1. Neoadjuvant followed by interval cytoreduction Francesco Fanfani Gynecologic Oncology Dpt. Obstetrics & Gynecology Catholic University - Rome francesco.fanfani@rm.unicatt.it

2. Role of surgery in the natural history of AOC Primary surgery IDS Secondary cytoreduction Palliation Role of the specialist in GYO 1.Time of surgery 2.Surgical skills and training 3.Data collection 4.Approved trial and International Society 5.Biological Background Decision making and judgement What to do When to do it Why to do it How to do it II look

3. Why Why should we select AOC patients for NACT instead of PDS ? PDS Less extensive surgery; easier optimal cytoreduction; good experience in other solid tumors tumor biology is more important than RT; good experience in other solid tumors NACT Several prospective data but no RCTs; prognostic value of RT; removal of chemo- resistant clones Lack of data on QoL lower complication rates

4. Choosing the best treatment approach in Advanced Ovarian Cancer Potential advantages of PDS Role of NACT UCSC experience Future perspectives

5. Hoskins, 1994 Bristow, 2002 Each 10% increase of optimal cytoreduction rate produces a 5.5% increase in median survival Survival effect of maximal cytoreductive surgery for advanced OC during the platinum era

6. Gynecologic oncology, 2010 RT = 0 (44%) Median PFS = 19.9 months “… all patients with no residual tumor had the best prognosis and in view of these results we believe that the gold standard of primary surgery should be considered as leaving no macroscopic tumor”

7. SITEEssen criteriaLeuven criteria Abdominal metastases Multiple parenchymatous liver metastases Infiltration of large parts of the pancreas (not only tail) and/or the duodenum Infiltration of the porta hepatis or truncus coeliacus Deep infiltration of the radix mesenterii Diffuse and confluent carcinomatosis of the stomach and/or small bowel Involvement of the SMA Intraephatic metastases Infiltration of the duodenum and/or pancreas and/or the large vessels of the porta hepatis or truncus coeliacus Extra-abdominal metastases Not completely resectable metastasesAll, excluding: resectable inguinal lymph nodes, solitary retrocrual or paracardial nodes, Pleural fluid cytologically malignant cells without presence of pleural tumors Pts characteristicsPoor PS-ECOG (Vergote I and Du Bois A, 2012) Criteria for NACT in FIGO stage IIIC-IV OC

8. Choosing the best treatment approach in Advanced Ovarian Cancer Potential advantages of PDS Role of NACT UCSC experience Future perspectives

9. RANDOMISED EORTC-GCG/NCIC-CTG TRIAL ON NACT + IDS VERSUS PCS

10. No residuals per country (PP analysis) Primary-OP (n = 310) NACT -> IDS (n = 322) Difference (%) Belgium 63% 87%24 Argentina (n=48)Excluded in NEJM Sweden (n=23)Not shown in NEJM The Netherlands 4 %28 %24 Italy 6 %39 %33 Norway 8 %50 %42 Spain 10 %42%32 UK 10 %43%33 Canada 11%41 %30 No residual after surgery19.4 %51.2 %31.8% Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS = 0 cm residual per country

11. Vergote et al., NEJM, 2010 Median OS 29 mo. Median PFS 12 mo. 30 mo. 12 mo. NACT PDS n.s. Compared with data retrieved from other prospective clinical trials in AOC and from retrospective series the OS and PFS reported by Vergote et al. seems to be too low

12. Choosing the best treatment approach in Advanced Ovarian Cancer Potential advantages of PDS Role of NACT UCSC experience Future perspectives

13. Ovarian cancer (1986-2010) Catholic University of the Sacred Heart N of patients 0 50 100 150 200 250 300 350 400 450 1986-901991-951996-20002001-20052006-2010 YEARS Total Number of OC patients: 1087 Stage IIIC-IV disease: 778 pts Early stage OC Advanced OC

14. Distribution of Surgical procedures Ovarian cancer (1986-2010) Catholic University of the Sacred Heart Surgery in AOC patients: 994 procedures PDS IDS IDS (referred from satellite centres) Secondary surgery Secondary surgery+HIPEC 45% 16% 21% 10% 8% 67% 33%

15. Median PFS at PDS - RT = 0cm: 29 mts - RT ≤ 1 cm: 14 mts - RT > 1 cm: 13 mts Median PFS at IDS - RT = 0cm: 15 mts - RT ≤ 1 cm: 14 mts - RT > 1 cm: 10 mts RT = 0 cm RT > 1 cm Role of surgical effort on PFS in Our experience p-value <0.0001

16. Cytoreductive surgery in AOC Institution (Authors, years) Number of ptsNumber of pts RT=0 at PDS UCSC (Scambia G, 2012) 300 (Jan 2005-Dec 2010) 97 (32%) MSKCC (Chi DS, 2012) 285 (Sep 1998-Dec 2006) 69 (24%) IEO (Peiretti M, 2012) 259 (Jan 2001-Dec 2008) 115 (44%) EORTC (Vergote I, 2010) 310 in PDS arm (Sep 1998-Dec 2006) 61 (19%)

17. 161 women who underwent laparotomy by OC completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of life questionnaires (QLQ‐C30 and QLQ‐OV28) presurgery and at 1 month It was observed a significant impact on HRQOL among gynecologic cancer patients, 1 month after laparotomy, particularly among those with Ovarian Cancer

18. CLINICAL EVALUATION  Adequate planning of surgery  Assessment of extrabdominal disease  Prediction of optimal cytoreductive surgery? A step by step approach to AOC

19.  CA125 levels Chi DS et al, 2009  Combined score: Age, ASA score, Albumine levels, Tumor burden Aletti DG et al, 2011 CLINICAL EVALUATION alone can not be safely used to predict optimal cytoreductive surgery A step by step approach to AOC

20.  CA125 levels Chi DS et al, 2009  Combined score: Age, ASA score, Albumine levels, Tumor burden Aletti DG et al, 2011 CLINICAL EVALUATION alone can not be safely used to predict optimal cytoreductive surgery A step by step approach to AOC  CT scan+ECOG PS Ferrandina G et al, 2010

22. Prediction of optimal cytoreduction: performance of CT and PS-ECOG CT scan: PPV ranging from 59.5 to 82.1; NPV from 50.4 to 74.3 PS-ECOG: PPV 85.7; NPV 54.7 N=195

23.  Combined score: Age, Tumor burden, ASA score, Albumine levels Aletti DG et al, 2011  CA125 levels  CT scan+ECOG PS Ferrandina G et al, 2010  Ultrasound Testa AC et al, 2012 Chi DS et al, 2009 A step by step approach to AOC CLINICAL EVALUATION and the prediction of optimal cytoreductive surgery

24. US score Unnecessarily explored (1 – NPV) (%) Inappropriately unexplored (1 – PPV) (%) 01.690 16.276 210.962 328.132 456.212 568.78 US score performance could be improved by instrumental/clinical data US score is not prospectively validated US score applicability is limited to other oncological centres At 5 points of US score NPV=31.3% PPV=92%

25.  Ca125: 17 retrospective  CT/MRI: 8 retrospective  Clinico-pathological variables: 5 retrospective A universally applicable clinical model that can predict which patients will undergo optimal cytoreduction remains elusive Int J Gynecol Cancer 2010; 201: S1-11 Is Clinical evaluation adequate to select AOC patients for NACT instead of PDS? A review (1980-2009)

26. Suspicious diagnosis of AOC CLINICAL EVALUATION  Planning of surgery  Assessment of extrabdominal disease  Prediction of the outcome of cytoreductive surgery?? LAPAROSCOPY A step by step approach to AOC Proposal for a treatment algorithm

27. Rationale  No definitive guidance or clinical recommendation for PCS vs. NACT.  A variable percentage, from 10 to 80%, of AOC patients will undergo only explorative laparotomy.  Parameters associated with the possibility of cytoreduction can be easily assessable by LPS.  The surgeon may be more comfortable with a direct visualization of the cancer spread.  LPS could reduce some laparotomy-related complications and could be taken into consideration in women showing several risk factors for incisional hernia (Fagotti et al., AJOG 2011)

28. 2005 2006 2008 2010 2011 2012 S-LPS can subjectively assess OC (prospective evaluation) Elaboration of an objective LPS-score (PIV) to assess OC (retrospective evaluation) Evolution of S-LPS as a new diagnostic tool in AOC Prospective validation of an objective LPS-score (PIV) to assess OC Retrospective validation of an objective LPS-score (PIV) to assess OC in an external centre Reproducibility of PIV for fellow in GYO Prospective multicentric validation of PIV. Reproducibility of PIV At IDS

29. Am J Obstet Gynecol. 2008 Predictive index parameter Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) Point value Ovarian masses (mono-bilateral) 60292960390 Omental cake 57816377732 Peritoneal carcinosis 69796781752 Diaphragmatic carcinosis 69846580802 Mesenteral retraction 50958577782 Bowel infiltration 70897884822 Stomach infiltration 1110010082822 Liver metastases 35947576762

30. Am J Obstet Gynecol. 2008 OVERALL LAPAROSCOPIC PREDICTIVE MODEL (PIV) ACCORDING TO DIFFERENT CUT-OFF VALUESPIV NPV (%) Unnecessarily explored (1 – NPV) (%) PPV (%) Inappropriately unexplored (1 – PPV) (%) 089.410.658.541.5 284.315.764.235.8 480.819.272.727.3 671.228.89010 859.540.51000 1051.448.61000

31. p = ns 2011 The laparoscopic assessment of peritoneal cancer diffusion according PIV can be carried out by a fellow in GYO after 12 months’ experience

32. Algorithm of AOC patients at the UCSC (Rome-Campobasso) S-LPS PIV>8 PIV<8 OPTIMAL CYTOREDUCTION NACT (3-4 cycles) RECIST/GCIC criteria PROGRESSION STABLE/PARTIAL RESPONSE COMPLETE RESPONSE IDS II-line CT IDS AOC

33. Institution (Authors, years) Number of ptsMedian PFS (months) Median OS (months) UCSC (Scambia G, 2012) 207 (Jan 2005-Dec 2010) 1645 MSKCC (Chi DS, 2012) 285 (Sep 1998-Dec 2006) 1750 IEO (Peiretti M, 2012) 259 (Jan 2001-Dec 2008) 2057 EORTC (Vergote I, 2010) 310 in PDS arm (Sep 1998-Dec 2006) 1230 Introducing S-LPS in the management of advanced epithelial ovarian, tubal, peritoneal cancer: impact on prognosis in a single institutional series

34. Chi DS et al, Gynecologic Oncology 2012 The MSKCC Model

35. Jan 2005-Dec 2010 300 Epithelial AOC pts § Poor ECOG-PS 59 pts (20%) Eligible 207 pts (69%) The UCSC Model Clinically unresectable 34 pts (11%) Optimal cytoreduction 7 pts (21%) LPS Optimal cytoreduction 12 pts (19%) NACT 47 pts (81%) NACT 27 pts (79%) Suboptimal cytoreduction 15 pts (7%) NACT 78 pts (38%) Optimal cytoreduction 114 pts (55%)

36. The UCSC Model LPS allows to:  Recruit 20% of pts with poor PS-ECOG or clinically unresectable disease for optimal PDS  Avoid unnecessary LPT in around 64.1% of AOC pts selected for NACT

37. Choosing the best treatment approach in Advanced Ovarian Cancer Potential advantages of PDS Role of NACT UCSC experience Future perspectives

38. FUTURE PERSPECTIVES  In the grey zone of OC pts with 8≤PIV≤12, can we safely avoid PDS?

39. Pre-op assessed for eligibility Excluded -Not meeting inclusion criteria (poor PS, older than 80, stage IV pulmonary, LPN, multiple hepatic) - Refused to participate Randomized Maximal surgical effortNACT + IDS Enrollment SCORPION (NCT01461850) Surgical Complications Related to Primary vs. IDS in Ovarian Neoplasms Allocation FU Analysis 8 < PI < 12 Starting date October 26, 2011  Recruiting

40. Conclusions  We confirm that patients with no residual tumor at PDS have the best prognosis  Delaying surgery after NACT seems a reasonable option when a right selection of patients is performed  More in depth evaluations are required to clarify the impact of NACT on the natural history of AOC

41. To resolve the controversies ….. compare opinions and….share data?