1 / 58

Advances in panceratic cancer management

Advances in panceratic cancer management. Christophe Louvet Hôpital Saint-Antoine Paris, France. Beyrouth, 14/11/08. Landscape of Pancreatic Cancer. More than 210 000 new cases per year around the world (2000) 2.1% of all cancers 10% of GI cancers + 1.7% / yr (men) ; + 2.1% / yr (women)

dimaia
Download Presentation

Advances in panceratic cancer management

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. Advances in panceratic cancer management Christophe Louvet Hôpital Saint-Antoine Paris, France. Beyrouth, 14/11/08

  2. Landscape of Pancreatic Cancer • More than 210 000 new cases per year around the world (2000) • 2.1% of all cancers • 10% of GI cancers • + 1.7% / yr (men) ; + 2.1% / yr (women) • 6th cause of cancer-related death • Pancreatic cancer mortality almost equal to incidence • 5-yr overall survival : 4%

  3. Landscape of Pancreatic Cancer • p53 mutation (70%) • K-ras mutation (90%) • p16 mutation (80%) • EGF-r overexpression (> 60%) • VEGF overexpression • Loss of somatostatin antiproliferative effect (loss of SSTR2 receptor)

  4. Definitive need for a pathological diagnosis Pancreatic mass : sometimes different from pancreatic tumor Pancreatic tumor : sometimes different from pancreatic adenocarcinoma

  5. Pancreatic cancer: current treatment options • Symptomatic treatment: • pain • jaundice • Resectable (stage I-II, 10 – 20%) : surgery followed by chemotherapy (chemoradiation ?) • Locally-advanced disease (stage III-IVA, 40%): chemoradiation ? chemotherapy ? • Metastatic disease (stage IVB, 40 – 50%): chemotherapy (gemcitabine)

  6. Aims of the initial work-up 1- diagnosis - if accessible met, biopsy of met - if no met US endoscopy CT-scan guided biopsy laparoscopy / laparotomy resection

  7. Aims of the initial work-up 2- guide for treatment strategy Resectable disease MDA criteria Surgery Resection of disease Adjuvant treatment ? No resection Go to LA

  8. MDA criteria • “ Potentially resectable disease: 1) no extrapancreatic disease, • a patent SMV-PV confluence (assuming the technical ability to resect and reconstruct this venous confluence), and • a definable tissue plane between the tumor and regional arterial structures including the celiac axis, common hepatic artery and SMA. “

  9. Adjuvant CTRT phase III studies N median survival p (months) GITSG, Arch Surg 1985 - Surgery 21 11 - RT (20 Gy x 2) + 5 FU D1-D3 < 0,02 then 5 FU weekly / 2 yrs 22 20 EORTC, Ann Surg 1999 - Surgery 54 12,6 0,09 NS - RT (20 Gy x 2) + 5 FU PC 60 17,1

  10. ESPAC 1

  11. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 p<0.001 30 30 20 20 10 10 0 0 24 36 48 60 72 0 12 24 36 48 60 72 84 0 12 84 CONKO-001: Surgery vs surgery followed by gemcitabine DFS OS p = 0.06

  12. Ongoing Adjuvant Trials in ResectedPancreatic Cancer

  13. Chemotherapy ? Chemoradiation ? Chemotherapy ? Chemoradiation ? Secondary surgery ? Aims of the initial work-up 2- guide for treatment strategy Locally-advanced disease « No met, no resection » « never resectable » « border-line resectable »

  14. Treatment of metastatic pancreatic cancerChemotherapy or BSC ? * p < 0.05

  15. Treatment of metastatic pancreatic cancerThe Burris Study n=129 Gemcitabine 1000 mg/m2 30 min infusion Weekly for 7 w , 1 w rest, then 3w /4w R Primary Objective : Clinical Benefit 5-Fluorouracil 600 mg/m2 30 min infusion weekly

  16. Treatment of metastatic pancreatic cancerThe Burris Study • Clinical Benefit • PS improvement (>20% in Karnofsky index) • and / or Pain decrease (> 20%) • and / or Antalgics consumption decrease (> 50%) • and / or Weight increase (> 7%) • For at least 1 month

  17. Treatment of metastatic pancreatic cancerThe Burris Study Treatment Clinical Benefit Gemcitabine 23.8% p = 0.0022 5-Fluorouracil 4.8%

  18. Treatment of metastatic pancreatic cancerThe Burris Study Gemcitabine 5-Fluorouracil n=63 n=63 5.65 months * Median Survival 4.41 months 46% 31% 6-months survival 9-months survival 24% 6% 12-months survival 18% 2% * p = 0.0025 Burris H A, et al.: JCO 15: 2403, 1997

  19. Gemcitabine: activation and mechanism of action • Gemcitabine: a deoxycytidine analogue • Requires intracellular uptake followed by sequential phosphorylation to active metabolite form Gem Gem Gem-MP Gem-DP Gem-TP • Blocks DNA synthesis/replication at several steps inhibition of RR * NT incorporation into DNA deoxycytidine kinase

  20. Treatment of metastatic pancreatic cancer • Gemcitabine 30’ infusion or 10 mg/m²/mn fixed dose rate ? RR 16.6% PFS 3.4 months OS 8 months 1-yr survival : 23% Gemcitabine 1500 mg/m² 10mg/m²/min R RR 2.7% PFS 1.9 months OS 5 months 1-yr survival : 0% Gemcitabine 2200mg/m² 30 min N=80 Tempero, JCO 2004

  21. Gem ± Marimasmat (Bramhall, 2002) 5.5 5.5 Gem ± Exatecan (O’Reilly, 2004) 6.2 6.7 Gem ± CPT-11 (Rocha-Lima, 2004) 6.6 6.3 Gem ± Pemetrexed (Richards, 2004) 6.3 6.2 Randomized phases III in Pancreatic Cancer Study OS gem (m) OS gem + drug X (m)

  22. Median survival 12-month (months, 95%CI) survival GEM 6.0 (5.4, 7.1) 19% GEM-CAP 7.4 (6.5, 8.5) 26% Hazard Ratio: 0.80 (95% CI: 0.65, 0.98) Log rank p=0.026; χ2LR=4.93 Gem vs Gem-Cap study (Cunningham)

  23. Gem ± 5FU bolus (Berlin, 2002) 5.4 6.7 Gem ± Capecitabine (Herrmann, 2005) 7.3 8.4 Gem ± 5FU/LV (Riess, 2005) 6.2 5.9 Gem ± Capecitabine (Cunningham, 2005)6.07.4 Gem ± Marimasmat (Bramhall, 2002) 5.5 5.5 Gem ± Exatecan (O’Reilly, 2004) 6.2 6.7 Gem ± CPT-11 (Rocha-Lima, 2004) 6.6 6.3 Gem ± Pemetrexed (Richards, 2004) 6.3 6.2 Randomized phases III in Pancreatic Cancer Study OS gem (m) OS gem + drug X (m)

  24. p Gem Gemox median 7.1 m 9.0 m 6-mth 60.4% 68.0% 8-mth45.3% 56.5% 9-mth 40.0% 48.1% 1-yr 27.8% 34.7% 0.13 GEM-GEMOX Study : Overall survival Overall Survival 1.0 Gem 0.9 Gemox 0.8 0.7 0.6 % survival 0.5 0.4 0.3 0.2 0.1 0.0 0 26 52 78 104 130 156 weeks Louvet C, et al. J Clin Oncol, 2005

  25. Gem : median = 4.9 months Gemox : median = 5.9 months Gem FDR : median = 6.0 months Gem vs Gemox : NS Gem vs Gem FDR : NS GEM FDR GEMOX

  26. Gem ± 5FU bolus (Berlin, 2002) 5.4 6.7 Gem ± Capecitabine (Herrmann, 2005) 7.3 8.4 Gem ± Cisplatin (Heinemann, 2003) 6.0 7.5 Gem ± 5FU/LV (Riess, 2005) 6.2 5.9 Gem ± Oxaliplatin (Louvet, 2004) 7.19.0 Gem vs Gem FDR vs Gemox (Poplin, 2006) 4.9 6.0 5.9 Gem ± Capecitabine (Cunningham, 2005)6.07.4 Gem ± Marimasmat (Bramhall, 2002) 5.5 5.5 Gem ± Exatecan (O’Reilly, 2004) 6.2 6.7 Gem ± CPT-11 (Rocha-Lima, 2004) 6.6 6.3 Gem ± Pemetrexed (Richards, 2004) 6.3 6.2 Randomized phases III in Pancreatic Cancer Study OS gem (m) OS gem + drug X (m)

  27. K-ras and farnesyltransferase inhibitors No positive results in clinical trials to date

  28. GEMCITABINE ± ERLOTINIB Phase III Study

  29. 5.9 6.4 S0205: Primary EndpointSurvival of All Patients HR = 1.09 (95% CI: 0.93, 1.27)

  30. CALGB 80303: Overall Survival by Treatment Arm Bevacizumab 5.8 moPlacebo 6.1 mo HR = 1.03 P = 0.78

  31. Gem ± 5FU bolus (Berlin, 2002) 5.4 6.7 Gem ± Capecitabine (Herrmann, 2005) 7.3 8.4 Gem ± Cisplatin (Heinemann, 2003) 6.0 7.5 Gem ± 5FU/LV (Riess, 2005) 6.2 5.9 Gem ± Oxaliplatin (Louvet, 2004) 7.19.0 Gem vs Gem FDR vs Gemox (Poplin, 2006) 4.9 6.0 5.9 Gem ± Capecitabine (Cunningham, 2005)6.07.4 Gem ± Marimasmat (Bramhall, 2002) 5.5 5.5 Gem ± Exatecan (O’Reilly, 2004) 6.2 6.7 Gem ± Tifarbinib (Van Cutsem, 2004) 6.0 6.4 Gem ± CPT-11 (Rocha-Lima, 2004) 6.6 6.3 Gem ± Erlotinib (Moore, 2005) 5.9 6.4 Gem ± Pemetrexed (Richards, 2004) 6.3 6.2 Gem ± Bevacizumab (Kindler, 2007) 6.1 5.8 Gem ± Cetiximab (Philip, 2007) 5.9 6.4 Randomized phases III in Pancreatic Cancer Study OS gem (m) OS gem + drug X (m)

  32. How to move on ? 1- Better knowledege on : pancreatic cancer cells relationships between tumoral, endothelial and stromal cells pancreatic cancer patients hopefully resulting in new drugs and new strategies

  33. Cetuximab Panitumumab EMD-72000 Matuzumab R Jak Src Gefitinib Erlotinib Lapatinib CI-1033 EKB-569 AEE788 EXEL 7647 BIBW2992 PDK PI3K Ras G protein SOS FT antisense oligonucleotide STAT STAT PIP2 PIP3 FT FTI Abl PTEN Sorafenib Enzastaurin PKC STAT AKt NF-B Rapamycine Tsemsirolimus/CCI-779 Everolimus/RAD001 AP23573 MEK mTOR Raf CI-1040 GSK3β Grb2 pRb STAT3 M A P K STAT5 ERK p70S6K elF-4E STAT5 proliferation survival elF-4E p53 c-Jun c-myc c-Fos p53 Ub Ub Ub Ub Ub STAT Gene transcription 19S 4E-BP 4E-BP STAT 20S Proteasome IMC-A12 CP-751 CP-871 IGFR EGFR1 EGFR1 Ub Ub Ub p21 Ub p27 Ub p53 I ? B Cell cycle prog . Cellular adhesion Proliferation Anti - apoptosis VEGF Cyclin D1D2 MYC TNF - ? IL6 Bcl2 NF ? B survival metastasis Bortezomib angiogenesis proliferation

  34. How to move on ? 1- Better knowledege on : pancreatic cancer cells relationships between tumoral, endothelial and stromal cells pancreatic cancer patients hopefully resulting in new drugs and new strategies 2- Optimize the available tools : Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients

  35. First-intention CRT : FFCD-SFRO trial Chauffert. ASCO 2006, # 4008 109 patients included, median f.u. : 16 months [1 – 60] Median survival : CRT = 8 months vs gemcitabine = 14 months 1-year survival : CRT= 24 % vs gemcitabine = 51 %

  36. selection CT CRT may increase survival in patients with LA disease stable after 3 months chemotherapy compared to CT continuation 10.8 months vs 7,4 months (p = 0.005) 15 months vs 11,7 months (p = 0.0009)

  37. Locally Advanced cancer of Pancreas study LAP 07 CRT EVALUATION : non progressive EVALUATION : non progressive EVALUATION EVALUATION EVALUATION Until progression Arm A1 : Arm A2 : Arm B1 : Arm B2 : CRT R1 R2 3 perfusions of gemcitabine (1000 mg/m2) Erlotinib 100 mg/d when combined to Gem 150 mg/d as single agent capecitabine irradiation Secondary surgery allowed in each arm at any time

  38. No Nodal RT Conventional

  39. How to move on ? 1- Better knowledege on : pancreatic cancer cells relationships between tumoral, endothelial and stromal cells pancreatic cancer patients hopefully resulting in new drugs and new strategies 2- Optimize the available tools : Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients Prophylactic anticoagulation ?

  40. How to move on ? 1- Better knowledege on : pancreatic cancer cells relationships between tumoral, endothelial and stromal cells pancreatic cancer patients hopefully resulting in new drugs and new strategies 2- Optimize the available tools : Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients Prophylactic anticoagulation ? Methods and endpoints

  41. ENDPOINTS AND METHODS Response rate : NO (particularly in LAPC) Clinical Benefit : NO (not commonly used) PFS : NO (no impact of 2nd line) OS : YES

  42. ENDPOINTS AND METHODS Response rate : NO (particularly in LAPC) Clinical Benefit : NO (not commonly used) PFS : NO (no impact of 2nd line) OS : YES Phase II studies ???

  43. ENDPOINTS AND METHODS Response rate : NO (particularly in LAPC) Clinical Benefit : NO (not commonly used) PFS : NO (no impact of 2nd line) OS : YES Phase II studies ??? Meta-analysis ???

  44. Need more than 500 pts to demonstrate survival advantage Randomized phases III in Pancreatic Cancer Study PFS/TTP(m) OS (m) N pts Gem ± 5FU/Capecitabine Gem ± 5FU bolus (Berlin, 2002) 3.4 6.7 362 Gem ± Capecitabine (Herrmann, 2005) 4.8 8.4 319 Gem ± 5FU/LV (Riess, 2005) 4.9 5.9 466 Gem ± Capecitabine (Cunningham, 2005)NA7.4 533 Gem ± Platinum-analogs Gem ± Cisplatin (Heinemann, 2003) 5.3 7.5 190 Gem ± Oxaliplatin (Louvet, 2004) 5.8 9.0 313 Gem ± erlotinib Gem ± Erlotinib (Moore, 2005) 3.7 6.4 530

  45. Gemcitabine-based Combinationsevidence from randomised trials *significant

  46. Gemcitabine-based Combinationsevidence from randomised trials *significant

  47. Gemcitabine-based Combinationsevidence from randomised trials *significant

More Related