Κανθίκμξ παπέμξ εκηένμο Κίθα Πιμηανπμπμύιμο
οπκόηεηα Cancer statistics 2013
Θκεηόηεηα Cancer statistics 2013
Πανάγμκηεξ θηκδύκμο Ηιηθία >50 εηώκ Δηαηνμθή δωηθό ιίπμξ θοηηθέξ ίκεξ Σνόπμξ δωήξ παποζανθία, θάπκηζμα, αιθμόι Οηθμγεκεηαθό ή αημμηθό ηζημνηθό CRC Φιεγμμκώδεηξ κόζμη εκηένμο ειθώδεξ θμιίηηδα, κόζμξ Crohn HNPCC Lynch syndrome I, II ύκδνμμα πμιοπμδίαζεξ FAP, ζύκδνμμα Gardner & Turcot, κεακηθή πμιοπμδίαζε
Κανθίκμξ παπέμξ εκηένμο Sporadic (average risk) (75-80%) Rare syndromes (<0.1%) Familial adenomatous polyposis (FAP) (1-2%) Hereditary nonpolyposis colorectal cancer (HNPCC) (3-5%) Family history (10-15%)
Γεκεηηθό μμκηέιμ θανθηκμγέκεζεξ Οptimum phase for early detection Normal colonic epithelium Dysplastic aberrant crypt foci Initial adenoma develops Intermediate adenoma Late adenoma Carcinoma Metastasis Mutation in APC Mutation in K-ras Mutation in DCC Mutation in p53 Other alterations?
Παράγοντας Κολονοσκόπηση Ηλικία 50 εηών Σςγγενήρ 1ος βαθμού με ΚΚ Ανά 10 έηη 10 έηη ππιν ηη νεόηεπη ηλικία εμθάνιζηρ ζηην οικογένεια και καηόπιν ανά 3-5 έηη 2 ζςγγενείρ 2ος βαθμού με ΚΚ ζηην ηλικία ηων 50 εηών και καηόπιν ανά 5 έηη Αηομικό ιζηοπικό αδενώμαηορ Αηομικό ιζηοπικό ΚΚ Αηομικό ιζηοπικό ΙΦΝΕ Σύνδπομο Lynch FAP attenfap ζ.peutz-jeghers ζ.νεανικήρ πολςποδίαζηρ Πολςποδίαζη MYH Ανά 3-5 έηη 1 έηορ μεηά ηην εγσείπηζη και καηόπιν αναλόγωρ 8-10 έηη μεηά ηην έναπξη ηων ζςμπηωμάηων και μεηά ανά 1-2 έηη ζε ηλικία 10 εηών ππιν ηη νεόηεπη πποζβολή ζηην οικογένεια (max εώρ 20-25 εηών)/ 1-2 έηη ζε ηλικία 10-15 εηών / έηορ ζε ηλικία 15-20 εηών /2-3 έηη ζε ηλικία 15-20 εηών /2-3 έηη ζε ηλικία 15 έηών / 2-3 έηη ζε ηλικία 25-30 εηών / 3-5 έηη
ηαδημπμίεζε
Κανθίκμξ παπέμξ εκηένμο 80% εμθακίδμκηαη με ημπηθή/πενημπηθή κόζμ 20% εμθακίδμκηαη με μεηαζηαηηθή κόζμ Distant (Stage IV) 20% Localized (Stage I/II) 50% Μεηαλύ ηωκ αζζεκώκ με πνώημε κόζμ, 40 % ζα εμθακίζμοκ οπμηνμπή Regional (Stage III) 30%
% of patients 5-εηήξ επηβίωζε ακάιμγα με ημ ζηάδημ 70-90% 65% 25-70% 5-10% All Stages Stages Ι-ΙΙ Stage ΙΙΙ Stage ΙV
MOSAIC: ζπεδηαζμόξ μειέηεξ FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m² R Stage II / III colon cancer LV5FU2 Primary end-point: disease-free survival Secondary end-points: safety, overall survival
Ειεύζενε κόζμο επηβίωζε Probability 1.0 0.9 DFS FOLFOX4 (n=1123) 78.7% LV5FU2 (n=1123) 73.3% 0.8 0.7 0.6 HR (95% CI): 0.76 (0.64 0.89); p=0.0008 0.0 0 6 12 18 24 30 36 42 48 54 60 66 DFS (months)
Probability 1 0,9 0,8 0,7 3εηήξ ειεύζενε κόζμο επηβίωζε ζηάδημ III FOLFOX4 (n=672) 71.8% LV5FU2 (n=675) 65.5% 0,6 0,5 Hazard ratio: 0.76 [0.62-0.92] 0 10 20 30 40 50 DFS (months) 24% risk reduction for stage III patients in the FOLFOX4 arm
Χεμεημζεναπεία μεηαζηαηηθήξ κόζμο Agent FDA approval status 5-FU 1962 Irinotecan 1998 (second-line) 2000 (first-line) Capecitabine 2001 (first-line) Oxaliplatin 2002 (second-line) 2004 (first-line)
ημπεομέκε ζεναπεία Agent FDA approval status Bevacizumab(anti-VEGFAb) 2004 Cetuximab(anti-EGFRAb) 2004 Panitumumab(anti-EGFRAb) 2006 Aflibercept (VEGF trap) 2012 Regorafenib (VEGFR TKI) 2012
Vascular Endothelial Growth Factor θαη αγγεημγέκεζε VEGF VEGF bfgf TGFβ-1 VEGF bfgf TGFβ-1 PLGF VEGF bfgf TGFβ-1 PLGF PD-ECGF VEGF bfgf TGFβ-1 PLGF PD-ECGF Pleiotrophin Continued VEGF expression
VEGF θαη πνόγκωζε Reduced overall survival Increased disease progression High VEGF levels Poor prognosis Increased risk of relapse Increased vascular permeability
Bevacizumab VEGF VEGF receptor Bevacizumab
AVF2107g: Μειέηε bevacizumab ζηεκ πνώηε γναμμή Phase III Previously untreated mcrc (n=923) Primary endpoint: OS R Avastin 5 mg/kg q2w + IFL (n=402) Placebo + IFL (n=411) Secondary endpoints: PFS, ORR, duration of response, safety and QoL
OS estimate PFS estimate AVF2107g: απμηειεζμαηηθόηεηα OS PFS 1.0 Avastin + IFL (n=402) Placebo + IFL (n=411) 1.0 Avastin + IFL (n=402) Placebo + IFL (n=411) 0.8 HR=0.66 p<0.001 0.8 HR=0.54 p<0.001 0.6 0.6 0.4 0.4 0.2 0.2 0 15.6 20.3 0 5 10 15 20 25 30 0 6.2 10.6 0 5 10 15 20 25 30 Time (months) Time (months)
AVF2107g: αζθάιεηα Selected grade 3/4 AE, % Avastin + IFL (n=393) Placebo + IFL (n=397) Patients with any event 85 74 Hypertension (grade 3 only) 11 2 Proteinuria (grade 3 only) 1 1 Leucopenia 37 31 Diarrhoea 32 25 Any thrombotic event 19 16 Pulmonary embolism 4 5 Deep thrombophlebitis 9 6 Bleeding 3 3 GI perforation 2 0
p=0.005 p=0.217 p 0.001 p=0.0002 p=0.0023 p 0.001 p 0.001 4.2 p 0.001 5.2 5.5 5.1 6.2 5.7 Median PFS (months) 7.2 8.0 8.5 8.3 9.0 9.2 9.4 9.1 10.6 Μειέηεξ Avastin - PFS 15 AVF0780g (n=104) AVF2107g (n=813) AVF2192g (n=209) NO16966 (n=1,400) AGITG MAX (n=313) ARTIST (n=214) AVEX (n=280) 10 5 0
p=0.137 p=0.582 p 0.001 p=0.160 p=0.0769 p=0.314 p=0.014 p=0.182 Median OS (months) 12.9 13.8 13.4 16.1 15.6 16.6 16.8 20.3 19.9 18.9 18.9 18.7 20.7 21.5 21.3 Μειέηεξ Avastin - OS 25 AVF0780g (n=104) AVF2107g (n=813) AVF2192g (n=209) NO16966 (n=1,400) AGITG MAX (n=313) ARTIST (n=214) AVEX (n=280) 20 15 10 5 0
E3200: μειέηε Avastin ζηε δεύηενε γναμμή Avastin 10 mg/kg q2w* + FOLFOX4 (n=286) mcrc patients previously treated with irinotecan and fluoropyrimidine (n=829) R FOLFOX4 (n=291) Avastin (n=243) Phase III Primary endpoint: OS Secondary endpoints: PFS, ORR, safety
OS estimate PFS estimate E3200: απμηειεζμαηηθόηεηα OS PFS 1.0 0.8 0.6 Avastin + FOLFOX4 (n=286) FOLFOX4 (n=291) HR=0.75 p=0.0011 1.0 0.8 0.6 Avastin + FOLFOX 4 (n=280) FOLFOX4 (n=279) HR=0.61 p<0.0001 0.4 0.4 0.2 0.2 0 10.8 12.9 4.7 7.3 0 0 10 20 30 40 0 10 20 30 Time (months) Time (months)
E3200: αζθάιεηα Selected grade 3/4 AE, % Avastin+ FOLFOX4 (n=287) FOLFOX4 (n=285) Grade 3 Grade 4 Grade 3 Grade 4 Hypertension 5.2 1.0 1.4 0.4 Proteinuria 0.7 0 0 0 Bleeding 3.1 0.3 0.4 0 Neuropathy 16 0.3 8.8 0.4 Cardiac ischaemia 0.3 0.3 0 0.4 Thromboembolism 3.1 0.3 1.1 1.4 Cerebrovascular ischaemia 0.3 0 0 0 GI perforation 1 0
Avastin + standard 1L chemo (either oxaliplatin or irinotecan-based) (n=820) PD ML18147: μειέηε ζοκέπηζεξ Avastin μεηά από πνόμδμ κόζμο R CT switch: Oxaliplatin Irinotecan Irinotecan Oxaliplatin Standard 2L chemo (oxaliplatin or irinotecan-based) until PD Avastin (2.5mg/kg/wk) + standard 2L chemo (oxaliplatin or irinotecan-based) until PD Phase III Primary endpoint: OS from randomisation Secondary endpoints: PFS, ORR, OS from start of 1L therapy
OS estimate PFS estimate ML18147: απμηειεζμαηηθόηεηα OS PFS 1.0 0.8 0.6 Avastin + chemo (n=409) Chemo (n=410) HR=0.81 (95% CI: 0.69 0.94) p=0.0062 1.0 0.8 0.6 Avastin + chemo (n=409) Chemo (n=410) HR=0.68 (95% CI: 0.59 0.78) p<0.0001 0.4 0.4 0.2 0.2 0 9.8 11.2 0 6 12 18 24 30 38 42 48 Time (months) 0 4.1 5.7 0 6 12 18 24 30 38 42 Time (months)
Αλημιόγεζε αζζεκμύξ με επαηηθέξ μεηαζηάζεηξ First-line therapy for patients with liver metastases Patient assessment Upfront resectable (~10%) Borderline resectable (~30%) Unresectable (~60%) Treatment goal Curative surgery Make eligible for curative surgery Extend survival and maintain quality of life Treatment strategy Chemotherapy resection Chemotherapy ± biologics Chemotherapy ± biologics
ORR (%) Πμζμζηά ακηαπόθνηζεξ με ηεκ πνμζζήθε bevacizumab 100 80 60 Gono (n=30) 80% Gruenberger (n=56) 73% Bοxer (n=45) 78% 40 20 0 Bevacizumab + FOLFOXIRI Bevacizumab Bevacizumab + XELOX + XELOX
Avastin θαη πεηνμονγεζημόηεηα επαηηθώκ μεηαζηάζεωκ Study Experimental arm n R0 resection rate (%) ORR (%) NO16966 Avastin + XELOX/FOLFOX4 211 12 NR First-BEAT Avastin + chemotherapy 704 12 NR ETNA Avastin + chemotherapy 159 13 NR Gruenberger Avastin + XELOX 56 13 73 BOXER Avastin + XELOX 45 20 78 GONO Avastin + FOLFOXIRI 30 40 80 Trials in patients with borderline resectable disease Avastin-based therapy leads to high response rates and allows R0 resection of liver metastases in some borderline resectable patients with mcrc
OS estimate Παζμιμγμακαημμηθή ακηαπόθνηζε με ηεκ πνμζζήθε bevacizumab 1.0 5-year OS 0.8 76% 0.6 0.4 0.2 0 Major pathological response Partial pathological response No pathological response p=0.036 0 12 24 36 48 60 72 Time (months) 42% 40%
OS estimate (%) Landmark Επηβίωζε αζζεκώκ 1.0 0.8 0.6 Liver resection 0.4 No liver resection 0.2 0 0 12 24 36 48 60 72 Time (months) 5-year survival rate was higher in patients undergoing hepatic resection (55.2%) than in patients with unresected disease (19.5%)
Binding of ligand to inactivate EGFR Dimerisation Modification of TK domain Activation of intracellular signalling pathways ATP P P P P Cell proliferation, survival, migration, adhesion and differentiation
ΕGFR ακαζημιείξ EGF EGFR EGFR Homodimer TGF-α ANTI-EGFR RAF RAS GTP RAS GDP EGFR MEK ERK JNK Nck JNKK PAK Rac PKC PLCγ PI3K S6K PTEN AKT mtor Proliferation Anti-apoptosis Angiogenesis Survival Metastasis Elk Myc Jun Fos
Μμκμθιωκηθά ακηηζώμαηα έκακηη ΕGFR Cetuximab IgG 1 mab Chimeric protein Panitumumab IgG 2 mab Fully humanized
Ρόιμξ RAS EGFR homodimer Other effector pathways GRB2 SHC KRAS GDP Gab SHp2 NRAS GDP NF1 SOS1 GAP KRAS GTP NRAS GTP Proliferation Survival
Oηθμγέκεηα RAS G domain Hypervariable region P loop Switch I Switch II KRAS4A KRAS4B NRAS HRAS 12 13 61 1 189 12 13 61 1 188 KKKKKK 12 13 61 1 189 12 13 61 1 10 16 32 38 59 67 85 165 189 C C C C CIIM CVIM CVVM CVLS
Πνμβιεπηηθή αλία wild-type kras
Response rate (%) PFS PFS Μειέηεξ cetuximab ζηεκ πνώηε γναμμή 1.0 CRYSTAL Cetuximab+ CT CT alone 0.8 0.6 32% risk reduction for progression HR=0.68 70 60 50 40 30 20 10 0 CRYSTAL p=0.0025 43 FOLFIRI (n=176) 59 Cetuximab + FOLFIRI (n=172) OPUS p=0.011 37 FOLFOX (n=73) 61 Cetuximab + FOLFOX (n=61) 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Cetuximab + FOLFIRI FOLFIRI 0 2 4 6 8 10 12 14 16 18 Time (months) Cetuximab + FOLFOX FOLFOX OPUS 43% risk reduction for progression HR=0.57 0 2 4 6 8 10 12 14 16 18 Time (months)
Survival (Mos) οζπεηηζμόξ ελακζήμαημξ θαη επηβίωζεξ 16 14 12 10 8 6 4 2 No reaction Grade 1 rash 0 CRC CRC CRC CRC Study: 9923 0141 BOND ΕΟRTC Grade 2 rash Grade 3 rash
Proportion Event-Free PRIME Μειέηε Panitumumab 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Events n (%) median PFS (95% CI) μήνες Panitumumab + FOLFOX4 (n=325) 270 (83) 10,0 (9,3 11,4) FOLFOX4 (n=331) 280 (85) 8,6 (7,5 9,5) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 Months HR = 0,80 (95%CI: 0,67 0,95) p = 0,01
Proportion Event-Free PRIME Μειέηε Panitumumab 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Events n (%) Median OS (95% CI) μήνες Panitumumab + FOLFOX4 (n=325) 214 (566) 23,9 (20,3 27,7) FOLFOX4 (n=331) 231 (70) 19,7 (17,6 22,7) HR = 0,88 (95%CI: 0,73 1,06) p = 0,17 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 Months
Proportion alive (%) PRIME OS WT RAS 100 90 80 70 60 50 40 30 20 10 0 Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 (n = 259) 128 (49) 26.0 (21.7 30.4) FOLFOX4 (n = 253) 148 (58) 20.2 (17.7 23.1) HR = 0.78 (95% CI, 0.62 0.99) P = 0.043 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months
PRIME πμζμζηά μεηαζηαζεθημμήξ ήπαημξ Panitumumab + FOLFOX4 (n=325) FOLFOX4 (n=331) Objective response rate, % 1 57 48 Patients with liver-only metastases at baseline, n (%) 61 (19) 57 (17) Patients with complete liver resection, n (%) 17 (28%) 10 (18%)
Kaplan-Meier Overall survival Estimate PRIME OS μεηά από μεηαζηαζεθημμή 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 Months Months Complete resection Incomplete resection Events (%) Median number of months 3 / 27 (11) Not reached 54 / 91 (59) 23.6 (19.4-30.9)
VEGF Trap - aflibercept
VELOUR: μειέηε aflibercept
VELOUR: απμηειεζμαηηθόηεηα
VEGFR ακαζημιείξ ηονμζηκηθήξ θηκάζεξ Agent # mcrc Trials CRC Patients Cediranib AZD2171 2 Phase III 3,194 Semaxinib SU5416 2 Phase III 2,084 Vatalanib PTK787 2 Phase III 2,050 Sunitinib SU11248 Phase III 1,623 Brivanib BMS-582664 Phase III 926 Regorafenib BAY 73-4506 Phase III 730 Sorafenib BAY 43-9006 Phase IIB 814 Vandetanib ZD6474 Phase IIB 356 Axitinib AG-013736 Phase IIB 299 Linifanib ABT-869 Phase IIB 147 Vargateg BIBF 1120 Phase II 166 Tivozanib AV-951 Phase II 80 Motesanib AMG-706 Phase IB 148 Pazopanib GW786034 Phase IB 94 >10,000
Survival distribution function Mειέηε regorafenib - 3ε γναμμή 1.00 0.75 Regorafenib Placebo Median 6.4 mos 5.0 mos 95% CI 5.9 7.3 4.4 5.8 Hazard ratio: 0.77 (95% CI: 0.64 0.94) 1-sided p-value: 0.0052 0.50 0.25 0 Placebo N=255 Regorafenib N=505 0 50 100 150 200 250 300 350 400 450 Days from randomization
Eπηβίωζε ζημκ μεηαζηαηηθό θανθίκμ παπέμξ εκηένμο