Radiol Oncol 2021; 55(1): 57-65. doi: 10.2478/raon-2020-0067 57 research article Surgical resection of synchronous liver metastases in gastric cancer patients. A propensity score-matched study Tomaz Jagric1, Matjaz Horvat2 1 Department of General and Abdominal Surgery, University Medical Centre Maribor, Slovenia 2 Faculty of Medicine, University of Maribor, Slovenia Radiol Oncol 2021; 55(1): 57-65. Received 25 June 2020 Accepted 15 October 2020 Correspondence to: Assist. Prof. Tomaž Jagrič, M.D., Ph.D., Department of General and Abdominal Surgery, University Medical Centre Maribor; Ljubljanska ulica 5; 2000 Maribor. E-mail: tomaz.jagric@gmail.com Disclosure: No potential conflicts of interest were disclosed. Background. The aim of the study was to determine the value of synchronous liver resection in patients with oligo- metastatic gastric cancer and the prognostic factors in these patients. Patients and methods. We compared the results of 21 gastric patients with liver metastases and synchronous liver resection (LMR) to 21 propensity score-matched patients with gastric cancer and liver metastases in whom liver resection was not performed (LM0) and to a propensity score-matched control group of 21 patients without liver me- tastases and stage III and IV resectable gastric cancer (CG). Results. The overall 5-year survival of LMR, LM0 and CG were 14.3%, 0%, and 19%, respectively (p = 0.002). Five-year survival was 47.5% for well-differentiated tumour compared to 0% in patients with moderate or poor tumour differen- tiation (p = 0.006). In addition, patients with R0 resection and TNM stage N0–1 had a significantly better survival com- pared to patients with TNM N stage N2–3 (5-year survival: 60% for N0–1 vs. 7.7% for N2–3; p = 0.007). Conclusions. The results presented in the study support synchronous liver resections in gastric patients and provide additional criteria for patient selection. Key words: gastric cancer; liver metastases; synchronous resection; propensity score Introduction Liver metastases occur in 3.5–14% of gastric cancer patients.1-8,12,15-17 Surgical resection has been shown to be a viable option in selected cases of gastric cancer patients with liver metastases. Since no randomised controlled trials are yet available re- garding the treatment of liver metastases in gastric cancer1-8, no clear-cut recommendations exist as to which patient could benefit the most from such treatment. The aim of our study was to determine the value of synchronous liver resection in patients with oligometastatic gastric cancer and to deter- mine the prognostic factors in these patients. We compared the results of propensity score-matched gastric cancer patients with and without liver re- sections as well as with a control group of stage III and IV patients without liver metastases. Patients and methods Patients Patient and tumour characteristics, preoperative di- agnostics and laboratory data, types of operations, perioperative complications and mortality from 1546 patient data has been included in our database since 1991. Histopathological descriptions were handled in accordance with the International Union Against Cancer 8th TNM classification of gastric cancer.11 Postoperative complications were defined according to the Clavien–Dindo classification.9 Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer58 Chemotherapy schemes varied during the study period. The administered preoperative and postop- erative regimens included: epirubicin + oxaliplatin, capecitabine + fluorouracil, capecitabine + oxalipl- atin, or 5-fluorouracil + leucovorin. For our analysis, only the patients who had synchronous liver me- tastases and gastric resection with curative intent (LMR) were selected. The results of these operations were compared to propensity score-matched (PSM) patients with liver metastases who had gastric can- cer resection, in whom the surgeon did not opt for additional liver resection (LM0). The decision regarding liver metastasis resection was obtained on the preoperative tumour board and during the operation at surgeon’s discretion. Patients were se- lected for liver resection, if they met the following criteria: (i) three or less metastases (oligometastatic gastric cancer); (ii) no distant metastases; (iii) resect- able primary tumour; (iv) good general health. The nomenclature of hepatic anatomy and resection was used according to the Brisbane 2000 system.10 Since we could not determine retrospectively whether pa- tients’ general state or advanced disease precluded liver metastases resection in LM0 group, we select- ed an additional PSM control group (CG). For CG, the propensity score-matched stage III and IV gas- tric cancer patients without having liver metastases resected with curative intent were used for estima- tion of treatment benefit. Follow-up was carried out by surgeons and oncologists. Informed consent was obtained from all individual participants included in the study. The study was approved by the local ethics committee of the University Medical Centre Maribor in Slovenia (UKC-MB-KME-58/20). Propensity score-matching The data from 1546 patients prospectively stored in our database was used for PSM. Patients were matched using the propensity score method as described by Rosenbaum and Rubin.18,19 The pro- pensity score for an individual was calculated on the given covariates of preoperative haemoglobin levels, age, American Society for Anaesthesiology (ASA) score and the International Union against Cancer (UICC) stage using the multivariate logistic regression model. With this method three groups of PSM patients containing 21 patients each was formed: (i) Patients with liver metastases and no liver resection (LM0); (ii) Patients with liver metas- tases and liver resection (LMR); (iii) Patients with stage III and IV gastric cancer and no liver resec- tion (CG). In all patients a gastrectomy with local curative intent was performed. Statistical analysis Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables as percentage. Continuous variables were com- pared with Student’s t-test for normally distribut- ed variables; nonparametric variables were tested with Mann-Whitney’s U-test. The cut-off levels of continuous variables were determined by means of receiver operator curves with cut-off value of AUC above 0.75 and p value of less than 0.05. Variables above the threshold p value of 0.1 were included for multivariate analysis. The Cox regression model was used for primary analysis. Estimates of treatment effect were expressed as hazard ratios with 95% confidence interval. Kaplan-Meier curves were constructed to determine time-to-event end- points. Differences in survivals between groups were determined with the Log-rank and Breslow tests. P value of >0.05 was selected as the level of significance. All statistical analyses were per- formed on SPSS for Windows 10 v. 22 (IBM). Results Patients In the final analysis 63 patients resected for gastric cancer were included. The characteristics of these patients, their tumours, and operations are pro- vided in Table 1. All three groups were balanced according to age, gender, tumour location, opera- tions, UICC and TNM stage and number of resect- ed lymph nodes. In the LM0 group, significantly less patients received chemotherapy compared to LMR and CG group (4.8% vs. 42.9% vs. 42.9%; p = 0.004). A D2 lymphadenectomy was performed significantly more often in the LMR and CG com- pared to patients in the LM0 group (LM0: 19%, LMR: 76.2% and CG: 81%; p < 0.0001). The number of harvested lymph nodes (LNs) per operation was significantly higher in LMR and CG compared to LM0 group (LM0: 18 ± 9 LNs, LMR: 27.6 ± 14.6 LNs; CG: 26 ± 17 LNs; p = 0.028). All patients in LM0 had locally microscopically negative resection margins. In LMR patients a R0 resection could be obtained in 85.7% compared to 100% in the CG (p = 0.076). LM0 patients had significantly more liver metasta- ses compared to LMR patients (p < 0.0001). Most of LM0 patients had more than three metastases (71.4%) compared to one liver metastasis usually present in LMR patients (90.5%). Patients with liver metastases (LM0 and LMR) had a tumour location almost exclusively in the middle and lower third Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer 59 TABLE 1. Patients’, tumour and operations characteristics of the included patients All patients PSM groups p LM0 LMR CG Age [years ± SD] 64.43 ± 9.9 64.9 ± 6.9 65.5 ± 10 62.7 ± 12.5 NS Gender [n(%)] Male Female 50(79.4) 13(20.6) 17(81) 4(19) 16(76.2) 5(23.8) 17(81) 4(19) NS CA 19-9 [ng(IQR)] 13(64.7) 20(32) 7(62) 5.5(351.7) NS CEA [ng(IQR)] 4(6.5) 3.5(26.7) 4(6) 3(17.25) NS Hb [g/l(IQR)] 112.5(28.25) 117.5(25) 105(41) 107(27.5) NS Chemotherapy [n(%)] Yes No 19(30.2) 44(69.8) 1(4.8) 20(95.2) 9(42.9) 12(57.1) 9(42.9) 12(57.1) 0.004 Dindo-Claviene 0 II IIIa IIIb V 50(79.4) 3(4.8) 1(1.6) 2(3.2) 7(11.1) 16(76.2) 1(4.8) 0(0) 0(0) 4(19) 18(85.7) 1(4.8) 0(0) 1(4.8) 1(4.8) 16(76.2) 1(4.8) 1(4.8) 1(4.8) 2(9.5) NS TNM T stage [n(%)] 1 2 3 4a 4b 5(7.9) 1(1.6) 36(57.1) 8(12.7) 13(20.6) 0(0) 0(0) 17(81) 2(9.5) 2(9.5) 2(9.5) 0(0) 8(38.1) 3(14.3) 8(38.1) 3(14.3) 1(4.8) 11(52.4) 3(14.3) 3(14.3) NS TNM N stage [n(%)] 0 1 2 3a 3b 6(11.1) 5(9.3) 15(27.8) 9(16.7) 19(35.2) 0(0) 3(23.1) 3(23.1) 1(7.7) 6(46.2) 3(14.3) 2(9.5) 8(38.1) 3(14.3) 5(23.8) 3(15) 0(0) 4(20) 5(25) 8(40) NS UICC stage [n(%)] IIIa IIIc IV 2(3.2) 4(6.3) 57(90.5) 0(0) 0(0) 21(100) 1(4.8) 2(9.5) 18(85.7) 1(4.8) 2(9.5) 18(85.7) NS Positive LNs [n(IQR)] 7(17.7) 11(23) 5.5(18.7) 12.5(12.2) All LNs [n±SD] 28.2±11.5 18±9 27.6±14.6 26±17 0.028 Grade [n(%)] Well Moderate Poor 6(12.5) 13(27.1) 29(60.4) 2(16.7) 4(33.3) 6(50) 2(10) 5(25) 13(65) 2(12.5) 4(25) 10(62.5) NS Type of gastrectomy [n(%)] Subtotal Total Total with distal esophagectomy Distal esophagectomy & proximal gastrectomy Stump resection 22(34.9) 34(54) 4(3.2) 2(1.6) 1(1.6) 12(57.1) 8(38.1) 0(0) 1(4.8) 0(0) 6(28.6) 14(66.7) 0(0) 1(4.8) 0(0) 4(19) 12(57.1) 4(19) 0(0) 1(4.8) NS Location [n(%)] Stump Entire Proximal Middle Distal 1(1.6) 6(9.5) 10(15.9) 20(31.7) 26(41.3) 0(0) 2(9.5) 2(9.5) 6(28.6) 11(52.4) 0(0) 9(42.9) 9(42.9) 2(9.5) 1(4.8) 1(4.8) 3(14.3) 6(28.6) 5(23.8) 6(28.6) 0.045 ASA score [n(%)] I II III 16(25.4) 32(50.8) 15(23.8) 6(28.6) 9(42.9) 6(28.6) 6(28.6) 12(57.1) 3(14.3) 4(19) 11(52.4) 6(28.6) NS Lymphadenectomy [n(%)] D1 D2 26(41.3) 37(58.7) 17(81) 4(19) 5(23.8) 16(76.2) 4(19) 17(81) < 0.0001 R0 [n(%)] 39(61.9) 0(0) 18(85.7) 21(100) < 0.0001 Number of liver metastases [n(%)] 1 2–3 > 3 23(54.8) 4(9.5) 15(35.7) 4(19) 2(9.5) 15(71.4) 19(90.5) 2(9.5) 0(0) 0(0) 0(0) 0(0) < 0.0001 Grade [n(%)] Well Moderate Poor 6(9.5) 13(27.1) 29(60.4) 2(16.7) 4(33.3) 6(50) 2(10) 5(25) 13(65) 2(12.5) 4(25) 10(62.5) NS Hospital stay [n(IQR)] 13(8.5) 12(6.5) 13.5(8) 14(12.7) NS ASA = American Society for Anaesthesiology; Ca 19-9 = carbohydrate antigen 19-9; CEA = carcinoembryonic antigen; CG = patients without liver metastases and stage III and IV resectable gastric cancer; Hb = serum hemoglobin levels; IQR = interquartile range; LM0 = patients with gastric cancer and liver metastases in whom liver resection was not performed; LMR = patients with synchronous liver metastases and gastric resection with curative intent; LNs = lymph nodes; NS = not significant; PSM = propensity score-matched; UICC = International Union against Cancer Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer60 of the stomach, while the tumour location in CG was evenly distributed in the whole stomach (p = 0.045). Surgery, morbidity and mortality There were no significant differences in the perio- perative mortality between the three groups. The perioperative morbidity in the LM0, LMR and CG was 23.8%, 14.3%, and 23.8%, respectively. Major morbidity (Dindo-Claviene > IIIb) was observed in 16.7%, 9.6%, and 14.3% in the LM0, LMR and CG group, respectively. The 30-day mortality was 9.5%, 4.8% and 9.5% in the LM0, LMR, and CG group, respectively. Although the differences were insignificant, the patients in the LMR group had the lowest perioperative morbidity and mortality. The results of surgical treatment are presented in Table 1. The characteristics of liver resections in LMR group are presented in Table 2. Metastasectomy of single metastasis was performed in most cases (57.1%), followed by segmental resection of a sin- gle metastasis (14.3%) and metastasectomy of more than 1 metastasis (14.3%). Major resection was performed only in one case (4.8%), and radio frequency ablation was performed in two cases (9.5%). The liver resections for 21 included cases, the involved liver segments and recurrence sites are documented in Table 3. The most frequent re- currence site was the liver followed by peritoneum. Notably 47.6% of cases did not have a documented recurrence after liver resection. In Table 4 the types of operations in the CG are presented. Additional resection of an involved or- gan was undertaken in 47.6% of cases. The most commonly infiltrated other organ was the tail of the pancreas (2 cases) and the local peritoneum of the bursa omentalis (8 cases). The most frequent additional resection in CG was the local peritonec- tomy, followed by left splenopancreatectomy with segmental colon resection and left splenopan- createctomy with left adrenal resection. Left pan- createctomy was associated with most morbidity, while mortality was the highest in patients with no additional resection. Multivariate analysis From the included predictors, age, gender, ASA score, Ca 19-9 serum levels, haemoglobin serum levels, additional liver resection, tumour grade, UICC stage, and TNM nodal stage were signifi- cantly associated with survival. The hazard ratios, 95% confidence intervals, and the p-values are list- ed in Table 5. Survival analysis None of the patients in the LM0 group survived 5 years. Their survival was significantly shorter com- pared to patients in the LMR group a cumulative FIGURE 1. Cumulative survivals of patients with liver metastases without resection, with liver resection and in the control group respectively. TABLE 2. Characteristics of liver resections in the group of patients with synchronous liver metastases and gastric resection with curative intent (LMR) n(%) Segment involvement I II II/III III IV V VI VII VIII 0(0) 2(8.6) 3(13) 9(39.1) 2(8.6) 2(8.6) 0(0) 3(13) 2(8.6) Liver resection Metastasectomia of 1 metastasis Metastasectomia of >1 metastasis Segmental resection Hepatectomy Radio frequency ablation 12(57.1) 3(14.3) 3(14.3) 1(4.8) 2(9.5) Dindo-Claviene morbidity 0 II IIIa IIIb V 18(85.7) 1(4.8) 0(0) 1(4.8) 1(4.8) Number of metastases 1 metastasis 2–3 metastasis > 3 metastasis 19(90.5) 2(9.5) 0(0) Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer 61 5-year survival of 14.3% (p = 0.002). The survival of LMR patients was comparable to the survival of CG patients who had a 5-year survival rate of 19%. The median survival was 4.2 months, 9.3 months and 10.2 moths in the LM0, LMR and CG group respectively. The survival plots for the cumulative survival of patients in each group are shown in Figure 1. The multivariate analysis identified age, gender, ASA score, carbohydrate antigen 19-9 (Ca 19-9) se- rum levels, haemoglobin serum levels, additional liver resection, tumour grade, UICC stage, and TNM nodal stage as significant predictors for sur- vival. These predictors were used to determine cut- off levels and determine the subgroup of patients with the greatest benefit of liver resection. With the ROC analysis we determined the cut-off for serum levels of Ca19-9, age, haemoglobin serum levels. Patients with Ca19-9 levels above 10 ng/ml had sig- nificantly worse survival (5-year survival: 0% vs. 15.4%; p = 0.003). The survival advantage was lost for R0 resections. Patients with TNM stage N0–1 had an insignificantly better survival compared to patients with TNM stage N2–3. If only R0 patients were included, patients with TNM stage N0–1 had a significantly better survival compared to patients with TNM N stage N2–3 (5-year survival: 60% for N0–1 vs. 7.7% for N2–3; p = 0.007). Patients with a A B C D E FIGURE 2. Survival of subgroups. Overall survival according age (A), tumour differentiation (B), serum CA-19 level (C), N stage of TNM (D) and serum haemoglobin (E). Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer62 was more pronounced in patients with R0 resec- tion. Five-year survival in these patients was 47.5% for well-differentiated tumours compared to 0% in patients with moderate or poor tumour differen- tiation (p = 0.006). Patients younger than 64 years had a 5-year survival of 15.6% compared to 3.8% in patients older than 64 years (p = 0.029). R0 re- sected patients with serum haemoglobin levels be- low 100 g/l before the operation had a significantly worse 5-year survival compared to patients with higher haemoglobin levels (5-year survival: 14.3% vs. 20.8%; p = 0.09). The multivariate analysis also determined gender and ASA score to be significant predictors for survival; however, we could not de- termine any cut-off levels for patient stratification. The survival plots of different subgroups are pre- sented in Figure 2. Discussion Liver metastases in gastric cancer patients usu- ally occur as part of a systemic failure and rarely present as isolated disease suitable for resec- tion.1-8,12,15-17 In the present study liver resection has only been performed in 1.36% of patients operated for gastric cancer. As a result of low incidence of resectable liver metastases prospective large-scale randomised controlled trials are not feasible and at present no clear-cut recommendations exist for liver resection of gastric cancer metastases.1-8,12,15-17 To evaluate potential benefits and prognostic fac- tors for synchronous liver metastases resections in gastric cancer patients we performed a retrospec- tive propensity score-matched study. The treatment of stage IV gastric cancer patients is still the subject of heated debates. The results of the REGATTA trial suggest that palliative resection in addition to chemotherapy does not improve sur- vival for stage IV gastric cancer patients compared to chemotherapy alone, putting in question the value of surgery in oligometastatic gastric cancer.21 However, in the REGATTA trail only palliative gastrectomies were performed limiting the value of these results in gastric cancer patients with po- tentially resectable liver metastases. In the light of emerging evidence proving benefits of liver mes- tastases resections in oligometastatic gastric cancer patients, we performed a retrospective analysis of stage IV gastric cancer patients with liver metasta- ses. The data from the present study is in accord- ance with the results of studies that show a signifi- cant increase in long-term survival in patients with liver resections in gastric cancer patients.1-8,12,15-17 TABLE 3. Characteristics of liver metastases and recurrence sites in the group of patients with synchronous liver metastases and gastric resection with curative intent (LMR) Case No. Involved segment Number of metastases Type of resection Recurrence site 1 II 1 Segmentectomy 0 2 IV 1 Metastasectomy 0 3 III 1 Segmentectomy Peritoneal carcinomatosis 4 II/III 1 Segmentectomy Liver metastases 5 III 1 Metastasectomy 0 6 VII 1 Metastasectomy 0 7 III 1 Metastasectomy Local recurrence 8 III 1 Segmentectomy Peritoneal carcinomatosis 9 VIII 1 Metastasectomy Liver metastases 10 III 1 Segmentectomy 0 11 V 1 Metastasectomy Local recurrence 12 IV, II 3 Metastasectomy Liver metastases 13 II/III 1 Metastasectomy Liver metastases 14 III 1 Metastasectomy 0 15 II/III 1 Left lateral secienectomy 0 16 III 1 Metastasectomy 0 17 III 1 Metastasectomy Peritoneal carcinomatosis 18 V, VIII 2 Metastasectomy Liver metastases 19 VII 1 Radio frequency ablation Liver metastases and peritoneal carcinomatosis 20 VII 1 Radio frequency ablation 0 21 III 1 Segmentectomy 0 TABLE 4. Morbidity and mortality of additional resections in in the control group of patients without liver metastases and stage III and IV resectable gastric cancer (CG) N (%) Morbidity (%) Mortality (%) Gastrectomy Subtotal Total Total with distal esophagectomy Stump resection 4(19) 12(57.1) 4(19) 1(4.8) 0(0) 2(16.6) 1(25) 0(0) 1(25) 1(25) 0(0) 0(0) Additional resection No additional resection Local peritonectomy Left splenopancreatectomy and segmental colon resection Left splenopancreatectomy and left adrenal resection 11(52.4) 8(4.8) 1(4.8) 1(4.8) 1(9.1) 1(12.5) 0(0) 1(100) 2(18.2) 0(0) 0(0) 0(0) well differentiated tumour had a significantly bet- ter survival compared to patients with moderate and poor tumour differentiation. This difference Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer 63 The multivariate analysis confirmed that liver resection is a significant predictor for long-term survival. Median overall survival of 4.2 months in LM0 group was similar to other studies that re- ported median survival of 0 to 15 months with un- resectable liver metastases.8 In contrast, the median overall survival in LMR group was significantly longer compared to LM0 group. In our study long- term survival of gastric cancer patients was only possible when liver metastases were resected. The comparison of results from the LM0 and LMR group might support the claim that liver re- sections have a positive impact on long-term sur- vival8,12,15-17; however, the retrospective nature of the study carries some risk of biased selection de- spite the PSM. At least six patients in LM0 group had potentially resectable metastases. Because we could not determine retrospectively the precise rea- sons for unresectability of liver metastases in these LM0 patients, local advanced stage, poor general state, anatomical location of the metastasis or some other factor not included in the propensity score calculation might have precluded a safe resection the time of operation. In order to better evaluate the potential benefit of liver resection in gastric cancer patients we compared the results of LMR patients to PSM control group of UICC stage III and IV gas- tric cancer patients (CG). In both groups, patients were well-balanced according to patients’ and tu- mour characteristics. In addition, no difference was observed in the adjuvant treatment between LMR and CG group. The long-term survival of patients in LMR was comparable to patients in CG. Based on these results, we concluded that liver resection offered a survival benefit comparable to propensity score-matched patients with stage III and IV dis- ease a R0 resection and without liver metastases. An important aspect of treatment effect evalua- tion is the safety of the procedure. The periopera- tive morbidity and mortality in the LMR group was 14.3% and 4.8% that compares favourably to results published in other studies.1-8,12-17 Notably, perioperative morbidity in LMR group was signifi- cantly better compared to CG group. This discrep- ancy in perioperative morbidity could in part be explained in the additional multivisceral resections in the CG. Pancreatic resections have been identi- fied in previous studies to increase morbidity and mortality.13,14 In fact, we observed that the pancreas tail resection was associated with 50% morbidity in the CG. This might explain a lower complication rate in the LMR group compared to CG group. The 5-year survival of LMR patients in our study was 14.3% which was comparable to other studies that reported the 5-year survival of 0% to 42% after liver resection.1-8,12,15-17 In their seminal multi-centric retrospective analysis of stage IV gastric cancer in Western patients Ministrini et al. reported 5-year survival of 11.8%.22 Although our results compare favourably to results of Ministrini et al., some stud- ies reported better long-term survival of up to 32% to 59%.12, 20 An important reason for better survival after liver resection in these repots might be that patients with metachronous liver resections were included. Metachronous resections have been de- termined to be a significant prognostic factor.7 In other studies patients proceeded to liver resection only after a course of chemotherapy, while patients in whom disease progression was determined might have been excluded. In the present report, only synchronous resections have been analysed. It was therefore impossible to exclude patients at risk for progression. In fact, patient selection is the most critical aspect of liver metastases treat- ment in gastric cancer patients. Unfortunately, no clear recommendations for patients’ selection exist yet. In our study, the multivariate analysis identi- fied age, gender, ASA score, Ca 19-9 serum levels, haemoglobin serum levels, additional liver resec- tion, tumour grade, UICC stage, and TNM nodal stage as significant predictors for long-term sur- vival in LMR patients. The most powerful predic- tor for long-term survival was the TNM N stage of the primary tumour. The 5-year survival of LMR patients with N0-1 stage was 47.5% and even 60% in patients with TNM stage N0-1 and R0 resec- tion. These results are comparable even to results TABLE 5. Cox proportional hazard model for survival after gastric cancer resection with liver metastases HR 95% CI p Lower Upper Age 1.497 1.213 1.846 <0.0001 Gender 55.237 4.626 659.594 0.002 ASA score 0.049 0.009 0.261 <0.0001 Ca 19-9 1 1 1.001 0.02 Hb 0.918 0.864 0.974 0.005 Additional liver resection 0.001 0 0.029 <0.0001 Tumour grade 8.276 1.971 34.753 0.004 UICC stage 0 0 0.003 0.002 TNM N stage 0.386 0.163 0.917 0.031 ASA = American Society for Anaesthesiology; Ca 19-9 = carbohydrate antigen 19-9; CI = confidence interval; Hb = serum hemoglobin levels [g/l]; HR = hazard ratio; UICC = International Union against Cancer Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer64 published by Tasubayashi et al. who reported a 5-year overall survival of 59%.12 Our results sug- gest that patients with a higher nodal stage of the primary tumour were at higher risk for systemic recurrence. They would probably progress after adjuvant treatment and would not be candidates for metachronous resection. Therefore, high nodal stage might be a valuable negative selection criteri- on when considering synchronous liver resection. As we further stratified patients, we deter- mined additional subgroups with the greatest sur- vival benefit. Patients with serum levels of Ca 19- 9 below 10 ng/ml had a 5-year survival of 15.4%. Similar long-term survival was observed in pa- tients younger than 64 years (15.6%). Patients with preoperative haemoglobin levels of more than 100 g/l had a 5YS of 20.8%. Next to the TNM N stage, tumour grade was found to have the most signifi- cant impact on long-term survival. Patients with a well-differentiated tumour had a 5-year survival of 47.5% compared to 0% in moderate to poor dif- ferentiated tumour. As these predictors are linked to inherent tumour biology, probably the most im- portant determinants for behaviour of liver metas- tases are intrinsic tumour properties that have yet to be determined in future studies. Our study has some limitations. It is a retrospec- tive study with a limited number of included pa- tients. Secondly, although the patients were select- ed with propensity score-matching, some selection bias could have still been present, since not all se- lection criteria have been included in the propensi- ty score calculation. And finally, only synchronous metastases have been included in the analysis. Conversely, since isolated liver metastases occur only in small number of resectable gastric cancer, most of the presently published studies have only a small number of cases. Still, these studies have a significant merit as they help build recommenda- tions for the treatment of liver metastases in gas- tric cancer patients. In the present paper we could show that synchronous liver resection in selected cases is beneficial since patients might expect simi- lar long-term survival as R0 resected stage IV gas- tric cancer patients without liver metastases. The liver resection was identified as an independent prognostic factor on multivariate analysis. Based on results of our study, we determined selection criteria for liver resection of synchronous gastric cancer metastases. Conclusions In conclusion, our results confirm that synchro- nous liver resection in gastric cancer patients is safe and offers significant survival benefit compared to chemotherapy alone. Moreover, after resection of liver metastases with curative intent, patients might expect similar long-term survival as PSM pa- tients with stage III and IV gastric cancer without liver metastases and R0 resection. In addition, we determined that patients benefiting the most from synchronous liver resection are patients younger than 64 years, with less than three liver metastases, Ca 19-9 serum levels below 10 ng/ml, well-differ- entiated primary tumours, and TNM N0–1 stage, provided an R0 resection can be obtained. Future prospective randomized studies will have to con- firm the value of these selection factors to provide clear-cut guidelines for treatment of gastric cancer patients with liver metastases. References 1. Takemura N, Saiura A, Koga R, Arita J, Yoshioka R, Ono Y, 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: 951-7. doi: 10.10007/s00423-012-0959-z 2. Sarel AI, Yelluri S. Gastric adenocarcinoma with distant metastasis: is gastrectomy necessary? Arch Surg 2007; 142: 14349. doi: 10.1001/arch- surg.142.2.143 3. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Transtuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-esophageal junction cancer (ToGa): a phase 3, open-label, randomised controlled trial. Lancet 2010; 37: 687-97. doi: 10.1016/s0140-6736(10)61121-x 4. Kataoka K, Kinoshita T, Moehler M, Mauer M, Shitara K, Wagner AD, et al, On behalf of EORTIC GITCG Group and JCOG SCGS Group. Current manage- ment of liver metastases from gastric cancer: what is common practise? New challenge of EORTIC and JCOG. Gastric Cancer 2017; 20: 904-12. doi: 10.1007/s10120-017-0696-7 5. Kinoshita T, Kinoshita T, Saiua A, Esaki M, Sakamoto H, Yamanaka T. Multicentre analysis of long-term outcome after surgical resection for gastric cancer liver metastases. Br J Surg 2015; 102: 102-7. doi: 10.1002/ bjs.9684 6. Zacherl J, Zacherl M, Scheuba C, Steininger R, Wenzel E, Mühlbacher Jakesz R, et al. Analysis of hepatic resection of metastasis originating from gastric adenocarcinoma. J Gastrointestinal Surg 2002; 6: 682-9. doi: 10.1016/ s1091-255x(01)00075-0 7. Schildberg CW, Croner R, Merkel S, Schellerer V, Müller V, Yedibela S, et al. Outcome of operative therapy of hepatic metastatic stomach carcinoma: A retrospective analysis. World J Surg 2012; 36: 872-8. doi: 10.1007/s00268- 012-1492-5 8. Sakamoto Y, Sano T, Shimada K, Esaki M, Saka M, Fukagawa T, et al. Favorable indications for hepatectomy in patients with liver metastasis from gastric cancer. J Surg Oncol 2007; 95: 534-9. doi: 10.1002/jso.20739 9. Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, et al. The Clavien-Dindo classification of surgical complications: five-year experi- ence. Ann Surg 2009; 250: 187-96. doi: 10.1097/SLA.0b013e3181b13ca2 Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer 65 10. Strasberg SM. Nomenclature of hepatic anatomy and resections: a review of the Brisbane 2000 system. J Hepatobiliary Surg 2005; 12: 351-5. doi: 10.1007/s00534-005-0999-7 11. Jiu-Yang Liu, Chun-Wei Peng, Xiao-Jun Yang, Chao-Qun Huang, Yan Li. The prognosis role of AJCC/UICC 8th Edition staging system in gastric cancer, a retrospective analysis. Am J Transl Res 2018; 10: 292-303. PMID: 29423014 12. Tatsubayashi T, Tanizawa Y, Miki Y, Tokunaga M, Bando E, Kawamura T, et al. Treatment outcomes of hepatectomy for liver metastases of gastric cancer diagnosed using contrast-enhanced magnetic resonance imaging. Gastric Cancer 2017; 20: 387-93. doi: 10.1007/s10120-016-0611-7 13. Hartgrink HH, van de Velde CJ, Putter H, Bonenkamp JJ, Klein Kranenbarg E, Songun I, et al. Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial. J Clin Oncol 2004; 22: 2069-77. doi: 10.1200/JCO.2004.08.026 14. Cuschieri A, Fayers P, Fielding J, Craven J, Bancewicz J, Joypaul V, et al. Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: Preliminary results of the MRC randomised controlled surgical trial. The surgical cooperative group. Lancet 1996; 347: 995-9. doi: 10.1016/ s0140-6736(96)90144-0 15. Jung JO, Nienhüser H, Schleussner N, Schmidt T. Oligometastatic gas- troesophageal adenocarcinoma: molecular pathophysiology and current therapeutic approach. Inter J Mol Sciences 2020; 21: 3-24. doi: 10.3390/ ijms21030951 16. Oki E, Tokunaga S, Emi Y, Kusumoto T, Yamamoto M, Fukuzawa K, et al. Kyushu Study Group of Clinical Cancer. Surgical treatment of liver metasta- sis of gastric cancer: a retrospective multicenter cohort study (KSCC1302). Gastric Cancer 2016; 19: 968-76. doi: 10.1007/s10120-015-0530-z 17. Fujitani K, Yang HK, Mizusawa J, Kim YW, Terashima M, Han SU, et al. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet 2016; 17: 309-18. doi: 10.1016/S1470- 2045(15)00553-7 18. Rosenbaum PR, Rubin DB. The central role of the propensity score in ob- servational studies for causal effects. Biometrika 1983; 70: 41-55. 10.1093/ biomet/70.1.41 19. Li M. Using the propensity score method to estimate causal effects: a review and practical guide. Organ Res Methods 2012; 15: 1-39. doi: 10.1177/1094428112447816 http://orm.sagepub.com 20. Makino H, Kunisaki C, Izumisawa Y, Tokuhisa M, Oshima T, Nagano Y, et al. Indication for hepatiec resection in treatment of liver metastasis from gastric cancer. Anticancer Res 2010; 30: 2367-76. doi: 10.1016/S1470- 2045(15)00553-7 21. Fujitani K, Yang HK, Mizusawa J, Terashima M, Han SU, Iwasaki Y, et al. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, ran- domised controlled trial. Lancet Oncol 2016; 17: 1-10. doi: 10.1016/S1470- 2045(15)00553-7 22. Ministrini S, Bencivenga M, Solaini L, Cipollari C, Sofia S, Marino E, et al. Stage IV gastric cancer: The surgical perspective of the Italian Research Group on Gastric Cancer. Cancers 2020; 12: 1-14. doi: 10.3390/can- cers12010158