Fernando Cotait MalufChairof Medical OncologyDepartment         São José Hospital     São Paulo São Paulo Brazil
•Advancedstagesatdiagnosis (~75%)•Highlychemotherapy-sensitive• Complete clinicalresponse to platinum-based CT: 70-85%•Sta...
• 81 studies• 6885 patients•StageIIIandIV•Cytoreductivesurgeryfollowedbyplatinum-based CT                                 ...
• CT platinum-basedversus CT NON platinum-based1,2   • HR death: 0.88 [0.79 – 0.98]•CT anthracyline-basedversus CT NON ant...
•MONOCT platinum-basedversus POLICT platinum-based1,2    • HR death: 0.91 [0.75 – 1.05]OvarianCancerMeta-Analysis Project ...
GOG 111 andOV 10(Intergroup)                                       McGuireetal, N Eng J Med, 1996;                        ...
GOG 172   Standard arm IV                                                  D1 Paclitaxel IV 135mg/m2/24hs                 ...
GOG randomized studies: IV vs IP                 PFS (m)           %Advantage   OS (m)        %Advantage                 I...
CarboplatinAUC 6 + Paclitaxel                 R            180mg/m2                 A                 N                 D ...
Progression-freeSurvival   Overall Survival                             Katsumata N, Lancet: 374, 2009
PrimaryCitoreduc                  Platinun-CT              R              A         tion                         x 6 cycle...
OverallSurvival   Overall Survivalvs Residual Disease                                 Vergote I, NEJM: 363 2010
Citoreduction CT         CT                                CitoreductionComplete         20.4%              50.0%resecti...
Citoreduction        CT                           CT        Citoreductio                                            nPos...
GOG-0218: Scheme                                          Arm                                                       Carbop...
GOG-218: Progression-Free Survival                                                                                        ...
GOG-218: Select Adverse Events           Onset between cycle 2 and 30 days after date of last treatment                   ...
ICON 7: Scheme                                                    CarboplatinAUC6* q3w    Stage I or IIa (grade           ...
ICON 7: Progression-Free Survival                       1.00                       0.75Proportion surviving               ...
ICON 7: Select Adverse Events               45                                                           39.6             ...
GOG 218 and ICON 7: Comparison of TrialsTrial                                      GOG-0218                               ...
PRI   0        3      6    12         18          24MA   Refractory                                  MonthsRYT        Resi...
< 6 months                                                                  12-18 months                 70               ...
Platinum-         Platinum- Sensitive     ResistantorRefrac                      tory  Platinum-basedTherapy
ICON-4/AGO-OVAR-2.2 Trial                                 CarboplatinAUC 5 a 6 EV                         R               ...
ICON-4/AGO-OVAR-2.2 Trial       Overall Survival                          Parmar MK, Lancet: 361, 2003
CALYPSO: Scheme                            R                            AInclusion Criteria:         N       CarboplatinAU...
CALYPSO: Progression-Free Survival                        Pujades E etal, J ClinOncol, 2010
OCEANS: Scheme                                                                                    CarboplatinAUC4 q3w     ...
OCEANS: Patients Characteristics                                                 CG + PL CG + BVCharacteristic            ...
OCEANS: Progression-free Survival                                                                               CG + PL   ...
OCEANS: Progression-free Survival vs Subgroups                                            Median PFS                      ...
OCEANS: Response Rate         Difference: 21.1%  %              p<0.0001100                      78.5     Duration of resp...
Median PFS                                            (months)                                   No. of CG + PL CG + BV   ...
Median PFS                                            (months)                                   No. of CG + PL CG + BV   ...
Platinum-                  Platinum-          Sensitive              ResistantorRefrac                                    ...
   LiposomalDoxorrubicin   Gemcitabine   Paclitaxel (weekly)   Docetaxel   Topotecan   Etoposide (oral)   Vinorelbi...
AURELIA/MO22224: Scheme                                                                              Progression          ...
 PARP inhibitors    Randomized Phase II trial: (Ledermann et al, ASCO , 2011)       N = 265       CT Olaparibvs Place...
ConvidadosInternacionais
09   state of the art of the management of advanced and recurrent ovarian cancer
09   state of the art of the management of advanced and recurrent ovarian cancer
09   state of the art of the management of advanced and recurrent ovarian cancer
09   state of the art of the management of advanced and recurrent ovarian cancer
09   state of the art of the management of advanced and recurrent ovarian cancer
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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
  • 09 state of the art of the management of advanced and recurrent ovarian cancer

    1. 1. Fernando Cotait MalufChairof Medical OncologyDepartment São José Hospital São Paulo São Paulo Brazil
    2. 2. •Advancedstagesatdiagnosis (~75%)•Highlychemotherapy-sensitive• Complete clinicalresponse to platinum-based CT: 70-85%•Stage III: 20-25% of complete remissionat 5y
    3. 3. • 81 studies• 6885 patients•StageIIIandIV•Cytoreductivesurgeryfollowedbyplatinum-based CT Bristowet al. J ClinOncol, 2002
    4. 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. 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. 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. 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. 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. 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. 10. Progression-freeSurvival Overall Survival Katsumata N, Lancet: 374, 2009
    11. 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. 12. OverallSurvival Overall Survivalvs Residual Disease Vergote I, NEJM: 363 2010
    13. 13. Citoreduction CT CT CitoreductionComplete 20.4% 50.0%resection Vergote I, NEJM: 363 2010
    14. 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. 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. 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. 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. 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. 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. 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. 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. 22. PRI 0 3 6 12 18 24MA Refractory MonthsRYT ResistentRE SensitiveATME HighlysensitiveNT
    23. 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. 24. Platinum- Platinum- Sensitive ResistantorRefrac tory Platinum-basedTherapy
    25. 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. 26. ICON-4/AGO-OVAR-2.2 Trial Overall Survival Parmar MK, Lancet: 361, 2003
    27. 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. 28. CALYPSO: Progression-Free Survival Pujades E etal, J ClinOncol, 2010
    29. 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. 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. 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. 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. 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. 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. 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. 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. 37.  LiposomalDoxorrubicin Gemcitabine Paclitaxel (weekly) Docetaxel Topotecan Etoposide (oral) Vinorelbine Ifosfamide
    38. 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. 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. 40. ConvidadosInternacionais
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