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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
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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 • 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
SYSTEMIC THERAPY FOR METASTATIC DISEASE What is the standard first line regimen? What is the best second line regimen?
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?
Chemotherapy in advanced gastric cancer: Phase II studies • First generation: 5FU-Mitomycin C FAM(5FU-Adriamycin-Mitomycin C) RR: 15 - 32%
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%.
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.
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.
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
Main chemotherapeutic agents available • AGENTS • Cisplatin • Anthracyclines • 5FU • Mitomycin C • Etoposide • Methotrexate • BCNU • CPT-11 • Taxanes • Oxaliplatin
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
CPT-11 : A Novel Anticancer Agent • A NEW MECHANISM OF ACTION: • TOPOISOMERASE 1 INHIBITION • NO PLEIOTROPIC RESISTANCE (MDR) PHENOMENA • BROAD SPECTRUM OF ACTIVITY
Topoisomerase 1 : How it Works - 1 SUPERCOILED DNA TOPOISOMERASE 1 BINDING OF TOPO 1 ON ONE DNA STRAND
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
Irinotecan : Consequenses of Topoisomerase I Inhibition “THE FORK COLLISION MODEL” COLLISION BETWEEN ADVANCING REPLICATION FORK AND STABILIZED TOPO 1-DNA/CPT-11 ADDUCT
Irinotecan : Mechanism of Cytotoxicity REPLICATION FORK ARREST AND IRREVERSIBLE DNA BREAKAGE CELL CYCLE INTERRUPTION CELL DEATH
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
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
CPT-11/CDDP OR CPT-11/5-FU Phase II Study Treated population, confirmed responses
CPT-11/CDDP OR CPT-11/5-FU Phase II Study Safety
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
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
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.