Gemcitabine and oxaliplatin in pancreatic cancer

1
Mediterranean School of Oncology Highlights in
the management of colorectal cancer Roma 1-2
Febbraio 2007
Optimal management of liver metastases The
opinion of the medical oncologist
Alfredo Falcone Dipartimento di Oncologia -
Azienda USL-6 di Livorno Cattedra di Oncologia
Medica - Università degli Studi di Pisa Istituto
Toscano Tumori
2
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

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IMPROVEMENTS IN THE TREATMENT OF CRC LIVER METS
More Surgery
Better Chemotherapy
Better Integration
Some Biologics
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Improvements in MCRC treatment in the last 10
years
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Active treatments available in MCRC
1990-1996
2000-2006
1. Surgery 2. Fluoropyrimidines

• Surgery (RF ablation)
• Fluoropyrimidines
• Irinotecan
• Oxaliplatin
• Bevacizumab
• Anti-EGFR monoclonal-Ab

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PATIENTS WITH CRC LIVER METS
UNRESECTABLE
RESECTABLE
Not easily resectable
Easily resectable
Potentially resectable
Never resectable
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What does RESECTABLE means?
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TRADITIONAL CRITERIA FOR RESECTION

• gt 12 months after resection of primary
• Unilobar disease
• lt 4 metastases
• gt 1 cm resection margin

According to these criteria approximately only
10 of patients are eligible for surgery
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The OncoSurge Decision Model in CRC liver mts

• SURGERY IS CONTRINDICATED WHEN

• Not-treatable extrahepatic disease
• Unfit for surgery (es. ASAgt3)
• Extensive liver involvement (gt70 liver or gt6
  liver segments or all 3 hepatic veins involved)
• Major liver insufficiency

IMMEDIATE RESECTION IS APPROPRIATE WHEN

• in case of adequate radiological margins
• absence of portal lymph nodes involvement
• number of mts is 4 or gt4 but unilobar
  involvement

Poston et al. J Clin Oncol 2005
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CHEMOTHERAPY(Fluoropyrimidines, Irinotecan,
Oxaliplatin)
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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

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Hepatic arterial infusion of chemotherapy after
resection of hepatic metastases from colorectal
cancer
156 pts
156 pts
P0.06
P0.21
Plt0.001
P0.21
N Kemeny et al, N Engl J Med 1999
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Adjuvant 5-FU/LV after resection of liver mets
FFCD ACHBTH AURC 9002 Trial
171 pts
171 pts
Curve PFS ed S con HR, e p
HR0.66 p 0.028
HR0.73 p 0.13
G. Portier et al. J Clin Oncol 2006
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EORTC-40983
FOLFOX-4 (6 cycles)
FOLFOX-4 (6 cycles)
Surgery
364 Pts with RESECTABLE liver only MTS
Surgery
Nordlinger et al. Proc. ASCO 2005 Gruenberger et
al. Proc. ASCO 2006
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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

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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)

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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
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RELATIONSHIP BETWEEN PERCENTAGE OF PTS RECEIVING
5FU, IRINOTECAN, AND OXALIPLATIN IN THE COURSE OF
THEIR DISEASE AND THE MEDIAN OVERALL SURVIVAL
Grothey, A. et al. J Clin Oncol 221209-1214,
2004
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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, plt.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
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FOLFOXIRI Phase II trials
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POST-CT SURGICAL RESECTIONS
First line FOLFOXIRI (74 pts)
Evaluated for surgery (30 pts)
Curative Surgery (19 pts)
40
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Masi G, Ann Surg Oncol 2005
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STUDY DESIGN
FOLFIRI CPT-11 180 mg/m2 1-h d.1 L-LV 100 mg/m2
2-h d.1,2 5FU 400 mg/m2 bolus d.1,2 5FU 600
mg/m2 22-h d.1,2 q. 2 wks x 12 cycles
R A N D O M

• Stratification
• Center
• PS 0/1-2
• Adjuvant CT

Douillard Lancet 2000
FOLFOXIRI CPT-11 165 mg/m2 1-h d.1 LOHP 85
mg/m2 2-h d.1 L-LV 200 mg/m2 2-h d.1 5FU
3200 mg/m2 48-h CI d.1 q. 2 wks x 12 cycles
Masi Ann Oncol 2004

• In pts progressed after FOLFIRI a second-line CT
  with an LOHP containing regimen (FOLFOX) was
  recommended

Falcone A. J Clin Oncol 2007 (in press)
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FOLFOXIRI SCHEDULE
Day 1 Day 2 Day 3
CPT-11 165 mg/m2
Oxaliplatin 85 mg/m2
5FU flat continuous infusion 3200mg/m2
L-LV 200 mg/m2
2 hours
48 hours
1 hour
Repeated every 14 days
Falcone A. J Clin Oncol 2007 (in press)
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RESPONSES (ITT analysis)
INVESTIGATORS ASSESSMENT
P 0.0002
Falcone A. J Clin Oncol 2007 (in press)
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RESPONSES (ITT analysis)
EXTERNALLY REVIEWED
Plt 0.0001
Falcone A. J Clin Oncol 2007 (in press)
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POST-CT SURGICAL RESECTIONS (all patients)
p0.033
Falcone A. J Clin Oncol 2007 (in press)
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POST-CT SURGICAL RESECTIONS (patients with liver
mts only)
P0.017
Falcone A. J Clin Oncol 2007 (in press)
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PROGRESSION FREE SURVIVAL
Falcone A. ASCO-GI 2007
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OVERALL SURVIVAL
19
13
Median follow up 36.2 months
Falcone A. ASCO-GI 2007
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SURVIVAL OF PTS RESECTED AFTER FOLFOXIRI
Actuarial 5-year survival 49
Personal unpublished data
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BEVACIZUMABANDCETUXIMAB
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TRIALS SUPPORTING THE USE OF BEVACIZUMAB PLUS CT
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TRIALS SUPPORTING THE USE OF CETUXIMAB /- CT
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Cetuximab studies in non-resectable liver
metastases non-selected patients
a5 patients could not be assessed for
confirmation of response because they underwent
secondary resection of metastases bMinor response
Rosenberg, et al. Proc ASCO 200220 (Abstract No.
536) Peeters M, et al. Eur J Cancer Suppl
20053188 (Abstract No. 664) Folprecht G, et
al. Ann Oncol (2005) Cervantes A, et al. Eur J
Cancer Suppl 20053181 (Abstract No. 642)
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PATIENTS WITH CRC LIVER METS
UNRESECTABLE
RESECTABLE
Not easily resectable
Easily resectable
Potentially resectable
Never resectable
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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

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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
  (CetuximabCT, FOLFOXIRI biologic, etc)

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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 CetuximabCPT)
• 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

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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

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Surgery in resectable MCRC
Score 0
Score 1
Score 2
Score 3
Score 4
Score 5
Fong Y et al. Ann Surg 230 309, 1999
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The Paul Brousse Experience (1988-1999)
Resectable
Resectable after CT
pts surviving
48
30
p0.01
33
23
Years
Adapted from Adam et al. Ann Surg 2004
240(4)644-657
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Neoadjuvant CT in pts with Liver MTS of CRC 5-FU
OXA
Not stated if Complete Resection
adapted from Leonard et al. JCO 2005 232038-2048
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Neoadjuvant CT in pts with Liver MTS of CRC 5-FU
CPT-11
A combination of systemic CT with
5-Fu/Irinotecan and HAI of pirarubicin has been
tested
48
Adjuvant chemotherapy with 5FU/LV after
potentially curative resection of mets from CRC.
A meta-analysis of two randomized trials
Two phase III studies (FFCD 9002, EORTC/NCI
CTG/GIVIO)
E. Mitry et al. Proc. ASCO 2006
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Phase III trial of IFL Bevacizumab in
metastatic CRC (AVF2107g) OS
Hurwitz et al. N Engl J Med 2004
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Combined analysis of bevacizumab 5-FU/LV vs
5-FU/LV o IFL OS
Kabbinavar F, et al. J Clin Oncol
2005233706-3712
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Phase III second-line FOLFOX4 Bevacizumab
(E3200) OS
1.0 0.8 0.6 0.4 0.2 0
HR0.76 A vs B p0.0018 B vs C p0.95
Probability
10.8
10.2
12.9
0
3
6
9
12
15
18
21
24
27
30
33
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Overall survival (months)
Alive
Dead
Median
Total
A FOLFOX4 bevacizumab
289
246
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12.9
B FOLFOX4
290
257
33
10.8
C Bevacizumab
243
216
27
10.2
HR hazard ratio
Giantonio BJ, et al. ASCO 2005
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(NCIs TRC-0301) responses
Chen HX et al. ASCO Annual Meeting 2004 Abstract
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