2. Metastatic liver tumors
Hany Said Abd El Baset
Ass. Prof. of hepatobiliary and pancraetic surgery
Member of liver transplantation team
Ain Shams University
5. COLORECTAL CANCER (CRC) is the
third most prevalent cancer in the world,
with more than 940 000 cases and nearly
500 000 deaths occurring annually
worldwide.
6. Almost 20% to 25% of patients with CRC
present with distant metastases at the time of
diagnosis. The liver is involved in 80% to 90% of
the cases, and in almost 50% it is the only site of
metastasis.
From 10% to 30% of CRC patients with newly
diagnosed disease and liver-only deposits have
resectable metastases at presentation.
7. Liver is the most common site for
hematogenous metastasis from colorectal
cancers
In patients with hepatic metastasis, the
extent of liver disease is the prime
determinant of survival
8. The outcome of untreated
metastatic colorectal cancer
Median survival is 5 to 10 month
2 years survival is unusual
5 years survival is extremely rare
9. The outcome of margin negative
hepatic resection
of metastatic colorectal cancer
5 year survival is 40% (25 – 45%)
10 year survival approaches 20% (19 –
24)
10.
11.
12.
13. Hepatectomy represents the only currently
established chance for cure or prolonged
disease free survival for resectable
colorectal liver metastasis.
15. Prognostic factors
Clinical and pathological variables of the
primary
Clinical variables associated with
presentation of liver metastases
Pathological characteristics of liver
metastases
16. Characteristics of patients and
primary tumor
Factor Effect on prognosis
age No difference
Gender Slightly better in women
Location of
primary
No significant difference
Cellular
differentiation of
primary
Not influence outcome independantly
Regional nodal
inolvement
Poorer overall survival
Synchronus liver
met.
Poor overall survival
17. N.B.
age greater than 70 years and poorely
differentiated histology of the primary
predict decrease overall survival. (Tanaka,
et al, 2004)
18. Clinical characteristics of liver
metastases
Poor prognostic criteria
Short disease free interval (<12 mo)
Multiple tumors
Bilobar tumors
Large size tumor (>5cm)
Elevated CEA (>200ng/ml)
19. Operative and pathological
characteristics
Negative free margin
High operative blood loss affects
perioperative complication and mortality
but not the long term survival
Intrabiliary invasion (mic up to 42% &
macroscopic in up to 12%) may affect
-ve free margin
20.
21.
22.
23. Molecular determinants of outcome
Expected to have very important impact on
the prognosis in the future
e.g. Transcription factor E2F1
25. Preoperative imaging
Computed tomography (triphasic CT)
routine for assessment
arterial# benign vascular lesion
hepatic arterial anatomy for
HAI pumps
portal venous phasemost important
for define metastases (low
vascular)
26. N.B. metastatic lesion from colorectal
primaries tend to respect the liver capsule
and inter-segmental planes and push
structures away, rather than invade
directly into them
27. MRI
Differentiate benign from malignant lesion
With MRCP define relationship with
vascular and biliary structure
Identify small lesion in fatty liver (obesity,
DM, post chemotherapy)
* The last indication is the main indication (not routinely used) esp. with
elevated CEA and failure of triphasic CT to identify lesion
28. ultrasonography
In expert hand, Duplex U/S is highly
sensitive in finding small metastatic
lesions, and identify its proximity to
vascular hilar structure, hepatic veins and
IVC.
29. Hepatic angiography and CT
portography
Main role with elevated tumor marker
without evidence of tumor in other
radiological investigation.
30. Positron Emisision tomography
in united state use of PET for staging,
diagnosis and restaging for colorectal
cancer was approved (Kelloff et al, 2005)
Improve long term outcome of resection by
improve patient selection (PET detect
unresectable lesions in up to 14% of patients predicted to be
resectable by CT)
31. Laparoscopic staging
Advantages:
avoid laparotomy in 78% of unresectable liver metastases
decrease morbidity
short hospital stay
decrease cost
avoid delay in systemic therapy
disadvantages:
if negative laparoscopy
increase anesthetic time
increase cost
So should be limited to patients who have a
significant risk of having unresectable disease.
34. Hepatectomy represents the only currently
established chance for cure or prolonged
disease free survival for resectable
colorectal liver metastasis.
38. Follow up after resection
First 2 years (repeat the following every 3 mo)
physical examination
CEA
pelvi-abdominal CT
CXR
Next 5 years (repeat the same investigation
every 6 month)
39. Synchronus resectable metastases
and timing of resection
Delaying hepatic resection
Micrometastases ----------> increase recurrence rate
Impaired liver function -- increase anastmotic
leakage
Simultaneous resection avoid the morbidity of
the second laparotomy
Simultaneous resection indicated when
overall operative mortality is not changed
(minor hepatectmoy, good general
condition, non obstructing CR primary,..)
40. Synchronus unresectable metastases and
timing of resection of the primary
Symptomatic patients (obstructed, perforated,
bleeding)
Resection of the primary
Chemotherapy
Restaging every 3 months
41. Asymptomatic patients
Primary resection followed by chemotherapy
decrease complication of the primary tumor
better tumor staging
decrease tumor load
Chemotherapy followed by restaging (resection
if resectable metastases or complicated primary)
liver disease is main determinant of survival
avoid mortality and morbidity of the operation
avoid delay of chemotherapy
45. What about the long term outcome of
patients who become resectable after
neoadjuvant therapy?
Similar to patients presented with
resectable lesion from the start
46.
47. is there is any prognostic data of
conversion from unresectable lesion to
resectable lesion
Bad prognostic criteria
multinodular extrahepatic disease
Lesion which may be resectable
large lesion critically located lesion
48. patients with tumor progression during
pre-operative chemotherapy have a
significantly worse outcome, with a 5 years
survival 8% versus 37% and 30% for
patients with objective tumor response or
tumor stabilization. (adam et al,2004b)
49. patients with tumor progression still had a
poor prognosis even when a potentially
curative hepatic resection was performed
50. Is the neoadjuvant therapy
a safe option?
Hepatic sinusoidal obstruction
Hepatic steatosis
Severe steatohepatitis (esp. in obese)
Make the operation more complex esp.
with major resection
N.B.
despit the operative complexity, the perioperative
morbidity and mortality in the trials of resection after
neoadjuvant therapy do not seem to be higher than
series of de novo hepatic resection (De La Camara et al,
2004, pozzo et al, 2004, Quenet et al, 2004))
55. inspite of higher R0 resection with
neoadjuvant therapy but it is not a routine
high cost
make the operation more complex especially
with major rresection
56. Adjuvant therapy
recurrence is the main issue after
resection. The commonest site of
recurrence is the liver followed by the lung.
The main role of adjuvant therapy is to
decrease the incidence of recurrence
58. Palliative chemotherapy
5–FU and leucovorin 15 mo
+ Irinotecan 20 mo
+ Oxaliplatin21 mo
Bevacizumab (Avastin) 26 mo
Cetuximab (Erbitux) 30 mo
59. Repeated resection for recurrence
after resection
No extra-hepatic disease
Good patient performance
Adequate hepatic reserve
5 year survival 34%. More than 1 lesion and
>5 cm size associated with decrease overall
survival
60. Locally ablative therapy
Limited hepatic metastases who are not surgically
candidate
No < 4
size < 4cm
superficial lesion need adequate expertise
Limited hepatic and pulmonary colorectal
metastases
67. Liver is the 2nd site of metastases of GIT
malignancy and predominant cause of
death.
Survival improvement of treated
colorectal liver metastases has prompted
research for management of liver
metastases from other sources.
68. 5 year survival of NECs without liver
metastases 90%
5 year survival of NECs with unresected
liver metastases 30%
Liver metastases is the most significant
factor affecting outcome
69. Neuroendocrine tumors
Slowly progressive tumors
Higher resctability of the primary and regional
Metastases through the portal tract
Clinical endocrinopathies α intrahepatic volume of
metastases
Intrahepatic metastases very long time extrahepatic
metastases
Mostly underlying normal liver
70. Character of neuroendocrine tumor
Gross:
Single or multiple
Solid or cystic
> 2 cm more liable to be malignant
Metastases is only sure gross sign for
malignancy
Gross vascular invasion mostly with
pancreatic NECs (may occur with others)
71. Microscopic:
Well differentiated
Rare atypia and mitosis
Stain positive for
Chromogranin A
Neurone specific enolase
Immunohistochemistry stain for one or more of hormonal
marker (even if non functioning)
75. Hepatic neuroencrine metastases
Staging
CT- MRI – Somatostatin Scintigraphy
Resected/ resectable primary
NEC
>90% hepatic
metastases resectable
resection± ablation
Recurrence (1st or
repeated)
Limited hepatic
metastsaes
Ablation Vs
resection
Diffuse hepatic
metasases
1.embolization/
chemoembolization (no
extra hep. Spread)
2.somatostatin analouge
3.systemic chemotherapy
<90% hepatic
metastases
irresectable
Liver transplantation
Unresctable primary NEC
Palliative operation as indicated
Hepatic metastases
limited
Percutaneous Vs
laparoscopic ablation
RFA
PEI
cryoablation
diffuse
1.Embolization or
chemotherapy
2. Somatostatin analouge
therapy
3. Systemic chemotherapy
76.
77.
78. Poor prognostic criteria of NECs
hepatic metastases:
Poorly differentiated NECs
>75% liver volume replacement
Progressive liver metastases (>25% volume
increase on two CT scan within 3 mo.)
Carcinoid heart disease
Non functioning pancreatic NECs (high grade
malignancy and more liver met.)
79. Indication of hepatic resection in
metastatic NECs
Curative
Palliative (cytoreduction)
Improve symptoms
Improve overall survival
Other method less effective d.t biological behavior of NECs
mainstay line of treatment in gastrointestinal NECs
metastatic to the liver
80. Hepatic resection for metastatic neuro endocrine cancer
Referrence No.patients Perioperative
mortality (No.)
Postoperative
symptoms control
(%)
5 yr survival (%)
Chen et al, 1998 15 0 -- 73
Chamberlain et al, 2000 34 2 90 76
Grazi et al,2000 19 0 95 92
Neve et al,2001 31 0 -- 47
Yao et al,2001 16 0 100 70
Jaek et al,2001 13 0 100 68
Ringe et al,2001 31 0 -- 47
Norton et al,2003 16 0 100 82
Sarmineto et al,2003 170 2 96 61
Knox et al,2004 13 -- 100 85
81.
82. Hepatic transplantation for metastatic NECs
Reference No. Patients Median follow
up (mo)
1 yr survival
(%)
5 yr survival
(%)
Actual 5 yr
disease free
survival
Frilling et al, 1998 4 54 50 50 0
Lehnert et al, 1998 103 -- 70 47 7
Lang et al,1999 10 33 100 -- 1
Pascher et al, 2000 4 42 100 50 1
Coppa et al, 2001 9 39 100 70 --
Ring et al, 2001 9 24 67 -- 0
Olausson et al,
2002
9 22 89 -- 0
El Rassi et al, 2002 5 52 80 40 0
Cahlin et al, 2003 7 36 100 0 0
Rosenau et al,
2002
19 38 89 80 3
Florman et al, 2004 11 30 73 36 1
Fenwick et al, 2004 2 70 100 50 1
83. RFA
• Local tumor control ± 80 %
• Effective ablation in met < 3cm
• Nearly 90% some symptomatic relief
• Duration of symptomatic relief around 10 mo
84. PEI
• Less effective than RFA
• Small tumor & RFA is contraindicated (near to great vs,
bile duct or colon)
86. Somatostatin analouge
Mechanism of action
A. Act through type 2 & 5 somatostatin receptor inhibit cellular
hormone release
B. Cell cycle arrest in G1 phase apoptosis and inhibit angiogenesis
87. Octreotide dose 100 – 500µg three times daily
Lanreotide 60 -120 mg every 4 weeks.
90. chemotherapy
In advanced and progressive tumors with failure of other
route
Pancreatic NECs (45-69%) better respnse than Carcinoid
(30%)
91. Interferon alpha
Mechanism
Inhibit cell cycle (G1/S phase)
Inhibit protein and hormone synthesis
Immunostimulant
Results
Symtomatic response 10–15%
Ds stabilization in 40–60%
92. Embolization and chemo-embolization
Neuroendocrine metastases are intense hyper vascular
objective tumor response and symptomatic relief 30-70%
No significantly differnce could be approved bet
embolization and chemoembolization
93. complication
Post embolization syndrome (fever, right hypochondrial
pain, nausea and elevation of transaminases)
Gall bladder necrosis
Hepatic abscess
Renal failure
Mortaltiy 2-7%
94. Primary hepatic NECs
Very rare
More in female aroud 50 yr
Mostly central or perihilarly within the liver
The same line of management of met. NECs
5 & 10 yr survival after hepatic resection 80 -68%
