Abstract
Background/Aim: This study investigated the influence of surgery for metasynchronous liver metastasis in gastric cancer on prognosis. Patients and Methods: A retrospective study was conducted involving 21 consecutive patients with gastric cancer with metasynchronous distant metastasis only in the liver after curative gastrectomy. The patients were divided into two groups: those who underwent hepatic resection and those who did not. The clinicopathological characteristics, recurrence-free survival (RFS), overall survival (OS), and disease-specific survival (DSS) were analysed. Results: Among 981 gastrectomies performed in Tottori University Hospital between 2005 and 2019, 930 were curative. Among 153 cases of recurrence during the follow-up, 21 consecutive cases involving the liver only and metasynchronous recurrent metastasis on imaging were included in this study. The study included 16 males and five females with a median age of 70 years. No statistical difference in RFS (237 vs. 201 days; p=0.788) was observed between the hepatectomy and non-hepatectomy groups; however, OS (1,564 vs. 608 days, p=0.008) and DSS (1,597 vs. 608 days, p=0.006) were significantly prolonged in the hepatectomy group. Univariate and multivariate analyses revealed that hepatectomy was the only independent prognostic factor (hazard ratio=0.33; p=0.042). Conclusion: Hepatic resection of heterogeneous liver metastases in gastric cancer seems to be a useful option that can be expected to cure the disease, which cannot be achieved by chemotherapy alone.
Despite recent developments in comprehensive treatment, including chemotherapy, gastric cancer with liver metastases remains to have poor prognosis (1–3). Metastasis in the liver is one of the most common patterns of hematogenous metastasis of gastric cancer (1, 3) and is a noncurative factor when considering gastrectomy. Systemic therapies, such as chemotherapy, are the standard treatment according to the guidelines for such situations (4, 5).
The most common recurrence patterns of patients who had previously been treated for gastric cancer are peritoneal and metachronous liver metastases (3). Compared with peritoneal metastasis, liver metastasis of gastric cancer is relatively influential; the significance of local therapy for metastatic hepatic lesions remains unclear. Moreover, hepatic metastases are frequently accompanied by extrahepatic metastases (6), making them difficult to be curatively resected. The Japanese guidelines for gastric cancer treatment report that surgical resection is weakly recommended if the number of liver metastases is small and there are no other noncurative factors (7); however, whether surgical resection prolongs patients’ survival remains controversial. Some studies have found that only hepatectomy for liver metastases could achieve long-term survival (8, 9), while other studies have shown that the effect of hepatectomy on survival of patients with gastric cancer with hepatic metastasis is doubtful (10).
Since there are some cases of long-term prognosis after hepatic resection for metasynchronous liver metastasis of gastric cancer in our institution, this study was designed to analyse the significance of hepatic resection of metasynchronous metastatic tumours from gastric cancer, and we conducted an observational study. Our hypothesis was that OS would be prolonged in patients who underwent hepatectomy for metasynchronous liver metastasis after gastrectomy compared with that in patients who did not undergo hepatectomy.
Patients and Methods
Data collection and definition. We retrospectively reviewed all medical records of the 981 patients with gastric cancer who underwent gastrectomy at Tottori University Hospital from 1 January 2005 to 31 December 2019. Of the 981 patients, 153 (15.6%) had recurrence after resection of the primary gastric tumour (Figure 1). The patients’ pathological statuses were redefined according to the 3rd English edition of the Japanese classification of gastric carcinoma (11). Liver metastases of all patients were diagnosed based on computed tomography or magnetic resonance imaging, and imaging was performed with contrast agents as a rule. The patients who were pointed to other metastases in addition to liver metastasis were excluded from this study. Accordingly, clinicopathological factors were collected from 21 patients selected in this study (Figure 1). Among them, 10 received hepatectomy, all of whom were histologically diagnosed with gastric cancer liver metastases.
Flow diagram for this retrospective study.
The following clinical data were included in the analysis: sex; age at the time of gastrectomy, recurrence, and hepatectomy; pre-gastrectomy tumour markers [carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9)]; operative procedures of gastrectomy; degree of lymphatic dissection (D1, D1+, or D2); pathological staging and findings according to the Japanese classification of gastric carcinoma (11); presence or absence of adjuvant chemotherapy after gastrectomy and hepatectomy; presence or absence of therapeutic chemotherapy after diagnosing hepatic metastasis; number and longest diameter of metastatic lesions; curability in hepatectomy; dates of gastrectomy, recurrence, hepatectomy, the last follow-up and death of the patient; patient outcomes; and recurrence site after hepatectomy.
The primary endpoint of this study was OS. As the primary end point, the OS time was defined as the time from the date the patient received gastrectomy to the date of death or the last follow-up. Furthermore, recurrence-free survival (RFS) was defined as the period between the date of gastrectomy and the appearance of liver recurrence lesions.
Inclusion criteria for hepatectomy. A series of 21 consecutive patients who were diagnosed with metasynchronous liver metastasis after gastrectomy were included to this study as mentioned above. The inclusion criteria of hepatectomy for metasynchronous liver metastasis in our institution are as follows: 1) European Clinical Oncology Group-Performance Status Score is maintained (0 or 1) and the patient must have surgical tolerance enough to withstand hepatectomy. 2) The number of lesions that can be seen on pre-operative images should not exceed 1-3. 3) Multiple lesions are localised in two segments of the Couinaud classification, even if they are multiple. 4) All other distant metastases, such as peritoneal dissemination, lung metastasis, and lymphatic metastasis, should be absent. 5) A macroscopically complete resection is feasible. 6) Patients should understand hepatectomy instability for curability and their preferences for surgery. Written consent for hepatic resection of hepatic metastatic lesions of gastric cancer was obtained from all 10 patients.
Ethics. All procedures in studies involving human participants were performed according to the ethical standards of the institutional and/or national research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this study, the approval of the Ethics Committee of Tottori University Faculty of Medicine was obtained (approval no. 17A135 and no. 20A243). This study does not contain any experiments or procedures involving animals performed by any author. For this type of study (retrospective), formal consent is not required.
Statistical analysis. Statistical Package for the Social Sciences (version 25.0; IBM Corp., Armonk, NY, USA) and EZR (Saitama Medical Centre, Jichi Medical University, Saitama, Japan) were used for all graph drawing and statistical analyses, and a two-sided p-value of less than 0.05 was considered statistically significant. Continuous data are presented as medians with ranges. The Mann–Whitney U-test was used to evaluate the differences in continuous variables, and Fisher’s exact tests or the chi-square test was used in categorical variables as indicated. Univariate and multivariate Cox regression analyses were applied to identify the independent clinically related factors for OS. Then, 95% confidence intervals (CIs) were obtained using the approach described by DeLong et al. (12). The OS and RFS rates were calculated according to the Kaplan–Meier method and compared using the log-rank test.
Results
Clinicopathological characteristics of the patients. The patients’ clinicopathological characteristics are summarised in Table I. Of the 21 patients, 16 were males and five were females, with a median age of 70 years at the time of gastrectomy (range=48-80 years). The median length of follow-up of the 21 patients after gastrectomy was 871 days (range=273-5,014 days). Of the 21 patients, 15 (71.4%) received adjuvant chemotherapy after curative gastrectomy. All patients were diagnosed with metasynchronous liver recurrence with a median age of 72 years at the time of recurrence (range=48-82 years) after curative gastrectomy and received chemotherapy after the diagnosis of liver recurrence. Ten patients (47.6%) underwent hepatectomy for liver metastasis, all of whom were histologically curatively resected. Comparing the two groups (the hepatectomy and non-hepatectomy groups; Table II), the median age at the time of gastrectomy tended to be significantly younger in the hepatectomy group (p=0.051). No statistically significant differences in the method type of gastrectomy, pre-operative tumour markers of gastrectomy, pathological characteristics, and stages of gastric cancer were observed between the two groups. No in-hospital mortality was observed after hepatectomy.
Clinicopathological features of patients with metasynchronous liver metastases.
Post-gastrectomy and post-hepatectomy adjuvant therapy. Nine patients (81.8%) in the non-hepatectomy group underwent postoperative adjuvant chemotherapy after curative gastrectomy. The chemotherapy regimen was S-1 in seven patients, paclitaxel in one patient, and tegafur and uracil in one patient. In contrast, five patients (50%) in the hepatectomy group received post-gastrectomy adjuvant chemotherapy. The regimen of chemotherapy was S-1 in all five patients.
After hepatectomy, six patients (60%) received adjuvant chemotherapy. The details of the regimen were as follows: S-1 in four patients, irinotecan in one patient, and hepatic arterial infusion chemotherapy (5-FU+cisplatin + adriamycin + mitomycin C) in one patient.
Long-term outcomes. No significant difference in DFS was observed between the two groups (237.0 days in the hepatectomy group vs. 201.0 days in the non-hepatectomy group; p=0.788; Table II and Figure 2A) and based on the criteria for hepatic resection as mentioned above, the survival rates were compared between 10 patients who underwent hepatic resection and 11 who did not. The Kaplan–Meier OS curves are shown in Figure 2B. OS of patients who underwent hepatectomy was significantly longer than that of patients who did not (median survival time: 608.0 days vs. 1,564.0 days; p=0.008). Moreover, the gastric cancer-specific survival rate was better in the hepatectomy group (608.0 days vs. 1,597.0 days; p=0.006) (Figure 2C). All patients in the non-hepatectomy group died of recurrent gastric cancer (Figure 3).
Comparison of clinicopathological factors between the hepatectomy and non-hepatectomy groups.
The Kaplan–Meier curves of patients with metachronous liver recurrences. A) Recurrence-free survival after gastrectomy showing no difference between the hepatectomy and non-hepatectomy groups (p=0.778). B) Overall survival curves of patients with metasynchronous liver recurrences. The survival rates of patients who underwent hepatectomy were significantly higher than that of patients who did not undergo hepatic resection (p=0.008). C) Gastric cancer-specific survival curves. The hepatectomy group had a significantly better prognosis than the non-hepatectomy group (p=0.006).
Swimmer’s plot of each patient. The hepatectomy group included patients with long-term recurrence-free survival, including some patients who underwent a second hepatectomy for a second recurrence, which could be considered a cure of gastric cancer. In contrast, all patients in the non-hepatectomy group died of gastric cancer.
During the subsequent observation period after hepatectomy, four patients had progressed without recurrence, and various metastases were observed in the remaining six patients (60%) (Table II and Figure 3). Of six patients, three showed liver recurrence again, two of whom underwent second hepatectomy. Of the two patients who underwent second hepatectomy, one patient had no recurrence after second hepatectomy and survived for more than 11 years before dying of other diseases.
Prognostic factors in patients with metasynchronous liver metastasis after gastrectomy. To investigate the prognostic factors in patients with metasynchronous liver metastases after curative gastrectomy, univariate analysis was performed. The results are presented in Table III. Long diameter of liver lesions, the number of metastatic lesions and hepatectomy were statistically associated with OS in univariate analysis. A further multivariate Cox proportional hazard model analysis confirmed that hepatectomy was the only and statistically significant independent predictive factor (hazard ratio=0.33; 95%CI=0.113-0.960; p=0.042).
Univariate and multivariate analyses for overall survival after gastrectomy following metasynchronous liver only recurrence.
Discussion
In some malignancies, such as ovarian cancer and neuroendocrine tumour, debulking surgery can improve prognosis (13, 14); however, in most gastrointestinal cancers, debulking surgery has not been shown to contribute to prolonging life prognosis, and some studies have shown that it may be harmful (15, 16). Presently, there is no definitive method for reliably determining other noncurative factors where distant metastases are not visible on imaging. For example, surgical resection of colorectal cancer with distant metastatic foci confined to the lungs or liver contributes to survival (17); however, in some patients who underwent distant metastatic resection with the intention of cure, the disease may relapse. This may be a limitation of pre-operative diagnosis.
In this single-centre study, we studied 21 consecutive patients who underwent curative gastrectomy and were subsequently diagnosed with metasynchronous liver metastasis of gastric cancer. Of these patients, 10 underwent hepatectomy and OS after gastrectomy in the hepatectomy group was significantly longer (1564.0 vs. 608.0 days; p=0.008); we revealed that hepatectomy was an independent prognostic factor for improved outcomes (hazard ratio=0.33; p=0.042).
The most common site of distant gastric cancer metastasis is the peritoneum and liver (3, 18, 19). Peritoneal dissemination is a distant change caused by the direct extension of cancerous tissue from the gastric wall through the peritoneum, whereas liver metastasis is a hematogenous process. In a recent study by Joe et al. on 1,178 patients with gastric cancer, peritoneal dissemination was observed in 46% of the patients and liver metastases in 30% (19). However, in practice, when other distant metastatic lesions are included, liver metastases alone are relatively uncommon (6). Based on the findings of a cohort of nearly 1,000 patients, the rate of liver metastasis alone was approximately 2.1%.
Several studies have revealed many favourable prognostic effects of hepatectomy for synchronous and metasynchronous gastric cancer liver metastases (20, 21), making a mixed cohort. According to various reports and meta-analyses, heterogeneous liver metastases have a better prognosis than simultaneous ones (22–26). The study by Ryu et al. (27) has reported the significance of hepatectomy with/without microwave coagulo-necrotic therapy for metasynchronous gastric cancer liver metastasis. To the best of our knowledge, this is the first report of a cohort of patients with only heterogeneous liver metastases from gastric cancer, with or without hepatic resection.
Unlike colorectal cancer, disseminated distant metastatic recurrence of gastric cancer is common, which makes the surgical treatment of atypical recurrence in gastric cancer difficult and may limit the efficacy of surgical intervention in hepatic metastatic disease of gastric cancer. In this study, we carefully reviewed retrospective images and selected 21 patients with postoperative gastric cancer and liver metastasis alone. Of the 21 patients, 10 underwent surgical hepatectomy, and some required multiple hepatectomies; however, four of these patients have progressed without gastric cancer recurrence. Some patients had recurrence after hepatic resection; however, only three patients survived for more than 5 years after gastrectomy, including recurrence-free patients after hepatic resection, but none of the patients in the group who did not undergo hepatic resection survived for 5 years (Figure 3). These results show that hepatectomy has potential survival benefit in patients diagnosed with metasynchronous liver metastasis after gastrectomy.
The limitations of this study were as follows: this is a retrospective study, the results are from a single-centre, the number of cases of hepatic metastases was small (21 patients), and the indications for hepatic resection are wide and ambiguous. A reason for this small number of cases is that it is relatively rare for the liver to be the only distant organ to have metastatic lesions after gastric cancer surgery. In this study, we analysed approximately 1,000 cases after radical gastrectomy and found that only 21 cases (approximately 2%) could be considered to have liver metastases alone. Since peritoneal dissemination recurrence is the most common metastasis after gastric cancer surgery, surgical intervention is difficult in these cases. Although the number of patients with isolated liver metastases is expected to be small, a prospective, multicentre study over a relatively long period is essential to investigate the efficacy of hepatic resection in these patients.
In conclusion, surgical resection may be a better treatment option for metasynchronous hepatic metastasis from gastric cancer if the metastatic lesion is limited only to the liver and the number of metastatic lesions is small. Since chemotherapy alone cannot provide long-term control of distant metastases of gastric cancer, setting an appropriate and strict indication for surgical intervention for the recurrence of hepatic metastasis with a possibility of cure is desirable.
Acknowledgements
The Authors thank Dr. Hiroshi Sunada (Advanced Medicine, Innovation and Clinical Research Center, Tottori University Hospital, Yonago) for providing valuable statistical advice and the nurses, doctors, and other staff responsible for patients’ care at Tottori University Hospital.
Footnotes
Authors’ Contributions
TaH wrote the manuscript. TepS and KG collected the data and conducted literature review. MM, YM, YS, KM and KK analysed the collected data from the patients. MY, NT, TerS, ToH and YF revised the manuscript for important intellectual content and technical details.
All Authors have read and approved the final manuscript. All Authors confirm that they have met the criteria for authorship as established by the International Committee of Medical Journal Editors.
Conflicts of Interest
The Authors declare that they have no competing interests in relation to this study.
- Received February 17, 2022.
- Revision received March 3, 2022.
- Accepted March 4, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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