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2. Secondary Cytoreduction In Recurrent Ovarian Cancer Robert L. Coleman, M.D. Professor & Vice Chair, Clinical Research Department of Gynecologic Oncology University of Texas, M.D. Anderson Cancer Center

3. Surgery in Relapsed Disease: Why? Palliation - bowel obstruction, fistula, etc Make a diagnosis - recurrence, lesion not amenable to biopsy, second primary, etc Evaluate extent of disease Cytoreduction

4. Surgery in Relapsed Disease: Why? Palliation - bowel obstruction, fistula, etc Make a diagnosis - recurrence, lesion not amenable to biopsy, second primary, etc Evaluate extent of disease Cytoreduction

5. Remember When… Gynecol Oncol 51: 127-135, 1993

6. Why Don’t We Have An Answer? Bias, Bias, Bias… For the most part, we do not know who and not to offer the procedure For the most part, we don’t have a reliable way to predict post-surgical goal Adjuvant therapy has changed

7. Background “Noise”: Platinum Sensitive Author TB Huinink Gordon ICON4 AGO OVA-301 CALYPSO OCEANS Year 1997 2001 2003 2006 2009 2010 2012 Agent Topotecan PLD Paclitaxel/Carbo Gem/Carbo PLD/Trabectedin PLD/Carbo Gem/Carbo/Bev TFI (mos) 46% > 6 mos 44% > 12 mos 75% > 12 mos 60% > 12 mos 67% > 6 mos 65% > 12 mos 60% > 12 mos Survival (mos) 15*(overall) 25 32 18 29 31 33 Range 15-33 mos

8. Secondary Cytoreduction: Typical Report? 57 patients – Neg SLL (PCR) – All platinum-based Median TFI: 20 mos Median survival overall: 19 mos Prognostic factor: residual disease (P < 0.0001) < 0.5 residual (14 pts) > 0.5 residual (24 pts) Not Explored (19 pts) Vaccarello Gynecol Oncol 57:61, 1995

9. Secondary Cytoreduction: Bias? Selection Bias? – Median time to recurrence between cohorts – Balance of surgical covariates PS Recurrence criteria (16/57 found by CA125) Volume of disease (median 2-5 cm) Location of disease – Is the survival in the subtotal resection cases any different than expected? Uncensored events – 4/19 unexplored pts dead in 3 mos < 0.5 residual (14 pts) > 0.5 residual (24 pts) Not Explored (19 pts) Vaccarello Gynecol Oncol 57:61, 1995

10. Summary Data

11. Whom are the Best Candidates?

12. Incomplete Responders Don’t Benefit? Successful cytoreduction – 72% Clinical CR’s – 44% Clinical PR’s – P = 0.004 Morbidity – Death (1) – Major (13) – Transfusion (62) Segna J Clin Oncol 11:434, 1993 Median = 11.7 mos

13. Patients with Preop Chemotherapy Don’t Benefit? All TFI > 6 mos and pretreated before referral 23 “resistant” - no response to platinum retreatment 19 “sensitive” – responded to treatment – 10 retreated with non- platinum – 9 retreated with platinum Preoperative Salvage Chemotherapy No Preoperative Chemotherapy P=0.001 Eisenkop, Cancer (2000) 88:144 CategoryNMedian OS “Resistant”2323 21.5 mos “Sensitive” – Other treatment1010 25.0 mos “Sensitive” - retreatment934.8 mos P4242 NS

14. Patients with Early TFI’s Don’t Benefit? Patients (n = 106) – Optimal (no visible tumor): 82% – All cisplatin based – Disease-free: 6 mos Time to second surgery: 16.8 mos (6 - 109) 6-12 mos 13-36 mos >36 mos Eisenkop Cancer 88:144, 2000

15. TTP Definitio n mos >12 >17.5 >36 >24 12-24 >24 >18 >30 >24 Survival by TTP Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Zang Salani Chi Oksefjell Total/Range N 30 27 60 30 114 25 148 46 117 55 157 217 814 Surgery Median mos 16 16.6 13 11.5 16.8 37.6 10-12 26 15.4 32 6-11 10 - 37.6 TTP Definition mos <12 <17.5 <12 <24 <12 3-12 <18 <12 6-24 Survival Median mos 8 8.8 8 15 25 42 12 6 18 3 30 19 6-42 (15) Survival median mos (P) 29 (0.004) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 40 (0.04) 49 (0.001) 51 (0.005) 54 (0.001) 12-57 (40)

16. Patients with Diffuse Disease Don’t Benefit? Salani, Cancer (2007) 109:685

17. Survival by Post-op Residuum Fader J Clin Oncol (2007) 25:2873 3838131355%55%

18. DESKTOP-I: Surgical Endpoint of Surgery at Relapse no residuals median OS 45.2 mo residuals > 10 mm residuals 1-10 mm Survival probability 0 1.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 0 12 243648 Months from Randomization

19. Developing a Prospective Eligibility Algorithm * Initial FIGO-stage I/II vs III/IV alternatively, if residual disease after 1st surgery is unknown VariablesHR (95% CI)P-value PS ECOG0 mm > 0mm 1 2.56 (1.49 – 4.42) < 0.001 Residual disease (after 1 st surgery) 0 mm > 0 mm 1 2.09 (1.20 – 3.64) 0.009 Ascites (cut-off 500 ml) < 500 ml ≥ 500 ml 1 4.26 (1.62 – 11.24) 0.003 Predictors of R0 at Secondary Cytoreduction

21. How do We Synthesize this Information? Incomplete responders to frontline therapy Patients undergoing salvage therapy first Patients with short TFI Patients with diffuse disease at surgery Patients with post op tumor residuum Poor Surgical Candidates

22. Candidate Selection

23. Modeling Tian Ann Surg Oncol (2012) 19:597

24. Background “Noise”: Platinum Sensitive Author TB Huinink Gordon ICON4 AGO OVA-301 CALYPSO OCEANS Year 1997 2001 2003 2006 2009 2010 2012 Agent Topotecan PLD Paclitaxel/Carbo Gem/Carbo PLD/Trabectedin PLD/Carbo Gem/Carbo/Bev TFI (mos) 46% > 6 mos 44% > 12 mos 75% > 12 mos 60% > 12 mos 67% > 6 mos 65% > 12 mos 59% > 12 mos Survival (mos) 15*(overall) 25 32 18 29 31 36 Range 15-36 mos

25. 242177451130CG + PL OCEANS: Primary analysis of PFS CG + PL (n=242) CG + BV (n=242) Events, n (%) 187 (77)151 (62) Median PFS, months (95% CI) 8.4 (8.3–9.7) 12.4 (11.4–12.7) Stratified analysis HR (95% CI) Log-rank p-value 0.484 (0.388–0.605) <0.0001 Months No. at risk 2422039233110CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0612182430 Carbo Carbo/Gem

26. OCEANS: Interim OS 1.0 0.8 0.6 0.4 0.2 0 Proportion alive 0 Months 612303642 No. at risk: 1824 2422351952680CG + PL13177 2422382004280CG + BV14682 CG + PL (n=242) CG + BV (n=242) Events, n (%)78 (32)63 (26) Median OS, months (95% CI) 29.9 (26.4–NE) 35.5 (30.0–NE) Stratified analysis HR (95% CI) Log-rank p-value 0.751 (0.537–1.052) 0.094 a NE = not estimable a p-value does not cross pre-specified boundary of 0.001

27. Comparison Group: No Surgery Platinum-Sensitive (n=84) Retrospective study focused on use of Paclitaxel/Platinum for recurrent disease Median TFI: 22 mos N = 21 (25% debulked) – Minimum 12 mos – 18 (86%) complete PFI: 11 vs 17 mos (p=0.04) OS - 3 yrs: No Difference Debulked at TFI > 12 mos Dizon, J Clin Oncol 20:1238, 2002

28. Where Do We Go From Here?

29. Phase III Surgical Trials: Recurrent Disease EORTC 55963: – Opened 8/2000 (N ~ 700) - Terminated – Chemo x 3 then randomized to IDS or Chemo x 3 (Similar to GOG 152 but in recurrent setting) GOG 213: – Opened 12/2007 (N ~ 660, 330 surgical arm) – Bifactorial Design: Surgery vs. No Surgery; Chemo ± bevacizumab DESKTOP III: – To open 8/2009 (N ~ 408) – Feasibility-directed patient selection (DESKTOP II) followed by randomization to Surgery vs. no Surgery (standard chemotherapy to follow)

30. EORTC 55963: Recurrence Protocol Recurrent ovary cancer > 12 month PFI >3 cycles upfront Stratify: Stage (I-IIA vs IIB-IV) PFI ( 2 yrs) Induction response No. of measurable lesions Tumor size ( 5 cm) Interval cytoreduction Maximal effort Followed by chemo x 3 cycles Chemotherapy x 3 cycles (6 weeks) RANDOMIZE Open: 8/2000 Accrual goal: 700 pts Closed: 2002 Induction Chemotherapy Platin (cisplatin or carboplatin) 3 cycles (q 3-4 weeks) 6 cycles weekly

31. AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) EOC, FT, PP PFI > 6 No prior recurrence chemotherapy Complete resection seems feasible and positive AGO score: PS ECOG 0 No ascites > 500 ml Prior complete debulking or initial FIGO I/II Secondary Cytoreduction Chemo Regimens post-randomization Carboplatin/paclitaxel Carboplatin/gemcitabine Carboplatin/PLD No surgery N = 100/408 planned

32. Frequency of complete resection by applying the AGO Score AGO DESKTOP OVAR II – Surgical Results With a prevalence or complete resection in 76% of the study collective = AGO score could prospectively predict complete resection in at least 2 out of 3 patients DESKTOP Hypothesis Score Pos 1st Relapse Score Pos 2nd Relapse Score Pos All Patients

33. AGO DESKTOP OVAR II – Surgical Results Harter P, Int J Gynecol Cancer (2011) 21:289 57% went to surgery 98 (76%) had R0

34. PI: Coleman Recurrent Ovarian, PPT and FT Cancer TFI ≥ 6 mos Recurrent Ovarian, PPT and FT Cancer TFI ≥ 6 mos YesYesNoNo RandomizeRandomize SurgerySurgery No Surgery Carboplatin Paclitaxel or GemcitabineCarboplatin GemcitabineCarboplatin Pac or Gem BevacizumabCarboplatin Bevacizumab BevacizumabBevacizumab GOG-213GOG-213 To Chemotherapy Randomization Randomization RandomizeRandomize Surgical Candidate?

35. Second-Line Biologic Combinations VEGF/R VDA PI3K/Akt/mTOR Angiopoeitin PARP FR-  : Farletuzumab Others Strategy would be to: – Compare to bevacizumab combinations – Combine with bevacizumab – Treat following bevacizumab progression or prior exposure

36. Summary Defined study population Strong recruitment bias exists in available trials Feasible – Success depends on endpoint Lasting chemosensitivity important to survival Null Hypothesis: – 2º debulking + chemo = chemo alone – Endpoint = Survival – Fair comparison requires balance of known risk factors Randomization

37. Thank You!

38. Primary objective: Proportion of complete resection in patients with positive AGO-score? (proportion = positive predictive value; PPV) Secondary objectives: 1. Assessment of selection quotient by applying the score (documentation of all platinum-sensitive relapsed patients within study period). 2. Feasibility and complications in surgery in relapsed ovarian cancer in a multi-center setting AGO DESKTOP OVAR II - OBJECTIVES

39. AGO DESKTOP OVAR II: DESIGN PS ECOG = 0 No residuals after primary surgery (or, if unknown: initially FIGO I/II) Absence of ascites > 500 ml Surgery is planned ? Yes No (basic collective 1) predictive score positive (all items) ? Yes (CRR 79%) No (CRR 43%) Laparotomyonly descriptive analysis of further therapy Platinum-based combination chemotherapy * CRR: Results from DESKTOP-OVAR I calculated numbers (1st endpoint): 110 pts. with positive score and a complete resection rate (CRR) of at least 75% will show with 95% probability that a positive score can predict CR in >2 of 3 pts.

40. DESKTOP I: - descriptive analysis in a multi- AGO-OVAR OP.1 centre setting - identify an appropriate endpoint - creation of a model for a predictive score for resectability (allowing pts. selection for further studies) DESKTOP II:- Validation of the predictive score AGO-OVAR OP.2 - descriptive analysis of the selection bias for offering surgery to ROC pts. DESKTOP III:- Prospectively randomized trial to AGO-OVAR OP.4 evaluate the impact on OS Objectives of the AGO DESKTOP series evaluating surgery in recurrent OC

41. Prospective Trials: DESKTOP II

42. AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer Platinum-sensitive recurrent cancer of the ovaries, fallopian tubes, or peritoneum PFI > 6 mos since first chemotherapy which was Platinum-based No prior chemotherapy for this 1st relapse Complete resection seems feasible and positive AGO score: PS ECOG 0 no ascites > 500 ml prior complete debulking or initial FIGO I/II (if data available) Cytoreductive surgery platinum-based chemotherapy* recommended * Recommended platinum-based chemotherapy regimens: - carboplatin/paclitaxel - carboplatin/gemcitabine - carboplatin/pegliposomal doxorubicin (if calypso-trial shows equivalence to carboplatin-paclitaxel) -or other platinum combinations in prospective trials No surgery

43. Prospective Trials: DESKTOP II

44. “Meta-analysis” of RCTs in Recurrent Ovarian Cancer Orlando, ASCO 2007, #5524

45. Summary of Phase III Combination Trials (Platinum-Sensitive) Recurrent Ovarian Cancer Drug B CarboplatinEpirubicinPlatinumPaclitaxelGemcitabineCarboplatinTopo/VP16Topo/Gem PLDTrabectadin TTP (wks) 65 vs. 78 43 vs. 52 HR: 0.76 23 vs. 35 HR: 0.72 HR: 0.84 25 vs 32 HR: 0.79 OS (wks) 109 vs. 122 104 vs. 130 HR: 0.82 75 vs 78 HR:0.961.131.07 ImmaturePNS0.023NSNSNSPNS<0.001<0.0010.57-0.9NSNS 0.019Comment TFI=17 mos, Gr 4 ANC 45% RBC 30%, PLT 25% TFI? (75% > 12 mos) Neuro 1 vs. 20%, Infect 17% Heme: 46 vs. 29% TFI? (60% > 12 mos) RR: 31% vs. 47% (0.0016) ANC/PLT more in combo TFI? (59% > 12 mos) Slight advantage for combo’s In PFS, more toxicity Effect seen in PS cohort; HFS Less in combo, ANC, LFTs  N190802356505 672 Drug A CarboplatinPlatinum*CarboplatinTopotecan ASCO 2006 ASCO 2006PLD ESMO 2008 ESMO 2008

46. Thank You!

47. GOG Debate 1992 “Secondary Cytoreduction” –Interval surgery –Debulking at SLL –Debulking at remote recurrence –Debulking for progressing disease Resolve: –Paucity of evidence- based data –Imprecise measures of biology (chemosensitivity, tumoral) –Randomized trials in these settings were warranted –Burden of Proof: Pro side Symptoms Diagnosis Chemotherapy #1 Primary Debulking Second-Look ± DebulkingProgression Chemo #2 Chemo #3+ SupportiveCare Death Consolidation Secondary Debulking Interval Secondary Debulking Secondary Debulking For Progression Or Complications Approved 1995 International Consensus Conference on Gynecologic Cancers

48. What Have We Learned… Defined study population Procedure is feasible – Success depends on endpoint Lasting chemosensitivity important to survival Strong recruitment bias exists in available trials Null Hypothesis: – 2º debulking + chemo = chemo alone – Endpoint = Survival – Fair comparison requires balance of known risk factors Sorted out through prospective cohort and retrospective trials Randomization

49. Factors Important to Secondary Cytoreduction Trials Cohort Factors – Sample size – Age – Stage at diagnosis – Received chemotherapy Platinum-based Completed planned therapy Disease Factors – LMP included – Optimal at first operation – Performed by reporting institutions – Measurable residual Following planned treatment Response Factors – Clinically, radiographically surgically ascertained Surgery Factors – Cohort being operated on – Definition of SLL – Definition of “Success” – Excluded Trial Design

50. Summary Data

51. Secondary Cytoreduction: Incomplete Responders Don’t Benefit? Response (First Therapy) Progressive disease No Change Partial Response Total N 7 1 6 14 Optimal - 0 4 4 (57%) Second Debulking Suboptimal - 1 2 3 DOD* 7 1 6 14 *At best median survival: 14 mos Heintz Gynecol Oncol 30:359, 1988

52. Secondary Cytoreduction: Patients with Postop Residuum Don’t Benefit? Patients (n = 106) – Optimal (no visible tumor): 82% – All cisplatin based – Disease-free: 6 mos Time to second surgery: 16.8 mos (6 - 109) Eisenkop Cancer 88:144, 2000 Residual No Residual

53. When is the Best Time To Consider?

54. Secondary Cytoreduction: When? Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Cytoreduction Progression Chemo #2 Chemo #3+ SupportiveCare Death Consolidation Cure Secondary Cytoreduction Second-Look

55. Secondary Cytoreduction: Patients with Early TFI’s Don’t Benefit? Patients (n = 33) – Stable (2) – Progressive (31) 7 (21%) platinum exposed Optimal secondary result: 4 (8%) Survival (debulking < 1 cm) – 19.5 vs. 8.3 mos (P = 0.004) Morris Gynecol Oncol 33: 1, 1989 < 12 mos ≥ 12 mos 7.3 mos

56. Secondary Cytoreduction: Patients with Early TFI’s Don’t Benefit? Patients (N = 100) – Response to chemotherapy Incomplete response (39) Recurrence (61) Cisplatin-based primary treatment Optimal was < 2 cm (61%) Survival advantage (P=0.0001) for debulking (27.1 vs 9 mos) Segna J Clin Oncol 11:434, 1993 Median = 8.8 mos

57. What are the Goals of Resection?

58. Secondary Cytoreduction: Patients with Postop Residuum Don’t Benefit? Cohort – N = 30 – All > 6 mos disease-free Median: 17.5 mos Surgery – Optimal (no visual): 57% – Median Survival: 21 mos Predictors of Cytoreduction: – Optimal (< 2 cm) initial surgical staging Gadducci Gynecol Oncol 79:344, 2000

59. Secondary Cytoreductive Therapy Meta-analysis of 40 cohorts, covering 2019 patients performed1 In more recent trials more patients complete surgery and increased overall survival – 10% increase in complete cytoreduction – 3.0 months increase in OS Recommended duration of disease-free interval >6 months (consensus) 1 Bristow et al., 2009. Gynecol Cancer. 112: 265-274

60. Secondary Cytoreduction: Recurrent Disease Munkarah Gynecol Oncol 95:273, 2004

61. Secondary Cytoreduction: Patients with Diffuse Disease Don’t Benefit? Salani, Cancer (2007) 109:685

62. Secondary Cytoreduction: Multivariate Analysis Who Benefits? Eisenkop, Cancer 88:144, 2000 Tay, Obstet Gynecol 99:1008, 2002

63. Secondary Cytoreduction Tay, Obstet Gynecol 99:1008, 2002

67. Zang: Secondary cytoreduction IGCS 2010 1100 patients from 11 centers Best PFI was 23mos Degree of residual disease is significant – 15.6 vs. 27 vs 57.7 mos OS Scoring PFI and Ascties and exten of recurrent disease Using a scoring system: SN: Question – what about NACT in the secondary cytosetting

68. Secondary Cytoreduction Controversial – Inconsistent definitions – High degree of case selection bias Benefit appears confined to patients like to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Diaphragm KidneyKidney Tumor Mass Renal Vein Resected Liver Vena Cava

69. Secondary Cytoreduction: For Whom? Assumptions – There are subgroups benefit; others that don’t – Non-invasive testing CA125 Radiographic (PET, MRI, CT) Immunologic Physical exam – Chemosensitivity remains

70. PET/CT Fusion Scanning

71. Identifying Clinically Occult Disease 22 patients with rising CA125 Negative (15) or “equivocal” (7) CT DFI: minimum 6 mos Outcome measure: positive study AND at least 1 macroscopic lesion (> 1 cm) 21/22 confirmed recurrent Bristow, Gynecol Oncol 90:519,2003 PET/CT “Positive” PET/CT “Negative” Total ≥ 1 cm 15 3 18 < 1 cm 1 3 4 Surgical Findings Total 16 6 22 SN: 83% SP: 75% PPV: 94% NPV: 50%

72. Tertiary Cytoreduction: Ovarian Cancer N = 26 pts (1990-2002) – Intent cytoreduction No palliative surgery (bowel obstruction, etc) – Optimal defined as ≤ 5 mm – TFI after secondary treatment N = 6, secondary debulking at SLL Gynecol Oncol 95:181, 2004

73. Tertiary Cytoreduction: Ovarian Cancer Median follow-up: 22.3 mos TFI 1 : 13.7 mos (1.1-80) – Optimal 1 : 81% (≤0.5 cm) TTS 2 : 25.6 mos (5.4-79) – TFI 2 : 13.4 mos (0.5-61) – Optimal 2 : 73% (54% no gross)

74. Tertiary Cytoreduction: Ovarian Cancer Leitao M. Gynecol Oncol 95:181, 2004

75. Tertiary Cytoreduction: EU Experience

76. Tertiary Cytoreduction Fotopoulou Ann Surg Oncol (2010)

77. “Quaternary” Cytoreduction? Sure, Why Not!

78. “Quaternary” Cytoreduction? Shih Gynecol Oncol (2009:on line)

79. “Quaternary” Cytoreduction? Sure, Why Not! Shih Gynecol Oncol (2009:on line)