Post on 13-Jan-2016
Mts epatiche - Roma 2007 1
Optimal Management of Liver Metastases: Present Results and Future Strategies
Highlights in the Management of CRC
Roma, 1-2 febbraio 2007
Carlo BaroneOncologia Medica
Università Cattolica del S. Cuore
Carlo BaroneOncologia Medica
Università Cattolica del S. Cuore
Me
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Mts epatiche - Roma 2007 2
CRC liver metastasesCRC liver metastases
1,025,152 new cases and 528,978 deaths per year in the world:
~ 50% CRC pts develop liver metastases~ 15% to 25% (118,000) operable~ 25% to 35% of operated pts alive at 5 years
~ 3% to 4% (40.000) of total can be really cured…
Decision Resources, Inc.Decision Resources, Inc.Globocan for Pharma induustries 2002Globocan for Pharma induustries 2002
Mts epatiche - Roma 2007 3
Survival in advanced colorectal cancer in 2005
0 1 2 3 4 5
100
50
0
%
survivin
g
Years after diagnosis of colorectal metastases
2005 Median survival:Chemotherapy 24 mos.Overall >30 months
5 year survival:1984 2%1994 5%2005 20%
?
1984 overall1994 overall2005 chemotherapy2005 overall
1984 1994 2005 8 mos 12 mos 27 mos
Dr. G. Poston, Pfizer Satellite Symposium, ECCO 2005
Mts epatiche - Roma 2007 4
Summary
The role of Surgery in CRC liver mtsPreoperative CT
Resectable mtsInitially not-resectable mts
Hepatotoxicity of CTThe need for a new staging systemThe role of targeted agents in the management of liver mtsAdjuvant chemotherapy, HAI o Sys
Mts epatiche - Roma 2007 5
5-Yr Survivalafter resection of CRC Liver Mts
Authors Year Patients Op. Mort. Survival
Foster
Iwatsuki
Nordlinger
Adson
Hughes
Scheele
Rosen
AFC
Gayowski
Fong
Minigawa
Ercolani
Choti
Adam
Abdalla
1981
1986
1987
1987
1988
1991
1992
1992
1994
1999
2000
2002
2002
2003
2004
259
60
80
141
859
219
280
1818
204
1001
235
257
133
615
190
5%
0%
5%
3%
--
5%
4%
2%
0%
2.8%
0%
0.8%
-
1%
-
22%
35%
25%
25%
33%
39%
25%
26%
32%
37%
38%
34%
58%
41%
58%
Mts epatiche - Roma 2007 6
5-year survival after resection of CRC liver metastasesAuthor Year Res. Y/N Survival %) P
Foster 1981 259 22 -Adson 1988 141/70 25 vs < 5 < .0001Hughes 1988 859 33 -Rosen 1992 280 25 -Stangl 1994 266/677 41 vs < 1 < .0001Gayowski 1994 204 32 -Scheele 1995 226/964 31 vs 0 < .0001Jaeck 1997 747 13 -Fong 1999 1001 37 -Adam 2000 615 41 -Scheele 2001 516 38 -Kato 2003 585/178 33 vs 3.4 < .001
30% to 40%
Mts epatiche - Roma 2007 7
Surgery alone versus no surgery
25%
60 pts not operated*
60 pts operated
10
20
30
40
50
60
70
80
90
100
% p
atie
nts
10 20 30 40 50 60 70 80
Survival (months)5 years
*Same survival for non-curative resections
SM Wilson, MA Adson. Arch Surg. 1976;4:330–4.
Mts epatiche - Roma 2007 8
Surgery ± chemotherapy vs no surgery
1.0 -
0.8 -
0.6 -
0.4 -
0.2 -
0.0 -0.0 1 2 3 4 5
Years from diagnosis
Pro
bab
ilit
y o
f su
rviv
al
Stangl R et al. Lancet 1994;343:1405–10.
Resection (n=340)
Regional chemotherapy (n=123)
Systemic chemotherapy (n=70)
No treatment (n=484)
Treatment
Mts epatiche - Roma 2007 9
Resection of CRC liver and lung metastases
Authors Year N5-year
survival
Mc Afee 1992 139 31%
Okumura 1996 39 33%
Ambiru 1998 25 43%
Murata 1998 30 44%
Regnard 1998 43 11%
Robinson 1999 25 43%
Kobayashi 1999 47 31%
Adam
1999 59 35%
30%
to 4
0%
Mts epatiche - Roma 2007 10
Patient survival based on level of surgery
1.0 -
0.8 -
0.6 -
0.4 -
0.2 -
0.0 -
Time from laparotomy /imaging (years)0 1 2 3 4 5 6 7 8 9 10
Figure 1. The number at the end of the curve indicates the number of patients surviving beyond 10 years.
J.Scheele and coll. Br.J.Surg. 1990, 77:1241.
7
Complete resection (n = 921)
Incomplete resection (n = 62)
Non-operated patients (n = 226)
Pro
bab
ilit
y o
f su
rviv
al
P < .0001
Mts epatiche - Roma 2007 11
Overall Survival with Res. of Multiple (>3) CR Mts with Relation to Response to Neoadj CT
0 -
0.2 -
0.4 -
0.6 -
0.8 -
1.0 -
Cu
mu
lati
ve s
urv
ival
0 1 2 3 4 5Years
100%
63%
84%
58%
0%
45%
Log rank: P=.0001
Downstaging: 42
Progression: 28
Stabilisation: 57
Adam R. Ann Oncol. 2003;14 Suppl2:ii13-16.
Mts epatiche - Roma 2007 12
Pre-operative chemotherapy in resectable CRC liver metastases
Treatment n RR RFS Survival Study
5-FU/LV (AIO) +
L-OHP 85 mg
pre-op
20 80%52% 2y
80% 2yWein, 2003
5-FU/LV (AIOm) + L-OHP 85 mg
pre-op42 34/40 - -
Lorenz, 2003
Oxaliplatin-based regimens
Mts epatiche - Roma 2007 13
Non-resectable liver mts Phase II – non-selected patients (A)
Regimen N RR Resection Author
AIO 53 42% 17% Wein
AIO/IRI/C225 19 68% 21% Lutz/Folprecht
FOLFOX/C225 43 81% 16% Tabernero
FOLFIRI/C225 40 43% 13% Rougier
FOLFOX/Gef 27 78% 22% Fisher
FOLFIRI int. 55 53% 31% Ducreux
Mts epatiche - Roma 2007 14
Regimen N RR Resection Author
FOLFOXIRI 74 71% 26% Falcone
FOLFOXIRI 28 79% 21% Roth
FOLFOXIRI 34 50% 15% Cals
FOLFOXIRI 32 72% 25% Masi
OCFL 30 78% 23% Seium
Non-resectable liver mts Phase II – non-selected patients (B)
Triplets
Mts epatiche - Roma 2007 15
Regimen N RR Resection Author
IFL 264 31% 1% Goldberg
FOLFOX 267 45% 4%
IROX 265 35% 4%
AIO 216 34% 1% Köhne
AIO+IRI 214 64% 3%
FOLFIRI 109 56% 9% Tournigand
FOLFOX 111 54% 22% (p = n.s.)
FOLFIRI 178 34% 5.1% Colucci
FOLFOX 182 36% 4.4%
Non-resectable liver mts Phase III – non-selected patients
Mts epatiche - Roma 2007 16
Regimen N RR Resection Author
FOLFOX 43 50% 33% Alberts
FOLFIRI 40 48% 33% UCSC
FOLFIRI 28 54% 11% Ho
FU/IRI 32 - 34% Slater
FOLFOXIRI 39 64% 43%deLa
Camara
FOLFOXIRI 26 73% 34% Quenet
OXA/IRI/FU 47 69% 26% Abad
FOLFIRINOX 34 71% 41%* Ychou* + 38.2% resection + RF or CS
Non-resectable liver mts Phase II – selected patients
Mts epatiche - Roma 2007 17
Neoadju treatment of CRC unresectable liver mts with IRI and 5-FU plus LV
Annals of Oncology 2004;15:933–9.
U.O.C. di Oncologia Medica
U.O.C. di Chirurgia Epatobiliare
Co-operation
Synchronous mts 67.5%
<3mts/>6 mts52.5%/27.5%
Largest mts >5 cm30%
Mts in hilum/bilobar/RL 17.5%55/27.5%
oxaliplatin85 mg/m2 2 h
FA200 mg/m² 2 h
5FU 1,200 mg/m² CI 46 h
FA200 mg/m² 2 hDAY 1 DAY 2
5FU bolus 400 mg/m² 5FU bolus 400 mg/m²
Mts epatiche - Roma 2007 18
Criteria for unresectabilityUCSC experience
*Major hepatectomy (more than 4 segments resection, according to Coineau) needed
Criteria Definition
Unfavourable location of metastases
Contiguity with at least 2 hepatic veins, the inferior vena cava, or the liver hilum
Number of metastases Synchronous*: >6 metastases in the same lobe OR synchronous or metachronous: >3 metastases in each of 2 lobes
Size of metastases Synchronous*: largest diameter of >5 cm in at least 1 metastasis if there were 6 lesions in the same lobe or 3 lesions in each of 2 lobes
Insufficient liver reserve
>70% of liver involvement
Extra-hepatic disease Metastases in areas other than the liver
Pozzo C, et al. Ann Oncol. 2004;15:933-39.
Mts epatiche - Roma 2007 19
Primary Endpoints
Pozzo C, et al. Ann Oncol. 2004;15:933-39.
5
42.547.5
27.5 25
0
10
20
30
40
50
60
CR PR CR+PR SD PD
%
Response
40
40 %
Candidatesfor Surgery
16
Neoadjuvant chemotherapy
13
33%
24 3
16
R0• 10 multiple segmental res.• 3 right lobectomies
Resection Rate
•2 carci
nosis
•1 N+
RR
RC RP SD PD
Mts epatiche - Roma 2007 20
Resection rate by response and main cause of unresectability
18%
PD=0%
Res
ecti
on
rat
e (%
)
0
10
20
30
40
50
60
70
Pozzo C, et al. Ann Oncol. 2004;15:933-39.
CR
+ P
R
58%
SD
0
10
20
30
40
50
60
70
Siz
e o
f m
ts
Lo
cati
on
N°
Liv
er
Re
ser
ve =
0
14%
36%
60%
By Response By Main Cause ofUnresectability
Mts epatiche - Roma 2007 21
Secondary Endpoints
Median Follow-up: 30 m (6-54) TTP (all) = 14.3 m Median OS = 30.6 m
Not resected = 24 m Resected = not reached
Months
Pat
ien
ts%
0,0 -
0,1 -
0,2 -
0,3 -
0,4 -
0,5 -
0,6 -
0,7 -
0,8 -
0,9 -
1,0 -
0 10 20 30 40 50 60 70
Non resected
Resected
Pozzo C, et al. Ann Oncol. 2004;15:933-39.
Overall Survival
Mts epatiche - Roma 2007 22
FOLFIRINOX as induction CT in pts with previously unresectable CRC liver mts
oxaliplatin85 mg/m2 2 h
FA400 mg/m² 2 h
5FU 2,400 mg/m² CI 46 h
irinotecan180 mg/m2 1 h 30
5FU bolus 400 mg/m²
Ychou M, et al. ESMO 2004, Abs 273.
Reason for un-resectability
Invasion of hilum 6 ptsContact with inferior VC 16 ptsInvasion of >2 hepatic veins 4 ptsRemnant liver <25% 12 ptsUnlikely R0 4 pts
Mts epatiche - Roma 2007 23
3
68 71
15.4 13.6
0
10
20
30
40
50
60
70
80
CR PR CR+PR SD PD
Primary Endpoints
%
Response
34
82 %
Candidatesfor Surgery
28
Neoadjuvant chemotherapy
14
41%6
1428
Resection Rate
RR
RC RP SD PD• 9 R0• 5 R1
•13 Res+ RF/CS•1 R2
•13 Res+
R
F/CS
•1 R2
Ychou M, et al. ESMO 2004, Abs 273.
Mts epatiche - Roma 2007 24
Secondary Endpoints
SURVIE GLOBALE, N=34
Délai J1C1/DDN (Mois)0 6 12 18 24 30 36
0.00
0.25
0.50
0.75
1.00
Median Follow-up = 30.9 m (26.4-35.6) TTP (resected and non-resected) = 11.9 m Median OS = 35.5 m MS RC post-surgery = not reached Survival (2 yrs) = 70%
Overall Survival(n = 34)
Median SurvivalRC post-surgery
(n = 27)
1.00
Ychou M, et al. ESMO 2004, Abs 273.
0.75
0.50
0.25
0.00
Mts epatiche - Roma 2007 25
FOLFOX4 for Pts with Unresectable Liver-only Mts from CRC: a NCCTG Phase II Study
Alberts, JCO 2005; 23:9243–9.
Reasons for Unresectability
Number 19 pts (45%) Localization 3 pts (7%) Size 3 pts (7%) Combination 15 pts (36%)Not available 2 pts (5%)
oxaliplatin85 mg/m2 2 h
FA200 mg/m² 2 h
5FU 1,200 mg/m² CI 46 h
5FU bolus 400 mg/m²5FU bolus 400 mg/m²
FA200 mg/m² 2 hDAY 1 DAY 2
Mts epatiche - Roma 2007 26Alberts SR, et al. JCO. 2005;23:9243-9
2.4
47.6
9.5
59.5
9.5
31
0
10
20
30
40
50
60
CR PR REGR RR SD PD
%
Response
42
40.5 %
Candidatesfor Surgery
16
Neoadjuvant chemotherapy
14
33%
253
17
R0
Resection Rate
•2 unresect
.
•1 part. R
es.
RR
RC RP SD PDRE
FOLFOX4 for Patients with Unresectable Liver-Only Mts from CRC: Primary Endpoints
Mts epatiche - Roma 2007 27
Time to Recurrence Time to Recurrence (from surgery)(from surgery)
OSOS Median follow-up: 36 m
Median OS: 26 m (95% C.I. 19-34 m)
Resected pts: not reached
3 yrs Surv. of res. pts: 67%
Resected ptsResected pts
Time to Progression Time to Progression (from registration)(from registration)
FOLFOX4 for Pts with Unresectable Liver-Only Mts from CRC: Secondary Endpoints
Mts epatiche - Roma 2007 28
Neoadj CT for Pts with CRC Unresectable Liver-Only Mts: phase II studies
UCSC, 2004 Ychou, 2004 Alberts, 2005
Median Follow-up 30.4 m
(6-54)
30.9 m
26.4-35.6)
36 m
(29-36)
TTP All Pts
Not res. Pts
14.3 m
5.2 m
11.9 m
Not reported
Not reported
Not reported
Median OS (all pts) 30.1 m 35.5 m 26 m
MS Res. Pts
Not res. Pts
Not reached
24 m
Not reached
Not reported
Not reached
Not reported
Survival (resected Pts) 70% (2.5 yrs) 70% (2 yrs) 67% (3 yrs)
Mts epatiche - Roma 2007 29
Liver metastasesLiver metastases
15% resectable15% resectable85% unresectable85% unresectable
• 10%-30% potentially resectable
• 70%-90% never resectable
• 10%-30% potentially resectable
• 70%-90% never resectable
ResectionResection
CT
30%?
Resectability in pts with CRC liver metastases – where are we now?
Mts epatiche - Roma 2007 30
laparotomy, liver exam and ultrasound
Does complete response mean cure?
Benoist et al. JCO 2006;24:3939-45
38 pts with 183 LMs received CTx
CT scan
66 (36%) LMs disappeared
in 9 pts : 20 LM sites (24%)There was residual
macroscopic disease
in 29 pts : 46 LM sites (76%)There no evidence residual
macroscopic disease
15 initially resectable pts had surgery – viable tumor cells at
LM sites in 12 (80%) pts
14 initially unresectable pts had surgery – after 1 year 74% of
LMs had recurred in 11 (79%) pts
Persistent macro- or microscopic disease or early recurrence in situ in 55/66 LMs (83%) = 32/38 pts
Mts epatiche - Roma 2007 31
66 LM disappeared on CT scan after chemotherapy
Surgery : Macroscopic cancer : 20 LM
No lesion : 46 LM
15 sites resected 31 sites left in place
Viable tumor cells : 12 In situ recurrence : 23
55/66 (83%) of metastases were not « cured »
Mts epatiche - Roma 2007 32
Chemotherapy-induced liver changes
Vauthey et al. JCO 2006
Steatohepatitis (Irinotecan)
Sinusoidal distention and obstruction
(oxaliplatin)
Mts epatiche - Roma 2007 33
Relation between type of liver damage and clinical outcome
Steatosis associated with higher infection rate (Kooby et al. 2003)
Steatohepatitis associated with higher mortality rate due to liver failure after surgery (Vauthey et al.,2006)
Vascular injury associated with higher rate of operative bleeding and transfusion requirement (Vauthey et al. 2006; Adam et al. 2005)
Mts epatiche - Roma 2007 34
Type of ChemotherapyNo. Patients
Pathologic liver histology
n (%)
No chemotherapy 66 0 (0)
With chemotherapy 87 44 (51)
5-FU 27 6 (22)
5-FU / Irinotecan 17 4 (23)
5-FU / Oxaliplatin 27 20 (74)
5-FU / Oxali + Irinotecan 16 14 (88)
Rubbia-Brandt, Ann Oncol 2004
Type of CT prior to resection
44/87 pts (51%) who received CT exhibited centrolobular lesions
Mts epatiche - Roma 2007 35
Incidence of steatohepatitis with modern CT regimens
Treatment N Evidence of fatty changes
5-FU/FA 25 6 (24%)
Iri/5-FU/FA 25 12 (48%)
Oxali/5-FU/FA 25 7 (28%)
Leonard et al ASCO 2005
Mts epatiche - Roma 2007 36
Preoperative (neoadjuvant) CT
Adam et al ASCO 2005 92 patients resected for liver metastases
17 pts no CT 23 pts FUFOL 52 pts FOLFOX
FOLFOX-treated patients had < steatosis and fibrosis than FUFOL-treated patients
No clinically relevant impact on outcome following resection
Adam et al. ASCO 2005; #3529
Mts epatiche - Roma 2007 37
EORTC 40983 study: Resectable liver mts
FOLFOX4 FOLFOX4 Surgery Surgery FOLFOX4FOLFOX4
RR
(N = 363)(N = 363)
Surgery aloneSurgery alone
Endpoints DFS and safety
6 cycles 6 cycles
More post-operative complications in FOLFOX arm(21.1% vs 9.7%): not definitive results
Mts epatiche - Roma 2007 38
Resectable liver mts: CT vs Surgery aloneKaroui/Nordlinger (2006)
Chemo group
n=45
Surgery alone
n=22
p
Sinusoidal dilation 22 (49%) 3 (14%) 0.005
Steatosis
<20%
20-50%
>50%
25 (56%)
6 (13%)
9 (20%)
10 (22%)
14 (64%)
6 (27%)
5 (23%)
3 (14%)
NS
Fibrosis
F0-F1
F2
25 (56%)
19 (42%)
15 (68%)
7 (32%)
NS
Karoui et al. Annals Surgery 2006
Postoperative morbidity was correlated with no. cyclesbut not type of chemotherapy
Mts epatiche - Roma 2007 39
Type of Chemotherapy
No.
pts
Sinusoidal
dilationn=22
Steatosis >30%n=36
Steatohepatitis
n=34
No CT 158 3 (2%) 9% 4%
5-FU 63 0 17% 5%
5-FU / IRI 94 4 (4%) 11% 20%
5-FU / Oxa 79 15 (19%) 4% 6%
90-day mortality 1% 1% 15%
Vauthey et al. JCO 2006
Hepatoxicity of preoperative CT
Mts epatiche - Roma 2007 40
Hepatoxicity of preoperative CTSummary
Both Oxa and IRI may induce hepatotoxicity Oxa induces a prevalenty vascular damage
(sinusoidal obstruction or distention), whreas IRI induces a steatohepatitis
The clinical impact of this toxicity is not clear, but it could be a concern in pts with resectable liver mts
Post-operative morbidity seems correlate with the number of cycles, not with the type of CT
Mts epatiche - Roma 2007 41
In 2006: A clear separation between resectable and unresectable?
Definition of resectability has evolved Many pts may be now considered resectable, as
a result of novel treatment strategies Resectability rates for liver only metastases
after chemotherapy 6%-60% Resection rates correlate with response to
chemotherapy 5-year survival rates after secondary liver
resection (possible after chemotherapy) are in line with those following primary liver resection
at 35%-50%
1. Folprecht et al. Ann Oncol, 2005; 2. Bismuth et al. Ann Surg, 1996; 3. Giacchetti et al. Ann Oncol, 1999
Mts epatiche - Roma 2007 42Poston GJ, JCO 2005
Which liver mts are resectable?
OncoSurge Strategy
Absolute Controindications
- Unresectable extrahepatic disease- More than 70% liver involvement- Liver failure- Surgically unfit
Not influencing factors
- Age/Primary tumor stage- Timing of mts detection- Past blood transfusion- Liver resection type- Preresection CEA- Previous hepatectomy
Immediate resection appropriate
- Adequate resection margins- No portal adenopathy-≤ 4 mts and unilobar involvement
Post-CT resection appropriate
- Independent of tumor response in the case of ≤ 4 mts and unilobar involvement- After tumour shrinkage for > 4 mts or bilobar liver involvement
Mts epatiche - Roma 2007 43
French guidelines (2003)
Resectable patients
Class 1 Easily resectable:
involvement of ≤4 of 8 liver segments, vena cava clear,
≥ 1 hepatic vein, contra-lateral portal pedicle
Class 2 Potentially resectable:
involvement of 5-6 segments,
± contra-lateral major named vascular structures
within liver
Gastroenterologie Clinique et Biologique 2003;Special issue II
Mts epatiche - Roma 2007 44
Resection rate of metastases and tumour response
Studies with all patients with metastatic CRC (solid line) R=0.74, P<0.001
Phase III studies in metastatic CRC(dashed line)R=0.67, P=0.024
Studies with selected patientsLiver metastases only, no extra-hepatic diseaseR=0.96, P=0.002
Folprecht et al, Ann Oncol 2005
Response rate,9,8,7,6,5,4,3
Re
sec
tio
n r
ate
,6 -
,5 -
,4 -
,3 -
,2 -
,1 -
0,0 -
Mts epatiche - Roma 2007 45
Limitations of present Stage IV
Does not:
allow stratification of patients according to prognosis
guide therapeutic decision making
permit comparison of results from radical/non-radical treatments
Mts epatiche - Roma 2007 46
Stage 4 – the catch-all
STAGE 4 CRC spread beyond N2
Potentially curable Resectable
Prognosis: long-term survival
IncurableUnresectable Prognosis: ≈6 months
A new system is needed to differentiate between these Stage 4 patients according to prognosis for
the appropriate decision-making process
Mts epatiche - Roma 2007 47
Staging: why a new staging?
Our perceptions of ‘resectable’ and ‘unresectable’ disease has been altered
The developments in the field of liver resection are not reflected in our approach to staging
Patients with mCRC no longer form a homogeneous group We need a staging system which
Can differentiate between the patient sub-groups with different prognosis (resectable, initially unresectable, never resectable)
Provides guidance for therapeutic decision making Provides clear indication for surgery or chemotherapy
Mts epatiche - Roma 2007 48
Guidance from Second Workshop, November 2005 Consensus for a proposed stratification of Stage 4 (IV)
patients:Stage 4a: easily resectable liver metastases
Stage 4b: resectable liver metastases
Stage 4c: liver metastases that are resectable after downsizing
Stage 4d: liver metastases that will never be resectable
Stage 5a: resectable extrahepatic disease
Stage 5b: unresectable extrahepatic disease
Consensus for a proposed stratification of Stage 4 (IV) patients:Stage 4a: easily resectable liver metastases
Stage 4b: resectable liver metastases
Stage 4c: liver metastases that are resectable after downsizing
Stage 4d: liver metastases that will never be resectable
Stage 5a: resectable extrahepatic disease
Stage 5b: unresectable extrahepatic disease
Mts epatiche - Roma 2007 49
Guidance from Second Workshop, November 2005
Makes the distinction between: Resectable
Easy Difficult
Initially unresectable
Never resectable Defines disease outside of the liver
Mts epatiche - Roma 2007 50
The compromise from the third workshop: may 2006 (1)
Consensus for a proposed stratification of Stage 4 (IV) patients:
Stage 4a: Resectable liver only metastases
Stage 4b: Initially unresectable liver only mts
Stage 4c: Liver only metastases that will never be resectable
Stage 5a: Resectable liver and extrahepatic disease
Stage 5b: Resectable extrahepatic disease only
Stage 5c: Unresectable extrahepatic disease
Mts epatiche - Roma 2007 51
What benefits might a new staging system bring?
Alert physicians to the possibility of curative intent strategies Will allow more direct comparison between institutions Will permit further stratification for sub-set analyses in future
trials Provide clear indications of the type of therapy such as:
Surgery for Stage 4a and Stage 5a (5b) ‘Neoadjuvant’ chemotherapy for Stage 4b Palliative chemotherapy for Stages 4c and 5c disease
Mts epatiche - Roma 2007 52
In Practice: Patients with resectable metastases
Neoadjuvant chemotherapy can be considered pending the results of EORTC study 40983
These patients also should not be overtreated
Increased risk of liver damage Risk of disappearance of metastases
which are not visible by the surgeon, but are not cured
Benoist Nordlinger JCO 2006
Mts epatiche - Roma 2007 53
In Practice: Patients with initially unresectable metastases
Surgery should be performed as soon as metastases become resectable
And chemotherapy should not be continued until best radiographic response is observed
Because administration of excessive number of cycles may result in increased damage to the liver and potential loss of the opportunity to do surgical resection
Mts epatiche - Roma 2007 54
Synchronous mts: When is it possible delay resection of liver mts?
1. Synchronous liver mets when a major hepatectomy is needed, especially for primary rectal cancer
2. Primary rectal T3-T4 with operable liver mets who can benefit from radiotherapy before systemic chemotherapy
3. Symptomatic colorectal cancer with operable liver mets who can have a benefit from an early tumor control
4. Patients with comorbidity who cannot afford an initial liver and primary tumor resection
Mts epatiche - Roma 2007 55
Role of new targeted therapies
Are they relevant?
Can they prevent progression of micrometastases to metastases?
Can bevacizumab be combined with surgery?
Can healthcare systems afford them?
Mts epatiche - Roma 2007 56
RR and resection rates of liver mts in unselected pts: CT + targeted agents
StudyCytotoxic + targeted agent combination
NResponse
rate
Resection
rate
Fisher FOLFOX4 + gefitinib 27 78% 22%
Peeters FOLFIRI + cetuximab 42 45% 21%
Cervantes FOLFOX4 + cetuximab
43 79% 19%
Folprecht 5-FU/FA (AIO) + irinotecan + cetuximab
21 67% 19%
Kopetz FOLFIRI + bevacizumab
23 74% 17%
Hurwitz IFL + bevacizumab 402 45%<2%
IFL 411 35%
Mts epatiche - Roma 2007 57
ACROBAT phase II study: FOLFOX4 + CET first-line in mCRC
Cetuximab + FOLFOX-4(n=43)
Overall response rate 79%
Complete response rate 9%
Disease control rate 95%
Progression-free survival (months)
12.3
Cervantes A, et al. Eur J Cancer Suppl 2005;3:181 (Abstract No. 642)
Population: EGFR-expressing mCRC; ECOG PS 2
Mts epatiche - Roma 2007 58
Resection of initially unresectable metastases
19
33
Remaining non-resectable R0 resections R1 resections
10 patients (23%) were rendered resectable by treatment
Metastases:
• Liver n=8
• Lung n=1
• Adrenal: n=1
Mts epatiche - Roma 2007 59
XELOX + Bevacizumab
32 patients with CRC liver mets 6 cycles XELOX + 5 cycles bevacizumab
(5-week break prior to surgery) 19/32 evaluable
15 liver resection 4 also had primary resection 14 patients responded 5 SD
XELOX + bevacizumab resumed 5 weeks post surgery Bev can be administered up to 5 weeks prior to surgery without
increasing the rate of surgical or wound healing complications
Gruenberger ESMO 2006 Abstract 374 P
Mts epatiche - Roma 2007 60
Preoperative chemotherapy may increase resection rate of liver CRC liver metastases
In unselected patients triplet combinations of cytotoxics induce higher response rate and resection rate
Hepatotoxicity could a major concern, expecially in patients with resectable liver metastases
Surgery should be performed as soon as metastases become resectable
Conclusion - 1
Mts epatiche - Roma 2007 61
A new staging system is available which can differentiate between patients subgroups and provide guidance for therapeutic decision making
No sufficient data are available to define the potential role of targeted agents, but the increase in response rate is expected to translate in higher resection rate and survival
Possibility of using targeted agents post-surgery as maintenance therapy to suppress micrometastases could be considered
Comparison with cytotoxic triplets is needed
Conclusion - 2
Mts epatiche - Roma 2007 62
Distinctive features of adjuvant CT after resection of liver mts - 1
High prevalence of local vs distant relapsesFacts
Blood network, lobule architecture and normal cells streaming are disrupted after S
Consequences
The biological situation after liver mts resection is different from that after resection of colon primary
Implications
Mts epatiche - Roma 2007 63
Distinctive features of adjuvant CT after resection of liver mts - 2
Different blood supply for mts > 2-3 mm (hepatic artery) and normal liver (portal vein)
Facts
Micromts may be not supplied by hepatic artConsequences
Results obtained with CT of unresectable liver mts cannot be extrapolated to adjuvant CT after liver mts resection
Implications
Mts epatiche - Roma 2007 64
Distinctive features of adjuvant CT after resection of liver mts - 3
Liver drug extractionFacts
Effects on hepatic and extrahep. mts related to extraction rate and administration route
Consequences
HAI has substantial pharmacodynamic and biological limits, but systemic CT not always ensure the target to be reached
Implications
Mts epatiche - Roma 2007 65
HAI adjuvant therapy after liver mts resection Phase III studies – selected patients (A)
Treatment N RFS MS Author
S + FU/MMC HAIS
1416
15% 5y25% 5yP>.05
25% 5y31% 5yP>.05
Rudroff, 1990
S + LV/FU HAIS
113113
14.2 m13.7 mP>.05
34.5 m40.8 mP>.05
Lorenz, 1998
S+FUDR HAI+FU/LV SysS
53(30)56(45)
46% 4y25% 4yP=.04
63.7 m49.0 mP=.60
Kemeny, 2002
Mts epatiche - Roma 2007 66
Surgery + HAI FU/LV vs SurgeryLorenz M, Ann Surg 1998
Pts “as treated”P>.05
Mts epatiche - Roma 2007 67
Surgery vs HAI FUDR + Sys FA/FUKemeny M, JCO 2002
Time to recurrence (assessable patients; n =75)
Time to liver recurrence (assessable patients; n = 75)
Overall survival (assessable patients; n = 75)
Overall survival (all patients; n = 109)
Mts epatiche - Roma 2007 68
HAI adjuvant therapy after liver mts resection Phase III studies – selected patients (B)
Treatment N RFS MS Author
HAI CT/IT+S+HAI CT/ITS
2020
--
2011
P<.05
Lygidakis, 1995
S+FUDR HAI+FU/LV SysS + FU/LV Sys
7482
57% 2y42% 2yP=.07
72.2 m59.3 mP=.21
Kemeny, 1999
S+HAI FU+oral FUS + oral FU
910
66.7% 3 y20.0% 3 y
P=.045
77.8% 3y50% 3 yP=.27
Tono, 2000
Mts epatiche - Roma 2007 69
Adjuvant HAI after resection of hepatic mts from CRCKemeny N et al, N Engl J Med 1999
HAI FUDR/DEX+ Sys FU
74 Patient
sRAND
SURGERY
82 Patient
s
• Completely resected CRC hepatic mts• No extrahepatic disease• Synchronous 32%• Metachronous 68%• Adj CT 39%• CT for mts 14%
Sys FU
End-points: Overall SurvivalSurvival without recurrence of hepatic mtsSurvival without any mts at two yrs
Mts epatiche - Roma 2007 70
Adjuvant HAI after resection of hepatic mts from CRCKemeny N et al, N Engl J Med 1999
P = 0.21 by log-rank
Median Survival
PFS
P = 0.06 by log-rank
Mts epatiche - Roma 2007 71
Adjuvant HAI after resection of hepatic mts from CRCKemeny N et al, N Engl J Med 1999
Up-dated resultsKemeny N, NEJM 2005
Combination therapy
Median OS: 68.4 m
Systemic therapy
Median OS: 58.8 m
N.S.
Only 26% of pts could have more than 50% of the HAI planned dose
Mts epatiche - Roma 2007 72
Prospective studies on HAI adjuvant therapy after liver mts resection A Metanalysis (Clancy TE, J Gastroint Surg 2005)
Lorenz
Rudroff
Lygidakis
Lygidakis
Tono
Tono
Kusunoki
Kusunoki
Rudroff
Kemeny
Kemeny Kemeny
Kemeny
Lorenz
Combined Combined
1-year Survival 2-year Survival
P = 0.59 P = 0.11
Mts epatiche - Roma 2007 73
HAI adj CT for pts having resection or ablation of liver CRC mtsCochrane Database Syst Rev 2006
Wagmann 1990: 12 pts, S+HAI FUDR vs S Rudroff 1990: 30 pts, S+HAI FU/MMC vs S Lorenz 1998: 226 pts, S+HAI FU/LV vs S Kemeny 2002: 109 pts, S+HAI FUDR+Sys vs S Lygidakis 1995: 40 pts, HAI CT/IT+S+HAI CT/IT
vs S Kemeny 1999: 156 pts, S+HAI FUDR+Sys vs
S+Sys Tono 2000: 19 pts, S+HAI FU+oral FU vs S+oral
FU
Nelson R and Freels S, 2006
Mts epatiche - Roma 2007 74
HAI adj CT for pts having resection or ablation of liver CRC mtsCochrane Database Syst Rev 2006
Lygidakis excluded
Mts epatiche - Roma 2007 75
HAI adj CT for pts having resection or ablation of liver CRC mtsCochrane Database Syst Rev 2006
Mts epatiche - Roma 2007 76
HAI adj CT for pts having resection or ablation of liver CRC mtsCochrane Database Syst Rev 2006
Mts epatiche - Roma 2007 77
HAI adj CT for pts having resection or ablation of liver CRC mtsCochrane Database Syst Rev 2006
Only studies with S as control
Mts epatiche - Roma 2007 78
HAI adj CT for pts having resection or ablation of liver CRC mtsCochrane Database Syst Rev 2006
Only studies with S as control
Mts epatiche - Roma 2007 79
HAI adj after liver metastasectomyMain concerns HAI may reduce hepatic recurrences, but its
effect on overall survival is uncertain in comparison to surgery alone
HAI requires surgical implantation of a hepatic arterial catheter and requires the use of an impantable pump
HAI is impaired both by technical difficulties and high rate of complications
Floxuridine is not authorized in Europe
Mts epatiche - Roma 2007 80
Neoadj CT in unresectable liver mts comparable with HAI or sys adj CT
UCSC, 2004 Ychou, 2004 Alberts, 2005
Median Follow-up 30.4 m
(6-54)
30.9 m
26.4-35.6)
36 m
(29-36)
TTP All Pts
Not res. Pts
14.3 m
5.2 m
11.9 m
Not reported
Not reported
Not reported
Median OS (all pts) 30.1 m 35.5 m 26 m
MS Res. Pts
Not res. Pts
Not reached
24 m
Not reached
Not reported
Not reached
Not reported
Survival (resected Pts) 70% (2.5 yrs) 70% (2 yrs) 67% (3 yrs)
Mts epatiche - Roma 2007 81
Portal Vein Infusion
Rationale Micromts are primarily dependent on the PV
for their nutrition The biliary tree is essentially fed by the
hepatic artery Phase I study
PV can be delivered safely, but OS and DFS seem lower than that reported with HAI (Faynsod M, JCO 2005)
Adjuvant therapy after primary CRC resection No advantage
Mts epatiche - Roma 2007 82
Prospective studies on systemic adj CT after liver mts resection
Treatment N RFS S Author
S+LV/FU
S
52
55
45% 4y
35% 4y
P=.35
57% 4y
47% 4y
P=.39
Langer, 2002
S+FU/LV
S
28
10
15 m
9 m
P=.35
SM 30m
SM 15m
P=.066
Loper-Ladron, 2003
S+FU/LV
S
86
87
33.5% 5y
26.7% 5y
P=.028
51.1% 5y
41.1% 5y
P=.13
Portier, 2006
Mts epatiche - Roma 2007 83
Phase II studies on systemic adj CT after liver mts resection
Treatment N RFS S Author
S+LV/FU/IRI/UFT 58 13.9 m 18 m Kono, 2005
S+IRI 29 45.2 m 85% 2y Mackay, 2005
Mts epatiche - Roma 2007 84
Adj sys FU/FA compared with S after resection of CRC liver mtsPortier G, JCO 2006
Sys FU/LV
86 Patient
sRAND
SURGERY
85 Patient
s
• Completely resected CRC hepatic mts• No extrahepatic disease• Stratification: - Size - Number - Time primary res- mts detection
No treatment
I End-point: Disease-free SurvivalII End-points: Overall Survival
Incidence of adverse effects
Mts epatiche - Roma 2007 85
Adj sys FU/FA compared with S after resection of CRC liver mtsPortier G, JCO 2006
P = 0.028
P = 0.13
DFS
Overall Survival
Suspended after 173 ptsdue to slow accrual
Mts epatiche - Roma 2007 86
Comparison HAI vs IV FU/LV for CRC liver mts – A randomized trial
HAI SysmPFS 7.7m 6.7m1y PF 28% 20%2y PF 4% 6%
p=.27
HAI Sys mOS 14.7m 14.8m1y S 57% 61%2y S 22% 27%
p=.79
Steady state venous concentrationof FU
Secondary Endpoints
HAI Sys RR 22% 19% mDR 7.6 m 7.5 m
Kerr DJ, The Lancet 2003
Mts epatiche - Roma 2007 87
Post-operative chemoimmunotherapy Phase III studies
Treatment N RFS MS Author
HAI CT/IT+S+HAI CT/ITS
2020
--
2011
P<.05
Lygidakis, 1995
S + HAI CT/ITS + HAI CT
3315
--
20.3 m9.9 m
Lygidakis, 1996
S + HAI CT/IT + sys CTS + sys CT/IT
6260
66% 2y48% 2y
92% 2y75% 2y
Lygidakis, 2001
S+TIL/IL2S+sys CT
2522
28% 3y37% 3yP=.27
55% 3y50% 3y
P=.7
Gardini, 2004
Mts epatiche - Roma 2007 88
Adj immunotherapy vs sys FU/FA after resection of CRC liver mtsGardini A, J Surg Oncol 2004
TIL/IL2
25 (14)
Patients
RAND
SURGERY
22 (14)
Patients
• Completely resected CRC hepatic mts• No extrahepatic disease• TIL from surgical specimen• In-vitro activation with IL2• Reinfusion with IL2
FU/LV
End-point: Disease-free SurvivalOverall Survival
Mts epatiche - Roma 2007 89
Adj immunotherapy vs sys FU/FA after resection of CRC liver mtsGardini A, J Surg Oncol 2004
Overall Survival
DFS
Mts epatiche - Roma 2007 90
Conclusions - 3
No clear advantage with HAI after resection of liver metastases, but not irrelevant technical and toxicity concerns
Few and low-powered prospective studies both with HAI and sys post-operative CT
Prognostic factors were not homogeneous Only one well-designed randomized study
with post-resection systemic CT, whose accrual was early stopped because of a too slow accrual rhythm
Mts epatiche - Roma 2007 91
Conclusions - 4
CT used in these trials is clearly inferior to currently available regimens
To date, immunotherapy has shown no value Neoadjuvant CT of unresectable liver mts
achieves results similar to (or better than) those obtained with adjuvant therapy
The assessment of resecability is a crucial step in decision making and prognosis
The control arm for future studies is a basic concern
Mts epatiche - Roma 2007 92
Does CT benefit pts after resection of liver mts from CRC?
The Portier’s study provides a proof of concept of adj CT in this pts population
Additional trials, using more modern systemic approaches, are needed
The potential benefit of adding HAI therapy to systemic therapy is still hypothetical
Added costs , toxicities and technical issue associated with placement of an HAI pump are a reality
Mts epatiche - Roma 2007 93
Metastatic CRC
85% unresectable 15% resectable
?% potentially resectable (after neoadjuvant)
• New staging system• Improved patient workup
• New endpoint• Timing?• Addition of targeted agents
CT
Cure?
Improved patient monitoring
• Syst. chemotherapy first?
• Patient selection
Resectability in pts with CRC liver metastases – where are we now?
> 30% resection
Mts epatiche - Roma 2007 94
Prediction: Survival in advanced colorectal cancer in 2015?
0 1 2 3 4 5
100
50
0
%
survivin
g
Years after diagnosis of colorectal metastases
2005 Median survival:Chemotherapy 24 mos.Overall >30 months
5 year survival:1985 ~1%1995 ~4%2005 20%2015 ?50%
8 mos 13 mos 30 mos 60 mos?
Dr. G. Poston, Pfizer Satellite Symposium, ECCO 2005