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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

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ncessant ovulation STC Endometriosis Pelvic contamination

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High-Grade Serous Low- Grade Serous EndometrioidClear CellMucinous TP53BRAFARID1A KRAS BRCA1/2KRASPI3KCA ERBB2 ampl NF1NRASPTEN CDK12ERBB2PPP2R1ACTNNB1 Homologous Recombination Repair genes MMR deficiency PPP2R1A Pathway alterations P3/Ras/Notch FoxM1 Serous Endometrioid Mucinous Borderline Mucinous Clear CellMucinous Endometrioid HG serous

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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

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Therapy depends on: Patients factor ( Age, performance, fertility desire) Tumor factors (Histology, grade, molecular - genetic alterations) Clinical factors ( Accurate diagnosis, extend of tumor, experienced team, effective hospital supply)

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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

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Staging Vertical incision Peritoneal cytology Exploration- Multiple Biopsies Omentectomy?(nfracolic) Appendectomy BP-PALND USO (TAH+ USO) 18

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Subclinic Metastasis (%) Stage I-II Cytology 26.411.3 Omen. 8.63.5 Diaphragm 7.30.0 LN 5.9-1413 Appen. 0.02.3 Ayhan et al, Obstet Gynecol, 2005 19 Ayhan et al Stg I

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Why Staging Procedure? To detect subclinical metastasis: 31-33% advanced staged 77% of these stage IIIC 20

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Early Stage EOC organ sparing * complementary Staging IA, Grade 1, 2 TAH + BSO *grade 3, 1c clear cell 21

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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

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Cytoreductive Surgery Middle & Lower Abdominal Hysterectomy Oopherectomy Bowel resection Appendectomy LND (Pelvic,aortic) VATSVATS Upper Abdominal Diaphragm Splenectomy Distal Pancreatectomy Liver resection Porta Hepatis resection Others PDS IDS SDS

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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

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Extended Surgery

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Alternatives for PDS (not standardized) Interval debulking (suboptimal PDS +3 cycle chemo+surgery add 3 cycle chemo) 1.Neoadjuvant chemo + Debulking (Biopsy proven EOC + 3 cycle chemo + surgery+ 3 cycle chemo)

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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

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Prevention Multiparity 5y use reduces risk 50%) Tubal ligation/Salpingectomy Oophprectomy Hysterectomy Lactation

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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

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Thank you for your attention