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

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Chemioterapia raka jajnika Radosaw Mdry Klinika Onkologii Uniwersytety Medycznego im. K. Marcinkowskiego w Poznaniu Slide 2 TIME LINE OF ADVANCES IN OVARIAN CANCER THERAPY 1960 1970 1980 1990 2000 CISPLATIN/ALKYLATOR COMBINATIONS COMBINATION WITH SIGNAL REGULATORS PACLITAXEL/ CARBOPLATIN ALKYLATORS CISPLATIN 5 YR SURVIVAL ADVANCED (III/IV) DISEASE 40%35%15% 0%0% 19601970198019902000 Slide 3 Slide 4 I linia Slide 5 GOG111 McGuire et al, N Engl J Med 334: 1-6, 1996 +5 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 Slide 6 OV10 Piccart et al, J Natl Cancer Inst 92: 699-708, 2000 +4 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 Slide 7 GOG132 Muggia et al, J Clin Oncol 18: 106-115, 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 Slide 8 ICON3 ICON Group, Lancet 360: 505-515, 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 Slide 9 GOG 158 Ozols et al, J Clin Oncol 21: 3194-3200, 2003 N = 792, FIGO III,Slide 10 OVAR-3 AGO Du Bois et al, J Natl Cancer Inst 95: 1320-2330, 2003 N = 798, FIGO IIB-IV,Slide 11 Slide 12 Slide 13 SCOTR0C Vasey et al, J Natl Cancer Inst 96: 1682-1691, 2004 HR 0,97 HR 1,13 N = 1077, FIGO IC-IV Carboplatin/ Paclitaxel vs. Carboplatin/Docetaxel Slide 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 Slide 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. Slide 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 26, 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 Slide 17 AGO GINECO Du Bois et al, J Clin Oncol 24: 1127-1135, 2006 N = 1282, FIGO IIB-IV Carboplatin/ Paclitaxel vs. Carboplatin/Paclitaxel/Epirubicin HR 0,95 HR 0,93 Slide 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: 1036-1045, 2006 Slide 19 GOG 182 / ICON 5 ASCO 2006 Slide 20 GOG 182 / ICON 5 ASCO 2006 Slide 21 GOG 182 / ICON 5 ASCO 2006 Slide 22 GOG 182 / ICON 5 ASCO 2006 Slide 23 GOG 182 / ICON 5 ASCO 2006 Slide 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 Slide 25 AGO OVAR9 A phase III study of paclitaxel, carboplatin, and gemcitabine in previously untreated patients with epithelial ovarian cancer FIGO stage ICIV (AGO-OVAR protocol OVAR-9) A. du Bois 2008 Slide 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 1 724 pts Wicej powika hematologicznych w ramieniu TCG Brak zysku z chth 3-lekowej Slide 27 Slide 28 Slide 29 Slide 30 W trakcie bada Slide 31 I linia - nowo 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 Slide 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 miednic CA125/CEA 25 Follow up = 4,8 lat Slide 33 Late-Breaker Presentation Vergote I i wsp - Neoadjuvant chemotherapy FIGO IIIC-IV 718 pts Operacja pierwotna 6 x chth z platyn 3x chth Operacja odroczona 3 x chth Slide 34 Late-Breaker Presentation Vergote I i wsp - Neoadjuvant chemotherapy Slide 35 Operacja pierwotna Operacja odroczona miertelno 28 dni 2,7%0,6% Posocznica8%2% Krwawienie 3/47%4% Slide 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 Slide 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 2008. Abstract 5536. 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 Slide 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 2008. Abstract 5536. 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. Slide 39 Gordon A, et al. ASCO 2008. Abstract 5536. 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 Slide 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 Slide 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 2008. Abstract 5506. Slide 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 2008. Abstract 5506. Slide 43