Chinese consensus on the diagnosis and treatment of gastric cancer with liver metastases

Abstract

Background:

The incidence of gastric cancer with liver metastases (GCLM) is 9.9–18.7%, with a median survival time of 11 months and a 5-year survival rate <20%. Multidisciplinary treatment (MDT) is gradually gaining recognition as the most important method. However, specific treatment plans remain unclear. The aim of study was to provide a consensus to improve the diagnosis and treatment of GCLM.

Methods:

We brought together experts from relevant medical fields across China, including the Chinese Research Hospital Association Digestive Tumor Committee, Chinese Association of Upper Gastrointestinal Surgeons, Chinese Gastric Cancer Association, and the Gastrointestinal Surgical Group of Chinese Surgical Society Affiliated to Chinese Medical Association, to discuss and formulate this consensus.

Results:

A consensus was reached on the diagnosis and treatment of GCLM. Moreover, we have developed a new clinical classification system, the Chinese Type for Gastric Cancer Liver Metastases, based on the likelihood of a surgical treatment being successful.

Conclusions:

The MDT mode should be implemented throughout all treatment of GCLM.

A Chinese version of this expert consensus has been published in the Chinese Journal of Practical Surgery (Volume 39, Issue 10, p. 405-411). Written permission was obtained from the Chinese Journal of Practical Surgery to disseminate the expert consensus in English.

Keywords

Chinese consensus gastric cancer liver metastases

Introduction

Gastric cancer (GC) is highly heterogeneous and has a high degree of malignancy. Hematogenous dissemination is one of the main ways in which gastric tumor cells spread; the liver is the organ most frequently involved.¹ The incidence of GC with liver metastases (GCLM) is 9.9–18.7%.^2,3 The incidence of synchronous GCLM is 73.3%, and that of metachronous GCLM is 26.7%.⁴ The median liver metastases-free interval for patients with metachronous GCLM is 14 months, with a median survival time of 11 months and a 5-year survival rate <20%.⁵ Excision of primary tumors and liver metastases can increase the 5-year survival rate to 23.8%.⁶

Modern technologies and new approaches to treatment provide more options for GCLM patients. Multidisciplinary treatment (MDT), where experts from different medical fields are involved in patient care, is gradually gaining recognition as the most important method. However, specific treatment plans remain unclear. In an effort to develop guidelines aiming to improve the diagnosis and treatment of GCLM, we brought together experts from relevant medical fields across China to discuss and formulate this consensus. Recommendation of ‘high’, ‘medium’ and ‘low’ indicated a favorable voting rate of at least 90%, 75–90%, and less than 75%, respectively.

Pathological characteristics and diagnosis

The pathological types of gastric primary tumors and liver metastases are usually the same. Most gastric primary tumors and liver metastases tend to be adenocarcinomas. According to the Lauren classification, adenocarcinomas can be classified as diffuse, intestinal, or mixed types.⁷ Additional rare types include adenosquamous carcinoma, medullary carcinoma, hepatoid adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. In addition to the pathological characteristics of the gastric primary tumor, the number and size of liver metastases also affect the prognosis.⁸ Synchronous liver metastases were defined as cases in which detection occurs before or during surgery, or within 6 months after primary tumor resection. Liver metastases occurring more than 6 months after primary tumor resection were classified as metachronous.⁹

Imaging examinations

Magnetic resonance imaging (MRI) and contrast-enhanced ultrasonography (CEUS) are necessary for the diagnosis of liver metastases in GC. The use of liver-specific contrast agent increases the likelihood of detection of even small liver metastases.^10–14 MRI can show the exact size, number, and position of the lesions, as well as the adjacent structures; however, intraoperative ultrasound is indispensable for detection of metastases that cannot be seen preoperatively.¹⁵ In addition, positron emission tomography (PET) can show the patient’s general condition, and, if present, the extrahepatic metastases, both of which are of great significance in the evaluation of cancer severity preoperatively and postoperatively.¹⁶ In addition, early metabolic changes on 18F-fluorodeoxyglucose (FDG) PET have been shown as a possible predictive marker for therapeutic response in advanced GC.¹⁷ Specifically, early changes in the FDG-uptake rate in liver metastases might be a useful prognostic factor.

Recommendations: PET should be performed wherever possible to confirm extrahepatic metastases and to increase the accuracy of clinical staging.

Recommendation level: high

Laparoscopic exploration

A laparoscopic exploration with extensive intraoperative peritoneal lavage can be used to rule out peritoneal carcinomatosis.^18,19

Recommendations: This examination should be performed for all GCLM patients scheduled for surgeries.

Recommendation level: high

Pathological examination

In addition to pathomorphological examination, certain immunohistochemistry and molecular tests are required, such as those for HER2,²⁰ PD1/PD-L1,²¹ and MSI/MMR.²² Percutaneous biopsy with pathological examination is the gold standard for confirming liver metastases. As percutaneous biopsy is an invasive test, it can be recommended only to GCLM patients with rare pathological types or lesions that cannot be confirmed by imaging examinations.

Serologic examination

High preoperative levels of serum tumor markers, such as CEA, CA19-9, CA72-4, CA125, or AFP, have been reported as significant risk factors for cancer recurrence rate in GCLM patients.^8,23–29 Low blood lymphocyte-to-monocyte ratio in GC patients after radical-intent surgery is associated with high recurrence rate, especially in livers.³⁰ The levels of serum tumor markers increased 2–3 months ahead of the imaging findings in some patients.³¹

Clinical typing

Excision of both gastric tumors and liver metastases can increase the 5-year survival rate of GCLM patients to >20%,^6,8,32–34 especially in selected narrow group of patients who meet strictly defined criteria.^9,35–38 However, the existing classification systems, such as the synchronous/metachronous system and the Japanese classification of gastric carcinoma, have limited value in clinical guidance. Therefore, based on existing studies,^{3,4,6,8,10,32–36,39–69} and following recommendations from experts, we have developed a new clinical classification system, the Chinese Type for Gastric Cancer Liver Metastases (C-GCLM), based on the likelihood of a surgical treatment being successful (Figure 1 and Table 1).

Figure 1.

Chinese type for GCLM.

Table 1.

Summary of the C-GCLM, a proposed classification system based on the likelihood of a surgical treatment being successful.

Type I	Gastric tumors: depth of invasion ⩽T4a; lymph node metastases within D2 lymph node dissection (not including Bulky N2) Bulky N2: at least one node of ⩾3 cm in diameter, or at least three consecutive nodes each of diameter ⩾1.5 cm, along the coeliac, splenic, common, or proper hepatic arteries
	Liver metastases: 1–3; maximal diameter ⩽4 cm or limited to one liver lobe without involving important vessels or bile ductsAssessment of resectability:Technological resectability of liver metastases judged by a hepatobiliary surgeon;Meets the resection standard of hepatic reservational function assessment.
Type II	Gastric tumors: depth of invasion = T4b or Bulky N2 or Bulky No. 16a2, b1.
	Liver metastases: out of the range of Type I, with potential technological resectability
Type III	Gastric tumors:Primary lesion directly and considerably invades adjacent tissues or organs;Regional lymph nodes such as mesenteric lymph nodes or paraaortic lymph nodes fixed, fused, or not resectable, as confirmed by imaging examinations or biopsy.
	Metastases:IIIa: multiple diffusely distributed metastatic lesions in both lobes without extrahepatic metastases;IIIb: extrahepatic metastases (one or more organs) with or without peritoneal carcinomatosis.

C-GCLM, Chinese type for gastric cancer liver metastases.

Multidisciplinary treatment mode

The MDT mode should be implemented all through the treatment of GCLM.^14,70 The diagnosis, clinical typing, therapeutic schedule, and follow-up plan should be discussed and decided by the MDT expert team.⁷¹

Synchronous resections of both primary and metastatic lesions are recommended to patients with the possibility of R0 resection.

If either primary or metastatic lesions are unresectable, the MDT team should develop a comprehensive treatment plan for the patient, with periodic appraisal and evaluation.

Comprehensive treatment plans based on chemotherapy are recommended to patients with unresectable lesions, both primary and metastatic.

Best supportive treatment will be applied to patients with poor performance status.

Palliative surgeries to relieve serious symptoms, such as bleeding or obstruction, should be considered when necessary.

The MDT team should discuss specific treatment plans for patients with extrahepatic metastases.

The flow chart of diagnosis and treatment by the MDT team is shown in Figure 2.

Figure 2.

Flow chart of diagnosis and treatment.

Comprehensive treatment

The comprehensive treatment for GCLM includes systemic treatments (chemotherapy, targeted treatment, and immunotherapy), surgeries, and radiotherapy.

Type I

According to the MDT assessment, Type I patients can choose surgical treatments or preoperative systemic treatments. Targeted treatment combined with chemotherapy is applied to HER2-positive patients.⁷² Standards of surgical treatments are gastrectomy with D2 lymph node dissection for primary gastric tumor and R0 resection for liver metastases. Excision extension of liver is classified as partial hepatectomy, segmentectomy, and hemihepatectomy. Types of surgeries include open surgery, laparoscopic surgery, and robotic surgery. Radiofrequency ablation (RFA) has been considered a less invasive therapeutic choice for liver metastases. It can be used alone,^42,73,74 or combined with surgical resection.^41,53 Postoperative chemotherapy is necessary, and should include at least 4–8 cycles. Response evaluation should be performed every 2–3 months.

Recommendations: Preoperative systemic treatments should be applied to Type I patients.

Recommendation level: high

Type II

Preoperative systemic treatments should be administered to patients who are in good performance status to ensure that surgery can take place as soon as possible. Additionally, local treatments for liver metastases such as transcatheter arterial chemoembolization (TACE)^5,42,75–77 and hepatic artery infusion chemotherapy (HAIC)^78–80 are recommended, as they can deliver high-concentration drugs to metastatic lesions as well as reduce the overall toxicity. TACE and HAIC can be used preoperatively or postoperatively. Conformal radiotherapy combined with chemotherapy can also be applied to preoperative therapy.¹⁸ Stereotactic radiation therapy or intensity modulated radiation therapy can handle the lesions at difficult locations, such as hepatic hila, and are especially suitable for single lesion with a diameter <5 cm. For patients in poor performance status who cannot undergo surgery, RFA is an appropriate alternative and can be used repeatedly.^81–83 In addition, microwave ablation,⁸⁴ percutaneous cryoablation,⁸⁵ proton beam therapy,⁸⁶ and radioembolization with 90Y microspheres,⁸⁷ have shown promising preliminary results in the treatments of GCLM. All these therapies were recommended for tumors <3 cm in diameter and ⩽5 in number in each treatment.

Recommendations: Surgical treatments should be performed only when R0 resection is intended.

Recommendation level: high

Type III

Chemotherapy is the preferred recommendation for Type III patients in good performance status. In Type III, immunotherapy plays an important role.⁸⁸ Immunotherapies include immune checkpoint inhibitors (PD-1/PD-L1 inhibitors),^89,90 chimeric antigen receptor T cells, and heat shock protein gp96. TACE and HAIC can also be used with patients who do not achieve disease control with first-line and second-line chemotherapy; in some cases, radiotherapy might be a more suitable approach. Palliative surgeries should only be considered to relieve major symptoms such as bleeding, perforation, or obstruction.

Recommendations: Cytoreductive surgeries are not encouraged. Patients can participate in clinical trials on immunotherapy under the guidance of the MDT group.

Recommendation level: high

Follow up

The items and interval time were summarized in Table 2.

Table 2.

Follow up.

Items	Interval time (months)
History, physical examination, nutritional status assessment, blood routine, blood biochemistry, serum tumor markers, and abdomen ultrasonography	1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60; thereafter once a year
Chest/abdomen/pelvic CT	6, 12, 18, 24, 36, 48, 60; thereafter as necessary
Abdomen MRI, PET-CT, upper GI endoscopy	Important clinical decision; when necessary

CT, computed tomography; GI, gastrointestinal; MRI, magnetic resonance imaging; PET, positron emission tomography.

Footnotes

Acknowledgements

We are especially grateful to the following advisors: Jiafu Ji (Peking University Cancer Hospital and Institute), Xinyu Qin (Zhongshan Hospital of Fudan University), Huimian Xu (First Hospital of China Medical University), and Zhenggang Zhu (Ruijin Hospital, Shanghai Jiao Tong University School of Medicine). Experts involved (alphabetical order): Baixuan Xu, Bo Wei, Chun Han, Guanghai Dai, Haiyi Wang, Hongguang Wang, Hongqing Xi, Huaiyin Shi, Jing Wang, Jing Yuan, Li Bai, Lin Chen, Maoqiang Wang, Ping Liang, Wei Xu, Xiaohui Du, Xinxin wang, Yukun Luo, Zhanbo Wang, Zhi Qiao, Zhikuan Wang, Zhiyu Han (Chinese People’s Liberation Army General Hospital); Lin Shen, Weihu Wang, Xiangqian Su, Ziyu Li (Peking University Cancer Hospital and Institute); Lu Zang, Min Yan, Minhua Zheng (Ruijin Hospital, Shanghai Jiao Tong University School of Medicine); Changming Huang, Zhaohui Zheng (Fujian Medical University Union Hospital); Fenglin Liu, Yihong Sun, (Zhongshan Hospital, Fudan University); Jian Suo, Quan Wang (the First Hospital, Jilin University); Kewei Jiang, Yingjiang Ye (Peking University People’s Hospital); Li Yang, Zekuan Xu (the First Affiliated Hospital of Nanjing Medical University); Peiwu Yu, Yongliang Zhao (Southwest Hospital, Third Military Medical University); Xiang Hu, Pin Liang (the First Affiliated Hospital of Dalian Medical University); Dongqiu Dai (the Fourth Affiliated Hospital of China Medical University); Fei Li (Xuanwu Hospital Capital Medical University); Gang Ji (Xijing Hospital of Airforce Medical University); Gang Zhao (Renji Hospital, Shanghai Jiaotong University School of Medicine); Guoli Li (Jinling Hospital, School of Medicine, Nanjing University); Guoxin Li (Nanfang Hospital, Southern Medical University); Han Liang (Tianjin Medical University Cancer Institute and Hospital); Hua Huang (Fudan University Shanghai Cancer Center); Hui Cao (Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University); Jiaming Zhu (the Second Hospital of Jilin University); Jiankun Hu (West China Hospital, Sichuan University); Jiren Yu (the First Affiliated Hospital, Medical College, Zhejiang University); Leping Li (Provincial Hospital Affiliated to Shandong University); Liguo Tian (Chinese Journal of Practical Surgery); Linghua Zhu (Sir Run Shaw Hospital, College of Medicine, Zhejiang University); Luchuan Chen (Fujian Medical University Cancer Hospital); Qingchuan Zhao (Xijing Hospital of Digestive Diseases, The Fourth Military Medical University); Wu Song (the First Affiliated Hospital, Sun Yat-sen University); Xiaogang Bi (Shanxi Provincial People’s Hospital); Xuedong Fang (China-Japan Union Hospital, Jilin University); Yajin Chen (Sun Yat-sen Memorial Hospital, Sun Yat-sen University); Yanbing Zhou (the Affiliated Hospital of Qingdao University); Yantao Tian (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College); Yingwei Xue (Harbin Medical University Cancer Hospital); Yinmo Yang (Peking University First Hospital); Yong Li (Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences); Yulong He (First Affiliated Hospital, Sun Yat-sen University); Zhenning Wang (the First Affiliated Hospital of China Medical University); Zhigang Jie (First Affiliated Hospital, Nanchang University); Zhongtao Zhang (Beijing Friendship Hospital, Capital Medical University). Contributors: Jiyang Li, Kecheng Zhang, Yunhe Gao, and Wenquan Liang (Chinese People’s Liberation Army General Hospital).

Funding

The author(s) received no financial support for the research, authorship, and publication of this article.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

D’Angelica

Gonen

Brennan

, et al. Patterns of initial recurrence in completely resected gastric adenocarcinoma. Ann Surg 2004; 240: 808–816.

Riihimaki

Hemminki

Sundquist

, et al. Metastatic spread in patients with gastric cancer. Oncotarget 2016; 7: 52307–52316.

Cheon

Rha

Jeung

, et al. Survival benefit of combined curative resection of the stomach (D2 resection) and liver in gastric cancer patients with liver metastases. Ann Oncol 2008; 19: 1146–1153.

Wang

Liang

Zhang

, et al. Prognostic significance of radical surgical treatment for gastric cancer patients with synchronous liver metastases. Med Oncol 2014; 31: 258.

Xiao

Zhang

. Prognostic analysis and liver metastases relevant factors after gastric and hepatic surgical treatment in gastric cancer patients with metachronous liver metastases: a population-based study. Ir J Med Sci 2019; 188: 415–424.

Petrelli

Coinu

Cabiddu

, et al. Hepatic resection for gastric cancer liver metastases: a systematic review and meta-analysis. J Surg Oncol 2015; 111: 1021–1027.

Smyth

Verheij

Allum

, et al. Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27: v38–v49.

Montagnani

Crivelli

Aprile

, et al. Long-term survival after liver metastasectomy in gastric cancer: systematic review and meta-analysis of prognostic factors. Cancer Treat Rev 2018; 69: 11–20.

Thelen

Jonas

Benckert

, et al. Liver resection for metastatic gastric cancer. Eur J Surg Oncol 2008; 34: 1328–1334.

10.

Tatsubayashi

Tanizawa

Miki

, et al. Treatment outcomes of hepatectomy for liver metastases of gastric cancer diagnosed using contrast-enhanced magnetic resonance imaging. Gastric Cancer 2017; 20: 387–393.

11.

Kim

Lee

, et al. Diagnostic accuracy and sensitivity of diffusion-weighted and of gadoxetic acid-enhanced 3-T MR imaging alone or in combination in the detection of small liver metastasis (</= 1.5 cm in diameter). Invest Radiol 2012; 47: 159–166.

12.

Jhaveri

Cleary

Audet

, et al. Consensus statements from a multidisciplinary expert panel on the utilization and application of a liver-specific MRI contrast agent (gadoxetic acid). AJR Am J Roentgenol 2015; 204: 498–509.

13.

Chinese Society of Abdominal Radiology. Chinese society of abdominal radiology expert consensus on liver magnetic resonance imaging with gadobenate dimeglumine. Chin J Hepatobiliarv Surg 2017; 9: 577–584.

14.

Chinese Society of Abdominal Radiology. Expert consensus on the clinical use of hepatobiliary specific MRI contrast agent, gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic-acid. Chin J Radio 2016; 9: 641–646.

15.

Arita

Ono

Takahashi

, et al. Routine preoperative liver-specific magnetic resonance imaging does not exclude the necessity of contrast-enhanced intraoperative ultrasound in hepatic resection for colorectal liver metastasis. Ann Surg 2015; 262: 1086–1091.

16.

Kinkel

Both

, et al. Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR imaging, PET): a meta-analysis. Radiology 2002; 224: 748–756.

17.

Wang

Guo

Zhou

, et al. The predictive and prognostic value of early metabolic response assessed by positron emission tomography in advanced gastric cancer treated with chemotherapy. Clin Cancer Res 2016; 22: 1603–1610.

18.

Ceniceros

Chopitea

Pardo

, et al. Intensified neoadjuvant multimodal approach in synchronous liver metastases from gastric cancer: a single institutional experience. Clin Transl Oncol 2018; 20: 658–665.

19.

Kuramoto

Shimada

Ikeshima

, et al. Extensive intraoperative peritoneal lavage as a standard prophylactic strategy for peritoneal recurrence in patients with gastric carcinoma. Ann Surg 2009; 250: 242–246.

20.

Saito

Nakanishi

Mochizuki

, et al. Preferential HER2 expression in liver metastases and EGFR expression in peritoneal metastases in patients with advanced gastric cancer. Gastric Cancer 2015; 18: 711–719.

21.

Kim

Cristescu

Bass

, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 2018; 24: 1449–1458.

22.

Smyth

Wotherspoon

Peckitt

, et al. Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the medical research council adjuvant gastric infusional chemotherapy (MAGIC) trial. JAMA Oncol 2017; 3: 1197–1203.

23.

Marrelli

Roviello

De Stefano

, et al. Risk factors for liver metastases after curative surgical procedures for gastric cancer: a prospective study of 208 patients treated with surgical resection. J Am Coll Surg 2004; 198: 51–58.

24.

Wang

Shen

Jiao

, et al. Predictive and prognostic value of serum AFP level and its dynamic changes in advanced gastric cancer patients with elevated serum AFP. World J Gastroenterol 2018; 24: 266–273.

25.

Chen

Jian

, et al. High level of serum AFP is an independent negative prognostic factor in gastric cancer. Int J Biol Markers 2015; 30: e387–e393.

26.

Shimada

Noie

Ohashi

, et al. Clinical significance of serum tumor markers for gastric cancer: a systematic review of literature by the task force of the Japanese gastric cancer association. Gastric Cancer 2014; 17: 26–33.

27.

Wang

Yang

Zhang

, et al. Prognostic value of carbohydrate tumor markers and inflammation-based markers in metastatic or recurrent gastric cancer. Med Oncol 2014; 31: 289.

28.

Kinoshita

Fushida

Harada

, et al. Type IV collagen levels are elevated in the serum of patients with peritoneal dissemination of gastric cancer. Oncol Lett 2010; 1: 989–994.

29.

Yamamoto

Baba

Toh

, et al. Peritoneal lavage CEA/CA125 is a prognostic factor for gastric cancer patients. J Cancer Res Clin Oncol 2007; 133: 471–476.

30.

Lin

Cao

, et al. Preoperative lymphocyte-to-monocyte ratio as a strong predictor of survival and recurrence for gastric cancer after radical-intent surgery. Oncotarget 2017; 8: 79234–79247.

31.

Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines (version 5). Tokyo, Japan: Kimbara Publishing Corporation, 2018.

32.

Long

Huang

, et al. Systematic review of partial hepatic resection to treat hepatic metastases in patients with gastric cancer. Medicine (Baltimore) 2016; 95: e5235.

33.

Markar

Mikhail

Malietzis

, et al. Influence of surgical resection of hepatic metastases from gastric adenocarcinoma on long-term survival: systematic review and pooled analysis. Ann Surg 2016; 263: 1092–1101.

34.

Markar

Mackenzie

Mikhail

, et al. Surgical resection of hepatic metastases from gastric cancer: outcomes from national series in England. Gastric Cancer 2017; 20: 379–386.

35.

Tiberio

Baiocchi

Morgagni

, et al. Gastric cancer and synchronous hepatic metastases: is it possible to recognize candidates to R0 resection? Ann Surg Oncol 2015; 22: 589–596.

36.

Kinoshita

Saiura

, et al. Multicentre analysis of long-term outcome after surgical resection for gastric cancer liver metastases. Br J Surg 2015; 102: 102–107.

37.

Tsujimoto

Ichikura

Ono

, et al. Outcomes for patients following hepatic resection of metastatic tumors from gastric cancer. Hepatol Int 2010; 4: 406–413.

38.

Imamura

Matsuyama

Shimada

, et al. A study of factors influencing prognosis after resection of hepatic metastases from colorectal and gastric carcinoma. Am J Gastroenterol 2001; 96: 3178–3184.

39.

Shinohara

Maeda

Hamada

, et al. Survival benefit of surgical treatment for liver metastases from gastric cancer. J Gastrointest Surg 2015; 19: 1043–1051.

40.

Oki

Tokunaga

Emi

, et al. Surgical treatment of liver metastasis of gastric cancer: a retrospective multicenter cohort study (KSCC1302). Gastric Cancer 2016; 19: 968–976.

41.

Cui

, et al. Minimally invasive surgery as a treatment option for gastric cancer with liver metastasis: a comparison with open surgery. Surg Endosc 2018; 32: 1422–1433.

42.

Zhang

Gao

, et al. Evaluation of hepatectomy and palliative local treatments for gastric cancer patients with liver metastases: a propensity score matching analysis. Oncotarget 2017; 8: 61861–61875.

43.

Liao

Peng

Long

, et al. Hepatectomy for liver metastases from gastric cancer: a systematic review. BMC Surg 2017; 17: 14.

44.

Song

Zhang

, et al. Surgical resection for hepatic metastasis from gastric cancer: a multi- institution study. Oncotarget 2017; 8: 71147–71153.

45.

Shirasu

Tsushima

Kawahira

, et al. Role of hepatectomy in gastric cancer with multiple liver-limited metastases. Gastric Cancer 2018; 21: 338–344.

46.

Schildberg

Croner

Merkel

, et al. Outcome of operative therapy of hepatic metastatic stomach carcinoma: a retrospective analysis. World J Surg 2012; 36: 872–878.

47.

Kim

Lee

Baek

, et al. Survival benefit of gastrectomy +/- metastasectomy in patients with metastatic gastric cancer receiving chemotherapy. Gastric Cancer 2011; 14: 130–138.

48.

Fan

Shan

, et al. Gastrectomy in comprehensive treatment of advanced gastric cancer with synchronous liver metastasis: a prospectively comparative study. World J Surg Oncol 2015; 13: 212.

49.

Chen

Zhang

. Indications analysis for multiorgan resection in advanced gastric cancer. Chin J Practical Surg 2017; 37: 1095–1098.

50.

Kataoka

Kinoshita

Moehler

, et al. Current management of liver metastases from gastric cancer: what is common practice? New challenge of EORTC and JCOG. Gastric Cancer 2017; 20: 904–912.

51.

Al-Batran

Homann

Pauligk

, et al. Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: the AIO-FLOT3 trial. JAMA Oncol 2017; 3: 1237–1244.

52.

Tiberio

Ministrini

Gardini

, et al. Factors influencing survival after hepatectomy for metastases from gastric cancer. Eur J Surg Oncol 2016; 42: 1229–1235.

53.

Guner

Son

Cho

, et al. Liver-directed treatments for liver metastasis from gastric adenocarcinoma: comparison between liver resection and radiofrequency ablation. Gastric Cancer 2016; 19: 951–960.

54.

Komeda

Hayashi

Kubo

, et al. High survival in patients operated for small isolated liver metastases from gastric cancer: a multi-institutional study. World J Surg 2014; 38: 2692–2697.

55.

Qiu

Deng

, et al. Hepatic resection for synchronous hepatic metastasis from gastric cancer. Eur J Surg Oncol 2013; 39: 694–700.

56.

Wang

Shen

Ling

, et al. Prognostic analysis of combined curative resection of the stomach and liver lesions in 30 gastric cancer patients with synchronous liver metastases. BMC Surg 2012; 12: 20.

57.

Takemura

Saiura

Koga

, et al. Long-term outcomes after surgical resection for gastric cancer liver metastasis: an analysis of 64 macroscopically complete resections. Langenbecks Arch Surg 2012; 397: 951–957.

58.

Miki

Fujitani

Hirao

, et al. Significance of surgical treatment of liver metastases from gastric cancer. Anticancer Res 2012; 32: 665–670.

59.

Liu

Zhai

, et al. Predictive factors improving survival after gastric and hepatic surgical treatment in gastric cancer patients with synchronous liver metastases. Chin Med J (Engl) 2012; 125: 165–171.

60.

Garancini

Uggeri

Degrate

, et al. Surgical treatment of liver metastases of gastric cancer: is local treatment in a systemic disease worthwhile? HPB (Oxford) 2012; 14: 209–215.

61.

Makino

Kunisaki

Izumisawa

, et al. Indication for hepatic resection in the treatment of liver metastasis from gastric cancer. Anticancer Res 2010; 30: 2367–2376.

62.

Ueda

Iwahashi

Nakamori

, et al. Analysis of the prognostic factors and evaluation of surgical treatment for synchronous liver metastases from gastric cancer. Langenbecks Arch Surg 2009; 394: 647–653.

63.

Sakamoto

Sano

Shimada

, et al. Favorable indications for hepatectomy in patients with liver metastasis from gastric cancer. J Surg Oncol 2007; 95: 534–539.

64.

Koga

Yamamoto

Ohyama

, et al. Liver resection for metastatic gastric cancer: experience with 42 patients including eight long-term survivors. Jpn J Clin Oncol 2007; 37: 836–842.

65.

Sakamoto

Ohyama

Yamamoto

, et al. Surgical resection of liver metastases of gastric cancer: an analysis of a 17-year experience with 22 patients. Surgery 2003; 133: 507–511.

66.

Kumagai

Tanaka

Yamagata

, et al. Liver metastasis in gastric cancer with particular reference to lymphatic advancement. Gastric Cancer 2001; 4: 150–155.

67.

Yoshikawa

Sasako

Yamamoto

, et al. Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer. Br J Surg 2009; 96: 1015–1022.

68.

Matsumoto

Sasako

Mizusawa

, et al. HER2 expression in locally advanced gastric cancer with extensive lymph node (bulky N2 or paraaortic) metastasis (JCOG1005-A trial). Gastric Cancer 2015; 18: 467–475.

69.

Wang

Shen

, et al. The Chinese society of clinical oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer. Cancer Commun (Lond) 2019; 39: 10.

70.

Chen

Shen

. Multidisciplinary therapy for gastric cancer with liver metastasis. Chin J Gastrointest Surg 2014; 17: 101–104.

71.

Xing

. Expert consensus on the diagnosis and treatment by the multidisciplinary treatment group for gastric cancer. Chin J Practical Surg 2017: 37–38.

72.

Bang

Van Cutsem

Feyereislova

, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376: 687–697.

73.

Chen

Tang

Dong

, et al. Radiofrequency ablation for liver metastasis from gastric cancer. Eur J Surg Oncol 2013; 39: 701–706.

74.

Dittmar

Altendorf-Hofmann

Rauchfuss

, et al. Resection of liver metastases is beneficial in patients with gastric cancer: report on 15 cases and review of literature. Gastric Cancer 2012; 15: 131–136.

75.

Chen

Gao

Yang

, et al. Comparison of safety and efficacy of different models of target vessel regional chemotherapy for gastric cancer with liver metastases. Chemotherapy 2016; 61: 99–107.

76.

Chen

Liu

, et al. Low-dose, short-interval target vessel regional chemotherapy through the hepatic artery combined with transarterial embolization in gastric cancer patients with liver metastases after failure of first-line or second-line chemotherapy: a preliminary analysis. Anticancer Drugs 2014; 25: 92–100.

77.

Vogl

Gruber-Rouh

Eichler

, et al. Repetitive transarterial chemoembolization (TACE) of liver metastases from gastric cancer: local control and survival results. Eur J Radiol 2013; 82: 258–263.

78.

Fukami

Kaneoka

Maeda

, et al. Adjuvant hepatic artery infusion chemotherapy after hemihepatectomy for gastric cancer liver metastases. Int J Surg 2017; 46: 79–84.

79.

Wang

Zhang

Qian

, et al. The effect of locoregional transarterial infusion chemotherapy on liver metastasis after gastric cancer resection. J Int Med Res 2012; 40: 1141–1148.

80.

Seki

Ohi

Ozaki

, et al. Hepatic arterial infusion chemotherapy using fluorouracil, epirubicin, and mitomycin C for patients with liver metastases from gastric cancer after treatment failure of systemic S-1 plus cisplatin. Acta Radiol 2016; 57: 781–788.

81.

Lee

Choi

Lee

, et al. Radiofrequency ablation for liver metastases in patients with gastric cancer as an alternative to hepatic resection. BMC Cancer 2017; 17: 185.

82.

Hwang

Kim

Jin

, et al. Combination of percutaneous radiofrequency ablation and systemic chemotherapy are effective treatment modalities for metachronous liver metastases from gastric cancer. Clin Exp Metastasis 2014; 31: 25–32.

83.

Hofer

Oberholzer

Beck

, et al. Ultrasound-guided radiofrequency ablation (RFA) for inoperable gastrointestinal liver metastases. Ultraschall Med 2008; 29: 388–392.

84.

Ryu

Takami

Wada

, et al. Oncological outcomes after hepatic resection and/or surgical microwave ablation for liver metastasis from gastric cancer. Asian J Surg 2019; 42: 100–105.

85.

Chang

Wang

, et al. CT-guided percutaneous cryoablation for palliative therapy of gastric cancer liver metastases. Cryobiology 2018; 82: 43–48.

86.

Fukumitsu

Okumura

Takizawa

, et al. Proton beam therapy for liver metastases from gastric cancer. J Radiat Res 2017; 58: 357–362.

87.

Sato

Lewandowski

Mulcahy

, et al. Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres–safety, efficacy, and survival. Radiology 2008; 247: 507–515.

88.

Zhang

Chen

. Current status and future directions of cancer immunotherapy. J Cancer 2018; 9: 1773–1781.

89.

Kang

Boku

Satoh

, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538–12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 390: 2461–2471.

90.

Shitara

Ozguroglu

Bang

, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 2018; 392: 123–133.