**2. Gastric cancer with liver metastasis (GCLM) and surgery**

Remote metastases as a sign of systemic disease reduce the overall patient survival. The most

**Figure 1.** Percentage of cases and 5-year relative survival by stage at diagnosis: gastric cancer. The earlier gastric cancer is diagnosed, the better chance a patient has of surviving 5 years after diagnosis. For gastric cancer, 26.0 and 29.0% of cases are diagnosed at the local and distant stage, respectively. Of note, the stage of disease is unknown at diagnosis in more than onethird of cases. The 5-year survival for localized gastric cancer is 65.4%, compared with 4.5% for distant stomach cancer [2].

For the sake of comparison, at present, the liver resection is currently accepted as a treatment for liver metastases of colorectal cancer with referred 5-year survival in 40–56% of patients [5]. Thanks to advances in surgical techniques and perioperative chemotherapy, the indication

Compared with colorectal cancer, the gastric cancer represents a more aggressive cancer dis-

Other metastatic lesions associated with gastric cancer such as peritoneal carcinomatosis or extensive involvement of the regional lymph nodes significantly deteriorates the patient's

GCLM is considered a systemic disease with adverse outcome and systemic chemotherapy is

common site for gastric cancer metastasis is the liver [4].

outcome, contraindicating the surgical treatment.

indicated as the first line of treatment [7].

range keeps expanding.

244 Gastric Cancer

ease with heterogenic nature [6].

Liver resection/RFA is not a frequent treatment modality for gastric cancer with liver metastasis (GCLM).

This is well documented by a Korean study, where in 10% of the 100,000 GCLM patients, only 4% had hepatic surgery. At present, there is no clear consensus supporting liver resection in this type of tumor [14].

In this respect, the study of Kinoshita et al. has become a breakthrough [15]. It describes a 5-year disease-free survival in 30% of carefully selected patients. This confirmed that a small sub-population of patients with GCLM may benefit from liver resection or RFA. The median recurrence-free survival time was 9 months.

Half of the patients had recurrence within 1 year, in spite of R0 resection and careful selection. On the other hand, there was sufficient number of patients with long-term survival. This can be explained by varying tumor sub-populations with differing biological behavior [15, 72].

The question is: Which GCLM patients are suitable for surgical intervention?

At present, there is no direct marker available, defining the degree of biological aggressiveness of the tumor (indicating or contra-indicating the surgical treatment), therefore we are left to rely on indirect prognostic factors—number of liver metastases, size of metastatic lesion [8, 72].

Several studies have attempted to identify the prognostic factors defining adverse outlook for patients and contraindicating surgical intervention.

Among these studies, a multicenter study by Japanese authors stands out [15]. This study defines three adverse prognostic factors:


The study noted a significant difference in survival between patients without a prognostic factor and patients with one of the three prognostic factors. The authors recommend to consider surgical intervention in the presence of any of the three risk factors.

Patients with lower number of risk factors had better 3- and 5-year survival following liver resection [15].

The indication for surgical intervention in GCLM is subject to overall clinical condition of the patient, but liver resection should definitely be contraindicated in the presence of all three adverse prognostic factors (no long-term survival was noted) [15].

Repeated hepatectomy was performed only in 14.4% of patients, which is significantly lower number of hepatectomies compared to patients with colorectal cancer. This is caused by different pathophysiological course of gastric cancer relapse [16].

Hepatic resection is presently considered and justified only in case of solitary relapsing metastasis of GCLM [16].

The role of chemotherapy in GCLM is not clearly defined. Neo-adjuvant chemotherapy is being brought forward that can be used to differentiate responders from nonresponders. Surgical intervention is contraindicated in nonresponders [17].

GCLM patients treated by systemic chemotherapy alone have 1.7% 5-year survival [17].

Several studies assessed the use of RFA in GCLM, recommending it for solitary lesions up to 30 mm in size, located in the periphery of the liver. No clear advantage of RFA compared to surgical resection has been shown [18, 72].

Surgical treatment is not able to provide patients with GCLM a complete cure. Half of the patients had recurrence within 1 year, in spite of R0 resection and careful selection. On the other hand, there was sufficient number of patients with long-term survival. This can be explained by varying tumor sub-populations with differing biological behavior [15].

The number of studies aimed to clarify the explanation of the process invasive gastric cancer growth, metastasis, and particularly its biological aggressiveness essentially failed.

We do not differentiate the varying degrees of biological aggressiveness of gastric cancer.

A small light in explanation of the above problem is cancer stem cells (CSCs) theory.

This theory proposes that CSCs serve not only as the basis for the development and progression of primary tumors, but also as the primary reason for tumor recurrence and metastasis (theory of minimal residual disease).

Micrometastases involving dormant cancer stem cells are mistaken for small macrometastases. These are distinct disease entities responsible for late recurrence (months, years) with high resistance to current chemotherapy.

The combined use of traditional therapies with targeted CSC-specific agents may target the whole cancer and offer a promising strategy for lasting treatment and even its cure.
