Optimal Management of Liver Metastases: Present Results and Future Strategies

1
Highlights in the Management of CRC
Roma, 1-2 febbraio 2007

• Optimal Management of Liver Metastases Present
  Results and Future Strategies

Mediterranean School of Oncology
Carlo Barone Oncologia Medica Università
Cattolica del S. Cuore
2
CRC 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. Globocan for Pharma
induustries 2002
3
Survival in advanced colorectal cancer in 2005
100
1984 overall 1994 overall 2005 chemotherapy 2005
overall
2005 Median survival Chemotherapy 24
mos. Overall gt30 months

• 5 year survival
• 1984 2
• 5
• 2005 20

surviving
50
?

• 1994 2005
• 8 mos 12 mos 27 mos

0
0 1 2
3 4 5
Years after diagnosis of colorectal metastases
Dr. G. Poston, Pfizer Satellite Symposium, ECCO
2005
4
Summary

• The role of Surgery in CRC liver mts
• Preoperative CT
• Resectable mts
• Initially not-resectable mts
• Hepatotoxicity of CT
• The need for a new staging system
• The role of targeted agents in the
  management of liver mts
• Adjuvant chemotherapy, HAI o Sys

5
5-Yr Survival after resection of CRC Liver Mts
6
5-year survival after resection of CRC liver
metastases
30 to 40
7
Surgery alone versus no surgery
Same survival for non-curative resections
patients
60 pts operated
25
60 pts not operated
10
20
30
40
50
60
70
80
Survival (months) 5 years
SM Wilson, MA Adson. Arch Surg. 197643304.
8
Surgery chemotherapy vs no surgery
Treatment
Resection (n340) Regional chemotherapy
(n123) Systemic chemotherapy (n70) No treatment
(n484)
Probability of survival
Years from diagnosis
Stangl R et al. Lancet 1994343140510.
9
Resection of CRC liver and lung metastases
30 to 40
10
Patient survival based on level of surgery
Probability of survival
P lt .0001
7
Time from laparotomy /imaging (years)
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,
771241.
11
Overall Survival with Res. of Multiple (gt3) CR
Mts with Relation to Response to Neoadj CT
100
84
Downstaging 42 Progression 28 Stabilisation 57
63
58
Cumulative survival
45
Log rank P.0001
0
0
1
2
3
4
5
Years
Adam R. Ann Oncol. 200314 Suppl2ii13-16.
12
Pre-operative chemotherapy in resectable CRC
liver metastases
Oxaliplatin-based regimens
13
Non-resectable liver mts Phase II
non-selected patients (A)
14
Non-resectable liver mts Phase II
non-selected patients (B)
Triplets
15
Non-resectable liver mts Phase III
non-selected patients
16
Non-resectable liver mts Phase II selected
patients
38.2 resection RF or CS
17
Neoadju treatment of CRC unresectable liver mts
with IRI and 5-FU plus LV

• Synchronous mts
• 67.5
• lt3mts/gt6 mts
• 52.5/27.5
• Largest mts gt5 cm
• 30
• Mts in hilum/bilobar/RL
• 17.555/27.5

U.O.C. di Oncologia Medica
Co-operation
U.O.C. di Chirurgia Epatobiliare
5FU bolus 400 mg/m²
5FU bolus 400 mg/m²
oxaliplatin 85 mg/m2 2 h
5FU 1,200 mg/m² CI 46 h
FA 200 mg/m² 2 h
FA 200 mg/m² 2 h
DAY 1
DAY 2
Annals of Oncology 2004159339.
18
Criteria for unresectabilityUCSC experience
Major hepatectomy (more than 4 segments
resection, according to Coineau) needed
Pozzo C, et al. Ann Oncol. 200415933-39.
19
Primary Endpoints
Response
Resection Rate

Neoadjuvant chemotherapy
40

• 2 carcinosis
• 1 N

16
RR
Candidates for Surgery
40
24
3
RC
RP

• R0
• 10 multiple segmental res.
• 3 right lobectomies

SD
PD
16
13 33
Pozzo C, et al. Ann Oncol. 200415933-39.
20
Resection rate by response and main cause of
unresectability
By Main Cause of Unresectability
By Response
60
58
36
Resection rate ()
CR PR
Size of mts
18
14
Liver Reserve 0
Location
SD
PD0
N
Pozzo C, et al. Ann Oncol. 200415933-39.
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

Overall Survival
Patients
Months
Pozzo C, et al. Ann Oncol. 200415933-39.
22
FOLFIRINOX as induction CT in pts with previously
unresectable CRC liver mts

• Reason for un-resectability
• Invasion of hilum 6 pts
• Contact with inferior VC 16 pts
• Invasion of gt2 hepatic veins 4 pts
• Remnant liver lt25 12 pts
• Unlikely R0 4 pts

5FU bolus 400 mg/m²
FA 400 mg/m² 2 h
5FU 2,400 mg/m² CI 46 h
oxaliplatin 85 mg/m2 2 h
irinotecan 180 mg/m2 1 h 30
Ychou M, et al. ESMO 2004, Abs 273.
23
Primary Endpoints
Response
Resection Rate
Neoadjuvant chemotherapy

• 13 Res RF/CS
• 1 R2

82
Candidates for Surgery
RR

• 13 Res RF/CS
• 1 R2

14
28
34
RC
RP
SD
PD
14 41
28

• 9 R0
• 5 R1

6
Ychou M, et al. ESMO 2004, Abs 273.
24
Secondary Endpoints

• 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

Median Survival RC post-surgery (n 27)
1.00
0.75
0.50
Overall Survival (n 34)
0.25
0.00
Ychou M, et al. ESMO 2004, Abs 273.
25
FOLFOX4 for Pts with Unresectable Liver-only Mts
from CRC a NCCTG Phase II Study

• Reasons for Unresectability
• Number 19 pts (45)
• Localization 3 pts (7)
• Size 3 pts (7)
• Combination 15 pts (36)
• Not available 2 pts (5)

5FU bolus 400 mg/m²
5FU bolus 400 mg/m²
oxaliplatin 85 mg/m2 2 h
5FU 1,200 mg/m² CI 46 h
FA 200 mg/m² 2 h
FA 200 mg/m² 2 h
DAY 1
DAY 2
Alberts, JCO 2005 2392439.
26
FOLFOX4 for Patients with Unresectable Liver-Only
Mts from CRC Primary Endpoints
Response
Resection Rate

Neoadjuvant chemotherapy
40.5

• 2 unresect.
• 1 part. Res.

RR
17
Candidates for Surgery
42
3
25
PD
SD
RP
RE
RC
16
14 33
R0
Alberts SR, et al. JCO. 2005239243-9
27
FOLFOX4 for Pts with Unresectable Liver-Only Mts
from CRC Secondary Endpoints
Resected pts
Resected pts
Time to Recurrence (from surgery)
Time to Progression (from registration)

• 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

OS
28
Neoadj CT for Pts with CRC Unresectable
Liver-Only Mts phase II studies
29
Resectability in pts with CRC liver metastases
where are we now?
CT
30?
30
Does complete response mean cure?
38 pts with 183 LMs received CTx
CT scan
66 (36) LMs disappeared
laparotomy, liver exam and ultrasound
in 9 pts 20 LM sites (24) There was residual
macroscopic disease
Persistent macro- or microscopic disease or early
recurrence in situ in 55/66 LMs (83) 32/38 pts
Benoist et al. JCO 2006243939-45
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
In situ recurrence 23
Viable tumor cells 12
55/66 (83) of metastases were not  cured 
32
Chemotherapy-induced liver changes
Sinusoidal distention and obstruction
(oxaliplatin)
Steatohepatitis (Irinotecan)
Vauthey et al. JCO 2006
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)

34
Type of CT prior to resection

 

• 44/87 pts (51) who received CT exhibited
  centrolobular lesions

Rubbia-Brandt, Ann Oncol 2004
35
Incidence of steatohepatitis with modern CT
regimens
Leonard et al ASCO 2005
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 lt steatosis and
  fibrosis than FUFOL-treated patients
• No clinically relevant impact on outcome
  following resection

Adam et al. ASCO 2005 3529
37
EORTC 40983 study Resectable liver mts
FOLFOX4 ? Surgery ? FOLFOX4 R (N
363) Surgery alone
6 cycles
6 cycles
Endpoints DFS and safety
More post-operative complications in FOLFOX
arm (21.1 vs 9.7) not definitive results
38
Resectable liver mts CT vs Surgery
aloneKaroui/Nordlinger (2006)
Postoperative morbidity was correlated with no.
cycles but not type of chemotherapy
Karoui et al. Annals Surgery 2006
39
Hepatoxicity of preoperative CT

 
Vauthey et al. JCO 2006
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

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
42
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 gt 4 mts or bilobar
  liver involvement

Poston GJ, JCO 2005
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
2003Special issue II
44
Resection rate of metastases and tumour response
Studies with selected patients Liver metastases
only, no extra-hepatic disease R0.96, P0.002
Studies with all patients with metastatic CRC
(solid line) R0.74, Plt0.001 Phase III
studies in metastatic CRC (dashed line) R0.67,
P0.024
Resection rate
Response rate
Folprecht et al, Ann Oncol 2005
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

46
Stage 4 the catch-all
STAGE 4
CRC spread beyond N2
A new system is needed to differentiate
between these Stage 4 patients
according to prognosis for the appropriate
decision-making process
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

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

49
Guidance from Second Workshop, November 2005

• Makes the distinction between
• Resectable
• Easy
• Difficult
• Initially unresectable
• Never resectable
• Defines disease outside of the liver

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

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

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
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

54
Synchronous mts When is it possible delay
resection of liver mts?

• Synchronous liver mets when a major hepatectomy
  is needed, especially for primary rectal cancer
• Primary rectal T3-T4 with operable liver mets who
  can benefit from radiotherapy before systemic
  chemotherapy
• Symptomatic colorectal cancer with operable liver
  mets who can have a benefit from an early tumor
  control
• Patients with comorbidity who cannot afford an
  initial liver and primary tumor resection

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?

56
RR and resection rates of liver mts in unselected
pts CT targeted agents
57
ACROBAT phase II study FOLFOX4 CET first-line
in mCRC
Population EGFR-expressing mCRC ECOG PS ?2
Cervantes A, et al. Eur J Cancer Suppl 20053181
(Abstract No. 642)
58
Resection of initially unresectable metastases

• 10 patients (23) were rendered resectable by
  treatment
• Metastases
• Liver n8
• Lung n1
• Adrenal n1

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
60
Conclusion - 1

• 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

61
Conclusion - 2

• 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

62
Distinctive features of adjuvant CT after
resection of liver mts - 1
Facts

• High prevalence of local vs distant relapses

Consequences

• Blood network, lobule architecture and normal
  cells streaming are disrupted after S

Implications

• The biological situation after liver mts
  resection is different from that after resection
  of colon primary

63
Distinctive features of adjuvant CT after
resection of liver mts - 2
Facts

• Different blood supply for mts gt 2-3 mm (hepatic
  artery) and normal liver (portal vein)

Consequences

• Micromts may be not supplied by hepatic art

Implications

• Results obtained with CT of unresectable liver
  mts cannot be extrapolated to adjuvant CT after
  liver mts resection

64
Distinctive features of adjuvant CT after
resection of liver mts - 3
Facts

• Liver drug extraction

Consequences

• Effects on hepatic and extrahep. mts related to
  extraction rate and administration route

Implications

• HAI has substantial pharmacodynamic and
  biological limits, but systemic CT not always
  ensure the target to be reached

65
HAI adjuvant therapy after liver mts resection
Phase III studies selected patients (A)
66
Surgery HAI FU/LV vs SurgeryLorenz M, Ann Surg
1998
Pgt.05
Pts as treated
67
Surgery vs HAI FUDR Sys FA/FUKemeny M, JCO 2002
Time to liver recurrence (assessable patients n
75)
Time to recurrence (assessable patients n 75)
Overall survival (assessable patients n 75)
Overall survival (all patients n 109)
68
HAI adjuvant therapy after liver mts resection
Phase III studies selected patients (B)
69
Adjuvant HAI after resection of hepatic mts from
CRCKemeny N et al, N Engl J Med 1999
S U R G E R Y
HAI FUDR/DEX Sys FU

• Completely resected CRC hepatic mts
• No extrahepatic disease
• Synchronous 32
• Metachronous 68
• Adj CT 39
• CT for mts 14

74 Patients
RAND
82 Patients
Sys FU
End-points Overall Survival Survival without
recurrence of hepatic mts Survival without any
mts at two yrs
70
Adjuvant HAI after resection of hepatic mts from
CRCKemeny N et al, N Engl J Med 1999
PFS
Median Survival
P 0.06 by log-rank
P 0.21 by log-rank
71
Adjuvant HAI after resection of hepatic mts from
CRCKemeny N et al, N Engl J Med 1999
Up-dated results Kemeny N, NEJM 2005
Systemic therapy Median OS 58.8 m
Combination therapy Median OS 68.4 m
N.S.
Only 26 of pts could have more than 50 of the
HAI planned dose
72
Prospective studies on HAI adjuvant therapy after
liver mts resection A Metanalysis (Clancy TE, J
Gastroint Surg 2005)
P 0.59
P 0.11
Kusunoki
Lorenz
Tono
Rudroff
Kemeny
Kemeny
Lorenz
Tono
Kusunoki
Lygidakis
Lygidakis
Rudroff
Kemeny
Kemeny
Combined
Combined
1-year Survival
2-year Survival
73
HAI adj CT for pts having resection or ablation
of liver CRC mtsCochrane Database Syst Rev 2006

• Wagmann 1990 12 pts, SHAI FUDR vs S
• Rudroff 1990 30 pts, SHAI FU/MMC vs S
• Lorenz 1998 226 pts, SHAI FU/LV vs S
• Kemeny 2002 109 pts, SHAI FUDRSys vs S
• Lygidakis 1995 40 pts, HAI CT/ITSHAI CT/IT vs
  S
• Kemeny 1999 156 pts, SHAI FUDRSys vs SSys
• Tono 2000 19 pts, SHAI FUoral FU vs Soral FU

Nelson R and Freels S, 2006
74
HAI adj CT for pts having resection or ablation
of liver CRC mtsCochrane Database Syst Rev 2006
Lygidakis excluded
75
HAI adj CT for pts having resection or ablation
of liver CRC mtsCochrane Database Syst Rev 2006
76
HAI adj CT for pts having resection or ablation
of liver CRC mtsCochrane Database Syst Rev 2006
77
HAI adj CT for pts having resection or ablation
of liver CRC mtsCochrane Database Syst Rev 2006
Only studies with S as control
78
HAI adj CT for pts having resection or ablation
of liver CRC mtsCochrane Database Syst Rev 2006
Only studies with S as control
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

80
Neoadj CT in unresectable liver mts comparable
with HAI or sys adj CT
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

82
Prospective studies on systemic adj CT after
liver mts resection
83
Phase II studies on systemic adj CT after liver
mts resection
84
Adj sys FU/FA compared with S after resection of
CRC liver mtsPortier G, JCO 2006
S U R G E R Y
Sys FU/LV

• Completely resected CRC hepatic mts
• No extrahepatic disease
• Stratification - Size - Number - Time
  primary res- mts detection

86 Patients
RAND
85 Patients
No treatment
I End-point Disease-free Survival II
End-points Overall Survival Incidence of
adverse effects
85
Adj sys FU/FA compared with S after resection of
CRC liver mtsPortier G, JCO 2006
Overall Survival
DFS
P 0.13
P 0.028
Suspended after 173 pts due to slow accrual
86
Comparison HAI vs IV FU/LV for CRC liver mts A
randomized trial
HAI Sys mPFS 7.7m 6.7m 1y PF 28 20 2y PF 4 6
HAI Sys mOS 14.7m
14.8m 1y S 57 61 2y S
22 27
p.27
p.79
Secondary Endpoints
HAI Sys RR 22 19 mDR
7.6 m 7.5 m
Steady state venous concentration of FU
Kerr DJ, The Lancet 2003
87
Post-operative chemoimmunotherapy Phase III
studies
88
Adj immunotherapy vs sys FU/FA after resection
of CRC liver mtsGardini A, J Surg Oncol 2004
S U R G E R Y
TIL/IL2

• Completely resected CRC hepatic mts
• No extrahepatic disease
• TIL from surgical specimen
• In-vitro activation with IL2
• Reinfusion with IL2

25 (14) Patients
RAND
22 (14) Patients
FU/LV
End-point Disease-free Survival Overall
Survival
89
Adj immunotherapy vs sys FU/FA after resection
of CRC liver mtsGardini A, J Surg Oncol 2004
DFS
Overall Survival
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

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

92
Does CT benefit pts after resection of liver mts
from CRC?

• The Portiers 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

93
Resectability in pts with CRC liver metastases
where are we now?
Metastatic CRC

• New staging system
• Improved patient workup

• Syst. chemotherapy first?

85 unresectable
15 resectable

• New endpoint
• Timing?
• Addition of targeted agents

CT

• Patient selection

? potentially resectable (after neoadjuvant)
gt 30 resection
Improved patient monitoring
Cure?
94
Prediction Survival in advanced colorectal
cancer in 2015?
2005 Median survival Chemotherapy 24
mos. Overall gt30 months
100

• 5 year survival
• 1985 1
• 1995 4
• 20
• 2015 ?50

surviving
50
8 mos 13 mos 30 mos
60 mos?
0
0 1 2
3 4 5
Years after diagnosis of colorectal metastases
Dr. G. Poston, Pfizer Satellite Symposium, ECCO
2005