Cytoreductive Surgery For Advanced Ovarian Cancer How Far .

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Cytoreductive Surgery for Advanced Ovarian CancerHow Far Should We Go To Achieve Optimal Status?Jonathan S. Berek, MD, MMSLaurie Kraus Lacob ProfessorStanford University School of MedicineDirector, Stanford Women’s Cancer CenterSenior Scientific AdvisorStanford Comprehensive Cancer Institute

Surgical Cytoreductionof Ovarian Cancer Optimal “debulking”( 1.5 cm) median survival longerthan suboptimal & similarto those whose diseasesmall prior to resection**Griffiths CT. Seminars Oncol 1975Berek JS, Leventhal J, Griffiths TC, Obstet Gynecol 1979

Cytoreductive Surgery forAdvanced Ovarian CancerAcknowledgementNeville F. Hacker, MDArchana Rao, MDHacker NF, Rao A. "Surgery for advanced ovarian cancer" in Epithelial Ovarian Cancer.ed. Hacker NF. Best Practice and Research in Obstetrics and Gynaecology. In press, 4-17

University of California Los AngelesUCLA School of Medicine, 1982

Fellows in American College of Surgeons, 1984

1st Edition of Berek and Hacker, 1985

Hacker NF, Berek JS, et al. Primary cytoreduction. Obstet Gynecol 1983Berek JS, Hacker NF, et al. Secondary cytoreduction. Obstet Gynecol 1983

Cytoreductive Surgeryin Ovarian CancerIs it the act of committing cytoreductionor the manner in which the diseasegrows, i.e., its tumor biology, thatpermits optimal debulking?Is the outcome a result of the surgery, orjust the natural history of the cancer?

Cytoreductive Surgery forAdvanced Ovarian Cancer Gold standard for most patients with stage IIImetastatic epithelial ovarian, fallopian tube &peritoneal (Ov-FT-P) cancers Requires appropriate surgical expertise Best performed in regional cancer centers

Cytoreductive Surgeryfor Advanced Ovarian CancerWhat are the factors that influence the maximalcytoreductive effort? Performance status of patientBiology of the diseaseExtent of metastatic diseaseDistribution of diseaseAggressiveness of surgeon

Cytoreductive Surgeryfor Advanced Ovarian CancerWhat is the most optimal status? 0.5 cm0Hoskins, et al. Gynecol Oncol 1992Farias-Eisner, Berek, Hacker, et al. Gynecol Oncol 1994Du Bois A, et al. Cancer 2009

Cytoreductive Surgeryfor Advanced Ovarian Cancer Stage IV disease– less clear how effective

How aggressive should we be? Pelvic viscera- colectomyLymphadenectomySmall intestinal resectionSplenectomyDiaphragm resectionHepatic resectionPulmonary-pleura resection

Berek &Hacker,2015

Berek &Hacker2015

Berek JS, et alObstet Gyncol 1986

Resection of a bulky, positive lower precaval lymph nodes,which were causing partial obstruction of the right ureterHacker2017

Resection of Lymph Nodes DuringCytoreductive Surgery Prospective, randomized study of patients whose tumorswere optimally cytoreduced in the peritoneal cavityunderwent systematic pelvic and paraaorticlymphadenectomy vs. resection of bulky nodes only. Well matched armsSystematic lymphadenectomy 216 (189 eval) ptsNodal debulking 211 (195 eval) pts PFS 27.4 vs. 22.4 (5 mo ) 5-year OS 48.5% vs. 47 %(95% CI 8.4-10.6%)Benedetti Panici P, Mangioni A, Hacker NF, et alJ Natl Cancer Inst 2005;97:560

CarcinomatosisHacker2017

Berek &Hacker 2015

Large omental cake densely adherent to andinfiltrating into the spleenBerek &Hacker2015

Radical Upper Abdominal SurgeryResection of transverse colon, omentum, spleen & distal pancreas to removemetastatic disease involving the omentum, spleen, & transverse mesocolonHacker 2017

PET/CT scan - ovarian cancer metastasis involving the liver & right diaphragm (L)Involved segment of right diaphragm resected, still attached to disease in liver (R)Hacker 2017

Resection of underlying disease in the liver.Hemostasis secured by sutures and application of hemostatic materialHacker2017

Cytoreductive Surgeryfor Advanced Ovarian Cancer Primary Debulking Surgery (PDS)vs.Neoadjuvant Chemotherapy (NACT) Interval debulking surgery (IDS)

Meta-analysis of the randomized EORTC andCHORUS Neoadjuvant versus PrimaryDebulking trials in advanced Ovarian CancerIgnace Vergote,Corneel Coens, Matthew Nankivell, Gunnar B. Kristensen, Max Parmar, Tom Ehlen,Gordon C. Jayson, Nick Johnson, Ann Marie Swart, René Verheijen, W. GlennMcCluggage, Tim Perren, Pier-Luigi Benedetti, Gemma Kenter, Antonio Casado, CesarMendiola, Gavin Stuart, Nick S. Reed,Sean Kehoe

Meta-analysis of the randomized EORTC andCHORUS Neoadjuvant versus PrimaryDebulking trials in advanced ovarian cancer Background and aims.– Pre-planned meta-analysis of 2 randomized trials (EORTC 55971–NEJM2010;363:943 - and MRC CHORUS– Lancet 2015;6763: 62223) comparingneoadjuvant chemotherapy (NACT) with primary debulking surgery (PDS) inadvanced ovarian-fallopian tube cancer Methods.– The patient data of both trials were updated and merged in one data base(data base lock EORTC June 6, 2015 and CHORUS May 20, 2015) Median follow-up: 7.6 years:– EORTC: 9.2 y– Chorus: 5.9 y

Randomized EORTC-GCG/NCIC-CTG TrialNACT IDS vs PDSOvarian, fallopian tube, or peritoneal cancerFIGO stage IIIc-IV (n 718)Randomization48 patients excluded from1 center N 670Primarydebulking surgeryNeoadjuvantchemotherapy3 x platinum-based CT3 x platinum-based CTInterval debulking(not obligatory)Interval debulking if no PD 3 x platinum-based CT 3 x platinum-based CTPrimary endpoint: Overall survivalSecondary endpoints: Progression-free survival, quality of life, complicationsVergote I, et al. N Engl J Med. 2010;363(10):943-953.

EORTC: NACT IDS vs PDS: ITTOverall SurvivalMedian survivalPDS: 29 monthsIDS: 30 monthsHR for IDS:0.98(0.84, 1.13)Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

CHORUS trial (Kehoe S et al)RandomizedN 552Progression/unfit/died 18Patient withdrew3Physician choice4No malignancy2Incomplete data1No post-op chemoIncomplete dataRandomized in errorPSN 276NACTN 274Primary surgeryN 248Neoadjuvant chemoN 252SurgeryN 214353Post-op chemoN 210Kehoe S, Lancet 2015,6763: 62223Post-op chemoN 1992Ineligible at disease conf 10Progression/unfit/died9Patient withdrew3Progression/unfit/diedComplete responseInsufficient responseIneligiblePatient choice295121No post-op chemo15

Overall survivalCHORUS TRIALPS(N 276)Overall survivalProportion aliveintention-to-treat population1.00Events0.75Median (months)(95% CI)HR* (95% CI)0.50211NACT(N 274)19922.8(19.1, 26.0)24.5(21.3, 29.1)0.87 (0.71, 1.05)1-year OS rate70%76%3-year OS rate32%34%0.259% IIA-IIIB in PDS withR0 rate of 16%0.0006121824303642485460667278849096Time from randomisation (months)NPSNCT276 222 185 151 126274 233 200 158 13263733244PS* HR adjusted for baseline stratification factors.17209122510NCTKehoe S, Lancet 2015, 386:249

Meta-analysisEORTC & Chorus trials (n 1220)EORTC(n 670)Chorus(n 550)TOTALMedian Age (y)626563Largest metastatic tumorsize (mm)808080CA125 at entry (KU/L)116110161089WHO .3%18.5%0.9%0.2%38.6%45.5%15.2%0.4%0.2%FIGO .5%

Meta-analysisEORTC and Chorus trials (n 1220)By study

Meta-analysisEORTC and Chorus trials (n 1220)By treatment arm

Meta-analysisEORTC and Chorus trials (n 1220)By treatment arm (n 831)

Meta-analysisEORTC and Chorus trials (n 1220)Overall survivalBy treatment arm (n 230)

EORTC: NACT IDS vs PDS: ITTSurvival Time: FIGO StageEvents / PatientsStatisticsEORTC 55971Upfront debulkingNeo-adj. Chemo (O-E) Var.III185 / 258188 / 253-6.492.7IV67/ 7657/ 8110.130.4252 /334(75.4 %)245 /334(73.4 %)TotalHR & CI*(Upfront debulking : Neo-adj. Chemo)3.8 123.1Test for heterogeneityChi-square 3.7, df 1: p 0.05*90% CI everywhereVergote I, et al. N Engl J Med. 2010;363(10):943-953. 1-HR % SD3% 9increase0.250.5 0.81.02.04.0Upfront debulking Neo-adj. ChemobetterbetterTreatment effect: p 0.1

EORTC: NACT IDS vs PDS: PP1Overall Survival: Largest Metastatic Tumor SizeEvents / PatientsStatisticsVar.EORTC 55971 Upfrontdebulking Neo-adj.chemo (O-E)0-49 mm53/ 9465/ 95-12.728.650-99 mm69/ 9064/ 886.932.5100-199 mm92/ 10583/ 1138.443 200 mm22/ 2621/ 24-0.810.3Total236 / 315(74.9 %)233 / 320(72.8 %)HR &CI*(Upfrontdebulking: Neo-adj.chemo)1.8 114.4Testfor heterogeneityChi-square 8.8,df 3:p 0.03*90%CI everywhere 5 cm: HR, 0.64; 95% CI: 0.45-0.93Vergote I, et al. N Engl J Med. 2010;363(10):943-953. 1-HR % SD2% 9increase0.250.5 0.81.02.04.0Upfront debulking Neo-adj. chemobetterbetterTreatment effect: p 0.1

Meta-analysisEORTC and Chorus trials (n 1220)Stage IIIC with metastases at diagnosis 5 cm (N 266)

ConclusionsEORTC-CHORUS meta-analysis1. 1220 patients with this group of Stage IIIC-IVovarian cancer with long-term follow-up (7 years)- NACT results in similar survival compared withPDS2. Only patients with biopsy proven stage IIIc or IVare candidates for neoadjuvant chemotherapy3. Interval debulking should be planned after 3courses of chemotherapy

ConclusionsEORTC-CHORUS meta-analysis4. Patients with stage IIIc and metastases 5 cm aregenerally better treated with primary debulking,depending on good general medical condition andno extensive spread on the bowel, or tumor oninoperable sites, e.g. around superior mesentericartery5. Patients with Stage IV disease are generally bettertreated with neoadjuvant chemotherapy, except forthose with pleural effusions only and easilyresectable Stage IV, e.g., inguinal nodes, spleen

How to Select Patients?

Laparoscopy to predict the result of primarycytoreductive surgery in patients with advancedovarian cancer: randomized controlled trialArmLaproscPDSTotaln“futile”PDS IDS1029910 (10%)39 (39%)3 (3%)28 (28%)201Rutten MJ, van Meurs HS, van de Vrie R, et al. J Clin Oncol 2017;35:613-625p 0.001 0.001

NACT- IDS vs. PDSCriticisms of Studies Low percentage of patients had optimal(no residual) resection of disease16-40% (4-10%) Poorer performance status than in mostupfront randomized prospective studies(high of 19-20% PS 2-3)

Discussion: PDS vs. NACT-IDSPerformance o774-75%3%Presented by: Jonathan S. Berek2-3

Discussion: PDS vs. NACT-IDSAge years median (Range)PDSNCTCHORUS276 pts66 yrs (26-87)274 pts65 yrs (34-88)EORTC336 pts62 yrs (25-86)334 pts63 yrs (33-81)JGOG 3016 57 yrs (25-87), MITO7 59 yrs (23-87)

Deaths within 28 days PostopSurgeryCHORUSEORTCPDSNACT14 (5.6%)1 (0.5%)(2.5%)(0.7%)PDS Disease progression 4 Pulmonary embolism 2; infection 3;problems with fluid balance or renal failure 2;hemorrhage 1; intra-operative problems 1 Still under review 1NACT Pulmonary embolism 1

Primary Debulking vs. NeoadjuvantchemoRx Interval Debulking Controversial Points– Extent of debulking surgery/surgicalexpertise– High mortality in PDS Median survivals much shorter than inmost upfront RCT in stage III ovariancancerPresented by: Jonathan S Berek

Primary Debulking vs. Neoadjuvant chemoRx Interval DebulkingCompared to most up-front RCTin Ov-FT-P patients Poorer than expected patient characteristics– Highly selected– older, sicker, larger mets! Higher tumor burden of recruited patients– 62% pts in EORTC mets 10 cm– 20% pts in CHORUS PS 2

Discussion: PDS vs. NACT-IDSComparison of JGOG Dose-dense vs.CHORUS/EORTC NACT Overall median survivals much shorter in thesetwo studies than in JGOG– PFS 10-11 months vs. 28 months– OS 22-24 months vs. 62 months Differences in performance status & age Good prognosis vs. poor prognosis patientsstudy populations in are very different!Presented by: Jonathan S Berek

JGOG 3016, NOVEL, Japanese Gynecologic Oncology GroupJGOG3016: Updated Overall SurvivalPatients surviving (%)median follow-up period: 6.4 yearsdd-TCc-TCTreatment n Deaths, n (%) Median OS 5-yr survival P value HR95%CIdd-TC 312139 (45)not reached58.7%0.039 0.79 0.63-0.99c-TC319168 (53)62.2 mos.51.1%

Primary Debulking vs. Neoadjuvant chemoRx Interval Debulking Therefore“the generalization of results from suchhighly selected adverse subgroups risksextrapolation to patients who are fit andpresent with potentially resectabledisease.”Fotopoulou C et al. J Clin Oncol 2017; 6:587-590

Discussion: PDS vs. NACT-IDSHow do we best select patients whoshould undergo PDS? Patient selection is key Need to minimize operative mortality–gynecologic oncologic surgeons in major centers Can we select patients by ‘Gestalt’e.g., a ‘clinical scoring algorithm’? Can we develop a molecular assay that canhelp us predict?Presented by: Jonathan S Berek

TRUSTTrial on Radical Upfront Surgical TherapyUpfront radical debulking surgeryversus interval radical debulkingsurgery in advanced ovarian cancer

Design-proposal neoadjuvant chemotherapyInternational phase IIIPts. With ovarian-,fallopian-tube orperitoneal-cancerFIGO stage IIIB, IIICand resectablestage IV(VATS or openassessmentif pleural effusionrecommended/mandatory) SC C C C C CP P P P P PBevacizumab 15mg/sq x15RC C CP P PSC C CP P PBevacizumab 15mg/sq x15Primary Endpoint OS ITT population; co primary Endpoint „per Protocol“ 50% resec.Secondary Endpoints PFS, resection rates, M‘nM after 6 months, QoL, „fragility Index“Strata: FIGO stage (III / IV), group/country, ECOG 0 vs 1/2Defined qualification process for participating centers to ensure highest surgicalquality ( 50% complete resection rate, 25 procedures/year)S surgery C Carboplatin AUC5 P Paclitaxel 175 mg/sqBev. 15mg 15 monsuggested therapy, also weekly paclitaxel possible if preferred or omission of Bev

Discussion: PDS vs. NACT-IDSTake-Home Message! Because this is by definition a poorerprognosis group, the findings of the 2 RCTscannot be generalized to all patients with stageIII ovarian cancer! Standard of care should still be primarydebulking surgery followed bychemotherapy for most patients.Presented by: Jonathan S Berek

ovarian cancer with long-term follow-up (7 years) - NACT results in similar survival compared with PDS 2. Only patients with biopsy proven stage IIIc or IV are candidates for neoadjuvant chemotherapy 3. Interval debu

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