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Chemioterapia raka jajnika Radosław Mądry Klinika Onkologii Uniwersytety Medycznego im. K. Marcinkowskiego w Poznaniu.

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Presentation on theme: "Chemioterapia raka jajnika Radosław Mądry Klinika Onkologii Uniwersytety Medycznego im. K. Marcinkowskiego w Poznaniu."— Presentation transcript:

1 Chemioterapia raka jajnika Radosław Mądry Klinika Onkologii Uniwersytety Medycznego im. K. Marcinkowskiego w Poznaniu

2 TIME LINE OF ADVANCES IN OVARIAN CANCER THERAPY CISPLATIN/ALKYLATOR COMBINATIONS COMBINATION WITH SIGNAL REGULATORS PACLITAXEL/ CARBOPLATIN ALKYLATORS CISPLATIN 5 YR SURVIVAL ADVANCED (III/IV) DISEASE 40%35%15% 0%0%

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4 I linia

5 GOG111 McGuire et al, N Engl J Med 334: 1-6, Mon. +14 Mon. N = 386, FIGO III/IV, >1cm Cisplatin/Cycloph. vs. Cisplatin/Paclitaxel Crossover to Paclitaxel 8% early 34% overall HR 0,7 HR 0,6

6 OV10 Piccart et al, J Natl Cancer Inst 92: , Mon. +10 Mon. N = 680, FIGO IIB/IIC/III/IV 6-9x Cisplatin/Cycloph. vs. 6-9x Cisplatin/Paclitaxel Crossover to Paclitaxel Higher (49%) HR 0,74 HR 0,73

7 GOG132 Muggia et al, J Clin Oncol 18: , 2000 HR 1,06 HR 0,99 +2,3 Mon. +3,9 Mon. N = 614, FIGO IIB/IIC/III/IV Cisplatin. vs. Cisplatin/Paclitaxel vs. Paclitaxel High Cross-over the high rate of early crossover to paclitaxel that had occurred in this single-agent platinum arm prior to progression (24%) Piccard 2003

8 ICON3 ICON Group, Lancet 360: , 2002 N = 2027, FIGO I-IV Carboplatin/Paclitaxel vs. Carboplatin vs CAP 1/3 cross-over to Paclitaxelu po progresji HR 0,93 HR 0,98

9 GOG 158 Ozols et al, J Clin Oncol 21: , 2003 N = 792, FIGO III, <1cm Cispl./Paclit. vs. Carbopl./Paclit. HR 0,88 ns HR 0,84 ns +1,3 Mon. +8,7 Mon.

10 OVAR-3 AGO Du Bois et al, J Natl Cancer Inst 95: , 2003 N = 798, FIGO IIB-IV, <1cm Cispl./Paclit. vs. Carbopl./Paclit. HR 1,05

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13 SCOTR0C Vasey et al, J Natl Cancer Inst 96: , 2004 HR 0,97 HR 1,13 N = 1077, FIGO IC-IV Carboplatin/ Paclitaxel vs. Carboplatin/Docetaxel

14 Badania negatywne I rzutu paclitaxel / carboplatin with or without epirubicin - Kristensen 2004 GOG 182 / ICON 5 Bookman 2005 paclitaxel / carboplatin with or without topotecan Scarfone 2006 paclitaxel / carboplatin with or without epirubicin Du Bois 2006 paclitaxel / carboplatin / 4x topotecan vs. follow up Pfisterer 2006 cisplatin plus topotecan followed by paclitaxel plus carboplatin versus standard carboplatin plus paclitaxel Hoskins 2008 paclitaxel / carboplatin with or without gemcitabine Du Bois 2008

15 NSGO-EORTC-NCIC-GEICO The addition of epirubicin to the standard carboplatin and paclitaxel treatment did not improve progression- free survival Kristensen 2004 ASCO Annual Meeting First line treatment of ovarian/tubal/peritoneal cancer FIGO stage IIb-IV with paclitaxel/carboplatin with or without epirubicin (TEC vs TC). A Gynecologic Cancer Intergroup study of the NSGO, EORTC GCG, and NCIC CTG. Results on progression free survival.

16 MITO Scarfone G, Scambia G, Raspagliesi F, et al. A multicenter, randomized, phase III study comparing paclitaxel/carboplatin versus topotecan/paclitaxel/carboplatin in patients with stage III (residual tumor > 1 cm after primary surgery) and IV ovarian cancer. Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology; June 2–6, 2006; Atlanta, Ga. abstract 5003 Conclusions: The addition of topotecan to standard PC primary chemotherapy does not increase RR and TTP in stage III (residual tumor > 1 cm) or IV OC compared to PC alone. The TPC regimen was well tolerated with a minority of patients experiencing G3/4 hematological toxicity

17 AGO GINECO Du Bois et al, J Clin Oncol 24: , 2006 N = 1282, FIGO IIB-IV Carboplatin/ Paclitaxel vs. Carboplatin/Paclitaxel/Epirubicin HR 0,95 HR 0,93

18 AGO OVAR GINECO N = 1308, FIGO IIB-IV 6x Carboplatin/Paclitaxel 4x Topotecan vs. Follow up HR 0,97 HR 1,01 Pfisterer et al, J Natl Cancer Inst 98: , 2006

19 GOG 182 / ICON 5 ASCO 2006

20 GOG 182 / ICON 5 ASCO 2006

21 GOG 182 / ICON 5 ASCO 2006

22 GOG 182 / ICON 5 ASCO 2006

23 GOG 182 / ICON 5 ASCO 2006

24 NCIC-EORTC-GEICO OV16 Hoskins PJ. A phase III trial of cisplatin plus topotecan followed by paclitaxel plus carboplatin versus standard carboplatin plus paclitaxel as first-line chemotherapy in women with newly diagnosed advanced epithelial ovarian cancer. A Gynecologic Cancer Intergroup Study of the NCIC CTG, EORTC, GCG, and GEICO. ASCO 2008

25 AGO OVAR9 A phase III study of paclitaxel, carboplatin, and gemcitabine in previously untreated patients with epithelial ovarian cancer FIGO stage IC–IV (AGO-OVAR protocol OVAR-9) A. du Bois 2008

26 AGO-OVAR-9; du Bois A i wsp Randomized phase-III GCIG study (AGO-OVAR-9, GINECO TCG, NSGO-OC-0102): gemcitabine-paclitaxel- carboplatin (TCG) vs. paclitaxel-carboplatin (TC) as first line treatment of ovarian cancr (OC) VII02 – IV04 FIGO IC-IV pts Więcej powikłań hematologicznych w ramieniu TCG Brak zysku z chth 3-lekowej

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30 W trakcie badań

31 I linia - nowość Phase III trial of induction gemcitabine (G) or paclitaxel (T) plus carboplatin (C) followed by elective T consolidation in advanced ovarian cancer (OC): Interim analysis of induction chemotherapy Gordon 2008 ASCO Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese Gynecologic Oncology Isonishi ASCO 2008

32 Vergote I i wsp - Neoadjuvant chemotherapy EORTC-GCG/NCIC-CTG randomised trial comparing primary debulking surgery with neoadjuvant chemotherapy in stage IIIC-IV ovarian, fallopian tube and peritoneal cancer IX98 – XII06 Potwierdzenie hist-pat raka jajnika LUB Sugestia cytologiczna + –guz w miednicy –zmiany przerzutowe 2 cm poza miednicą –CA125/CEA 25 Follow up = 4,8 lat

33 Late-Breaker Presentation Vergote I i wsp - Neoadjuvant chemotherapy FIGO IIIC-IV 718 pts Operacja pierwotna 6 x chth z platyną 3x chth Operacja odroczona 3 x chth

34 Late-Breaker Presentation Vergote I i wsp - Neoadjuvant chemotherapy

35 Operacja pierwotna Operacja odroczona Śmiertelność 28 dni 2,7%0,6% Posocznica8%2% Krwawienie 3/4°7%4%

36 Late-Breaker Presentation Vergote I i wsp - Neoadjuvant chemotherapy Operacja pierwotna Chth neoadj. OS29 msc30 mscHR: 0,98; CI: 0,85-1,14 PFS11 msc HR: 0,99; CI: 0,87-1,13

37 Phase III trial of induction gemcitabine (G) or paclitaxel (T) plus carboplatin (C) followed by elective T consolidation in advanced ovarian cancer (OC): Interim analysis of induction chemotherapy. Gordon A, et al. ASCO Abstract Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m 2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m 2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m 2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m 2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m 2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days

38 Phase III trial of induction gemcitabine (G) or paclitaxel (T) plus carboplatin (C) followed by elective T consolidation in advanced ovarian cancer (OC): Interim analysis of induction chemotherapy Response Rates Gordon A, et al. ASCO Abstract Best response, n (%) Induction GC (n = 66) Induction TC (n = 58) P Value CR*30 (45.5)26 (44.8) PR13 (19.7)12 (20.7) SD5 (7.6)8 (13.8) PD6 (9.1)4 (6.9) Data not available12 (18.2)8 (13.8) ORR (CR + PR)43 (65.2)38 (65.5).999 DCR (CR + PR + SD)48 (72.7)46 (79.3).410 *CR required a normalized CA-125.

39 Gordon A, et al. ASCO Abstract Toxicity, n (%) Induction GC (n = 219) Induction TC (n = 220) P Value Hematologic G3/4 thrombocytopenia 88 (40.2) 55 (25.1) 30 (13.6) 10 (4.5).0001 G3/4 anemia52 (23.7)20 (9.1).0001 Nonhematologic G2 neuropathy 24 (11.0)43 (19.5).0165 G2 alopecia79 (36.1)110 (50.0).0038 Platelet transfusion7 (3.2)0 (0).0073 Phase III trial of induction gemcitabine (G) or paclitaxel (T) plus carboplatin (C) followed by elective T consolidation in advanced ovarian cancer (OC): Interim analysis of induction chemotherapy Toxicity

40 NOVEL (New Ovarian ELaborate); Isonishi S i wsp Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese Gynecologic Oncology ASCO 2008: J Clin Oncol 2008; 26 (20 May suppl): A pts Follow up - 29 msc

41 Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese Gynecologic Oncology. Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m 2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m 2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m 2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO Abstract 5506.

42 P =.72 Evaluated by WHO criteria Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Clinical Responses Measurable Patients, % c-TC (n = 135) dd-TC (n = 147) Objective response 5356 CR 1620 PR 3836 NC 3129 PD 73 NE 912 Isonishi S, et al. ASCO Abstract 5506.

43 TreatmentnEventMedian PFS, mosP ValueHR95 %CI c-TC dd-TC Isonishi S, et al. ASCO Abstract 5506.

44 NOVEL (New Ovarian ELaborate); Isonishi S i wsp Analiza podgrup – nie uzyskano poprawy PFS przy raku jasnokom. i śluzowym. Większa toksyczność hematologiczna w dd-CT. Neurotoksyczność podobna w obu grupach. c-TCdd-CT 2-letnie OS (p=0,05) 77,7%83,6%

45 GOG 218: Bev in Primary Adjuvant Treatment and Consolidation Therapy GOG Statistical Report, July GOG 218 Patients with FIGO stage III epithelial ovarian or primary peritoneal cancer with any gross (macroscopic or palpable) residual disease or FIGO stage IV Paclitaxel 175 mg/m 2 over 3 hours x 6 cycles + Carboplatin AUC 6 x 6 cycles + Placebo every 3 weeks x 5 (cycles 2-6) Paclitaxel 175 mg/m 2 over 3 hours x 6 cycles + Carboplatin AUC 6 x 6 cycles + Bevacizumab 15 mg/kg every 3 weeks x 5 (cycles 2-6) Placebo every 3 weeks x 16 Bevacizumab 15 mg/kg every 3 weeks x 16

46 GOG 170D: Bevacizumab as Maintenance (Ongoing Phase III Trial) Patients with stage III/IV ovarian epithelial or primary peritoneal cancer (N = 2000) Arm 1: Paclitaxel over 3 hrs and Carboplatin over 30 mins on Day 1; Placebo* over mins on Day 1 every 21 days for 6 courses; Placebo over mins on Day 1 every 21 days for up to 22 courses Arm 2: Paclitaxel and Carboplatin as in Arm 1 Day 1; Bevacizumab* over mins on Day 1 every 21 days for 6 courses; Placebo over mins on Day 1 every 21 days for up to 22 courses Arm 2: Paclitaxel and Carboplatin as in Arm 1 Day 1; Bevacizumab* over mins on Day 1 every 21 days for 6 courses; bevacizumab over mins on Day 1 every 21 days for up to 22 courses *Beginning with course 2. Beginning with course 7. ClinicalTrials.gov. Available at: Primary endpoint: OS Secondary endpoints: PFS, severe toxicity and severe AEs, QoL, translational objectives by angiogenic markers and gene arrays

47 ICON-7 EOC, PP cancer Paclitaxel Carboplatin placebo Paclitaxel Carboplatin Bevacizumab x 12 cykli

48 IP

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50 HISTORY OF IP CHEMO Weisberger 1955 –Nitrogen mustard intraperitoneally for malignant ascites Jones 1978 –signicantly greater concentrations of certain chemotherapeutic drugs in the peritoneal cavity than in the blood. SWOG/GOG –The first phase III trial –since 1980s, presented in 1996 –In favor of IP arm

51 CLINICAL ASPECTS OF IP CHEMO Front-line chemotherapy Consolidation 2nd-line chemotherapy

52 PHASE III TRIALS OF IP vs IV CISPLATIN BASED CHEMOTHEPAY (Hamilton, 2006)

53 PHASE III TRIALS OF IP vs IV CISPLATIN BASED CHEMOTHEPAY Study Identifier / Year published Control RegimenExperimental RegimenTarget population No. of patients SWOG/GOG-104 (Alberts et al. 1996) Cisplatin 100 mg/m 2 IV Ctx 600 mg/m 2 IV q 3 weeks x 6 Cisplatin 100 mg/m 2 IP Ctx 600 mg/m 2 IV q 3 weeks x 6 Stage III < 2 cm residual 546 Greece (Polyzos et al. 1999) Crbpt 350 mg/m 2 IV Ctx 600 mg/m 2 IV q 3 weeks x 6 Crbpt 350 mg/m 2 IV Ctx 600 mg/m 2 IV q 3 weeks x 6 Stage III 2 cm residual 90 GONO (Gadducci et al. 2000) Cisplatin 50 mg/m 2 IV Ctx 600 mg/m 2 IV Epidox 60 mg/m 2 IV q 4 weeks x 6 Cisplatin 50 mg/m 2 IP Ctx 600 mg/m 2 IV Epidox 60 mg/m 2 IV q 4 weeks x 6 Stage II-IV < 2 cm residual GOG-114/SWOG (Markman et al. 2001) Cisplatin 75 mg/m 2 IV Tax 135 mg/m 2 (24 hr) IV q 3 weeks x 6 Crbpt AUC 9 IV q 28 days x 2 Cisplatin 100 mg/m 2 IP Tax 135 mg/m 2 (24 hr) IV q 3 weeks x 6 Stage III < 1 cm residual 462 Taiwan (Yen et al. 2001) Cisplatin 50 mg/m 2 IV Ctx 500 mg/m 2 IV Epi/Adr 50 mg/m 2 IV q 3 weeks x 6 Cisplatin 100 mg/m 2 IV Ctx 500 mg/m 2 IV Epi/Adr 50 mg/m 2 IV q 3 weeks x 6 Stage III < 1 cm residual GOG-172 (Armstrong et al. 2006) Cisplatin 75 mg/m 2 IV Tax 135 mg/m 2 (24 hr) IV q 3 weeks x 6 Tax 135 mg/m 2 (24 hr) IV Cisplatin 100 mg/m 2 IP Tax 60 mg/m 2 IV on day 8 q 3 weeks x 6 Stage III < 1 cm residual 415

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55 MAIN RESULTS Eight randomized trials studied 1819 women receiving primary treatment for ovarian cancer. Women were less likely to die if they received an intraperitoneal (IP) component to the chemotherapy (hazard ratio (HR) =0.79; 95% confidence interval (CI): 0.70 to 0.90)and the disease free interval (HR =0.79; 95%CI: 0.69 to 0.90) was also significantly prolonged. There may be greater serious toxicity with regard to gastrointestinal effects, pain and fever but less ototoxicity with the intraperitoneal than the intravenous route.

56 HAZARD RATIO FOR TIME TO RECURRENCE (IP vs IV CH)

57 HAZARD RATIO FOR TIME TO DEATH (IP vs IV CH)

58 Alberts et al, N Engl J Med: , Mon. HR 0,76 n = 546 FIGO III, <2cm Cisplatin 100 mg/m2 i.v. vs. i.p. +Cyclophosphamid i.v. GOG 104 (Alberts et al, 1996) CISPLATIN IV vs. IP

59 OS GOG 104 (Alberts et al, 1996) CISPLATIN IV vs. IP

60 As compared with IV cisplatin, IP cisplatin significantly improves survival and has significantly lower toxic effects in patients with stage III ovarian cancer and residual tumor mass of 2cm or less. The only same dose-intensity in both arms phase 3 RCT GOG 104 (Alberts et al, 1996) CISPLATIN IV vs. IP

61 GOG 111 –Median survival from 24 months (P+C) to 38 months ( P+T) GOG 104 (Alberts et al, 1996) CISPLATIN IV vs. IP

62 GOG 114 (Markman et al, 2001) CISPLATIN/PACLITAXEL vs. CARBO – PACLITAXEL / CISPLATIN IP Markman et al, J Clin Oncol 19: , 2001 n = 462 FIGO III, <1cm 6x CP i.v. vs. 2x Carboplatin AUC9 – 6x Paclitaxel i.v. /Cisplatin i.p. HR 0,78 +6 Mon. HR 0, Mon.

63 GOG 114 (Markman et al, 2001) CISPLATIN/PACLITAXEL vs. CARBO – PACLITAXEL / CISPLATIN IP PFS OS

64 GOG 114 (Markman et al, 2001) CISPLATIN/PACLITAXEL vs. CARBO – PACLITAXEL / CISPLATIN IP The 2nd phase 3 RCT to show IP cisplatin is superior to IV cisplatin in small volume residual advanced ovarian cancer The 1st phase 3 trial in ovarian cancer to a median survival of >5 years Trial demonstrated that IP cisplatin favorably impacts survival, even through IV paclitaxel is a component of regimen

65 GOG 114 (Markman et al, 2001) CISPLATIN/PACLITAXEL vs. CARBO – PACLITAXEL / CISPLATIN IP More complications in IP arm –Neutropenia, thrombocytopenia –G-I & metabolic toxicities Carbopltin x 2 cycles ( AUC 9)

66 GOG 172 (Armstrong et al, 2006) CISPLATIN/PACLITAXEL IV vs. IP Armstrong et al, N Engl J Med 354: n = 415 FIGO III, < 1 cm 6x CP vs. 6x Paclitaxel i.v. d1+ Cisplatin i.p. d2 + Paclitaxel i.p. d8 42% all 6 IP cycles HR 0,77 HR 0,73 +5,5 Mon. +15,9 Mon.

67 GOG 172 (Armstrong et al, 2006) CISPLATIN/PACLITAXEL IV vs. IP

68 PFS OS GOG 172 (Armstrong et al, 2006) CISPLATIN/PACLITAXEL IV vs. IP

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70 Significantly survival benefit in IP arm The 65.6 months median survival is the longest survival reported to date from a randomized trial in advanced ovarian cancer

71 GOG 172 (Armstrong et al, 2006) CISPLATIN/PACLITAXEL IV vs. IP The IP regimen uses higher and more frequent dosing than the IV regimen Toxicities were greater on the IP arm Fewer patients on the IP arm were able to complete 6 cycles of therapy

72 GOG 172 (Armstrong et al, 2006) CISPLATIN/PACLITAXEL IV vs. IP Although fewer than half the patients assigned to the IP group received six cycles of IP treatment, the group as a whole had a significant improvement in survival as compared with the intravenous group. It is possible that most of the benefit of IP therapy occurs early, during the initial cycles, or that the benefit of IP therapy may be greater if more patients can successfully complete six cycles of treatment.

73 IP vs IV IN ADVANCED OVARIAN CANCER Progression-free survival InvestigatorsNo. ofProgression-free survival (mo) year publishedptsControl armExp. Arm Alberts et al, NDND Polyzos et al, Gadducci et al, Markman et al, Yen et al, NDND Armstrong et al, p = 0.01; 2 p = 0.05

74 IP vs IV IN ADVANCED OVARIAN CANCER Overall survival InvestigatorsNo. of Overall survival (mo) year publishedptsControl armExp. Arm Alberts et al, Polyzos et al, Gadducci et al, Markman et al, Yen et al, Armstrong et al, p = 0.02; 2 p = 0.05; 3 p = 0.03

75 IP CHEMOTHERPAY IN OPTIMAL STAGE III OVARIAN CANCER WHY DID IT TAKE SO LONG? It was not a sexy drug The treatment was cumbersome There was always a reason why the results were interpreted differently –GOG 104: not better than using paclitaxel –GOG 114: because 8 cycles were used –GOG 172: it is toxic, but …

76 Conclusions on IPCT Combined use of IV and IP chemotherapy leads to a significant survival benefit in women with optimally debulked EOC (median + 12 mo). Based on the most recent trials, strong consideration should be given to a regimen with IP cisplatin (100 mg/m²) and a taxane (whether IV or IP). Toxicities, inconvenience and costs of IP therapy are justified by the improved survival. Vermorken 2007

77 FIRST LINE

78 the standard treatment approaches are subdivided into: –Treatment options for patients with optimally cytoreduced stage III disease. –Treatment options for patients with suboptimally cytoreduced stage III and stage IV disease. it is preferable to treat patients with several cycles of chemotherapy before interval debulking surgery.

79 Konsolidacja / leczenie podtrzymujące Still investigational

80 StudyPatientsRandomizationResults Scarfone 02 n=162 III-IV, SSL, pCR Pt-Tax based Epirubicin x 4 vs observation OSNS Pfisterer (2003) n=1308 IIb-IV Tax-Carbo Topotecan x 4 vs observation PFSNS OSNS De Placido (2004) n=273 III-IV, SSL, pCR < 2 cm, Pt-based Topotecan x 4 vs observation PFSNS OSNS Markman 03 N=277 III-IV Tax-Carbo, cCR Paclitaxel 3 or 12 cycles PFS 21 mo vs 28 mo P < Consolidation/Maintenance Therapies Cytotoxic therapy

81 Markman et al, JCO 2003; 21:

82 Final Results of After-6 Protocol Methods: 200 pts in cCR (48%) or pCR (52%) after 6 cycles of platinum/paclitaxel were randomized to observation or 175 mg/m² paclitaxel x 6 q 3 weeks Results: –No difference in PFS or OS. –Irrespective of treatment arm median PFS was 34.4 mo with PCR and 24.5 mo with cCR –3-yr survival 87% (pCR) and 79% (cCR): p=0.04 Conte et al, ASCO abstract #5505 (2007)

83 II linia

84 Chore platyno - wrażliwe Wznowa > 6 mieśięcy Re -platynizacja Chore platyno - oporne Wznowa < 6 miesięcy Leki nie oparte na platynie Tradycyjny podział wznowy raka jajnika po leczeniu I rzutu

85 Chore platyno - oporne

86 *Approved by the US Food and Drug Administration. Clinical trial –GOG 126 (cytotoxic) series –GOG 170 (biologic) series –Trabectedin –Patupilone –Phenoxodiol –TLK286 Pegylated liposomal doxorubicin* Topotecan* Paclitaxel* Docetaxel Gemcitabine Oral etoposide Bevacizumab Therapeutic Approaches for Relapsed Platinum-Resistant Disease

87 Topotecan vs PLD: Survival in Platinum Refractory/Resistant Subset Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.

88 Treatment nCR, %PR, %SD, %CB, %Median PFS, wks Median OS, wks Topotecan PLD P value Gordon AN, et al. J Clin Oncol. 2001;19: Intent-to-treat analysis Primary endpoint: PFS Topotecan vs PLD: Survival in Platinum Refractory/Resistant Subset

89 years survival ratesn123 Topotecan %17.2%9.5% PLD %21.1%13.8% Gordon AN, et al. Gynecologic Oncology 2004 Topotecan vs PLD: Survival in Platinum Refractory/Resistant Subset

90 GOG-126: Phase II Trial Series in Platinum Resistant/Refractory OC StudyNRegimenPrincipal Grade 3/4 Toxicity ORR, % GOG 126-N [1] 48 Paclitaxel 80 mg/m 2 weekly Neuropathy (grade 3): 4% Fatigue (grade 3): 8% 20.9 GOG 126-J [2] 60 (58 eval) Docetaxel 100 mg/m 2 every 3 weeks Neutropenia (grade 4): 75% 22.4 GOG 126-H [3] 41 Oral etoposide 50 mg/m 2 * 21 of 28 days Neutropenia (grade 3: 20%; grade 4: 25%) 26.8 Markman M, et al. Gynecol Oncol. 2006;101: Rose PG, et al. Gynecol Oncol. 2003;88: Rose PG et al. J Clin Oncol. 1998;16: *30 mg/m 2 for prior radiotherapy.

91 Gemcitabine 1000 mg/m 2 IV on Days 1, 8 every 21 days PLD 50 mg/m 2 IV Day 1 every 28 days Crossover* Each treatment given for up to 2 cycles after CR attained *Optional; allowed in case of progressive disease, undue toxicity, or cumulative PLD dose of 500 mg/m 2. Gemcitabine 1000 mg/m 2 IV on Days 1, 8 every 21 days PLD 50 mg/m 2 IV Day 1 every 28 days Patients with platinum- resistant taxane- pretreated ovarian cancer (N = 195) Mutch D, et al. SGO Abstract 28. Gemcitabine vs PLD: Phase III Recurrent (Platinum Resistant)

92 Gemcitabine (median:15.6 weeks) PLD (median: 13.3 weeks) Log-rank P =.87 Mutch D, et al. SGO Abstract 28. Gemcitabine vs PLD Phase III Recurrent (Platinum Resistant): PFS

93 Chore platyno - wrażliwe

94 Blackledge G, et al. Br J Cancer. 1989;59: Thigpen JT, personal communication. Interval, %Platinum, Response Other Agents, Response 0-6 mos mos mos mos9430 Chemosensitive Disease: TFI

95 Retreatment With Cisplatin-Based Regimen Markman, et alGore, et al Markman M, et al. J Clin Oncol. 1991;9: Gore ME, et al. Gynecol Oncol. 1990;36: Effect of Platinum-Free Interval on Response Rate Response Rate (%) < > 24 27% 33% 59% 17% 27% 57% n = 39 n = 20 n = 14 n = 29 n = 11 n = Months Response Rate (%) < > Months

96 Chemosensitive Disease: Major Trials TrialRegimen ICON 4/AGO-OVAR 2.2Carboplatin ± paclitaxel GCIG OVAR 2.5Carboplatin ± gemcitabine PLD/TopotecanPLD vs topotecan

97 ICON 4/AGO-OVAR 2.2 Paclitaxel + Platinum-based chemotherapy (n = 392) Platinum-based chemotherapy (n = 410) Patients with platinum-sensitive recurrent ovarian cancer TFI 6 months (N = 802) Parmar MK, et al. Lancet. 2003;361: parallel randomized, multicenter trials

98 Parmar MK, et al. Lancet. 2003;361: Time Since Completion of Last Chemotherapy, % Platinum (n = 410) Paclitaxel/ Platinum (n = 392) Total (N = 802) 12 mos > 12 mos ICON 4/AGO-OVAR 2.2: Patient Characteristics

99 Difference: 12% (-0.1 to 24.0); P =.06 Parmar MK, et al. Lancet. 2003;361: Response, % Platinum (n = 128) Paclitaxel/ Platinum (n = 119) ORR (CR + PR)5466 ICON 4/AGO-OVAR 2.2: Response

100 Hazard ratio: 0.76 (95% CI: ; P =.0004) Absolute difference at 1 year: 10% (95% CI: 4-15) 50% (paclitaxel/platinum) vs 40% Parmar MK, et al. Lancet. 2003;361: ICON 4/AGO-OVAR 2.2: Progression-Free Survival Patients at risk Paclitaxel + platinum Conventional treatment

101 Patients at risk Paclitaxel + platinum Conventional treatment Parmar MK, et al. Lancet. 2003;361: ICON 4/AGO-OVAR 2.2: Overall Survival Hazard ratio: 0.82 (95% CI: ; P =.023) Absolute difference at 2 years: 7% (95% CI: 1-12) 57% (paclitaxel/platinum) vs 50%

102 ICON 4/AGO-OVAR 2.2: Previous Taxanes OS PFS Paclitaxel/PlatinumPlatinum No Yes No Yes P =.49 P =.62 Parmar MK, et al. Lancet. 2003;361:

103 Randomized, phase III trial Gemcitabine (1000 mg/m 2 ) Days 1 and 8 Carboplatin (AUC = 4) Day 1 every 21 days x 6 cycles (n = 178) Carboplatin (AUC = 5) Day 1 every 21 days x 6 cycles (n = 178) Patients with platinum- sensitive recurrent ovarian cancer 6 months out from initial platinum therapy (N = 356) Pfisterer J, et al. J Clin Oncol. 2006;24: AGO-OVAR 2.5 (GCIG): Gemcitabine/ Carboplatin vs Carboplatin

104 Gemcitabine/Carboplatin (n = 178) Carboplatin (n = 178) Platinum-free interval, % 6-12 mos39.9 > 12 mos First line therapy, % Platinum taxane Platinum nontaxane Platinum monotherapy1.1 Pfisterer J, et al. J Clin Oncol. 2006;24: AGO-OVAR 2.5 (GCIG): Platinum-free Interval and Previous Treatment

105 Parameter, %Gemcitabine/ Carboplatin (n = 178) Overall response (CR + PR)* CR PR Stable disease Progressive disease Pfisterer J, et al. J Clin Oncol. 2006;24: AGO-OVAR 2.5 (GCIG): Response Data *P =.0016

106 Pfisterer J, et al. J Clin Oncol. 2006;24: AGO-OVAR 2.5 (GCIG): Progression-free Survival HR: 0.72 (95% CI: ); P =.0031 Median: 8.6 mos (range: ) Median: 5.8 mos (range: )

107 Pfisterer J, et al. J Clin Oncol. 2006;24: HR: 0.96 (95% CI: ); P =.7349 Median: 18.0 mos (range: ) Median: 17.3 mos (range: ) AGO-OVAR 2.5 nie zaplanowane do oceny całkowitego przeżycia. AGO-OVAR 2.5 (GCIG): Overall Survival* Carboplatin

108 Therapy, %Gemcitabine/Carboplatin (n = 178) Carboplatin (n = 178) Any therapy postrecurrence or progression Chemotherapy regimen regimens regimens Unspecified no. regimens Hormonal/immunologic/ biologic therapy Radiation Other therapynot specified AGO-OVAR 2.5 (GCIG): Therapy After Recurrence/Progression

109 Patients with advanced ovarian cancer (90% stage II/IV) Recurrent or failed platinum-based therapy Measurable disease Median age: 60 years (range: 25-87) (N = 474) Topotecan 1.5 mg/m 2 /d IV for 5 consecutive days every 3 weeks PLD 50 mg/m 2 IV every 4 weeks Stratification by platinum sensitivity and presence/absence of bulky disease Gordon AN, et al. J Clin Oncol. 2001;19: Pegylated Liposomal Doxorubicin vs Topotecan: Phase III Study Design

110 Patient Group, %PLDTopotecanP Value Platinum sensitive (n = 220; PLD: 109; T: 111) Platinum refractory (n = 254; PLD: 130; T: 124) Gordon AN, et al. J Clin Oncol. 2001;19: PLD vs Topotecan: Response Rates

111 Gordon AN, et al. Gynecol Oncol. 2004;95:1-8. PLD vs Topotecan: Median Survival Median Survival Pegylated liposomal doxorubicin: 62.7 weeks Topotecan: 59.7 weeks HR: 1.23 (95% CI: ; P =.038)

112 Gordon AN, et al. Gynecol Oncol. 2004;95:1-8. PLD vs Topotecan: Median Survival (Platinum-Sensitive Disease) Median Survival Pegylated liposomal doxorubicin: weeks Topotecan: 70.1 weeks HR: (95% CI: ; P =.017)

113 Ferrero JM, et al. Ann Oncol. 2007;18: Patients with advanced ovarian cancer –N = 105 (104 received treatment) –TFI 6 months PLD 30 mg/m 2 + carboplatin AUC 5 every 4 weeks Selected patient characteristics –ECOG PS 1-2: 47% –2 prior regimens: 39% –Measurable disease: 57% GINECO Phase II Trial: Schema

114 *Median 6 cycles of therapy. Ferrero JM, et al. Ann Oncol. 2007;18: OutcomePLD/Carboplatin (n = 104)* ORR (CR+ PR), %63 CR, %38 PFS, mos9.4 OS, mos32 GINECO Phase II Trial: Results

115 Dostępna analiza pośrednia Pegylated liposomal doxorubicin (PLD)-carboplatin (C) (C-D) vs paclitaxel-carboplatin (C-P) in relapsing sensitive ovarian cancer (OC): A 500-patient interim safety analysis of the CALYPSO GCIG Intergroup phase III study. Åvall-Lundqvist 2008 J Clin Oncol / ASCO Conclusions: This planned interim safety analysis on the first 500 patients confirmed different toxicity profiles in the two arms, with less drug-related SAE and less early therapy termination in the C-D arm.

116 Chemosensitive Disease: Conclusions Platinum regimens superior to nonplatinum regimens tested to date Paclitaxel/carboplatin yields superior PFS and OS compared with carboplatin Gemcitabine/carboplatin produces superior response and PFS compared with carboplatin PLD/carboplatin produces excellent response, PFS, and OS

117 Chemosensitive Disease: Doublets Paclitaxel/carboplatin Gemcitabine/carboplatin PLD/carboplatin

118 An Open-label Multicenter Randomized Phase 3 Study Comparing CAELYX ® and YONDELIS with CAELYX alone in Relapsed Ovarian Cancer ESMO 2008 II linia - nowość

119 Cluster of Ecteinascidia turbinata, a sea squirt or tunicate from the Caribbean Sea Yondelis: Tetrahydroisoquinoline alkaloid, MW=762. Yondelis, trabectedin, ET : PharmaMar starts clinical development of ET : Joint development of ET-743 by Johnson & Johnson Pharm R&D andPharmaMar

120 Yondelis, trabectedin, ET-743 Wiązanie do rowka mniejszego łańcucha DNA Najaktywniejsza w fazie G1 Działanie w czasie transkrypcji Interakcja z mechanizmami naprawczymi DNA

121 An Open-label Multicenter Randomized Phase 3 Study Comparing CAELYX ® and YONDELIS with CAELYX alone in Relapsed Ovarian Cancer Advanced Recurrent Epithelial Ovarian Cancer –One prior regimen –Evaluable and measurable disease –Platinum sensitive and resistant Primary endpoint: OS Other endpoints: PFS, RR, Safety Translational Research Pharmacokinetics Pharmacogenomics Pharmacoeconomics Quality of Life Circulating tumor cells RANDOMIZERANDOMIZE Caelyx® 50 mg/m 2 q 4 wks Caelyx® 30 mg/m 2 plus Yondelis® 1.1mg/m2 Every 3 weeks Accrual 7/11/2006: 374/650

122 33rd ESMO Congress Stockholm, September 2008

123 OVA-301 Study Shows Significant Prolongation In Progression Free Survival Positive final results of the Phase III randomized pivotal study of Yondelis® in ovarian cancer were presented during the Presidential Symposium at the ESMO congress in Stockholm. ESMO selects clinical studies that may result in a change in the current standard of care for presentation at the 2008 Presidential Symposium.

124 Progression-free survival (PFS) Median PFS was 7.3 months (trabectedin + PLD) vs 5.8 months in control arms (PLD) The hazard ratio (HR) was 0.79 (p=0.019) 21% reduction in the risk of progression or death during the observation period. Response rate 28% ( trabectedin and PLD) vs 19% in control arms (PLD)

125 Overall survival The interim survival data presented at ESMO are immature (55% censored) and the final analysis will be conducted after the occurrence of 520 events. Nonetheless, a positive trend with a 15% reduction in the risk of death favored patients treated with the Yondelis® and PLD combination.

126 Toxicity Neutropenia was the most common toxicity (77%) in the combination arm compared with 38% of patients in the Doxil®-only arm Similarly, reversible liver enzyme (transaminase) elevations were more common with the combination although without permanent liver damage or other clinical consequences. The addition of trabectedin enabled a lower dose of Doxil®, which may have contributed to the lower incidence of Doxil®-related toxicity observed with the combination. Specifically, hand and foot syndrome was seen in 54% of patients receiving alone compared with 24% of patients treated with trabectedin + Doxil. Similarily, stomatitis occurred in fewer patients receiving the trabectedin + Doxil® combination (20%) compared with those receiving Doxil® monotherapy (33%).

127 Podsumowanie I rzut: –Karboplatyna / Paclitaxel –Cisplatyna / Paclitexel IP II rzut: –Chore platyno – oporne: PLD, topotekan, gemcitabine –Chore platyno – wrażliwe: Karboplatyna/ paclitaxel vel gemcitabine, PLD

128 Pytanie bez odpowiedzi - III rzut - sekwencyjność chemioterapii - miejsce VP-16 - Leczenie celowane


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