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MCO 2011 - Slide 22 - P. Rougier - Gastric and pancreatic cancers (part I)

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MCO 2011 - Slide 22 - P. Rougier - Gastric and pancreatic cancers (part I)

  1. 1. Gastric cancer: Current standards and next steps Philippe ROUGIER, Sce HGE-Oncologie Digestive HEGP, 75015 PARIS [email_address] UFR PIFO UVSQ Université Versailles-Saint Quentin en Yveline
  2. 2. Gastric cancer: a global disease <ul><li>4th most common malignant disease ~ 930,000 </li></ul><ul><li>2nd most common cause of cancer-related death worldwide ~700,000 </li></ul><ul><li>Falling incidence of distal gastric cancer </li></ul><ul><li>Increasing incidence of proximal gastric cancer </li></ul><ul><li>Wide geographical variation </li></ul>www.cancer.gov Kamangar F et al. J Clin Oncol 2006;24:2137–50  20 / 100 000 <10 / 100 000  10 -  20 / 100 000 Incidence (males)
  3. 3. Gastric cancer: trend of age-adjusted mortality rate but GE-junction incidence is rising 14/04/11 *Standardized to world population Year 80 60 40 20 0 1955 1960 1965 1970 1975 1980 1985 1990 Japan Denmark US white Annual rates per 100,000
  4. 4. Carcinogenesis of gastric cancers <ul><ul><li>Pathological classification: Lauren: intestinal vs diffuse type </li></ul></ul><ul><li>Proximal Cancers : diffuse type ? </li></ul><ul><li>Distal Cancers: mainly intestinal type: </li></ul><ul><ul><li>Intestinal: 85% role of atrophic gastritis & H pylori </li></ul></ul><ul><ul><li>Diffuse: 12% </li></ul></ul><ul><ul><li>Familial: 3% </li></ul></ul>14/04/11
  5. 5. Coréa 1975 ( Lancet 1975;2:58-9) Carcinogenesis <ul><li>Superficial chronic Gastritis (corps gastrique, pangastrique++) </li></ul><ul><li>atrophic Gastritis(50%) </li></ul><ul><li>Intestinale Metaplasia (8%) </li></ul><ul><li>Severe Dysplasia (1/100) </li></ul><ul><li>Intestinal Type gastric Cancer </li></ul>14/04/11 HP <ul><li>HP Virulence (CagA, VacA), </li></ul><ul><li>Immunogenotype hote (IL1, TNF) </li></ul><ul><li>environnement (Salt, low antioxydant nutrition, tobacco…) </li></ul>
  6. 6. Primary staging procedures <ul><li>Evaluation of organ function </li></ul><ul><li>Tumour markers: CEA and CA 19-9: recommended. </li></ul><ul><li>Imaging: </li></ul><ul><ul><li>Gastroscopy with biopsies </li></ul></ul><ul><ul><li>Spiral CT scan abdomen + contrast & chest Xray or CT thorax </li></ul></ul><ul><ul><li>Endoscopic ultrasound (EUS): no complete consensus ; may be a role to take a decision for superficial disease or linitis </li></ul></ul><ul><ul><ul><li>High resolution CT scan: same information as EUS </li></ul></ul></ul><ul><ul><li>no systematic role for MRI </li></ul></ul><ul><ul><li>FDG-PET: very selected patients, mainly GE Junction. </li></ul></ul><ul><ul><li>Staging laparoscopy +/- peritoneal lavage: not done routinely because no clear therapeutic implications </li></ul></ul>
  7. 7. Gastric Cancers: TREATMENT <ul><ul><li>SURGERY </li></ul></ul><ul><ul><li>(NEO) ADJUVANT TREATMENTS </li></ul></ul><ul><ul><li>TREATMENT OF ADVANCED CASES </li></ul></ul>
  8. 8. <ul><li>Multidisciplinary discussion and treatment in expert teams and centers </li></ul><ul><li>Relation between volume of the center and outcome after gastric cancer surgery has been established </li></ul>Expert discussion on gastric cancer Barcelona ESMO/WCGIC 2010 E Van Cutsem Ann Oncol 2011 2 types of Resections Distal - Total
  9. 9. Type of surgical procedure in resectable gastric cancer <ul><li>Extend of resection </li></ul><ul><ul><li>Partial vs total: depending on location, margins (> 5 cm) and histology: diffuse type/signet cells </li></ul></ul><ul><ul><li>Partial gastrectomy for distal cancer (antrum) </li></ul></ul><ul><ul><li>Total gastrectomy for cancer from the upper part of the stomach </li></ul></ul><ul><ul><ul><li>Proximal gastrectomy increasingly performed </li></ul></ul></ul><ul><ul><li>Diffuse type/ signet cells: total gastrectomy </li></ul></ul><ul><ul><li>GE junction tumours depending on extent of disease: esophago+prox.gastrectomy, esophago+total gastrectomy </li></ul></ul><ul><li>D2 LN dissection preferred: better long term outcome </li></ul><ul><li>Splenectomy: not done, unless direct invasion </li></ul><ul><li>laparoscopic resection: clinical trials </li></ul>Expert discussion on gastric cancer ESMO / WCGC June 30 – July 3, 2010, Barcelona
  10. 10. P rognostic markers in resectable gastric cancer <ul><li>clinical: prognostic : PS , nutritional status , a ge </li></ul><ul><li>biochemica l: evidence is weak </li></ul><ul><ul><li>prognostic: WBC, CEA, CA19-9, LFT, albumin </li></ul></ul><ul><li>pathological : prognostic: TNM stage </li></ul><ul><ul><li>including ratio of involved lymph nodes </li></ul></ul><ul><ul><li>histology (Lauren); </li></ul></ul><ul><ul><li>response on neoadjuvant treatment </li></ul></ul><ul><li>Molecular : MMP9, p53, MSI </li></ul>Expert discussion on gastric cancer ESMO / WCGC June 30 – July 3, 2010, Barcelona
  11. 11. Kattan et al. J Clin Oncol 2003; 21:3647-3650 Lymph Nodes (LN) invasion play a major role in the prognosis and AJCC classification <ul><li>Poor prognosis even after resection </li></ul><ul><li>for stage II, IIIA and IIIB </li></ul><ul><li>(N1 1-6 metastatic LN (regional); N2 7-15 metastatic LN ; N3 >15 metastatic LN) </li></ul>Stade 0                   pTis N0 M0 Stade I A                pT1 N0 M0 Stade I B pT1N1; T2a/bN0M0 Stade II                pT1N2 ; T2a/b N1 pT3 N0 M0 Stade III  A              pT2 a/bN2 or pT3N1 or pT4N0M0 Stade III B               pT3 N2 M0 Stade IV                  pT4N1-3M0 ; pT1-3N3M0 all T all N M1 Disease Specific Survival
  12. 12. complementary treatment in gastric cancer ? <ul><li>Ajuvant treatment </li></ul><ul><li>Neoadjuvant / perioperative tt </li></ul><ul><li>Chemotherapy (CT) ? </li></ul><ul><li>Radio-chemotherapy (RT-CT) </li></ul>
  13. 13. Adjuvant Chemotherapy: the facts <ul><li>Gastric cancer </li></ul>Meta-Analysis of Randomized Trials Based on 15 phase III trials 3,514 pts Individual data Hazard Ratio: 0.82 R. Risk of Death: decreased -18% GASTRIC “ Global Advanced/Adjuvant stomach Tumor Research through International Collaboration”ASCO 2009
  14. 14. Adjuvant chemotherapy: GASTRIC Meta-analysis <ul><li>Gastric cancer </li></ul>HR:0.82 p<0.0001 + 7% at 5 years + 8% at 10 years years 5y 10y Surgery 51% 40% Any CT 58% 48% Meta-Analysis of Randomized Trials interim Results Based on 3,514 pts Results: HR: 0.82 5 y survival: 58% vs 51% + 7% at 5-years GASTRIC “Global Advanced/Adjuvant stomach Tumor Research through International Collaboration” ASCO 2009
  15. 15. S1 compound in adjuvant (2007) Benefit on DFS & OS at 3 year (+ 12% and + 10.4%) Benefit non dependant on age or sexe… mainly stage II and IIIa tumors 100 50 0 2 3 4 5 1 Ans HR = 0,68 [0,52-0,87] p = 0,0024 Overall survival (n = 1 059) 100 50 0 2 3 4 5 1 Ans HR = 0,62 [0,50-0,77] p < 0,0001 Disease free Survival (n = 1 059) % % ASCO GI 2007 – D’après Sasako et al., Tokyo, Japon, abstr. 8 actualisé ; lancet 80,5 % 70,1 % Surgery + S-1 Surgery only 72,2 % 60,1 % Surgery + S-1 Surgery only
  16. 16. Adjuvant chemotherapy in gastric cancer conclusion <ul><li>Increase the overall survival </li></ul><ul><li>between 5 and 10% benefit at 5 years </li></ul><ul><li>Decrease the risk of death by 18% </li></ul><ul><li>No regimen is superior to 5FU monochemotherapy </li></ul><ul><li>No superiority of protocols continaing cis-platinum </li></ul>
  17. 17. Adjuvant treatment in gastric cancer ? <ul><li>Chemotherapy (CT) ? </li></ul><ul><li>Radio-chemotherapy (RT-CT) </li></ul>
  18. 18. <ul><li>582 pts </li></ul><ul><li>gastric ADK & GEJ </li></ul><ul><li>Stade IB-IV (M0) </li></ul>5FU-AF (5j) surgery RT 45 Gy 5FU-AF 5FU-AF X 2 Follow-up Mac Donald et al. N Engl J Med 2001 Adjuvant Radio-chemotherapy in Gastric Cancer: The only randomized Trial Against Surgery Only SWOG 9008/INT 0116 phase III trial: o verall survival per treatment arm R
  19. 19. Updated Results (2009) of INT 0116 (SWOG 9008) trial with a 11 years follow-up Overall survival Recurrence free survival 0 20 40 60 80 100 % 0 24 48 72 96 120 144 168 192 Months after Registration 0 20 40 60 80 100 % 0 24 48 72 96 120 144 168 192 Months after Registration J.S. Mac Donald et al., ASCO 2009, A 4515 OS: HR = 1.35 (1,09-1,66) p=0,005 RFS: HR = 1.52 (1,23-1,86) p<0,001 <ul><ul><li>BUT </li></ul></ul><ul><ul><li>54% of patients with surgery <D1 </li></ul></ul><ul><ul><li>Grade 3/4 toxicity 41%/32%! </li></ul></ul><ul><ul><li>33% of inadequate RxTT planing </li></ul></ul>5-FU + leucovorin + RT Observation 282 277 213 239 27 19 N Events Median in Months P < .0001 5-FU + leucovorin + RT Observation 282 277 211 231 35 27 N Events Median in Months P = .0051
  20. 20. Adjuvant radio-chemotherapy in gastric cancer conclusion <ul><li>Increase the overall survival </li></ul><ul><li>About 10% benefit at 5 years </li></ul><ul><li>Decrease the risk of death </li></ul><ul><li>In patients with suboptimal surgery </li></ul><ul><li>No comparison with chemotherapy </li></ul><ul><li>Not feasible in all patients </li></ul>
  21. 21. Discussion Adjuvant Tt in Gastric Cancer is not for all ! <ul><li>Surgery </li></ul>- Delayed surgical recovery - Poor food intake - Dumping syndrome etc. - Poor performance status - Treatment refusal ~50%? BUT : tolerance is often poor with - Treatment delays - Dose reductions - Early termination ~50% receive Adjuvant Treatment “ in the Real life”
  22. 22. Adjuvant treatments in Gastric Cancer: conclusion HR:0.82 ; p<0.0001 <ul><li>- < 10% absolute 5-year survival benefit </li></ul><ul><li>- < 50% of the pts able to receive adjuvant tt </li></ul><ul><li>Interest of peri-operative or neoadjuvant tts </li></ul><ul><li>In resectable but infiltrating tumor </li></ul>
  23. 23. Objectives of preoperative (radio)Chemotherapy <ul><li>Downstaging of the tumor </li></ul><ul><li>Facilitation of surgery </li></ul><ul><li>Decreases the risk of recurrence and distant M </li></ul><ul><li>Increases overall survival </li></ul><ul><li>Better tolerated & more efficient than adjuvant </li></ul>
  24. 24. Gastric & EGJ Cancer : Perioperative Chemotherapy: the MAGIC and the French Trials <ul><li>Surgery alone </li></ul>R Stage ≥II “ locally advanced” Chemo Surgery Chemo <ul><li>MAGIC trial : ECF x 3  Surgery  ECF x 3 (503 pts) </li></ul><ul><li>French trial : FP x 2  Surgery  FP x 4 (224 pts) </li></ul>E: farmorubicin, C: cisplatin, F: 5FU (fluorouracil) in continuous infusion
  25. 25. MAGIC Trial gastric cancer: 2/3, low esophageal adenocarcinoma: 1/3 of pts D Cunningham et al. N Engl J Med 2006 ; 355: 11-20. CSC Perioperative CT S Benefit to CSC arm 2-y survival 50% 415 + 9% 5-y survival 36% 23% + 13% Medial survival 24 mo 20 mo + 4 mo
  26. 26. ___ S ___ CT + S years French trial: Gastric Cancer + cardia FNCLCC 94012 - FFCD 9703 results: Overall survival and resection rate At risk 5-year survival:S: 24% (16-33%) vs S+CT: 38% (28-47%) = +14% p=0.021 resection R0: S: 74% vs S+CT: 87% = +13% p=0.04 Logrank p = 0.021 Hazard Ratio = 0.69 (95% CI 0.50-0.95) Boige, V et al. ASCO 2007 # 4510 gastric cancer: 1/4, low esophageal adenocarcinoma: 3/4 of pts
  27. 27. <ul><li>C Schuhmacher et al., ASCO 2009, A 4510 </li></ul>144 patients gastric ADK / cardia Loc avanced 5-FU 2000 mg/m²/24H/w AF 500 mg/m²/2H/w + CDDP 50 mg/m²/2 w (D1=D48) Surgery X 2 surgery <ul><li>Main Criteria : overall survival </li></ul><ul><li>Needs: 360 pts : for an increase m OS from 17 -> 24 mths </li></ul><ul><ul><li>Arrest for too low accrual in 2008 after 144 pts randomized </li></ul></ul><ul><ul><li>Intensive work-up (coelioscopy) </li></ul></ul>EORTC Phase III trial : neoadjuvant CT in gastric cancer R
  28. 28. R0 Resection Rate Neoadjuvant chemotherapy improves The R0 resection rate in 2 out of 3 studies P = n.s. P = 0.04 P = 0.04 MAGIC (n=503) ACCORD (n=224) EORTC (n=114) CTX CHIR CTX CHIR CTX CHIR 69% 66% 87% 74% 82% 67%
  29. 29. Survival Hazard Ratios Neoadjuvant chemotherapy improves the survival in stage 2 and 3 gastric cancer in 2 out of 3 studies MAGIC (n=503) ACCORD (n=224) EORTC (n=114) CTX CHIR CTX CHIR CTX CHIR 0.75 (0,.60; 0.93) 0.69 (0.50; 0.96) 0.84 (0.52; 1.35)
  30. 30. Neoadjuvant Therapy eficacy is confirmed in a Meta-Analysis ASCO 2010 Ronellenfitsch, U. et al. ASCO 2010 #4022
  31. 31. Perioperative chemotherapy in gastric cancer conclusion <ul><li>Favor the down staging in 4 studies </li></ul><ul><li>Increase the R0 rection rate in 2 studies </li></ul><ul><li>Increase the overall survival in 2 studies </li></ul><ul><li>+ 10 to 15% benefit in survival at 5 years in 2/3 studies </li></ul><ul><li>Decrease the risk of recurrence </li></ul><ul><li>Superiority over adjuvant chemotherapy ? </li></ul>
  32. 32. Neo-adjuvant and adjuvant therapy for gastric cancer: different strategies Post-operative Chemoradiotherapy (trend to perioperative CT in academic centers) Peri-operative Chemotherapy (ECF- 5FU/cisplatin) Post-operative Chemotherapy (S-1 or combination) Postoperative CT
  33. 33. Treatment of metastatic gastric cancer ? <ul><li>chemotherapy </li></ul><ul><li>Targetted therapy TT </li></ul>
  34. 34. PALLIATIVE chemotherapy … improves survival and quality of life Efficacy : 11 m vs 4,3 m, p < 0,00001 Cochrane DatabaseSystRev. 2010 Mar 17;3:CD004064 in selected patients < 1 years Chemo BSC HR 95%CI Murad Cancer 1993 FAMTX 30 10 0,33 0,17 - 0,64 Pyrhonen BJC 1995 FEMTX 21 20 0,25 0,25 - 0,47 Scheithauer Ann Hematol 1996 ELF 52 51 0,49 0,33 - 0,74 total 103 81 0,39 0,28 - 0,52
  35. 35. Pronostic Index: 4 factors <ul><li>PS gr 2 or 3 </li></ul><ul><li>Hepatic Metastases </li></ul><ul><li>Peritoneal Carcinomatosis </li></ul><ul><li>Alkaline Phosph > 100 UI </li></ul>Chau et al. J Clin Oncol 2004 ECF vs FAMTX ECF vs MCF Fuc vs FUcMMC 1080 patients <ul><li>0 = « good » : 11.8 months </li></ul><ul><li>1 or 2 = intermediate: 7.4 months </li></ul><ul><li>3 or 4 = poor : 4.1 months </li></ul>
  36. 36. <ul><li>old </li></ul>« modern » < 1 year ? PALLIATIVE chemotherapy … multiple products and regimens DCF mDCF IF FOLFIRI EOX FOLFOX FLO regimens <ul><li>Taxane </li></ul><ul><li>Oxaliplatine </li></ul><ul><li>Oral 5FU </li></ul><ul><li>Irinotecan </li></ul><ul><li>5FU / antimetabolite </li></ul><ul><li>Anthracyclins </li></ul><ul><li>CisPlatinum </li></ul>
  37. 37. Méta-analyse US <ul><li>Polychemo> single drug </li></ul><ul><li>Combination 5FU / CDDP / Anthra > 5FU / CDDP </li></ul><ul><li>Combination 5FU / CDDP / Anthra > 5FU / Anthra </li></ul>Wagner A et al. J Clin Oncol 2006 Cochrane DatabaseSystRev. 2010 Mar 17;3:CD004064
  38. 38. Méta-analyse GASTRIC (Données individuelles) GASTRIC metaanalyse group, ASCO 2009
  39. 39. <ul><li>« anciens » </li></ul>Palliative Chemotherapy <ul><li>5FU / antimetabolite </li></ul><ul><li>Anthracyclins </li></ul><ul><li>CisPlatinum </li></ul><ul><li>FAMTX (5FU + Doxorub + HD Metho.) </li></ul><ul><li>FUP (5FU + Cisplatin) </li></ul><ul><li>ECF (Epirubicin + Cisplatin + 5FU) </li></ul><ul><li>ELF (Etoposide + Leucoverin + 5FU) </li></ul><ul><li>EAP (Etoposide + Doxo. + Cisplatin) </li></ul>= LV5FU2 - P Cap - P Taieb J et al, Ann Oncol. 2002 Aug;13(8):1192-6. Kang et al, ASCO 2006
  40. 40. <ul><li>SSP (objectif principal) : </li></ul>Non Inferiority : XP versus FP (étude ML17032) XP (n=160) FP (n=156) Médianes 5.6mois (95%IC : 4.8–6.9) 5.0mois (95% IC : 3.9–5.7) Mois 2 4 6 8 10 12 14 16 18 20 22 24 26 1.0 0.8 0.6 0.4 0.2 0.0 Kang et al, Ann Oncol; 20: 666–673, 2009 N = 316 Cisplatine : 80 mg/m2 à J1 + Xeloda : 2g/m2 J1 -14 Ou + 5FU : 800 mg/m2 J1 – 5 Toutes les 3 semaines 0 median overall survival(months) : 10,5 (9,3-11,2) 9,3 (7,4-10,6) Capecitabine ? (Xeloda®)
  41. 41. Moiseyenko V et al, ASCO 2005 Van Cutsem E et al. JCO 2006; 24: 4991-7 Tax325 trial Docétaxel 75 mg/m 2 J1 CDDP 75 mg/m2 J1 5FU 750 mg/m2 PC J1 à J5 / 3 sem CDDP 100 mg/m2 J1 5FU 1000 mg/m2 PC J1 à J5 / 4 sem VS n OR TTP OS TCF CF 221/227 224/230 37% 0.01 25% 5.6 0.0004 3.7 9.2 0.02 8.6 Tox grade 3-4 Non hematol : 81% / hematol 82% 30% febrile neutropenia VS Non hematol : 75% Hematol : 56% 13% febrile neutropenia Docetaxel (taxoter ® ) ?
  42. 42. Alternatives to DCF less toxic as efficients ? … P236 – JFHOD 2011 S. Pernot et al T-FOX (Tax 50mg/m 2 + FOLFOX4) N = 46
  43. 43. <ul><li>E : Epirubicine50mg/m 2 , </li></ul><ul><li>C : Cisplatine60mg/m 2 , </li></ul><ul><li>F : 5FUc 200mg/m 2 /j </li></ul>REAL 2 ECF E O F E O X EC X X : Xeloda 1000 mg/m 2 /j O : Eloxatin 130 mg/m 2 / 3 sem. 5 FU Vs X Cisplatin vs Oxaliplatine N Engl J Med 358;1 january 3, 2008 Non infériorité Primary objective =Survival N = 1002 Oxaliplatine ? (Eloxatine®)
  44. 44. REAL-2 trial ASCO 2006 - D. Cunningham et al., abstract 4017 actualisé
  45. 45. <ul><li>Stratification : </li></ul><ul><li>Mesurable or not </li></ul><ul><li>PS WHO 0-1 or 2 </li></ul><ul><li>Adj (R)CT or not </li></ul><ul><li>Linitis or not </li></ul><ul><li>Cardial or gastric </li></ul><ul><li>Center </li></ul>FNLCC-GERCOR-FFCD 0307 FOLFIRI / ECX as first line CT : A: B: ECX until progression ; then FOLFIRI 2d line FOLFIRI until progression ; then ECX 2d line Delay between Randomisation & : 1/ Progression Or 2/ Arrest of tt Or 3/ Death <ul><li>Objective I : Time to TT failure in 1 rst line (TET) </li></ul><ul><li>Objectives II : </li></ul><ul><li>PFS, OS, (TTF 2 d line) </li></ul><ul><li>Toxicity, </li></ul><ul><li>Response, QoL* </li></ul><ul><li>QLQC30 et STO-22 </li></ul>ECX : D1 = Epirubicin 50 mg/m² (15 min.), Cisplatin 60 mg/m² (1 h) ; D2 to 15 : Capecitabine 1 g/m² x 2/d. D1 = D21 Cumulated dose of Epirubicin < 900 mg/m² (max 18 cures) FOLFIRI : D1 = Irinotecan 180 mg/m² (90 min) + LV 400 mg/m² (2h), 5FU b 400 mg/m², 5FU c.i. 2400 mg/m² (46h). D 1 = D14 Guimbaud R et al ASCO 2010 Irinotecan ? (campto®)
  46. 46. FNLCC-GERCOR-FFCD 0307 FOLFIRI / ECX as first line CT : primary objective : Time to First line treatment Failure p (Log-rank) = 0.008 HR ( B vs A) = 0.77 [0.63;0.94] ECX 1 rst line : 4.24 m [3.48; 4.65] FOLFIRI 1 rst line : 5.09 m [4.53; 5.68] Overall Survival : ECX 1 ère ligne) : 9.49 m. [ 8.77; 11.14] FOLFIRI 1 ère ligne) : 9.72 m . [8.54; 11.27] p (Log-rank)= 0.95 HR (B vs A)= 1.01 [0.82; 1.24] less toxicity with FOLFIRI = Guimbaud R et al ASCO 2010 Bras A 209 108 33 8 4 2 1 1 1 Bras B 207 123 50 19 6 3 2 1 0 TTF 0.0 0.2 0.4 0.6 0.8 1.0 Time (months) 0 4 8 12 16 20 24 28 32
  47. 47. <ul><li>« old » </li></ul>Palliative Chemotherapy: synthesis « modern » regimens => Many regimens available ; not a single protocol as standard DCF mDCF IF FOLFIRI EOX FOLFOX FLO FUP ECF (ECX) <ul><li>5FU / antimetabolite </li></ul><ul><li>Anthracyclins </li></ul><ul><li>CisPlatinum </li></ul><ul><li>Taxane </li></ul><ul><li>Oxaliplatine </li></ul><ul><li>Oral 5FU </li></ul><ul><li>Irinotecan </li></ul>
  48. 48. Targeted therapies ? Metastatic Potential Immortalisation Angiogenesis Independence From Growth factors => Loss ef ‘tumor Suppression’ Tt / Anti growth factors Apoptosis inhibition Inspiré de Hanahan & Weinberg, Cell 2000 et JC Soria 2009 <ul><li>Inhibiteurs de La transduction du Signal </li></ul><ul><li>- Famille HER (HER2, EGFR…) </li></ul><ul><ul><li>Ac monoclonaux </li></ul></ul><ul><ul><li>TK inhibiteurs </li></ul></ul><ul><li>HGF/Met (ALK4) </li></ul><ul><li>RAS/RAF/MEK </li></ul><ul><li>PI3K </li></ul><ul><li>IGF1 (CP751, 871) </li></ul><ul><li>Inhib. Farnesyl Transf. </li></ul><ul><li>Inhib PDGF et C-kit </li></ul><ul><li>Agents anti-invasion </li></ul><ul><li>Inhib MMP (AG3340…) </li></ul><ul><li>Chimiokines et leurs récepteurs (modulateurs) </li></ul><ul><li>Inhib. Src (dasatinib, bosutinib…) </li></ul><ul><li>Agents anti-angiogéèniques </li></ul><ul><li>Inhib VEGF </li></ul><ul><li>Anti corps anti VEGF (beva, VEGF-TRAP…) </li></ul><ul><li>anti VEGF oraux (AZD2171, PTK/ZK, SU11248, BAY 43-9006, pazopanib, enzastaurine) </li></ul><ul><li>VAD: AS104, AVE 8062 </li></ul><ul><li>Agents proapoptotiques </li></ul><ul><li>-anti Bcl2 (oblimersen) </li></ul><ul><li>-MDM2 </li></ul><ul><li>-ONYX-015 </li></ul><ul><li>-Ad5CMV-p53 </li></ul><ul><li>Antagonistes Survitin </li></ul><ul><li>Anti-trai2 (AMG655) </li></ul>
  49. 49. Gastric Cancer : targeted therapies 14/04/11 Targets Agent Randomised trials Phase Line Résults Métalloprotéase Marimastat Bramhall BJC 2002 III 2 Négative mTOR Okamoto et al. Jpn J Clin Oncol 2009 Everolimus GRANITE III 2-3 ongoing HER2 Lapatinib Trastuzumab ToGA III 1 Positive VEGF Shah MA et al. JCO 2006 Bevacizumab MRC-STO3 AVAGAST III III Périop 1 ongoing Négatif EGFR Cetuximab Panitumumab EXPAND REAL-3 MEGA III III IIR 1 Périop 1 ongoing ongoing ongoing HGF/c-Met GSK 089 AMG 102 MEGA IIR 1 ongoing Anti-VEGFR2 PXL108454 + taxol ImClone CP12-0922 IIR 2 ongoing
  50. 50. Anti-HER Anti-angiogenicss
  51. 51. Ac anti-HER2 : essai ToGA Bang YJ et al. Lancet 2010 Aug 28;376(9742):687-97. <ul><li>Phase III </li></ul><ul><li>1 rst line (M+ ou LA) </li></ul><ul><li>ADK gastric or EGJ </li></ul><ul><li>with HER2 surexpression </li></ul><ul><ul><li>IHC : HER2 3+ </li></ul></ul><ul><ul><li>or FISH : + </li></ul></ul><ul><li>22% (810 out of 3807 tumours ) : HER2 « + » </li></ul><ul><li>584 : 15% included in ToGA </li></ul><ul><li>33% Cardia vs 21% Stomach, p<0,001 </li></ul><ul><li>32% Intestinal vs 6% Diffuse, p<0,001 </li></ul>
  52. 52. Patients’ Characteristics Highest recruitment was from Korea, Japan, China and Russia F, fluoropyrimidine; C, cisplatin a n=287; b n=293 Characteristics F+C n=290 F+C + trastuzumab n=294 Sexe, % male / Female 75 / 25 77 / 23 Age, median (range) years 59.0 (21–82) 61.0 (23–83) weight, median (range) kg 60.3 (28–105) 61.5 (35–110) Région, n (%) Asia C/S America Europe other 166 (56) 26 (9) 95 (32) 9 (3) 158 (53) 27 (9) 99 (33) 14 (5) Type CG ( centralised) Intestinal Diffus Mixe 74.2 a 8.7 a 17.1 a 76.8 b 8.9 b 14.3 b Gastrectomy 21.4 24.1
  53. 53. Months 0,2 0,4 0,6 0,8 1,0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 FU/cap + cisplat n= 290 FU/cap + cisplat + trastuzumab n= 294 Événements RR = 0,74 (IC: 0,60-0,91) p = 0,0046 Van Cutsem E et al., ASCO 2009 13,8 m 11,1 m IHC3+ or 2+FISH+ : 11,8 m vs 16 m Primary objective : overall survival ( 10 m => 13 m) 5FU or cape-CDDP + trastuzumab vs 5FU or cape-CDDP phase III ToGA IHC 3+ et/ou FISH+ 0,0
  54. 54. Efficacité (survie): analyse de sous-groupe Risk ratio 0.2 1 2 5 0.4 0.6 3 4 All All 584 0.60, 0.91 0.74 GEJ Primary site 106 0.42, 1.08 0.67 Stomach 478 0.60, 0.96 0.76 Region Asia 319 0.61, 1.11 0.82 C/S America 52 0.21, 0.90 0.44 Europe 190 0.44, 0.89 0.63 Other 23 0.48, 3.08 1.22 0–1 ECOG PS 527 0.56, 0.89 0.71 2 57 0.51, 1.79 0.96 279 0.84 <60 Age group 0.62, 1.14 >60 305 0.49, 0.88 0.66 Fluoropyrimidine 5-FU 73 0.40, 1.23 0.70 Capecitabine 511 0.60, 0.95 0.75 Category Subgroup N 95% CI HR Diffuse GC type 51 0.56, 2.05 1.07 Intestinal 438 0.54, 0.88 0.69 Mixed 91 0.51, 1.46 0.86 1–2 No. metastatic sites 298 0.68, 1.26 0.93 >2 285 0.43, 0.77 0.57 No Yes Prior gastrectomy 451 133 0.72 0.81 0.57, 0.91 0.49, 1.34 Favours T Favours no T
  55. 55. Efficacité (survie): selon le statut HER2 Subgroup Median OS (months) All 11.1 13.8 vs Pre-planned analysis IHC0/FISH+ IHC1+/FISH+ IHC2+/FISH+ IHC3+/FISH+ IHC3+/FISH- 7.2 10.2 10.8 12.3 17.7 10.6 8.7 12.3 17.9 17.5 Exploratory analysis IHC0 or 1+/FISH+ IHC2+/FISH+ or IHC3+ 8.7 11.8 10.0 16.0 vs vs vs vs vs vs vs 0.92 1.24 0.75 0.58 0.83 0.48, 1.76 0.70, 2.20 0.51, 1.11 0.41, 0.81 0.20, 3.38 Hazard ratio 95% CI 0.74 0.60, 0.91 1.07 0.65 0.70, 1.62 0.51, 0.83 Risk ratio Favours T Favours no T 584 61 70 159 256 15 131 446 N 0.2 0.4 0.6 1 2 3 4 5
  56. 56. Algorythme for characterisation of HER2 in GC/JOG 0 FISH/SISH* + – Eligible for trastuzumab +1 +3 IHC Tumoral tissue +2 *cut off for FISH, SISH = HER2:CEP17 ratio ≥2
  57. 57. Synthesis <ul><li>Trastuzumab reduce the risk of death by 26% when combined to “standard” chemotherapy using “5FU” + CDDP (HR 0,74) </li></ul><ul><li>Increases the overall survival </li></ul><ul><ul><li>From 11.1 to 13.8 m; p=0,0046 in gastric cancer patients HER2-+ </li></ul></ul><ul><ul><li>& from 11.8 months to 16.0 m ; HR 0,65 ) in gastric cancer patients with a high HER2 expression (IHC 2+/FISH+ or IHC 3+) </li></ul></ul><ul><li>PFS and RR are also ameliorated. </li></ul><ul><li>Tolerance is acceptable with about 6% of EF diminution </li></ul>
  58. 58. Anti HER1 (EGFR) Acanti-EGFR (Acanti-EGFR : Cmab, Pmab) TKI (erlotinib, gefitinib) Surexpression : > 50% Mutations Kras / Braf : rare.
  59. 59. Anti-EGFR: phase II in gastric cancer 14/04/11 Essai Phase Tumeur Stade Ligne nb Agent Chimiothérapie OR (%) PFS (m) SG (mois) Fahlke ASCO 2009 II E LA/M+ 1 30 Cetux Docetaxel, CDDP 27 ND ND Pinto Br J Cancer 2009 II E, C LA/M+ (96%) 1 72 Cetux (jà PD) Docetaxel, CDDP (x 6) 41 5.0* 9.0 Kanzler ASCO 2009 II E, C LA/M+ 1 49 Cetux FU, CPT11 42 8.5 16.6 Pinto Ann Oncol 2007 II E, C LA/M+ (87%) 1 38 Cetux (jà PD) FU, CPT11 (x 12) 44 8.0* 16.0 Zhang ASCO GI 2009 II E LA/M+ 1 52 Cetux Cape, CDDP 48 5.2* ND Han Br J Cancer 2009 II E M+/ récid. 1 40 Cetux (jà PD) FU, LOHP (x 12) 50 5.5* 9.9 Kim Invest New Drugs 2009 II E M+ / récid. 1 44 Cetux (jà PD) Cape, LOHP (x 8) 52 6.5 11.8 Woell ASCO 2009 II E LA/M+ 1 51 Cetux CPT11, LOHP 63 5.7* 8.7 Lordick Br J Cancer 2010 II E M+ 1 52 Cetux FU, LOHP 65 7.6* 9.5 Yeh ASCO 2009 II E LA/M+ 1 35 Cetux FU, CDDP 69 10.0 15.0 Tebbutt Br J Cancer 2010 IIR E, C, O M+ 2 38 Cetux Docetaxel 6 2.1 5.2
  60. 60. Anti EGFR in phase III Anti-HER(Ac) <ul><li>Cetuximab(erbitux®) : EXPAND </li></ul><ul><ul><li>XP vs XP + cetuximab </li></ul></ul><ul><ul><li>Clos, n = 870 (obj : SSP) </li></ul></ul><ul><li>Panitumumab(vectibix®) : REAL 3 </li></ul><ul><ul><li>EOX vs EOX + Pmab </li></ul></ul><ul><ul><li>En cours </li></ul></ul>EGFR
  61. 61. Ab Anti-VEGF : AvaGast trial Y. Kang et al., ASCO 2010, LBA #4007 Phase III 1 ère ligne (M+ ou LA ) ADK gastriques ou JOG
  62. 62. AVAGAST: P hase III in 1rst line tt gastric adenocarcinomas Xeloda*/cisplatin + placebo / 3 w Xeloda*/cisplatin + Avastin 7.5 mg/kg , / 3 w Gastric Cancers Locally advanced Metastatic (n=774) R <ul><li>Primary objective: Survival </li></ul><ul><li>secondaries: PFS, RR & duration OR, tolerance, QoL </li></ul>Kang, et al. ASCO 2010 *5-FU also allowed if Xeloda contraindicated Xeloda 1 , 000 mg/m 2 bid , d1-21 cisplatin 80 mg/m 2 , d1 After a maximum of 6 cycles of cisplatin, patients can continue with Xeloda and Avastin • Asie Pacifique : 50% • Europe : 32% • Amérique : 19% <ul><li>95% M+ • </li></ul><ul><li>IP OMS 1-0 : 95% • </li></ul><ul><li>Estomac : 87% / JOG 13% • </li></ul><ul><li>Intestinal : ~40% / diffus : ~50% • </li></ul>
  63. 63. Overall Survival Y. Kang et al ., ASCO 2010 , LBA 4007 10,1 m vs 12,1 m HR = 0,87 ( p = 0.1 ) AVAGAST Survival rate 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 3 6 9 12 15 18 21 24 XP + Bev XP + Placebo Studymonths
  64. 64. PFS Y. Kang et al ., ASCO 2010 , LBA 4007 10,1 m vs 12,1 m HR = 0,87 ( p = 0,1 ) AVAGAST Survival rate 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 3 6 9 12 15 18 21 24 XP + Bev XP + Placebo Studymonths XP + placebo XP + Beva . HR America 6, 8 m 11,5 m 0,63 Europe 8,6 m 11,1 m 0,85 Asie – Pacifique 12,1 m 13,9 m 0,97 … Efficacity to be reevaluted ?
  65. 65. Overall Survival: sub-group Analysis Pan-America * 29 patients with locally advanced disease only Kang, et al. ASCO 2010  2 No Disease status ECOG performance Prior gastrectomy Region Site of primary disease No. of metastatic sites at baseline Disease measurability Histologic type All Locally advanced* Metastatic 0 Yes Europe All  1 Asia Stomach GE junction  1 Measurable Non-measurable Intestinal Diffuse Mixed Subgroup Category 2 Hazard Ratio 0 1
  66. 66. Avastin in gastric cancer treatment <ul><li>AVAGAST study is negative on its primary objective: O. survival. </li></ul><ul><li>Important differences exist according to regions </li></ul><ul><li>Risk of 2 to 3% of perforation and less than 1% of death </li></ul><ul><li>Need for studies able to characterise the sub-group which may benefit from avastin. </li></ul><ul><li>Ongoing studies: </li></ul><ul><ul><li>MAGIC-B: P hase III neoadjuvant/adjuvant study in resectable gastric cancer test ECX +/- bevacizumab.(1100 pts) </li></ul></ul><ul><ul><li>ML22367: P hase III randomised trial in first-line metastatic gastric cancer in China test XP +/- bevacizumab (200 pts) </li></ul></ul>
  67. 67. Second line treatment for metastatic gastric cancer <ul><li>Second line treatment benifits outcome of selected patients </li></ul><ul><ul><li>PS </li></ul></ul><ul><ul><li>organ function </li></ul></ul><ul><ul><li>expectations of patients </li></ul></ul><ul><li>OPTIONS: depend on earlier lines </li></ul><ul><ul><li>irinotecan / Folfiri </li></ul></ul><ul><ul><li>docetaxel or paclitaxel </li></ul></ul><ul><ul><li>later lines: capecitabine/ mitomycine: low degree of evidence </li></ul></ul><ul><ul><li>clinical trial </li></ul></ul>
  68. 68. GASTRIC CANCER – CONCLUSION 1 <ul><li>Major problem </li></ul><ul><li>Surgery remains the main curative treatment </li></ul><ul><li>Results of surgical resection are poor with reccurrence rates ranging from 60 to 80% </li></ul><ul><li>Perioperative (neoadjuvant +/- adjuvant) chemotherapy, even with old drugs, is a valid option in resectable GC. </li></ul><ul><li>Relation between volume of the center and outcome after gastric cancer surgery has been established </li></ul>
  69. 69. GASTRIC CANCER – CONCLUSION 2 <ul><li>Chemotherapy improve survival in metastatic GC : oxaliplatine, taxoter and irinotecan combinations with 5FU are valid options </li></ul><ul><li>Trastuzumab is the only targeted therapy with a demonstrated activity in HER2 hyperexpression </li></ul><ul><li>Multidisciplinary discussion and treatment in expert teams and centers </li></ul><ul><li>Relation between volume of the center and outcome after gastric cancer surgery has been established </li></ul>

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