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