Surgical Management of Colorectal Hepatic Metastases
Elin R. Sigurdson, M.D., Ph.D.
Fox Chase Cancer Center
ASCO 2006
Colorectal Hepatic Metastases
Surgery
R0 Resection
Patients Median Survival (mths)
5-Yr OS (%)
Hughes 607 33
Nordlinger 1568 31 28
Scheele 473 44 41
Fong 895 45 37
Adjuvant Therapy After Liver Resection
ECOG Study Design
Liver Resection
Hepatic Arterial Infusion+
Systemic
(HAI + SYS)
Control
Adjuvant Therapy After Liver Resection
MSKCC Study Design
Liver Resection
Hepatic Arterial Infusion+
Systemic
(HAI + SYS)
Systemic (SYS)
0 50 100 150
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
portio
n S
urv
ivin
g
HAI+SYSSYS
Updated Overall Survival
p=0.10
Kemeny NE. N Engl J Med 2005;352(7):734-5.
5 years 10 years
0 20 40 60 80 100 120 140
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
portio
n P
rogre
ssio
n-F
ree
HAI+SYSSYS
Updated Progression Free Survival
p=0.02
Kemeny NE. N Engl J Med 2005;352(7):734-5.
Meta-analysis
Adjuvant chemotherapy after liver resection
FFCD
1. Number of mets(1 vs. ≥ 2)
2. Maximum size of mets(≤ 5 vs. > 5 cm)
3. Disease free interval(≤ 1 vs. > 1 year)
4. Prior adjuvant chemo
ENG
1. Number of mets(1 vs. ≥ 2)
2. Treatment center
3. Disease free interval(≤ 6 vs. > 6 months)
4. Liver vs. lung mets
5. Prior adjuvant chemo
• Meta-analysis
• Progression Free Survival by treatment group
Time (months)
0 20 40 60 80
Sur
viva
l
0,0
0,2
0,4
0,6
0,8
1,0
Adjuvant chemotherapySurgery alone
• Meta-analysis
• Overall survival by treatment group
Time (months)
0 20 40 60 80
Sur
viva
l
0,0
0,2
0,4
0,6
0,8
1,0
Adjuvant chemotherapySurgery alone
Colorectal Hepatic Metastases
Surgery vs Surgery + Adjuvant Chemo
R0 Resection Patients Median Survival (mths)
5-Yr OS (%)
Scheele 473 44 41
Fong 895 45 37
Meta-analysis
S 140 47 41
Colorectal Hepatic Metastases
Surgery vs Surgery + Adjuvant Chemo
R0 Resection Patients Median Survival (mths)
5-Yr OS (%)
Scheele 473 44 41
Fong 895 45 37
Meta-analysis
S 140 47 41
S + 5-FU 138 61 53
Colorectal Hepatic Metastases
Surgery vs Surgery + Adjuvant Chemo
R0 Resection Patients Median Survival (mths)
5-Yr OS (%)
Scheele 473 44 41
Fong 895 45 37
Meta-analysis
S 140 47 41
S + 5-FU 138 61 53
Kemeny
S + 5-FU 82 58 48
Colorectal Hepatic Metastases
Surgery vs Surgery + Adjuvant Chemo
R0 Resection Patients Median Survival (mths)
5-Yr OS (%)
Scheele 473 44 41
Fong 895 45 37
Meta-analysis
S 140 47 41
S + 5-FU 138 61 53
Kemeny
S+5-FU 82 58 48
S+HAI/5FU 74 68 56
ToxicityHAI FUDR/IV 5-FU vs HAI FUDR/IV
CapOX
FUDR + 5-FU FUDR + CapOx
Alk Phos 20% -> 2% 1.9%
Bilirubin 30% -> 1% 3.7%
Paresthesias 16.7%
Nausea/vomiting 12% 33%
Diarrhea 29% 26%
Abdominal pain 13%
Fatigue 11%
ToxicityHAI FUDR/IV 5-FU vs HAI FUDR/IV
CapOX
FUDR + 5-FU FUDR + CapOx
Alk Phos 20% -> 2% 1.9%
Bilirubin 30% -> 1% 3.7%
Paresthesias 16.7%
Nausea/vomiting 12% 33%
Diarrhea 29% 26%
Abdominal pain 13%
Fatigue 11%
Villejuif
Liverpool
TorinoGeneva
Zurich
LiverMetSurvey (retrospective) : 2122 patients with liver resections
• To analyze survivals in relation to pertinent prognostic factors
• To provide information on a multi-institutional basis on currently pending questions regarding indications, type of surgery, adjuvant treatments, role of chemotherapy, etc.
LIVERMETSURVEY: Objectives
Colorectal Hepatic Metastases
Clinical Risk Score
Risk factors (1 point each):
• Node-positive primary cancer
• Disease-free interval < 12 months
• > 1 tumor
• Tumor size > 5 cm
• CEA > 200 ng/m
Fong Y. Ann Surg. 1999. 230:309.
Colorectal Hepatic Metastases
Clinical Risk Score
SURVIVAL
Score 2-year 5-year
0 79% 60%
1-2 74% 42%
3 67% 20%
4-5 45% 18%
Fong Y. Ann Surg. 1999. 230:309.
Years
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Su
rviv
al (
%)
90%
42%
59%
26%
LiverMetSurveyOverall Survivals After Resection (n=1900)
> 3 nodules : 398
3 nodules : 1369
Log rank p < 0.0001
Years
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Su
rviv
al (
%)
92%
48%
64%
31%
85%
24%
42%
10%
LiverMetSurvey
Survival by Tumor Number
Unilateral : 1001
Bilateral : 759
Log rank p = 0.0002
Years
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Su
rviv
al (
%)
92%
47%
63%
33%
89%
38%
56%
19%
LiverMetSurvey
Survival by Extent of Disease
50 mm : 498
< 50 mm : 1023
Log rank p = 0.03
Years
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Su
rviv
al (
%)
92%
45%
60%
29%
88%
38%
56%
22%
LiverMetSurvey
Survival by Tumor Size
With Chemo pre hep1 : 825
Without chemo : 676
Log rank p = 0.002
Years
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Su
rviv
al (
%)
90%
50%
65%
26%
89%
38%
56%
25%
LiverMetSurvey
Survivals by Preop Chemo
Colorectal Hepatic Metastases
Clinical Risk Score
MSKCC Meta-analysis
LiverMet
Survey
Node +ve primary +
DFI < 12 mth + +
Number of mets + (>1) + (>1) + (>3)
Bilobar mets +
Tumor size > 5 cm + + +
CEA > 200 ng/ml +
Colorectal Hepatic Metastases
Clinical Risk Score
MSKCC Meta-analysis
LiverMet
Survey
Node +ve primary +
DFI < 12 mth + +
Number of mets + (>1) + (>1) + (>3)
Bilobar mets +
Tumor size > 5 cm + + +
CEA > 200 ng/ml +
A GERCOR Study
Patients and Methods
Histologically proven colorectal cancer
Unresectable metastases
No prior CT except adjuvant CT if ended 6 months before study entry
WHO PS 2
Adequate hematological, renal and liver functions
< 80 years
RRAANNDDOOMMIISSAATTIIOONN
FOLFOX4 until progression
FOLFOX7 x 6 cysLV5FU2 x 12 cyFOLFOX7 x6 cy
A
B
Optimox 1 study designInclusion criteria
Evaluation after 4, 6 and then every 6 cycles
Optimox 1 Surgery
Overall Survival since R0-R1 surgeryOverall survival from R0-1 metastases surgery
0 25 50 75 100 125 150 175 200 225 2500.0
0.2
0.4
0.6
0.8
1.0 all patients N=85 median OS 32.4 months
FOLFOX4 N=49 median OS 38.4 months
FOLFOX7 N=36 median OS 30.8 months
weeks
pro
bab
ilit
y
Optimox 1 Surgery
OS according to time to surgeryOS according to time to surgery for R0-1 metastases
0 25 50 75 100 125 150 175 200 225 2500.0
0.2
0.4
0.6
0.8
1.0 Surgery <6 months N=30 median OS 34.3 months
Surgery >6 months N=55 median OS 31.5 months
weeks
pro
bab
ilit
y
Colorectal Hepatic Metastases
Surgery vs Surgery + Adjuvant Chemo
R0/1 Resection Patients Median Survival (mths)
5-Yr OS (%)
Meta-analysis
S 140 47 41
S + 5-FU 138 61 53
Kemeny
S+5-FU 82 58 48
S+HAI/5FU 74 68 56
Optimox 1
S+FOLFOX 98 32 36
Adding Bevacizumab to Preoperative Chemotherapy for Liver Metastases
First Beat-Study
• Chemotherapy– FOLFOX (n=9)– CAPOX (n=9)– FOLFIRI (n=7)
• Resection– Liver (n=27)– Lung (n= 3)– Peritoneal (n= 1)– Other (n=1)
Adding Bevacizumab to Preoperative Chemotherapy for Liver Metastases
First Beat-Study
• Complications (7/31)– Stomach perforation– Pleural effusion– Wound infection– Portal vein thrombosis/MI– Bowel obstruction– Ascites– Ileus/cornea infection
Resectable Hepatic Metastases
• Adjuvant chemotherapy after potentially curative resection: A meta-analysis.– Mitry e, Fields A, Bleiberg H et al.
• Adjuvant systemic capecitabine and oxaliplatin administered with HAI FUdR– Alberts SR, Mahoney M, Donohue J, et al.
Preoperative Chemotherapy for Hepatic Metastases
• Optimox 1 study.– Perez-Staub N, Lledo G, Paye F et al.
• LiverMetSurvey: Efficacy of preop chemotherapy– Adam R, Aloia T, Figueras J et al
• First Beat-study– Michael M, Vancutsem E, Kretzschmar A et al
LiverMetSurvey(2,122 patients)
• Mortality 1.2%
• Median survival 46 months
• 5-Year survival 42%
• Preoperative chemotherapy did not benefit solitary metastases– PC 45% vs no PC 58% 5YS
Adjuvant Chemotherapy for Solitary Hepatic Metastases
Kemeny NE
• Factors associated with survival in univariate analysis
– Progression Free Survival
Median PFS (months)
p (log rank
test)
Treatment groupChemotherapySurgery alone
27.9 18.8
0.058
Number of metastases
12+
27.216.8
0.036
Previous adjuvant CT
NoYes
21.133.0
0.081
Maximum size of metastases *
≤ 5 cm> 5 cm
23.815.7
0.052
* FFCD trial, 171 patients
Only factors associated with PFS with a p value < 0.1 are presented
With Chemo pre hep1 : 226
Without chemo : 363
Log rank p = 0.54
Years
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Su
rviv
al (
%)
94%
45%
68%
32%
90%
58%
33%
LiverMetSurvey: Multifactorial Analysis
Survival by Preop Chemo AND Tumor Number = 1
Years
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Su
rviv
al (
%)
With Chemo pre hep1 : 139
Without chemo : 22
Log rank p = 0.07
85%
12%
39%
5%
67%
22%25%
LiverMetSurvey: Multifactorial Analysis
Survival by Preop Chemo AND Tumor Number ≥ 5
Five Year Survival
Survival by Number of Metastases
Number of mets
HAI + SYS SYS LiverMet
PC
LiverMet
No PC
1 36 40 45 58
2-4 45 41
> 4 19 18
>5 22 12
Colorectal Hepatic Metastases
LiverMet Survey: Risk Analysis
Risk factors analyzed
• Age and sex
• Primary tumor site
• Disease-free interval
• Tumor size
• Tumor number
• Bilaterality of tumor
• Preoperative chemotherapyR Adam, Abstract 3521.
Optimox 1 Surgery:DFS according to time to surgery
DFS according to time to surgery for R0-1 metastases
0 25 50 75 100 125 1500.0
0.2
0.4
0.6
0.8
1.0
Surgery <6 months N=30 median OS 12.0 months
Surgery >6 months N=55 median OS 8.7 months
weeks
pro
bab
ilit
y
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