Surgical treatment of liver metastases of gastric cancer: is local treatment in a systemic disease worthwhile?

Transcription

1 DOI: /j x HPB ORIGINAL ARTICLE Surgical treatment of liver metastases of gastric cancer: is local treatment in a systemic disease worthwhile? Mattia Garancini, Fabio Uggeri, Luca Degrate, Luca Nespoli, Luca Gianotti, Angelo Nespoli, Franco Uggeri & Fabrizio Romano Department of Surgery, San Gerardo Hospital, University of Milan Bicocca, Monza, Italy Abstracthpb_ Objectives: The prognosis of patients with liver metastases of gastric cancer (LMGC) is dismal, but little is known about prognostic factors in these patients; thus justification for surgical resection is still controversial. The purpose of this study was to review recent outcomes of hepatectomy for LMGC and to determine which patients represent suitable candidates for surgery by assessing surgical results and clinicopathologic features. Methods: Outcomes in 21 patients with LMGC who underwent hepatectomy between 1998 and 2007 were assessed. Isolated metastases and potential to perform a curative resection were requisite indications for surgery. Surgical outcome and clinicopathologic features of the hepatic metastases were analysed. Results: Overall 1-, 3- and 5-year survival rates after hepatic resection were 68%, 31% and 19%, respectively; three patients survived for >5 years without recurrence. Univariate analysis revealed a solitary metastasis, negative margin (R0) resection and the presence of a peritumoral fibrous capsule as significant favourable prognostic factors. These characteristics were present in all of the three patients who survived for >5 years. Conclusions: Solitary metastases from gastric cancer should be treated surgically and confer a better prognosis. Surgical resection should provide microscopically negative margins (R0). A new prognostic factor, the presence of a pseudocapsule, may be associated with improved prognosis. Keywords gastric cancer, liver resection, metastases, prognosis, fibrous pseudocapsule, surgery Received 25 August 2011; accepted 5 December 2011 Correspondence Fabrizio Romano, Department of Surgery, San Gerardo Hospital, University of Milan Bicocca, Via Donizetti 106, Monza, Italy. Tel: Fax: fabrizio.romano@ unimib.it, fabriziorom@hotmail.com Introduction Although the effectiveness of liver resection for metastatic colorectal cancer has already been established, 1 3 reports of hepatic resection for liver metastases of gastric cancer (LMGC) are rare and its efficacy is still controversial. 4 In fact, a number of studies have reported that the effects and benefits of hepatic resection in either synchronous or metachronous gastric hepatic metastases (GHM) are dubious. 5 Surgical indications for liver metastases from colorectal cancer have been expanded to include all technically resectable metastases under four or more. 6 Yet, the surgical indications for LMGC must be carefully determined because of the more severe biologic nature of this disease. 7 Most patients with gastric cancer with concomitant liver metastases are excluded as candidates for potential curative surgery because of the presence of synchronous distant extrahepatic or locally advanced disease. 8 In fact, GHM often represent only part of a generalized spread of the primary tumour. Furthermore, very few patients with GHM are good candidates for liver surgery because most patients have multiple, scattered, bilobar lesions. 9 Patients with isolated metastases are unusual and accounted for 0.5% of patients in a series reported by Linhares

2 210 HPB et al. 10 Baba et al. have shown that outcomes in patients who undergo non-curative resection for advanced gastric cancer are extremely poor. 11 Several authors have reported limited experiences of surgical resection of GHM in selected patients, with 5-year survival rates of 0 38% Therefore, identifying the patients who are most likely to benefit from surgical intervention in the presence of GHM is clinically important. The aim of this study was to review a single-institution experience to determine the benefits of hepatic resection in patients with GHM and to identify important prognostic factors. Materials and methods A total of 984 patients with gastric cancer (adenocarcinoma) underwent surgery at the Department of Surgery, San Gerardo Hospital, University of Milan Bicocca, between January 1998 and December Of these, 36 patients (3.7%) had synchronous liver metastases and 31 patients (3.2%) developed metachronous liver metastases after resection of the primary gastric cancer. Of these 67 patients, 21 (31.3%) consecutive patients underwent hepatic resection with intent to cure and were selected for this study. Outcomes in these patients were retrospectively reviewed. Criteria for resection of hepatic metastases from gastric cancer were as follows: (i) no local relapse of the primary tumour in metachronous metastases and curative resection of the primary tumour and lymph node involvement proved or thought to be technically possible in synchronous disease; (ii) no evidence of disseminated disease after staging investigations, and (iii) ability to achieve a microscopically margin-negative (R0) hepatic resection. Patients undergoing synchronous en bloc resections of gastric cancer directly invading the liver were not included in this study. Synchronous liver metastases were defined by detection before or during surgery, or within 3 months of primary tumour resection. The following clinicopathologic factors were analysed and subgroups divided according to each variable were compared: age; gender; status of serosal invasion; histologic differentiation of the primary tumour; status of lymph node metastases; temporal relationship of metastases with primary disease (synchronous or metachronous); tumour distribution; size and number of liver metastases; type of hepatic resection; surgical margin and completeness of the resection; presence of a pseudocapsule between the metastasis and the liver parenchyma (defined as a wall of fibrotic tissue between the tumour and the normal parenchyma); histologic differentiation of the GHM, and vascular invasion present within the GHM. In each patient intraoperative liver ultrasound was performed to assess the extent and number of hepatic lesions and their relationships to intrahepatic vascular and biliary structures. Preoperative workup included computed tomography and/or magnetic resonance imaging. Liver surgical procedures were classified as anatomic resection (segmentectomy and hemi-hepatectomy) or limited resection (for all resections less extensive than segmentectomy). Operative death was defined as death occurring within 30 days of the operation; in-hospital death was defined as any death occurring before discharge. Morbidity included any type of complication, whether surgical or non-surgical. Overall survival time was measured from the date of hepatic resection to the date of death from any cause. All patients were observed at intervals of 3 4 months during the first 2 years of the study and every 6 months or 12 months thereafter for 3 years. Statistical analysis Data were analysed using spss Version 19 (SPSS, Inc., Chicago, IL, USA) for survival analysis, univariate analysis and Kaplan Meier curves. Comparisons of categorical and continuous variables were performed using the chi-squared test and the Wilcoxon test, respectively. Survival data were compared with the log rank test. Variables with a P-value of <0.1 in the univariate analysis were entered into a Cox regression analysis. A P-value of <0.05 was considered to indicate statistical significance. Results Of the 21 patients, 14 were men. The median age of the patients was 64 years (range: years). Clinicopathologic characteristics of the patients and data on primary tumours and metastases are depicted in Table 1. Surgical procedures for primary gastric cancer included 11 partial gastrectomies and 10 total gastrectomies. The primary gastric tumour proved to be well to poorly differentiated adenocarcinoma of the stomach in all patients. Serosal invasion was present in eight patients. The median maximum size of the metastatic tumours was 3.0 cm (range: cm). Tumour locations are reported in Table 1. Hepatic resections included four hemi-hepatectomies, five segmentectomies (anatomical resections) and 12 wedge resections (non-anatomical or limited resections). Blood transfusion was required in five patients. In the nine patients who underwent metachronous liver resection, the median interval between gastric resection and the diagnosis of hepatic metastasis [disease-free interval (DFI)] was 10 months (range: 5 15 months). These patients showed no evidence of hepatic involvement at the time of surgery for the primary tumour. In 19 patients the resection was classified as curative (R0), whereas microscopically positive margins were identified in two patients. With regard to pathologic features in the peritumoral section of the metastatic lesion, fibrosis (fibrous pseudocapsule) was found in 12 patients. In-hospital and 30-day postoperative mortality was zero. The overall morbidity rate was 19.0% (four patients); complications comprised transient liver failure, bile leakage, pleural effusion and wound infection in one patient each. Median follow-up was 20 months (range: 6 90 months). Overall 1-, 3- and 5-year survival rates were 68%, 31% and 19%, respectively. Median survival was 11 months. Rates of 1-, 3- and 5-year disease-free survival were 51%, 25% and 14%,

3 HPB 211 Table 1 Clinicopathologic characteristics and their prognostic significance Variable Patients, n Proportion surviving, % P-value 1 year 3 years Gastric carcinoma Lymph node metastasis N0 N N Serosal invasion Absent Present Hepatic metastases Solitary Multiple Lobar distribution Unilobar Bilobar Tumour size <5 cm cm Histologic differentiation Good Moderate, poor Vascular invasion Absent Present Fibrous pseudocapsule Present Absent Surgery Timing of hepatectomy Synchronous Metachronous Resection margin Negative Positive Type of surgery Anatomic Non-anatomic respectively. Three patients remain alive and disease-free at >5 years after the surgical procedure. All three of these patients had a solitary metastasis with a fibrous pseudocapsule. In the 19 patients in whom was achieved, 1-, 3- and 5-year survival rates were 71%, 35% and 24%, respectively, whereas the marginpositive procedures in two patients resulted in impaired survival and both patients died within 1 year of resection. Recurrence occurred in 14 patients. In 13 of these patients, disease recurred within the liver. No patient underwent a second hepatic resection for recurrent intrahepatic metastasis. The results of univariate analysis identifying poor prognostic factors are depicted in Table 1. Discussion In a review of the literature, hepatectomy was found to be indicated in only % of gastric cancer patients with liver metastases. 4 Unfortunately, most hepatic metastases from gastric adenocarcinoma are multiple, bilateral and combined with peritoneal or lymph node metastases, which directly invade adjacent

4 212 HPB organs, thereby precluding a radical surgical approach. 4 At specialized treatment centres, the proportion of surgery carried out for LMGC is 7%, whereas that of hepatic resection for all types of hepatic malignancies is 12%. 15 Resectability does not seem to be affected by the presence of metachronous or synchronous metastases. 16 The effectiveness of hepatic resection for GHM has not been well defined. In addition, clinicopathologic factors that affect the prognosis of patients with gastric cancer with hepatic metastases have not been comprehensively identified. Nevertheless, the presence of hepatic metastases is a statistically significant poor prognostic factor for patients with gastric cancer. 17 In recent series, 1-year survival rates have ranged from 42% to 90% and 5-year survival rates from 0% to 38% (Table 2). Most studies concerning this issue come from Japan, where reported longterm survival rates exceed 30% in some series. 14,18 By contrast, Zacherl et al. reported a study in which no patients survived 5 years after resection. 15 Bines et al. 19 reported one longterm survivor in seven patients and other series have shown longterm survival rates of 11 19%. Although they are few, some longterm survivors after hepatic resection have been reported. Therefore, determining the indications for liver resection in the presence of GHM is crucial. The 5-year survival rate identified in this series is 19%. Three longterm survival patients were identified, by contrast with findings in another report from a Western country. 15 None of the clinicopathologic features related to the primary gastric cancer were predictors of survival. Ochiai et al. 20 reported that hepatic resection should only be attempted in patients with synchronous or metachronous metastases in the absence of serosal or microscopic lymphovascular invasion of the primary tumour. 21 Zacherl et al. 15 reported that tumour localization in primary gastric cancer was a marginally predictive negative factor for the overall survival of patients. Tsujimoto et al. 22 identified gastric cancer tumour size as a predictor of poor survival. In the current study, the presence of a solitary metastasis was a positive predictor for survival. The number of metastatic nodules in the liver has been reported to be an important prognostic factor in previous studies. Okano et al. 18 reported 3-year survival rates of 56% in patients with a single metastasis and 0% in patients with multiple metastases. Koga et al. 16 and Shirabe et al. 21 reported no longterm survivors in patients with multiple gastric liver metastases. In a more recent study, Sakamoto et al. 23 also reported the value of a solitary lesion, adding to the evidence in support of unilobar distribution as a good predictive factor for survival. However, Saiura et al. 24 reported two longterm survivors with more than three metastases and concluded that, if curative resection (R0) can be achieved, hepatic resection should not be abandoned even in patients with multiple liver metastases. In fact, even in this series proved key to achieving good survival and every effort should be made to achieve radical resection with an adequate margin because this is the only factor on which the surgeon can have any direct influence. Miyazaki et al. 25 demonstrated significant differences in the size of the tumour-free resection margin (<10 mm or >10 mm) in long- and short-term survivors. Thelen et al. 13 reported that a positive resection margin should be considered a powerful determinant of poor outcome. Nomura et al. 26 showed that the recurrence rate in the remnant liver was higher in patients with a surgical margin of <5 mm. Isono et al. 27 reported that micrometastases around the macroscopic tumour were found more frequently in hepatic metastases from gastric cancer than in those from colorectal cancer. According to the pattern of recurrence, relapse developed most commonly in the liver (median: 70%; range: %), indicating that relapse monitoring should focus on the remaining liver. A sensible strategy for improving survival would involve close observation for a second relapse in the liver and the provision of adjuvant chemotherapies after surgery. In this series, only one patient received a postoperative hepatic arterial infusion; this patient survived 38 months. In terms of adjuvant therapy, however, no conclusions can be based on these data. The timing of hepatic resection has been reported to be a significant prognostic factor and some papers have reported synchronous hepatectomy as a significant poor prognostic factor. 5,19 Nevertheless, an analysis of the data reported in the recent literature showed that 22 of 48 5-year survivors underwent synchronous hepatectomy. 23 Thus, synchronous hepatectomy should not be a contraindication for hepatic resection. The data reported in the present study show comparable median survival rates in patients with synchronous and metachronous lesions. With regard to perioperative morbidity, the current results confirm the observation of Bines et al. 19 that synchronous liver resection carries a higher risk. Moreover, the DFI between gastric and hepatic resection has been reported to represent a prognostic factor. Fujii et al. 28 showed that a DFI of >1 year had a significant survival advantage as a result of the slow-growing nature of this tumour. However, this trend was not confirmed in the present study. The aggregation of lymphocytes enclosing the metastatic tumour was reported as a good prognostic factor by Fujii et al. 28 This may be explained by the favourable action of tumourinfiltrating lymphocytes (TILs) in preventing tumour extension in gastric cancer patients. 29 Okano et al. 18 demonstrated that the presence of fibrous pseudocapsules around liver metastases is a promising indicator of a better prognosis and is closely associated with patient survival. The formation of a pseudocapsule should be considered as a protective immunoinflammatory reaction against the metastastic nodule and as representing the host defence reaction of creating a wall to stop tumour diffusion. Conclusions Although some authors hold the view that metastatic gastric cancer represents a systemic disease and indicates a diffuse cancer, and that surgery has no role in its treatment, a considerable proportion of patients in the present as well as former series were

5 HPB 213 Table 2 Literature analysis regarding hepatectomy for liver metastases from gastric cancer Author(s) (year) n Period Resection criteria Resectability rate, % S/M TG/STG Major/ minor liver surgery Solitary Multiple uni-/bilobar R1, % Overall survival at 1, 3, 5 years Longterm survivors, %(n) Recurrence Follow-up, months Prognostic factors for poor survival Ochiai et al. 21 No extrahepatic lesions NA 13/8 NA % 19% (4) Primary serosal invasion (1994) 20 No carcinosis Primary venous invasion Primary lymphatic invasion Miyazaki et al. 21 No extrahepatic lesions NA 11/10 5/ NA 45%, 24% (5) 76.1% NA Primary serosal invasion (1997) 25 19%, No carcinosis 11/3 11% Primary venous invasion Primary lymphatic invasion Surgical margin of <10 mm Imamura et al No extrahepatic lesions NA 7/10 NA 6/ % 47%, 0 76% NA Primary serosal invasion (2001) 12 22%, No carcinosis 4/5 0% Primary venous invasion Primary lymphatic invasion Extrahepatic disease Ambiru et al No extrahepatic lesions NA 18/22 19/21 21/ %, 15% (6) 75% 88 Resection margin of <10 mm (2001) 5 28%, No carcinosis 5/16 18% Synchronous Fujii et al NA NA 3/7 3/7 6/4 6 4 NA 60%, 10% (1) 80% DFI <1 year on metachronous (2001) 28 20%, 2/2 20% Diameter >5 cm Absence of TILs Zacherl et al No extrahepatic lesions NA 10/5 9/6 3/ %, 0 90% NA Primary site (proximal) (2002) %, No carcinosis 2/5 0% Synchronous Multiple bilobar metastases R1 resection Saiura et al No extrahepatic lesions 15.6% 7/3 NA 6/ % 65%, (2002) 24 38%, 3 segments 4/1 20% 20% (2) 80% 1 68 Primary lymphatic invasion Okano et al No extrahepatic lesions 17% 13/6 NA 7/ %, 14% (3) 74% NA Multiple (2002) 18 34%, No carcinosis 2/7 34% Synchronous Absence of pseudocapsule Sakamoto et al No extrahepatic lesions 8% 12/10 10/12 3/ %, 20% (5) 68% NA Multiple (2003) 14 38%, No carcinosis 1/5 38% Bilobar Metastases >5 cm Shirabe et al NA NA 16/20 17/19 10/16 NA NA 0 64%, (2003) 21 43%, 26% 11% (4) 83.3% NA Lymphatic invasion Venous invasion Number of metastases

6 214 HPB Table 2 Continued Author(s) (year) n Period Resection criteria Resectability rate, % S/M TG/STG Major/ minor liver surgery Solitary Multiple uni-/bilobar R1, % Overall survival at 1, 3, 5 years Longterm survivors, %(n) Recurrence Follow-up, months Prognostic factors for poor survival Koga et al No extrahepatic lesions 17% 20/22 NA 7/ %, 20% (8) 67% 1 86 Multiple (2007) 16 48%, No carcinosis 42% Serosal invasion Sakamoto et al No extrahepatic lesions 12% 16/21 10/27 5/ % 60%, 6% (2) 81% NA Bilobar (2007) 23 27%, 9/7 11% Metastases >4 cm No carcinosis Thelen et al No carcinosis NA 15/9 NA 8/ % 38%, (2008) 13 16%, 5/6 10% 8% (2) 65% 1 67 Resection margin Cheon et al No extrahepatic lesions 7.5% 18/4 7/15 3/ NA 77%, (2008) %, No carcinosis 3/1 23% 15% (3) 63.6% Multiple metastases Hepatic function Nomura et al No extrahepatic lesions NA 9/8 NA 3/14 NA NA % 25% (4) 70.5% Presence of micrometastases (2009) 26 No carcinosis 5 lesions Tsujimoto et al No extrahepatic lesions NA 9/8 NA 6/ NA 31% 30% (5) 70% NA Primary size >6 cm (2010) 22 No carcinosis D2 resection Unilobar Present study (2010) No extrahepatic lesions 31% 12/9 10/11 4/ % 68%, 14.2% (3) 66% 6 90 Multiple 31%, No carcinosis 4/5 19% Resection margin positive Absence of pseudocapsule S, synchronous; M, metachronous; TG, total gastrectomy; STG, subtotal gastrectomy; NA, data not available; DFI, disease-free interval; TILs, tumour-infiltrating lymphocytes.

7 HPB 215 found to be tumour-free at >5 years after liver resection. The present authors believe that surgery may provide a benefit and should be part of a multidisciplinary approach in patients with LMGC. 31 Solitary metastases, the ability to achieve, and the presence of a pseudocapsule are determinants of improved survival. Conflicts of interest None declared. References 1. Kemeny N. (2006) Management of liver metastases from colorectal cancer. Oncology 20: Minagawa M, Makuuchi M, Torzilli G, Takayama T, Kawasaki S, Kosuge T et al. (2000) Extension of the frontiers of surgical indication in the treatment of liver metastases from colorectal cancer. Ann Surg 231: Primrose JN. (2010) Surgery for colorectal liver metastases. Br J Cancer 102: Shirabe K, Wakiyama S, Gion T, Watanabe M, Miyazaki M, Yoshinaga K et al. (2006) Hepatic resection for the treatment of liver metastases in gastric carcinoma: review of the literature. HPB (Oxford) 8: Ambiru S, Miyazaki M, Ito H, Nakagawa K, Shimizu H, Yoshidome H et al. (2001) Benefits and limits of hepatic resection for gastric metastases. Am J Surg 181: Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. (1999) Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 230: Kakeji Y, Morita M, Maehara Y. (2010) Strategies for treating liver metastases from gastric cancer. Surg Today 40: Ueda K, Iwahashi M, Nakamori M, Nakamura M, Naka T, Ishida K et al. (2009) Analysis of the prognostic factors and evaluation of surgical treatment for synchronous liver metastases from gastric cancer. Langenbecks Arch Surg 394: Fujisaki S, Tomita R, Nezu T, Kimizuka K, Park E, Fukuzawa M. (2001) Prognostic studies on gastric cancer with concomitant liver metastases. Hepatogastroenterology 48: Linhares E, Monteiro M, Kesley R, Santos CE, Filho OS, Simoes JH. (2003) Major hepatectomy for isolated metastases from gastric adenocarcinoma. HPB (Oxford) 5: Baba H, Okuyama T, Hiroyuki O, Anai H, Korenaga D, Maehara Y. (1992) Prognostic factors for non-curative gastric cancer: univariate and multivariate analysis. J Surg Oncol 51: Imamura H, Matsuyama Y, Shimada R, Kubota M, Nakayama A, Kobayashi A et al. (2001) A study of factors influencing prognosis after resection of hepatic metastases from colorectal and gastric carcinoma. Am J Gastroenterol 96: Thelen A, Jonas S, Benckert C, Lopez-Hänninen E, Neumann U, Rudolph B et al. (2008) Liver resection for metastatic gastric cancer. Eur J Surg Oncol 34: Sakamoto Y, Ohyama S, Yamamoto J, Yamada K, Seki M, Ohta K et al. (2003) Surgical resection of liver metastases of gastric cancer: an analysis of a 17-year experience with 22 patients. Surgery 133: Zacherl J, Zacherl M, Scheuba C, Steininger R, Wenzl E, Muhlbacher F et al. (2002) Analysis of hepatic resection of metastases originating from gastric adenocarcinoma. J Gastrointest Surg 6: Koga R, Yamamoto J, Ohyama S, Saiura A, Seki M, Yasuyuki S et al. (2007) Liver resection for metastatic gastric cancer: experience with 42 patients including eight longterm survivors. Jpn J Clin Oncol 37: Kwak CM, Wu CW, Lo SS, Shen KH, Hsieh MC, Lui WY. (2004) Survival of gastric cancer with concomitant liver metastases. Hepatogastroenterology 51: Okano K, Maeba T, Ishimura K, Karasawa Y, Goda F, Wakabayashi H et al. (2002) Hepatic resection for metastatic tumours from gastric cancer. Ann Surg 235: Bines SD, England G, Deziel DJ, Wiit TR, Doolas A, Roseman DL. (1993) Synchronous, metachronous and multiple hepatic resections of liver tumours originating from primary gastric tumours. Surgery 114: Ochiai T, Sasako M, Mizuno S, Kinoshita T, Takayama T, Kosuge T et al. (1994) Hepatic resection for metastatic tumours from gastric cancer: analysis of prognostic factors. Br J Surg 81: Shirabe K, Shimada M, Matsumata T, Higashi H, Yakeishi Y, Wakiyama S et al. (2003) Analysis of the prognostic factors for liver metastases of gastric cancer after hepatic resection. A multi-institutional study of the indications for resection. Hepatogastroenterology 50: Tsujimoto H, Ichikura T, Ono S, Sugasawa H, Hiraki S, Sakamoto N et al. (2010) Outcomes for patients following hepatic resection of metastatic tumours from gastric cancer. Hepatol Int 4: Sakamoto Y, Sano T, Shimada K, Esaki M, Saka M, Fukagawa T et al. (2007) Favourable indications for hepatectomy in patients with liver metastases from gastric cancer. J Surg Oncol 95: Saiura A, Umekita N, Inoue S, Maeshiro T, Miyamoto S, Matsui Y et al. (2002) Clinicopathological features and outcome of hepatic resection for liver metastases from gastric cancer. Hepatogastroenterology 49: Miyazaki M, Itoh H, Nakagawa K, Ambiru S, Shimizu H, Togawa A et al. (1997) Hepatic resection of liver metastases from gastric carcinoma. Am J Surg 92: Nomura T, Kamio Y, Takasu N, Moriya T, Takeshita A, Mizutani M et al. (2009) Intrahepatic micrometastases around liver metastases from gastric cancer. J Hepatobiliary Pancreat Surg 16: Isono T, Miyazaki M, Udagawa I, Koshikawa H, Iimura F, Itoh H. (1992) The clinicopathological study of intrahepatic micrometastases in hepatic metastases carcinoma: comparison between hepatic metastases from gastric cancer and colorectal cancer. J Jpn Soc Cancer Ther 27: Fujii K, Fujioka S, Kato K, Machici Y, Kutsuna Y, Ishikawa A et al. (2001) Resection of liver metastases from gastric adenocarcinoma. Hepatogastroenterology 48: Romano F, Cesana G, Caprotti R, Bovo G, Uggeri F, Piacentini MG et al. (2006) Preoperative IL-2 immunotherapy enhances tumour infiltrating lymphocytes (TILs) in gastric cancer patients. Hepatogastroenterology 53: Cheon SH, Rha SY, Jeung HC, Im CK, Kim SH, Kim HR et al. (2008) Survival benefit of combined curative resection of the stomach and liver in gastric cancer patients with liver metastases. Ann Oncol 19: Kim NK, Park YS, Heo DS, Suh C, Kym SY et al. (1993) A phase III randomized study of 5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin and mitomycin C versus 5-fluorouracil alone in the treatment of advanced gastric cancer. Cancer 71: