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09 state of the art of the management of advanced and recurrent ovarian cancer

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  • Tables 5.2.1.3.1, 5.2.1.3.3, 5.2.1.3.4
  • Transcript

    • 1. Fernando Cotait MalufChairof Medical OncologyDepartment São José Hospital São Paulo São Paulo Brazil
    • 2. •Advancedstagesatdiagnosis (~75%)•Highlychemotherapy-sensitive• Complete clinicalresponse to platinum-based CT: 70-85%•Stage III: 20-25% of complete remissionat 5y
    • 3. • 81 studies• 6885 patients•StageIIIandIV•Cytoreductivesurgeryfollowedbyplatinum-based CT Bristowet al. J ClinOncol, 2002
    • 4. • CT platinum-basedversus CT NON platinum-based1,2 • HR death: 0.88 [0.79 – 0.98]•CT anthracyline-basedversus CT NON anthracyline-based3 •Absolutesurvivalbenefit: 5% ( p = 0.02)•CisplatinversusCarboplatin1,2 • HR death: 1.02 [0.93 – 1.12]•Platinum-dosenotassociatedwithsurvivalbenefit3 OvarianCancerMeta-Analysis Project (GynecolOncol, 2002) 1 AdvancedOvarianCancerTrialistsGroup (2002) 2 OvarianCancerMeta-Analysis Project (J ClinOncol, 1991) 3
    • 5. •MONOCT platinum-basedversus POLICT platinum-based1,2 • HR death: 0.91 [0.75 – 1.05]OvarianCancerMeta-Analysis Project (GynecolOncol, 2002) 1AdvancedOvarianCancerTrialistsGroup (2002) 2 ICON 3: CarboplatinvsCarboplatin + Paclitaxel
    • 6. GOG 111 andOV 10(Intergroup) McGuireetal, N Eng J Med, 1996; n=386,suboptimalcytoreduction III/IV SLPSG PT 18m 38m PC 13m 24mPiccartetal, J Nat CancerInst, 2000;n=668, debulkingsurgery, II-IVSLPSGPT 17m 35mPC 12m 25m
    • 7. GOG 172 Standard arm IV D1 Paclitaxel IV 135mg/m2/24hs D1 D2 D2 CisplatinIV 75mg/m2 IV IVExperimental arm IV/IP D1 Paclitaxel EV 135mg/m2/24hs D2 CisplatinIP100mg/m2 D1 D2 D8 D8 PaclitaxelIP60mg/m2 IVIP IP Armostrong e al, NEJM, 2006; N=429, optimaldebulkingsurgery, stage III SLPSG PT IV 19m 50m PT IV/IP 24m 65m Only 42% ofptscompletedtreat. IV/IP arm
    • 8. GOG randomized studies: IV vs IP PFS (m) %Advantage OS (m) %Advantage IV IP IV IPAlberts -- -- 41 49Markman 22 28 27 52 63Armstrong 19 24 20 50 65 25 * Statisticallysignificant : p < 0.05
    • 9. CarboplatinAUC 6 + Paclitaxel R 180mg/m2 A N D q 21 days x 6 cyclesAdvancedOvaria OnCancer M I CarboplatinAUC 6 + Paclitaxel(n = 637) Z A 80mg/m2 d1,8,15 T I q 21 days x 6 cycles O N Katsumata N, Lancet: 374, 2009
    • 10. Progression-freeSurvival Overall Survival Katsumata N, Lancet: 374, 2009
    • 11. PrimaryCitoreduc Platinun-CT R A tion x 6 cycles N DAdvancedOv OarianCancer M I(III/IV) Z A(n = 718) T I Platinun-CT Platinun-CT IntervalCytored O N x 3 cycles uction x 3 cycles Vergote I, NEJM: 363 2010
    • 12. OverallSurvival Overall Survivalvs Residual Disease Vergote I, NEJM: 363 2010
    • 13. Citoreduction CT CT CitoreductionComplete 20.4% 50.0%resection Vergote I, NEJM: 363 2010
    • 14. Citoreduction CT  CT Citoreductio nPos-op Death 2.5% 0.7%Hemorraghe G III/IVInfection 7.1% 8.1% 4.1% 1.7%DVT/PE 2.5% 0% Vergote I, NEJM: 363 2010
    • 15. GOG-0218: Scheme Arm Carboplatin(C) AUC 6 Paclitaxel (P) 175 mg/m2 I RFirst-line : Epithelial A PlaceboOV, PP or F N D 1:1:1 Carboplatin(C) AUC 6• Stage III optimal• Stage III suboptimal O M Paclitaxel (P) 175 mg/m2 II• Stage IV I n=1800 (planned) Z BEV 15 mg/kg Placebo E Carboplatin(C) AUC 6 Stratification III • PS Paclitaxel (P) 175 mg/m2 • Stage/Citoreduction BEV 15 mg/kg 15 months
    • 16. GOG-218: Progression-Free Survival Arm I Arm II Arm III 1.0 CP CP + BEV CP + BEV  BEV (n=625) (n=625) (n=623)Proportion surviving progression free 0.9 423 418 360 Patients with event, n (%) (67.7) (66.9) (57.8) 0.8 Median PFS, months 10.3 11.2 14.1 0.7 Stratified analysis HR 0.908 0.717 (95% CI) (0.759–1.040) (0.625–0.824) 0.6 One-sided p-value (log rank) 0.080a <0.0001a 0.5 0.4 0.3 0.2 CP (Arm I) 0.1 + BEV (Arm II) + BEV → BEV maintenance (Arm III) 0 0 12 24 36 Months since randomization
    • 17. GOG-218: Select Adverse Events Onset between cycle 2 and 30 days after date of last treatment Arm I Arm II Arm III CP CP + BEV CP + BEV  BEVAdverse event (grade when limited), n (%) (n=601) (n=607) (n=608)GI eventsa (grade ≥2) 7 (1.2) 17 (2.8) 16 (2.6)Hypertension (grade ≥2) 43 (7.2)b 100 (16.5)b 139 (22.9)bProteinuria (grade ≥3) 4 (0.7) 4 (0.7) 10 (1.6)Pain (grade ≥2) 250 (41.7) 252 (41.5) 286 (47.1)Neutropenia (grade ≥4) 347 (57.7) 384 (63.3) 385 (63.3)Febrile neutropenia 21 (3.5) 30 (4.9) 26 (4.3)Venous thromboembolic event 35 (5.8) 32 (5.3) 41 (6.7)Arterial thromboembolic event 5 (0.8) 4 (0.7) 4 (0.7)CNS bleeding 0 0 2 (0.3)Non-CNS bleeding (grade ≥3) 5 (0.8) 8 (1.3) 13 (2.1)RPLS 0 1 (0.2) 1 (0.2) RPLS = reversible posterior leukoencephalopathy syndrome aPerforation/fistula/necrosis/leak bp<0.05
    • 18. ICON 7: Scheme CarboplatinAUC6* q3w Stage I or IIa (grade Paclitaxel 175mg/m2 q3w 3 or clear cell) or stage IIb–IV EOC, PP, FTC CarboplatinAUC6* q3w (n=1,520) Paclitaxel 175mg/m2 q3w Bevacizumab 7.5mg/kg q3w• Open-label study 18 cycles• Endpoints – primary: PFS – secondary: RR, OS, safety, QoL, cost effectiveness, translational• Stratification – FIGO stage/surgery; time since surgery; GCIG group
    • 19. ICON 7: Progression-Free Survival 1.00 0.75Proportion surviving Control Experimental 0.50 Events, n (%) 130 (17) 111 (15) Log-rank p=0.098 0.25 Hazard ratio (95% CI) 0.81 (0.63–1.04) Sobrevida 1-ano, % 93 95 0 0 3 6 9 12 15 18 21 24 27 30 Time (months)
    • 20. ICON 7: Select Adverse Events 45 39.6 Control (n=753) 40 Research (n=745) 35 29.1 28.3 30Patients (%) 25.9 25 20 15 11.6 12.5 9.2 10 6.7 6.2 4.4 5.0 4.1 5 3.6 2.8 2.5 2.1 2.0 1.31.7 0.41.3 1.5 0.4 0.4 0 0 0 ATE = arterial thromboembolism; CHF = congestive heart failure; RPLS = reversible posterior leucoencephalopathy syndrome; VTE = venous thromboembolism
    • 21. GOG 218 and ICON 7: Comparison of TrialsTrial GOG-0218 ICON7Number of patients 1,800 1,520Setting/design •Double-blinded, placebo-controlled • Open-label •First-line setting •First-line setting •3-arm study: • 2-arm study: Arm I: CT + placebo Arm A: carboplatin/paclitaxel (CT) Arm II: CT + Bevacizumab (5 cycles) Arm B: CT + Bevacizumab Arm III: CT + Bevacizumab (extended) •Bevacizumab continued for 12 months •Bevacizumab continued for 16 months •Bevacizumab dose: 2.5mg/kg/week •Bevacizumab dose: 5mg/kg/week •Flexibility in AUC for carboplatin •Rigid AUC for carboplatinPatient population Post-cytoreductive surgery Post-cytoreductive surgery Sub-optimally debulked stage III/IV I or IIa (grade 3 or clear-cell histology) Macroscopic optimally debulked stage III IIb–IV (all grades and histological types)Target disease Epithelial ovarian, fallopian tube or primary Epithelial ovarian, fallopian tube or primary peritoneal cancer peritoneal cancerStratification • PS (0–1 vs 2) • FIGO stage • Stage (III vs IV) • ≤ vs>4 weeks after surgery • GCIG groupPrimary endpoint • Investigator-assessed PFS data • Investigator-assessed PFS data • Exploratory: IRC-assessed PFS data
    • 22. PRI 0 3 6 12 18 24MA Refractory MonthsRYT ResistentRE SensitiveATME HighlysensitiveNT
    • 23. < 6 months 12-18 months 70 > 18 months 59 60Overall Response 50 33 Rate (%) 40 30 20 12 10 0 Intervalfrom prior platinumtreatment (months)
    • 24. Platinum- Platinum- Sensitive ResistantorRefrac tory Platinum-basedTherapy
    • 25. ICON-4/AGO-OVAR-2.2 Trial CarboplatinAUC 5 a 6 EV R OR A N Cisplatin75mg/m2 EV D q 21 daysPlatinum- Osensitiveovariancancer MΔT >6 m I CarboplatinAUC 5 EV Z OR A Cisplatin50mg/m2 EV T + I Paclitaxel 175mg/m2 EV O Q 21 days N Parmar MK, Lancet: 361, 2003
    • 26. ICON-4/AGO-OVAR-2.2 Trial Overall Survival Parmar MK, Lancet: 361, 2003
    • 27. CALYPSO: Scheme R AInclusion Criteria: N CarboplatinAUC 5 EV + Paclitaxel 175 D mg/m2 IV 3• Platinum-sensitive (> 6 O m) M q21dx6 cycles• 1 or 2 prior platinum- I based CT Z• Measurable disease A (image or CA125) T CarboplatinAUC 5 EV + DoxoLipossomal I 30 mg/m2 IV 1 h O N q 28 days x6 cycles* *or until PD in patients with stable disease or response Pujades E etal, J ClinOncol, 2010
    • 28. CALYPSO: Progression-Free Survival Pujades E etal, J ClinOncol, 2010
    • 29. OCEANS: Scheme CarboplatinAUC4 q3w Gemcitabine 1000mg/m2 Placebo PD days 1 and 8 q3w Pretreated Placebo platinum-sensitive, EOC, PP or FTC (n=480) CarboplatinAUC4 q3w Gemcitabine 1000mg/m2 Bev. PD days 1 and 8 q3w 15mg/kg •Endpoints Bevacizumab 15mg/kg – primary: PFS – secondary: ORR, OS, response duration, safety – exploratory: IRC, CA125 response, ascites •Stratification: time to recurrence, cytoreductive surgeryEOC = epithelial ovarian; PP = primary peritoneal; FTC = fallopian tube carcinoma
    • 30. OCEANS: Patients Characteristics CG + PL CG + BVCharacteristic (n=242) (n=242)Median age, years 61 60 (range) (28−86) (38–87)Age ≥65 years, % 38 35Race, % White 92 90 Other 8 10ECOG PS 0, % 76 75Histologic subtype, % Serous 84 78 Mucinous/clear cell 3 5 Other 14 17Platinum-free interval, % 6–12 months 42 41>12 months 58 59Cytoreductive surgery for recurrent disease, % 10 12
    • 31. OCEANS: Progression-free Survival CG + PL CG + BV (n=242) (n=242) Events, n (%) 148 (61) 119 (49) 1.0 Median PFS, 8.6 12.3 Proportion progression free months (95% CI) (8.3–10.2) (10.7–14.6) 0.8 Stratified analysis 0.451 HR (95% CI) (0.351–0.580) Log-rank p-value <0.0001 0.6 0.4 0.2 0 0 6 12 18 24 30No. at risk MonthsCG + PL 242 168 31 8 3 0CG + BV 242 195 73 22 7 0
    • 32. OCEANS: Progression-free Survival vs Subgroups Median PFS (months) No. of CG + PL CG + BV CG + BV CG + PL Baseline risk factor patients (n=242) (n=242) HR (95% CI) better better All patients 484 8.4 12.4 0.49 (0.40–0.61) Platinum-free interval, 6–12 202 8.0 11.9 0.41 (0.29–0.58) months >12 282 9.7 12.4 0.55 (0.41–0.73) Cytoreductive surgery Yes 54 7.5 16.7 0.50 (0.24–1.01) for recurrent disease No 430 8.4 12.3 0.49 (0.39–0.62) Age, years <65 306 8.5 12.5 0.47 (0.36–0.62) ≥65 178 8.4 12.3 0.50 (0.34–0.72) Baseline ECOG PS 0 367 8.6 12.5 0.47 (0.36–0.60) 1 116 8.3 10.6 0.61 (0.39–0.95) 0.2 0.5 1 2 5 HR
    • 33. OCEANS: Response Rate Difference: 21.1% % p<0.0001100 78.5 Duration of response CG + PL CG + BV 80 (n=139) (n=190) 60 57.4 PR = 61 Median, months 7.4 10.4 40 PR = 48 HR (95% CI) 0.534 (0.408–0.698) 20 p<0.0001a CR = 9 CR = 17 aCompared for descriptive purposes only 0 CG + PL CG + BV (n=242) (n=242)
    • 34. Median PFS (months) No. of CG + PL CG + BV CG + BV CG + PLBaseline risk factor patients (n=242) (n=242) HR (95% CI) better betterAll patients 484 8.4 12.4 0.49 (0.40–0.61)Platinum-free interval, 6–12 202 8.0 11.9 0.41 (0.29–0.58)months >12 282 9.7 12.4 0.55 (0.41–0.73)Cytoreductive surgery Yes 54 7.5 16.7 0.50 (0.24–1.01)for recurrent disease No 430 8.4 12.3 0.49 (0.39–0.62)Age, years <65 306 8.5 12.5 0.47 (0.36–0.62) ≥65 178 8.4 12.3 0.50 (0.34–0.72)Baseline ECOG PS 0 367 8.6 12.5 0.47 (0.36–0.60) 1 116 8.3 10.6 0.61 (0.39–0.95) 0.2 0.5 1 2 5 HR
    • 35. Median PFS (months) No. of CG + PL CG + BV CG + BV CG + PLBaseline risk factor patients (n=242) (n=242) HR (95% CI) better betterAll patients 484 8.4 12.4 0.49 (0.40–0.61)Platinum-free interval, 6–12 202 8.0 11.9 0.41 (0.29–0.58)months >12 282 9.7 12.4 0.55 (0.41–0.73)Cytoreductive surgery Yes 54 7.5 16.7 0.50 (0.24–1.01)for recurrent disease No 430 8.4 12.3 0.49 (0.39–0.62)Age, years <65 306 8.5 12.5 0.47 (0.36–0.62) ≥65 178 8.4 12.3 0.50 (0.34–0.72)Baseline ECOG PS 0 367 8.6 12.5 0.47 (0.36–0.60) 1 116 8.3 10.6 0.61 (0.39–0.95) 0.2 0.5 1 2 5 HR
    • 36. Platinum- Platinum- Sensitive ResistantorRefrac tory Median OS 6 Retrospectiveanalysis: 111 pts months Recurrence< 3m orØ ResponseSV <4months 32%SV <12months 73% Markmanet al. GynecolOncol, 2004
    • 37.  LiposomalDoxorrubicin Gemcitabine Paclitaxel (weekly) Docetaxel Topotecan Etoposide (oral) Vinorelbine Ifosfamide
    • 38. AURELIA/MO22224: Scheme Progression Chemotherapy alone (physician’s choice): Physician’s choice: paclitaxel 80mg/m2qw or Bevacizumab EOC, PP or FTC topotecan4mg/m2 days 1, 8 and 15 15mg/kg q3w or that relapsed q4w or 1.25mg/kg days 1–5 q3wor SOC PLD 40mg/m2 q4w within <6 months after platinum- based chemotherapy Bevacizumab 10mg/kg q2w or (n=300) 15mg/kg q3w+ SOC chemotherapy (physician’s choice, as in control arm)•Endpoints Progression– primary: PFS– secondary endpoints: ORR (RECIST and/or CA125), biological progression-free interval, OS, QoL, safety•FPI: = epithelial of care PP =(recruitment: 24 months) EOC October 2009 primary peritoneal; FTC = fallopian tube carcinoma; PLD = pegylated liposomal doxorubicin; SOC = standard ovarian;
    • 39.  PARP inhibitors  Randomized Phase II trial: (Ledermann et al, ASCO , 2011)  N = 265  CT Olaparibvs Placebo  PFS: 8.4 vs 4.8 months (p< 0.00001)  Phase II trial: (Penson et al, ASCO , 2011)  N = 41  Carboplatin + Gemcitabine + Iniparib  OR: 70%
    • 40. ConvidadosInternacionais

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