Alfredo FalconeDipartimento di Oncologia - Azienda USL-6 di Livorno

Cattedra di Oncologia Medica - Università degli Studi di PisaIstituto Toscano Tumori

Mediterranean School of OncologyHighlights in the management of colorectal cancer

Roma – 1-2 Febbraio 2007

Optimal management of liver metastases:

The opinion of the medical oncologist

Liver Metastases in Colorectal Cancer

60% of CRC pts develop liver mets 25% synchronous 35% methacronous

50% of initial recurrences are confined to the liver

In 20-30% of advanced CRC pts liver is the only site of mets

IMPROVEMENTS IN THE TREATMENT OF CRC LIVER METS

IMPROVEMENTS IN THE TREATMENT OF CRC LIVER METS

More More

SurgerySurgery

SomeSome

BiologicsBiologics

BetterBetter

ChemotherapyChemotherapy

BetterIntegration

Improvements in MCRC treatment in the last 10 years

1990-1996 2000-2006

Response Rate 20% 40-60%

Median PFS 4 mos 7-10 mos

Median OS 12 mos 18-22 mos

II-III line treatment ? YES

Post-CT resection of mets (liver)

? YES

Active treatments available in MCRC

1. Surgery

2. Fluoropyrimidines

1. Surgery (+RF ablation)

2. Fluoropyrimidines

3. Irinotecan

4. Oxaliplatin

5. Bevacizumab

6. Anti-EGFR monoclonal-Ab

1990-1996 2000-2006

UNRESECTABLE

“Not easily”resectable

“Easily”resectable

“Potentially”resectable

RESECTABLE

PATIENTS WITH CRC LIVER METS

“Never”resectable

????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????

What does What does

“RESECTABLE” “RESECTABLE”

means?means?

> 12 months after resection of primary

Unilobar disease

< 4 metastases

> 1 cm resection margin

“TRADITIONAL” CRITERIA FOR RESECTION

“TRADITIONAL” CRITERIA FOR RESECTION

According to these criteria approximately only 10%

of patients are eligible for surgery

The OncoSurge Decision Model in CRC liver mts

Poston et al. J Clin Oncol 2005

SURGERY IS CONTRINDICATED WHEN:

Not-treatable extrahepatic disease Unfit for surgery (es. ASA>3) Extensive liver involvement (>70% liver or >6 liver

segments or all 3 hepatic veins involved)

Major liver insufficiency

in case of adequate radiological marginsabsence of portal lymph nodes

involvement number of mts is ≤4 or >4 but unilobar

involvement

IMMEDIATE RESECTION IS APPROPRIATE WHEN:

CHEMOTHERAPY(Fluoropyrimidines, Irinotecan, Oxaliplatin)

Chemotherapy in initially resectable liver mets

• Pre-operative CT so far is not indicated in “easily” or “immediately” resectable patients (oncosurge)

• Pre-operative CT is rationale and there is a general consensus in its use in “not easily” or “marginally” resectable pts

• Post-operative CT is rationale and generally recommended, but limited data support its use

N Kemeny et al, N Engl J Med 1999

P<0.001 P=0.21

Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer

156 pts 156 pts

P=0.06 P=0.21

Adjuvant 5-FU/LV after resection of liver mets: FFCD ACHBTH AURC 9002 Trial

G. Portier et al. J Clin Oncol 2006

Curve PFS ed S con HR, % e p

171 pts171 pts 171 pts171 pts

HR=0.66; p= 0.028 HR=0.73; p= 0.13

364 Pts with

RESECTABLEliver only

MTS

FOLFOX-4 FOLFOX-4 (6 cycles)(6 cycles)

Surgery Surgery

Surgery Surgery FOLFOX-4 FOLFOX-4 (6 cycles)(6 cycles)

EORTC-40983EORTC-40983

Completed CT

RR ResectedPerioperative

morbidityPerioperative

mortality

Surgery NA NA 84.4% 13.3% 0.9%

Chemo-Surgery

71% 39% 84.7% 24.5% 1.6%

Nordlinger et al. Proc. ASCO 2005Gruenberger et al. Proc. ASCO 2006

Chemotherapy in initally unresectable MCRC and liver mets

• Initial use of a doublet is better than single agent• Important to expose patients to 5FU, CPT, LOHP• Infusional 5-FU is preferable to bolus• Capecitabine can probably be an alternative to 5-FU • Reevaluate for surgery responding patients • More responses = more resections• Initial use of a triplet is better than a doublet in selected patients• Chemotherapy-free intervals do not reduce efficacy in selected

patients

Trials supporting the use of doublets

CPT-11/5FU-LV– Saltz, NEJM 2000 (IFL)

– Douillard, Lancet 2000 (FOLFIRI)

– Koehne, JCO 2005 (AIO-IRI)

LOHP/5FU-LV– De Gramont, JCO 2000 (FOLFOX4)

– Giacchetti, JCO 2000 (Chronoinfusion)

– Grothey, ASCO 2002 (FUFOX)

Trials supporting equivalent efficacy of doublets containing CPT11 or LOHP with infusional 5FU/LV

Tourningard JCO 2004 –FOLFIRI vs FOLFOX6

Colucci JCO 2005 –FOLFIRI vs FOLFOX4

N.B.: When these studies were performed no adjuvant LOHP was in use

Grothey, A. et al. J Clin Oncol; 22:1209-1214, 2004

RELATIONSHIP BETWEEN PERCENTAGE OF PTS RECEIVING 5FU, IRINOTECAN, AND OXALIPLATIN IN THE COURSE OF THEIR

DISEASE AND THE MEDIAN OVERALL SURVIVAL

RELATIONSHIP BETWEEN PERCENTAGE OF PTS RECEIVING 5FU, IRINOTECAN, AND OXALIPLATIN IN THE COURSE OF THEIR

DISEASE AND THE MEDIAN OVERALL SURVIVAL

Response rate

,9,8,7,6,5,4,3

Rese

ctio

n r

ate ,6

,5

,4

,3

,2

,1

0,0

CORRELATION BETWEEN TUMOR RESPONSE AND RESECTION RATES

CORRELATION BETWEEN TUMOR RESPONSE AND RESECTION RATES

Studies incl. selected pts.(liver metastases only, no extrahepat. disease) r=.96, p=.002

Studies incl. all patients with metastatic CRC (solid line) r=.74, p<.001

Phase III studies in metastatic CRC(dashed line) r=.67, p=.024, p=.024

G Folprecht, A Grothey, S Alberts, HR Raab, and CH Köhne , Ann Oncol 2005

FOLFOXIRIJ Clin Oncol 2002

(N=42)

sFOLFOXIRIAnn Oncol 2004

(N=32)

Response Rate 71% (12%CR)

72% (13%CR)

Median PFS 10.4 mos 10.8 mos

Median OS 26.5 mos 28.4 mos

FOLFOXIRI: Phase II trialsFOLFOXIRI: Phase II trials

First line

FOLFOXIRI

(74 pts)Evaluated

for surgery

(30 pts)

Curative

Surgery

(19 pts)

POST-CT SURGICAL RESECTIONSPOST-CT SURGICAL RESECTIONS

40%

26%

Masi G, Ann Surg Oncol 2005

STUDY DESIGNSTUDY DESIGN

FOLFIRI*FOLFIRI*CPT-11 180 mg/m2 1-h d.1L-LV 100 mg/m2 2-h d.1,25FU 400 mg/m2 bolus d.1,25FU 600 mg/m2 22-h d.1,2 q. 2 wks x 12 cycles

FOLFOXIRI**FOLFOXIRI**CPT-11 165 mg/m2 1-h d.1LOHP 85 mg/m2 2-h d.1L-LV 200 mg/m2 2-h d.15FU 3200 mg/m2 48-h CI d.1q. 2 wks x 12 cycles

StratificationCenterPS 0/1-2Adjuvant CT

RANDOM

In pts progressed after FOLFIRI a second-line CT with an LOHP

containing regimen (FOLFOX) was recommended

* Douillard Lancet 2000

** Masi Ann Oncol 2004

Falcone A. – J Clin Oncol 2007 (in press)

FOLFOXIRI SCHEDULEFOLFOXIRI SCHEDULE

5FU flat continuous infusion3200mg/m2

L-LV 200 mg/m2

Oxaliplatin 85 mg/m2

2 hours

Repeated every 14 days

CPT-11165 mg/m2

48 hours

Day 1 Day 2 Day 3

1 hour

Falcone A. – J Clin Oncol 2007 (in press)

FOLFIRI122 pts

FOLFOXIRI122 pts

Complete 6% 8%

Partial 35% 58%

Complete + Partial 41%* 66%*

95% Confidence Interval 0.32-0.50 0.56-0.74

Stable 33% 21%

Progression 24% 11%

Not evaluable 2% 2%

*P = 0.0002

RESPONSES (ITT analysis)RESPONSES (ITT analysis)

INVESTIGATORS’ASSESSMENT

INVESTIGATORS’ASSESSMENT

Falcone A. – J Clin Oncol 2007 (in press)

FOLFIRI(122 pts)

FOLFOXIRI(122 pts)

Complete 6% 7%

Partial 28% 53%

Complete + Partial 34%* 60%*

95% Confidence Interval 0.25-0.43 0.51-0.68

Stable 34% 21%

Progression 24% 11%

Not evaluable 8% 8%

*P< 0.0001

EXTERNALLYREVIEWED

EXTERNALLYREVIEWED

RESPONSES (ITT analysis)RESPONSES (ITT analysis)

Falcone A. – J Clin Oncol 2007 (in press)

FOLFIRI(122 pts)

FOLFOXIRI(122 pts)

R0 6%*(7 pts) 15%*(18 pts)

R1 1% 2%

Explorative 8% 1%

* p=0.033

POST-CT SURGICAL RESECTIONS(all patients)

POST-CT SURGICAL RESECTIONS(all patients)

Falcone A. – J Clin Oncol 2007 (in press)

FOLFIRI(42 pts)

FOLFOXIRI(39 pts)

R0 12%*(5 pts) 36%*(14 pts)

* P=0.017

POST-CT SURGICAL RESECTIONS(patients with liver mts only)

POST-CT SURGICAL RESECTIONS(patients with liver mts only)

Falcone A. – J Clin Oncol 2007 (in press)

FOLFIRI

122 pts

FOLFOXIRI

122 pts

Progressed 114 111

Median PFS 6.9 m 9.9 m

HR: 0.65 (95%CI: 0.47-0.83)

log-rank P value = 0.0009

PROGRESSION FREE SURVIVALPROGRESSION FREE SURVIVAL

0 6 12 18 24 30 36 420

20

40

60

80

100

months

Perc

en

t su

rviv

al

Falcone A. – ASCO-GI 2007

OVERALL SURVIVALOVERALL SURVIVAL

FOLFIRI

122 pts

FOLFOXIRI

122 pts

Died 96 84

Median OS

16.7 m 23.6 m

HR: 0.74 (95%CI: 0.55-0.99)

log-rank P value = 0.042

19%13%

0 12 24 36 48 600

20

40

60

80

100

months

Perc

en

t su

rviv

al

Median follow up: 36.2 months

Falcone A. – ASCO-GI 2007

SURVIVAL OF PTS RESECTED AFTER

FOLFOXIRI

SURVIVAL OF PTS RESECTED AFTER

FOLFOXIRI

Personal unpublished data

Actuarial 5-year survival: 49%

0 12 24 36 48 600

25

50

75

100 OS, median 40.8 months

Entered: 37Died: 16Median Follow up: 34.3 months

Months

Per

cen

t su

rviv

al

BEVACIZUMABAND

CETUXIMAB

TRIALS SUPPORTING THE USE OF BEVACIZUMAB PLUS CT

TRIALS SUPPORTING THE USE OF BEVACIZUMAB PLUS CT

Trial Design Results

First line

AVF2107IFL+ BV

IFLIncreased RR, PFS, OS

TREE2OXA based+BV

OXA basedIncreased RR

Combined analisys

5FU+BV

5FU or IFLIncreased RR, PFS, OS

Second line E3200

FOLFOX4+BV

FOLFOX4

BV

Increased RR, PFS, OS

TRIALS SUPPORTING THE USE OF CETUXIMAB +/- CT

TRIALS SUPPORTING THE USE OF CETUXIMAB +/- CT

Trial Design Results

Third line

BOND1Irinotecan+C225

C225Increased RR, PFS

NCIC-C017C225

BSCIncreased OS Press Release

Second line EPICIrinotecan+C225

Irinotecan

Increased RR, PFS Press Release

First line

CALGBFOLF-OX or -IRI

+ C225

Promising RR

Early Stopped

CRYSTAL

COIN

FOLFIRI + C225

FOLFOX + C225

Increased RR, PFS

Press Release

PENDING

cetuximab + IFL

cetuximab + FOLFIRI

cetuximab + AIO/irinotecan

cetuximab + FOLFOX-4

No. of patients 29 42 21 42

Response rate (CR+PR)

48% 45%a 67% 81%

Stable disease (SD) 10% 38% 29% 17%

Disease control

[CR+PR+MRb+SD]90% 83% 96% 98%

Resection of metastases N/A 24% 24% 23%

aa5 patients could not be assessed for confirmation of response because they underwent secondary resection of metastases; bMinor response

Rosenberg, et al. Proc ASCO 2002;20 (Abstract No. 536); Peeters M, et al. Eur J Cancer Suppl 2005;3:188 (Abstract No. 664); Folprecht G, et al. Ann Oncol (2005); Cervantes A, et al. Eur J Cancer Suppl 2005;3:181 (Abstract No. 642)

Cetuximab studies in non-resectable liver metastases – non-selected patients

Cetuximab studies in non-resectable liver metastases – non-selected patients

UNRESECTABLE

“Not easily”resectable

“Easily”resectable

“Potentially”resectable

RESECTABLE

PATIENTS WITH CRC LIVER METS

“Never”resectable

RESECTABLE PATIENTS

• In “easily” or “immediately” resectable patients (oncosurge) surgery up-front and consideration for adjuvant CT (5FU-LV, FOLFOX, FUDR)

• In “not easily” or “marginally” resectable patients and after a multidisciplinary evaluation, an active CT for 2-3 months (doublet or triplet) followed by surgery and further CT

UNRESECTABLE, BUT POTENTIALLY RESECTABLE PATIENTS

• Systemic CT with a a triplet (FOLFOXIRI) or a doublet (FOLFIRI or FOLFOX) + Bevacizumab reevaluating resectability every 2-3 months

• Consider studies with an “intensive” approach (Cetuximab+CT, FOLFOXIRI + biologic, etc…)

UNRESECTABLE, BUT NEVER RESECTABLE PATIENTS

• Fit patients, aggressive disease– Systemic CT with a first-line doublet (FOLFIRI or FOLFOX)

combined with bevacizumab or a triplet (FOLFOXIRI) and followed after PD by other active agents (FOLFOX or FOLFIRI or Cetuximab+CPT)

• Unfit patients, less aggressive disease– Sequential treatment beginninig with a fluoropyrimidine +

bevacizumab (if not controindicated)– “Personalized” first-line doublet + bevacizumab followed

after PD by other active agents (mainly in pts unfit for advanced tumor)

– Consider interruption of CT after 2-3 months if SD or response and restart after 2 months break or at progression

– BSC

CONCLUSIONS• Il the lat 10 years we have made substantial

progress in the treatment of pts with CRC liver mets. However the chances of long-term survival or cure remain limited

• Our therapeutic options are increased, treatment has become complex and a multidisciplinary approach is fundamental

• Need for further improvements through the development of better systemic and local treatments, better selection of pts, better integration