PDS vs NACT+İDS İn ASEOC Ayhan Ali, MD Baskent University School of Medicine Department of Obstetrics and Gynecology Division of Gynecologic Oncology

Ovarian Cancer No effective screening More than 60% stage III-IV Agressive cytoreduction + chemotherapy(TC) Cure rate is 25-30%(5y)

Therapy depends on: Patients’ factor Tumor factors Genetic alterations (Age, performance) Tumor factors (Histology, grade, molecular) Genetic alterations Surgeon factor Clinical factors (Accurate diagnosis, extend of tumor, experienced team, high-volume hospital)

Currently Standard Upfront Therapy İn Advanced stage EOC In advanced epithelial OC primary debulking surgery aiming to remove all visible tumor tissue followed by adjuvant CT with Platinum/Taxane±Bevacizumab

Pre-operative work-up History-Examination (systemic, abdominal, pelvic) Lab studies (cyto, chemical marker… etc ) Imaging ( USG, CT, if needed MRI,PET, diff MRI if needed) L/S (open) or Small Incision L/T ( Primary or metastatic possibility of surgery – Fagotti’s, Bristow’s, Leuven-Essen criterias) M. Petrillo et al. Gyn Oncol 139 (2015) 5-9 Vergote et al. J Clin Ocol Vol 34 No 32 (Nov 10), 2016 Leisewortz et al.Int J Gynecol Cancer 2017

Genomic Profiling, Defining Populations and Determining Clinical Activity of an Agent

OC Mutations by Histology Norquist et al JAMA Oncol 2016

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

Extended Surgery

Limitation of PDS (Metastatic sites and dissemination) 658 patients 578 upfront surgery 191 had residual disease p: 0.001 Location of Residuel Tm ALL N:191 TR 1-10 mm N:144 (75,4%) TR>10 mm N:47 24,6% p Small intestine 150(79,8%) 124(87,9%) 26(55,3%) <0.001 Portahepatis Lig.hepatoduodenale 19(10,1%) 7(5%) 12(25,5%) Parenchymal Liver met. 8(4,3%) 1(0,7%) 7(14,9%) Supradiaphragmatic 25(14,9) 21(14,9%) 1.000 Pancreas 15(8%) 4(2,8%) 11(23,4%) Stomach 6(3,2%) 2(1,4%) 4(8,5%) 0.035 T.coeliacus 5(2,7%) 3(6,4%) 0.101 Residue OAS (months) R0 56 0-10 mm 32 >10 mm 17 Heitz et al Gynecol Oncol 2016 May;141(2):264-70

ESGO criteria of inoperability in advanced ovarian cancer (I) Central or multisegmental parenchymal liver metastases • Multiple parenchymal lung metastases (preferably histologically proven) • Nonresectable lymph node metastases • Brain metastases

ESGO criteria of inoperability in advanced ovarian cancer (II) Diffuse deep infiltration of the root of small bowel mesentery • Diffuse carcinomatosis of the small bowel involving such large parts that resection would lead to a short bowel syndrome (remaining bowel <1.5 m) • Diffuse involvement/deep infiltration of stomach/duodenum** head or middle part of pancreas*** • Involvement of truncus coeliacus, hepatic arteries, left gastric artery**** Querleu D et.al. IJGC 2016

What is the Survival Impact of Cytoreduction Overall survival, stage IIIC ovarian cancer, 1989–2003. Residual disease Pts Median OS (mo) Micro 67 106 <0,5cm 70 66 0,5-1cm 99 48 1-2cm 53 33 >2cm 176 34 D.S. Chi et al. / Gynecologic Oncology 103 (2006) 559–564

HR (95% CI) 1-10 mm vs 0 mm 2.62 (2.26;2.81) >10 mm vs 1-10 mm 1.36 (1.24;1.60) 0 mm n:1046 898 690 539 389 232 111 58 32 17 7 E:563 1-10 mm n:975 653 311 178 117 75 43 22 14 11 5 E:817 >10 mm n:1105 610 234 146 85 46 16 2 1 E:995 HR (95% CI) 1-10 mm vs 0 mm 2.70 (2.37;3.07) >10 mm vs 1-10 mm 1.36 (1.21;1.49) du Bois et al. Cancer 2009 0 mm n:1046 996 900 773 566 333 147 70 36 19 8 E:359 1-10 mm n:975 886 669 451 293 157 73 18 12 5 E:653 >10 mm n:1105 933 650 435 247 116 40 15 6 2 E:829

A review about cytoreduction Tumor Size N MOS No Gross Residue 3593 77.8 Residu tm <1cm 4780 39 Residu tm >1cm 3518 31.1 S.-J. Chang, R.E. Bristow / Gynecologic Oncology 125 (2012) 483–492

Survival impact of Optimal Debulking(Ro vs Others) 447 patients n: PFS OAS RD 0 cm 199 24 57 RD 0.1-0.5 cm 138 16 35 RD 0.5-1 cm 51 12 29 RD > 1 cm 59 22 Wallace et al. Gynecol Oncol 2017

What about Extended Surgery PCR vs ES 5-year OS(%) Median OS(mts) 5-year PFS(%) Primary Cytoreduction 35 43 14 Extended Surgery 47 54 31 Also significantly more optimal cytoreduction and less gross tumor in ES D.S. Chi et al. / Gynecologic Oncology 114 (2009) 26–31

GOG 182 2655pts with optimal CR(<1cm) 482(18,1%) pts - 590UAP performed 351 (13,1%) diaphragmatic surgery 112 (4,2%) liver surgery 108 (4%) splenectomy 12 (0,5%) pancreatectomy 7 (0,2%) porta hepatis surgery UAS vs non UAS PFS : 18,2 vs 14,8 mts (p<0,01) OAS : 49,8 vs 43,7 mts (p: 0,01) No RT (n:141) vs Minimal (<1cm) RT (n:341) OAS : 54,6 vs 40,4 mts (p: 0,0005) UAS should be performed when no residual tm is attainable N. Rodriguez et al /Gynecologic Oncology 130(2013) 487-492

MSKCC Primary Cytoreduction OS and CGR Rates Leary et al. ESGO Educational Book 2016

Liver Resection in EOC Study Ptx N Optimal CRS (%) Negative Resection Margin (%) OS (m) Meredith et al (2003) 26 80,8 NA 26,3 Optimal 27,3 Suboptimal 8,6 Yoon et al (2003 24 66,7 54,1 62 Loizzi et al (2005) 29 25 Abood et al (2008) 10 100 50 33 Pekmezci et al (2010) 8 Roh et al (2010) 18 38 (3-78) Niu et al (2012) 60 90 39 (5-79) Neumann et al (2012) 70 Optimal 42 Suboptimal 4,6 Kolev et al (2014) 27 92,6% 88,9 56 (12-249) 11 Gasparri et al., J Cancer Research Clin Oncol Dec 2015

Survival Impact of Splenectomy OAS% DFS% Splenectomy 33 66,6 30,3 No splenectomy 99 59,6 33,3 Splenic met prevelance : 2,3-7,1% Incidence up to 20% in autopsies Zapardel et al; Intenational Journal of Gynecological Cancer, vol 22,2012

Survival Impact of Diaphragmatic Surgery(n:181) 5 yrs s. % Surgery 41 55 Non Surgery 140 28 Aletti et al, Gynecol Oncol 2006; 100, 283

Porta Hepatis Surgery 11 patients, heterogenous history of disease Multidisciplinary approach for prevention of morbidity Limited number direct survival effect is unclear Indirectly YES Y.J. Song et al. / Gynecologic Oncology 121 (2011) 253–257

Optimal Debulking Surgery in Stage IV Ovarian Ca Study Optimal debulking n (%) Criteria (cm) Optimal Median OS* (m) Suboptimal Median OS* (m) Curtin et al 1997 41 (45) ≤2 40 19 Liu et al 1997 14 (30) 37 17 Munkarah et al 1997 31 (31) 25 15 Bristow et al 1999 25 (30) ≤1 38 10 Akahira et al 2001 70 (31) 32 16 Aletti et al 2008 50 (46) Winters et al 2008 78 (22) 0.1-1 29 20 * All SS Curr Treat Options in Oncol 2016; 17:1

NACT Setting: A Translational Research Oppurtinity Leary et al. ESGO Educational Book 2016

Tumor Biology Effects The Response to First-Line Platinum-Based Chemotherapy Response rates in High Grade Serous OC approaches to 75% Tumor Subtype No. Of patients With Evaluable Disease Activity Study Low Grade Serous OC 24 < 5% Schmeler et al Clear Cell OC 23-68, 4 studies 22%-41% Kita et al, Sugyama et al, Ho et al, Takano et al Muscinous OC 9-50, 5 studies 13%-60% Hess et al, Alexandre et al, Pectasides et al, Gore et al, Shimada et al Leary et al. ESGO Educational Book 2016

PDS vs IDS in Stage III or IV Year Study Primary Endpoint Study Arm n Stg IV (%) No Residual PFS (Months) OAS (months) 2016 Scorpion (Fagotti’s) Surgical Comp. NACT PCS 55 7 15 58 46 Not reported 2015 CHORUS OS 274 276 25 39 17 12.0 10.7 24.1 22.6 2014 JCOG 0602 152 149 30 32 63 2010 EORTC 5591 334 336 24 23 51 19 12 29 Wright et al. Gynecol Oncol 143 (2016) 3-15

Rates of NACT usage İncreased overall to 22 % Up to 34 % in Stage III C Up to 62 % in Stage IV İn USA S Clinical Oncology

What About Long Term Survival? PDS vs IDS Median survival (m)* PDS IDS Total OS 43 33 41 PFS 17 14 16 *All SS n:14182 (PDS; 11871 + IDS; 2311) median follow-up 43 m Subgroups after Complete Resection Median survival (m)* PDS IDS OS 69 46 PFS 29 18 *All SS Ann Surg Oncol. 2016 May;23(5):1666-73

PDS vs IDS Any Residual *R0 Resection n:14182 (PDS; 11871 + IDS; 2311) median follow-up 43 m Ann Surg Oncol. 2016 May;23(5):1666-73

PDS (Only one or never) 43 36 NACT+IDS (More than one) 27,3 31 Multiple Cycles of NACT Associated with Poor Survival in Bulky Stage IIIC and IV Ovarian Cancer n:408 Median OS (m) 5y OAS (%) PDS (Only one or never) 43 36 NACT+IDS (More than one) 27,3 31 p: 0,032 IJGC 2015; 25: 1398-1404

PDS:240 NACT:270 Groups 1. R0 2. ≤1cm single location (≤1cm-SL) 3 PDS:240 NACT:270 Groups 1. R0 2. ≤1cm single location (≤1cm-SL) 3. ≤1cm multiple location (≤1cm-ML) 4. Suboptimal residual (>1cm)

OVERALL SURVIVAL: PDS 95 total deaths (39.6%) Median OS -R0: Not yet reached -≤1cm-SL: 64 months -≤1cm-ML: 50 months -Suboptimal: 49 months

OVERALL SURVIVAL:NACT 132 total deaths (48.9%) Median OS -R0: 58 months -≤1cm-SL: 37 months -≤1cm-ML: 26 months -Suboptimal: 33 months

patients undergoing neo-adjuvant versus adjuvant chemotherapy Stage III&IV Kaplan-Meier OS (A) and PFS (B) curves in function of type of protocol comparing patients undergoing neo-adjuvant versus adjuvant chemotherapy Kessous et al. Gynecologic Oncology 144 (2017) 474–479

Stage IIIC Kessous et al. Gynecologic Oncology 144 (2017) 474–479

PDS vs IDS in Stage IV PDS (n:1488) 27 15 63 IDS (n:308) 29 35 32 Median OS (m) Complete Cytoreduction % OAS (m) PDS (n:1488) 27 15 63 IDS (n:308) 29 35 32 Ann Surg Oncol. 2016 May;23(5):1666-73

263 patients were included in the study analysis Gynecologic Oncology 144 (2017) 474–479 263 patients were included in the study analysis 127 patients received NACT with IDS Platinum sensitivity 72.2% Debulking results Complete 65.9% PFS: 14.5 mo OS: 71 mo Sub optimal 34.1% PFS: 8 mo OS: 36 mo 136 patients had primary debulking and adjuvant CT 77.4% Complete 40.2% PFS: 40 mo OS:106 mo 59.8% PFS: 10 mo OS: 55 mo Higher rates of CR But OAS?

What About Survival Impact of HIPEC In After NACT 245 EOC pts 3 cycles of NACT ( at least stable disease ,NO progressive or refractory) PLUS Surgery ( complete resection or maxımum 10 mm residual tm) ± HİPEC (100 mg per sq Cisplatin) HİPEC :122 pts Without HİPEC:123 pts

HİPEC vs NO HİPEC 45,7 m vs 33,7 m P=0,02 HİPEC vs NO HİPEC 14,2 m vs 10,7 m P=0,003

NACT+IDS Short Term Advantages (n:1607, AOC Patients) Optimal cytoreduction Peri-operative morbidity Mortality Quality of life* Better QOL than PDS* Fatigue Role of function Emotional function Cognitive function Yang et al journal.pone 01186725 2017

What about the Cost? Retrospective cohort, btw 2000-2009, newly diagnosed stage III/IV EOC n=8188 Cumulative lifetime costs was NACT $ 134,576 PDS $ 117,159 Significantly lower surgical complication costs -$4987 but higher CT-related costs $6874 for the NACT group NACT is cost-effective in “normal levels” in the high-risk subgroup: -Stage IV tumor -Older age -Poor performance status However not for the overall sample or for non-high risk pts Poonawalla et al. Value in Health 18 (2015) 387-395

The Incidence of (+) LN in Advanced Ovarian Cancer = 66% Survival İmpact Of Lymphadenectomy İn Advanced Stage Ovarian Cancer The Incidence of (+) LN in Advanced Ovarian Cancer = 66% 49% positive LN > 1 cm diameter 17% had positive LN > 1cm not identified by palpation or inspection Eisenkop SM et al, Gynecol Oncol 2001

SEER Data 1988-2001 13.918 pts Extension of LND M.Variant Survival analsis Survival Increased with the number of Lypmh node

Lymphadenectomy in ASEOC No res. Tm. (n:996) LNE (+) LNE (-) Median S. (mts) 103 84 5-year S. (%) 67,4 59,2 Lymphadenectomy associated with superior survival in patients with NO residual disease du Bois et al. J Clin Oncol Vol. 28 No. 10 April 2010

57 32 48,1 24,7 LNE (+) LNE (-) Median S. (mts) 5-year S. (%) suspect LN (n:527) LNE (+) LNE (-) Median S. (mts) 57 32 5-year S. (%) 48,1 24,7 significant impact of lymphadenectomy ONLY IN PATIENTS WITH CLINICALLY SUSPECT NODES (HR 0.72; 95% CI, 0.53 to 0.98;P.0379) 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) du Bois et al. J Clin Oncol Vol. 28 No. 10 April 2010

Opimally debulked 158 pts Advanced stage LND ≥20 nodes 96 pts LNS:<20 nodes 62 pts LND significantly İmproved PFS and OS

Data From GOG 182 1.871 stage III C RP exploration 269 LN met- 420 LN met + Without RP exploration

3 randomısed controlled 11 retrospective study Lyphadenectomy is accociated with greater 5 year OS for all stages(p<0,001) But Higer PFS and Lower Recurrence Rate was observerd in Advances Stage EOC(p=0,011)

Survival after recurrence Retrospective study 261 pts Survival after recurrence Survival After REC LN 135 NO LN 126 P value 43 m 32 m 0,013

İncreased relaparotomy İnfections Mortality within 60 days No LNE LİON Results M.O.S Median PFS Complication LNE 65,5 m 25,5 m Longer surgery time İncreased Blood loss İncreased relaparotomy İnfections Mortality within 60 days No LNE 69,2 m P value 0,65

New Approaches in the Management of EOC Gene based chemotherapy Novel biologic agents ( VEGF. PARP. m-TOR. inhibitors etc…) IP chemotherapy (Regular and HIPEC) NACT Check-point inhibitors (Vaccination & Immune therapy)

Conclusion OC remains as the most lethal GYN neoplasm No effective screening programme More than 60% is advanced stage Currently PDS with no residual tm + Adjuvant CT is the standard of care NACT + IDS is not standard yet just in selected cases Platinum resistance after NACT is controversial NACT + IDS does not extend OAS? (unclear)

Conclusion Incorporate the patient’s 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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