Current Opinion in the Colorectal Cancer Treatment
Dott. Carlo Garufi
Oncologia Medica C
Istituto Regina Elena – Roma
5FU/FA Capecitabine or FOLFOX
Treatment Strategies in ACC in2007
I II IIIIFL+BEVA
FOLFIRI+BEVA
FU/FA+BEVACAPE+BEVA
FU/FA CAPE
FOLFOX
FOLFOX+BEVA
FOLFIRI
FOLFOX
CETU+IRI FOLFOX
CETU+IRI
FOLFOX
FOLFIRI
FOLFIRI
FOLFOX
CETU+IRI
CETU+IRI
CETU+IRI
FOLFOX
IRI O FOLFIRI
CETU + IRI
FOLFOX
CETU + IRI
CETU+IRI
FOLFOX
Adjuvant CHT
Cancro colon-retto avanzato:tutti i trattamenti sono uguali?
FOLFOX = FOLFIRI
CAPOX = CAPIRITournigand 2004, Colucci 2005, Grothey 2004
FOLFOX > IFLGoldberg 2004
The use of all available drugs is strongly suggested
Grothey 2004
Statistical ConsiderationsGoldberg Tournigand Colucci
Pts required per arm
375 109 (49 events)
176
Power 90% 80% 80%
α-error 5% 5% 5%
Primary Objective
To detect a HR of 0.75 in TTP between each experimental regimen and control
To detect a 20% difference in the proportion of patients without second progression at 15 m (60% in arm A, 40% in arm B)
To detect a 15%
difference in Objective
response
Cancro colon-retto avanzato: ruolo del bevacizumab
BEVA+ IFL >IFL in Prima LineaHurwitz H 2004
BEVA + FOLFOX4 >FOLFOX4 in II lineaGiantonio BJ 2005
ma ……
The addition of Bevacizumab to IFL increases PFS and OS
Saltz L ASCO 2007
Saltz L ASCO 2007
Aggiunta di BEVA alle doppiettein prima linea
• Bevacizumab aumenta OS se usato con IFL
• Non aumenta OS se usato con XELOX o FOLFOX4
Canro colorettale e Cetuximab
Cetuximab is the most active drug in pretreated patients
Lentz 2005
Cetuximab + FOLFOX4 is a very active regimen (Resp Rate >60%)
Colucci 2006, Tabernero 2004
CRYSTAL Trial: Study Design
Stratification factors: – Regions– ECOG PS
Populations– Randomized patients n=1217– Safety population n=1202– ITT 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 (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion)+ FA every 2 weeks
REGFR-expressing
metastatic CRC
Van Custen et al, ASCO 2007
CRYSTAL Trial: Study Endpoint
• Primary endpoint:
– Progression-free survival time (as assessed by blinded independent review)
• Secondary endpoints:
– Overall response rate (independently reviewed)
– Disease control rate (CR+PR+SD)
– Overall survival time
– Quality of life (EORTC QLQ C30)
– Safety
CRYSTAL trial: Primary endpoint PFS met ITT population independent review
Progression-free survival time (months)
PF
S e
sti
mat
e
1.0
0.8
0.9
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
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 18 200 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 mo
8.0 mo
FOLFIRI, n=599
Cetuximab + FOLFIRI, n=599
FOLFIRI, n=599
Cetuximab + FOLFIRI, n=599
1-year PFS rate23% vs 34%
Subjects at risk
FOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1Cetuximab + FOLFIRI
599 499 392 298 196 103 58 29 12 5 1
Subjects at risk
FOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1Cetuximab + FOLFIRI
599 499 392 298 196 103 58 29 12 5 1
CRYSTAL Trial: Primary End-Point PFS
CRYSTAL trial:Independent Assessment of Response
38,7
46,9
0
10
20
30
40
50
60
Response rate
Per
centa
ge
(%)
FOLFIRI alone, n=599Cetuximab + FOLFIRI, n=599
p-value* = 0.0038
FOLFIRI
%
Cetuximab
+ FOLFIRI
%
CR
PR
SD
PD
0.3
38.4
46.7
9.0
0.5
46.4
37.4
8.8
ORR95%CI
38.7[34.8 - 42.8]
46.9[42.9 - 51.0]
DCR** 85.5 84.3
*Cochran-Mantel-Haenszel (CMH) test ** DCR: disease control rate
CRYSTAL trial: Primary endpoint PFS subgroup:liver metastases only
Progression-free survival time (months)
0 2 4 6 8 10 12 14 16 18 200 2 4 6 8 10 12 14 16 18 20
PF
S e
sti
mat
e
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cetuximab + FOLFIRI, n=122
FOLFIRI, n=134
HR = 0.637; 95% CI = [0.432-0.941]
Stratified log-rank p-value = 0.023
9.2 mo
11.4 mo
Subjects at risk
FOLFIRI alone 134 115 93 68 36 18 6 3 7 4 1Cetuximab + FOLFIRI
122 100 84 74 51 26 15 6 2 1 1
CRYSTAL trial:Subgroup analysis of PFS time by
on-study skin reactions: cetuximab + FOLFIRI
Skin reaction grade 0 or 1, n=244
*There were no grade 4 skin reactions
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
Progression-free survival time (months)
1.00
0.75
0.50
0.25
0.00
PF
S e
sti
mat
e
Skin reaction grade 2, n=243
Skin reaction grade 3*, n=112
11.3 mo5.4 mo 9.4 mo
Skin reaction grade 0 or 1, n=244
*There were no grade 4 skin reactions
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
Progression-free survival time (months)
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
Progression-free survival time (months)
1.00
0.75
0.50
0.25
0.00
PF
S e
sti
mat
e
1.00
0.75
0.50
0.25
0.00
PF
S e
sti
mat
e
Skin reaction grade 2, n=243
Skin reaction grade 3*, n=112
11.3 mo5.4 mo 9.4 mo
CRYSTAL Trial: Conclusions
• The CRYSTAL trial met its primary objective of demonstrating that the addition of
cetuximab to FOLFIRI in the first-line treatment of EGFR-detectable mCRC
significantly increased PFS
– There was a 15% risk reduction for progression in patients treated with cetuximab
plus FOLFIRI compared to FOLFIRI
• The addition of cetuximab to FOLFIRI was associated with:
– Higher response rates (p=0.0038)
– Threefold higher R0 resection rates for initially unresectable disease (p=0.0034)
• Skin reactions showed a strong correlation with efficacy
Differences in Treatment Strategies Between US and Europe
United States Europe
First-line chemo FOLFOX » FOLFIRI
FOLFOX = FOLFIRI
XELOX Frequent Uncommon
BEV in first-line Majority of patients Minority of patients
BEV continuation beyond progression
Frequently Uncommon
EGFR Antibodies Common in second- and third-line, single agent or combination
Common in combination
A. Grothey WCGC 2007
Unsolved Questions
• Is there a clear advantage in survival with the use of polichemotherapy rather then monochemotherapy as first line treatment? (Seymour 2007, Punt 2007)
• What is the role of the stop and go strategy? (GISCAD 2006, )
• What is the role of triplet in patients with liver metastases? (Falcone A. 2006, Garufi C 2007)
• Is colorectal cancer a unique clinical disease?
Lancet 2007
FOCUS TRIAL
CAIRO TRIAL
CAIRO TRIAL
Which strategy as first line treatment?
• Perhaps the answer is to define a “Minimal Therapy” or an “Intense Therapy”
• Introduction of the concept of “Continuum Treatment”(Hoff ASCO 2007)
(Hoff ASCO 2007)
(Hoff ASCO 2007)
(Hoff ASCO 2007)
Unsolved Questions
• Is there a clear advantage in survival with the use of polichemotherapy rather then monochemotherapy as first line treatment? (Maughan T. 2003)
• What is the role of the stop and go strategy? (GISCAD ASCO2006, OPTIMOX2 ASCO 2007)
• What is the role of triplet in patients with liver metastases? (Falcone A. 2006, Garufi C)
• Is colorectal cancer a unique clinical disease?
Rationale
• Chemotherapy-free intervals have been previously studied in patients receiving 5-FU based therapy
Hejna et al. (Br J Cancer 1998) Maughan et al. (Lancet 2003)
• New combination therapies have improved survival but there is still the risk of cumulative toxicities like Oxaliplatin sensory neuropathy
• Clinical rationale: quality of life preservation, costs reduction and social impact improvement
Continuos vs Intermittent Therapy ?MRC Trial
Maugan et al., Lancet 2003
“Our findings provided no clear evidence of benefit in continuing therapy indefinitly until disease progression”
GISCAD Trial: Design (ASCO 2006)
R
N=336
Evaluation
Primary end point: OSNon inferiority : 15< Median OS (months)< 11
4 mos
FOLFIRI
Greem ASCO 2007 Discussant
STOP and GO STRATEGY
• At this time there are no clear advantage from a stop and go strategy. It seems that continuing treatment until progression, if not hampered by severe toxicity, is still a valid option
We should consider Stage IV different groups of colorectal
cancer patients
• Clinical History (PS, comorbidity, age)
• Interdisciplinary Teams (surgery and/or RT)
• Different median survival (<12 e >24 mesi)
• Necessity to identify new prognostic factors
We need new trials for old and new Prognostic Factors
• Gender (Giacchetti S. et al JCO 2006)
• Hb (Tampellini M. et al Br J Cancer 2006)
• LDH (Koehne et al ASCO 2006)
• Resectability (Poston G et al JCO 2006)
• Genic Polimorphysm (Toffoli G et al JCO 2006)
Clinical determinants of survival in patients with 5-fluorouracil- based treatment for metastatic colorectal
cancer: results of a multivariate analysis of 3825 patients
C.-H. Kohne, D. Cunningham, F. Di Costanzo, B. Glimelius, et al
Ann. Onc., 2002; 13(2): 308 - 317.
Diferent Stage IV Disease in Different Patients
• Disseminated Disease • Local Recurrences • Peritoneal Carcinosis• Non-measurable Disease • Lung Metastases • Liver Metastases - Resected - Resectable - Non-resectable
Diferent Stage IV Disease in Different Patients
• Disseminated Disease • Local Recurrences • Peritoneal Carcinosis• Non-measurable Disease • Lung Metastases • Liver Metastases - Resected - Resectable - Non-resectable
EPOC: STUDY DESIGN
Elegibility Criteria
Rationale for timing of chemotherapy
Objectives of the trial
Surgery
PFS in resected patients
Diferent Stage IV Disease in Different Patients
• Disseminated Disease • Local Recurrences • Peritoneal Carcinosis• Non-measurable Disease • Lung Metastases • Liver Metastases - Resected - Resectable - Non-resectable
Treatment of liver metastases from colorectal cancer
Liver Metastases
85% non-resectable 15% resectable
Neoadiuvant Cht
Potentially resectable
(4-30%)
• R0•R0 uncertain
?
FA/FU FA/OXA o CPT11
5-FU/FA/OXA/CPT11 Biologic agents
5-year survival rate
Liver Resection = the only chance of survival
Adam R. PBH
What is non-resectable disease?
Classical Contraindications to liver resection: ≥ 4 metastases ; Size; Extraepatic Disease; Hilar location Resection margin < 1 cm; Incomplete Resection
Adam R., et al. Ann Surg Onc 2000
9
48
1226
0
10
20
30
40
50
large Multi-nodular ill-located extra-hepatic
1. Size 2. Multinodular3. Ilar location4. Extraepatic disease
5. Patients with >3 metastases who receive chemo-therapy in order to stabilize liver disease before surgery
6. Patients who present with huge resectable liver metastases at the time of resection of the primary tumor and need extended liver surgery. Primary tumor has to be resected.
Non-Resectability Criteria (IRE):
Response rate and surgery of metastases(First line 5-FU, LV and l-OHP)
Chrono 4-10
Chrono 5-16
Flat 5-16
0 30 40 50 60
40
30
10
0
Objective responses (%)
Co
mp
lete
res
ect
ion
of m
eta
sta
ses
(%)
r = 0.96 ; p = 0.0007
94-96
93-94
90-93
90-93
Secondary surgery of metastases : major prognostic factor of survival
20
70
Lévi F 2000
There is a strong and highly significant correlation between response rate and liver resections
Folprecht 2005
NON RESECTABLE « HEPATIC » PATIENTS
Multi Unilobar Multi Bilobar Multi Bilobar
Remnant Liver<30% ≤3 nod. ≤30 mm >3 nod >30 mm
Hepatectomy +RxF or Cryo
2-Stage Hepatectomy
Portal Embolization
Adam R
The Triplets
• “Triplets” are combinations of a fluoropyrimidin (5-FU o Capecitabine) modulated by LV + L-OHP and CPT-11
• Triplets come from original doublets combinations as FOLFOX, CPT-11+FF, or chronomodulated FFL.
Triplets were developped to answer to the following reasons:
1) To increase activity of the combination
2) To increase the number of resectable patients
3) To allow a reduction of cumulative toxicity
4) To have a tolerable acute toxicity
The Triplets
0 10 20 300
25
50
75
100
Months
Per
cen
t su
rviv
al
FOLFIRI
122 pts
FOLFOXIRI
122 pts
Progressed 108 96
Median PFS 6,8 m 9,8 m
HR: 0.60 (95%CI: 0.44-0.78)
log-rank P value < 0.001
PROGRESSION FREE SURVIVALPROGRESSION FREE SURVIVAL
Median follow up 14.0 months
FOLFIRI
122 pts
FOLFOXIRI
122 pts
R0 6%* 14%*
R1 1% 2%
Explorative 8% 1%
* P=0.05
Trattamento neoadiuvante: tripletta vs doppietta
Masi et al.
Studio POCHER
• PreOperative
• Chemotherapy
• Hepatic
• Resection
CPT-11 130 mg/m2day 1 peak 13:00
Chronomodulated delivery scheme(5d on/16d off or 4d on/10d off)
Time (clock hour)10:00 16:00 22:00 04:00 10:00
Flo
wra
te (
arb.
Uni
ts)
5-FU(600-1100 mg/m²/d)
LV(300 mg/m²/d)
L-OHP(25 mg/m²/d)
Cetuximab 400-250 mg/m2 day1
FFL4-10 day2-5 q 2 settimane
Istituto Regina Elena Roma
Ospedale S Maria degli Angeli Pordenone
CPT-11+L-OHP CPT-11+L-OHP in micein mice
D’Attino et alD’Attino et al
BJC ‘02BJC ‘02
CPT-11 bolus vs chrono + CPT-11 bolus vs chrono + FF FF 4-104-10
Garufi et alGarufi et al EJC ‘06EJC ‘06
CPT-11 + FF CPT-11 + FF 5-165-16
Garufi et alGarufi et al Cancer ‘01Cancer ‘01
EORTC 05011 EORTC 05011
CPT-11CPT-11 + FFL + FFL
Garufi et alGarufi et al ASCO 2007ASCO 2007
POCHER DevelopmentPOCHER Development
CPT-11bolus + FFLCPT-11bolus + FFL
Garufi et alGarufi et al BJC ‘03BJC ‘03
Cetuximab + Cetuximab + CPT-11CPT-11 + FFL + FFL
EORTC study 05011 Colorectal
DayDay 22--55•• OxaliplatinOxaliplatin 20 mg/m²/d20 mg/m²/d•• 55--FU FU 700 mg/m²/d700 mg/m²/d•• LeucovorinLeucovorin 300 mg/m²/d300 mg/m²/d
1616 0404
55--FUFU--LVLV
DayDay 11 IrinotecanIrinotecan180 mg/m²180 mg/m²
LL--OHPOHP
05
06
09
14
02 08
00 02 0422
0110
13
16
14
17
20
18
21
00
Randomized deliveryRandomized deliverypeakpeak time (h)time (h)
Fixed delivery peak timesFixed delivery peak times(h)(h)
Coordinator: C. Garufi – IRE - Rome
Garufi C. et al ASCO 2007
Peak Time for Diarrhea
Tolerability over the first 3
cycles: best timing h13:00
Tolerability is defined as no reduction or cycle delay. Dose reduction or cycle delay for not related reasons were not considered an event
Garufi C. et al
ASCO 2007
Resezioni Epatiche Post-Chemioterapia
1ª Line Chemotherapy
EORTC 05011-IRE
40 Patients
Candidate to Surgery
9 Pts (33%)
Radical Resections
8 Pts (30%)
Liver Mets only
27 Paz. (67%)
Patient with non-resectable colorectal liver metastases
Evaluation of Inclusion/Exclusion criteriaInformed consent
Treatment with CPT11/5FU-FA/L-OHP + CetuximabFirst evaluation of response after 4 cycles
Resectable
SurgeryNot before than 4 cycles and within 45 days from
the last cycle
Chemo + Cetuximab for 4-6 cycles
Evaluation for resectability
Non-resectable
Chemo + Cetuximab will be continued until PD,
unacceptable toxicity or patient refusal
Partial response, disease stabilization: other 2 cycles
POCHER Trial design
Study Design
• Primary End-Point: Resection rate
• Secondary End-Points: Rate of Pathological Complete ResponseResponse RateTolerabilityTime to disease ProgressionOverall Survival
Number of patients required with p0 =10% e p1= 25%: 40
Patients with unresectable colorectal liver metastases • study of EGFR pathway (FAS/FAS –lL sistem and AKT signalling)
• role of amplification and polisomy of EGFR gene
•evaluation of rest/activity rhythm (RAR) measured by Actigraph
• measurement ol serum levels of Cytokines TGF-α, TNF and IL-6
• Relationship between RAR and Quality of Life
Role of Erbitux plus a combination of CPT-11/5-fluorouracil/leucovorin/oxaliplatin combination as neoadjuvant
chemotherapy in patients with colorectal liver metastases
Chemotherapy Schedules for Colorectal Cancer Liver Metastases and Resectability
Schedule Author Selected Patients
N°. of Patients
RR (%) Resezioni R0(%)
FOLFOX4 Alberts Yes 42 52 30
FFL4-10 crono Giacchetti Yes 151 59 32
FOLFOX4 + Cetuximab
GOIM2402 No 53 60 21
FOLFOX4 + Cetuximab
André No 43 72 23
FOLFIRI Pozzo Yes 40 51 33
AIO+CPT-11 + Cetuximab
Folprecht No 19 68 21
CRYSTAL VanCutsem No 132 46.9 9.8
CPT-11+5-FU+FA+L-OHP
Tripletta crono Garufi Yes 27 45 30
FOLFOXIRI Falcone No 74 71 26
FOLFOXIRI De la Camara Yes 212 64 43
FOLFOXIRI Quenet Yes 26 73 35
POCHER Garufi Yes 15 86 69
Conclusions
• Cetuximab containing regimens as 1° line are associated with high response rate in patients with colorectal liver metastases
• POCHER combination is able to induce resectability in 69% of patients initially considered as non-resctable with our criteria
• These results must be confirmed in randomized studies which compare doublets or triplets ± cetuximab in selected patients and in selected centers