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Capecitabine: the new standard chemotherapy in advanced gastric cancer?

Werner Scheithauer Professor of Internal Medicine, Cancer Center at the Vienna University Hospital, Austria. Capecitabine: the new standard chemotherapy in advanced gastric cancer?. Werner Scheithauer University Hospital Vienna, Austria. Gastric cancer: a global disease.

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Capecitabine: the new standard chemotherapy in advanced gastric cancer?

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  1. Werner ScheithauerProfessor of Internal Medicine,Cancer Center at the Vienna University Hospital, Austria

  2. Capecitabine: the new standard chemotherapy in advanced gastric cancer? Werner Scheithauer University HospitalVienna, Austria

  3. Gastric cancer: a global disease Second most common cause of cancer mortalityWorldwide: 934,000 new cases and 700,000 deaths/year Gastric cancer incidence 20/100,000 10 to 20/100,000 <10/100,000 www.cancer.gov Kamangar F, et al. J Clin Oncol 2006;24:2137–50

  4. Stage at diagnosis Japan1 17% Resectable 15% 68% Locally advanced Metastatic 10–15% 25–30% Western countries2 25–30% Resectable 30–35% Locally advanced Metastatic Unstaged 1http://www.ncc.go.jp/en/ncch/annrep/20002sanofi-aventis Internal Epidemiology Data

  5. Palliative chemotherapy for advanced gastric cancer (AGC) • Non-measurable lesions • Variable study inclusion criteria • Heterogeneous patient populations • Inadequate number of patients • Response rate rather than survival

  6. Chemotherapy improves survival in metastatic gastric cancer (MGC) 12 10 8 6 4 2 0 Chemotherapy Best supportive care (BSC) Median OS (months) FAMTX1 (n=30) BSC1 (n=10) FEMTX2 (n=21) BSC2 (n=20) ELF3 (n=31) BSC3 (n=30) CLF4 (n=51) BSC4 (n=52) OS = overall survival; 5-FU = 5-fluorouracilFAMTX = 5-FU, doxorubicin, methotrexateFEMTX = 5-FU, epirubicin, methotrexateELF = etoposide, leucovorin, 5-FUCLF = cisplatin, leucovorin, 5-FU 1Murad AM, et al. Cancer 1993;72:37–41; 2Pyrhonen S, et al. Br J Cancer 1995;71:587–91; 3Glimelius B, et al. Ann Oncol 1997;8:163–8; 4Scheithauer W, et al. Second International Conference on Biology, Prevention and Treatment of GI Malignancy, Koln, Germany, 1995;68 (Abstract)

  7. Survival has improvedwith conventional regimens BSC1 4 months 5-FU monotherapy2,3 7 months FAM2,4 6–7 months FAMTX5–7 6–7 months FP2,3,6 and ECF5,8,9 7–9 months Median OS FAM = 5-FU, doxorubicin, mitomycin CFP = 5-FU, cisplatin; ECF = epirubicin, cisplatin, 5-FU 1Wagner AO, et al.Cochrane Database Syst Rev 2005;2:CD004064; 2Kim NK, et al. Cancer 1993;71:3813–183Ohtsu A, et al. J Clin Oncol 2003;21:54–9; 4Wils JA, et al. J Clin Oncol 1991;9:827–31 5Waters JS, et al. Br J Cancer 1999;80:269–72; 6Vanhoefer U, et al. J Clin Oncol 2000;18:2648–577Cocconi G, et al. Ann Oncol 2003;14:1258–63; 8Ross P, et al. J Clin Oncol 2002;20:1996–20049Webb A, et al. J Clin Oncol 1997;15:261–7

  8. Chemotherapy in patients with MGC • Conventional regimens prolong survival and achieve acceptable response rates BUT . . . • Median OS still <12 months • Complete response rate is low • Response duration is short • Inconvenient drug administration • Regimens may be toxic • No standard treatment • all options have similar survival outcomes and safety profiles • FP/ECF most common reference therapy in Europe There is a clear need for new active treatments

  9. New treatment options for AGC aim to improve survival Epirubicin Cisplatin Fluorouracil

  10. New treatment options for AGC aim to improve survival Epirubicin? Oxaliplatin Capecitabine, S-1 • Paclitaxel • Irinotecan • Docetaxel

  11. Capecitabine: the new standard chemotherapy in AGC?

  12. Can XP improve PFS versus FP?International phase III study in MGC (ML17032) RANDO MIS ATION XP Capecitabine 1,000mg/m2 b.i.d. day 114 cisplatin 80mg/m2 day 1 every 3 weeks n=156 AGC and/orMGC (n=316) FP 5-FU c.i. 800mg/m2 day 15 cisplatin 80mg/m2 day 1 every 3 weeks n=160 • Primary endpoint: non-inferiority in PFS Kang Y-K, et al. Ann Oncol2006;17(Suppl. 6):vi19 (Abstract O-003) PFS = progression-free survival; b.i.d. = twice dailyc.i. = continuous infusion

  13. Why should XP be moreeffective than FP? • FP is a reference regimen for AGC • Capecitabine monotherapy is effective and well tolerated in AGC1–4 • ORR: 19–34%; SD: 30–56% • median TTP: 2.8–4.8 months • median OS: 8.1–10.0 months • XP was effective and well tolerated in phase II study5 • ORR: 55%; SD: 16.7% • median TTP: 5.8 months • median OS: 10.1 months 1Hong YS, et al. Ann Oncol 2004;15:1344–72Leon-Rodriguez E, et al. Ann Oncol2002;13(Suppl. 5):191 (Abstract 708)3Sakamoto J, et al. Anticancer Drugs 2006;17:231–64Koizumi W, et al. Oncology 2003;64:232–6 5Kim TW, et al. Ann Oncol 2002;13:1893–8 ORR = overall response rateSD = stable diseaseTTP = time to progression

  14. XP (n=139) FP (n=137) Primary endpoint met:XP improves PFS versus FP (HR=0.81) 1.0 0.8 0.6 0.4 0.2 0 HR=0.81 (95% CI: 0.63–1.04) Compared to HR upper limit 1.25, p=0.0008 Estimated probability 5.0 5.6 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Months Per protocol HR = hazard ratio; CI = confidence interval Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)

  15. PFS: robust results in subgroups Favours XP Favours FP PP population Prior chemotherapy No prior chemotherapy Male Female 65 years >65 years KPS <80% KPS 80% 1 metastatic site 2 metastatic sites 276 28 248 185 91 238 38 30 246 98 178 0.2 0.6 1.0 1.4 1.8 2.2 2.6 HR (95% CI) Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003) KPS = Karnofsky performance status

  16. XP versus FP also showsnon-inferiority in OS (HR=0.85) 1.0 0.8 0.6 0.4 0.2 0 XP (n=139) FP (n=137) HR=0.85 (95% CI: 0.64–1.13) Compared to HR upper limit 1.25, p=0.0076 Estimated probability 9.3 10.5 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 Months Per protocol Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)

  17. Superior response ratewith XP versus FP Intent-to-treat (ITT), investigators’ assessment RECIST = Response Evaluation Criteria in Solid TumoursCR = complete response PR = partial responsePD = progressive disease Kang Y-K, et al. Ann Oncol2006;17(Suppl. 6):vi19 (Abstract O-003)

  18. Similar incidence of grade 3/4 adverse events: XP versus FP Grade 3/4 adverse events (AEs) 60 50 40 30 20 10 0 XP (n=156) FP (n=155) Patients (%) HFS Nausea/vomiting Diarrhoea Stomatitis Febrileneutropenia Leucopenia Neutropenia Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003) HFS = hand-foot syndrome

  19. XP: a potential new standardchemotherapy in AGC • As effective as FP • Improved tolerability • Avoids inconvenience and complicationsassociated with infused 5-FU

  20. Multicentre phase III REAL-2 trial:can capecitabine improve OS versus 5-FU? Locally advanced or metastatic oesophagogastric cancer (n=1,002) R A N D O M I S A T I O N Epirubicin Cisplatin Fluorouracil Epirubicin Oxaliplatin Fluorouracil Epirubicin Cisplatin Capecitabine Epirubicin OxaliplatinCapecitabine • Epirubicin 50mg/m2 day 1 • Cisplatin 60mg/m2 vs oxaliplatin 130mg/m2day 1 • 5-FU 200mg/m2c.i. daily vs capecitabine 500–625mg/m2b.i.d. p.o. daily • For 24 weeks: eight cycles every 3 weeks p.o. = orally Cunningham D, et al. N Engl J Med 2008;358:36–46

  21. Why should EOC be moreeffective than ECF? • Capecitabine is effective and well tolerated in AGC • XP has become a new reference regimen for AGC • Oxaliplatin has shown promising activity in phase II trials EOC = epirubicin, oxaliplatin, capecitabineFOLFOX = 5-FU, leucovorin, oxaliplatin; FU(inf)/Ox = 5-FU infusion, oxaliplatin FUFOX = 5-FU, oxaliplatin; FLO = 5-FU, leucovorin, oxaliplatin

  22. REAL-2: can capecitabine replace 5-FU, can oxaliplatin replace cisplatin? • In combination treatments of oesophagogastric cancer • can capecitabine replace 5-FU? • can oxaliplatin replace cisplatin? • Primary endpoint of non-inferiority in OS for capecitabine versus 5-FU, oxaliplatin versus cisplatin (PP population) • based on ECF 1-year survival of 35%, 1,000 patients(250 per arm) needed to show non-inferiority (80% power, one-sided a=0.05) • upper limit of HR for experimental arms compared with standard arms should be <1.23 • secondary endpoint: superiority in OS among the four regimens (intent-to-treat) Cunningham D, et al. N Engl J Med 2008;358:36–46

  23. REAL-2: primary endpoint met – non-inferior OS with capecitabine versus 5-FU 1.0 0.8 0.6 0.4 0.2 0 Capecitabine combinations (n=480) 5-FU combinations (n=484) Estimated probability HR=0.86 (95% CI: 0.80–0.99) 9.6 10.9 0 12 24 36 48 60 72 Months Per protocol Cunningham D, et al. N Engl J Med 2008;358:36–46

  24. Similar OS with oxaliplatinversus cisplatin 1.0 0.8 0.6 0.4 0.2 0 Oxaliplatin combinations (n=474) Cisplatin combinations (n=490) Estimated probability HR=0.92 (95% CI: 0.8–1.1) 10.0 10.4 0 12 24 36 48 60 72 Months Per protocol Cunningham D, et al. N Engl J Med 2008;358:36–46

  25. Superior OS with EOC versus ECF Median OS (months) ECF (n=249) 9.9 EOC (n=239) 11.2 1.0 0.8 0.6 0.4 0.2 0 Estimated probability HR=0.80 (95% CI: 0.66–0.97)Log-rank p=0.02 0 12 24 36 48 60 72 Months Intent-to-treat Cunningham D, et al. N Engl J Med 2008;358:36–46

  26. Capecitabine-based regimensare well tolerated 60 50 40 30 20 10 0 Grade 3/4 AEs ECF (n=236) ECC (n=241) EOF (n=235) EOC (n=239) * * Patients (%) * * * * * HFS Nausea/vomiting Diarrhoea Stomatitis Febrileneutropenia Neutropenia Thromboembolicevents *p<0.05compared with ECF Cunningham D, et al. N Engl J Med 2008;358:36–46 Starling N, et al. Proc ASCO GI 2007 (Abstract 74)

  27. REAL-2 versus ML17032: consistent efficacy with capecitabine regimens • Response evaluated every 3 months in REAL-2,1every 1.5 months in ML170322 • In REAL-2,1 maximum treatment duration: 6 months 1Cunningham D, et al. N Engl J Med 2008;358:36–46 2Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003) * Intent-to-treat *

  28. Capecitabine plus platinum-based chemotherapy approved in Europe BSC1 FAMTX2 FP3 IF4 ECF5 EOF5 DCF3 XP6 ECx5 EOx5 0 2 4 6 8 10 12 Months IF = irinotecan + 5-FU 1Murad AM, et al. Cancer 1993;72:37–41 2Vanhoefer U, et al. J Clin Oncol 2000;18:2648–57; 3Van Cutsem E, et al. J Clin Oncol 2006;24:4991–7 4Dank M, et al. J Clin Oncol 2005;23(Suppl. 16S):403s (Abstract 4003);5Cunningham D, et al. N Engl J Med 2008;358:36–46; 6Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)

  29. Putting the evidenceinto practice: case study • 45-year-old male; ECOG PS: 0 • Chief complaint: epigastric pain • No dysphagia or weight loss • Gastroscopy: largeulceroinfiltrative lesionencircling the antral lumen • Biopsy: tubularadenocarcinoma, M/D ECOG = Eastern Cooperative Oncology Group; PS = performance status

  30. Abdomen and pelvis computed tomography (CT)

  31. Patient received EOC chemotherapy Before treatment After cycle 2: PR After cycle 4: ++PR After cycle 8: CR? 10 November 2004 22 August 2004 01 October 2004 07 February 2005

  32. Carcinoembryonic antigen (CEA) levels 18 16 14 12 10 8 6 4 2 0 CEA (ng/mL) Upper limit of normal August 04 October 04 January 05 February 05 December 04 November 04 September 04

  33. Patient received EOC chemotherapy Before treatment After cycle 7 Biopsy: no cancer

  34. Patient was in remission for9 months without chemotherapy • Chemotherapy stopped in February 2005 • Patient followed-up every 3 months • abdomen and pelvis CT • gastrofiberscopy (GFS) • CEA

  35. CT scans 22 September 2006revealed disease progression

  36. Patient receivedsecond-line chemotherapy • Re-induction of EOC • four cycles: SD (for 4 months) • Irinotecan 150mg/m2 day 1, 14 plus mitomycin C 8mg/m2 day 1 every 4 weeks1,2 • four cycles: SD (for 2 months) • Docetaxel 75mg/m2 every 3 weeks3 • three cycles: PD 1Giuliani F, et al. Am J Clin Oncol 2005;28:581–5 2Bamias A, et al. J Chemother 2003;15:275–81 3Lee JL, et al. Cancer Chemother Pharmacol 2008;61:631–7

  37. 4 December 2007: patient with PD,alive no longer receiving treatment CEA: 20.9ng/mL

  38. What other capecitabine-basedoptions are available?

  39. Integrating docetaxel in the treatmentof AGC: high efficacy with capecitabine 1Kang Y-K, et al. J Clin Oncol 2004;22(Suppl. 14S):329s (Abstract 4066) 2Van Cutsem E, et al. J Clin Oncol 2006;24:4991–7

  40. Capecitabine: the backbone of future standards in gastric cancer HER2 = human epidermal growth factor receptor 2; AOGC = advanced oesophagogastric cancerXELOX = capecitabine + oxaliplatin

  41. Conclusions • Capecitabine is effective and well tolerated • can replace 5-FU in current treatment regimensfor AGC • Further data will support the use of capecitabine in this indication • Capecitabine is an effective, safe and convenient oral therapy for gastric cancer

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