Download - Surgical Management of Colorectal Hepatic Metastases

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


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




5-Yr OS (%)

Scheele 473 44 41

Fong 895 45 37

Meta-analysis

S 140 47 41

S + 5-FU 138 61 53




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




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%

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


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.


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


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



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


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 (

%)


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


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

Download - Surgical Management of Colorectal Hepatic Metastases

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