncol 2012 Bristow RE,
meta-analysis of 6885 patients. J Clin Oncol 2002;20(5):1248-5.
FIGO data 5y OAS 1958 %26.8 2001 %49,7
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SEER data 18 2006-2010 Diagnosis Median Age 63 Death Median Age
71
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Risk Factors for Ovarian Cancer RR x % ncreased risk
0.4-0.6Hysterectomy & Tubal ligation 0.6OC use 4yrs
0.4-0.6Multiparity Decreased risk 1-1.5Early menarche 1.5-2Late
menopause 2-3Nulliparity 2-5Infertility 6-710LynchII/HPNCC
16-1927BRCA2 mut. 16-2930-40BRCA1 mut. 5-79.4Family History
11.4-1.8 Baseline lifetime risk
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DNA mismatch repair genes (10%) DNA mismatch repair genes (10%)
BRCA1-BRCA2 Mutations (27%) BRCA1-BRCA2 HNPCC (Lynch II)
Breast-Ovarian cancer Site specific familial ovarian cancer Most
common sporadic About 10 % genetic
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Germ Line BRCA testing at diagnosis 17-20% of OC patients
25-30% of high grade serous histology have a mutation in BRCA
Family history up to 44% have no family history Alsop K et al,
Journal Clinical Oncology 2012 Shrader KA et al, Obstetrics and
Gynecology 2012 Pennington KP et al, Clinical Cancer Research 2014
National Comprehensive Cancer Network Guidelines 2014
Recommendation of national guidelines is that ALL women with OC
should be genetically tested
Pathological Background Type I Endometrioid, Clear Cell,
Mucinous, Low Grade Serous 25% of cases 10% of deaths Good
prognosis Genetic stability KRAS,BRAF,PTEN,PI3KCA,ERBB2 Clinical
exam + US Type II High Grade Serous, endometrioid,
Undifferentiated, MMT 75% of cases 90% of deaths Poor prognosis
Genetic instability P53,BRCA1-2,CCNE1 Novel Biomarkers Kurman and
Shih 2010
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Ovarian Cancer Early Stage Advanced Stage Stage I (Ia Ib Ic)
Local (Stage II) Other (Stage III-IV) FIGO (Surgical
Pathologic)
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New Changes in Staging 2014 Ia-Ib - not only ovaries but also
Fallopian Tubes Ic1 - ntraoperative spillage Ic2 - previous rupture
Ic3 - Positive cytology or ascites II - The same (ovary & tube)
IIIA1i - RLN inv max dimension 10mm IIIA1ii - RLN inv max dimension
> 10mm IIIA2 - Microscopic extrapelvic peritoneal inv +/- RLNM
IIIB - Macroscopic extrapelvic peritoneal inv(2cm), +/- RLNM, liver
and spleen capsule inv IVA - Pleural positive cytology IVB -
nguinal LN involvement & ExtraAbdominal LN- organ inv -
Parenchymal metastases
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RR (response rate), PFS >>> OS, PRO (patient reported
outcomes), CBR (clinical benefit rate), MOE (magnitude of effect)
QoL (quality of life), should be included in evaluation End-Point
of Treatment
Pre-operative work-up History-Examination
(systemic,abdominal,pelvic) Lab studies (cyto, chemical marker etc
) Imaging ( USG,CT,if needed MRI,PET) Laparascopy (open) or Small
Incision laparatomy ( metastatic,possibility of surgery?)
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Front-line therapy in EOC Surgery (Staging -debulking) Adjuvant
(IV or IV+IP comb) Doubled vs Tripled (anti-angiogenesis?)(PFS yes
OS ?) Close follow up
FSS in EOC 25-30% of all EOC are early stage at the diagnosis
14% of EOC will occur under 40 years Of these 62% will be stage I
and IIa Not all, many of these desire to preserve fertility
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Conservative surgery in EOC Staging USO Preserve one ovary +
Tube+ Uterus Evaluation of endometrium with D/C
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Indication of FSS in EOC 1. Stage Ia Grade 1 Stage Ia Grade 2
(limited) 2. Stage Ic, Grade 3, Clear cell + Chemotherapy ACOG
2007,ESMO 2008 Fertility task force of ESGO Oncofertile group of
TGOG
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Main Problems in FSS in EOC A) In preserved ovary 1) occult
metastasis 2) Relapse in spared ovary B) Is there any relationship
between relapse, death and preservation of ovary, uterus or other
risk factors C) Is there a place of complementary surgery after
childbearing
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Rate of Contralateral Ovarian Recurrences and Death of Disease
(DOD) I. Zapardiel et al EJSO 40(2014) 387-393 Patient (%) 683(100)
Overall Relapse n(%) 80(11,7) Ovarian Relapse n (%) 33(4,8) Death
of Disease n (%) 30(4,4)
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OUTCOMES - INVASIVE EOC PatientsPregnanciesBirthRecurrenceDeath
Colombo et al56251632 Zanetta et al84332253 Duska et al62211 Morice
et al34107 4 Schilder et al52172652 Park et al6222 116 Raspagliesi
et al 103300 Colombo et al247672
Total328119(%36)104(%87)42(%13)20(%6)
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Fertility Results after Conservative for EOC Patients n 697
Mean Age years 29 FIGO Stage n (%) 1A 419(60) 1B 6(1) 1C 252(36)
2-3 20(3) Successful conception n % 215(74) (childbearing desire)
Abortions n(%) 38(18) IVF n (%) 5 I. Zapardiel et al EJSO 40(2014)
387-393
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Adjuvant Therapy in Early Stages No Further Tx Tx IC 3, clear
80% Carbo (AUC=5-6) + 175mg/m 2 paclitaxel Stage IA-IB Grade1-2 DFS
90% OS94,8 84,0 29
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Surgical Route in Conservative surgery Laparatomy (open)
spillage 9 % Endoscopic spillage 88% Morcelation Upstage (adhesions
to adjacent tissue) 23 % 1a 1b grade 1-2 receive adjuvant chm Use
Protection bag
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Impact of capsule rupture on Survival PFSOS Unruptured+++
Intra-op+++ (if complete stg + adjuvant) Debatable Pre-opPoorer
than others Poorer than others Recc rate : unruptured < intra-op
< preop EJSO 39 (2013) 279-289
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L/T vs L/S in Early Stage 77 pts stg 1-2 L/S:24 L/T :53 Op
time: 224min vs 193 min Tm recc: 2 pts vs 2pts DFS : 59 mts vs
66mts Similar complication rates No statistically difference
between techniques Yu-Jin koo et al. J Gynecol Oncol Vol.25,
No.2:111-117, 2013
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Survival 925 patients with early stage disease were subjected
to Radical Surgery +Chemo (ICON1 and ACTION Studies) 5 yrs DFS76% 5
yrs OS82% J Natl Cancer Inst, 2003:95:105-112
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Prognostic Factors in Early Stage EOC Stage (a,b,c) Grade ( 1
vs 3) Age Histology (G2/3 serous clear cell vs others) Cytology
Ascites LVS Biomarkers (ca125?,HE4) Molecular markers
(p53,p16?,PTEN?,BRCA?)
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A new prognostic index PI formula 2 x age + 86 (if grade 2) -
105 (if grade 3) + 53 (if stg b or c) 130 (if stg 2) + 53 (if no
LND) - 43 (for adj CT 3times) + 10 calibrating costant Park HJ et
al. 2012 Gynecologic Oncology 269 high risk %60 Total 177 pts 5y
RFS
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Advanced EOC (Stage II, III, IV) Surgery
(Cytoreduction-Debulking) + Adjuvant (Chemo) (Platin + Taxane +
Bev) Follow-up Team-Work-up: Gyneco, Med Onc, Rad Onc, Gyn
Pathol
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History of Optimal Cytoreduction Griffith (1975) 1.6 cm (OS was
inversely proportion to residual mass under 1.6cm) Than 2 cm
Definition was revised by GOG (97, 52, 158, 172) as a 1 cm or less
(optimal) Today; NO MACROSCOPC RESDUAL DSEASE
Median survival increases at least 5.5% for each 10% increase
of CYTOREDUCTON Bristow et all 2002 JCLN oncol 20:1248 Gynecol
Oncol 1992 Am J Obstet Gynecol 1986
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Median Survival (mts) StudyNDefinitionOptimal Suboptimal Liu et
al.47
P.-E. Colombo et al. / EJSO 35 (2009) 135e143 Initial surgery
group 5year OS(%) No residual tm 50 RT 1cm 14
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Residual Tumor - mOS Residual TmOS (mts) None 69 1-10mm 31
>1cm 15 P. Harter et al. / Gynecologic Oncology 121 (2011)
615619
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Median PFS by residual disease after PDS Median OS by residual
disease after PDS PFS (mts) OS (mts) Cum Surv 020406080100120
020406080100120 0.2 0.4 0.6 0.8 1 0.2 0.4 0.6 0.8 1 NG Residual
Diss 1cm >1cm NG 1cm >1cm Residual Diss 78 mts 50 mts 36 mts
24 mts 17 mts 13 mts D.S. Chi et al. / Gynecologic Oncology 124
(2012)
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Extension of surgery - OS P. Harter et al. / Gynecologic
Oncology 121 (2011) 615619 Median OS(mts) 19972000 26 20002003 37
20042008 45
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A review about cytoreduction S.-J. Chang, R.E. Bristow /
Gynecologic Oncology 125 (2012) 483492 Tumor SizeNMOS No Gross
Residu359377.8 Residu tm 1cm351831.1
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396 patients FIGO stages IIBIV Surgery extends by time 19972000
(51 pts) 20012003 (86 pts) 20042008 (259 pts) complete resection
increased from 33% to 62% Residuals 1 cm increased from 65% to 86%
P. Harter et al. / Gynecologic Oncology 121 (2011) 615619
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PCR vs ES 5-year OS(%) Median OS(mts) 5-year PFS(%) Primary
Cytoreduction 354314 Extended Surgery 475431 Also significantly
more optimal cytoreduction and less gross tumor in ES D.S. Chi et
al. / Gynecologic Oncology 114 (2009) 2631
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Surgeon Factor 14 studies involving 19,043 pts Treatment by GYO
showed higher rates of: comprehensive staging of FIGO I/II (4 of 4
studies) optimal debulking in FIGO III/IV (4 of 6 studies)
state-of-the-art chemotherapy (2 of 2 studies) superior survival (5
of 9 studies) Significant advantage for at least 1 parameter in 13
of 14 studies
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Therapeutic Benefit of Lymphadenectomy in AOC du Bois et al
JOURNAL OF CLINICAL ONCOLOGY VOLUME 28 NUMBER 10 APRIL 1 2010 No
res. Tm. (n:996) LNE (+)LNE (-) Median S. (mts) 10384 5-year S. (%)
67,459,2 Lymphadenectomy associated with superior survival in
patients with NO residual disease
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OS after LNE or no LNE in patients with postoperative residual
tumor of 1 to 10 mm and with or without preoperative/intraoperative
clinically uspect LNs (comparison 2A; cohort 2) suspect LN (n:527)
LNE (+) LNE (-) Median S. (mts) 5732 5-year S. (%) 48,124,7 du Bois
et al JOURNAL OF CLINICAL ONCOLOGY VOLUME 28 NUMBER 10 APRIL 1 2010
significant impact of lymphadenectomy ONLY IN PATIENTS WITH
CLINICALLY SUSPECT NODES (HR 0.72; 95% CI, 0.53 to
0.98;P.0379)
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189 patients Os mnt Pfs mnt LND+6622 LND-409 Patients with NGR
OS and PFS higher in LND+ arm Patients with GR- B no diff in OS and
PFS
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Systematic vs resection of Bulky nodes The only
randomised-controlled study Benedetti-Panici at all 2005 J Natl
Cancer nst P=216 vs 211 RD1 cm 6 month PFS benefit (p=0.02) in
systematic group Same OS
NACT+ID Advanced age Poor performance Unresectable tumor Open
Laparascopy or small incision
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PDS vs NA CT PDS vs NA CT n:704 pt ( in stage IIIc + IV) PDS
NACT OS29mos 30mos PFS11mos 11mos Optimal CytR.R42% 83% Morbidity
High Low From Vergote I. et al 2008 Prospective RCT :
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What is new ? Advances in std therapy Weekly paclitaxel better
than 3w conventional therapy(standart vs dense dose chm) Targeted
thrp Anti-angiogenesis in first line treatment (bevacizumab,
tyrosine kinase inhibitors,) Anti-angiogenesis in relapsed disease
(bevacizumab, tyrosine kinase inhibitors, angiopoietin inhibitor-
AMG386) PARP inhibitors BRCA gene mut carriers M-TOR nhbtors
Targeting Folate rct EFGR and HER2
inhibitors(transtuzubab,pertuzumab,getifinib
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Risk reduction Screening US, Image scoring systems Bomarkers
(ca125, HE4) Chemoprevention OCP Tamoxifen Prophylactic Surgery BSO
Hysterectomy Tubal ligation Salpingectomy
Prevention for BRCA mutant patients 2482 patients 247 RRS - no
Breast Ca 1372 patients with no surgery 98 Breast Ca Risk reducing
Oophorectomy decreases ovarian cancer and breast cancer Domchek et
al, JAMA 2010
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Trials for Screening University of Kentucky 25,327 Japanese
Shizuoka Cohort 82,487 PLCO Cancer Screening 68,616 United Kingdom
202,638 N 25,32741,68830,63098,305 Strategy USGExam USG CA125 USG
ca125 USG USG+Ca125 (ROCA) Result Longer 5-yrs survival in screened
group More stage 1 ovarian cancer in screened group No mortality
benefit MMS had a superior PPV and sensitivity Usha Menon et al.
Gynecologic Oncology 132 (2014) 490-495
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Screening Conclusion Routine Screening is not recommended Ca125
and Tv-US for BRCA positive women ACS,ACOG,NCCN,SGO, Canadian Task
Force on Periodic Health Examination, USPSTF
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Conclusion Incorporate the patients genetic and their tumor
characteristics Effects therapeutic options (IP CT, PARP inh) Early
diagnose or close follow up for family members Risk reduction for
secondary or synchronous cancers
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OC remains as the most lethal GYN neoplasm Patient profile same
Management and treatment has improved within years In last 30 yrs
survival improved 2yrs Not only surgery but also biologic behavior
of tumor Conclusion