الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Summary and Conclusion
Colorectal cancer (CRC) is the third most commonly
diagnosed malignancy accounting for 11% of cancers in men
and women and also is the third leading cause of cancer
mortality each year (Berenson et al., 2006).
Among patients who have CRC, a majority will
eventually develop liver metastases. In 30% to 40% of CRC
patients, metastases are confined to the liver when they are
initially found (Penna et al., 2006).
The development of metastases is the main cause of
death. Liver metastases are diagnosed in10–25% of patients at
the time of resection of their primary colorectal tumor (Welch
et al., 1997).
Patients with liver metastases from colorectal cancer
should be evaluated by experienced surgeons and radiologists
and oncologists as the treatment can include multimodalities
(Primrose et al., 2000).
Hepatic resection is the gold standard in the treatment of
colorectal liver metastases, and it is the only curative option in
patients with hepatic metastases from CRC is margin-free
resection where the 5-year overall survival rates in selected
Summary and Conclusion
135
cases range from 37 to 58%. In the case of synchronous
metastases, the primary tumour must always be operated on if
symptomatic, irrespective of the resectability of the metastases.
Standard practice remains to resect the primary and metastases
together or resect the primary and the metastases in a stepwise
fashion followed by adjuvant chemotherapy (McLoughlin et
al., 2006).
Improved surgical outcomes are the result of a more
systematic understanding of intrahepatic anatomy, improved
surgical techniques,better anesthetic management, and
improved postoperative care (Khatri et al., 2005).
Portal vein embolization may be combined in the
treatment of patients with huge metastases Preoperative portal
vein embolization induced hypertrophy in the normal liver
which will be remnant and decreased the likelihood of liver
insufficiency occurring after extensive liver resection (Azoulay
et al., 2006).
Perioperative chemotherapy results in longer DFS and
OS times. It is not clear whether it is the neoadjuvant or the
adjuvant component that provides the benefit. There is likely to
be a subgroup of patients who benefit from having neoadjuvant
chemotherapy, but it is not recommended for all patients with
Summary and Conclusion
136
initially resectable disease. It is a reasonable approach to give
neoadjuvant and adjuvant FOLFOX with or without
bevacizumab to high-risk patients with initially resectable
disease. These include those with multiple lesions and lesions
≤5 cm.For most patients with colorectal metastases,
systemically administered chemotherapy and also the targeted
therapy is the only treatment option, allowing not only
downsizing of liver disease but also a reduction in the risk of
distant recurrence (De Gramont et al., 2012).
In patients who are initially unresectable, there are
effective options for conversion into surgical candidates.
FOLFOX plus bevacizumab is effective and has a favorable
side-effect profile, whereas irinotecan carries a higher risk for
hepatic toxicity. Cetuximab and FOLFIRI or FOLFOX can be
considered for patients with wt KRAS tumors as conversion
therapy; however, irinotecan causes a higher risk for
steatohepatitis with an attendant slightly higher surgical
complication rate. A maximum of six cycles of chemotherapy is
recommended. Active agents, in addition to the original 5FU,
include irinotecan, capecitabine, oxaliplatin, bevacizumab,
cetuximab, and panitumumab. The efficacy of three cytotoxiccontaining
(triple-drug) regimens needs to be compared with
combinations of two cytotoxics plus a targeted agent (biologic)
Summary and Conclusion
137
in this clinical setting. Cetuximab and bevacizumab currently
do not have evidence to support their use after liver resection
(Nordlinger et al., 2007).
First, we assumed that adding bevacizumab to any
chemotherapy backbone would represent an advance. By the
time that the IFL/bev data became available, the N9741 trial
had shown us that FOLFOX was a superior regimen to IFL.
Having no desire to resurrect IFL, which, as a result of the use
of bolus 5FU and weekly irinotecan has greater toxicity than
FOLFOX, regulatory authorities wisely approved bevacizumab
for use in conjunction with a ―5FU-containing regimen.‖This,
of course, translated into a de facto approval of FOLFOX plus
bevacizumab which, without fırst line effıcacy data, became the
most widely used front line regimen in the United States
(ASCO, 2013).
Several other antiangiogenesis agents are currently in
development. ZIV- Aflibercept is a recombinant fusion
molecule of the human VEGF receptor (Tang et al., 2008).
Regorafenib is another targeted drug for advanced
colorectal cancer. It is a type of targeted therapy known as a
kinase inhibitor. regorafenib was FDA approved on February
2013 (Grothey et al., 2013).
Summary and Conclusion
138
Selective internal radiation therapy (SIRT) using Y-90
which is a pure Beta emitter is a new modality that can provide
extremely high local tumor doses ranging from 50-150 Gy to
more than 1000 Gy, in contrast to the traditional whole-liver
external beam radiation where radiation doses have to be
limited to 30 Gy and it may be valuable in colorectal cancer
liver metastatic patients which was not suitable to resection,
RFA and cryotherapy (Kennedy et al., 2007).
Hepatic cryotherapy is generally reserved for patients
with liver are not surgically resectable. Some centers offer liver
metastases from colorectal cancer in whom one or more lesions
cryotherapy as an alternative to surgical resection and can only
accompany either an open or a laparoscopic surgical approach
(Bipat et al., 2007).
RFA can substitute for surgical resection, when adequate
margins are not possible to achieve, typically used in patients
with no evidence of extrahepatic disease preoperatively or
intraoperatively who do not meet the criteria for surgical
resection of their tumors. Although RFA has a lot of advantages
in the treatment of metastatic liver tumors, it still has a few
disadvantages and complications (Wood et al., 2006).
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139
Conclusion
For patients who present with mCRC confined to the
liver, resection of the primary tumor and the metastases should
be performed in a simultaneous procedure if feasible. In those
with high-risk features, neoadjuvant chemotherapy provides an
opportunity to gather information on the biological activity of
the tumor and its chemoresponsiveness, in addition to
improving resectability. The aim is to avoid a futile liver
resection; however, there is evidence that, despite progression
on chemotherapy in initially resectable disease, the 5-year
survival rates are respectable.
Local treatments such as RFA and chemoembolisation
are inferior to R0 hepatectomy, but when used judiciously they
prolong survival in patients with unresectable disease.
Perioperative chemotherapy results in longer DFS and OS
times. There is likely to be a subgroup of patients who benefit
from having neoadjuvant chemotherapy, but it is not
recommended for all patients with initially resectable disease.
It is a reasonable approach to give neoadjuvant and
adjuvant FOLFOX with or without bevacizumab to high-risk
patients with initially resectable disease. In patients who are
initially unresectable, there are effective options for conversion
into surgical candidates. FOLFOX plus bevacizumab is
Summary and Conclusion
140
effective and has a favorable side-effect profile, whereas
irinotecan carries a higher risk for hepatic toxicity.
Cetuximab and FOLFIRI or FOLFOX can be considered
for patients with wt KRAS tumors as conversion therapy;
however, irinotecan causes a higher risk for steatohepatitis with
an attendant slightly higher surgical complication rate.
Depending on the initial response and disease free interval, a
regimen may be reused or an alternative strategy may be
pursued. What is known is that liver resection provides the only
reasonable possibility for cure of mCRC and that the rate of
resection can be increased by judicious use of cytotoxic and
targeted agents