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MCO 2011 - Slide 23 - P. Rougier - Gastric and pancreatic cancers (part II)
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MCO 2011 - Slide 23 - P. Rougier - Gastric and pancreatic cancers (part II)

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MCO 2011 - Slide 23 - P. Rougier - Gastric and pancreatic cancers (part II) MCO 2011 - Slide 23 - P. Rougier - Gastric and pancreatic cancers (part II) Presentation Transcript

  • Medical treatment of pancreatic cancer UVSQ University of Versailles Saint Quentin en yveline Philippe Rougier Digestive Oncology Hopital Européen Georges Pompidou 75015 Paris ; France [email_address] Pancreas: A complex anatomy
  • Pancreatic cancer: a major therapeutic challenge
    • Pancreatic cancer is a fatal disease
      • fourth/fifth-leading cause of cancer-related deaths
      • overall survival is amongst the shortest of any solid tumour
    • Treatment options are limited ….
    1 Burris H, et al. J Clin Oncol 1997;15:2403 – 13
  • Medical treatment of metastatic pancreatic cancer
    • Metastatic PC
      • Past history of chemotherapy
      • New active regimens ?
      • Targeted therapy
      • Second line treatments
      • Prevention of vascular complications
    • Adjuvant TT
      • Radiochemotherapy
      • chemotherapy
  • 1997: Gemcitabine became a standard of care in advanced pancreatic cancer 0 2 4 6 8 10 12 14 16 18 20 100 80 60 40 20 0 Weekly b 5-FU Weekly Gemcitabine Survival time (months) Patients surviving (%) 1 Burris H, et al. J Clin Oncol 1997;15:2403 – 13 Gemcitabine 5-FU p Median survival (mo) 5.65 4.41 0.0025 Clinical benefit (%) 23.8 4.8 0.0022 1-year survival (%) 18 2
  • Heinemann V, BMC Cancer 2008 Platin salts Fluoropyrimidines Autres in favor of Gem + X in favor of Gem alone Meta-analysis: combinations in first line Not done on individal data G + Platinum salts G + FU derivatives
  • Medical treatment of metastatic pancreatic cancer
    • Metastatic PC
      • Past history of chemotherapy
      • New active regimens ?
      • Targeted therapy
      • Second line treatments
      • Prevention of vascular complications
    • Adjuvant TT
      • Radiochemotherapy
      • chemotherapy
  • PRODIGE 4 / Accord 11 trial Phase III : Gemzar vs Folfirinox
    • T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press
    GEMZAR (Burris) FOLFIRINOX* primary endpoint : OS Gain : 7 to 10 months ADK pancreas M+ N = 342 Stratification : center PS : 0 vs 1 head vs other localisation 6 months of chemotherapy recommended CTscan every 2 months In each arm : R * Folfirinox : d1 = d14 - Oxaliplatin 85mg/m 2 d1 - Irinotecan 180mg/m 2 d1 - folinic acid 400mg/m 2 d1 - 5FU 2400 mg/m 2 / d1-2
  • Disease characteristics T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press Characteristic Folfirinox N=171 Gemcitabine N=171 p Synchronous metastases Metachronous metastases 156 (91.2%) 15 (8.8%) 161 (94.2%) 10 (5.8%) NS NS Median nr. of T sites CA19-9  59 ULN 2 (1-6) 68 (41.5%) 2 (1-6) 77 (46.7%) NS NS Measurable site Liver Pancreas Nodes Lungs Peritoneal 149 (88.2%) 89 (52.7%) 48 (28.4%) 33 (19.5%) 33 (19.5%) 150 (87.7%) 91 (53.2%) 39 (22.8%) 49 (28.7%) 32 (18.7%) NS NS NS 0.049 NS
  • Safety: hematological adverse events (Aes) 5.4 42.5% of the pts received G-CSF in the F arm vs 5.3% in the G arm One toxic death occurred in each arm T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press AE, % per patient Folfirinox N=167 Gemcitabine N=169 p All Grade 3/4 All Grade 3/4 Grade 3/4 Neutropenia 79.9 45.7 54.8 18.7 0.0001 Febrile Neutropenia 7.2 2.4 0.6 0.009 Anemia 90.4 7.8 94.6 5.4 NS Thrombocytopen. 75.2 9.1 54.8 2.4 0.008
  • Objective Response Rate T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press Folfirinox N=171 Gemcitabine N=171 p Complete response 0.6% 0% Partial response 31% 9.4% 0.0001 CR/PR 95% CI [24.7-39.1] [5.9-15.4] Stable disease 38.6% 41.5% Disease control CR+PR+SD 70.2% 50.9% 0.0003 Progression 15.2% 34.5% Not assessed 14.6% 14.6% Median duration of response 5.9 mo. 4 mo. ns
  • Progression-Free Survival Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo HR (95% CI): 0.47 (0.37-0.59) ; p < 0.0001 T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press
  • Overall Survival T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press Median survival [CI 95%]: 11.1 mo .[ 9 - 13.1] vs 6.8 mo .[ 5.5 - 7.6] P = <0.0001 ; HR = 0.57 [0.45 – 0.73]
  • Time to definitive QoL degradation T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press
  • Conclusions
    • Folfirinox more toxic but … with manageable toxicity => higher rate of gr. 3/4 febrile neutropenia (5.4%) => vigilant pt selection, education, monitoring, management
    • Folfirinox regimen is an efficient outpatient schedule :
      • Significantly improves PFS
      • Delays QoL degradation
      • Significantly improves overall survival (HR 0.57, p<0.0001) => + 4.3 mths compared to gemcitabine alone.
      • Folfirinox is a new standard of care for patients with metastatic pancreatic cancer, bilirubin <1.5 UNL and PS 0-1 in France (“tncd.org)
    • Folfirinox will be tested in other indications (adjuvant, neoadjuvant …)
    T. Conroy et al ., ASCO 2010, A 4010 ; N Engl J Med 2011 in press
  • Medical treatment of metastatic pancreatic cancer
    • Metastatic PC
      • Past history of chemotherapy
      • New active regimens ?
      • Targeted therapy
      • Second line treatments
      • Prevention of vascular complications
    • Adjuvant TT
      • Radiochemotherapy
      • chemotherapy
  • Combining gemcitabine with biological therapies
    • Gemcitabine + Marimastat Bramhall, Br J Cancer 2002
    • Gemcitabine + Tipifarnib van Cutsem, JCO 2004
    • Gemcitabine + Cetuximab Philip, ASCO 2007
    • Gemcitabine + Bevacizumab Kindler, ASCO 2007
    • Gemcitabine + Tarceva Moore, JCO 2007
  • PA.3: Overall Survival in metastatic pancreatic cancer 1.00 0.75 0.50 0.25 0 0 6 12 18 24 30 36 Time (months) Gemcitabine + Tarceva Gemcitabine + placebo Survival probability HR=0.80 (0.66–0.98); p=0.029 Led to EU approval for the treatment of metastatic pancreatic cancer
    • Erlotinib (Tarceva R ) improves OS
    • only in case of skin reaction ? Is it clinically meaningful ?
    Moore, JCO 2007 Gemcitabine + Tarceva Gemcitabine + placebo n 200 197 Median survival, months 5.93 5.06
  • Conatumumab / AMG 479, phase II in Metastatic Pancreatic Cancer … phase III in progress Patients à risque H. L. Kindler et al ., ASCO 2010, A 4035 Trend in favor of anti IGFR efficacy ? Events Median OS (95% CI), mthis HR (95% CI) a p Conatumumab + gemcitabine 32 (78%) 7.5 (4.8, 10.0) 0.87 (0.53, 1.43) 0.59 AMG 479 + gemcitabine 29 (69%) 8.7 (5.3, 12.2) 0.67 (0.41, 1.12) 0.12 Placebo + gemcitabine 34 (81%) 5.9 (4.1, 9.7) 41 39 38 33 29 25 23 23 19 14 14 11 7 5 3 1 0 0 0 0 0 0 0 0 0 42 39 37 34 30 28 22 21 20 17 17 15 13 8 6 6 4 3 3 3 2 1 1 1 0 42 39 38 30 26 20 19 16 15 14 13 12 6 3 2 2 1 1 1 1 0 0 0 0 0 0.0 0.2 0.4 0.6 0.8 1.0 Survie globale 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Mois
  • Pancreatic cancer: recent progress ?
    • Past history of chemotherapy
    • New active regimens ?
    • Targeted therapy
    • Second line treatments
    • Prevention of vascular complications
  • Clinical trials investigating second-line chemotherapy in gemcitabine-pretreated pts with advanced pancreatic cancer c c Treatment regimen No. of patients KPS 90-100% / ECOG 0-1 Metastatic disease (%) RR (%) DCR (%) PFS/TTP (months) OS (months) Oxa/5-FU CI/LV vs BSC 46 NA NA NA NA OFF:5.25 BSC:2.5 OFF:10 BSC:8.5 Oxa/5-FU CI/LV vs 5-FU CI/LV (nb = 168) OFF:77 FF: 91 OFF:54% FF: 50 % OFF:85.5 FF: 89.2 NA NA OFF:3.25 FF: 2.25 OFF:6.5 FF: 3.25 Oxa/5-FU CI/LV 30 33 % 97 23 53 5.1 5.8 FOLFOX-4 42 62 % 83 14 52 4 6.7 Modified FOLFOX 30 97 % NA NA 20 1.4 4 vs modified FOLFIRI 30 100 % 28 1.9 4 Oxa + Gem 33 88 % 64 21 58 4.2 6.0 Oxa + Cap 39 80 % NA 3 23 NA 5.8 Oxa + irinotecan 30 30 % 100 10 33 4.1 5.9 Oxa + raltitrexed 41 61 % 100 24 51 1.8 5.2 Cisplatin + irinotecan + Gem + 5-FU + LV 34 NA 100 24 44 3.9 10.3 Cap + Gem + docetaxel 35 52 100 29 60 NA 11.2
  • 5FU- Folinic-Ac (FF) Oxaliplatin-5FU- Folinic-Ac (OFF) non resecable Cancer (Localy avanced or Metastatic) Progression under Gem Karnowsky >60 n=165 Pelzer et al, ASCO 2008 A 4508 FF : 5FU 2000 mg/m²/24h, ac. folinic 200 mg/m² in 30 mn D1- D 8- D 15- D 22 OFF : FF + Oxaliplatin 85 mg/m² D 8- D 22 D 1= D 43 Primary endpoint : Overall Survival Second line chemotherapy: CONKO-3 trial R Per protocol FF OFF p PFS (weeks) 9 13 0.012 Overall Survival (weeks) 13 26 0.014
    • Overall survival
    • Primary endpoint of the study
    Progression free-survival FFCD 0301: strategic trial: which 1rst line and 2d line ? ARM A FUP -> Gem ARM B Gem -> FUP P (log-rank) Median mths [95% CI] 6.63 [5.27 – 8.07] 8.03 [5.93 – 9.97] 0.77 ARM A ARM B P Median mths [95% CI] 3.83 [2.36 – 7.03] 4.73 [2.43-8.23] 0.9
  • Recommendations for second line tt
    • Increased Nb of patients treaited in 2 nd line
    • no robust data ; phase III needed
    • Fluoropyrimidines : interest if PS > 1
    • Combinaisons : if PS 0-1
      • OFF or FOLFOX are a « standard » (randomised trial)
      • What about Capox / GEMOX or CDDP or FOLFIRI ?
      • Capecitabine + erlotinib ?
    • Pronostic & predictive Factors needed
  • Medical treatment of metastatic pancreatic cancer
    • Metastatic PC
      • Past history of chemotherapy
      • New active regimens ?
      • Targeted therapy
      • Second line treatments
      • Prevention of vascular complications
    • Adjuvant TT
      • Radiochemotherapy
      • chemotherapy
  • venous thromboembolic event : VTE Advanced pancreatic adenocarcinoma : CONKO 004 trial Efficacy of preventive anticoagulation ? LMWH decreases the risk of VTES But does not influence significantly the OS H. Riess et al ., ASCO 2010, , A 4033 énoxaparine (Lovenox ® ) 1 mg/kg/j for 3 months then 40 mg/j N = 312 CT N = 152 CT + enoxaparine N = 160 p VTE at 3 months 9,9 % 1,25 % < 0,01 VTE at 12 months 15% 5% severes haemorragic Complications   ns TTP 5.4 months 5 months P = 0.94 Overall Survival 8 months 8.3 months P = 0.5
    • FUTURE ?
    • Better selection of patients:
    • Predictive factors for response to Gemcitabine
    • Predictive factors for toxicity to Gemcitabine
    • Better drugs and combinations ?
  • Gemcitabine: mechanism of action Human equilibrative nucleoside transporter 1 (hENT1) Human concentrative nucleoside transporter 1 (hCNT1) Human concentrative nucleoside transporter 3 (hCNT3) CDA: gemcitabine catabolism enzyme
    • OS Median:
    • -2 factors: not reached
    • 1 factor: 18.7 months
    • 0 factor: 12.2 months
    hENT1 low hENT1 elevated p OS PFS 13.3 months 8.4 months Not reached 46.8 months 0.0001 hCNT3 low hCNT3 elevated OS PFS 12.6 months 8.6 months Not reached 23.5 months 0.02
  • CDA: enzyme of gemcitabine catabolism cytidine deaminase (CDA) enzymatic activity and toxicity/efficacy of gemcitabine (?) ACTIVE METABOLITES 2’-dFdU (inactive) Cytidine Deaminase (CDA) gene polymorphism Gemzar ®
  • Adjuvant treatment of pancreatic cancer
    • surgery
    • Chemo-radiotherapy RTCT ?
    • Chemotherapy ?
  • In absence of metastase and local infiltration: Whipple = Cephalic Duodeno Pancreatectomy
  • non-resecability criteria
    • R1 or R2 CDP is contre-indicated:
      • No long term survival & 5% risk of post-op death …
    • Distant metastase
    • Local extension :
        • Mesenteric artery
        • Lymph nodes
        • peri-pancreatic tissue
        • veina cava or aorta
        • Portal vein thrombosis & occlusion of the superior mesenteric vein
  • Stenting in case of icterus in non resectable case or metastses
  • Quality of Pathological exam +++
  • Medical treatment of metastatic pancreatic cancer
    • Metastatic PC
      • Past history of chemotherapy
      • New active regimens ?
      • Targeted therapy
      • Second line treatments
      • Prevention of vascular complications
    • Adjuvant TT
      • Radiochemotherapy
      • chemotherapy
  • 9 m vs 11 m p = 0,01 11 m vs 20 m p = 0,03
    • Feb 1994- June 2000
    • 11 countriess
    • 237 DC/ 289 patients
    • Median follow-upi: 47 mois
    ESPAC 1: Radiochimiotherapy vs no radiochimiotherapy : 5 year’survival 10% vs 20% (p = 0.05 ) Neoptolemos JP, NEJM, 2004
  • ESPAC1: Chemotherapy vs No chemotherapy : Survival at 5 years 21% vs 8% (p = 0.009)
  • DFS : 13.4 vs 6.9 m p < 0.001 Overall survival : 22.1 vs 20.2 m p < 0.06 CONKO-001:adjuvant Gemcitabine ?
  • Neoptolemos J, ASCO 2009, LBA4505 = No difference ESPAC 3 (V2): FU/FA or Gem ? Survival ESPAC 3 (V2): Toxicity Grade 3-4 5-FU/AF Gemcitabine p Thrombopénie 0 % 1,5 % 0,0034 Mucite 10 % 0 % < 0,001 Diarrhée 13 % 2 % < 0,001
  • SYNTHESIS: MEDICAL TREATMENTS IN PANCREATIC CANCER IN 2011: METASTASES (1)
    • Gemcitabine is still a standard ( grade A ):
      • - hENT1 / 3 elevated ?
      • - non extensisve CDA ?
    • Gemcitabine + erlotinib improves survival ( grade B )
      • - in selected patients ? (skin rashes)
    • Combinations of Gemcitabine with capecitabine, platinum salts only marginally improve the efficacy ( when RR is concerned) ( grade B and experts opinion )
    • FOLFIRINOX improve the OS in selected population. (PS: 0-1) and is a new standard ( grade A )
    • Second line chemotherapy may be offer in patients in with good prognostic factors
        • - FOLFOX following Gem
        • - Gem following FOLFORINOX) ;
        • - Interest of addition of Erlotinib under investigation.
    • Biological markers for response, survival and toxicity must be developped and used to favor better therapeutic index +++.
    SYNTHESIS: MEDICAL TREATMENTS IN PANCREATIC CANCER IN 2011: METASTASES (2)
    • Chemotherapy is more efficient than combined radiochemotherapy after R0 resection.
    • Gemcitabine and 5FU/folinic acid improve survival
    • In the same range.
    • Radiochemotherapy using new schedule and after chemotherapy may improve survival and/or reduce the local recurrence rate. It is indicated in case of R1 or R2 resection.
    SYNTHESIS: MEDICAL TREATMENTS IN PANCREATIC CANCER IN 2011: ADJUVANT