advances in the adjuvant treatment of colorectal cancer stefano cascinu clinica di oncologia medica...
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Advances in the adjuvant treatment of colorectal cancer
Stefano CascinuClinica di Oncologia Medica
Ancona
COLON CANCER2004
COLON CANCER2004
Estimated New Cases in Europe and Estimated New Cases in Europe and ItalyItaly
DeathDeath
UE: 213.000 110.000UE: 213.000 110.000
I: 32.000 16.000 I: 32.000 16.000
ADJUVANT CT VS CONTROL: AGE < vs > 70 YRS
Sargent 2001
1990 FU/levamisole better than surgery alone
1994 FU/LV better than surgery alone
1996 FU/LV better than FU/levamisole
1996 6 months FU/LV = 12 months FU/LV
1996 Levamisole unnecessary
1996 HD LV = LD LV
1998 Weekly = monthly schedules
2001 Elderly benefit from therapy
ADJUVANT COLON CANCER:ADJUVANT COLON CANCER:
MAIN STEPS FROM 1990 to 2002MAIN STEPS FROM 1990 to 2002
Infusional 5-FU?Intraportal + systemic 5-FU?Oral fluoropyrimidines?Oxaliplatin?Irinotecan
ADJUVANT COLON CANCER :ADJUVANT COLON CANCER :
Questions answered from 2002:
Open questions on Open questions on adjuvant therapy adjuvant therapy
Patient selectionStage CStage B2
Treatment choice
MOSAICMOSAICMOSAICMOSAIC
2246 Patients
Stage III 60%
FOLFOX-4
LV5FU2
RANDOM
André T, NEJM 2004
0,5
0,6
0,7
0,8
0,9
1
0 10 20 30 40 50
MOSAIC: DFS in stage IIIMOSAIC: DFS in stage IIIMOSAIC: DFS in stage IIIMOSAIC: DFS in stage III
DFS 3-y
FOLFOX4 72.2%
LV5FU2 65.3%
Hazard ratio: 0.76 (0.62 – 0.92)
24% risk reduction for stage III patients
Benefit of Adjuvant CT in stage Benefit of Adjuvant CT in stage IIIIII
Benefit of Adjuvant CT in stage Benefit of Adjuvant CT in stage IIIIII
Bolus 5FU
FOLFOX4
Relative Risk Reduction
40% +24%
Absolute Benefit 13% +7%
Number Needed to Treat
8:1 5:1
N. of Recurrence Saved
1/4 1/2.5
Trial Pts Treatment Data
MOSAIC224
6FOLFOX-4 x 6 mos5FULV2 x 6 mos
3-y DFS4-y DFSSafety
NSABP C-07
2407
FLOX x 6 mos Bolus 5FULV w x 6
mos
3-y DFSSafety
ROCHE NO1696
8
1886
XELOX x 6 mosBolus 5FULV w/q4w x
6 mosSafety
Trials evaluating LOHP in the Trials evaluating LOHP in the adjuvant settingadjuvant setting
Trials evaluating LOHP in the Trials evaluating LOHP in the adjuvant settingadjuvant setting
ROCHE NO16968ROCHE NO16968ROCHE NO16968ROCHE NO16968
1886 Patients
Stage III
XELOX q3w x6 mos
Bolus 5FU/LV qw or q4w x6 mos
RANDOM
Schmoll, PASCO 2005
Grade 3/4 AEs (%) 5FU/LV XELOXFOLFO
X*Diarrhea 17.1 15.6 10.8Stomatitis 7.9 0.6 2.7Nausea 3.9 4.1 5.1Vomiting 2.5 5.0 5.8Neurosensory 0 8.1 12.4HFS 0.2 3.6 2.0Neutropenia 10.9 5.3 41.1Febrile Neutropenia 3.8 0.2 1.8Treatment related Deaths
0.5 0.7 0.5
ROCHE NO16968: SAFETYROCHE NO16968: SAFETYROCHE NO16968: SAFETYROCHE NO16968: SAFETY
* Data from MOSAIC trial
NSABP C-07NSABP C-07NSABP C-07NSABP C-07
2407 Patients
Stage III 71%
FLOXqw x6 mos
FU/LVqw x6 mos
RANDOM
Wolmark N, PASCO 2005
MOSAIC(FOLFOX4)
C-07(FLOX)
3-y DFS 78% 77%
Absolute Benefit
+5% +5%
HR 0.77 0.79
Diarrhea g3-4 11% 36%
Deaths 0.5% 1.2%
NSABP C-07 vs MOSAICNSABP C-07 vs MOSAICNSABP C-07 vs MOSAICNSABP C-07 vs MOSAIC
ADJUVANT CT FOR STAGE III
COLON CANCER TODAY …
ADJUVANT CT FOR STAGE III
COLON CANCER TODAY …
Study Author N Treatment Arms 5-y DFS
GERCORAndrè2003
9055FULV2 x 6-9mFU/LV q4w x 6-9m
67%67%
INT-0153Poplin 2005
9405FU PVI/Lev x 6m FU/LV/Lev q4w x 6m
63%61%
SAFFAChau2005
8015FU PVI x 3mFU/LV q4w x 6m
73%67%
X-ACTTwelves
20051987
Capecitabine x 6mFU/LV q4w x 6m
64%60%
NSABP C-06
Wolmark
20051608
UFT/LV x 6mFU/LV qw x 6m
67%68%
Adjuvant Infusional or Oral Adjuvant Infusional or Oral 5FU 5FU
Adjuvant Infusional or Oral Adjuvant Infusional or Oral 5FU 5FU
Advantages
• Toxicity ( ↓ diarrhea, stomatitis, neutropenia)
• Duration (3 months 5FU PVI)
• Compliance (oral 5FU)
Disadvantages
• Efficacy ( = 5FU/LV)
• CVC complications (infusional 5FU)
• Compliance (oral 5FU)
Adjuvant Infusional or Oral 5FU Adjuvant Infusional or Oral 5FU Adjuvant Infusional or Oral 5FU Adjuvant Infusional or Oral 5FU
Heterogeneous prognosis of stage III
Weakness of FOLFOX
Patients’ characteristics/preferences
Why consider a monotherapy? Why consider a monotherapy?
Prognostic factors for stage IIIPrognostic factors for stage III
T, N, grade
Number of N removed/examined
MSI, TGF-1 RII, 18q LOH
TS, TP, DPD, p53
LDH-5, FLK-1
Gene signature
Known
Unknown
Green FL, Ann Surg 2002
Prognosis of stage III patientsPrognosis of stage III patients
Gill S, J Clin Oncol 2004
5y-DFS of resected colon cancer5y-DFS of resected colon cancer
Weakness of FOLFOXWeakness of FOLFOX
Toxicity
Long term safety
• Neurotoxicity
• Secondary leukemia
Long term efficacy
• 3-y DFS vs 5-y OS
NCI Gr 3 (%) FOLFOX4 LV5FU2
Thrombocytopenia 1.7 0.4
Neutropenia 41.1 4.7
Febrile neutropenia 0.7 0.1
Neutropenic sepsis 1.1 0.1
Diarrhoea 10.8 6.7
Stomatitis 2.7 2.2
Vomiting 5.9 1.4
Allergy 3.0 0.2
Alopecia (Gr 2) 5.0 5.0
All cause mortality 0.5 0.5
MOSAIC: toxicityMOSAIC: toxicity
0
2
4
6
8
10
12
14
Pati
en
ts w
ith
Gra
de 3
Neu
rop
ath
y (
%)
13%
5%
1%0.5%*
During Treatment
28-DayFollow up
6-MonthFollow up
18-MonthFollow up
MOSAIC: Incidence of Grade 3 NeuropathyMOSAIC: Incidence of Grade 3 Neuropathy
Andrè T, NEJM 2004 * 4% grade 2-3
Median DI: 820 mg/sqm
Atypical cumulative neurotoxicity• Rare situation described with cumulative doses > 1000
mg/sqm
• Presentation: Lhermitte’s sign/Urinary retention
• Involvement of dorsal root, spinal cord and parasympathetic
“Coasting” phenomenon• 10-15% of patients symptoms emerge or worsen after
oxaliplatin discontinuation
• This toxicity is not adequately described
• In the MOSAIC 12 patients developed grade 3 sensor
neurotoxicity after the end of treatment
OXALIPLATIN CRHONIC NEUROTOXICITYOXALIPLATIN CRHONIC NEUROTOXICITY
Taleb S, Cancer 2002
Oxaliplatin-Related Acute Myelogenous Leukemia
Oxaliplatin-Related Acute Myelogenous Leukemia
• 56-year-old woman• FOLFOX-4 (12 cycles)• FOLFOX-6 + BV (9 cycles)
• 65-year-old woman• Irinotecan (3 cycles)• FOLFOX-4 (3 cycles)
Merrouche Y, Ann Oncol 2005Carneiro BA, Oncologist 2006
3-y DFS as surrogate of 5-y OS3-y DFS as surrogate of 5-y OS
Sargent D, J Clin Oncol 2005
Analisys of 18 randomized trials (5FU-based)
What does DFS means?What does DFS means?
1) Disease Relapse
2) Death from any cause
3) Second colorectal cancer
4) Second non colorectal cancer
• Sargent: 1+2
• MOSAIC, X-ACT: 1+2+3
• PETACC-3, ACCORD: 1+2+3+4
What does DFS means?What does DFS means?
1) Disease Relapse
2) Death from any cause
3) Second colorectal cancer
4) Second non colorectal cancer
• Sargent: 1+2
• MOSAIC, X-ACT: 1+2+3
• PETACC-3, ACCORD: 1+2+3+4
RFS
Trial TreatmentStag
ePatients
CALGBC89803
IFLBolus 5FU/LV w
III 1246
ACCORD2FOLFIRI5FULV2
III HR
400
PETACC-3FOLFIRI or AIO-
IRI5FULV2 or AIO
III 2111 No benefit in DFS Excessive toxicity with IFL
Trials evaluating IRINOTECAN in Trials evaluating IRINOTECAN in the adjuvant settingthe adjuvant setting
Trials evaluating IRINOTECAN in Trials evaluating IRINOTECAN in the adjuvant settingthe adjuvant setting
Neutropenia Febrile neutropenia Death during treatment
43%
4% 2.8%5%
1% 1%0
10
20
30
40
50
Pat
ien
ts (
%)
P < .00001
P < .0005 P < .008
LV5FU2 + Irinotecan
LV5FU2 alone
Saltz LB, PASCO 2004
CALGB C89803: IFL vs FLCALGB C89803: IFL vs FL
PETACC-3: FOLFIRI-AIOIRI vs FLPETACC-3: FOLFIRI-AIOIRI vs FL
Results Stage III
HR P-value
DFS 0.89 0.091
RFS 0.86 0.045
Van Cutsem E, PASCO 2005
PETACC-3: FOLFIRI-AIOIRI vs FLPETACC-3: FOLFIRI-AIOIRI vs FL
Results Stage III
HR P-value
DFS 0.89 0.091
RFS 0.86 0.045
Risk adjusted for T and N
HR P-value
DFS 0.85 0.021
RFS 0.82 0.009Van Cutsem E, PASCO 2005
PETACC-3 vs MOSAIC: toxicityPETACC-3 vs MOSAIC: toxicity
Grade 3/4 AEs (%) FOLFIRI FOLFOXDiarrhea 11.9 10.8Stomatitis 1.4 2.7Nausea 5.1 5.1Vomiting 5.8 5.8Neurosensory NR 12.4HFS NR 2.0Neutropenia 28.2 41.1Febrile Neutropenia 0.3 1.8Treatment related Deaths
0.3 0.5
Patients preference/attitudesPatients preference/attitudes
www.adjuvantonline.com
5FU basedFOLFOX
Patients preference/attitudesPatients preference/attitudes
Stefano Bollani … … il jazzista che ama divertire la gente …
Gino Castaldo, La Repubblica 2005
Completion of Therapy by Medicare
Patients With Stage III Colon Cancer
Completion of Therapy by Medicare
Patients With Stage III Colon Cancer
3193 stage III colon cancer patients recorded in 1992 –
1996 SEER program
Risk of cancer-related mortality was significantly lower
among those completing chemotherapy (5FU based)
• relative risk = 0.79 (0.69-0.89)
Factors associated with incomplete adjuvant CT
• Physical frailty
• Treatment complications
• Lack of social and psychological support.
Dobie S, JNCI 2006
Relative risks of adjuvant CT completionRelative risks of adjuvant CT completion
Dobie S, JNCI 2006
Age
Marital status
Comorbidities
MOSAIC: pazienti MOSAIC: pazienti anzianianziani
Nessuna differenza tra pazienti con piu’o meno di 65 anni
Author (year)(Ref.)
Number patients
Oxaliplatin/
5FU dose
Neurotoxicity (grade 1-4)
Neurotoxicity (grade 3-4)
Patients younger than 70 yearsDe Gramont (00) (8)
210 85 mg/m2 5FU ci
68% 18%
Andre’ (99) (20)
97 85 mg/m25FU ci
94% 28%
Goldberg (04) (7)
254 85 mg/m2 5FU ci
- 18%
Maindrault (01) (21)
48 130 mg/m25FU ci
97% 11%
Hochster (03) (6)
42 85 mg/m2 5FU bolus
36% 12%
Ravaioli (03) (5)
45 130 mg/m2 5FU bolus
42% 2.2%
Rothenberg (03) (22)
152 85 mg/m2 5FU ci
51% 5%
Patients older than 70 yearsDe Gramont (00)(8)
43 85 mg/m2 5FU ci
96 21%
Andre (99)(20)
18 85 mg/m2 5FU ci
45% 29%
Aparicio (03)(12)
44 85 mg/m2 5FU ci
- 16%
Adjuvant CT for stage IIIAdjuvant CT for stage III
FOLFOX-4 is the reference treatment
Assessment of long term safety/efficacy is mandatory
Monotherapy could be a reasonable choice considering:
• Risk of recurrence
• Patients characteristics
• Patients preference/attitudes
Ongoing studies for stage IIIOngoing studies for stage III
Study Treatment Arms Duration
AVANTFOLFOXFOLFOX + bevacizumabXELOX + bevacizumab
6 months1 year1 year
NSABP C-08FOLFOXFOLFOX + bevacizumab
6 months1 year
PETACC-8FOLFOXFOLFOX + cetuximab
6 months6 months
INT-0147FOLFOXFOLFOX + cetuximab
6 months6 months
ITALYFOLFOX/XELOXFOLFOX/XELOX
6 months3 months
Stage II patients – to Stage II patients – to
treat ?treat ?
-mf-
COLON CANCERCOLON CANCER20042004
COLON CANCERCOLON CANCER20042004
Estimated New Cases in Europe and ItalyEstimated New Cases in Europe and Italy
N- T 3-4 (15-28%)N- T 3-4 (15-28%)
UE: 213.000UE: 213.000 31.950-59.64031.950-59.640
I: 32.000 4800- 8960I: 32.000 4800- 8960
DeathsDeaths
UE: 110.000 UE: 110.000
I: 16.000I: 16.000
Stage II
CURED 70%CURED 70%
UE: 22.365-41748UE: 22.365-41748
Italy: 3.360-6.272Italy: 3.360-6.272
RELAPSED: 30%RELAPSED: 30%
UE:9.585-17.892UE:9.585-17.892
Italy: 1.440-2.688Italy: 1.440-2.688
AJCC Cancer StagingAJCC Cancer Staging Colorectal Cancer 2002 Colorectal Cancer 2002
81% 77%53-68% 46-61% 27-64% 21-59%
LOW vs HIGH
LOW vs HIGH
LOW vs HIGH
T1-2,N1T3-4,N1any T,N2
IIIAIIIBIIIC
82% 79%74% 70%
LOW vs HIGH
LOW vs HIGH
T3,N0T4,N0
IIAIIB
5yrs DFS (Surgery +CT)
GradingAJCC Stage2002
TNM Stage
Adjuvant chemotherapy for Adjuvant chemotherapy for stage II colon cancerstage II colon cancer
PROS
NSABP metanalysis
GILL (ASCO 2003)
Dutch trial
CONS
IMPACT metanalysis
Seer – Medicare data
INT 0035QUASARQUASAR
CCOPEBC Meta-analysis CCOPEBC Meta-analysis 20042004
4187 pts with stage II colon cancer from 18 RCT
Mortality RR 0.70 (95 % CI = 0.44 – 1.11 p.13)
I.P. 5-FU(5 RCT)
Mortality RR 0.86 (95 % CI = 0.73 – 1.01 p.07)
FU + LEV + FUFA(8 RCT)
Mortality RR 0.90 (95 % CI = 0.71 – 1.13 p.35)
FU + LEV(3 RCT)
Mortality RR 0.87 (95 % CI = 0.75 – 1.01 p.07)Global
Figueredo A, JCO 2004Figueredo A, JCO 2004
ASCO guidelines for stage II ASCO guidelines for stage II colon cancercolon cancer
ASCO guidelines for stage II ASCO guidelines for stage II colon cancercolon cancer
“High risk”
NCDBNCDB35787 pts35787 pts
NCDBNCDB35787 pts35787 pts
1-2 Nodes Neg examined1-2 Nodes Neg examined 5 yrs OS = 64 %5 yrs OS = 64 %1-2 Nodes Neg examined1-2 Nodes Neg examined 5 yrs OS = 64 %5 yrs OS = 64 %
25 Nodes Neg examined25 Nodes Neg examined 5 yrs OS = 86 %5 yrs OS = 86 % 25 Nodes Neg examined25 Nodes Neg examined 5 yrs OS = 86 %5 yrs OS = 86 %
At least At least 1313 to be examined to be examinedAt least At least 1313 to be examined to be examined
• < 6 nodes< 6 nodes• TT44
• PerforationPerforation• GG33
• < 6 nodes< 6 nodes• TT44
• PerforationPerforation• GG33
JCO 2004JCO 2004JCO 2004JCO 2004
Disease Free Survival - Stage II Disease Free Survival - Stage II patientspatients
0,5
0,6
0,7
0,8
0,9
1
0 10 20 30 40 50
Hazard ratio [95% CI]: 0.82 [0.57-1.17]Hazard ratio [95% CI]: 0.82 [0.57-1.17]
Probability
DFS (months)
20% risk reduction for stage II patients in the FOLFOX arm
FOLFOX (n=451) 86.6%LV5FU2 (n=448) 83.9%
3-year
HIGH RISK STAGE IIHIGH RISK STAGE II COLON CANCER: COLON CANCER: MOSAIC SUBPOPULATION DATAMOSAIC SUBPOPULATION DATA
HICKISH, ASCO 2004HICKISH, ASCO 2004
On the basis of the MOSAIC results, adjuvant therapy for stage II patients with FOLFOX FOLFOX provides an improvement of 3.8% in 4-provides an improvement of 3.8% in 4-year DFS compared with optimized year DFS compared with optimized (infusional) FU/LV therapy.(infusional) FU/LV therapy.
On the basis of these findings, with an admitted uso OFF Label between-trial extrapolation, the best estimate is that FOLFOX improves DFS by 6% to 7% improves DFS by 6% to 7% compared with surgery alonecompared with surgery alone in patients with stage II disease Grothey and Sargent, JCO
2005
22 novembre 200522 novembre 2005United States Pharmacopeia USPUnited States Pharmacopeia USP
Indica l’impiego del FOLFOX stadio IIIndica l’impiego del FOLFOX stadio IICome trattamento applicabile off-labelCome trattamento applicabile off-label
USP non FDA USP non FDA Ma spesso le assicurazioni rimborsano Ma spesso le assicurazioni rimborsano
sulla base delle sue indicazionisulla base delle sue indicazioni
ProspettivaProspettiva
Individuare i pazienti ad alto rischio per trattare solo quelli.
Ottimizzazione benefici
Riduzione costi
Riduzione tossicità
THE MEDICAL ALGORITHMS PROJECTTHE MEDICAL ALGORITHMS PROJECTWWW.MEDALREG.COM/REGISTRATION/SELECTION.PHPWWW.MEDALREG.COM/REGISTRATION/SELECTION.PHP
CRC : HAZARD RATI O PER GLI STADI I ICRC : HAZARD RATI O PER GLI STADI I I
FATTORE HR 95% CI p
PERITONEO + 2.88 1.7 - 4.9 .0001
INVAS. VENOSA 2.70 1.6 - 4.5 .0001
MARGINE + 2.61 1.4 - 4.8 .002
PERFORAZIONE 9.43 3.3 - 27.0 .0001
CRC : SCORE PER GLI STADI I ICRC : SCORE PER GLI STADI I I
FATTORE STATO PUNTI
PERITONEO + SI 1 NO 0
INVAS. VENOSA SI 1 NO 0
MARGINE + SI 1 NO 0
PERFORAZIONE SI 2 NO 0
CRC : I NDI CE PROGNOSTI CO PER GLI STADI I ICRC : I NDI CE PROGNOSTI CO PER GLI STADI I I
SCORE 5 YRS OS 95% CI
0 94% 85- 98
1 79% 70- 86
2 54% 40- 66
3- 5 30% 8- 57
Prognostic factorsPrognostic factors
COX COX MultivariateMultivariate AnalysisAnalysis ( 74 ( 74 ptspts ))
0,980.34,2.840,99Tumor size
0,980.25,6.081,22Grade
0,270.60,6.321,94T stage
0,610.95,1.030.99Age
P value95% CIHRFactor
0,980.34,2.840,99Tumor size
0,980.25,6.081,22Grade
0,270.60,6.321,94T stage
0,610.95,1.030.99Age
P value95% CIHRFactor
23- gene signature 0,17 0.06,0.51 0,001
Nucleus
Antireceptor Antibodies
± Toxins
Tyrosine Kinase Inhibitors
Hormone Agonists/ Antagonists
Farnesyl Transferase
Inhibitors
Apoptosis Agonists
Antisense
Angiogenesis Inhibitors (Angiostatin, Endostatin
& Anti-VEGF)
Metalloproteinase Inhibitors
Matrix Degradation(Collagenases,Gelatinases &Stromelysins)
Immune System Activation (Vaccines, Monoclonal antibodies)
Tumor Cell
Growth Factor Receptors
Intracellular Signaling Molecules
AntimetabolitesMicrotubule inhibitors
Targeted Therapies
Select studies of angiogenic factors and Select studies of angiogenic factors and their role in colon cancer progression and their role in colon cancer progression and
metastasismetastasisFACTOR N° K-PZ. ASSOCIATIONS STUDY
Angiogenin 65 MVD Etoh (200)
Angiomodulin 89 Poor prognosis Adachi (2001)
Interleukine-10 53 Poor prognosis Kawakami (2001)
PD-ECGF 96 Thrombospondin expr less MVD Takahashi (1996)
Thrombospondin-1 150 MVD, PD-ECGF in infiltrat. cells Maeda (2001)
Thrombospondin-2 61 Smaller MVD, fewer hepatic recurr. Tokunaga (1999)
UPAR 44 Fewer liver metast., better prognosis Nakata (1998)
VEGF 614 VEGF, vessel count Werther (2000)
VEGF 121 Poor prognosis Cascinu (2000)
VEGF 145+30 polyps
Poor prognosis Lee (2000)
VEGF 52 MVD, VEGFR-2 positivity metastas. Takahashi (1995)
VEGF 28 MVD, survival in node-negative Pz. Takahashi (1997)
MVD= microvessel density; PD-ECGF= plateled-derived endothelial cell growth factor; uPAR= urokinase-like plasminogen activator receptor; VEGF= vascular endothelial growth factor; VEGFR-2= vascular endothelial growth factor receptor 2.
Espressione del VEGF nella Espressione del VEGF nella neoplasia primitivaneoplasia primitiva
0 20 40 60 80
Follow-up (months)
% S
urvi
val
High VEGF
Low VEGF
P=0.0003
Takahashsi et al Arch surg 1997
Cascinu S, et al. Clin Cancer Res, 2000
Median survival (months)IFL + placebo: 15.6 (95% CI: 14.3–17.0) vsIFL + bevacizumab: 20.3 (95% CI: 18.5–24.2)Hazard ratio = 0.66 (95% CI: 0.54–0.81)p<0.001
Pro
bab
ilit
y o
f su
rviv
al
1.0
0.8
0.6
0.4
0.2
00 10 20 30 40
Survival (months)
IFL + bevacizumab
IFL + placebo
15.6 20.3
Hurwitz H, et al. N Engl J Med 2004;350:2335–42
Phase III trial of IFL ± Phase III trial of IFL ± bevacizumab bevacizumab in metastatic CRC (AVF2107g): in metastatic CRC (AVF2107g): survivalsurvival
CI = confidence interval
Planned phase III trials of bevacizumab in adjuvant CRC
Trial n Cancer Treatment
NSABP C-08 2,500 Colon FOLFOX ± bevacizumab
BO17920 3,450 Colon FOLFOX vs FOLFOX + bevacizumab vs CapeOx + bevacizumab
QUASAR 2 3,750 CRC Capecitabine vs CapeIRI vs CapeIRI + bevacizumab
E5205 3,125 CRC FOLFOX-6 ± bevacizumab
CapeOx = capecitabine + oxaliplatinCapeIRI = capecitabine + irinotecan
BO17920 study design Randomised, open-label study
Primary endpoint: disease-free survivalSecondary endpoints: safety, overall survival350 centres in 36 countries
Duration of treatment phases 24 weeks 24 weeks
Bevacizumab alone(7.5mg/kg every
3 weeks)
Bevacizumab alone(7.5mg/kg every
3 weeks)
ObservationObservation
Bevacizumab alone(7.5mg/kg every
3 weeks)
Bevacizumab alone(7.5mg/kg every
3 weeks)
FOLFOX-4FOLFOX-4
FOLFOX-4 + bevacizumab(5mg/kg every
2 weeks)
FOLFOX-4 + bevacizumab(5mg/kg every
2 weeks)
XELOX + bevacizumab (7.5mg/kg every
3 weeks)
XELOX + bevacizumab (7.5mg/kg every
3 weeks)
Surgery for stage II + stage III colon cancer
(n=3,450)
Surgery for stage II + stage III colon cancer
(n=3,450)
FOLFOX6 + bevacizumab
5mg/kg every 2 weeks
Duration of treatment 24 weeks
Dukes’ C colon
cancer (n=2,500)
Observation
Bevacizumab 5mg/kg every 2
weeks
FOLFOX6 + placebo
24 weeks
Randomised, phase III trial of adjuvant bevacizumab plus FOLFOX6 (NSABP-C08): study design
AVF2107g: possiblebevacizumab-related toxicity
NB: not adjusted for different time on therapy
Patients (%)
IFL + placebo (n=397)
IFL + bevacizumab (n=393)
Bleeding Grade 3/4
2.5
3.1
Any thromboembolic event Arterial Venous
16.2 1.0
15.2
19.4 3.3
16.1
Deep thrombophlebitis Grade 3
6.3
8.9
Pulmonary embolus Grade 4
5.1
3.6
Any hypertension Grade 3
8.3 2.3
22.4 11.0
Any proteinuria Grade 2 Grade 3
21.7 5.8 0.8
26.5 3.1 0.8
Hurwitz H, et al. N Engl J Med 2004;350:2335–42
Bevacizumab does not increase wound healing/bleeding complications when given 28–60 days following cancer surgery
ComplicationIFL/placebo(n=155) (%)
IFL/bevacizumab (n=150) n (%)
5-FU/LV/bevacizumab(n=37) (%)
Abscess 0 0 0
Perforatedlarge intestine
0 1 (0.67) 0
Perforated stomach ulcer
0 1 (0.67) 0
All types (total)
0 2 (1.3) 0Scappaticci F, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3530
Wound healing complications
Bevacizumab does not increase wound healing/bleeding complications when given 28–60 days following cancer surgery
(cont’d)
Haemorrhage
IFL/placebo (n=155)
n (%)
IFL/bevacizumab(n=150)
n (%)
5-FU/LV/bevacizumab(n=37) (%)
GI 1 (0.65) 0 0
Rectal 0 1 (0.67) 0
All types 1 (0.65) 1 (0.67) 0
Bleeding complications
Scappaticci F, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3530
EGFR-targeting therapies
Tyrosine kinase inhibitors(gefitinib, erlotinib, CI-1033,
EKB-569, AEE788, GW572016, PKI-166)
Monoclonalantibodies
(cetuximab, ABX-EGF, EMD 72000, h-R3, MDX-447)
Signal Transduction
Ligands
R R
K K
Salomon (1995); Chow (1997)31-48%Bladder
Salomon (1995); Watanabe (1996);Rieske (1998)
40-63% Glioma
Bartlett (1996); Fischer-Colbrie (1997)35-70% Ovarian
Klijn (1992); Beckman (1996); Bucci (1997); Walker (1999)
14-91% Breast
Salomon (1995); Yoshida (1997)50-90% Renal Carcinoma
Fujino (1996); Rusch (1997);Fontanini (1998)
40-80% NSCLC
Salomon (1995); Uegaki (1997)Abbruzzese (2001)
30-95% 95%
PancreaticAdvanced Stage
Salomon (1995); Grandis (1996)80-100%Head and Neck
Salomon (1995); Messa (1998)Goldstein (2001); Cunningham (2003)
25-77% 75-82%
ColorectalColorectal – Advanced stage
References% EGFR (range)Tumor Type
EGFR Expression in Human Tumors
EGFR as a prognostic factor
EGFR expression mostly correlates with poor prognosis, EGFR expression mostly correlates with poor prognosis, decreased survival and/or increased metastasisdecreased survival and/or increased metastasis
EGFR expression also linked to reduced response, and/or EGFR expression also linked to reduced response, and/or increased resistance, to chemotherapyincreased resistance, to chemotherapy
Tumor Tumor typetype
PrognosiPrognosiss
SurvivalSurvivalRisk of Risk of
metastasmetastasisis
ReferencesReferences
ColorectalColorectal PoorPoor --IncreasIncreas
ededHemming Hemming
(1992)(1992)
Lung Lung (NSCLC)(NSCLC)
PoorPoorPoorPoor
Decreased Decreased OSOS--
--IncreasIncreas
eded
Ohsaki Ohsaki (2000)(2000)Pavelic Pavelic (1993)(1993)
Head & Head & Neck Neck (SCCHN)(SCCHN)
PoorPoor
Decreased Decreased DFSDFS
Decreased Decreased OSOS
--
Grandis Grandis (1998)(1998)Maurizi Maurizi (1996)(1996)
BOND study: grade 3/4 BOND study: grade 3/4 toxicitiestoxicities
Combination
Monotherapy
Diarrhea 45 (21%) * 2 (2%) Asthenia 29 (14%) 12 (10%) Neutropenia 20 (10%) * 0 (0%) Acneiform
rash20 (9%) 6 (5%)
Toxic effects were more frequent with the combination
Severity and incidence were similar to those expected with irinotecan alone
Cunningham D et al. NEJM 2004* p<0.001
Surgery for stage II + stage III colon
cancer ?
RANDOMIZATION
………….+ cetuximab
folfox
Cetuximab in adjuvant trials
EGFR status?