Recent Advances in the Surgical Management of Ovarian Cancer

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1 Recent Advances in the Surgical Management of Ovarian Cancer Neil S. Horowitz, M.D. Assistant Professor, Harvard Medical School Division of Gynecologic Oncology Brigham and Women s/dana Farber

2 Ovarian Cancer Annual deaths in the United States: 2009 Uterine Cervix Vulva Vagina + other Ovary 14,600 Jemal A CA Cancer J Clin 2009

3 Debulking Surgery for Ovarian Cancer First recognized by Joe V. Meigs 1934 Tumors of the Female Pelvic Organs Confirmed by Griffiths in 1975

4 Theoretic Benefits of Cytoreduction Physiologic Improved bowel function and metabolism Decrease nausea and vomiting Removal of large, poorly vascularized tumor Improved chemo delivery Increased fraction of G 0 cells migrate to high growth fraction Decrease chance of acquired drug resistance Smaller tumor mass less immunosuppressive

5 Cytoreduction Techniques Simple Radical TAH/BSO Sigmoid resection Pelvic and PA LND Peritoneal stripping Bowel resection Splenectomy Omentectomy Resection of. Ureter/Bladder Recto-sigmoid Multiple bowel loops Diaphragm Liver, Kidney, Spleen Radical oophorectomy Diaphragm stripping

6 Primary debulking surgery (PDS)

7 Effect of Residual Disease on Survival Gynecologic Oncology Group definition: < 1 cm residual disease Fader, AN. JCO 2007;25(20):

8 Success rates of debulking

9 Meta-analysis analysis of retrospective studies Meta-analysis analysis ( ) 98) cohorts (Stage III/IV) N = 6,885 patients Results Each 10% in primary cytoreduction = 2 month in survival time (P = 0.03)» < 25% optimal,median survival = 23 mo» > 75% optimal, median survival = 34 mo CONC: Stage III/IV ovarian cancers Median Survival (Months) should be referred to centers with high % Cytoreduction rates of optimal PDS Bristow R JCO 2002

10 ULTRARADICAL SURGERY Memorial Sloan-Kettering Experience 140 stage IIIC/IV pts Switched to more comprehensive debulking of upper abd disease:» Diaphragm resection» Splenectomy» Distal pancreatectomy» Liver resection» Porta hepatis tumor» Opt PDS Optimal PDS 1-cm residual disease increased from 50 to 76% Longer OR time, more EBL No difference in rate of major complications or length of hosp stay Chi DS - Gynecol Oncol 2004

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12 Change surgical paradigm MSKCC stage IIIC/IV ovarian cancers Grp 1: 168 pts ( ) 1999) v Grp 2: 210 pts ( ) 2004) Extensive upper abdominal procedures in Grp 2 only Optimal PDS <1-cm residual: 46 to 80%

13 Change surgical paradigm Median OS 43 vs 54 mo 5-yr OS: 35 to 47% Chi DS Gynecol Oncol 2009

14 What is optimal? 29 v16 v 13 mo 68 v 40 v 33mo 64 v 30 v 19 mo Winter WE et al, JCO 2008 Bookman M, JCO 2009

15 Biology or Surgery?

16 Can CA125 Predict Debulking N = 277 pts 33% required radical upper abdominal procedures 40% preop CA125 < 500 U/mL Chi DS, Gyncologic Oncology 2009

17 CT Scan Prediction of Cytoreduction N = 41 pts Bristow RE, Cancer 2000

18 CT Scan Prediction of Cytoreduction 85% of pts ultimately having optimal debulking were identified correctly at PI > 4 Bristow RE, Cancer 2000 PI < 4, 100% had optimal debulk (NPV)

19 CT Scan Prediction of Cytoreduction Axtell AE, JCO 2007

20 CT Scan Prediction of Cytoreduction Axtell AE, JCO 2007

21 Can Laparoscopy Predict? Fagotti, AJOG 2008

22 Can Laparoscopy Predict? Fagotti, AJOG 2008

23 Predicting Optimal vs Suboptimal Debulking RNA from 44 serous ovarian cancers (19 opt, 22 subopt) Affymetrix microarray of 22,000 genes 32 genes distinguished optimal vs suboptimal with 73% accuracy Retinoic acid receptor beta, P2X6 MAP2K4 Favorable survival associated with debulking due to biology Berchuck A, AJOG 2004

24 Role of Lymphadenctomy? Exploratory analysis of 3 AGO trials 1,924 patients No LAD LAD No gross residual 84 mo 103 mo (p=0.01) Residual 1-10 mm 35 mo 39 mo (p=0.06) du Bois A, JCO 2010

25 Fertility Sparing Surgery for Stage I Ovarian Cancer 211 patients (126 =IA, 85=IC) 41% optimally staged; 60% adjuvant platinum chemo 8.5%(18 pts) recurrence rate 5 in contralat ovary, 8 alive and NED 54% (45/84 pts) G0 achieved 65 pregnancies, 56 healthy babies Group I: Stage IA, good histology; Group 2: stage IA CC or IC favorable histology Group 3: Stage IA/IC, grade 3, IC CC Satoh T, JCO 2010

26 Secondary Cytoreduction Surgical cytoreduction of tumor volume correlates with prolongation of patient survival The role of secondary surgery in the standard management of disease recurrence remains poorly defined Patients who develop recurrent disease may be eligible for secondary cytoreduction if Response to first-line therapy Limited number of recurrent disease sites Good PS Fader, AN. JCO 2007;25(20):

27 Secondary Cytoreduction Impact on Survival Fader, AN. JCO 2007;25(20):

28 DESKTOP-OVAR OVAR I Survival Probability No Residuals Median OS 45.2 mos Months Residuals > 10 mm Median OS 19.7 mos Residuals 1-10 mm Median OS 19.6 mos Harter P, et.al. Ann Surg Oncol.2006;13(12):

29 Secondary Debulking Candidate Selection DFI Single Site Only 6-12 Months Yes Months Yes > 30 Months Yes Multiple Sites; No Carcinomatosis Yes / No Yes Yes Carcinomatosis No Yes / No Yes Optimal patient meets > 3 of the following criteria DFI > 12 months No liver metastasis Solitary tumor Tumor size < 6 cm Good performance status hi DS, et al. Cancer. 2006;106: ; Onda T, et al. Br J Cancer. 2005;92(6):

30 Phase III GOG 213 Recurrent Ovarian, PPT, or FT Cancer; TFI > 6 months Surgical Candidate? Yes No Randomize Randomize Surgery No Surgery Carboplatin / Paclitaxel Carboplatin / Paclitaxel / Bevacizumab Chemotherapy Randomization Bevacizumab vailable at

31 DESKTOP-OVAR OVAR III Recurrent Ovarian, FT or PPT, TFI > 6 mo from 1st platinum-based chemotherapy, prior complete debulking, PS 0, and absence of ascites > 500 ml Randomize Secondary Cytoreductive Surgery No Surgery Platinum-Based Combination Chemotherapy vailable at:

32 IGCS Bangkok/Oct 2008 ASCO/April 2009

33 Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) Randomisation Primary Debulking Surgery Neoadjuvant chemotherapy 3 x Platinum based CT 3 x Platinum based CT Interval debulking (not obligatory) Interval debulking if no PD > 3 x Platinum based CT > 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications

34 Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Study conduct September 1998 and December patients randomised in 60 institutions (median accrual/institution 5; range: patients). 498 events were needed to perform the final analysis, and were reached in August 2008 Median follow-up was 4.8 years.

35 Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Surgical findings and results PDS (n = 329) NACT -> IDS (n = 339)* Mets before > 2 cm 95% 68% Mets before > 10 cm 62% 27% No residual after surgery 21% 53% 1 cm after surgery 46% 82% * % calculated on the 306 patients who underwent IDS.

36 NACT + IDS versus PDS: ITT Overall survival (years) O N Number of patients at risk : Treatment Upfront debulking s Neoadjuvant chemo

37 Overall Survival of IP vs IV Chemotherapy as per GOG 172 Compared to NACT

38 Conclusions 1 - Optimal debulking surgery is the strongest independent prognostic factor for overall survival - should remain the goal of every surgical effort but the timing does not seem to play a role. 2 Neoadjuvant chemo with interval debulking may be considered preferred treatment due to the lower morbidity and similar survival

39 Conclusions Optimal cytoreduction (defined as microscopic) is associated with improved survival The ability to achieve optimal cytoreduction is likely a factor of tumor biology and surgeon aggressiveness. No reliable way to predict pre-operatively the ability to achieve optimal cytoreduction NACT is an acceptable treatment in certain populations. Secondary cytoreduction, in the appropriate patient population, maybe associated with improved survival.