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Chemioterapia raka jajnika

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

2 TIME LINE OF ADVANCES IN OVARIAN CANCER THERAPY
ALKYLATORS CISPLATIN/ALKYLATOR COMBINATIONS COMBINATION WITH SIGNAL REGULATORS 1960 1980 2000 1970 1990 CISPLATIN PACLITAXEL/ CARBOPLATIN 5 YR SURVIVAL ADVANCED (III/IV) DISEASE 40% 35% 15% 0% 1960 1970 1980 1990 2000

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4 I linia

5 GOG111 +5 Mon. HR 0,7 +14 Mon. HR 0,6 N = 386, FIGO III/IV, >1cm
Cisplatin/Cycloph. vs. Cisplatin/Paclitaxel Crossover to Paclitaxel 8% ‘early’ 34% overall +5 Mon. HR 0,7 +14 Mon. HR 0,6 McGuire et al, N Engl J Med 334: 1-6, 1996

6 OV10 +4 Mon. HR 0,74 +10 Mon. HR 0,73 N = 680, FIGO IIB/IIC/III/IV
6-9x Cisplatin/Cycloph. vs. 6-9x Cisplatin/Paclitaxel Crossover to Paclitaxel Higher (49%) +4 Mon. HR 0,74 +10 Mon. HR 0,73 Piccart et al, J Natl Cancer Inst 92: , 2000

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

8 ICON3 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 ICON Group, Lancet 360: , 2002

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

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

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

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 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 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

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

18 AGO OVAR GINECO HR 0,97 HR 1,01 N = 1308, FIGO IIB-IV
6x Carboplatin/Paclitaxel 4x Topotecan vs. Follow up 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) VII’02 – IV’04 FIGO IC-IV 1 724 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 IX’98 – XII’06 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

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

35 Late-Breaker Presentation Vergote I i wsp - Neoadjuvant chemotherapy
Operacja pierwotna Operacja odroczona Śmiertelność ≤ 28 dni 2,7% 0,6% Posocznica 8% 2% Krwawienie 3/4° 7% 4%

36 Late-Breaker Presentation Vergote I i wsp - Neoadjuvant chemotherapy
Operacja pierwotna Chth neoadj. OS 29 msc 30 msc HR: 0,98; CI: 0,85-1,14 PFS 11 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. Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days Clinical CR Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Gordon A, et al. ASCO Abstract 5536.

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 Best response, n (%) Induction GC (n = 66) Induction TC (n = 58) P Value CR* 30 (45.5) 26 (44.8) PR 13 (19.7) 12 (20.7) SD 5 (7.6) 8 (13.8) PD 6 (9.1) 4 (6.9) Data not available 12 (18.2) ORR (CR + PR) 43 (65.2) 38 (65.5)  .999 DCR (CR + PR + SD) 48 (72.7) 46 (79.3) .410 DCR, disease control rate Gordon A, et al. ASCO Abstract 5536. *CR required a normalized CA-125.

39 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 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 anemia 52 (23.7) 20 (9.1) Nonhematologic  G2 neuropathy 24 (11.0) 43 (19.5) .0165 G2 alopecia 79 (36.1) 110 (50.0) .0038 Platelet transfusion 7 (3.2) 0 (0) .0073 Gordon A, et al. ASCO Abstract 5536.

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): A5506 637 pts Follow up - 29 msc

41 Conventional TC (c-TC) Dose-dense weekly TC (dd-TC)
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 Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others NOVEL, New Ovarian Elaborate Trial Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Isonishi S, et al. ASCO Abstract 5506.

42 Patients, % c-TC (n = 135) dd-TC (n = 147)
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 53 56 CR 16 20 PR 38 36 NC 31 29 PD 7 3 NE 9 12 NOVEL, New Ovarian Elaborate Trial Isonishi S, et al. ASCO Abstract 5506. P = .72 Evaluated by WHO criteria 42

43 Treatment n Event Median PFS, mos P Value HR 95 %CI c-TC 319 200 17.2 dd-TC 312 160 28.0 .0015 0.714 Isonishi S, et al. ASCO Abstract 5506.

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

45 GOG 218: Bev in Primary Adjuvant Treatment and Consolidation Therapy
Paclitaxel 175 mg/m2 over 3 hours x 6 cycles + Carboplatin AUC 6 x 6 cycles + Placebo every 3 weeks x 5 (cycles 2-6) Placebo every 3 weeks x 16 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/m2 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 Paclitaxel 175 mg/m2 over 3 hours x 6 cycles + Carboplatin AUC 6 x 6 cycles + Bevacizumab 15 mg/kg every 3 weeks x 5 (cycles 2-6) Bevacizumab 15 mg/kg every 3 weeks x 16 GOG Statistical Report, July 2008. 45

46 GOG 170D: Bevacizumab as Maintenance (Ongoing Phase III Trial)
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 Patients with stage III/IV ovarian epithelial or primary peritoneal cancer (N = 2000) 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. Primary endpoint: OS Secondary endpoints: PFS, severe toxicity and severe AEs, QoL, translational objectives by angiogenic markers and gene arrays ClinicalTrials.gov. Available at: 46

47 ICON-7

48 IP

49

50 HISTORY OF IP CHEMO Weisberger 1955 Jones 1978 SWOG/GOG
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 Front-line C/T: after primary debulking Consolidation C/T: after Op+C/T 2nd-line C/T: for persistence or recurrence tumor

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 Regimen Experimental Regimen Target population No. of patients SWOG/GOG-104 (Alberts et al. 1996) Cisplatin 100 mg/m2 IV Ctx 600 mg/m2 IV q 3 weeks x 6 Cisplatin 100 mg/m2 IP Stage III < 2 cm residual 546 Greece (Polyzos et al. 1999) Crbpt 350 mg/m2 IV < or > 2 cm residual 90 GONO (Gadducci et al. 2000) Cisplatin 50 mg/m2 IV Epidox 60 mg/m2 IV q 4 weeks x 6 Cisplatin 50 mg/m2 IP Stage II-IV 113+ GOG-114/SWOG (Markman et al. 2001) Cisplatin 75 mg/m2 IV Tax 135 mg/m2 (24 hr) IV Crbpt AUC 9 IV q 28 days x 2 < 1 cm residual 462 Taiwan (Yen et al. 2001) Ctx 500 mg/m2 IV Epi/Adr 50 mg/m2 IV 118+ GOG-172 (Armstrong et al. 2006) Tax 60 mg/m2 IV on day 8 415

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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)
SWOG/GOG 104 : (1996) by Alberts GOG 114 (2001) by Markman GOG 172 (2006) by Armstrongs

58 GOG 104 (Alberts et al, 1996) CISPLATIN IV vs. IP
n = 546 FIGO III, <2cm Cisplatin 100 mg/m2 i.v. vs. i.p. +Cyclophosphamid i.v. +8 Mon. HR 0,76 Alberts et al, N Engl J Med: , 1996

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

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

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

62 GOG 114 (Markman et al, 2001) CISPLATIN/PACLITAXEL vs
GOG 114 (Markman et al, 2001) CISPLATIN/PACLITAXEL vs. CARBO – PACLITAXEL / CISPLATIN IP n = 462 FIGO III, <1cm 6x CP i.v. vs. 2x Carboplatin AUC9 – 6x Paclitaxel i.v. /Cisplatin i.p. +6 Mon. HR 0,78 +11 Mon. HR 0,81 Markman et al, J Clin Oncol 19: , 2001

63 GOG 114 (Markman et al, 2001) CISPLATIN/PACLITAXEL vs
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
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
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
HR 0,77 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 +5,5 Mon. HR 0,73 +15,9 Mon. Armstrong et al, N Engl J Med 354: 34-43

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

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

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

70 GOG 172 (Armstrong et al, 2006) CISPLATIN/PACLITAXEL IV vs. IP
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
Investigators No. of Progression-free survival (mo) year published pts Control arm Exp. Arm Alberts et al, ND ND Polyzos et al, Gadducci et al, Markman et al, Yen et al, ND ND Armstrong et al, 1 p = 0.01; 2 p = 0.05

74 IP vs IV IN ADVANCED OVARIAN CANCER Overall survival
Investigators No. of Overall survival (mo) year published pts Control arm Exp. Arm Alberts et al, Polyzos et al, Gadducci et al, Markman et al, Yen et al, Armstrong et al, 1 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 2008 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 Consolidation/Maintenance Therapies Cytotoxic therapy
Study Patients Randomization Results Scarfone ’02 n=162 III-IV, SSL, pCR Pt-Tax based Epirubicin x 4 vs observation OS NS Pfisterer (2003) n=1308 IIb-IV Tax-Carbo Topotecan x 4 PFS NS De Placido (2004) n=273 < 2 cm, Pt-based Markman ’03 N=277 III-IV Tax-Carbo, cCR Paclitaxel 3 or 12 cycles PFS 21 mo vs 28 mo P < 0.005

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

85 Chore platyno - oporne

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

87 Topotecan vs PLD: Survival in Platinum Refractory/Resistant Subset
PLD, pegylated liposomal doxorubicin; CR, complete response; PR, partial response; SD, stable disease; CB, clinical benefit; PFS, progression-free survival; OS, overall survival Gordon AN, et al. Gynecol Oncol. 2004;95:1-8. 87

88 Topotecan vs PLD: Survival in Platinum Refractory/Resistant Subset
Treatment n CR, % PR, % SD, % CB, % Median PFS, wks Median OS, wks Topotecan 124 0.8 5.6 42.7 49.1 13.6 41.3 PLD 130 11.5 27.7 40.0 9.1 35.6 P value .733 .455 PLD, pegylated liposomal doxorubicin; CR, complete response; PR, partial response; SD, stable disease; CB, clinical benefit; PFS, progression-free survival; OS, overall survival Intent-to-treat analysis Primary endpoint: PFS Gordon AN, et al. J Clin Oncol. 2001;19: 88

89 Topotecan vs PLD: Survival in Platinum Refractory/Resistant Subset
years survival rates n 1 2 3 Topotecan 124 43.2% 17.2% 9.5% PLD 130 41.5% 21.1% 13.8% PLD, pegylated liposomal doxorubicin; CR, complete response; PR, partial response; SD, stable disease; CB, clinical benefit; PFS, progression-free survival; OS, overall survival Gordon AN, et al. Gynecologic Oncology 2004 89

90 GOG-126: Phase II Trial Series in Platinum Resistant/Refractory OC
Study N Regimen Principal Grade 3/4 Toxicity ORR, % GOG 126-N[1] 48 Paclitaxel 80 mg/m2 weekly Neuropathy (grade 3): 4% Fatigue (grade 3): 8% 20.9 GOG 126-J[2] 60 (58 eval) Docetaxel 100 mg/m2 every 3 weeks Neutropenia (grade 4): 75% 22.4 GOG 126-H[3] 41 Oral etoposide 50 mg/m2* 21 of 28 days Neutropenia (grade 3: 20%; grade 4: 25%) 26.8 GOG, Gynecologic Oncology Group *30 mg/m2 for prior radiotherapy. 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: 90

91 Gemcitabine vs PLD: Phase III Recurrent (Platinum Resistant)
Crossover* Gemcitabine 1000 mg/m2 IV on Days 1, 8 every 21 days PLD 50 mg/m2 IV Day 1 every 28 days Patients with platinum-resistant taxane-pretreated ovarian cancer (N = 195) PLD 50 mg/m2 IV Day 1 every 28 days Gemcitabine 1000 mg/m2 IV on Days 1, 8 every 21 days PLD, pegylated liposomal doxorubicin; CR, complete response 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/m2. Mutch D, et al. SGO Abstract 28. 91

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

93 Chore platyno - wrażliwe

94 Chemosensitive Disease: TFI
Interval, % Platinum, Response Other Agents, Response 0-6 mos 10 15 7-12 mos 29 20 13-18 mos 63 30 19-24 mos 94 TFI, treatment-free interval Blackledge G, et al. Br J Cancer. 1989;59: Thigpen JT, personal communication. 94

95 Effect of Platinum-Free Interval on Response Rate
Retreatment With Cisplatin-Based Regimen n = 14 n = 39 59% 60 60 57% 50 50 40 n = 20 40 33% n = 39 n = 11 Response Rate (%) Response Rate (%) 30 27% 30 27% n = 29 20 20 17% 10 10 < 12 13-24 > 24 < 12 13-24 > 24 Months Months Markman, et al Gore, et al Markman M, et al. J Clin Oncol. 1991;9: Gore ME, et al. Gynecol Oncol. 1990;36: 95

96 Chemosensitive Disease: Major Trials
Regimen ICON 4/AGO-OVAR 2.2 Carboplatin ± paclitaxel GCIG OVAR 2.5 Carboplatin ± gemcitabine PLD/Topotecan PLD vs topotecan ICON, International Collaborative Group for Ovarian Neoplasia; GCIG, Gynecologic Cancer Intergroup; AGO-OVAR, AGO Ovarian Cancer Study Group; PLD, pegylated liposomal doxorubicin; GINECO, Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire 96

97 Patients with platinum-sensitive recurrent ovarian cancer
ICON 4/AGO-OVAR 2.2 2 parallel randomized, multicenter trials Paclitaxel + Platinum-based chemotherapy (n = 392) Patients with platinum-sensitive recurrent ovarian cancer TFI ≥ 6 months (N = 802) ICON, International Collaborative Group for Ovarian Neoplasia; AGO-OVAR, AGO Ovarian Cancer Study Group; TFI, treatment-free interval Platinum-based chemotherapy (n = 410) Parmar MK, et al. Lancet. 2003;361: 97

98 Paclitaxel/ Platinum (n = 392)
ICON 4/AGO-OVAR 2.2: Patient Characteristics Time Since Completion of Last Chemotherapy, % Platinum (n = 410) Paclitaxel/ Platinum (n = 392) Total (N = 802) ≤ 12 mos 27 23 25 > 12 mos 73 77 75 ICON, International Collaborative Group for Ovarian Neoplasia Parmar MK, et al. Lancet. 2003;361: 98

99 ICON 4/AGO-OVAR 2.2: Response
Platinum (n = 128) Paclitaxel/ Platinum (n = 119) ORR (CR + PR) 54 66 ICON, International Collaborative Group for Ovarian Neoplasia; ORR, overall response rate; CR, complete response; PR, partial response Difference: 12% (-0.1 to 24.0); P = .06 Parmar MK, et al. Lancet. 2003;361: 99

100 ICON 4/AGO-OVAR 2.2: Progression-Free Survival
Hazard ratio: 0.76 (95% CI: ; P = .0004) Absolute difference at 1 year: 10% (95% CI: 4-15) 50% (paclitaxel/platinum) vs 40% ICON, International Collaborative Group for Ovarian Neoplasia; CI, confidence interval Patients at risk Paclitaxel + platinum Conventional treatment 392 179 52 25 17 410 157 45 17 7 Parmar MK, et al. Lancet. 2003;361: 100

101 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% ICON, International Collaborative Group for Ovarian Neoplasia; CI, confidence interval Patients at risk Paclitaxel + platinum Conventional treatment 392 306 167 96 43 18 410 295 150 68 33 11 Parmar MK, et al. Lancet. 2003;361: 101

102 ICON 4/AGO-OVAR 2.2: Previous Taxanes
Paclitaxel/Platinum Platinum PFS No P = .62 Yes OS ICON, International Collaborative Group for Ovarian Neoplasia No P = .49 Yes 0.5 1.0 1.5 2.0 Parmar MK, et al. Lancet. 2003;361: 102

103 AGO-OVAR 2.5 (GCIG): Gemcitabine/ Carboplatin vs Carboplatin
Randomized, phase III trial Patients with platinum-sensitive recurrent ovarian cancer ≥ 6 months out from initial platinum therapy (N = 356) Gemcitabine (1000 mg/m2) Days 1 and 8 Carboplatin (AUC = 4) Day 1 every 21 days x 6 cycles (n = 178) AGO-OVAR, AGO Ovarian Cancer Study Group; GCIG, Gynecologic Cancer Intergroup Carboplatin (AUC = 5) Day 1 every 21 days x 6 cycles (n = 178) Pfisterer J, et al. J Clin Oncol. 2006;24: 103

104 AGO-OVAR 2.5 (GCIG): Platinum-free Interval and Previous Treatment
Gemcitabine/Carboplatin (n = 178) Carboplatin (n = 178) Platinum-free interval, % 6-12 mos 39.9 > 12 mos 59.6 60.1 First‑line therapy, % Platinum taxane 70.2 71.3 Platinum nontaxane 28.7 27.5 Platinum monotherapy 1.1 AGO-OVAR, AGO Ovarian Cancer Study Group; GCIG, Gynecologic Cancer Intergroup Pfisterer J, et al. J Clin Oncol. 2006;24: 104

105 AGO-OVAR 2.5 (GCIG): Response Data
Parameter, % Gemcitabine/ Carboplatin (n = 178) Overall response (CR + PR)* 47.2 30.9 CR 14.6 6.2 PR 32.6 24.7 Stable disease 38.2 38.8 Progressive disease 7.9 16.3 AGO-OVAR, AGO Ovarian Cancer Study Group; GCIG, Gynecologic Cancer Intergroup *P = .0016 Pfisterer J, et al. J Clin Oncol. 2006;24: 105

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

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

108 Gemcitabine/Carboplatin (n = 178)
AGO-OVAR 2.5 (GCIG): Therapy After Recurrence/Progression Therapy, % Gemcitabine/Carboplatin (n = 178) Carboplatin (n = 178) Any therapy postrecurrence or progression 83.7 78.7 Chemotherapy 75.8 72.5 1 regimen 16.3 13.5 2 regimens 12.4 15.7 ≥ 3 regimens 9.6 10.7 Unspecified no. regimens 37.6 32.6 Hormonal/immunologic/ biologic therapy 19.7 18.0 Radiation 5.1 Other therapy—not specified 15.2 AGO-OVAR, AGO Ovarian Cancer Study Group; GCIG, Gynecologic Cancer Intergroup 108

109 Pegylated Liposomal Doxorubicin vs Topotecan: Phase III Study Design
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) PLD 50 mg/m2 IV every 4 weeks Stratification by platinum sensitivity and presence/absence of bulky disease PLD, pegylated liposomal doxorubicin Topotecan 1.5 mg/m2/d IV for 5 consecutive days every 3 weeks Gordon AN, et al. J Clin Oncol. 2001;19: 109

110 PLD vs Topotecan: Response Rates
Patient Group, % PLD Topotecan P Value Platinum sensitive (n = 220; PLD: 109; T: 111) 28 29 .964 Platinum refractory (n = 254; PLD: 130; T: 124) 12 7 .118 PLD, pegylated liposomal doxorubicin; T, topotecan Gordon AN, et al. J Clin Oncol. 2001;19: 110

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

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

113 GINECO Phase II Trial: Schema
Patients with advanced ovarian cancer N = 105 (104 received treatment) TFI ≥ 6 months PLD 30 mg/m2 + carboplatin AUC 5 every 4 weeks Selected patient characteristics ECOG PS 1-2: 47% 2 prior regimens: 39% Measurable disease: 57% GINECO, Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire; TFI, treatment-free interval; PLD, pegylated liposomal doxorubicin; AUC, area under the curve; ECOG, Eastern Cooperative Oncology Group; PS, performance status Ferrero JM, et al. Ann Oncol. 2007;18: 113

114 GINECO Phase II Trial: Results
Outcome PLD/Carboplatin (n = 104)* ORR (CR+ PR), % 63 CR, % 38 PFS, mos 9.4 OS, mos 32 *Median 6 cycles of therapy. GINECO, Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire; PLD, pegylated liposomal doxorubicin; CR, complete response; PFS, progression-free survival; OS, overall survival Ferrero JM, et al. Ann Oncol. 2007;18: 114

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 PFS, progression-free survival; OS, overall survival, PLD, pegylated liposomal doxorubicin 116

117 Chemosensitive Disease: Doublets
Paclitaxel/carboplatin Gemcitabine/carboplatin PLD/carboplatin PLD, pegylated liposomal doxorubicin 117

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

119 Yondelis™, trabectedin, ET-743
1996: PharmaMar starts clinical development of ET : Joint development of ET-743 by Johnson & Johnson Pharm R&D andPharmaMar Cluster of Ecteinascidia turbinata, a “sea squirt” or tunicate from the Caribbean Sea Yondelis: Tetrahydroisoquinoline alkaloid, MW=762.

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 R A N D O M I Z E Caelyx® 30 mg/m2 plus Yondelis® 1.1mg/m2 Every 3 weeks Advanced Recurrent Epithelial Ovarian Cancer One prior regimen Evaluable and measurable disease Platinum sensitive and resistant Caelyx® 50 mg/m2 q 4 wks Translational Research Pharmacokinetics Pharmacogenomics Pharmacoeconomics Quality of Life Circulating tumor cells Primary endpoint: OS Other endpoints: PFS, RR, Safety Accrual 7/11/2006: 374/650

122 33rd ESMO Congress Stockholm, 12-16 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: II 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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