Surgical resection for hepatic metastasis from gastric cancer: a multi- institution study

Background The beneficial effect of surgical resection for hepatic metastasis from gastric cancer (HMGC) remains elusive. This study was conducted to analyze surgical outcomes of HMGC and determine the prognostic factors associated with survival. Results The in-hospital mortality rate was zero, and the overall morbidity rate was 56%. The overall 1-, 3-, and 5-year survival rate after surgery was 87.5%, 47.6%, and 21.7%, respectively, with a median survival time of 34.0 months. Multiple liver metastases (hazard ratio [HR] =1.998; 95% confidence interval [CI] = 1.248-3.198; P = 0.004) and ≥ T3 stage of the primary gastric cancer (HR = 2.065; 95% CI = 1.201–3.549; P = 0.009) were independent prognostic determinants in the multivariate analysis. Materials and Methods Data on surgical resection of 96 patients with HMGC at six institutions in China were analysed retrospectively. Prognostic factors were assessed by multiple stepwise regression analysis using the Cox model. Conclusions Surgical resection for HMGC is feasible and beneficial to long-term survival in selected patients.


INTRODUCTION
It was reported that about 14% gastric cancer patients developed hepatic metastasis, and more than 30% gastric cancer patients developed metachronous liver metastasis after surgical resection of the primary gastric cancer [1]. Although previous studies  reported that hepatectomy may provide an opportunity of long-term survival in these patients ( Table 1), most of these studies were conducted on the single-institution basis including no more than 50 cases, and therefore the beneficial effect of hepatectomy are not well-defined. The objective of this study was to analyze the outcome of surgical resection of hepatic metastasis from gastric cancer (HMGC) and determine prognostic factors associated with survival in a relatively large multi-institution cohort of patients.
The 1-, 3-and 5-year overall survival (OS) rate of the entire cohort of patients after surgery was 87.5%, 47.6% and 21.7%, respectively, with a median survival time of 34.0 months ( Figure 1). Several factors were found to be associated with poor prognosis in univariate analysis (

DISCUSSION
Although solid clinical evidence exists to support surgical resection as the optimal option for the treatment of colorectal liver metastasis (CLM), data evaluating the postoperative outcome of HMGC are limited and controversial (Table 1). This may be explained by the fact that most patients with HMGC presented with multiple lobar metastases, gross peritoneal dissemination, extensive lymph node metastases, distant metastasis, or direct invasion to other organs at time of diagnosis, and therefore were considered unamenable to surgery [5]. It was reported that patients with potentially resectable HMGC treated with systemic chemotherapy had a median survival of 5.5 months, and the number of 3-year survivors was zero [23]. A systematic review of 870 patients from 23 studies performed by Petrelli and colleagues in 2015 demonstrated that resection of HMGC was associated with a 22-month median survival and a 23.8% 5-year OS rate [33]. A similar systematic review was published by Markar et al in 2016, which included 991 patients and come to similar conclusions, with a median 5-year OS of 27% [34]. In accordance with these two reports, the present study also confirmed the benefit of surgical resection for HMGC in achieving longterm survival in a relatively large cohort of patients drawn from multi-centers in China. The 5-year OS rate after surgery was 21.7% with a median survival time of 34.0 months.
Safety is an important concern in such an aggressive management strategy. Hepatic resection of metachronous liver disease is technically demanding because of intraabdominal adhesions caused by previous surgery. Synchronous resection of the HMGC and primary tumor may be associated with increased post-operative complications. However, in the present study and previous reports, resection could be safely performed with acceptable operative mortality and morbidity [19][20][21][22][23][24][25][26][27][28]. It should be noted that this favourable outcome may be attributed to careful selection of patients with limited disease, as reflected by major hepatectomy is not performed frequently [27]. In addition, patients with HMGC usually had no underlying cirrhosis, a factor associated with a high risk of postoperative liver failure because of the limited regenerative capacity of the liver remnant.
Multivariate analysis in our series disclosed that multiple liver metastases and ≥ T3 stage of the primary gastric cancer were independent prognostic determinants. These data may have important implications in helping select patients for surgical resection. There is evidence that postoperative complications, especially major complications, have a negative impact on long-term survival after oncological surgery [35]. Immunosuppression secondary to septic complications may increase the growth of occult micrometastasis, and some complications may make patients unfit for adjuvant therapy or delay the time interval. However, we did not find that OS was significantly reduced in patients with complications in our study. The fact that there were only Oncotarget 71151 www.impactjournals.com/oncotarget 11.4% of patients with major complications in current study, it is possible that failure to detect a clinically significant difference represents a type-II error.
Percutaneous radiofrequency ablation (RFA) is generally accepted as a safe, effective and minimally invasive treatment for patients with CLM [36]. However, few studies have focused on RFA for HMGC. RFA may contribute to local control of single liver-only metastatic lesions [37]. No reliable data on the comparative therapeutic efficacy of RFA and hepatic resection for resectable HMGC are available at present, and therefore RFA should not be recommended as an alternative to surgical resection at this disease stage.
Recurrence following surgical resection of HMGC is common and mostly occurs in the remaining liver tissue. Repeat hepatectomy seems beneficial to patients with solitary intrahepatic recurrence [25,27]. Unfortunately, very few patients are potential candidates for hepatic resection because of extensive metastases [27].
The efficacy of adjuvant chemotherapy after liver resection of HMGC remains unclear. Qiu et al. [24] reported that patients who received adjuvant chemotherapy had significantly better survival. However, our and other studies [9,25,27] were unable to confirm their conclusion. These different findings may be explained by differences in the regimens used, the timing and duration of cytotoxic agent administration, and patient selection between these studies. Unlike CLM, it seems impossible to test the clinical significance of adjuvant chemotherapy for HMGC in a prospective manner because of the rarity of candidates [27].
The study has some limitations, including the retrospective nature and possible bias in patient selection. More data are needed to further verify the conclusion of the present study.
In conclusion, this large-cohort study has demonstrated that surgical resection for HMGC is feasible and beneficial to long-term survival in selected patients.

Patients
Included in this study were 96 patients who underwent surgical resection for HMGC between January 2001 and January 2012 in six medical institutions in China. The study was approved by the ethics committee of each contributing institution. Written informed consent forms were not required from the patients due to the retrospective approach of the study. In general, surgical resection of HMGC followed the following criteria: (1) curative resection (microscopic tumor removal based on the histopathologic evaluation) of the primary tumor and liver metastasis thought to be technically accessible; and (2) no sign of concomitant extrahepatic metastasis on preoperative imaging. Data were collected retrospectively by reviewing the medical records, including patient age and sex at hepatic resection; pathological characteristics of the primary gastric cancer and hepatic metastasis; and short-and long-term outcomes after surgery. Postoperative mortality was defined as any death occurring within 30 days of surgery or within the same hospital stay. Postoperative complications were defined as occurrence of any medical or surgical complication during the hospital stay and graded according to the Clavien-Dindo classification [38]. The primary tumor stage and regional lymph node status were classified according to the 7th edition of the International Union Against Cancer of gastric cancer [39]. The types of hepatectomy were classified in accordance with the Brisbane 2000 nomenclature [40].

Statistical analysis
Overall survival was determined by Kaplan-Meier analysis. Factors related to survival selected by univariate analysis with P < 0.05 were entered into a multivariate analysis using Cox proportional hazard regression model to determine the independent risk factors for survival. All statistical analyses were performed using SPSS for Windows (version 11.0; SPSS Institute, Chicago, IL, USA). P < 0.05 was considered statistically significant.