Journal of Surgical Oncology 2015;111:1021–1027
Hepatic Resection for Gastric Cancer Liver Metastases: A Systematic Review and Meta-Analysis FAUSTO PETRELLI, MD, ANDREA COINU, MD, MARY CABIDDU, MD, MARA GHILARDI, MD, KAREN BORGONOVO, MD, VERONICA LONATI, AND SANDRO BARNI, MD Department of Oncology, Division of Medical Oncology, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy
Background: Resection of liver metastases from gastric cancer (GC) is rarely performed, and the outcome after hepatic surgery has not been systematically evaluated in the literature. The aim of this study was to perform a systematic review of outcome and prognostic factors for survival after liver metastasectomy for GC. Methods: We performed a meta-analysis of published studies that focused on long-term outcomes (5-year overall survival [OS]) after surgical management of liver metastases from GC, and included more than 10 patients each. Pooled hazard ratios (HRs) were calculated for variables considered as potential prognostic factors for OS in at least three publications. Results: Twenty-three studies comprising a total of 870 patients were considered in this analysis. The pooled weighted median OS was 22 months (95%CI 17.6–27.2). The pooled 5-year OS after liver resection was 23.8% (95%CI 19–29.3%). The pooled 5-year OS rates for metachronous and synchronous metastases were 30% (95%CI 24.7–35.8%) and 22.6% (95%CI 14–34.4%), respectively. Parameters associated with poor survival were (i) multiple metastases, and (ii) large size of metastases. Conclusions: Hepatic resection of GC liver metastases is associated with an acceptable 5-year OS, in particular after surgery of metachronous lesions, and could be offered to selected patients.
J. Surg. Oncol. 2015;111:1021–1027. ß 2015 Wiley Periodicals, Inc.
KEY WORDS: gastric cancer; liver metastases; surgery; 5-year survival; meta-analysis
INTRODUCTION Gastric cancer (GC) is a lethal disease, with a high rate of mortality after diagnosis. In fact, in approximately 50% of patients the disease extends beyond locoregional confines, and only one-half of those who appear to have locoregional tumor involvement can undergo a potentially curative resection. The most common metastatic sites are the liver, peritoneal surface, and distant lymph nodes. Palliative surgery in advanced disease is potentially useful for patients with obstructive or bleeding primary GC. The real benefits in terms of costs and morbidity of surgery of the primary tumor (palliative gastrectomy) have to be compared with other forms of palliation, such as radiotherapy, endoscopic procedure, or surgical bypass. Recently, a retrospective analysis of 19 studies evaluating outcomes after palliative gastrectomy reported a higher 1-year survival in patients undergoing gastrectomy versus conservative management (odds ratio (OR) ¼ 4.9, 95% confidence interval (CI) ¼ 3.2–7.5, P < 0.0001) or gastrectomy versus nonresection treatment (OR ¼ 2.6, 95%CI ¼ 1.7–4.3, P < 0.0001) [1]. In a similar meta-analysis [2], patients with stage IV disease were those that received the best advantage from surgical resection of primary GC. Combined hepatic resection, in fact, was beneficial for patients who were also offered a palliative gastrectomy (hazard ratio [HR] ¼ 0.30; 95%CI 0.15–0.61; P ¼ 0.0008). The mainstay of treatment for systemic disease in patients with good performance status, is palliative chemotherapy with platinum-based doublets or triplets, with the aim of prolonging overall survival (OS) and disease-related symptoms. Surgery of distant metastases (in particular liver disease) is not contemplated according to current guidelines in patients with stage IV GC because of lack of data from prospective trials. An anecdotal series [3–8] reported in the literature from a single institution presents encouraging long-term survival of patients treated with radical resection of isolated liver metastases from GC. The reason for such limited evidence is the rarity of this condition, due to the widespread nature of metastatic disease in GC.
ß 2015 Wiley Periodicals, Inc.
In a surgical database, a rate 25% indicating substantial heterogeneity. A randomeffects model based on the DerSimonian-Laird estimator was used wherever there was significant heterogeneity, and a fixed-effect model based on the Mantel-Haenszel estimator was used when there was no significant heterogeneity [10]. The results of this systematic review were reported in conformance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [11].
RESULTS The initial search revealed 676 titles. After the abstracts of these articles (Fig. 1) had been reviewed, 76 articles were considered potentially useful for inclusion, and their full text was retrieved and Journal of Surgical Oncology
Prognostic Factors of Survival in Multivariate Analysis Different clinicopathological variables were evaluated for association with OS. Covariates that remained significant as univariate analysis were analyzed according to multivariate analysis. Those variables that were associated with outcomes in at least three papers were large size of metastases and number of hepatic metastases (>1). A formal meta-analysis of HRs was possible only for the number of liver lesions, with five publications reporting data (single vs. multiple). The pooled HR for multiple compared to single metastases was 2.22 (95%CI 1.75–2.81, P < 0.0001; I2 ¼ 0.0001, P for heterogeneity 0.46 according to fixed effect model).
DISCUSSION Treatment of metastatic GC has been moderately modified in this last decade, with the paradigm changed only for HER2þ disease that has now the possibility to receive trastuzumab plus chemotherapy, with a few months incremental in median survival. Surgical resection of liver or other distant metastases is not a standard of care for gastroesophageal carcinomas, with survival improvement from this procedure recognized only for colorectal cancer, where the resectability of liver lesions represents one of the aims of cure. The biology and invasiveness of GC with widespread diffusion in the abdominal cavity at presentation (extra regional nodal disease, peritoneal carcinomatosis, and/or liver metastases), usually limits the utility of surgical procedures for oligometastic disease. Aggressive peritoneal cytoreduction with hypertermic intraperitoneal chemotherapy is the only treatment option with encouraging survival data in the advanced disease setting, although it is associated with substantial surgical morbidity even in expert hands [30–32]. In this meta-analysis we found that the median and 5-year OS rate after surgery for GC liver metastases ranged from 8.8 to 48 months and 0–60%, respectively, with a pooled value of 22 months and 24%, with a 5-year OS of 30% for metachronous lesions. In particular, the two variables associated with better OS and presented in at least three papers are the presence of a single lesion and small size tumors, with the first covariate reported more frequently in the 23 articles analyzed. A similar systematic review was published by Kerkar et al. which included 19 studies and come to similar conclusions, with a pooled
Liver Metastases From Gastric Cancer
Fig. 1.
1023
Flow diagram of study selection process.
5-year OS of 13%, and similar prognostic variables were found to be associated with better outcome [33]. They identified patients with small or isolated disease, long disease-free survival (>1 year), lesions amenable to resection with negative margins, and no extrahepatic disease as the ideal candidates for liver resection. These results are in concordance with the analysis performed by Adam and colleagues in 2006 that evaluated 1,452 patients with noncolorectal and nonneuroendocrine liver metastases surgically removed [26]. Overall and disease-free survivals at 5 years were 36 and 21%, and at 10 years were 23 and 15%, respectively. Their series included only 16% of gastrointestinal primaries. In multivariate analysis, factors associated with poor prognosis were patient age >60 years, nonbreast origin, melanoma or squamous histology, diseasefree interval 1 of 70.8/29.2 14 hepatectomy; 10 limited resection
29/13
NA
8/9
12/9
8/7
NA 18/4
19/21
NA
Timing Liver surgery n° M þ n° (synchr/ (solitary/ metacr) multiple)
Retrospective/ 89/1452* NA France/ 1983–2004 40 18/22 Retrospective/ Japan/ 1975 –1999 32.5 HAI 12 18
Imamura/2001
Garancini/2012
Dittmar/2012
91.6 Cheon/2008
Seven
40 (>10 mm.)
Ambiru/2001
Adam/2006
Author/year
Type of study/ country/years of enrollment
TABLE I. Characteristics of Included Studies
11
NA
31.1
NA
NA
32.8 adj CT
31.5 adj CT; 15.7 HAI; 10.5 intraportal CT
18.7 neoadj CT; 62.5 adj CT; 25 HAI
21
31.2
22.3
48
NA
45.8 neoadj CT; 62.5 adj CT
17
12
GC:15; GEJ:14
NA
Retrospective/Korea/ 2003–2010
NA
CT (%)
Median OS (months)
34
37.1
40.1
31.1
0
19
27
22.8
3/9
27% GC; 12% GEJ
5-year OS (%)
NA
NA
Size > 5 cm.
35 < hemihepatectomia; 7 > hemihepatectomia
pT4, size > 5 cm., N° of Mþ>3
NA
NA
NA
NA
sectionectomy þ RFA; Three hemihepatectomy; One sectionectomy
11/1
21 < hemihepatectomy; 19> hemihepatectomy
NA
Covariates associated with OS
1024 Petrelli et al.
Journal of Surgical Oncology 15/9
53/0
9/8
24
53
17
15
39
30
15§
10/5
39/0
30/0
15/0
8/7
31/8
22/8
NA
13/4
33/20
13/11
NA
21/16
11/0
16/9
Nine nonanatomic; Three bisegmentectomy; Three hemiepatectomy;
Hepatectomia nas
23 lobectomy; Seven partial hepatectomy
11 surgical anatomic hepatectomia; Six surgical nonanatomic hepatectomia Hepatectomy þ three RFA & HAI
19 surgical anatomic hepatectomia; Six surgical nonanatomic hepatectomia Seven tumorectomia; Two lobectomia; Two segmentectomia 25 non-anatomic limited resections; Seven segmentectomia; Five hemihepatectomy 10 hemihepatectomia; 21 anatomical segmental resection Eight major hepatectomia; 16 minor hepatectomia 52 hepatectomia; One RFA
Type of local therapy (N° pts)
NA
19.3 adj CT
100
86.4
100 adj CT
14.3 adj CT; 7.1 HAI
NA
100 adj CT
NA
NA
53.3 HAI
82.4 adj CT
NA
86,8
41.5 adj CT
NA
100
70.8
6.4 neoadj CT; 29 adj CT
56 adj CT
NA
74
CT (%)
R0 (%)
8.8
14
11
NA
34
13
9
NA
31
19
38
Median OS (months)
0
10.3
16.7
60
31.5
9.3
10
13
11
27.3
29.4
5-year OS (%)
NA
pNþ of primary GC, N° of Mþ
Peritoneal Mþ, N° of Mþ>1
NA
Size > 6 cm., D2 lymphadenectomy
NA
R1–2 resection margins
NA
Bilobar M þ, size > 4 cm.
NA
N° of M þ
Covariates associated with OS
*, among 1,452 patients with noncolorectal non neuroendocrine liver metastases; N°, number of; R0, radical resection margins; HAI, hepatic artery infusion; NA, not available; OS, overall survival; intra-OP RFA, intraoperative radiofrequency ablation; **, only patients that had surgery with curative intent; °, Five patients underwent radiofrequency ablation; Mþ, metastases; §, including two patients treated with liver surgery þ microwave coagulation therapy and three patients treated with hepatic artery infusion þ microwave coagulation therapy ; °°, Anatomical: hemihepatectomy, sectorectomy, and segmentectomy; nonanatomical: limited resection.
Zacherl/2002
Wang/2014
Wang/2012
Retrospective/ Japan/ 1991 –2005 Retrospective/ China/ 2003 –2008 Retrospective/ China/ 1996 –2008 Retrospective/ Austria/ 1980–1999
17/14
31
Schildberg/2012 Retrospective/ Germany/ 1972–1978 Thelen/2008 Retrospective/ Germany/ 1988–2002 Tiberio/2014 Retrospective/ Italy/ 1997– 2011 Tsujimoto/2010 Retrospective/ Japan/ 1980 –2007
Ueda/2009
16/21
37
Retrospective/ Japan/ 1990 –2005
8/3
Sakamoto/2007
11
Retrospective/ Korea/ 1988–1996
25/0
Roh/2005
25
Retrospective/ China/ 1998 –2009
N° pts
Timing Liver surgery n° M þ n° (synchr/ (solitary/ metacr) multiple)
Qiu/2013
Author/year
Type of study/ country/years of enrollment
TABLE I. (Continued)
Liver Metastases From Gastric Cancer 1025
1026
Petrelli et al.
Fig. 2. Pooled analysis of 5-year OS for patients with resected gastric cancer liver metastases.
prognosis could have been selected for an operation (liver limited disease only) by an expert surgeon (mainly Asiatic series are reported). Usually, infact, only the series with more satisfactory results in term of patient’s selection and outcome, are more likely to undergo publication. These cases are probably rarely encountered in clinical practice. However, this is the largest systematic review of surgical resection of liver metastases from GC ever published. In about 900 patients, it found a remarkable 24% OS rate at 5 years. This rate is similar to the survival rate after resection of colorectal cancer liver metastases found by Adam in his seminar paper published in 2004 [36]. Additionally, it is relevant to state that our data for most of these case series derive from an earlier era, when the available systemic agents and diagnostic procedures were limited. In fact, during that time a relatively limited number of subjects underwent adjuvant or preoperative chemotherapy. It is conceivable that in the present era more patients can be offered curative surgery due to increased exposure to neoadjuvant chemotherapy that could permit downsizing and downstaging of initially unresectable disease, and due to the improved skills of Western abdominal surgeons as well. The availability of metabolic imaging (e.g., FDG-PET) now permits a rapid and prognostically sound response evaluation. In fact, treatment response can be detectable at an earlier stage by FDG-PET than by computed tomography because FDG uptake by cancer cells decreases according to the treatment response. So FDGPET can contribute to the selection of a more appropriate treatment modality by detecting easily distant metastases and evaluation of treatment response [37]. Newer ablative techniques, such as radiofrequency ablation, can also be used in selected cases, in Journal of Surgical Oncology
particular when small and solitary liver metastases appear [38,39]. A better selection of subjects deriving different benefits from chemotherapy (intestinal and proximal cancers vs. diffuse histology), and a reclassification of GCs would probably change the cure of this deadly disease through a refinement, by molecular selection, of GC cases [40,41].
CONCLUSIONS In conclusion, the pooled median and 5-year OS after hepatic resection of GC liver metastases from 23 studies were 22 months and 24%, respectively. Patients with a limited number and small-size of metachronous metastases are those that live longest. The suggestions that arise from this pooled analysis deserve further confirmation through a dedicated, randomized clinical trial. Stage IV GC patients should now be informed about the possibility of longer survival with aggressive surgical approaches in conjunction with cytotoxic drugs and biologic therapies, and could even be offered the option of surgery for liver metastases, which may be for a definite cure.
REFERENCES 1. Lasithiotakis K, Antoniou SA, Antoniou GA, et al.: Gastrectomy for stage IV gastric cancer. A systematic review and meta-analysis. Anticancer Res 2014;34:2079–2085. 2. Sun J, Song Y, Wang Z, et al.: Clinical significance of palliative gastrectomy on the survival of patients with incurable advanced
Liver Metastases From Gastric Cancer
3. 4.
5. 6. 7. 8. 9. 10. 11. 12. 13.
14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
gastric cancer: A systematic review and meta-analysis. BMC Cancer 2013;13:577. Linhares E, Monteiro M, Kesley R, et al.: Major hepatectomy for isolated metastases from gastric adenocarcinoma. HPB (Oxford) 2003;5:235–237. Cheon SH, Rha SY, Jeung HC, 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. Koga R, Yamamoto J, Ohyama S, 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. Okano K, Maeba T, Ishimura K, et al.: Hepatic resection for metastatic tumors from gastric cancer. Ann Surg 2002;235:86–91. Shirabe K, Wakiyama S, Gion T, et al.: Hepatic resection for the treatment of liver metastases in gastric carcinoma: Review of the literature. HPB (Oxford) 2006;8:89–92. Ambiru S, Miyazaki M, Ito H, et al.: Benefits and limits of hepatic resection for gastric metastases. Am J Surg 2001;181:279–283. Wang H, Pawlik TM, Duncan MD, et al.: Inpatient survival after gastrectomy for gastric cancer in the 21st century. J Surg Res 2014;190:72–78. Higgins JPT, Green S. Cochrane handbook for systematic reviews of intervention. Vol. 5. Chichester: Wiley-Blackwell, 2008. Moher D, Liberati A, Tetzlaff J, et al.: “Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement,” PLoS Medicine 2009;6:e1000097. Baek HU, Kim SB, Cho EH, et al.: Hepatic resection for hepatic metastases from gastric adenocarcinoma. J Gastric Cancer 2013;13:86–92. Dittmar Y, Altendorf-Hofmann A, Rauchfuss F, 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. Garancini M, Uggeri F, Degrate L, et al.: Surgical treatment of liver metastases of gastric cancer: Is local treatment in a systemic disease worthwhile? HPB (Oxford) 2012;14:209–215. Komeda K, Hayashi M, Kubo S, 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. Makino H, Kunisaki C, Izumisawa Y, et al.: Indication for hepatic resection in the treatment of liver metastasis from gastric cancer. Anticancer Res 2010;30:2367–2376. Qiu JL, Deng MG, Li W, et al.: Hepatic resection for synchronous hepatic metastasis from gastric cancer. Eur J Surg Oncol 2013;39:694–700. Roh HR, Suh KS, Lee HJ, et al.: Outcome of hepatic resection for metastatic gastric cancer. Am Surg 2005;71:95–99. Schildberg CW, Croner R, Merkel S, et al.: Outcome of operative therapy of hepatic metastatic stomach carcinoma: A retrospective analysis. World J Surg 2012;36:872–878. Thelen A, Jonas S, Benckert C, et al.: Liver resection for metastatic gastric cancer. Eur J Surg Oncol 2008;34:1328–1334. Tiberio GA, Baiocchi GL, Morgagni P, et al.: Gastric cancer and synchronous hepatic metastases: Is it possible to recognize candidates to R0 resection? Br J Surg 2015;102:102–107. Tsujimoto H, Ichikura T, Ono S, et al.: Outcomes for patients following hepatic resection of metastatic tumors from gastric cancer. Hepatol Int 2010;4:406–413. Ueda K, Iwahashi M, Nakamori M, 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.
Journal of Surgical Oncology
1027
24. Wang W, Liang H, Zhang H, et al.: Prognostic significance of radical surgical treatment for gastric cancer patients with synchronous liver metastases. Med Oncol 2014;31:258. 25. Wang YN, Shen KT, Ling JQ, 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. 26. Adam R, Chiche L, Aloia T, et al.: Hepatic resection for noncolorectal nonendocrine liver metastases: Analysis of 1,452 patients and development of a prognostic model. Ann Surg 2006;244:524–535. 27. Zacherl J, Zacherl M, Scheuba C, et al.: Analysis of hepatic resection of metastasis originating from gastric adenocarcinoma. J Gastrointest Surg 2002;6:682–689. 28. Kinoshita T, Kinoshita T, Saiura A, et al.: Multicentre analysis of long-term outcome after surgical resection for gastric cancer liver metastases. Br J Surg. 2014;102:102–107. 29. Imamura H, Matsuyama Y, Shimada R, 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. 30. Mi DH, Li Z, Yang KH, et al.: Surgery combined with intraoperative hyperthermic intraperitoneal chemotherapy (IHIC) for gastric cancer: A systematic review and meta-analysis of randomised controlled trials. Int J Hyperthermia 2013;29:156–167. 31. Montori G, Coccolini F, Ceresoli M, et al.: The treatment of peritoneal carcinomatosis in advanced gastric cancer: State of the art. Int J Surg Oncol 2014;2014:912418. 32. Elias D, Goere D, Dumont F, et al.: Role of hyperthermic intraoperative peritoneal chemotherapy in the management of peritoneal metastases. Eur J Cancer 2014;50:332–340. 33. Kerkar SP, Kemp CD, Avital I. Liver resections in metastatic gastric cancer. HPB (Oxford) 2010;12:589–596. 34. Shridhar R, Almhanna K, Hoffe SE, et al.: Increased survival associated with surgery and radiation therapy in metastatic gastric cancer: A surveillance, epidemiology, and end results database analysis. Cancer 2013;119:1636–1642. 35. Yoshida K, Yamaguchi K, Okumura N, et al. The roles of surgical oncologists in the new era: minimally invasive surgery for early gastric cancer and adjuvant surgery for metastatic gastric cancer. Pathobiology 2011;78:343–352. 36. Adam R, Delvart V, Pascal G, et al.: Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg 2004;240:644–657.discussion 657–8. 37. Shimada H, Okazumi S, Koyama M, et al.: Japanese Gastric Cancer Association Task Force for Research Promotion: Clinical utility of 18 F-fluoro-2-deoxyglucose positron emission tomography in gastric cancer. A systematic review of the literature. Gastric Cancer 2011;14:13–21. 38. Hwang JE, Kim SH, Jin J, 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. 39. Chen J, Tang Z, Dong X, et al.: Radiofrequency ablation for liver metastasis from gastric cancer. Eur J Surg Oncol 2013;39: 701–706. 40. Bittoni A, Scartozzi M, Giampieri R, et al.: Clinical evidence for three distinct gastric cancer subtypes: Time for a new approach. PLoS One. 2013;8:e78544. 41. Cancer Genome Atlas Research Network Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014.513: 202–209.
Hepatic Resection for Gastric Cancer Liver Metastases: A Systematic Review and Meta-Analysis FAUSTO PETRELLI, MD, ANDREA COINU, MD, MARY CABIDDU, MD, MARA GHILARDI, MD, KAREN BORGONOVO, MD, VERONICA LONATI, AND SANDRO BARNI, MD Department of Oncology, Division of Medical Oncology, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy
Background: Resection of liver metastases from gastric cancer (GC) is rarely performed, and the outcome after hepatic surgery has not been systematically evaluated in the literature. The aim of this study was to perform a systematic review of outcome and prognostic factors for survival after liver metastasectomy for GC. Methods: We performed a meta-analysis of published studies that focused on long-term outcomes (5-year overall survival [OS]) after surgical management of liver metastases from GC, and included more than 10 patients each. Pooled hazard ratios (HRs) were calculated for variables considered as potential prognostic factors for OS in at least three publications. Results: Twenty-three studies comprising a total of 870 patients were considered in this analysis. The pooled weighted median OS was 22 months (95%CI 17.6–27.2). The pooled 5-year OS after liver resection was 23.8% (95%CI 19–29.3%). The pooled 5-year OS rates for metachronous and synchronous metastases were 30% (95%CI 24.7–35.8%) and 22.6% (95%CI 14–34.4%), respectively. Parameters associated with poor survival were (i) multiple metastases, and (ii) large size of metastases. Conclusions: Hepatic resection of GC liver metastases is associated with an acceptable 5-year OS, in particular after surgery of metachronous lesions, and could be offered to selected patients.
J. Surg. Oncol. 2015;111:1021–1027. ß 2015 Wiley Periodicals, Inc.
KEY WORDS: gastric cancer; liver metastases; surgery; 5-year survival; meta-analysis
INTRODUCTION Gastric cancer (GC) is a lethal disease, with a high rate of mortality after diagnosis. In fact, in approximately 50% of patients the disease extends beyond locoregional confines, and only one-half of those who appear to have locoregional tumor involvement can undergo a potentially curative resection. The most common metastatic sites are the liver, peritoneal surface, and distant lymph nodes. Palliative surgery in advanced disease is potentially useful for patients with obstructive or bleeding primary GC. The real benefits in terms of costs and morbidity of surgery of the primary tumor (palliative gastrectomy) have to be compared with other forms of palliation, such as radiotherapy, endoscopic procedure, or surgical bypass. Recently, a retrospective analysis of 19 studies evaluating outcomes after palliative gastrectomy reported a higher 1-year survival in patients undergoing gastrectomy versus conservative management (odds ratio (OR) ¼ 4.9, 95% confidence interval (CI) ¼ 3.2–7.5, P < 0.0001) or gastrectomy versus nonresection treatment (OR ¼ 2.6, 95%CI ¼ 1.7–4.3, P < 0.0001) [1]. In a similar meta-analysis [2], patients with stage IV disease were those that received the best advantage from surgical resection of primary GC. Combined hepatic resection, in fact, was beneficial for patients who were also offered a palliative gastrectomy (hazard ratio [HR] ¼ 0.30; 95%CI 0.15–0.61; P ¼ 0.0008). The mainstay of treatment for systemic disease in patients with good performance status, is palliative chemotherapy with platinum-based doublets or triplets, with the aim of prolonging overall survival (OS) and disease-related symptoms. Surgery of distant metastases (in particular liver disease) is not contemplated according to current guidelines in patients with stage IV GC because of lack of data from prospective trials. An anecdotal series [3–8] reported in the literature from a single institution presents encouraging long-term survival of patients treated with radical resection of isolated liver metastases from GC. The reason for such limited evidence is the rarity of this condition, due to the widespread nature of metastatic disease in GC.
ß 2015 Wiley Periodicals, Inc.
In a surgical database, a rate 25% indicating substantial heterogeneity. A randomeffects model based on the DerSimonian-Laird estimator was used wherever there was significant heterogeneity, and a fixed-effect model based on the Mantel-Haenszel estimator was used when there was no significant heterogeneity [10]. The results of this systematic review were reported in conformance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [11].
RESULTS The initial search revealed 676 titles. After the abstracts of these articles (Fig. 1) had been reviewed, 76 articles were considered potentially useful for inclusion, and their full text was retrieved and Journal of Surgical Oncology
Prognostic Factors of Survival in Multivariate Analysis Different clinicopathological variables were evaluated for association with OS. Covariates that remained significant as univariate analysis were analyzed according to multivariate analysis. Those variables that were associated with outcomes in at least three papers were large size of metastases and number of hepatic metastases (>1). A formal meta-analysis of HRs was possible only for the number of liver lesions, with five publications reporting data (single vs. multiple). The pooled HR for multiple compared to single metastases was 2.22 (95%CI 1.75–2.81, P < 0.0001; I2 ¼ 0.0001, P for heterogeneity 0.46 according to fixed effect model).
DISCUSSION Treatment of metastatic GC has been moderately modified in this last decade, with the paradigm changed only for HER2þ disease that has now the possibility to receive trastuzumab plus chemotherapy, with a few months incremental in median survival. Surgical resection of liver or other distant metastases is not a standard of care for gastroesophageal carcinomas, with survival improvement from this procedure recognized only for colorectal cancer, where the resectability of liver lesions represents one of the aims of cure. The biology and invasiveness of GC with widespread diffusion in the abdominal cavity at presentation (extra regional nodal disease, peritoneal carcinomatosis, and/or liver metastases), usually limits the utility of surgical procedures for oligometastic disease. Aggressive peritoneal cytoreduction with hypertermic intraperitoneal chemotherapy is the only treatment option with encouraging survival data in the advanced disease setting, although it is associated with substantial surgical morbidity even in expert hands [30–32]. In this meta-analysis we found that the median and 5-year OS rate after surgery for GC liver metastases ranged from 8.8 to 48 months and 0–60%, respectively, with a pooled value of 22 months and 24%, with a 5-year OS of 30% for metachronous lesions. In particular, the two variables associated with better OS and presented in at least three papers are the presence of a single lesion and small size tumors, with the first covariate reported more frequently in the 23 articles analyzed. A similar systematic review was published by Kerkar et al. which included 19 studies and come to similar conclusions, with a pooled
Liver Metastases From Gastric Cancer
Fig. 1.
1023
Flow diagram of study selection process.
5-year OS of 13%, and similar prognostic variables were found to be associated with better outcome [33]. They identified patients with small or isolated disease, long disease-free survival (>1 year), lesions amenable to resection with negative margins, and no extrahepatic disease as the ideal candidates for liver resection. These results are in concordance with the analysis performed by Adam and colleagues in 2006 that evaluated 1,452 patients with noncolorectal and nonneuroendocrine liver metastases surgically removed [26]. Overall and disease-free survivals at 5 years were 36 and 21%, and at 10 years were 23 and 15%, respectively. Their series included only 16% of gastrointestinal primaries. In multivariate analysis, factors associated with poor prognosis were patient age >60 years, nonbreast origin, melanoma or squamous histology, diseasefree interval 1 of 70.8/29.2 14 hepatectomy; 10 limited resection
29/13
NA
8/9
12/9
8/7
NA 18/4
19/21
NA
Timing Liver surgery n° M þ n° (synchr/ (solitary/ metacr) multiple)
Retrospective/ 89/1452* NA France/ 1983–2004 40 18/22 Retrospective/ Japan/ 1975 –1999 32.5 HAI 12 18
Imamura/2001
Garancini/2012
Dittmar/2012
91.6 Cheon/2008
Seven
40 (>10 mm.)
Ambiru/2001
Adam/2006
Author/year
Type of study/ country/years of enrollment
TABLE I. Characteristics of Included Studies
11
NA
31.1
NA
NA
32.8 adj CT
31.5 adj CT; 15.7 HAI; 10.5 intraportal CT
18.7 neoadj CT; 62.5 adj CT; 25 HAI
21
31.2
22.3
48
NA
45.8 neoadj CT; 62.5 adj CT
17
12
GC:15; GEJ:14
NA
Retrospective/Korea/ 2003–2010
NA
CT (%)
Median OS (months)
34
37.1
40.1
31.1
0
19
27
22.8
3/9
27% GC; 12% GEJ
5-year OS (%)
NA
NA
Size > 5 cm.
35 < hemihepatectomia; 7 > hemihepatectomia
pT4, size > 5 cm., N° of Mþ>3
NA
NA
NA
NA
sectionectomy þ RFA; Three hemihepatectomy; One sectionectomy
11/1
21 < hemihepatectomy; 19> hemihepatectomy
NA
Covariates associated with OS
1024 Petrelli et al.
Journal of Surgical Oncology 15/9
53/0
9/8
24
53
17
15
39
30
15§
10/5
39/0
30/0
15/0
8/7
31/8
22/8
NA
13/4
33/20
13/11
NA
21/16
11/0
16/9
Nine nonanatomic; Three bisegmentectomy; Three hemiepatectomy;
Hepatectomia nas
23 lobectomy; Seven partial hepatectomy
11 surgical anatomic hepatectomia; Six surgical nonanatomic hepatectomia Hepatectomy þ three RFA & HAI
19 surgical anatomic hepatectomia; Six surgical nonanatomic hepatectomia Seven tumorectomia; Two lobectomia; Two segmentectomia 25 non-anatomic limited resections; Seven segmentectomia; Five hemihepatectomy 10 hemihepatectomia; 21 anatomical segmental resection Eight major hepatectomia; 16 minor hepatectomia 52 hepatectomia; One RFA
Type of local therapy (N° pts)
NA
19.3 adj CT
100
86.4
100 adj CT
14.3 adj CT; 7.1 HAI
NA
100 adj CT
NA
NA
53.3 HAI
82.4 adj CT
NA
86,8
41.5 adj CT
NA
100
70.8
6.4 neoadj CT; 29 adj CT
56 adj CT
NA
74
CT (%)
R0 (%)
8.8
14
11
NA
34
13
9
NA
31
19
38
Median OS (months)
0
10.3
16.7
60
31.5
9.3
10
13
11
27.3
29.4
5-year OS (%)
NA
pNþ of primary GC, N° of Mþ
Peritoneal Mþ, N° of Mþ>1
NA
Size > 6 cm., D2 lymphadenectomy
NA
R1–2 resection margins
NA
Bilobar M þ, size > 4 cm.
NA
N° of M þ
Covariates associated with OS
*, among 1,452 patients with noncolorectal non neuroendocrine liver metastases; N°, number of; R0, radical resection margins; HAI, hepatic artery infusion; NA, not available; OS, overall survival; intra-OP RFA, intraoperative radiofrequency ablation; **, only patients that had surgery with curative intent; °, Five patients underwent radiofrequency ablation; Mþ, metastases; §, including two patients treated with liver surgery þ microwave coagulation therapy and three patients treated with hepatic artery infusion þ microwave coagulation therapy ; °°, Anatomical: hemihepatectomy, sectorectomy, and segmentectomy; nonanatomical: limited resection.
Zacherl/2002
Wang/2014
Wang/2012
Retrospective/ Japan/ 1991 –2005 Retrospective/ China/ 2003 –2008 Retrospective/ China/ 1996 –2008 Retrospective/ Austria/ 1980–1999
17/14
31
Schildberg/2012 Retrospective/ Germany/ 1972–1978 Thelen/2008 Retrospective/ Germany/ 1988–2002 Tiberio/2014 Retrospective/ Italy/ 1997– 2011 Tsujimoto/2010 Retrospective/ Japan/ 1980 –2007
Ueda/2009
16/21
37
Retrospective/ Japan/ 1990 –2005
8/3
Sakamoto/2007
11
Retrospective/ Korea/ 1988–1996
25/0
Roh/2005
25
Retrospective/ China/ 1998 –2009
N° pts
Timing Liver surgery n° M þ n° (synchr/ (solitary/ metacr) multiple)
Qiu/2013
Author/year
Type of study/ country/years of enrollment
TABLE I. (Continued)
Liver Metastases From Gastric Cancer 1025
1026
Petrelli et al.
Fig. 2. Pooled analysis of 5-year OS for patients with resected gastric cancer liver metastases.
prognosis could have been selected for an operation (liver limited disease only) by an expert surgeon (mainly Asiatic series are reported). Usually, infact, only the series with more satisfactory results in term of patient’s selection and outcome, are more likely to undergo publication. These cases are probably rarely encountered in clinical practice. However, this is the largest systematic review of surgical resection of liver metastases from GC ever published. In about 900 patients, it found a remarkable 24% OS rate at 5 years. This rate is similar to the survival rate after resection of colorectal cancer liver metastases found by Adam in his seminar paper published in 2004 [36]. Additionally, it is relevant to state that our data for most of these case series derive from an earlier era, when the available systemic agents and diagnostic procedures were limited. In fact, during that time a relatively limited number of subjects underwent adjuvant or preoperative chemotherapy. It is conceivable that in the present era more patients can be offered curative surgery due to increased exposure to neoadjuvant chemotherapy that could permit downsizing and downstaging of initially unresectable disease, and due to the improved skills of Western abdominal surgeons as well. The availability of metabolic imaging (e.g., FDG-PET) now permits a rapid and prognostically sound response evaluation. In fact, treatment response can be detectable at an earlier stage by FDG-PET than by computed tomography because FDG uptake by cancer cells decreases according to the treatment response. So FDGPET can contribute to the selection of a more appropriate treatment modality by detecting easily distant metastases and evaluation of treatment response [37]. Newer ablative techniques, such as radiofrequency ablation, can also be used in selected cases, in Journal of Surgical Oncology
particular when small and solitary liver metastases appear [38,39]. A better selection of subjects deriving different benefits from chemotherapy (intestinal and proximal cancers vs. diffuse histology), and a reclassification of GCs would probably change the cure of this deadly disease through a refinement, by molecular selection, of GC cases [40,41].
CONCLUSIONS In conclusion, the pooled median and 5-year OS after hepatic resection of GC liver metastases from 23 studies were 22 months and 24%, respectively. Patients with a limited number and small-size of metachronous metastases are those that live longest. The suggestions that arise from this pooled analysis deserve further confirmation through a dedicated, randomized clinical trial. Stage IV GC patients should now be informed about the possibility of longer survival with aggressive surgical approaches in conjunction with cytotoxic drugs and biologic therapies, and could even be offered the option of surgery for liver metastases, which may be for a definite cure.
REFERENCES 1. Lasithiotakis K, Antoniou SA, Antoniou GA, et al.: Gastrectomy for stage IV gastric cancer. A systematic review and meta-analysis. Anticancer Res 2014;34:2079–2085. 2. Sun J, Song Y, Wang Z, et al.: Clinical significance of palliative gastrectomy on the survival of patients with incurable advanced
Liver Metastases From Gastric Cancer
3. 4.
5. 6. 7. 8. 9. 10. 11. 12. 13.
14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
gastric cancer: A systematic review and meta-analysis. BMC Cancer 2013;13:577. Linhares E, Monteiro M, Kesley R, et al.: Major hepatectomy for isolated metastases from gastric adenocarcinoma. HPB (Oxford) 2003;5:235–237. Cheon SH, Rha SY, Jeung HC, 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. Koga R, Yamamoto J, Ohyama S, 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. Okano K, Maeba T, Ishimura K, et al.: Hepatic resection for metastatic tumors from gastric cancer. Ann Surg 2002;235:86–91. Shirabe K, Wakiyama S, Gion T, et al.: Hepatic resection for the treatment of liver metastases in gastric carcinoma: Review of the literature. HPB (Oxford) 2006;8:89–92. Ambiru S, Miyazaki M, Ito H, et al.: Benefits and limits of hepatic resection for gastric metastases. Am J Surg 2001;181:279–283. Wang H, Pawlik TM, Duncan MD, et al.: Inpatient survival after gastrectomy for gastric cancer in the 21st century. J Surg Res 2014;190:72–78. Higgins JPT, Green S. Cochrane handbook for systematic reviews of intervention. Vol. 5. Chichester: Wiley-Blackwell, 2008. Moher D, Liberati A, Tetzlaff J, et al.: “Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement,” PLoS Medicine 2009;6:e1000097. Baek HU, Kim SB, Cho EH, et al.: Hepatic resection for hepatic metastases from gastric adenocarcinoma. J Gastric Cancer 2013;13:86–92. Dittmar Y, Altendorf-Hofmann A, Rauchfuss F, 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. Garancini M, Uggeri F, Degrate L, et al.: Surgical treatment of liver metastases of gastric cancer: Is local treatment in a systemic disease worthwhile? HPB (Oxford) 2012;14:209–215. Komeda K, Hayashi M, Kubo S, 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. Makino H, Kunisaki C, Izumisawa Y, et al.: Indication for hepatic resection in the treatment of liver metastasis from gastric cancer. Anticancer Res 2010;30:2367–2376. Qiu JL, Deng MG, Li W, et al.: Hepatic resection for synchronous hepatic metastasis from gastric cancer. Eur J Surg Oncol 2013;39:694–700. Roh HR, Suh KS, Lee HJ, et al.: Outcome of hepatic resection for metastatic gastric cancer. Am Surg 2005;71:95–99. Schildberg CW, Croner R, Merkel S, et al.: Outcome of operative therapy of hepatic metastatic stomach carcinoma: A retrospective analysis. World J Surg 2012;36:872–878. Thelen A, Jonas S, Benckert C, et al.: Liver resection for metastatic gastric cancer. Eur J Surg Oncol 2008;34:1328–1334. Tiberio GA, Baiocchi GL, Morgagni P, et al.: Gastric cancer and synchronous hepatic metastases: Is it possible to recognize candidates to R0 resection? Br J Surg 2015;102:102–107. Tsujimoto H, Ichikura T, Ono S, et al.: Outcomes for patients following hepatic resection of metastatic tumors from gastric cancer. Hepatol Int 2010;4:406–413. Ueda K, Iwahashi M, Nakamori M, 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.
Journal of Surgical Oncology
1027
24. Wang W, Liang H, Zhang H, et al.: Prognostic significance of radical surgical treatment for gastric cancer patients with synchronous liver metastases. Med Oncol 2014;31:258. 25. Wang YN, Shen KT, Ling JQ, 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. 26. Adam R, Chiche L, Aloia T, et al.: Hepatic resection for noncolorectal nonendocrine liver metastases: Analysis of 1,452 patients and development of a prognostic model. Ann Surg 2006;244:524–535. 27. Zacherl J, Zacherl M, Scheuba C, et al.: Analysis of hepatic resection of metastasis originating from gastric adenocarcinoma. J Gastrointest Surg 2002;6:682–689. 28. Kinoshita T, Kinoshita T, Saiura A, et al.: Multicentre analysis of long-term outcome after surgical resection for gastric cancer liver metastases. Br J Surg. 2014;102:102–107. 29. Imamura H, Matsuyama Y, Shimada R, 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. 30. Mi DH, Li Z, Yang KH, et al.: Surgery combined with intraoperative hyperthermic intraperitoneal chemotherapy (IHIC) for gastric cancer: A systematic review and meta-analysis of randomised controlled trials. Int J Hyperthermia 2013;29:156–167. 31. Montori G, Coccolini F, Ceresoli M, et al.: The treatment of peritoneal carcinomatosis in advanced gastric cancer: State of the art. Int J Surg Oncol 2014;2014:912418. 32. Elias D, Goere D, Dumont F, et al.: Role of hyperthermic intraoperative peritoneal chemotherapy in the management of peritoneal metastases. Eur J Cancer 2014;50:332–340. 33. Kerkar SP, Kemp CD, Avital I. Liver resections in metastatic gastric cancer. HPB (Oxford) 2010;12:589–596. 34. Shridhar R, Almhanna K, Hoffe SE, et al.: Increased survival associated with surgery and radiation therapy in metastatic gastric cancer: A surveillance, epidemiology, and end results database analysis. Cancer 2013;119:1636–1642. 35. Yoshida K, Yamaguchi K, Okumura N, et al. The roles of surgical oncologists in the new era: minimally invasive surgery for early gastric cancer and adjuvant surgery for metastatic gastric cancer. Pathobiology 2011;78:343–352. 36. Adam R, Delvart V, Pascal G, et al.: Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg 2004;240:644–657.discussion 657–8. 37. Shimada H, Okazumi S, Koyama M, et al.: Japanese Gastric Cancer Association Task Force for Research Promotion: Clinical utility of 18 F-fluoro-2-deoxyglucose positron emission tomography in gastric cancer. A systematic review of the literature. Gastric Cancer 2011;14:13–21. 38. Hwang JE, Kim SH, Jin J, 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. 39. Chen J, Tang Z, Dong X, et al.: Radiofrequency ablation for liver metastasis from gastric cancer. Eur J Surg Oncol 2013;39: 701–706. 40. Bittoni A, Scartozzi M, Giampieri R, et al.: Clinical evidence for three distinct gastric cancer subtypes: Time for a new approach. PLoS One. 2013;8:e78544. 41. Cancer Genome Atlas Research Network Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014.513: 202–209.
