1 / 24

THE ROLE OF IRINOTECAN (CPT-11) IN THE MANAGEMENT OF ADVANCED GASTRIC CANCER

THE ROLE OF IRINOTECAN (CPT-11) IN THE MANAGEMENT OF ADVANCED GASTRIC CANCER. Dr. Ayala Hubert Sharrett Institute of Oncology Hadassah Medical Center Jerusalem. GASTRIC CANCER. 600 new patients / year in Israel Associated with high case fatality rate

calvin-briggs
Download Presentation

THE ROLE OF IRINOTECAN (CPT-11) IN THE MANAGEMENT OF ADVANCED GASTRIC CANCER

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. THE ROLE OF IRINOTECAN (CPT-11) IN THE MANAGEMENT OF ADVANCED GASTRIC CANCER Dr. Ayala Hubert Sharrett Institute of Oncology Hadassah Medical Center Jerusalem

  2. GASTRIC CANCER • 600 new patients / year in Israel • Associated with high case fatality rate • Majority of patients will have locally advanced or • metastatic disease • Surgery offers the best prospect for long-term • disease control • Median survival for metastatic disease is less • than 1 year

  3. SYSTEMIC THERAPY FOR METASTATIC DISEASE What is the standard first line regimen? What is the best second line regimen?

  4. YOUR PREFERED REGIMEN • 5-FU • FAM (5FU-Adriamycin-Mitomycine C) • FAMTX (5FU-Adriamycin-Methotrexate) • FAB (5FU-Adriamycin-BCNU) • FUP / FAP (5FU-Cisplatin ± Adriamycin) • EAP (Etoposide-Adriamycin-Cisplatin) • EFL (Etoposide-5FU-Leucovorin) • ECF (Epirubicin-cisplatin-5FUciv) • EMF (Epirubicine-mitomycin C-5FUciv) • TC / TCF (Taxotere-cisplatin ±5FU) • 5FU-CPT-11 • Cisplatin-CPT-11 • Others?

  5. Chemotherapy in advanced gastric cancer: Phase II studies • First generation: 5FU-Mitomycin C FAM(5FU-Adriamycin-Mitomycin C) RR: 15 - 32%

  6. Chemotherapy in advanced gastric cancer: Phase II studies • Second generation: • FAMTX (5FU-Adriamycin-Methotrexate) • FAB(5FU-Adriamycin-BCNU) • FAP(5FU-Adriamycin-Cisplatin) • FUP(5FU-Cisplatin) • EAP (Etoposide-Adriamycin-Cisplatin) • ELF (Etoposide-5FU-Leucovorin) RR: 36 - 52%.

  7. Chemotherapy in advanced gastric cancer: Randomized studies • First versus Second generation: • EORTC (213 patients) (JCO,9,827,1991) • RR Time to progr. survival • FAM: 9% - 29 wks. • FAMTX: 41% - 42 wks. • KIM N.K. (324 patients) (Cancer 71, 3813, 1993) • FU: 26% 9 wks. 30 wks. • FAM: 25% 12 wks. 29 wks. • FUP: 51% 21 wks. 37 wks.

  8. Chemotherapy in advanced gastric cancer: Randomized studies • Second generation regimens: EORTC-AIO (245 patients)(JCO, 18: 2648, 2000) RRSurvival 5FU-Adriamycin-Methotrexate :12%6.7 months. 5FU-Cisplatin : 20% 7.2 months. Etoposide-5FU-Leucovorin : 9% 7.2 months.

  9. How to go further?

  10. Chemotherapy in advanced gastric cancer: New issues • Intensive weekly regimen with growth factors (PELF, Italy) • Revisited old drug: • 5-FU in protracted continuous infusion • High doses 5-FU. • Oral fluoropyrimidines (UFT, Capecitabine, S-1) • New drugs: • CPT-11 • Taxanes • Oxaliplatin • Others • New drugs combined with older regimens

  11. Main chemotherapeutic agents available • AGENTS • Cisplatin • Anthracyclines • 5FU • Mitomycin C • Etoposide • Methotrexate • BCNU • CPT-11 • Taxanes • Oxaliplatin

  12. Camptothecin: Origin 1966: DISCOVERY OF THE ANTITUMOR ACTIVITY OF CAMPTOTHECIN (CPT), PLANT ALKALOID OF THE CAMPTOTHECA ACUMINATA TREE 1983: SYNTHESIS OF CPT-11: WATER-SOLUBLE SEMISYNTHETIC ANALOG OF CPT H H C2H5 H H H O O HO H A B C A B C A B C N N O N N O N N O N D D D E E E N HO O HO HO O O CPT CPT-11 SN-38 (IRINOTECAN, HCl) ACTIVE METABOLITE IN VIVO

  13. CPT-11 : A Novel Anticancer Agent • A NEW MECHANISM OF ACTION: • TOPOISOMERASE 1 INHIBITION • NO PLEIOTROPIC RESISTANCE (MDR) PHENOMENA • BROAD SPECTRUM OF ACTIVITY

  14. Topoisomerase 1 : How it Works - 1 SUPERCOILED DNA TOPOISOMERASE 1 BINDING OF TOPO 1 ON ONE DNA STRAND

  15. Irinotecan : Mechanism of Topoisomerase I Inhibition CPT-11 CPT-11 BINDING TO THE TOPO I-DNA COMPLEX WITHOUT AFFECTING THE CLEAVAGE REACTION Before strand passage After strand passage STABILIZATION OF CLEAVABLE COMPLEX = INHIBITION OF RELIGATION STEP

  16. Irinotecan : Consequenses of Topoisomerase I Inhibition “THE FORK COLLISION MODEL” COLLISION BETWEEN ADVANCING REPLICATION FORK AND STABILIZED TOPO 1-DNA/CPT-11 ADDUCT

  17. Irinotecan : Mechanism of Cytotoxicity REPLICATION FORK ARREST AND IRREVERSIBLE DNA BREAKAGE CELL CYCLE INTERRUPTION CELL DEATH

  18. Study Treatment (mg/m2) Eval. Pts RR(%) Med Surv(mo) Shirao (’97) CPT-1170,d1,15 + CDDP80,d1 24 42 NR Boku (’97) CPT-1170,d1,15 + CDDP80,d1 44 48 10.1 Ajani (2001) CPT-1165,qw + CDDP30qw 38 58 9 Pozzo (ASCO ’01) CPT-11200,d1+ CDDP60,d1 CPT-1180+ FA + 5FU2000/22h 7274 2834 6.910.7 Grau (ASCO ’01) CPT-11300, + Mitomycin10 8 50 9 Findlay (ASCO ’01) CPT-11125qw+ FA + 5FU500qw 19 23 6.3 Irinotecan based combinations as 1st line therapy in gastric cancer CPT-11=irinotecan, CDDP=cisplatin, FA=folinic acid

  19. CPT-11/CDDP OR CPT-11/5-FU Phase II/III Study Phase II Phase III CPT-11 CDDP A N A L Y S E CPT-11 5-FU (AIO) A N A L Y S E R R CPT-11 5-FU (AIO) CDDP 5-FU Accrualongoing

  20. CPT-11/CDDP OR CPT-11/5-FU Phase II Study Treated population, confirmed responses

  21. CPT-11/CDDP OR CPT-11/5-FU Phase II Study Safety

  22. CPT-11/CDDP OR CPT-11/5-FU Phase II Study CPT-11 + 5-FU/FA is active with promising TTP and Survival combined with a very good safety profile Phase III CPT-11 + 5-FU vs CDDP+ 5-FU ongoing MST: 6.8 vs 10.7 mos 1YS: 24.8% vs 44.2% RR: 28% vs 42% Pozzo C. ASCO 2001 / Abs. 531 PD Randomized Phase II 1st line

  23. CPT-11 based combinations as 2nd line therapy in gastric cancer • Baker (ASCO 2001) Campto 50mg/m2 + cisplatin 30mg/m2 d1,8,15,22 q6w. No. Of patientsResponse Rate Previous Treatment 29 31% Cisplatin, taxanas, etoposide, 5-FU

  24. Systemic therapy for metastatic disease Conclusions • Gastric cancer is a chemosensitive tumor. • CPT-11 is a promising agent in gastric cancer and could already be considered as an additional tool in our therapeutic arsenal. • Ongoing phase III randomized trial should allow us to establish the role of this agents in the systemic treatment of gastric cancer. • In the future, we may consider CPT-11 based combination therapy as neo-adjuvant and adjuvant treatments.

More Related