surgical management of colorectal hepatic metastases
DESCRIPTION
Surgical Management of Colorectal Hepatic Metastases. Elin R. Sigurdson, M.D., Ph.D. Fox Chase Cancer Center ASCO 2006. Colorectal Hepatic Metastases Surgery. Adjuvant Therapy After Liver Resection ECOG Study Design. Liver Resection. Hepatic Arterial Infusion + Systemic (HAI + SYS). - PowerPoint PPT PresentationTRANSCRIPT
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Surgical Management of Colorectal Hepatic Metastases
Elin R. Sigurdson, M.D., Ph.D.
Fox Chase Cancer Center
ASCO 2006
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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
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Adjuvant Therapy After Liver Resection
ECOG Study Design
Liver Resection
Hepatic Arterial Infusion+
Systemic
(HAI + SYS)
Control
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Adjuvant Therapy After Liver Resection
MSKCC Study Design
Liver Resection
Hepatic Arterial Infusion+
Systemic
(HAI + SYS)
Systemic (SYS)
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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
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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.
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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
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• 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
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• 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
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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
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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
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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
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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
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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%
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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%
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Villejuif
Liverpool
TorinoGeneva
Zurich
LiverMetSurvey (retrospective) : 2122 patients with liver resections
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• 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
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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.
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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.
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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)
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> 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
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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
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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
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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
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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 +
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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 +
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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
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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
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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
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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
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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)
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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
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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.
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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
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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
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Adjuvant Chemotherapy for Solitary Hepatic Metastases
Kemeny NE
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• 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
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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
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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
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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
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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.
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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