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New horizons in gastric and pancreatic cancer

New horizons in gastric and pancreatic cancer. Professor Wolff Schmiegel Ruhr University Bochum, Germany. Gastric cancer: a global disease. Second most common cause of cancer mortality Worldwide: 934 000 new cases and 700 000 deaths/year. Gastric cancer incidence.  20 / 100 000.

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New horizons in gastric and pancreatic cancer

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  1. New horizons in gastricand pancreatic cancer Professor Wolff SchmiegelRuhr UniversityBochum, Germany

  2. Gastric cancer: a global disease Second most common cause of cancer mortalityWorldwide: 934000 new cases and 700000 deaths/year Gastric cancer incidence 20/100000 10 20/100000 www.cancer.gov Kamangar F et al. J Clin Oncol 2006;24:2137–50 <10/100000

  3. Advanced gastric cancer:chemotherapy prolongs survival CTX BSC FavoursCTX FavoursBSC • No standard regimen established worldwide n Protocol Murad 19931 30 10 FAMTX 21 20 FEMTX Pyrhönen 19952 52 51 ELF Scheithauer 19953 Total (95% CI)4 103 81 0.2 0.5 1.0 2.0 5.0 HR 1. Murad AM et al. Cancer 1993;72:37–41 2. Pyrhönen S et al. Br J Cancer 1995;71:587–91 3. Scheithauer W et al. Ann Hematol 1995;73:A181 4. Wagner AD et al. J Clin Oncol 2006;24:2903–9

  4. Cisplatin based combinations – Randomised Phase III trials

  5. Oxaliplatin based combinations –Phase II trials

  6. Multicentre Phase III REAL-2 trial:Xeloda vs 5-FU, oxaliplatin vs cisplatin Locally advanced or metastatic oesophagogastric cancer (n=1002) R A N D O M I S A T I O N Epirubicin Cisplatin Fluorouracil Epirubicin Oxaliplatin Fluorouracil Epirubicin Cisplatin Xeloda Epirubicin OxaliplatinXeloda • Epirubicin 50mg/m2 day 1 • Cisplatin 60mg/m2 vs oxaliplatin 130mg/m2day 1 • 5-FU 200mg/m2 ci daily vs Xeloda 500–625mg/m2bid po daily • For 24 weeks: eight cycles every 3 weeks Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017)

  7. REAL-2: survival by regimen ECF vs EOX (ITT) Median OS (months) ECF (n=249): 9.9 EOX (n=239): 11.2* Estimated probability 1.0 0.8 0.6 HR=0.80 (95% CI: 0.66–0.97)Log-rank p=0.02 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months Intent-to-treat Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017)

  8. cisplatin fluorouracil New treatment options for AGC epirubicin

  9. oxaliplatin Xeloda, S-1 New treatment options for AGC epirubicin ? • Paclitaxel • Irinotecan • Docetaxel

  10. Irinotecan vs cisplatin incombination with 5-FU: similar efficacy Dank M et al. J Clin Oncol 2005;23(Suppl. 16S) (Abst 4003)

  11. Irinotecan vs cisplatin incombination with 5-FU: safety Patients (%) Grade 3/4 AEs IF (n=167) CF (n=166) Nausea/vomiting Diarrhoea Stomatitis Febrileneutropenia Neutropenia Dank M et al. J Clin Oncol 2005;23(Suppl. 16S) (Abst 4003)

  12. Addition of docetaxel to 5-FUand cisplatin: prolonged TTP Estimated probability ORR (%) 37 25 100 DCF (n=221) CF (n=224) 75 50 HR=1.47 (95% CI: 1.19–1.82) Log-rank p<0.001 25 3.7 5.6 0 0 3 6 9 12 15 18 21 24 Months Van Cutsem E et al. J Clin Oncol 2006;24:4991–7

  13. Addition of docetaxel to 5-FUand cisplatin: increased toxicity Patients (%) Grade 3/4 AEs DCF (n=221) CF (n=224) * * * * Nausea/vomiting Anaemia Diarrhoea Stomatitis Febrileneutropenia Neutropenia Neurosensory *p<0.05 Van Cutsem E et al. J Clin Oncol 2006;24:4991–7

  14. Progress so far in AGC:OS with first-line regimens BSC1 FAMTX2 FAMTX3 CF4 CF5 ECF3 IF4 DCF5 Months 1. Murad AM et al. Cancer 1993;72:37–41; 2. Vanhoefer U et al. J Clin Oncol 2000;18:2648–57 3. Waters JS et al. Br J Cancer 1999;80:269–72; 4. Dank M et al. J Clin Oncol 2005;23(Suppl. 16S) (Abst 4003); 5. Van Cutsem E et al. J Clin Oncol 2006;24:4991–7

  15. New horizons in gastric cancer • Gastric cancer is the fourth most commonly diagnosed cancer • Combination chemotherapy yields a significant advantage in the management of AGC • No single regimen has emerged or has beenaccepted as clearly superior • Complicated regimens • Slow progress in clinical research • few, underpowered trials • Novel effective, safe and simple regimens needed

  16. AGC – The future "...and if you‘re not completely confused by now, stay tuned for more exciting data to come" Dr Chau, UK Dr Kang, Korea

  17. Pancreatic cancer: a deadly disease • The most deadly GI cancer • 230000 new cases diagnosed worldwide every year • 227000 deaths per year • Incidence is rising • Aetiology largely unknown • family aggregation • cigarette smoking

  18. Pancreatic cancer is difficult to treat • Screening or early detection methods not developed • detected mainly at advanced stage • Only 10–20% are resectable • greater chance of cure in patients with ampullary, duodenal and neuroendocrine tumours • Debilitating disease • need to also improve QoL and symptoms

  19. 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 Pancreatic cancer –Survival according to stage Survival distribution function Locally advanced 9.1 months p=0.001 Metastatic5.4 months Months Poplin E et al. J Clin Oncol 2006;24(Suppl. 18S) (Abst LBA4004)

  20. Gemcitabine monotherapy – Historical standard in first-line: registration study Patients surviving (%) Median survival GEM 5.7 Mo 5-FU 4.4 Mo Clinical benefit GEM 23.8% 5-FU 4.5% 100 5-FU 80 GEM 60 40 20 Log-rank p=0.026 0 0 4 8 12 16 20 Burris H et al. J Clin Oncol 1997;15:2403–13 Survival time (months)

  21. High unmet clinical needs in pancreatic cancer • Few effective therapies • 23% increase in OS with gemcitabine vs 5-FU • Most deadly cancer • majority of patients will die within 5–6 months from diagnosis • OS is shortest of any solid tumour • 5-year survival: 3–4% • Targeted therapy may provide a survival advantage

  22. UK NCRI GEMCAP: Xeloda + gemcitabine in advanced pancreatic cancer RANDO MIS ATION GEMCAP Gemcitabine 1000mg/m2 d1, 8, 15 q4w Xeloda 830mg/m2 bid d121 q4w Advanced pancreatic cancer n=508 Gemcitabine 1000mg/m2 weekly x7 q8w, thereafter weekly x3q4w • Primary endpoint: OS Cunningham D et al. Eur J Cancer 2005;(Suppl. 3):4 (Abst PS11)

  23. GEMCAP in advanced pancreatic cancer: improved OS Estimated probability 1-year survival (%) GEMCAP (n=267) 26 Gemcitabine (n=266) 19 100 75 50 HR=0.80 (95% CI: 0.65–0.98) Log-rank p=0.026 25 6.0 7.4 0 0 3 6 9 12 15 18 21 24 27 Months Cunningham D et al. Eur J Cancer 2005;(Suppl. 3):4 (Abst PS11)

  24. GEMCAP is well tolerated GEMCAP (n=145) Gemcitabine (n=153) Grade 3/4 AEs Patients (%) 50 40 30 20 10 0 HFS Nausea Anaemia Asthenia Vomiting Diarrhoea Neutropenia Thrombocytopenia Cunningham D et al. Eur J Cancer 2005;(Suppl. 3):4 (Abst PS11)

  25. Xeloda-containing combinations:response rates and survival 1. Heinemann V et al. Eur J Cancer 2005;(Suppl. 3):209 (Abst 735) 2. Javle MM et al. Ann Oncol 2006;17(Suppl. 9):ix310 (Abst 1079PD)

  26. Chemotherapy for pancreatic cancer: towards improved survival with Xeloda *p<0.05 1. Cunningham D et al. Eur J Cancer 2005;(Suppl. 3):4 (Abst PS11)2. Herrmann R et al. Eur J Cancer 2005;(Suppl. 3):203 (Abst 717)3. Oettle H et al. Ann Oncol 2005;16:1639–454. Heinemann V et al. J Clin Oncol 2006;24:3946–525. Louvet C et al. J Clin Oncol 2005;23:3509–16

  27. Anti-EGFR (EMD55900) combined treatment in pancreatic cancer – Phase I Cohort A Cohort B Cohort C Survival probability 1.0 0.8 0.6 0.4 0.2 0.0 20 40 60 80 100 Weeks Schmiegel W et al. Proc Natl Acad Sci USA 1997;94:12622–6

  28. Targeted therapies for pancreatic cancer: Tarceva prolongs OS *p<0.05NS: not significant 1. Moore MJ et al. J Clin Oncol 2007 (In press)2. Van Cutsem E et al. J Clin Oncol 2004;22:1430–8 3. Shapiro J et al. J Clin Oncol 2005;23(Suppl. 16S) (Abst 4012) 4. Bramhall SR et al. Br J Cancer 2002;87:161–7

  29. GEM/Tarceva:relation between rash and survival OS 1-year survival (months) (%)Grade 0 (n=74) 5.28 10 Grade 1 (n=108) 5.75 11 Grade 2 (n=103) 10.51 43 Estimated probability 1.0 0.8 0.6 0.4 0.2 0 HR (rash)=0.71, p<0.0001 0 5 10 15 20 Months Data on file, OSI Pharmaceuticals Inc.

  30. AVITA: Gem + Tarceva ± Avastin forfirst-line advanced pancreatic cancer RANDO MIS ATION Tarceva gemcitabine Avastin PD* Previously untreated metastatic pancreatic cancer (n=600) Tarceva gemcitabine placebo PD* • Primary endpoint: OS *No cross-over will be permitted

  31. New horizons in pancreatic cancer • Many trials failed • Poor survival and short response duration • Limited treatment options • Toxicity with most active therapies • Novel, more effective and safer treatments needed • Targeted therapies, such as Tarceva, provide a survival advantage

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