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01-01-2015 | Gastric cancer | Book chapter | Article

11. Gastric Cancer: Molecular Mechanisms, Diagnosis, and Treatment

Authors: Gopi K. Prithviraj, M.D., Khaldoun Almhanna, M.D., M.P.H.

Publisher: Springer International Publishing

Abstract

Gastric cancer is one of the most frequently diagnosed cancers worldwide, with a relative 5 year survival of 27.7 %. The clinical outcome for advanced gastric cancer remains poor, with 5-year relative survival of only 3.9 %. Many risk factors have been identified in relation to gastric cancer, including Helicobacter pylori, Epstein-Barr virus infection, family history of gastric cancer, and the presence of pathologic changes such as atrophic gastritis, intestinal metaplasia, and high-grade dysplasia. At this time, the current standard of care in the first-line treatment of advanced or metastatic gastric cancer includes a platinum plus fluoropyrimidine backbone, while the primary treatment of early stage disease is resection with consideration for neoadjuvant, perioperative, or adjuvant chemotherapy. While early-stage gastric cancers may be successfully treated with surgical and medical therapy, metastatic gastric cancer continues to have a limited overall survival despite treatment. Herein we discuss the pathogenesis, screening, diagnosis, and treatment of gastric cancer, including future directions such as targeted therapies.
Literature
1.
Jemal A et al (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90PubMedCrossRef
2.
Howlader N, Noone AM, Krapcho M, Garshell J, Neyman N, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds) (2012) SEER cancer statistics review, 1975–2010. National Cancer Institute, Bethesda
3.
(2013) SEER cancer statistics factsheets: stomach cancer. National Cancer Institute, Bethesda
4.
Bertuccio P et al (2013) Dietary patterns and gastric cancer risk: a systematic review and meta-analysis. Ann Oncol 24(6):1450–1458PubMedCrossRef
5.
Lunet N, Lacerda-Vieira A, Barros H (2005) Fruit and vegetables consumption and gastric cancer: a systematic review and meta-analysis of cohort studies. Nutr Cancer 53(1):1–10PubMedCrossRef
6.
D’Elia L et al (2012) Habitual salt intake and risk of gastric cancer: a meta-analysis of prospective studies. Clin Nutr 31(4):489–498PubMedCrossRef
7.
Ge S et al (2012) Association between habitual dietary salt intake and risk of gastric cancer: a systematic review of observational studies. Gastroenterol Res Pract 2012:808120PubMedCentralPubMedCrossRef
8.
Hernandez-Ramirez RU et al (2009) Dietary intake of polyphenols, nitrate and nitrite and gastric cancer risk in Mexico City. Int J Cancer 125(6):1424–1430PubMedCentralPubMedCrossRef
9.
Tsugane S, Sasazuki S (2007) Diet and the risk of gastric cancer: review of epidemiological evidence. Gastric Cancer 10(2):75–83PubMedCrossRef
10.
Leung WK, Sung JJ (2002) Review article: intestinal metaplasia and gastric carcinogenesis. Aliment Pharmacol Ther 16(7):1209–1216PubMedCrossRef
11.
Vannella L, Lahner E, Annibale B (2012) Risk for gastric neoplasias in patients with chronic atrophic gastritis: a critical reappraisal. World J Gastroenterol 18(12):1279–1285PubMedCentralPubMedCrossRef
12.
Vannella L et al (2010) Risk factors for progression to gastric neoplastic lesions in patients with atrophic gastritis. Aliment Pharmacol Ther 31(9):1042–1050PubMed
13.
Whiting JL et al (2002) The long term results of endoscopic surveillance of premalignant gastric lesions. Gut 50(3):378–381PubMedCentralPubMedCrossRef
14.
Meining A et al (2001) Atrophy-metaplasia-dysplasia-carcinoma sequence in the stomach: a reality or merely an hypothesis? Best Pract Res Clin Gastroenterol 15(6):983–998PubMedCrossRef
15.
Correa P, Piazuelo MB, Wilson KT (2010) Pathology of gastric intestinal metaplasia: clinical implications. Am J Gastroenterol 105(3):493–498PubMedCentralPubMedCrossRef
16.
Rugge M et al (1994) Gastric epithelial dysplasia in the natural history of gastric cancer: a multicenter prospective follow-up study. Interdisciplinary Group on Gastric Epithelial Dysplasia. Gastroenterology 107(5):1288–1296PubMedCrossRef
17.
Hirota WK et al (2006) ASGE guideline: the role of endoscopy in the surveillance of premalignant conditions of the upper GI tract. Gastrointest Endosc 63(4):570–580PubMedCrossRef
18.
Vannella L et al (2013) Systematic review: gastric cancer incidence in pernicious anaemia. Aliment Pharmacol Ther 37(4):375–382PubMedCrossRef
19.
Hsing AW et al (1993) Pernicious anemia and subsequent cancer. A population-based cohort study. Cancer 71(3):745–750PubMedCrossRef
20.
Mellemkjaer L et al (1996) Pernicious anaemia and cancer risk in Denmark. Br J Cancer 73(8):998–1000PubMedCentralPubMedCrossRef
21.
Marshall BJ, Warren JR (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1(8390):1311–1315PubMedCrossRef
22.
Uemura N et al (2001) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345(11):784–789PubMedCrossRef
23.
Correa P, Piazuelo MB (2011) Helicobacter pylori infection and gastric adenocarcinoma. US Gastroenterol Hepatol Rev 7(1):59–64PubMedCentralPubMed
24.
(1993) An international association between Helicobacter pylori infection and gastric cancer. The EUROGAST Study Group. Lancet 341(8857):1359–1362
25.
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1994) Schistosomes, liver flukes, and Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum 61(1):177–220
26.
Parkin DM (2004) International variation. Oncogene 23(38):6329–6340PubMedCrossRef
27.
Ma JL et al (2012) Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. J Natl Cancer Inst 104(6):488–492PubMedCentralPubMedCrossRef
28.
Fuccio L et al (2009) Meta-analysis: can Helicobacter pylori eradication treatment reduce the risk for gastric cancer? Ann Intern Med 151(2):121–128PubMedCrossRef
29.
Song HJ, Kim KM (2011) Pathology of Epstein-Barr virus-associated gastric carcinoma and its relationship to prognosis. Gut Liver 5(2):143–148PubMedCentralPubMedCrossRef
30.
Fukayama M, Ushiku T (2011) Epstein-Barr virus-associated gastric carcinoma. Pathol Res Pract 207(9):529–537PubMedCrossRef
31.
Chen JN et al (2012) Epstein-Barr virus-associated gastric carcinoma: a newly defined entity. J Clin Gastroenterol 46(4):262–271PubMedCrossRef
32.
Boysen T et al (2009) EBV-associated gastric carcinoma in high- and low-incidence areas for nasopharyngeal carcinoma. Br J Cancer 101(3):530–533PubMedCentralPubMedCrossRef
33.
van Beek J et al (2004) EBV-positive gastric adenocarcinomas: a distinct clinicopathologic entity with a low frequency of lymph node involvement. J Clin Oncol 22(4):664–670PubMedCrossRef
34.
Yang P et al (2009) Overweight, obesity and gastric cancer risk: results from a meta-analysis of cohort studies. Eur J Cancer 45(16):2867–2873PubMedCrossRef
35.
Turati F et al (2013) A meta-analysis of body mass index and esophageal and gastric cardia adenocarcinoma. Ann Oncol 24(3):609–617PubMedCrossRef
36.
Ladeiras-Lopes R et al (2008) Smoking and gastric cancer: systematic review and meta-analysis of cohort studies. Cancer Causes Control 19(7):689–701PubMedCrossRef
37.
Ferrari F, Reis MA (2013) Study of risk factors for gastric cancer by populational databases analysis. World J Gastroenterol 19(48):9383–9391PubMedCentralPubMedCrossRef
38.
Bagnardi V et al (2001) A meta-analysis of alcohol drinking and cancer risk. Br J Cancer 85(11):1700–1705PubMedCentralPubMedCrossRef
39.
Tersmette AC et al (1990) Meta-analysis of the risk of gastric stump cancer: detection of high risk patient subsets for stomach cancer after remote partial gastrectomy for benign conditions. Cancer Res 50(20):6486–6489PubMed
40.
Kelley JR, Duggan JM (2003) Gastric cancer epidemiology and risk factors. J Clin Epidemiol 56(1):1–9PubMedCrossRef
41.
Gong EJ et al (2014) Risk factors and clinical outcomes of gastric cancer identified by screening endoscopy: a case–control study. J Gastroenterol Hepatol 29(2):301–9
42.
Foschi R et al (2008) Family history of cancer and stomach cancer risk. Int J Cancer 123(6):1429–1432PubMedCrossRef
43.
Yaghoobi M, Bijarchi R, Narod SA (2010) Family history and the risk of gastric cancer. Br J Cancer 102(2):237–242PubMedCentralPubMedCrossRef
44.
Gupta N et al (2011) Endoscopy for upper GI cancer screening in the general population: a cost-utility analysis. Gastrointest Endosc 74(3):610–624 e2PubMedCrossRef
45.
Yeh JM et al (2010) Cost-effectiveness of treatment and endoscopic surveillance of precancerous lesions to prevent gastric cancer. Cancer 116(12):2941–2953PubMedCentralPubMedCrossRef
46.
Hamashima C et al (2008) The Japanese guidelines for gastric cancer screening. Jpn J Clin Oncol 38(4):259–267PubMedCrossRef
47.
Nam JH et al (2012) Association of the interval between endoscopies with gastric cancer stage at diagnosis in a region of high prevalence. Cancer 118(20):4953–4960PubMedCrossRef
48.
Aikou S et al (2011) Tests for serum levels of trefoil factor family proteins can improve gastric cancer screening. Gastroenterology 141(3):837–845, e1-7PubMedCentralPubMedCrossRef
49.
Cui L et al (2013) Gastric juice MicroRNAs as potential biomarkers for the screening of gastric cancer. Cancer 119(9):1618–1626PubMedCrossRef
50.
Grabsch HI, Tan P (2013) Gastric cancer pathology and underlying molecular mechanisms. Dig Surg 30(2):150–158PubMedCrossRef
51.
Lauren P (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31–49PubMed
52.
Cancer, T.I.A.f.R.o. (2010). In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds) WHO classification of tumours of the digestive system (IARC WHO classification of tumours), 4th edn. World Health Organization, Geneva, Switzerland
53.
Hu B et al (2012) Gastric cancer: classification, histology and application of molecular pathology. J Gastrointest Oncol 3(3):251–261PubMedCentralPubMed
54.
Parsonnet J et al (1991) Helicobacter pylori infection in intestinal- and diffuse-type gastric adenocarcinomas. J Natl Cancer Inst 83(9):640–643PubMedCrossRef
55.
Crew KD, Neugut AI (2006) Epidemiology of gastric cancer. World J Gastroenterol 12(3):354–362PubMedCentralPubMed
56.
Deng N et al (2012) A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 61(5):673–684PubMedCentralPubMedCrossRef
57.
Salih BA, Gucin Z, Bayyurt N (2013) A study on the effect of Helicobacter pylori infection on p53 expression in gastric cancer and gastritis tissues. J Infect Dev Ctries 7(9):651–657PubMedCrossRef
58.
Fitzgerald RC et al (2010) Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet 47(7):436–444PubMedCentralPubMedCrossRef
59.
Mao J et al (2014) Roles of Wnt/beta-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment. Cell Death Dis 5:e1039PubMedCentralPubMedCrossRef
60.
Bang YJ et al (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376(9742):687–697PubMedCrossRef
61.
(2013) NCCN clinical practice guidelines in oncology, Version 2.2013, Gastric Cancer
62.
Kang YK (2014) Dovitinib for gastric cancer with FGFR2 amplification, NCT01719549. Available from: http://​clinicaltrials.​gov
63.
Fan XY et al (2011) Association between RUNX3 promoter methylation and gastric cancer: a meta-analysis. BMC Gastroenterol 11:92PubMedCentralPubMedCrossRef
64.
Wanebo HJ et al (1993) Cancer of the stomach. A patient care study by the American College of Surgeons. Ann Surg 218(5):583–592PubMedCentralPubMedCrossRef
65.
Schwartz IS (1987) Sister (Mary?) Joseph’s nodule. N Engl J Med 316(21):1348–1349PubMed
66.
Mizutani M et al (2005) Anatomy and histology of Virchow’s node. Anat Sci Int 80(4):193–198PubMedCrossRef
67.
Sperry K, Wall J (1980) Adenocarcinoma of the stomach with eruptive seborrheic keratoses: the sign of Leserp-Trelat. Cancer 45(9):2434–2437PubMedCrossRef
68.
Poveda F et al (1994) Systemic polyarteritis nodosa as the initial manifestation of a gastric adenocarcinoma. J Intern Med 236(6):679–683PubMedCrossRef
69.
Weintroub S, Stavorovsky M, Griffel B (1975) Membranous glomerulonephritis. An initial symptom of gastric carcinoma? Arch Surg 110(7):833–838PubMedCrossRef
70.
Graham DY et al (1982) Prospective evaluation of biopsy number in the diagnosis of esophageal and gastric carcinoma. Gastroenterology 82(2):228–231PubMed
71.
Puli SR et al (2008) How good is endoscopic ultrasound for TNM staging of gastric cancers? A meta-analysis and systematic review. World J Gastroenterol 14(25):4011–4019PubMedCentralPubMedCrossRef
72.
Edge S, Byrd DR et al (2010) AJCC cancer staging manual
73.
Kim SJ et al (2009) Peritoneal metastasis: detection with 16- or 64-detector row CT in patients undergoing surgery for gastric cancer. Radiology 253(2):407–415PubMedCrossRef
74.
Davies J et al (1997) Spiral computed tomography and operative staging of gastric carcinoma: a comparison with histopathological staging. Gut 41(3):314–319PubMedCentralPubMedCrossRef
75.
Mouri R et al (2009) Usefulness of endoscopic ultrasonography in determining the depth of invasion and indication for endoscopic treatment of early gastric cancer. J Clin Gastroenterol 43(4):318–322PubMedCrossRef
76.
Kwee RM, Kwee TC (2007) Imaging in local staging of gastric cancer: a systematic review. J Clin Oncol 25(15):2107–2116PubMedCrossRef
77.
Chen J et al (2005) Improvement in preoperative staging of gastric adenocarcinoma with positron emission tomography. Cancer 103(11):2383–2390PubMedCrossRef
78.
Stahl A et al (2003) FDG PET imaging of locally advanced gastric carcinomas: correlation with endoscopic and histopathological findings. Eur J Nucl Med Mol Imaging 30(2):288–295PubMedCrossRef
79.
Smyth E et al (2012) A prospective evaluation of the utility of 2-deoxy-2-[(18) F]fluoro-D-glucose positron emission tomography and computed tomography in staging locally advanced gastric cancer. Cancer 118(22):5481–5488PubMedCrossRef
80.
Muntean V et al (2009) Staging laparoscopy in gastric cancer. Accuracy and impact on therapy. J Gastrointestin Liver Dis 18(2):189–195PubMed
81.
Mezhir JJ et al (2010) Positive peritoneal cytology in patients with gastric cancer: natural history and outcome of 291 patients. Ann Surg Oncol 17(12):3173–3180PubMedCrossRef
82.
Soetikno R et al (2005) Endoscopic mucosal resection for early cancers of the upper gastrointestinal tract. J Clin Oncol 23(20):4490–4498PubMedCrossRef
83.
Ono H et al (2001) Endoscopic mucosal resection for treatment of early gastric cancer. Gut 48(2):225–229PubMedCentralPubMedCrossRef
84.
Yoon H et al (2013) Risk factors of residual or recurrent tumor in patients with a tumor-positive resection margin after endoscopic resection of early gastric cancer. Surg Endosc 27(5):1561–1568PubMedCrossRef
85.
Yada T, Yokoi C, Uemura N (2013) The current state of diagnosis and treatment for early gastric cancer. Diagn Ther Endosc 2013:241320PubMedCentralPubMedCrossRef
86.
Yoo JH et al (2012) Risk factors for perforations associated with endoscopic submucosal dissection in gastric lesions: emphasis on perforation type. Surg Endosc 26(9):2456–2464PubMedCrossRef
87.
Oda I et al (2013) Complications of gastric endoscopic submucosal dissection. Dig Endosc 25(Suppl 1):71–78PubMedCrossRef
88.
Folli S et al (1995) Early gastric cancer: prognostic factors in 223 patients. Br J Surg 82(7):952–956PubMedCrossRef
89.
Morita S et al (2008) Outcome of pylorus-preserving gastrectomy for early gastric cancer. Br J Surg 95(9):1131–1135PubMedCrossRef
90.
Hiki N et al (2009) Survival benefit of pylorus-preserving gastrectomy in early gastric cancer. J Am Coll Surg 209(3):297–301PubMedCrossRef
91.
Zeng YK et al (2012) Laparoscopy-assisted versus open distal gastrectomy for early gastric cancer: evidence from randomized and nonrandomized clinical trials. Ann Surg 256(1):39–52PubMedCrossRef
92.
Cuschieri A et al (1999) Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Co-operative Group. Br J Cancer 79(9–10):1522–1530PubMedCentralPubMedCrossRef
93.
Hartgrink HH et al (2004) Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial. J Clin Oncol 22(11):2069–2077PubMedCrossRef
94.
Songun I et al (2010) Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 11(5):439–449PubMedCrossRef
95.
Sano T et al (2004) Gastric cancer surgery: morbidity and mortality results from a prospective randomized controlled trial comparing D2 and extended para-aortic lymphadenectomy – Japan Clinical Oncology Group study 9501. J Clin Oncol 22(14):2767–2773PubMedCrossRef
96.
Wu CW et al (2006) Nodal dissection for patients with gastric cancer: a randomised controlled trial. Lancet Oncol 7(4):309–315PubMedCrossRef
97.
Zhang H et al (2010) Does D3 surgery offer a better survival outcome compared to D1 surgery for gastric cancer? A result based on a hospital population of two decades as taking D2 surgery for reference. BMC Cancer 10:308PubMedCentralPubMedCrossRef
98.
Dikken JL et al (2010) Impact of the extent of surgery and postoperative chemoradiotherapy on recurrence patterns in gastric cancer. J Clin Oncol 28(14):2430–2436PubMedCrossRef
99.
Cunningham D et al (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355(1):11–20PubMedCrossRef
100.
Sumpter K et al (2005) Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF. Br J Cancer 92(11):1976–1983PubMedCentralPubMedCrossRef
101.
Ychou M et al (2011) Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 29(13):1715–1721PubMedCrossRef
102.
Schuhmacher C et al (2010) Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954. J Clin Oncol 28(35):5210–5218PubMedCentralPubMedCrossRef
103.
Macdonald JS et al (2001) Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345(10):725–730PubMedCrossRef
104.
Smalley SR et al (2012) Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol 30(19):2327–2333PubMedCentralPubMedCrossRef
105.
Jansen EP et al (2007) A phase I-II study of postoperative capecitabine-based chemoradiotherapy in gastric cancer. Int J Radiat Oncol Biol Phys 69(5):1424–1428PubMedCrossRef
106.
Lee J et al (2012) Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol 30(3):268–273PubMedCrossRef
107.
Bang YJ et al (2012) Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 379(9813):315–321PubMedCrossRef
108.
Sakuramoto S et al (2007) Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 357(18):1810–1820PubMedCrossRef
109.
Wagner AD et al (2010) Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev (3):CD004064 http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​20238327
110.
Van Cutsem E et al (2006) Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24(31):4991–4997PubMedCrossRef
111.
Van Cutsem E, Boni C et al (2011) Randomized phase II study (GATE study) of docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer (abstract). J Clin Oncol 29(Suppl 15):Abstract 4018
112.
Webb A et al (1997) Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15(1):261–267PubMedCrossRef
113.
Pluschnig U et al (2013) Modified EOX (Epirubicin, Oxaliplatin and Capecitabine) as palliative first-line chemotherapy for gastroesophageal adenocarcinoma. Anticancer Res 33(3):1035–1039PubMed
114.
Cunningham D et al (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358(1):36–46PubMedCrossRef
115.
Al-Batran SE et al (2008) Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 26(9):1435–1442PubMedCrossRef
116.
Kang YK et al (2009) Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol 20(4):666–673PubMedCrossRef
117.
Kim BG et al (2010) A phase II study of irinotecan with biweekly, low dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFIRI) as first line therapy for patients with recurrent or metastatic gastric cancer. Am J Clin Oncol 33(3):246–250PubMed
118.
Rosati G et al (2007) Phase II trial of a biweekly regimen of fluorouracil and leucovorin plus irinotecan in patients with previously untreated advanced gastric cancer. J Chemother 19(5):570–576PubMedCrossRef
119.
Jo JC et al (2007) Docetaxel monotherapy as a second-line treatment after failure of fluoropyrimidine and platinum in advanced gastric cancer: experience of 154 patients with prognostic factor analysis. Jpn J Clin Oncol 37(12):936–941PubMedCrossRef
120.
Lee JL et al (2008) A phase II study of docetaxel as salvage chemotherapy in advanced gastric cancer after failure of fluoropyrimidine and platinum combination chemotherapy. Cancer Chemother Pharmacol 61(4):631–637PubMedCrossRef
121.
Hironaka S et al (2013) Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol
122.
Kadokura M et al (2013) Weekly paclitaxel as second-line chemotherapy in Japanese patients with advanced gastric cancer. Anticancer Res 33(10):4547–4552PubMed
123.
Thuss-Patience PC et al (2011) Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer – a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer 47(15):2306–2314PubMedCrossRef
124.
Lee JA et al (2009) Radiation therapy for gastric cancer bleeding. Tumori 95(6):726–730PubMed
125.
Hashimoto K et al (2009) Palliative radiation therapy for hemorrhage of unresectable gastric cancer: a single institute experience. J Cancer Res Clin Oncol 135(8):1117–1123PubMedCrossRef
126.
Tey J et al (2007) The role of palliative radiation therapy in symptomatic locally advanced gastric cancer. Int J Radiat Oncol Biol Phys 67(2):385–388PubMedCrossRef
127.
Yoshikawa T et al (2009) A phase I study of palliative chemoradiation therapy with paclitaxel and cisplatin for local symptoms due to an unresectable primary advanced or locally recurrent gastric adenocarcinoma. Cancer Chemother Pharmacol 64(6):1071–1077PubMedCrossRef
128.
Kim MM et al (2008) Clinical benefit of palliative radiation therapy in advanced gastric cancer. Acta Oncol 47(3):421–427PubMedCrossRef
129.
Du J et al (2008) Laparoscopically-assisted palliative total gastrectomy in patients with stage IV or metastatic gastric cancer: is it worthwhile? Hepatogastroenterology 55(86–87):1908–1912PubMed
130.
Chen S et al (2012) Significance of palliative gastrectomy for late-stage gastric cancer patients. J Surg Oncol 106(7):862–871PubMedCrossRef
131.
Lin SZ et al (2008) Palliative gastrectomy and chemotherapy for stage IV gastric cancer. J Cancer Res Clin Oncol 134(2):187–192PubMedCrossRef
132.
Jeurnink SM et al (2007) Stent versus gastrojejunostomy for the palliation of gastric outlet obstruction: a systematic review. BMC Gastroenterol 7:18PubMedCentralPubMedCrossRef
133.
Takeno A et al (2013) Clinical outcome and indications for palliative gastrojejunostomy in unresectable advanced gastric cancer: multi-institutional retrospective analysis. Ann Surg Oncol 20(11):3527–3533PubMedCrossRef
134.
Fleischer D, Sivak MV (1984) Endoscopic Nd: YAG laser therapy as palliative treatment for advanced adenocarcinoma of the gastric cardia. Gastroenterology 87(4):815–820PubMed
135.
Suzuki H et al (1989) Endoscopic laser therapy in the curative and palliative treatment of upper gastrointestinal cancer. World J Surg 13(2):158–164PubMedCrossRef
136.
Fuchs CS et al (2013) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet
137.
Wilke H et al (2014) RAINBOW: a global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy. J Clin Oncol 32(suppl 3; abstr LBA7)
138.
Shah MA et al (2011) Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol 29(7):868–874PubMedCentralPubMedCrossRef
139.
El-Rayes BF et al (2010) A phase II study of bevacizumab, oxaliplatin, and docetaxel in locally advanced and metastatic gastric and gastroesophageal junction cancers. Ann Oncol 21(10):1999–2004PubMedCentralPubMedCrossRef
140.
Ohtsu A et al (2011) Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 29(30):3968–3976PubMedCrossRef
141.
Bang YJ et al (2011) Phase II study of sunitinib as second-line treatment for advanced gastric cancer. Invest New Drugs 29(6):1449–1458PubMedCentralPubMedCrossRef
142.
Moehler M et al (2011) An open-label, multicentre biomarker-oriented AIO phase II trial of sunitinib for patients with chemo-refractory advanced gastric cancer. Eur J Cancer 47(10):1511–1520PubMedCrossRef
143.
Kim C et al (2012) Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer. Invest New Drugs 30(1):306–315PubMedCrossRef
144.
Sun W et al (2010) Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. J Clin Oncol 28(18):2947–2951PubMedCentralPubMedCrossRef
145.
Martin-Richard M et al (2013) Multicenter phase II study of oxaliplatin and sorafenib in advanced gastric adenocarcinoma after failure of cisplatin and fluoropyrimidine treatment. A GEMCAD study. Invest New Drugs
146.
Martinelli E et al (2009) Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin Exp Immunol 158(1):1–9PubMedCentralPubMedCrossRef
147.
Pinto C et al (2007) Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 18(3):510–517PubMedCrossRef
148.
Lordick F et al (2010) Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Br J Cancer 102(3):500–505PubMedCentralPubMedCrossRef
149.
Lordick F et al (2013) Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol 14(6):490–499PubMedCrossRef
150.
Waddell T et al (2013) Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol 14(6):481–489PubMedCentralPubMedCrossRef
151.
Trarbach T et al (2013) Phase I study of matuzumab in combination with 5-fluorouracil, leucovorin and cisplatin (PLF) in patients with advanced gastric and esophagogastric adenocarcinomas. Invest New Drugs 31(3):642–652PubMedCrossRef
152.
Rao S et al (2010) Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with epirubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: a randomised, multicentre open-label phase II study. Ann Oncol 21(11):2213–2219PubMedCrossRef
153.
Wainberg ZA et al (2011) Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction. Br J Cancer 105(6):760–765PubMedCentralPubMedCrossRef
154.
Rojo F et al (2006) Pharmacodynamic studies of gefitinib in tumor biopsy specimens from patients with advanced gastric carcinoma. J Clin Oncol 24(26):4309–4316PubMedCrossRef
155.
Hecht JB et al (2013) Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): the TRIO-013/LOGiC Trial. In: 2013 ASCO annual meeting. Chicago, IL
156.
Bang YJ (2013) A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer (AGC) in Asian population: Tytan study. In: 2013 gastrointestinal cancers symposium
157.
Nakajima M et al (1999) The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer 85(9):1894–1902PubMedCrossRef
158.
Shah MA et al (2013) Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. PLoS ONE 8(3):e54014PubMedCentralPubMedCrossRef
159.
Cejka D et al (2008) Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo. Cancer Biol Ther 7(9):1377–1385PubMedCrossRef
160.
Okamoto I et al (2010) Phase I clinical and pharmacokinetic study of RAD001 (everolimus) administered daily to Japanese patients with advanced solid tumors. Jpn J Clin Oncol 40(1):17–23PubMedCentralPubMedCrossRef
161.
Doi T et al (2010) Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J Clin Oncol 28(11):1904–1910PubMedCrossRef
162.
Ohtsu A et al (2013) Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol 31(31):3935–3943PubMedCrossRef