The treatment of metastaticcolorectal cancer in 2007
Prof Eric Van Cutsem, MD, PhD
Gastrointestinal Oncology Unit
University Hospital Gasthuisberg
Leuven - Belgium
CRC is a major health concern
• Life-time risk for CRC 4–6%1
• Worldwide– Third most common cancer2
– > 1000 000 new cases2
– Second leading cause of cancer death (~529 000)2
• 400 000/year patients in Europe develop CRC2
• 25% present with metastatic disease
• 40–50% eventually develop metastatic disease
• > 200 000 deaths/year in Europe2
1. Winawer S, Fletcher R, et al. Gastroenterol 2003: 124; 544-60 2. GLOBOCAN. http://www-dep.iarc.fr 2002
First-lineSecond-
lineThird-
lineAdjuvantDiagnosis
Neo-adjuvant/Surgery
Maximising patient outcomes in CRC Maximising patient outcomes in CRC
• Colorectal cancer treatment in a context of Continuum of Care:
– Treatment Plan throughout the continuum of care, based on best available evidence
– More effective drugs now available and trend towards a targeted and possibly “tailored” therapy
– Multi-Disciplinary Approach: i.e. resection of liver metastases
Goldberg R, Rothenberg M, Van Cutsem E et al. Oncologist 2007
Colorectal liver metastases
• Disease is limited to the liver:- Unresectable liver metastases
– Neoadjuvant or induction chemotherapy followed by resection if response
– Resectable liver metastases• Neoadjuvant and/or adjuvant chemotherapy
The role of neo-adjuvant and adjuvant chemotherapy for livermetastases of
colorectal cancer
Patterns of resectability in patients with CRC liver metastases
Metastatic CRC
85% unresectable 15% resectable
• 10-20% potentially resectable• 80-90% never resectable
neoadjuvant chemotherapy to increase resectability?
• Class I
• Class II
neoadj. and/or adjuv. CT to
increase cure rate?
5-Yr Survival after resection of CR Livermetastases
22%35%25%25%33%39%25%26%32%37%38% 34%58%41%58%
5%0%5%3%--
5%4%2%0%
2.8%0%
0.8%-
1%-
2596080141859219280
1818204
1001235257133615190
198119861987198719881991199219921994199920002002200220032004
FosterIwatsukiNordlingerAdsonHughesScheeleRosenAFCGayowskiFongMinigawaErcolaniChotiAdamAbdalla
SurvivalOp. Mort.PatientsYearAuthors
EORTC 40983: Study design
Randomize
SurgeryFOLFOX4 FOLFOX4
Surgery
6 cycles
(3 months)
N=364 patients with < 4
resectable livermetastases
6 cycles
(3 months)
Nordlinger B et al, Proc ASCO 2007
EORTC 40983: Results
P=0.0250.73(0.55-0.97)
+9.2%(33.2% to 42.4%)
152151All resectedPatients
P=0.0410.77 (0.60-1.00)
+8.1%(28.1% to 36.2%)
171171All eligiblePatients
P=0.0580.79(0.62-1.02)
+7.2%(28.1% to 35.4%)
182182All patients
P-valueHazardRatio
(Confidence Interval)
% absolute difference
in 3-year PFS
N pts Surgery
N ptsCT
Nordlinger B et al, Proc ASCO 2007
Progression-free survival in eligible patients
HR= 0.77; CI: 0.60-1.00, p=0.041
Periop CT
28.1%
36.2%
+8.1%At 3 years
(years)0 1 2 3 4 5 6
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :125 171 83 57 37 22 8115 171 115 74 43 21 5
Surgery only
Nordlinger B et al, Proc ASCO 2007
Cytotoxic chemotherapy formetastatic CRC
Survival
Med (mo) 1 yr (%) 2 yr (%)
– Best Supp. Care 6 < 30 < 10– 5-FU + FA 11-12 45 20-30
• Capecitabine 12 50 20-30 • Irinotecan 18 60-70 30-40• Oxaliplatin 18 60-70 30-40
TheThe issues issues thatthat face us to face us to achieveachieve a a continuum continuum ofof carecare
1st line chemo 3rd line chemo2nd line chemo
1st 1st biologicbiologic 2nd 2nd biologicbiologic
HowHow to to startstart??
AtAt progressionprogressionchange change chemochemo,,
biologicbiologic or or bothboth??
IndependentIndependentsequencessequences??
Van Cutsem E. Editorial J Clin Oncol. 2006
Sistin Chape: UniversalJudgement of Michelangelo
The emerging Integrated Circuit of
the Cell
J. FOLKMAN: 1971The Angiogenic Switch and
Antiangiogenic Therapy
SomaticMutation
SmallAvascular
Tumor
Tumor Secretion of Proangiogenic
Factors Stimulates Angiogenesis
Rapid Tumor Growth and Metastasis
Angiogenic Inhibitors May Reverse this
Process
Tumour blood vesselsNormal blood vessels
Maturation/stabilisation factors present
Basal integrin expression
Less dependent on cell survival factors
Less permeable
Leaky
Preferential expression of �v�3, �v�5, and �5�1 integrins
Fewer supporting cells
Growth and survival factors (e.g., VEGF) present
Supporting cells present
Tumour vasculature resulting from VEGF-mediated angiogenesis is abnormal
Jain., Semin Oncol 2002;29 (Suppl. 16):3–9; Carmeliet, Nat Med 2003;9:653–60;Lee et al., J Biol Chem 2003;278:5277–84
................... .....
.... ..... .... .....
................... .....
.... .....
................... .....
................... .....
................... .....
Maturation factors present
Normal and Tumor VasculatureTumor Blood VesselsNormal Blood Vessels
Reduced integrinexpression
Minimally dependent oncell survival factors
.... ..... Less permeable
Leaky
Preferential expression of
αvβ3 αvβ5 & α5β1integrins
Fewer pericytes
Growth and survival factors (eg, VEGF)
present
.... .....
Supporting pericytespresent
Blau and Banfi. Nat Med. 2001;7:532.Jain. Nat Med. 2001;7:987.
Tumor Vasculature is AbnormalNormal colon Nearby colorectal cancer
Tumor vasculature is dilated, highly chaotic, and tortuous, with a lack of hierarchicalvessel arrangement
Carmeliet P, et al. Nature 2000;407:249–57Konerding et al; Microenvironment of Human Tumors 2002
Anti-VEGF
Reducesinterstitial fluid pressure
vessel density
Increasesdrug delivery
Anti-VEGF antibody ‘normalises’the tumour vasculature
Jain R. Nature Med 2001;7:987–9; Willett CG, et al. Nat Med 2004;10:145–7; Tong R, et al, Cancer Res 2004;64:3731–6
VEGFVEGFVEGF VEGF
receptorreceptor--22
Cation Cation channelchannel
↑↑ PermeabilityPermeability
Antibodies inhibiting VEGFAntibodies inhibiting VEGF(e.g. (e.g. bevacizumabbevacizumab))
Antibodies inhibiting Antibodies inhibiting VEGF receptorsVEGF receptors
Soluble VEGF receptorsSoluble VEGF receptors(VEGF(VEGF--TRAP)TRAP)
Small-moleculesinhibiting VEGF receptors
(TKIs)(e.g. PTK-787)
RibozymesRibozymes((AngiozymeAngiozyme))
– P– PP–
P–
– P– P
P–P–
– P– P
P–P–
Migration, permeability, DNA synthesis, survivalMigration, permeability, DNA synthesis, survival
LymphangiogenesisLymphangiogenesisAngiogenesisAngiogenesis
Agents targeting the VEGF pathway
Clinical Results in Metastatic ColorectalCancer
Bevacizumab in combination with chemotherapy in metastastic CRC
– pivotal trial: IFL: increased activity in first line– 5-FU/FA monotherapy: increased activity in first line– FOLFOX: increased activity in second line– Oxaliplatin based: increased activity in first line
– Cetuximab +/- irinotecan: high activity in irinotecan refractoryCRC
– Bolus 5-FU/FA plus bevacizumab: not active in irinotecan and oxaliplatin refractory CRC
Median progression-free survival6.2 vs 10.6 monthsHR=0.54 p<0.0001
Hurwitz H, et al. N Engl J Med 2004;350:2335–42
Superior PFS + OS with 1st line IFL + bevacizumab vs IFLPr
obab
ility
of b
eing
pro
gres
sion
free
1.0
0.8
0.6
0.4
0.2
00 10 20 30
Time (months)
IFL + bevacizumabIFL + placebo
6.2m 10.6mPr
obab
ility
of s
urvi
val
1.0
0.8
0.6
0.4
0.2
00 10 20 30 40
Time (months)
IFL + bevacizumabIFL + placebo
15.6m 20.3m
Median survival 15.6 vs 20.3 monthsHR=0.66 p<0.001
Bevacizumab: Safety Overview
Bevacizumab does not increase chemotherapy related toxicities.
Bevacizumab has specific side effects: – Hypertension– Proteinuria– Thromboembolic events: arterial– Bleeding: minor mucosal (epistaxis) and major hemorrhage (non small
cell lung cancer)– Gastrointestinal perforation– Wound healing/postoperative bleeding
Kabbinavar F et al. J Clin Oncol 2003;21:60–5Hurwitz H et al. NEJM 2004;350:2335–42
Giantonio BJ, et al. Presented at: 2005 Gastrointestinal Cancers Symposium; 27–29 January 2005; Hollywood, FL, USA. Abstract 169a
Arterial thromboembolic events*
Risk factors for arterial thromboembolic events included– history of prior arterial thromboembolic events such as stroke or heart attack– age of 65 years or older
Arterial events included in analysis– CVA (stroke), transient ischemic attack, subarachnoid hemorrhage– myocardial infarction, angina (unstable angina), arterial thrombosis and other arterial
thromboembolic events
4.5% (45/1004)2.0% (15/741)Arterial TE events
0.8% (8/1004)0.4% (3/741)Mortality
bevacizumab plus chemotherapy
Chemotherapy alone
*Pooled analysis of five randomised trials
EGFR pathway inhibition
pEGFR
pMAPK
Ki67
p27
pEGFR
pMAPK
Ki67
p27
pAkt
1
K
2
KShc
PI3KShc
Grb2
Grb2Ras
Sos
Sos
Raf
MEK1/2
Akt
MAPK
Cell cycleprogression
Survival Proliferation
PTEN
GSK-3mTOR FKHR
Bad
D1 Cyclin
p27
SKIN TUMOR
Tabernero J et al 2003
Tyrosine kinaseinhibitors
(gefitinib, erlotinib,CI-1033, EKB-569, …)
Monoclonalantibodies
(cetuximab, panitumumab, matuzumab, ...)
Signal Transduction
R R
Ligand
K K
Anti-EGF Receptor Therapies
CELL MEMBRANECELL MEMBRANE
Cetuximab +/- irinotecan in irinotecan refractory CRC: Response Ratio
56[49-62]
23[18-29]
32[24-42]
11[6-18]
0
10
20
30
40
50
60
Response Rate Disease Control(CR+PR+SD)
Perc
enta
gecetuximab + irinotecan
(n=218)cetuximab (n=111)
***
* p=0.0074; ** p<0.001; [] = 95% CI
Cunningham D … Van Cutsem E. N Engl J Med 2004
Panitumumab PD Follow-up6.0 mg/kg Q2W+ BSC
BSC PD Follow-up
RRAANNDDOOMMIIZZEE
Optional Optional Panitumumab Panitumumab
Crossover StudyCrossover Study
Stratification:Stratification:•• ECOG score: 0ECOG score: 0--1 vs. 21 vs. 2•• Geographic regionGeographic region
PanitumumabPanitumumab in in mCRCmCRC: phase 3 trial: phase 3 trial
1:1
Key inclusion:Key inclusion:•• Disease progression on CT scan Disease progression on CT scan
after after fluoropyrimidinefluoropyrimidine, , irinotecanirinotecanand and oxaliplatinoxaliplatin
•• EGFrEGFr membrane staining on membrane staining on ≥≥ 1% 1% tumor cellstumor cells
Van Cutsem E et al. J Clin Oncol 2007
Even
t-fre
e Pr
obab
ility
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Weeks from Randomization0 8 16 24 32 40 48 56
Hazard ratio=0.54 (95% CI: 0.44, 0.66)
Stratified log-rank testp < 0.000000001
ProgressionProgression--Free SurvivalFree Survival
Panitumumab
BSC
Patients at risk:PanitumumabBSC
231 118 49 31 13 5 1232 75 17 7 3 1 1
Primary Analysis, All RandomizedAnalysis Set, Central Radiology Van Cutsem E et al. J Clin Oncol 2007
0%
10%
20%
30%
40%
50%
60%
KaplanKaplan-- Meier ProgressionMeier Progression--Free Survival Rates at Free Survival Rates at Prespecified Time PointsPrespecified Time Points
49%49%
30%30%35%35%
14%14%
26%26%
9%9%5%5%
18%18%
4%4%1%1%1%1% 1%1%
4%4%
10%10%
Panitumumab (N=231)Panitumumab (N=231)BSC (N=232)BSC (N=232)
Wk 8Wk 8 Wk 12Wk 12 Wk 16Wk 16 Wk 24Wk 24 Wk 32Wk 32 Wk 40Wk 40 Wk 48Wk 48
Primary Analysis, All Randomized Analysis Set, Central Radiology
% P
rogr
essi
on F
ree
(95
% C
I)
Patients at risk:Patients at risk:PanitumumabPanitumumabBSCBSC
118118 4949 3131 1313 55 117575 1717 77 33 11 11
76763131
Van Cutsem E et al. J Clin Oncol 2007
EGFR-inhibitor induced skin reactions
1 2 3 4 5 6 7 8 9
Descriptionof severe cases
THERAPY SUGGESTIONS
Post inflammatory effectsAcne-like rash
paronychia
dry skin
Topical anti-acne creams (drying effect)
+/- tetracyclines
+/- antihistamines
pruritus
Pulse dye laser Emollients Hydrocolloid dressing
or
Propylene glycol+/-acetylsalicyl
Anti-septic soaks
Silver nitrate (pyogenicgranuloma)
fissura
S Segaert & E Van Cutsem, Ann Oncology 2005
Study: 9923 0141 BOND Saltz (2001)1 Saltz (2004)2 Cunningham Van Cutsem Xiong (2004)5 Kies (2002)6
(2004)3 (2004)4
Correlation of rash and survival after treatment with cetuximab
1. Saltz et al. Proc ASCO 2001. 2. Saltz et al. J Clin Oncol 2004. 3. Cunningham D…Van Cutsem E. N Engl J Med 2004. 4. Van Cutsem et al. EORTC/NCI Geneva 2004.
5. Xiong H et al. J Clin Oncol 2004. 6. Kies et al. Proc ASCO 2002.
Surv
ival
(mon
ths)
16
1412
10
86
4
2
0CRC CRC CRC CRC Pancreatic SCCHN
No reaction Grade 2Grade 1 Grade 3
CRYSTAL trial:Study design
Stratification factors:RegionsECOG PS
PopulationsRandomized patients n=1217Safety population n=1202ITT population: n=1198
FOLFIRI
irinotecan (180 mg/m2)+ 5-FU 400 mg/m2 bolus +
2400 mg/m2 as 46-hr continuous infusion)
+ FA every 2 weeks
Cetuximab + FOLFIRI
Cetuximab IV 400 mg/m2 on day 1,then 250 mg/m2 weekly
+ irinotecan (180mg/m2) + 5-FU (400 mg/m2 bolus +
2400 mg/m2 as 46-hr continuous infusion)
+ FA every 2 weeks
REGFR-expressing
metastatic CRC
Van Cutsem E et al, Proc ASCO 2007
CRYSTAL trial: Primary endpoint PFS met ITT population independent review
Progression-free survival time (months)
PFS
estim
ate
1.0
0.8
0.9
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 2 4 6 8 10 12 14 16 18 20
HR = 0.851; 95% CI = [0.726-0.998]Stratified log-rank p-value = 0.0479
8.9 mo8.0 mo
FOLFIRI, n=599
Cetuximab + FOLFIRI, n=599
1-year PFS rate23% vs 34%
Subjects at riskFOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1Cetuximab + FOLFIRI
599 499 392 298 196 103 58 29 12 5 1Van Cutsem E et al, Proc ASCO 2007
CRYSTAL trial:Surgery with curative intent
2,5
1,5
6
4,3
0
1
2
3
4
5
6
7
Surgery with curativeintent
No residual tumor afterresection
Per
cent
age
(%)
*CMH test
n=599 / group n=599 / group
p=0.0034*
odds ratio 3.0
[95% CI: 1.4 - 6.5]
FOLFIRI alone Cetuximab + FOLFIRI
4.5
9.8
0
1
2
3
4
5
6
7
8
9
10
Perc
enta
ge (%
)n=134 / n=122
No residual tumor in patientswith liver metastases
ITT population(pre-planned)
Liver metastases only population(exploratory)
Van Cutsem E et al, Proc ASCO 2007
Phase 1–2 studies ongoing / plannedCombination with radiotherapyin rectal cancer
Studies ongoing / plannedAdjuvant treatment
Phase 2 studies show high resection rate of initially unresectable metastases
mCRC: liver metastases
Promising activity in phase 2 studiesFirst-line treatment
Proven activityChemorefractory patients
StatusClinical setting
ChallengesChallenges withwith EGFR EGFR inhibitorsinhibitors in CRC: in CRC: determiningdetermining the best the best treatmenttreatment strategiesstrategies
Tailored Treatment Tailored Treatment
PTEN
IL-8 VEGF
Ki67 p27Bcl-2 BclXl Angiogenesis
Can we find parameters to predict response to EGFR inhibitors?
FOLFOX /Xelox+
bevacizumab¹
FOLFOX /Xelox+
bevacizumab¹
FOLFIRI +bevacizumab¹
FOLFIRI +bevacizumab¹
No prioradjuvant therapy
Treatment Algorithm for Metastatic CRC
FOLFOX / Xelox
FOLFOX / Xelox
Irinotecan+ cetuximab
Irinotecan+ cetuximab
FOLFIRIFOLFIRI
FOLFIRIFOLFIRI
FOLFOX / Xelox
FOLFOX / Xelox
Irinotecan+ cetuximab
Irinotecan+ cetuximab
¹ if no cardiovascular contraindications
Capecitabine(5-FU/FA) ±
bevacizumab¹
Capecitabine(5-FU/FA) ±
bevacizumab¹
Individualisation of treatment in metastatic CRC with increasing number of active agents
Individual personal treatment
Tumor
TSTP
P53 MSI
Topo I
…..
Patient
Pharmacogenetic : cytotoxic metabolism
Novel targets: EGFR, VEGF, Cox-2, IGF…
Is progress made in chemotherapy and other treatments options of colon cancer? Yes
The dream ….
The reality ...