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Current status and progress in gastric cancer with liver metastasis—— a review
LIU Jing, CHEN Lin
Department of General Surgery, Chinese People’s Liberation Army General Hospital,
Beijing 100853, China (LIU Jing, CHEN Lin)
School of Medicine, Nankai University, Tianjin 300071, China (LIU Jing, CHEN
Lin)
Correspondence to: Prof. CHEN Lin, Department of General Surgery, Chinese
People’s Liberation Army General Hospital, 28 Fuxing Road, Beijing 100853, China
(Tel: 86-10-66938128. Email: [email protected])
Keywords: gastric cancer; liver metastasis; diagnostic imaging; therapeutics
Objective: This review discusses the current status and progress of gastric
cancer with liver metastasis (GCLM), involving: (1) the routes, subtypies and
prognosis of GCLM (2) the related genes and molecules in its metastatic
mechanism (3) the feasibility and value of each imaging modalities (4) the
up-to-date treatment options.
Data sources: The data used in this review were mainly from Medline and
PubMed published in English from 2005 to August 2010. The search term was
“gastric cancer” and “liver metastasis”.
Study selection: Articles regarding the the characteristics, the diagnostic
modalities and various therapeutic options of GCLM were selected.
Results: The prognosis of GCLM is influenced by the clinicopathological
characteristics of primary tumours as well as liver metastases. Improved
understanding of related genes and molecules will lead to the development of
early detection and targeted therapies. For the diagnosis of GCLM, each
imaging modality has its relative benefits. However, for the therapeutic options,
there is still no consensus statement.
Conclusion: Early detection and characterization of liver metastases is crucial
for the prognosis of gastric cancer patients. Multidisciplinary team discussions
are required to design the optimal treatment strategy, which is tailored
according to the clinicopathological characteristics of each patient.
Gastric cancer is the fourth most common cancer and the second leading cause
of cancer deaths worldwide .1 In China, incidence rate and mortality rate for gastric
cancer in 2006 were 35.02 and 26.08 per 100,000 person respectively, which are
second only to lung cancer.2 The prognosis is generally rather poor, with a 5-year
survival rate below 30%.1 Early detection and adequate treatment is an important way
to reduce death rate from gastric cancer, the high mortality is predominantly due to
late presentation. The development of liver metastases is a fatal event for gastric
cancer patients and remains a major cause of cancer-related death, with a 5-year
survival rate as low as 0~10% in unselected cases.
Liver metastases from gastric cancer refers to the liver lesions originating from
primary gastric cancer, which was proved by imaging studies, histological studies or
laparotomy. In 2%~9.9% patients, liver metastases is defined by detection before or
during surgery of primary gastric cancer(synchronous metastases); while 13.5%~30%
represent the evolution of the disease after a potentially curative surgical treatment
(metachronous metastases). 3-8
However, there is still no widespread agreement regarding the definition of
synchronous or metachronous liver metastases. Hwang et al. defined synchronous
metastasis as metastasis occurring within 1 year after gastrectomy, while Thelen et al.
has chosen 6 months as the cut-off point in their research.9, 10 Metachronous liver
metastasis is usually detected within a 2-year period of time following initial
gastrectomy. 3 According to the distribution of liver metastases, the degree can be
classified as follows, H1: metastases were limited to one of the lobes, H2: there were
a few scattered metastases in both lobes, and H3: there were numerous scattered
metastases in both lobes.11
ROUTES FOR LIVER METASTASIS OF GASTRIC CANCER
Gastric cancer spreading to liver are mainly through hematogenous route,
lymphatic dissemination, and serosal invasion of the primary tumor.
Hematogenous metastasis is the most generally accepted theory for the
development of liver metastasis, which has been supported by clinicopathological
analyses of resected specimens, showing a relationship between venous invasion and
liver metastasis.12 Gastric cancer cells in the blood vessel are disseminated to various
organs through the portal vein, therefore, liver becomes the first filter of cancerous
cells. Based on the phenomenon of lymphatico-venous communication and lymph
flow reflux by lymphatic obstruction, lymphatic involvement is closely linked with
the establishment of liver metastasis.13 In particular, extranodal invasion was a
significant risk factor.14 Intrahepatic metastasis from the initial liver metastases were
also present in 58.8% of patients of liver metastases from gastric cancer. They were
located in the vicinity of the liver metastasis, within 5.0 mm of the tumor border.
These micrometastases may be one of the major explanations for the high recurrence
rate in the remnant liver after hepatic metastasectomy or thermal ablation.15
SUBTYPES OF GASTRIC CANCER LIKELY TO METASTASIZE TO
THE LIVER
Gastric cancer with liver metastases(GCLM) is known to consist of the
following histological types：differentiated adenocarcinoma, poorly differentiated
adenocarcinoma, endocrine carcinoma and hepatoid adenocarcinoma. These subtypes
have unique characteristics, but share common pathological features such as scant
fibrous stroma and abundant tumor blood vessels.16
Based on Lauren’s classification, gastric cancer was divided into intestinal-type
and diffuse –type. Intestinal-type is more likely to develop liver metastases, due to
higher expression of EMPPRIN, which could stimulate MMP and VEGF expression
of surrounding stromal cells.17
Besides the two traditional manners of the classification of gastric cancer,
several investigators have defined gastric cancer into 4 categories: gastric, gastric and
intestinal mixed, intestinal, and null phenotype according to the immunopositivity of
human gastric mucin stainings; MUC5AC and MUC6 are recognized as gastric
phenotypic markers, while MUC2 and CD10 are as intestinal phenotypic markers.18-20
Wakatsuki et al demonstrated that intestinal phenotype gastric cancer had the highest
rate of postoperative liver metastasis.20
PROGNOSIS OF GCLM
To our knowledge, 6 studies related to the prognosis and the clinicopathological
prognostic factors of GCLM with a patient number beyond 40 have been published
within the recent 5 years. The prognosis of liver metastases remains poor with an
median survival time (MST) ranging from 5 to 34 months after the diagnosis of liver
metastasis, and even worse if concomitant extrahepatic metastases are present.4, 7-9,
21-23
MST was slightly, but not significantly longer in metachronous liver metastases
patients than in synchronous liver metastases patients.4, 9, 21 (MST: 5 m versus 4 m, P
= 0.439; 34 m versus 22 m, P=0.774)
The clinicopathological factors of primary gastric cancer may influence survival
in GCLM. Survival rate in relation to depth of invasion reveals that serosal invasion
is a marginally non- favorable prognostic factor.4 In a study for 72 sychronous GCLM
patients, tumor depth of invasion≤T2 was picked up for the predictor of survival by
a univariate analysis.8 A multicentric survey reported that the 1 year survival rate for
T1,T2,T3 and T4 was 50%,52%,27% and 0, respectively (P=0.019). Survival rates
were decreased in relation to advanced N stage. Tiberio et al. also reported that the
presence of lymph node metastases independent from the extension of the metastatic
spread N1-3 was associated with worse prognosis.7 For H1, 2 patients without
peritoneal dissemination, lymph node metastases (N2, 3versus N0,1) was an
independent non-favorable prognostic factors of survival.8
According to the distribution of liver metastases, the MST for H1, H2, and H3
GCLM patients were 16.6, 10.2, and 4.4 months, respectively (P<0.02). 8 The number
of liver metastases is another significant prognostic factor. 4, 21 The 1-,3-, 5- years
survival rates in solitary liver metastasis patients(79.2%,33.3% and
23.8%,respectively) were significantly higher than multiple liver metastases patients
(51.3%,7.8% and 2.6%,respectively).21
GCLM RELATED GENES AND MOLECULES
Vascular endothelial growth factor (VEGF) family is a major inducer of
angiogenesis and lymphangiogenesis that can promote the growth and metastasis of
tumor. VEGF-A play an important role in occurrences of distant metastases of GC
patients by acting though VEGFR-1 and VEGFR-2.24 Kaplan et al. found that
VEGFR-1 originated from hematopoietic progenitor cells in bone marrow and
functions as a cancer niche to facilitate metastasis.25 The formation of liver
metastases of gastric cancer was most likely when isolated tumor cells circulated in
the presence of high levels of VEGFR-1.26 VEGF-D involved in lymphatic spreading
of gastric cancer cells, which is an important contributor to liver metastasis from
gastric cancer via lymphatic metastasis after radical gastrectomy.24, 27 In the primary
tumor of GCLM patients, the number of VEGFR -3 positive vessels was significantly
much higher than that in primary tumor of gastric cancer patients without any
recurrence 24.
The proto-oncogene c-met encodes a 190 kDa heterodimeric transmembrane
tyrosine kinase which has been identified as the receptor of hepatocyte growth factor
(HGF).28 HGF binds to met, induces receptor homodimerization, phosphorylation of
the cytoplasmic tyrosine kinase domain and activation of met-mediated signaling,
which allows the activation of different downstream pathways, including
phosphatidylinositol 3-kinase-Akt signaling and Ras-mitogen-activated protein kinase
pathways, ultimately leads to pleiotropic responses such as proliferation, motility,
morphogenesis, and angiogenesis in the process of tumor invasion and metastasis. 29,
30
A higher degree of c-Met protein expression is strongly associated with tumor
invasion and liver metastasis, which can be a promising indicator of liver metastasis
in gastric cancer patients.31, 32 These observations have led to the development of
agents that can effectively inhibit HGF/met signaling through direct inhibition of the
receptor (anti-Met antibodies), through inactivation of its ligand HGF (AMG102,
L2G7), by interfering with HGF binding to MET (NK4), or by inhibiting Met kinase
activity (PHA-665752 and SU11274).32
MAGE-A family genes are expressed in malignant tumours, whereas they are
not expressed in adult tissue except the testis and placenta.33 MAGE-A protein and
the expression of MAGEA10 gene in patients with gastric cancer was significantly
higher in patients with liver metastasis than in patients without; moreover,
MAGE-A10 can be a predictive marker for metachronous liver metastasis even in
low-stage gastric cancers.34 MAGE-A10 mRNA expression is much specific to the
prediction of liver metastases from gastric cancer, as it was found in only 2 and 0% of
the cases of primary lesion and liver metastasis in colon cancer, respectively.35
E-cadherin, a metastasis-suppressor gene, is the strongest molecule for
homophilic adhesion of epithelial cells and plays an important role in the formation of
epithelial architecture; loss or reduction of E-cadherin expression may induce the
dissociation of cells from primary tumours, due to loosened intercellular adhesion. 36
Compared with the normal tissues, the expression level of E-cadherin in gastric
cancer decreased in primary tumors and further decreased in metastases.37 The
process of epithelial-to-mesenchymal transition has been reported to be an important
event characterized by loss of E-cadherin during malignant tumour progression and
metastasis.35 Tyrosine phosphorylation of β-catenin, overexpression of c-erbB-2 and
activation of ERas in the primary tumors all contribute to the loss of E-cadherin
function, resulting in reduced cell-cell adhesion and in cellular transformation,
playing a crucial role in promoting gastric cancer cell survival and metastases to
liver.38, 39
Besides those mentioned above, up-regulation of a group of molecules and genes
such as osteopontin, phosphatase of regenerationliver-3, BUBR1, HSP90AA1,
CCNE1, urokinase-type plasminogen activator and matrix metalloproteinase
(MMP)-2, 9, down-regulation and/or promoter methylation of some tumor
suppressors such as Nm23-H1, KISS1 and KAI1, GRIM-19, NR4A2, NR3C1 in
tumor tissues or sera have been demonstrated to be associated with the development
of liver metastases from and poor outcome of gastric cancer. 40-46
DIAGNOSIS OF GCLM
Imaging modalities
The presence of hepatic metastases greatly affects prognosis and treatment
protocol design of patients with gastric cancer. Accurate detection and
characterization of hepatic metastases, including differentiating malignant lesions
from benign process and evaluating the extent of the metastatic burden, is critical for
a patient’s diagnostic workup. In 2002, a meta-analysis has compared the accuracy
and examined the ability to detect hepatic metastases of several imaging methods.
When the required specificity was set at greater than 85%, the most sensitive method
was 18F-fluorodeoxyglucose positron emission tomography (PET) with a sensitive of
90%, followed by magnetic resonance imaging (MRI;76%), computed tomography
(CT;72%), and ultrasonography (US;55%).47
Ultrasonography
Conventional transabdominal ultrasonography is routinely used as the first-line
imaging modality in detection of liver metastases, and it also plays a substantial role
for intraprocedural localization during biopsy and therapeutic interventions such as
thermal ablation, providing real-time imagine with no ionizing radiation to the
operator.48
Liver metastases from gastrointestinal primary tumors frequently present as
hyperechoic lesions. Internal echogenicity with posterior acoustic shadowing is a
feature of calcified metastases, which can be seen with mucinous adenocarcinomas of
the gastrointestinal tract.49 The reported sensitivity values of US is quite lower than
CT or MRI, ranging from 40% to 77% which will drop to 20% for small lesions
(especially<1cm) or for isoechoic lesions compared with the surrounding liver
parenchyma.50, 51 Thus, incidental hepatic lesion detection on abdominal US
frequently initiates a request for an additional cross-sectional imaging study with
greater accuracy such as CT or MRI.
The development of new ultrasound contrast agents and sonographic techniques
has considerably improved the possibilities of US in the detection of hepatic
metastases, as well as in the guidance and evaluation of response of therapeutic
procedures. Contrast-enhanced ultrasound (CEUS) have clearly improved the
sensitivity in detecting liver metastases to 80%~90%, which has no statistical
difference in the diagnostic performance with CT, and is especially helpful for liver
metastasis smaller than 10mm.50 CEUS alone was sufficient to classify 89.0% of the
focal liver lesions as benign or malignant. It served as a one-stop diagnostic test for
80.8% of the patients, reducing the need for CT or MR scans and providing savings in
terms of radiation exposure, time, and money.52
Computed tomography
In clinical practice, CT is the mainstay of oncological imaging for its excellent
availability, good patient tolerance, and reproducibility of examinations. As
metastatic hepatic lesions are usually hypovascular, the optimal CT strategy is helical
scanning during the portal venous phase of enhancement. This technique improves
lesion conspicuity by increasing the attenuation of normal liver tissue; occasionally,
rim enhancement of a hypoattenuating metastasis can be seen.53 The advent of
multi-detector row computed tomography (MDCT) effectively replaced computed
tomography during arterial portography for diagnosis of hepatic metastases. MDCT
has high accuracy for evaluating staging, especially for the detecting of enlargement
of lymph nodes (LN), distant metastases, and for predicting the resectability of gastric
cancers preoperatively. The accuracy of MDCT for overall M staging was high
(85.6%), for identifying liver metastases, the sensitivity was 80.0%.54 CT scan is a
standard test for the detection of the liver metastases, however, the reported
sensitivity for small metastases <1.5 cm are low.55 A comparison between total
liver-volume perfusion CT (CTP) and four- phase CT has been done recently,
revealed that CTP increased sensitivity to 89.2 from 78.4% (P=0.046) and specificity
to 82.6 from 78.3% (P=0.074), which indicated that CTP is a noninvasive,
quantitative, and feasible technique.56
Magnetic resonance imaging
MRI is considered to be the optimal diagnostic modality for evaluation of
suspected hepatic metastases, with reported sensitivity of 80% to 100% and
specificity up to 97%.57 The diagnostic performance of MRI for small lesions (<1.0
cm in size) has been shown to be superior to helical CT.58 Modern comprehensive
liver-imaging protocols generally use a variety of sequences to optimize lesion
detection and characterization. DW-MRI was found to be sensitive for detection of
small liver lesions(less than 1 cm) that mimicked small intrahepatic vessels, however,
as there is an overlap of apparent diffusion coefficient (ADC) values between
different types of lesions, the predominant limitation of the DW-EPI sequence is the
differentiation between benign and malignant lesions.59 Metastatic liver tumors often
coexist with benign focal hepatic lesions, such as hemangiomas or cysts. Thus,
discrimination between them is important for the treatment and prognosis of patient
with gastric cancer. Contrast-enhanced MR imaging can demonstrate tissue-specific
physiological information, thereby facilitating liver lesion characterization, which
may facilitate the accurate diagnostic workup of patients in order to avoid invasive
procedures for lesion characterization such as biopsy.
Gadolinium- enhanced-T2-weighted images, SPIO-enhanced T2-weighted MR
images have been reported to have the ability to make the differentiation of primary
malignant, metastatic, and benign lesions in the liver.60 However, with the increasing
awareness of the potential risks of contrast material administration in patients with
severe renal failure, there is a strong clinical need for methods to diagnose liver
metastases without exogenous contrast material. Nasu et al. retrospectively compared
the accuracy of respiratory triggered diffusion-weighted echo-planar imaging
(DW-EPI) in combination with unenhanced T1- and T2-weighted imaging versus
SPIO-enhanced imaging and revealed that there was no significant differences for the
sensitivity and specificity between the two image sets.61 DW-MRI, combined with
unenhanced T1- and T2-weighted imaging can be a reasonable alternative to contrastenhanced MRI for the detection of liver metastases.61
Moreover, DW-MRI is a promising, noninvasive technique for helping predict
and detect therapeutic responses to chemotherapy in patients of GCLM. An early
increase in the mean ADC and a low pre-therapy mean ADC can help predict good
response to chemotherapy in these patients.62
Positron emission tomography
For overall patient management, Positron emission tomography (PET) using
Fluorine-18 fluorodeoxyglucose (FDG), i.e.,18F-FDG PET and FDG-PET with CT,
i.e., PET/CT have the added advantage over MRI and CT of providing not only
anatomic but also functional information. The major advantages of PET
predominantly referred to the ability of detection of extrahepatic disease and the early
evaluation of therapeutic response rather than its sensitivity in the detection of hepatic
metastases. One series found a sensitivity and specificity of 85% and 74% for
FDG-PET in the detection of liver metastases originating from gastric cancer.63
Recent studies demonstrated that the detection rate of liver lesions was significantly
lower for PET/CT than for Gd-EOBDTPA–enhanced MRI (64% and 85%; P =0.002),
which is especially relevant in small liver metastases 1 cm or less in diameter.64
The detection of extra-hepatic metastases is an essential factor influence the
therapeutic options. FDG-PET has the advantage in the diagnostic performance for
extra-hepatic metastatic disease, with PET reportedly identifying 10% to 20% more
sites of extrahepatic disease than by CT alone. 58 Furthermore, FDG PET has been
successfully used to monitor the effect of chemotherapy. CT-observed tumour
response depends on tumour size reduction, which is a relative late sign of response.
An earlier sign of response is the chemotherapy-induced reduction in tumour
metabolic rate, which could be detected by FDG-PET.65 PET also has the potential to
evaluate the efficacy of a radiofrequency thermal ablation (RFA) procedure by
indicating macroscopic tumor-free margin as total photopenia and macroscopic
residual tumor as focal uptake. Such an assessment would allow a second RFA
treatment to be performed early—at a time when efficacy is likely to be higher than if
waiting for a lesion to appear on CT or MRI months later.66
Tumor marker
Serum assay of tumor markers may be useful for an early diagnosis of liver
metastases during follow-up, but the positivity of tumor markers in recurrent gastric
cancer is not site-specific.
Daniele et al has made an prospective study and demonstrated that the
combination of the 3 markers (CEA, CA19-9, and CA 72-4) was proved to be highly
sensitive for predicting liver metastases, as an increase in serum levels was observed
in 96.4%patients; in the remaining patient, preoperative levels for all 3 markers were
negative and the histologic type was diffuse. 3 An RT-PCR analysis of CEA mRNA
in the peripheral blood seems to be a promising tool for the early detection of
micrometastatic circulating tumor cells in gastric carcinoma patients.67 Recent
research on the prognostic value of preoperative CEA, CA 19-9, CA 72-4, and AFP
levels in gastric cancer reported that CEA was significantly more frequently positive
in the patients with liver metastases, as well as CA 19-9 in patients with lymph node,
peritoneal, and serosal involvement, CA 72-4 in patients with lymph node, peritoneal
and liver involvement.68 Moreover, CEA level was significantly higher for bilobar
metastases than unilobar involvement.69 Alpha-fetoprotein (AFP)-positive gastric
cancer is strongly associated with hematogenous factors such as venous invasion,
hepatic metastasis and aggressive biological factors.70
Gastric cancer metastasised to the liver was found to overexpress HER2 at a
significantly higher incidence than primary gastric cancers. All these gastric cancer
liver metastasis cell lines are highly sensitive to gefitinib, whereas most of the HER2
low expressing lines are not.71
SALL4 expression was observed in the neofetal stomach in gestational week 9
and disappeared thereafter. It was also identified in 15% of gastric carcinomas,
associated with intestinal-type histology (P=0.0001) and synchronous liver metastasis
(P=0.0047). AFP and GPC3 were closely associated with SALL4 expression in
gastric carcinoma (both, P<0.0001). SALL4 was positive in all AFP-producing
gastric cancer , which is a sensitive marker for AFP-producing gastric cancer.72
TREATMENT STRATEGIES
Standard treatment has not been well established for GCLM. If no specific
treatment was given , the survival of patients with metastatic gastric cancer would be
extremely poor with an MST of 3-5 months.73 Palliative chemotherapy is primarily
used in these patients and the reported MST is approximately seven months.74
Hepatic resection has been widely accepted as a proper modality for treating
colorectal metastases. However, the benefits of gastrectomy and hepatic
metastasectomy for either the synchronous or metachronous GCLM are still a matter
of debate. Many other therapeutic options for treating GCLM have also been reported,
such as hepatic arterial infusion chemotherapy (HAIC), transcatheter arterial
chemoembolization(TACE) and thermal ablation, however, the efficacy and safety of
these treatments have not been fully evaluated. Therefore, there is still no widely
accepted indication or contraindication for each therapeutic options.
Palliative gastrectomy for synchronous GCLM
The rationale for offering palliative gastrectomy to GCLM patients is as follows:
(1)The potential life-threatening symptoms such as obstruction, perforation or
bleeding can be relieved by removing a bulky symptomatic tumor .(2) The removal of
the tumor load makes the residual tumor more responsive to adjuvant treatment.(3)
Volume and tumor burden reduction diminishes the metabolic demands made on the
patient by the tumor.(4) As tumor itself can produce immunosuppressive cytokine,
reducing the tumor burden may also have some immunologic benefits. 75-77
Several studies have shown that gastrectomy can prolong the survival in gastric
cancer with concomitant liver metastases, while others hold the opposite attitude.22, 69,
78, 79
Some reports have shown the survival benefits of gastrectomy for incurable
advanced gastric cancer. An MST of 8.0-16.3 months with gastrectomy was reported,
compared to 2.4-6.8 months without. 22, 75, 80 In addition, the survival benefit of
gastrectomy was obtained only in patients with a single non-curative factor.81 As a
result, for synchronous liver metastases patients with multiple metastatic sites (such
as peritoneal dissemination, lung metastases or ovary metastases, etc), palliative
gastrectomy may be of no survival benefits. For liver-only synchronous metastases
patients, gastrectomy might prolong the survival, especially if combined with
adjuvant therapy as part of multimodality treatment. 69, 82 Kwok et al. revealed that
gastrectomy might prolong the survival in patients with unilobar metastasis, but not in
those with bilobar diseases.69
Kim et al. reveal that palliative resections are not associated with an increased
postoperative mortality rate.83 Hartgrink et al. did not recommend palliative resection
for patients more than 70 years of age, because when morbidity, hospital stay, and
mortality are considered, no benefit existed for patients over the age of 70 undergoing
palliative resection.84 In patients with gross metastatic disease, potential benefits and
risks must be balanced before palliative resection is undertaken.
Palliative gastrectomy for synchronous GCLM might be associated with survival
advantage in selected group of patients. A multicenter, prospective, randomized trial
is being conducted in Japan and Korea to investigate the superiority of gastrectomy
followed by chemotherapy to chemotherapy alone in clinically stage IV advanced
gastric cancer with a single non-curable factor, in terms of survival benefit and safety
associated with gastrectomy or chemotherapy.85
Hepatic Metastasectomy
The vast majority of liver metastases from gastric cancer are multiple, bilobar,
and frequently combined with peritoneal or extensive lymph node metastases and
tumors in adjacent organs. Therefore, many patients with liver metastasis are not
suitable candidates for hepatic resection, even if only a solitary hepatic metastasis is
involved.
Selected patients accounting for 0.2%~37.9% of all cases with liver metastasis
can undergo hepatic resection, with the survival rates ranging from 15%–77%
survival at 1 year, 0%–42% survival at 5 years and an MST of 8.8-34 months. 6, 86
Previous studies showed that recurrence after hepatic resection for liver metastasis
from gastric cancer was 63.6-91% and that rates of recurrence in the remaining liver
were 47-76%.Therefore, the clinical benefit of resection for liver metastasis from
gastric cancer has not been widely accepted and remains controversial.
The long-term results after hepatic resection are disappointing, recurrence and
death rate are high within 2 years of surgery, however, long-term survivors after
hepatectomy do exist. 87Therefore, the determination of selection criteria for hepatic
resection is crucial and patients with appropriate risk factor status should be proposed
whenever possible.
The indications for hepatic resection for metastases have not been established.
The criteria for hepatic resection raised by Okano et al. are broadly defined: Hepatic
resection is indicated in patients (1) with synchronous metastases who have no
peritoneal dissemination or other distant metastases and (2) with metachronous
metastases, but no other recurrent lesion. Ambiru et al. added a third criterion, i.e.
complete resection of hepatic metastases with acceptable postoperative hepatic
function.88 A recent research from Japan revealed that in patients with H1and2
synchronous metastases without peritoneal dissemination who received surgical
treatment for primary and hepatic metastatic tumors, the cumulative 1- and 5-year
survival rates were 80.0% and 60.0%, which is dramatically enlongated in
comparison to previous reports. The high survival rates indicated an accurate patient
selection of H1and2 without peritoneal dissemination for hepatic surgical treatment
and confirmed that synchronous metastasis is not a contraindication for hepatectomy.8
The significant prognostic factors are mainly related to the following 4 aspects:
the condition of primary gastric cancer, number or distribution of liver metastases,
timing of the hepatectomy, and the surgical margin. Regarding the primary gastric
cancer, Tsujimoto et al. noted D2 lymphadenectomy of the primary gastric cancer
were the most important predictors of survival after hepatic resection.89 It has been
reported that serosal invasion4, 87, venous invasion5, 90, lymphatic invasion87, 90,tumor
diameter5, 89, lymph node metastasis90 and histological type 91 of the primary gastric
tumor are significant prognostic factors in patients undergoing hepatic resection for
liver metastasis. As for the aspect of liver metastases , it is reported that number 4, 6, 86,
90, 91
, distribution5, 21, 86 timing91 and tumor size 5 are significant prognostic factors.
The presence of fibrous pseudomenbrane is another factor of prognostic value.91
Whether surgical margin of hepatic metastases is a prognostic factor remains
controversial. Koga et. al, considered resection margins as an independent prognostic
factor for survival 4, however, Cheon et. al. reported that positive surgical margin did
not greatly affect patient survival negatively. 6 Anyway, positive surgical margins
should be avoided if possible .
The high incidence of intrahepatic recurrence may result from the occult
intrahepatic metastases even at the time of surgery.15A second hepatic resection is
rarely indicated, postoperative monitoring for the remaining liver and adjuvant
chemotherapy is a sensible strategy for improving survival.
As we mentioned above, complete surgical resection of the primary gastric
tumor and liver metastases is a promising treatment for this disease. The GYMSSA
trial is being conducted to compare gastrectomy, metastasectomy plus systemic
therapy versus systemic therapy alone. This trial will either help validate or reject the
notion based on retrospective data that aggressive surgical resections in combination
with systemic chemotherapy might improve outcomes in metastatic gastric cancer.
The inclusion criteria for liver metastases is unilateral or bilateral, ≤ 5 lesions and ≤
15 cm total diameter. 92 The feasibility of hepatic metastasectomy is expected to be
clarified in its subgroup analysis.
Ablative therapy
As most of the patients with GCLM are not candidates for resection, local
ablative therapies have emerged as a possible alternative or complement to resection.
Ablative techniques include radiofrequency thermal ablation (RFA), microwave
ablation( MWA) and cryoablation. Thermal ablative technologies are increasingly
being used either alone or in combination with resection to treat patients of liver
metastases. Cryoablation of the liver has largely fallen out of the favor because of
reported higher postoperative complications and worse local recurrence rates.93
RFA and MWA are effective and low risk treatment modalities in patients with liver
metastases, which both allow flexible treatment approaches, including percutaneous,
laparoscopic, or open surgical access, with convenient ultrasonographic or computed
tomographic guidance.94, 95 The procedure is safe with low mobility and can be
performed repeatedly on an outpatient basis with good palliative effect. Several
reports have show their experience of thermal ablative technologies in the treatment
of hepatocellular cancer or colorectal hepatic metastasis, however, only a few small
series have been reported on the experience of GCLM.
In 2010, Kim et al reported their retrospective experience of RFA versus
systemic chemotherapy of gastric cancer patients with liver-only metastases. Of the
29 patients in the study, 20 underwent gastric resection plus RFA and 9 underwent
gastric resection plus systemic chemotherapy. The RFA group showed an overall one-,
three- and five-year survival rates of 66.8%, 40.1% and 16.1% respectively, and an
MST of 30.7 months. Compared to systemic chemotherapy group, RFA group has a
76% decreased death rate, suggested that a use of RFA as a liver-directed treatment
may provide greater survival benefit than chemotherapy and is an alternative option
for the treatment of liver-only metastases from gastric cancer.96 A second RFA can
also be performed for recurrent liver metastasis from gastric cancer.97 The size and
number of the liver metastasis are the most important factors in determining whether
complete local ablation can be achieved.98
Lesions measuring less than 5cm in diameter have been reported to have 95.3%
chance of being destroyed, however, for tumors measuring greater than 5cm, the rate
for completely ablated decreased to less than 50%.99 For tumors measuring smaller
than 5cm, the number of tumors present is a significant prognostic factor for survival
rate; for those measuring larger than 5cm , it is the size rather than the number of the
liver metastasis is the most important factor.100
MWA offers many of the benefits of RFA and still has a number of advantages
over the current RFA systems, such as higher intratumoral temperatures, larger
ablation volumes, faster ablation times, no heat sink effect, less dependency on the
electrical conductivities of tissue and energy delivery less limited by the exponential
rising electrical impedances of tumor tissue.101, 102 Liang et al reported on their
10-year experience of MWA on 128 patients with 282 liver metastases nodules,
including 26 patients with the primary disease of non-colorectal gastrointestinal
cancer. The 5-year cumulative survival rates of all 128 patients were 31.89% .Tumor
size of liver metastases, primary tumor differentiation have been shown to correlate
with survival.103
Generally, the therapeutic results for most GCLM patients were disappointing
due to intrahepatic recurrences. The data on RFA or MWA on GCLM remains
somewhat limited. As thermal therapy continues to be adopted, additional prospective
data will be required to better define its safety and efficacy.
Transarterial therapy
Transarterial administration of anticancer drugs can be performed either alone as
hepatic arterial infusion (HAI), or combined with vascular occlusive agents
[transarterial chemoembolization (TACE) or bland vascular embolization (TAE).]
Transarterial therapy of liver matastases takes advantages of the first-pass effects of
cytotoxic agents, delivering higher local drug concentration to unresectable liver
tumors with fewer significant systemic side effects.104 It can be used for liver-only
metastases patients as an effective method of local control or be performed as a
neoadjuvant therapeutic regimen, aiming at lesion size reduction so that the lesion can
later be effectively ablated percutaneously or resected. Moreover, it can also be used
in combination with intravenous chemotherapy as a palliative measure in cases of
extrahepatic spread or post-surgical recurrence .
There have been few reports of transarterial intervention therapy for GCLM,
with the responding rates ranging from 62.5% to 83%, MST ranging from 16.5 to
36.1 months. 105-107 The development of extrahepatic lesions during HAI therapy
could be an important factor determining prognosis.106 Ojima et al reported that local
benefits to the liver could be obtained by performing HAI for a long period of time
for synchronous GCLM patients. The amount of 5-FU of 500 mg was an appropriate
quantity, with a response rate as high as 83%. However, HAI was not associated with
any improvement in the survival rate, which was conditional on the possibility of
gastrectomy.106Yamakado et al. reported a prospective study that evaluated the
efficacy of HAI followed by RFA for treatment of GCLM. After HAI in all patients,
RFA was performed for all residual liver tumors, resulting in complete tumor necrosis,
with an MST of 16.5 months.107
Transarterial administration of anticancer drugs combined with vascular
occlusive agents can achieve higher tissue drug concentrations which may elicit an
increased antitumor response. The vascular occlusive agents can be either temporary
[usually microspheres, degradable starch microspheres (DSM), collagen and gelatine
sponge (Gelfoam)] or permanent [polvinyl alcohol (Ivalon)]. Hirasawa et al. reported
the effects of transcatheter arterial chemoembolization(TACE) using DSM in GCLM
patients after prior systemic chemotherapy. Infusion of epirubicin hydrochloride
(40–70 mg/body) following arterial chemoembolization with DSM and mitomycin C
(4–12 mg/body) was administered. The response rate was 62.5% and the MST was
36.1 months. 105
Patients with a tumor burden of more than 75% of the liver from gastric cancer
may have limited benefits from TACE, due to the development of complications such
as liver abscess, infarction and tumor rupture. TACE is an effected treatment for
hypervascular metastases from gastric cancer, however, for hypovascular metastases,
TACE is not recommended. 108
Systemic chemotherapy
For the vast majority of patients with gastric cancer, liver involvement may
reflect generalized disease. Local control may not be sufficient, especially for those
with extra-hepatic metastases. Systemic chemotherapy apart from surgical resection
and local control is an appropriate option with the hope of prolonged survival.
However, the best chemotherapy regimen for metastatic gastric cancer is uncertain.
Recently, new chemotherapy regimens, including S-1, irinotecan, and taxanes, have
been investigated intensively. The Japan Clinical Oncology Group (JCOG) 9912 trial
demonstrated that S-1 is non-inferior to fluorouracil (hazard ratio, 0.83 [95%
confidence interval (CI), 0.68–1.01]), Irinotecan plus cisplatin is not superior to
fluorouracil (hazard ratio,0.85; 95% CI, 0.70–1.04). In subgroup analyses, the effect
of irinotecan plus cisplatin on progression-free survival and overall survival was
greater in patients with target lesions, such as lymph node metastases or liver
metastases, than in those without target lesions.109 The multicenter phase III study
(SPIRITS trial) verified that S-1 plus cisplatin holds promise of becoming a standard
first-line treatment for patients with advanced gastric cancer. The MST was
significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to
S-1 alone. However, in subgroup analyses, the effect of S-1 plus cisplatin on overall
survival was greater in patients without target tumors than in those with target tumors.
110
The multinational phase III study (FLAGS trial) demonstrated CDDP +S-1 was at
least noninferior to 5-FU +CDDP (hazard ratio, 0.92; 95% CI, 0.80–1.05) and
resulted in a significantly better safety profile than 5-FU +CDDP. Therefore, S-1
+CDDP is considered to be one of the standard regimens for advanced gastric cancer
based on these results.111 A phase II study of docetaxel and S-1 combination therapy
revealed that the response to docetaxel-S-1 was not affected by the type of organs
involved or the histologic tumor type. The highest overall response rates among the
metastatic sites were observed for patients in the subgroup of with liver metastases
(64.7%).112 The phase III study of docetaxel and S-1 versus S-1 (JACCRO GC-03) is
ongoing.113
A pilot study was undertaken to assess the effect of weekly docetaxel, cisplatin
and fluorouracil (DCF) as a preoperative treatment for gastric cancer with multiple
synchronous liver metastases. The response rate was 100% according to the RECIST
criteria. As the high response to weekly DCF, it should be verified through phase II
and III trials as an important part of the comprehensive treatment for GCLM.114 A
phase II study of S-1, docetaxel and cisplatin combination chemotherapy in patients
with unresectable metastatic gastric cancer revealed that DCS combination
chemotherapy is highly active against unresectable metastatic gastric cancer and can
be given safely with proper management of adverse events.25.8% patients achieved
downstaging, including liver metastases patients, who got the chance of gastrectomy
and RFA for liver metastases after 3 DCS courses. 115 The combination of CPT-11
plus S-1 is reported to achieve a high response rate (58%) for GCLM when a certain
regiment is employed. Kochi et al. reported that treatment with CPT-11 plus S-1
achieved higher response rate and significantly better survival than CDDP plus S-1
without severe toxicity in GCLM patients 116
Newer generation of cytotoxic agents have shown promising activity for patients
with metastatic gastric cancer. Further studies for their role as adjuvant and
neoadjuvant therapy are warranted.
CONCLUSIONS AND FUTURE PROSPECTS
Early detection and characterization of liver metastases is crucial for the
prognosis of gastric cancer patients. Improved understanding of related genes and
molecules such as VEGF family, HGF/met signal pathway, E-cadherin, etc. will
assist in the development of promising tumor marker for the early detection of
patients with high risk of liver metastasis. Moreover, it will also led to the
development of targeted therapies and perhaps can serve as a predictive marker for
chemosensitivity.
Each imaging modality has its relative benefits in the evaluation of GCLM:
Helical multidetector CT is widely available for larger lesions, whereas MRI has
superior performance versus helical CT in detection and characterization of small
liver metastases. US is frequently used as a guiding technology for percutaneous
lesion sampling and therapeutic interventions. PET-CT is superior in the detection of
extrahepatic disease versus other modalities. CEUS is a non-invasive and promising
tool in detecting liver metastases as well as in the guidance and evaluation of
response of therapeutic procedures.
Palliative gastrectomy and hepatic metastasectomy for GCLM patients is
reasonable，however, the indication for this protocol must be strictly selected. The
optimal treatment strategies should be tailored according to the clinicopathological
characteristics of each patient. Therefore, multidisciplinary team discussions are
required to evaluate the extent of the disease , the feasibilities and benefits of each
treatment modalities. Results from prospective studies or a detailed meta-analysis will
be necessary to select patients who will have the greatest benefits from each treatment
strategies.
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