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159
chemotherapy. Although a combined colon and liver resection can be considered in
stable symptomatic patients with easily resectable liver lesions, acutely ill patients
should undergo the simplest operation that will treat the acute symptoms. In asymptomatic patients with synchronous disease, a decision must be made not only about
the timing of chemotherapy but also about the timing of colorectal resection in relation to hepatectomy. There is evidence that the colorectal resection can be safely
performed at the same time as the hepatectomy in well-selected patients [ 27 , 28 ].
For CLM presenting in a metachronous manner, the presence of a long disease-free
interval and an easily resectable solitary metastasis may support a decision to pursue upfront hepatectomy followed by adjuvant chemotherapy.
Second, although often grouped together in the discussion of CLM, colon cancer
and rectal cancer have different treatment algorithms. The management of CLM in
the setting of a rectal primary must account for local staging after assessment with
endorectal ultrasound or pelvic magnetic resonance imaging . A patient with CLM
in the setting of a locally advanced rectal cancer is an ideal candidate for upfront
systemic chemotherapy , as the primary lesion will require neoadjuvant chemoradiation . A single- or two-stage resection may then be performed. In contrast, there is no
clear role for neoadjuvant chemoradiation for primary colon cancers.
Third, the extent and anticipated morbidity of the planned hepatectomy must be
considered. Criteria for resectability have changed signifi cantly over time. Early in
the surgical experience with CLM, bilobar disease was regarded as a contraindication to resection [ 4 ], but the current surgical paradigm classifi es as resectable any
patient with CLM that can be technically removed with negative margins and an
adequate functional liver remnant [ 29 ]. Assessment of pre-operative liver function
should include a history focusing on alcohol intake and risk factors for hepatitis
along with liver enzymes, bilirubin, prothrombin time, and platelet levels.
Percutaneous biopsy may be performed for confi rmation of suspected chronic liver
disease. Patients with pre-existing cirrhosis are poor candidates for resection of
CLM. In general, upfront hepatectomy should be reserved for cases in which CLM
can be completely resected with a minor liver resection and a low predicted risk of
post-operative complications. When metastatic disease is technically resectable but
requires a more extensive resection, portal vein embolization (PVE) of the lobe
containing the bulk of the metastatic disease can be employed to encourage hypertrophy of the lobe that will remain after resection. Patients who require PVE are
ideal candidates for neoadjuvant chemotherapy as hepatic regeneration occurs even
as systematic cytotoxic agents are administered and complications do not appear to
be increased [ 30 ]. However, in all patients receiving systemic therapy before sur-
gery , the risk of post-operative liver failure after a major liver resection in the setting
of potential chemotherapy-induced hepatotoxicity must be mitigated.
13 When Should Patients with Liver Metastases from Colorectal Cancer Receive…
160
Recommendations Based on the Data
Given the limitations of the major relevant RCTs and retrospective studies, there is
equipoise regarding the optimal timing of chemotherapy in relation to surgery for
CLM. Nonetheless, a few general management recommendations can be made.
First, in the absence of extrahepatic disease, patients with resectable colorectal liver
metastases, if physiologically fi t, should be treated with both resection and chemotherapy (evidence quality moderate; strong recommendation). Second, in patients
who present with synchronous colorectal liver metastases and a symptomatic primary tumor requiring surgery, surgery should not be delayed for the administration
of neoadjuvant chemotherapy (evidence quality low; weak recommendation). Third,
in patients who present with synchronous colorectal liver metastases and an asymptomatic primary tumor, administration of neoadjuvant chemotherapy should be
strongly considered by a multidisciplinary team prior to a one-stage or two-stage
resection (evidence quality low; weak recommendation). Proceeding directly to
hepatectomy with a plan for adjuvant therapy only may be reasonable when there is
a solitary, small liver metastasis that can be safely resected at the time of the colectomy and there is low clinical suspicion of occult disease. Fourth, in patients who
present with metachronous colorectal liver metastases, administration of neoadjuvant chemotherapy should be strongly considered by a multidisciplinary team prior
to hepatectomy (evidence quality low; weak recommendation). Proceeding directly
to hepatectomy with a plan for adjuvant therapy only may be reasonable when there
is a solitary, small liver metastasis that can be safely resected with a low risk of
complications, when the disease-free interval is greater than 12 months, and there is
low suspicion for additional occult disease. Finally, in patients who present with
synchronous colorectal liver metastases and a locally advanced primary rectal cancer , administration of neoadjuvant chemotherapy targeting the liver should be
strongly considered in conjunction with neoadjuvant chemoradiation for the pelvis
(evidence quality low; weak recommendation).
A Personal View of the Data
Advances in liver resection techniques and anti- cancer drugs over the past 20 years
have greatly improved the ability to treat patients with CLM. Although there is
insuffi cient evidence to make strong generalizable recommendations for the timing
of chemotherapy in relation to hepatectomy in these patients, it is clear that a multidisciplinary approach should be pursued including medical oncologists, radiation
oncologists when appropriate, and surgeons experienced in surgical oncology,
colorectal surgery , and hepatobiliary surgery . Patients with CLM who have a high
suspicion of aggressive or occult disease are likely the best candidates for neoadjuvant chemotherapy. Such suspicion should arise in the presence of a large tumor
burden, a short disease-free interval, and a high CEA level. Patients with small,
M.D. Sur and E.A. Choi
161
solitary CLM without suspicion of occult disease may be considered for an upfront
surgical approach. Results of the NSABP C-11 trial are eagerly awaited, and further
investigations into the timing of targeted therapy with respect to surgery are warranted as well.
In the absence of extrahepatic disease, patients with resectable colorectal
liver metastases, if physiologically fi t, should be treated with both resection
and chemotherapy . (evidence quality moderate; strong recommendation)
In patients who present with synchronous colorectal liver metastases and a
symptomatic primary tumor requiring surgery , surgery should not be delayed
for the administration of neoadjuvant chemotherapy . (evidence quality low;
weak recommendation)
In patients who present with synchronous colorectal liver metastases and
an asymptomatic primary tumor, administration of neoadjuvant chemotherapy should be strongly considered by a multidisciplinary team prior to a onestage or two-stage resection . Upfront surgery may be considered when there
is a solitary, small liver metastasis that can be safely resected at the time of the
colectomy and there is low suspicion for occult disease. (evidence quality
low; weak recommendation)
In patients who present with metachronous colorectal liver metastases,
administration of neoadjuvant chemotherapy should be strongly considered
by a multidisciplinary team prior to hepatectomy . Upfront surgery may be
considered when there is a solitary, small liver metastasis that can be safely
resected with a low risk of complications, when the disease-free interval is
greater than 12 months, and there is low suspicion for occult disease. (evidence quality low; weak recommendation)
In patients who present with synchronous colorectal liver metastases and a
locally advanced primary rectal cancer , administration of neoadjuvant chemotherapy targeting the liver should be strongly considered in conjunction with
neoadjuvant chemoradiation for the pelvis. (evidence quality low; weak
recommendation)
13 When Should Patients with Liver Metastases from Colorectal Cancer Receive…
162
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and liver resection for synchronous colon cancer liver metastases: a population study. Ann
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165© Springer International Publishing Switzerland 2016
J.M. Millis, J.B. Matthews (eds.), Diffi cult Decisions in Hepatobiliary
and Pancreatic Surgery, Diffi cult Decisions in Surgery: An Evidence-Based
Approach, DOI 10.1007/978-3-319-27365-5_14
Chapter 14
What Is the Best Way to Assess Hepatic
Reserve Prior to Liver Resection
in the Cirrhotic Patient?
Yilei Mao and Shunda Du
Abstract Postoperative liver failure still remains a major cause of mortality after
partial hepatectomy, which results from an insuffi cient functional remnant liver.
Therefore, the accurate evaluation of liver function is very important, particularly in
cirrhotic patients who require hepatectomy. Traditional tests, such as serological
indicators, Child-Pugh score, MELD score and ICG clearance test, are important in
predicting and reducing the risks of hepatectomy. However, these tests only provide
functional data on the entire liver, not on specifi c anatomic parts of the liver. Ideally,
assessments of liver function should include both anatomical information and function of the whole and partial liver, providing reliable information for accurate evaluation of surgical risks.
99m
Tc-galactosyl serum albumin scintigraphy, can assess the
liver function quantitatively. It combined with single photon emission computed
tomography, CT and three-dimensional reconstruction, may be a better measure of
liver function, especially of remnant liver function.
Keywords Hepatic reserve • Hepatectomy • Cirrhosis • Galactosyl serum albumin
Introduction
Liver resection is the accepted gold standard of treatment for liver tumors.
Improvements in surgical methods and instruments have greatly reduced the perioperative mortality . However, the major cause of mortality after partial hepatectomy is
liver failure , which results from an insuffi cient functional remnant liver mass [ 1 ].
Conversely, the erroneous results of liver function tests may mislead the surgeon to
make a wrong decision such as precluding some patients with large liver tumor s
from undergoing surgery , even if surgery is benefi cial. Therefore, the accurate
Y. Mao (*) • S. Du
Department of Liver Surgery , Peking Union Medical College (PUMC) Hospital ,
1# Shuai-Fu-Yuan, Wang-Fu-Jing , Beijing 100730 , China
e-mail:
yileimao@126.com; pumch-liver@hotmail.com
166
evaluation of liver function is very important, particularly in patients with damaged
livers who require hepatectomy or liver transplant ation [ 2 ].
Liver function includes the uptake, metabolism, conjugation and excretion.
Among the methods used to evaluate liver function in practice are serological tests
which are the earliest and most commonly used in determining whole liver function.
Clinical scoring systems, such as Child-Pugh and model for end-stage liver disease
( MELD ) scores can roughly evaluate the risks of hepatectomy . The indocyanine
green (ICG) clearance test is a widely used quantitative test of liver function in
patients who scheduled for major hepatectomy. Although these tests can assess
whole liver function, they cannot assess remnant liver function and predict the risk
of liver failure post-operation. Computed tomography ( CT ) volumetry can provide
anatomic information on remnant liver volume (RLV), but anatomic volume is not
equal to functional volume, especially in patients with cirrhosis . In recent years,
99m
Tc- galactosyl serum albumin (
99m
Tc-GSA) scintigraphy combined with single
photon emission computed tomography (SPECT) and CT with three-dimensional
imaging, is relatively accurate in measuring the whole and regional liver function.
99m
Tc-GSA scintigraphy may therefore be a promising method to plan surgical incisions and to predict operative risk. Based on a two-compartment kinetic model, a
novel system was developed that provides 3D functional evaluation for any anatomical component of liver, and hepatectomy simulation with a freehand drawing
tool. The result was showed by the parameter ‘UI’ which had high accuracy in predicting the risk of liver failure. In the future, many new methods will be established
which can assess hepatic reserve accurately prior to liver resection in the cirrhotic
patient.
Search Strategy
A literature search of English language publications since January, 2004 was used
to identity published data on preoperative assessment of hepatic reserve in cirrhotic
patients undergoing hepatectomy using the PICO outline (Table 14.1 ). Databases
searched were PubMed, Embase, and Cochrane Evidence Based Medicine . Terms
used in the search were “cirrhotic patients/ cirrhosis ”, “ liver resection / hepatectomy”, “liver function/hepatic reserve/ Child-Pugh Score /indocyanine green clearance test (ICG)/model for end-stage liver disease ( MELD ) score/
Monoethylglycinexylidide (MEGX) test/galactose elimination capacity Test/computed tomography volumetry/galactosyl serum albumin (GSA)/transient elastography (TE)”, “postoperative complications/postoperative hepatic failure/ ascites /
hyperbilirubinemia /prolongedprothrombin time/length of stay/ mortality / morbidity /
quality of life ”, and “preoperative/prior to liver resection ”. Eleven cohort studies,
two systematic reviews and one meta-analysis, and four review articles were
included in our analysis (Table 14.2 ). The other perspective cohort study [ 3 ] was
enrolled about GSA which was accepted by the Annals of Surgical Oncology. The
data was classifi ed using the GRADE system.
Y. Mao and S. Du
167
Results
Liver function includes the uptake, metabolism, conjugation and excretion. The
serological tests are the earliest and most commonly used and still play important
role. But any one serological indicator can show only one aspect not comprehensive
function, and whole liver function not local. So different clinical scoring systems
and metabolic quantitative liver function tests were developed to assess hepatic
reserve .
The Child-Pugh Scoring System
The Child scoring system, fi rst proposed in 1964, was originally developed to predict the outcome of cirrhotic patients undergoing surgical therapy for portal hypertension. This system was modifi ed by Pugh et al. [ 4 ] in 1973, and called the
Child-Pugh score. It includes total plasma bilirubin level, plasma albumin level, and
prothrombin time together with the presence or absence of encephalopathy and
ascites . Of all the tools for assessing liver function, the Child-Pugh system is simple
but very useful [ 5 ]. It is widely used in hepatocellular carcinoma and cirrhosis
patients, who will undergo resection or transplantation. Thus Child-Pugh is more
relevant for liver resection s, compared with MELD score system. A classifi cation of
grade A of the Child-Pugh grading system is a typical indication for liver resection.
And liver transplant ation is selected if oncological indications meets the established
criteria [ 6 ]. Schneider showed that, for patients classifi ed Child-Pugh A, the mortal-
ity is minimal at <5 % while for grade B cirrhotics the 1-year liver failure -related
morality is almost 20 %, and for grade C cirrhosis is 55 %[ 7 ].
However, the Child-Pugh grading system only provides a rough evaluation for
global liver function reserve, so more quantitative liver function tests may need for
preoperative assessment .
Table 14.1 PICO table for perioperative assessment of hepatic reserve in the cirrhotic patient
P (Patients) I (Intervention) C (Comparator group)
O (Outcomes
measured)
Cirrhotic patient
undergoing liver
resection
Novel preoperative liver
function test, such as:
indocyanine green(ICG)
clearance test, model for
end-stage liver disease
( MELD) score, transient
elastography,
99m
Tc galactosyl serum albumin
scintigraphy, etc
Classical preoperative liver
function test, such as:
Child-Pugh score, model for
end-stage liver disease
( MELD) score, indocyanine
green(ICG)clearance test,
computed tomography ( CT)
volumetry, etc
Postoperative
complications,
mortality
14 What Is the Best Way to Assess Hepatic Reserve Prior to Liver Resection…
168
Table 14.2 Incidence of different liver function assessments and clinical outcomes
Author (year) N Age
Child- Pugh
score
MELD
score ICGR
15
TE
(kPa) GSA
LOS
(d) Ascites
Postoperative
LF Mortality
Study type
( quality of
evidence)
Matteo (2012) 90 64 A:90 % 8.3 NR 16.2 NR 9 20 % 28.9 % 2.2 % Prospective
cohort (low)
Other: 10 %
Jeff (2013) 105 59 5 NR 4.2 % 9.4 NR NR NR NR 1.9 % Prospective
cohort (low)
Scheingraber
(2008)
95 60 NR NR ICG-PDR was
used
NR NR NR NR 24.2 % 3.2 % Prospective
cohort (low)
Ohwada (2006) 75 63 A: 96 % NR ICG -k and
ICGR
15
NR NR NR NR 11 % 1 % Prospective
cohort (low)
B: 4 %
James (2013) 28 59 A: 96.4 % 7.2 11.8 % 10.2 NR 6 4/28 NR / Prospective
cohort (low)
B: 3.6 %
Hirohisa (2014) 548 66 NR NR 12.5 % NR LHL15: 0.92 NR NR NR 0.89 % Prospective
cohort (low)
Cucchetti
(2006)
200 64 5 8.8 NR NR NR NR 5 % 7.5 % NR Prospective
cohort (low)
Cescon (2009) 466 64 5.4 8.9 NR NR NR NR 4.9 % 4.9 % NR Prospective
cohort (low)
Kwon (2006) 178 62 A: 73 % NR GSA- Rmax
and ICGR15
values
correlate well
NR GSA-RL NR 13.5 % NR 1.12 Retrospective
cohort (low)
B: 27 %
Kaibori (2008) 191 66.5 A: 86.4 % NR 18.0 %:
9.7 %
NR HA/
GSA- Rmax
ratio
NR NR 8.38 % 1.57 % Prospective
cohort (low)
B: 13.6 %
Mao (2014) 142 53.3 A: 76.1 % NR Negative
associate with
UI
NR UI NR UI can
distinguish
UI can predict NR Prospective
cohort (low)
B: 21.1 %
C: 2.8 %
MELD model for end-stage liver disease, TE transient elastography, GSA
99m
Tc- galactosyl serum albumin scintigraphy, LOS length of stay, NR not reported,
LHL the ratio of uptake by the liver to that by the liver and the heart at 15 min in GSA, LF liver failure
Y. Mao and S. Du
169
The Model for End-Stage Liver Disease ( MELD ) Score
The limitations of the Child-Pugh score led to the development of MELD . MELD
score was originally developed to evaluate the survival rate of patients undergoing
transjugular intrahepatic portosystemic shunt procedures, and was thereafter modifi ed to evaluate patients with liver disease undergoing surgery . MELD score is a
constellation of serum bilirubin, creatinine concentration, INR and etiology of liver
disease, and is calculated using the formula: 11.2 × Ln(INR) + 9.57 × Ln[creatinine(
mg/dL)] + 3.78 × Ln [bilirubin(mg/dL)] + 6.43 × (etiology: 0 if cholestatic or alcoholic, 1 otherwise), with the score rounded to the nearest integer [ 8 ].
The MELD score is used to allocate organs for liver transplant ation [ 9 , 10 ]. The
application of this system to determine organ allocation reduced 15 % of the mortality rate in liver transplant candidates [ 11 ]. Cholangitas et al. [ 9 ] stated that MELD
score was shown to be useful for the prediction of long-term survival in patients
with cirrhosis . Ascites, jaundice , prolonged prothrombin time, increase of serum
creatinine and bilirubin levels, and decrease of albumin serum level are typical
markers of impaired liver function. Cucchetti et al. has showed that MELD score
can be used to predict the development of post-operative liver failure after hepatectomy for patients with cirrhosis undergoing resection of hepatocellular carcinoma,
with a pre-operative score of 11 being associated with a poor outcome [ 12 ].
In subsequent clinical applications, outcomes were different in patients with the
same score and different serum concentrations of sodium. So some modifi ed MELD
formulas that have been proposed to predict the prognosis of liver disease, such as
MELD-Na score, integrated MELD (iMELD), MELD to sodium (MESO), United
Kingdom end-stage liver disease (UKELD), etc. However, they cannot accurately
predict the actual survival time of patients undergoing hepatectomy . At present, they
are mainly used to assess the severity and prognosis of chronic liver diseases, and to
evaluate the patients awaiting liver transplant ation [ 13 ].
Computed Tomography ( CT ) Volumetry
At present, CT volumetry is the most often used imaging method to determine
whether hepatectomy can be performed safely. Pre-operative estimations have been
shown to correlate well with actual volumes resected. But the safety limit for the
remnant liver volume in patients with normal liver remains controversial. Kubota
et al. found that resections of 60 % of non-tumorous liver was possible in patients
with normal livers [ 14 ]. Shoup et al. stated that a liver resection can be safely per-
formed if the functional remnant liver volume(RLV) is larger than 25–30 % when
using computed tomography volumetry [ 15 , 16 ]. If the patients have underlying
liver disease, then a margin of 40 % is taken into account [ 17 ]. Several studies found
that in the presence of cirrhosis , a resection of >2 segments should only be performed of the estimated remnant functional liver was >40 %, while if it’s <40 %, a
pre-resection portal vein embolization (PVE) should be advised [ 18 , 19 ].
14 What Is the Best Way to Assess Hepatic Reserve Prior to Liver Resection…