Liver Metastasis Of Gastric Cancer Research Articles

Surgical treatment of gastric cancer liver metastasis: Focus on controversy

Surgical treatment of gastric cancer liver metastasis: Focus on controversy

208P Neoadjuvant capecitabine plus paclitaxel in gastric cancer patients with liver metastasis: an open-label, uncontrolled, prospective phase II clinical study

Aim/Background: There is no standard treatment strategy for liver metastases of gastric cancer in NCCN guideline and results of neoadjuvant chemotherapy from several previous studies are controversial. This study is to determine the overall survival, radical resection rate, objective response rate and safety of neoadjuvant capecitabine plus paclitaxel in gastric cancer patients with liver metastasis. Methods: Patients diagnosed as gastric adenocarcinoma with liver metastasis were enrolled. Patients were treated with three cycles of capecitabine (1000mg/m2 PO, bid on day 1 to day 14) plus paclitaxel (80mg/m2IV on day1 and day 8 every three weeks) followed by radical resection. Primary endpoint was overall survival (OS) and secondary endpoints were radical resection rate, objective response rate (ORR), time to progression (TTP), and safety. All patients were evaluated every six weeks during chemotherapy. Radical resection was performed four to six weeks after termination of neoadjuvant chemotherapy. Results: 30 patients were eligible for the study, and the median age was 59.5 years (range, 44 to 76 years). 23 patients died after follow-up of 2 years. The median OS was 11.4 months (95% CI: 9.0 ∼ 15.3), whereas it was 13.9 months (95% CI: 4.8 to not estimated) in surgery group and 10.1 months (95% CI: 5.7 to 14.8) in non-surgery group, respectively. The ORR was 53.3% (complete response, 0%; partial response, 53.3%), and the radical resection rate was 23.3% (95% Clopper-Pearson CI: 9.9 ∼ 42.3). ORR of neoadjuvant therapy was a significant independent factor associated with overall survival (hazard ratio: 0.363, 95% CI: 0.140 ∼ 0.943; p = 0.0374). The median TTP was 6.1 months (95% CI: 4.8 ∼ 11.0), while chemotherapy cycles was significantly associated with TTP (HR = 2.770, 95% CI: 1.043 ∼ 7.355; p = 0.0409). Based on criterion of CTCAE 3.0, only 5 patients (16.7%) reported grade 3 adverse events and no grade 4/5 adverse event was reported. Conclusions: Neoadjuvant capecitabine plus paclitaxel is effective and safe to improve the overall survival and resection rate of gastric cancer patients with liver metastasis. Clinical trial identification: NCT 01167049 Disclosure: All authors have declared no conflicts of interest.

Surgical treatment of liver metastasis of gastric cancer: a retrospective multicenter cohort study (KSCC1302).

The necessity of surgical treatment of liver metastases of gastric cancer is still controversial. We conducted a multicenter retrospective cohort study of liver-limited metastasis of gastric cancer treated surgically between 2000 and 2010. In this study, 103 patients were registered, with nine patients excluded from the analysis as they did not meet the eligibility criteria. Of the 94 patients, 69 underwent surgical resection, 11 underwent surgical resection combined with radiofrequency ablation or microwave coagulation therapy for small or deep tumors, and 14 underwent radiofrequency ablation or microwave coagulation therapy only. Synchronous and metachronous metastases were found in 37 and 57 patients, respectively. The 3- and 5-year overall survival rates of all the patients were 51.4 and 42.3%, respectively. The 3- and 5-year relapse-free survival rates were 29.2 and 27.7%, respectively. No significant difference in prognosis was observed between the patients who underwent surgical resection and those who underwent ablation therapy. The patients with hepatic solitary lesions and low-grade lymph node metastases of primary gastric cancer had significantly better overall survival and relapse-free survival. To our knowledge, this study is the largest series and first multicenter cohort study of liver-limited metastasis of gastric cancer. The study indicated that patients with a single liver metastasis with a grade lower than N2 lymph node metastasis of the primary lesion are the best candidates for liver resection.

Influence of the TNF-α gene polymorphism - 308 G/A in the development of chronic gastritis and gastric cancer.

Influence of the TNF-α gene polymorphism - 308 G/A in the development of chronic gastritis and gastric cancer.

Multidisciplinary treatment of liver metastases of gastric cancer

Multidisciplinary treatment of liver metastases of gastric cancer

Liver Metastasis of Early Gastric Cancer with Mixed Histology after Endoscopic Submucosal Dissection.

The Japanese Classification of Gastric Carcinoma histologically classifies endoscopically resected gastric cancer into differentiated and undifferentiated types according to the presence or absence of tubular structures on histology. The former includes papillary adenocarcinoma and tubular types, and the latter includes poorly differentiated adenocarcinoma, signet ring cell carcinoma and mucinous adenocarcinoma. However, gastric cancer sometimes contains a mixture of differentiated and undifferentiated components, and the clinical outcomes of the histological mixture are unknown, especially following endoscopic resection of early gastric cancer (EGC). This case was within the guideline indications for endoscopic submucosal resection (ESD), although it contained a partly signet ring cell carcinoma component; it recurred after 19 months with multiple lymph node and liver metastases. This case shows that additional surgical resection after ESD should be performed for patients with any mixed signet ring cell component, even in mild or moderately differentiated EGC.

Multicentre analysis of long-term outcome after surgical resection for gastric cancer liver metastases.

The efficacy of surgical resection for gastric cancer liver metastases (GCLMs) is currently debated. Hitherto, no large-scale clinical studies have been conducted. This retrospective multicentre study analysed a database of consecutive patients with either synchronous or metachronous metastases who underwent surgical R0 resection for GCLM between 1990 and 2010. Clinical data were collected from five cancer centres in Japan. Survival curves were assessed, and clinical parameters were evaluated to identify predictors of prognosis. A total of 256 patients were enrolled. The mean(s.d.) number of hepatic tumours resected was 2.0(2.4). The surgical mortality rate was 1.6 per cent. Median follow-up was 65 (range 1-261) months. Recurrences were detected in 192 patients (75.0 per cent). The median interval from hepatic resection to recurrence was 7 (range 1-72) months, and the dominant site of recurrence was the liver (72.4 per cent). Actuarial 1-, 3- and 5-year overall and recurrence-free survival rates were 77.3, 41.9 and 31.1 per cent, and 43.6, 32.4 and 30.1 per cent, respectively. Median overall and recurrence-free survival times were 31.1 and 9.4 months respectively. Multivariable analysis identified serosal invasion of the primary gastric cancer (hazard ratio (HR) 1.50; P = 0.012), three or more liver metastases (HR 2.33; P < 0.001) and liver tumour diameter at least 5 cm (HR 1.62; P = 0.005) as independent predictors of poor survival. Clinically resectable GCLM is rare, but strict and careful patient selection can lead to long-term survival following R0 surgical resection.

Treatment results of synchronous liver metastases of gastric cancer and colon

Treatment results of synchronous liver metastases of gastric cancer and colon

Y-box binding protein 1 expression in gastric cancer subtypes and association with cancer neovasculature.

Y-box binding protein 1 (YB-1) expression in cancer cells is closely associated with malignant progression and poor prognosis in various cancers. Recently, we demonstrated that YB-1 expression in cancer cells is an immunomarker for patient prognosis and liver metastasis of gastric cancer (GC), and identified YB-1 as an excellent biomarker of angiogenic and proliferating endothelial cells in cancers. We further explored the expression patterns of YB-1 in gastric vasculature and the relationship with the clinical pathologic characteristics, as well as YB-1 phenotype in cancer cells. Immunohistochemical analysis of YB-1 was performed using 163 surgically resected primary GC specimens. YB-1 expression in cancer cells significantly differed with respect to Lauren type, JGCA classification, vascular invasion (VI), and microvessel density (MVD) of cancers (P = 0.018, P = 0.002, P < 0.001, and P < 0.001, respectively). No correlation was found between cancer-cell YB-1 expression and TNM stage or lymphatic invasion. However, YB-1 expression in vascular endothelial cells significantly correlated with N stage, M stage, TNM stage, and MVD of cancers (P < 0.001, P = 0.013, P < 0.001, and P < 0.001, respectively). Notably, cases with YB-1 expression in cancer vasculature also demonstrated YB-1 expression in cancer cells (P = 0.040). YB-1 may promote GC development through its function in both cancer cells and cancer vascular cells, and thus represent a potential biomarker in this disease.

High survival in patients operated for small isolated liver metastases from gastric cancer: a multi-institutional study.

Although several studies have reported the outcomes of surgery for the treatment of liver metastases of gastric cancer (GLM), indications for liver resection for gastric metastases remain controversial. This study was designed to identify prognostic determinants that identify operable hepatic metastases from gastric cancer and to evaluate the actual targets of surgical therapy. Retrospective analysis was performed on outcomes for 24 consecutive patients at five institutions who underwent gastrectomy for gastric cancer followed by curative hepatectomy for GLM between 2000 and June 2012. Overall 5-year survival and median survival were 40.1 % and 22.3 months, respectively. Uni- and multivariate analyses showed that liver metastatic tumour size less than 5 cm was the most important predictor of overall survival (OS, p = 0.03). Four patients survived >5 years. Repeat hepatectomy was performed in three patients. Two of these patients have remained disease-free since the repeat hepatectomy. GLM patients with metastatic tumour diameter less than 5 cm maximum are the best candidates for hepatectomy. Hepatic resection should be considered as an option for gastric cancer patients with liver metastases.

Purification of a Pd20-TNFα fusion protein that prevents liver metastasis of gastric cancer.

The specific binding peptide pd20 of gastric cancer cells with a high potential for liver metastasis was fused with human tumour necrosis factor (TNF) α, and a prokaryotic expression vector was established to express the pd20-TNFα fusion protein. After purification and identification, the preventive effects of the fusion protein on liver metastasis of gastric cancer were observed in mice. The whole gene synthesis method was used for pd20-TNFα fusion gene preparation, and a pd20-TNFα prokaryotic expression vector was constructed. The vector was induced and expressed in Escherichia coli BL21. The expression products were analysed and verified by SDS-PAGE electrophoresis and Western blot analysis. The Ni-NTA column method was used to purify the fusion protein, and the L929 cytotoxicity method was used to detect biological activity. Flow cytometry apoptosis experiments and invasion assays were performed to observe the effects of the fusion protein on apoptosis and metastasis of gastric cancer cells with high potential for liver metastasis. Thirty nude mice with liver metastasis of gastric cancer were established and then randomly divided into three groups of ten mice each. The Pd20-TNFα recombinant protein (1.2 × 10(6) U/kg day) or standard TNFα (1.2 × 10(6) U/kg day) saline was administered via tail vein injection for 7 consecutive days. The pathological changes in various organs of nude mice were observed 4 weeks later. The size of the gastric cancer, the incidence of liver metastasis and the number of liver metastases were measured and calculated. We successfully constructed a Pd20-TNFα recombinant plasmid and prepared the fusion protein. Detection of the pd20-TNFα protein by immunofluorescence showed a very strong expression in liver tissue, suggesting a targeting of the fusion protein to the liver. The L929 cytotoxicity assays showed that the pd20-TNFα fusion purified protein had a significant lethal effect on L929 cells, with a killing activity of up to 7.6 × 10(6) IU/ml. The apoptosis experiments showed that as the concentration of the fusion protein increased, the early gastric cancer cell apoptosis also increased, with the early apoptosis rate increasing from 5.99 % to 9.04 %. Cell invasion experiments showed that the purified pd20-TNFα fusion protein significantly inhibited the in vitro invasion of XGC9811-L cells, with the penetrating cells being significantly decreased compared with the control group per unit time (P < 0.01). Vector experiments showed that the pd20-TNFα recombinant protein group had significantly reduced cancer lesions and liver metastasis in nude mice compared with the control group. We successfully purified a pd20-TNFα fusion protein and confirmed that it had significant biological activity promoting early gastric cancer cell apoptosis, thereby inhibiting gastric cancer cell invasion.

Risk factors in metachronous liver metastasis from gastric cancer

To explore the clinicopathological characteristics and related risk factors in metachronous liver metastasis of gastric cancer. Clinical data of 115 patients with metachronous liver metastasis in Tianjin Medical University Cancer Institute and Hospital between 1996 and 2008 were analyzed retrospectively. Among 115 patients, the 1-, 3- and 5-year non-hepatic metastasis rates were 45.3%, 14.8% and 3.5% respectively. Univariate Log-rank test indicated that location, tumor size, tumor differentiation, depth of invasion, lymph node metastasis, vascular invasion, nervous invasion, soft tissue invasion, and modes of gastrectomy were significant factors associated with hepatic metastasis after radical gastrectomy. On multivariate analysis, the size of gastric cancer, vascular invasion, tumor differentiation, and lymph node metastasis were independent factors associated with metachronous liver metastasis of gastric cancer. The size of gastric cancer, vascular invasion, tumor differentiation and lymph node metastasis are important factors associated with the risk of hepatic metastasis from gastric cancer in patients after radical gastrectomy.

Tumor-Reactive CD8+ T Cells in Metastatic Gastrointestinal Cancer Refractory to Chemotherapy

To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive cytotoxic T cells. Expansion of CD8(+) tumor-infiltrating lymphocytes (TIL) and cancer cell lines was attempted from gastrointestinal cancer metastases in 16 consecutive patients for the study of antitumor immune recognition. Retroviral transduction of genes encoding T-cell receptors (TCR) was used to define HLA-restriction elements and specific reactivity. TIL were expanded from metastases in all patients, and new tumor cell lines were generated in 5 patients. Autologous tumor recognition without cross-reactivity against allogeneic HLA-matched gastrointestinal tumors was found in CD8(+) TIL from 3 of these 5 patients. In a patient with gastric cancer liver metastases, the repertoire of CD8(+) TIL was dominated by cytolytic sister clones reactive to 2 out of 4 autologous cancer cell lines restricted by HLA-C*0701. From the same patient, a rare CD8(+) TIL clone with a distinct TCR recognized all four cancer cell lines restricted by HLA-B*4901. In a patient with bile duct cancer, two distinct antitumor cytolytic clones were isolated from a highly polyclonal CD8(+) TIL repertoire. TCRs isolated from these clones recognized epitopes restricted by HLA-A*0201. In a third patient, CD8(+) TIL reactivity was progressively lost against an autologous colon cancer cell line that displayed loss of HLA haplotype. This study provides a basis for the development of immunotherapy for patients with advanced gastrointestinal malignancies by first establishing the presence of naturally occurring tumor-reactive CD8(+) TIL at the molecular level.

Lower serum folate is associated with development and invasiveness of gastric cancer.

To evaluate the associations of serum folate level with development, invasiveness and patient survival of gastric cancer. In this nested case-control study, patients with newly diagnosed gastric cancer undergoing gastrectomy were enrolled, and patients receiving chemotherapy prior to surgery, with other concurrent malignancy, or of the aboriginal and alien populations were excluded. In total, 155 gastric cancer patients and 149 healthy controls were enrolled for determination of serum folate levels and their correlation with gastric cancer. Using the median value of serum folate computed among the overall population as the cutoff value, the associations between serum folate and gastric cancer in all cases and different age and gender subgroups were analyzed by multivariate logistic regression analysis. In the patient cohort of gastric cancer, receiver-operating characteristic analyses were performed to calculate the best cutoff values of serum folate, and the associations between serum folate levels and clinicopathological features were further analyzed by multivariate regression analysis. Survival analyses were conducted using the Cox proportional hazards model. The mean serum folate level was significantly lower in gastric cancer patients than that in controls (3.71 ± 0.30 ng/mL vs 8.00 ± 0.54 ng/mL, P < 0.01), and folate levels were consistently lower in gastric cancer patients regardless of age and gender (all P < 0.01). Using the median serum folate value as the cutoff value, low serum folate was significantly associated with gastric cancer risk in the whole population (OR = 19.77, 95%CI: 10.54-37.06, P < 0.001) and all strata (age < 60 years OR = 17.39, 95%CI: 7.28-41.54, age ≥ 60 years (OR = 21.67, 95%CI: 8.27-56.80), males (OR = 17.95, 95%CI: 7.93-40.62), and females (OR = 20.95, 95%CI: 7.66-57.31); all P < 0.001. In the patient cohort of gastric cancer, the respective cutoff values showed that low serum folate levels were significantly associated with serosal invasion (OR = 2.54, 95%CI: 1.23-5.23), lymphatic invasion (OR = 2.23, 95%CI: 1.17-4.26), and liver metastasis (OR = 6.67, 95%CI: 1.28-34.91) of gastric cancer (all P < 0.05). Serum folate level below 1.90 ng/mL was associated with poor patient survival (HR = 1.84, 95%CI: 1.04-3.27, P < 0.05) in univariate analysis. Lower serum folate levels were significantly associated with gastric cancer development and invasive phenotypes. The role of folate depletion in gastric cancer invasion warrants further study.

Combination of percutaneous radiofrequency ablation and systemic chemotherapy are effective treatment modalities for metachronous liver metastases from gastric cancer

This study evaluated the efficacy of percutaneous radiofrequency ablation (RFA) for the treatment of metachronous liver metastases of gastric cancer. We enrolled a total of 44 patients who underwent percutaneous RFA for the treatment of metachronous liver metastases after resection of a primary gastric adenocarcinoma from January 2002 to November 2011. The primary endpoint of this study was overall survival (OS) and recurrence-free survival (RFS) after RFA. Systemic chemotherapy was combined with RFA in 40 patients; the OS and RFS of the patients with liver-only metastasis who underwent RFA and chemotherapy were 20.9 months (95 % CI 18.4–23.4) and 9.8 months (95 % CI 9.2–10.5), respectively. On multivariate analysis, the factors independently, negatively associated with OS were extrahepatic metastatic lesions (HR 12.6, 95 % CI 3.7–42.9; p = 0.001), no chemotherapy (HR 43.3, 95 % CI 7.4–251.3; p = 0.001), and tumor number ≥2 (HR 2.6, 95 % CI 1.2–5.9; p = 0.015). The factors independently, negatively associated with RFS were extrahepatic metastatic lesions (HR 3.6, 95 % CI 1.6–7.8; p = 0.003) and bilobar intrahepatic distribution (HR 3.9, 95 % CI 1.5–9.9; p = 0.001). The efficacy of percutaneous RFA for metachronous liver metastases of gastric cancer is limited to patients with a single, unilobar metastasis without extrahepatic metastatic lesions. Combined systemic chemotherapy is very important for the prolongation of OS.

Repeat Hepatectomy for Recurrent Liver Metastasis From Gastric Carcinoma

The efficacy of repeat hepatectomy for recurrent hepatocellular carcinoma and colorectal liver metastases is widely accepted. However, the benefits of such treatment for intrahepatic recurrence of gastric cancer liver metastasis remain unknown. This study sought to clarify the survival benefit for patients undergoing repeat hepatectomy for gastric cancer liver metastasis. A total of 73 patients underwent hepatectomy for gastric cancer liver metastasis from January 1993 to January 2011. Macroscopically curative surgery was performed in 64 patients. Among them, repeat hepatectomy was performed in 14 of the 37 patients with intrahepatic recurrence. Among these 14 patients, clinicopathologic factors were evaluated by univariate and multivariate analysis to identify the factors affecting survival. The overall 1-, 3-, and 5-year survival rates after a second hepatectomy were 71, 47, and 47 %, respectively. The median survival was 31 months. Operative morbidity and mortality rates of repeat hepatectomy were 29 and 0 %, respectively. Multivariate analysis identified the duration of the disease-free interval as the only independent significant factor predicting better survival. In selected patients, repeat hepatectomy for recurrent gastric cancer liver metastasis may offer the same chance of cure as the primary hepatectomy. Disease-free intervals exceeding 12 months predict good patient survival after repeat hepatectomy.

Effectiveness of percutaneous radiofrequency ablation for metachronous liver metastases of gastric cancer.

136 Background: This study evaluated the efficacy of percutaneous radiofrequency ablation (RFA) for the treatment of metachronous liver metastases of gastric cancer. Methods: We enrolled a total of 44 patients who underwent RFA for the treatment of metachronous liver metastases after resection of a primary gastric adenocarcinoma from January 2002 to November 2011. The primary endpoint of this study was overall survival (OS) and recurrence-free survival (RFS) after RFA. Results: Systemic chemotherapy was combined with RFA in 40 patients.The OS and RFS after RFA for all patients were 14.7 (95% CI, 10.1-19.2) and 6.1 months (95%, CI 4.2-8.1). the OS and RFS of the patients with liver-only metastasis who underwent RFA and chemotherapy were 20.9 months (95% CI 18.4-23.4) and 9.8 months (95% CI 9.2-10.5), respectively. On multivariate analysis, the factors independently, negatively associated with RFS were bilobar intrahepatic distribution (HR 3.9, 95% CI 1.5-9.9, p=0.001), and extrahepatic metastatic lesions (HR 3.6, 95% CI 1.6-7.8, p=0.003). The factors independently, negatively associated with OS were extrahepatic metastatic lesions (HR 12.6, 95% CI 3.7-42.9, p=0.001), no chemotherapy (HR 43.3, 95% CI 7.4-251.3, p=0.001), and tumor number (≥ 2) (HR 2.6, 95% CI 1.2-5.9, p=0.015). Conclusions: The efficacy of RFA for metachronous liver metastases of gastric cancer is limited to patients with a single, unilobar metastasis without extrahepatic metastatic lesions. Combined systemic chemotherapy is very important for the prolongation of overall survival.

Surgical Treatment of Liver Metastases from Gastric Cancer

Background: Hepatectomy for gastric metastases remains controversial. We aimed at assessing the surgical results, clinicopathological features of gastric cancer liver metastases (GCLM) and prognostic factors. Methods: The outcome of 28 consecutive patients with synchronous (n = 24) or metachronous (n = 4) GCLM was retrospectively analyzed. Curatively, initial hepatectomies such as segmentectomy and hemihepatectomy or non-anatomical limited liver resection less extensive than segmentectomy followed complete primary gastric cancer (GC) resections. Results: Median survival time was 16 months (range, 5 - 66 months). The actuarial overall 12-, 36-, and 60-month survival rates after hepatectomy were 67.8% (n = 19), 39.2% (n = 11), and 28.5% (n = 8), respectively. In multivariate analysis, absent GC serosal invasion-hazard ratio (HR) 1; 95% confidence interval (CI) 1.2 - 9.9; P = 0.020; solitary LM-HR 1; 95% CI 1.6 - 16.0; P = 0.005, and curative liver resection with negative resection margin (R0)-HR 1, 95% CI 2.2 - 18.0; P = 0.001 were independent prognostic factors. Conclusions: Surgery of GCLM is a good indication in well-selected patients with an absent serosal invasion of primary tumour, single GCLM and attainment of R0 liver resection. For most GCLM patients, however, there are no other therapeutic modalities. Thus systemic chemotherapy remains the best hope for a longer patient’s survival and an improved individual quality of life.

胃癌肝転移に対する肝切除成績の検討

胃癌肝転移に対する肝切除成績の検討

An isolate alpha-fetoprotein producing gastric cancer liver metastasis emerged in a patient previously affected by radiation induced liver disease

We report a case of an isolated hepatic neoplasia which originated in a site of the liver previously affected by radiation induced liver disease (RILD) in a patient resected for gastric cancer and referred to us for high serum alpha-fetoprotein (AFP) levels. This case challenged us in distiguishing, even histologically, between primary liver cancer and AFP producing gastric cancer metastasis. Only a panel of immunohistochemical markers allowed the definitive diagnosis of liver metastasis of endodermal stem cell-derived and AFP producing gastric cancer. We discuss the criteria for a differential diagnosis, as well as the possible link between RILD and emergence of liver neoplasia.