A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: Evidence does not translate?

References

• Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127:2893-917; PMID:21351269; http://dx.doi.org/10.1002/ijc.25516
   PubMed Web of Science ®Google Scholar
• Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol 2006; 12:354-62; PMID:16489633
   PubMed Web of Science ®Google Scholar
• Lauren P. 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 1965; 64:31-49; PMID:14320675
   PubMedGoogle Scholar
• Shah MA, Khanin R, Tang L, Janjigian YY, Klimstra DS, Gerdes H, Kelsen DP. Molecular classification of gastric cancer: a new paradigm. Clin Cancer Res 2011; 17:2693-701; PMID:21430069; http://dx.doi.org/10.1158/1078-0432.CCR-10-2203
   PubMed Web of Science ®Google Scholar
• Fiocca R, Luinetti O, Villani L, Mastracci L, Quilici P, Grillo F, Ranzani GN. Molecular mechanisms involved in the pathogenesis of gastric carcinoma: interactions between genetic alterations, cellular phenotype and cancer histotype. Hepatogastroenterology 2001; 48:1523-30; PMID:11813565
   PubMed Web of Science ®Google Scholar
• Becker KF, Atkinson MJ, Reich U, Becker I, Nekarda H, Siewert JR, Höfler H. E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res 1994; 54:3845-52; PMID:8033105
   PubMed Web of Science ®Google Scholar
• Oliveira C, Moreira H, Seruca R, de Oliveira MC, Carneiro F. Role of pathology in the identification of hereditary diffuse gastric cancer: report of a Portuguese family. Virchows Arch 2005; 446:181-4; PMID:15735979; http://dx.doi.org/10.1007/s00428-004-1156-4
   PubMed Web of Science ®Google Scholar
• Carneiro F, Huntsman DG, Smyrk TC, Owen DA, Seruca R, Pharoah P, Caldas C, Sobrinho-Simões M. Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening. J Pathol 2004; 203:681-7; PMID:15141383; http://dx.doi.org/10.1002/path.1564
   PubMed Web of Science ®Google Scholar
• Cunningham D, Jost LM, Purkalne G, Oliveira J, Force EGT. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of gastric cancer. Ann Oncol 2005; 16(Suppl 1):i22-3; PMID:15888740; http://dx.doi.org/10.1093/annonc/mdi812
   PubMed Web of Science ®Google Scholar
• Chen WW, Wang F, Xu RH. Platinum-based versus non-platinum-based chemotherapy as first line treatment of inoperable, advanced gastric adenocarcinoma: a meta-analysis. PloS One 2013; 8:e68974; PMID:23874831; http://dx.doi.org/10.1371/journal.pone.0068974
   PubMed Web of Science ®Google Scholar
• Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet 2009; 374:477-90; PMID:19625077; http://dx.doi.org/10.1016/S0140-6736(09)60617-6
   PubMed Web of Science ®Google Scholar
• Glimelius B, Hoffman K, Haglund U, Nyren O, Sjoden PO. Initial or delayed chemotherapy with best supportive care in advanced gastric cancer. Ann Oncol 1994; 5:189-90; PMID:8186165
   PubMed Web of Science ®Google Scholar
• Scheithauer W, Van Cutsem E. The role of oxaliplatin in the management of upper gastrointestinal tract malignancies. Colorectal Dis 2003; 5(Suppl 3):36-44; PMID:23573559; http://dx.doi.org/10.1046/j.1463-1318.5.s3.5.x
   PubMedGoogle Scholar
• Wagner AD, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J, Fleig WE. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010:CD004064; PMID:20238327
   PubMed Web of Science ®Google Scholar
• Cunningham D, Okines AF, Ashley S. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2010; 362:858-9; PMID:20200397; http://dx.doi.org/10.1056/NEJMc0911925
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, et al. 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 2006; 24:4991-7; PMID:17075117; http://dx.doi.org/10.1200/JCO.2006.06.8429
   PubMed Web of Science ®Google Scholar
• Lordick F, Lorenzen S, Yamada Y, Ilson D. Optimal chemotherapy for advanced gastric cancer: is there a global consensus? Gastric Cancer 2013; 17:213-25
   PubMed Web of Science ®Google Scholar
• Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 2008; 9:215-21; PMID:18282805; http://dx.doi.org/10.1016/S1470-2045(08)70035-4
   PubMed Web of Science ®Google Scholar
• Iacovelli R, Pietrantonio F, Farcomeni A, Maggi C, Palazzo A, Ricchini F, de Braud F, Di Bartolomeo M. Chemotherapy or targeted therapy as second-line treatment of advanced gastric cancer. A systematic review and meta-analysis of published studies. PloS One 2014; 9:e108940; PMID:25268988; http://dx.doi.org/10.1371/journal.pone.0108940
   PubMed Web of Science ®Google Scholar
• Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol 2014; 15:78-86; PMID:24332238; http://dx.doi.org/10.1016/S1470-2045(13)70549-7
   PubMed Web of Science ®Google Scholar
• Cunningham D, Oliveira J, Group EGW. Gastric cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2008; 19(Suppl 2):ii23-4; PMID:18456755
   PubMed Web of Science ®Google Scholar
• Wong H, Yau T. Molecular targeted therapies in advanced gastric cancer: does tumor histology matter? Therap Adv Gastroenterol 2013; 6:15-31; PMID:23320047; http://dx.doi.org/10.1177/1756283X12453636
   PubMed Web of Science ®Google Scholar
• Cidon EU, Ellis SG, Inam Y, Adeleke S, Zarif S, Geldart T. Molecular targeted agents for gastric cancer: a step forward towards personalized therapy. Cancers 2013; 5:64-91; PMID:24216699; http://dx.doi.org/10.3390/cancers5010064
   PubMedGoogle Scholar
• Ooi CH, Ivanova T, Wu J, Lee M, Tan IB, Tao J, Ward L, Koo JH, Gopalakrishnan V, Zhu Y, et al. Oncogenic pathway combinations predict clinical prognosis in gastric cancer. PLoS Genet 2009; 5:e1000676; PMID:19798449; http://dx.doi.org/10.1371/journal.pgen.1000676
   PubMed Web of Science ®Google Scholar
• Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, et al. 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 2010; 376:687-97; PMID:20728210; http://dx.doi.org/10.1016/S0140-6736(10)61121-X
   PubMed Web of Science ®Google Scholar
• Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, et al. 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 2011; 29:3968-76; PMID:21844504; http://dx.doi.org/10.1200/JCO.2011.36.2236
   PubMed Web of Science ®Google Scholar
• Kim YH, Sasaki Y, Lee KH, Rha SY, Park S, Boku N, Komatsu Y, Kim T, Kim S, Sakata Y. Randomized phase II study of nimotuzumab, an anti-EGFR antibody, plus irinotecan in patients with 5-fluorouracil-based regimen-refractory advanced or recurrent gastric cancer in Korea and Japan: Preliminary results. ASCO Meet Abstr 2011; 29:87
   Google Scholar
• Okines AF, Ashley SE, Cunningham D, Oates J, Turner A, Webb J, Saffery C, Chua YJ, Chau I. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for advanced esophagogastric cancer: dose-finding study for the prospective multicenter, randomized, phase II/III REAL-3 trial. J Clin Oncol 2010; 28:3945-50; PMID:20679619; http://dx.doi.org/10.1200/JCO.2010.29.2847
   PubMed Web of Science ®Google Scholar
• Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, Sahmoud T, Shen L, Yeh KH, Chin K, et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol 2013; 31:3935-43; PMID:24043745; http://dx.doi.org/10.1200/JCO.2012.48.3552
   PubMed Web of Science ®Google Scholar
• Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, et al. 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 2013; 14:490-9; PMID:23594786; http://dx.doi.org/10.1016/S1470-2045(13)70102-5
   PubMed Web of Science ®Google Scholar
• Yi JH, Lee J, Lee J, Park SH, Park JO, Yim DS, Park YS, Lim HY, Kang WK. Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum. Br J Cancer 2012; 106:1469-74; PMID:22460270; http://dx.doi.org/10.1038/bjc.2012.100
   PubMed Web of Science ®Google Scholar
• Rao S, Starling N, Cunningham D, Sumpter K, Gilligan D, Ruhstaller T, Valladares-Ayerbes M, Wilke H, Archer C, Kurek R, et al. 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 2010; 21:2213-9; PMID:20497967; http://dx.doi.org/10.1093/annonc/mdq247
   PubMed Web of Science ®Google Scholar
• Eatock MM, Tebbutt NC, Bampton CL, Strickland AH, Valladares-Ayerbes M, Swieboda-Sadlej A, Van Cutsem E, Nanayakkara N, Sun YN, Zhong ZD, et al. Phase II randomized, double-blind, placebo-controlled study of AMG 386 (trebananib) in combination with cisplatin and capecitabine in patients with metastatic gastro-oesophageal cancer. Ann Oncol 2013; 24:710-8; PMID:23108953; http://dx.doi.org/10.1093/annonc/mds502
   PubMed Web of Science ®Google Scholar
• Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, Sun G, Yang Y, Wang L, Xu N, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol 2013; 31:3219-25; PMID:23918952; http://dx.doi.org/10.1200/JCO.2013.48.8585
   PubMed Web of Science ®Google Scholar
• Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383:31-9; PMID:24094768; http://dx.doi.org/10.1016/S0140-6736(13)61719-5
   PubMed Web of Science ®Google Scholar
• Hecht, JR, Bang, Y-J, Qin, S, Chung, H-C, Xu, J-M, Park, JO, Jeziorski, K, Shparyk, Y, Hoff, PM, Sobrero, AF. 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. ASCO Meet Abstr 2013; 31:LBA4001
   Google Scholar
• Wilke H, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov ON, Kim T-Y, Cunningham D. 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 rainbow IMCL CP12-0922 (I4T-IE-JVBE). ASCO Meet Abstr 2014; 32:LBA7
   Google Scholar
• Kasper S, Schuler M. Targeted therapies in gastroesophageal cancer. Eur J Cancer 2014; 50:1247-58; PMID:24495747
   PubMed Web of Science ®Google Scholar
• Okines AF, Reynolds AR, Cunningham D. Targeting angiogenesis in esophagogastric adenocarcinoma. Oncologist 2011; 16:844-58; PMID:21632459; http://dx.doi.org/10.1634/theoncologist.2010-0387
   PubMed Web of Science ®Google Scholar
• Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol 2011; 29:868-74; PMID:21189380; http://dx.doi.org/10.1200/JCO.2010.32.0770
   PubMed Web of Science ®Google Scholar
• Shah MA, Ramanathan RK, Ilson DH, Levnor A, D'Adamo D, O'Reilly E, Tse A, Trocola R, Schwartz L, Capanu M, et al. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 2006; 24:5201-6; PMID:17114652; http://dx.doi.org/10.1200/JCO.2006.08.0887
   PubMed Web of Science ®Google Scholar
• Qi WX, Shen Z, Tang LN, Yao Y. The role of anti-VEGF agents in the treatment of advanced gastric cancer: a meta-analysis of randomized controlled trials. Tumour Biol 2014; 35:7675-83; PMID:24801910; http://dx.doi.org/10.1007/s13277-014-2037-3
   PubMed Web of Science ®Google Scholar
• Lieto E, Ferraraccio F, Orditura M, Castellano P, Mura AL, Pinto M, Zamboli A, De Vita F, Galizia G. Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is an independent prognostic indicator of worse outcome in gastric cancer patients. Ann Surg Oncol 2008; 15:69-79; PMID:17896140; http://dx.doi.org/10.1245/s10434-007-9596-0
   PubMed Web of Science ®Google Scholar
• Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, Wotherspoon A, Saffery C, Middleton G, Wadsley J, et al. 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 2013; 14:481-9; PMID:23594787; http://dx.doi.org/10.1016/S1470-2045(13)70096-2
   PubMed Web of Science ®Google Scholar
• Roth A, Moehler MH, Mauer M, Schad A, Karrasch M, Praet M, Lim, ML, Das-Gupta, A, Lutz, MP. Lapatinib in combination with ECF/x in EGFR1 or HER2-overexpressing first-line metastatic gastric cancer (GC): A phase II randomized placebo controlled trial (EORTC 40071). ASCO Meet Abstr 2010; 28:TPS205
   Google Scholar
• Breithaupt K, Bichev, D, Lorenz M, Bohnen, D, Dogan, Y, Schlattmann, P, Salah-Eddin Al-Batran, Moehler, MH, Thuss-Patience PC. PaFLO: Pazopanib with 5-fluorouracil, leucovorin, and oxaliplatin (FLO) as first-line treatment in advanced gastric cancer: A randomized phase II study of the Arbeitsgemeinschaft internistische Onkologie (AIO). ASCO Meet Abstr 2012; 30:TPS4138
   Google Scholar
• Moehler MH, Kim YH, Tan IB, Balogh A, Sanchez TK, Bang Y-J. Sequential ipilimumab (Ipi) versus best supportive care (BSC) following first-line chemotherapy (Ctx) in patients (pts) with unresectable locally advanced or metastatic gastric or gastro-esophageal junction (GEJ) cancer: A randomized, open-label, two-arm, phase II trial (CA184–162) of immunotherapy as a maintenance concept. ASCO Meet Abstr 2013; 31:TPS4151
   Google Scholar
• Pavlakis N, Goldstein D, Sjoquist KM, Martin A, Tsobanis E, Yip S, Shannon J, Burge ME, Cronk MF, Tebbutt NC. INTEGRATE: A randomized phase II double-blind placebo-controlled study of regorafenib in refractory advanced esophagogastric cancer (AOGC)–A study by the Australasian Gastrointestinal Trials Group (AGITG). ASCO Meet Abstr 2013; 31:TPS4157
   Google Scholar
• Tabernero J, Hoff PM, Shen L, Ohtsu A, Yu R, Eng-Wong J, Kang Y-K. Pertuzumab (P) with trastuzumab (T) and chemotherapy (CTX) in patients (pts) with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer: An international phase III study (JACOB). ASCO Meet Abstr 2013; 31:TPS4150
   Google Scholar
• Cunningham D, Bang Y-J, Tabernero J, Shah MA, Lordick F, Hack SP. MetGastric: A randomized phase III study of onartuzumab (MetMAb) in combination with mFOLFOX6 in patients with metastatic HER2-negative and MET-positive adenocarcinoma of the stomach or gastroesophageal junction. ASCO Meet Abstr 2013; 31:TPS4155
   Google Scholar
• Richards D, Kocs DM, Spira AI, David McCollum A, Diab S, Hecker LI, Cohn A, Zhan F, Asmar L. Results of docetaxel plus oxaliplatin (DOCOX) +/− cetuximab in patients with metastatic gastric and/or gastroesophageal junction adenocarcinoma: results of a randomised Phase 2 study. Eur J Cancer 2013; 49:2823-31; PMID:23747051; http://dx.doi.org/10.1016/j.ejca.2013.04.022
   PubMed Web of Science ®Google Scholar
• Koizumi W, Yamaguchi K, Hosaka H, Takinishi Y, Nakayama N, Hara T, Muro K, Baba H, Sasaki Y, Nishina T, et al. Randomised phase II study of S-1/cisplatin plus TSU-68 vs S-1/cisplatin in patients with advanced gastric cancer. Br J Cancer 2013; 109:2079-86; PMID:24045669; http://dx.doi.org/10.1038/bjc.2013.555
   PubMed Web of Science ®Google Scholar
• Bang Y-J. 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. ASCO Meet Abstr 2013; 31:11
   Google Scholar
• Cohen DJ, Christos PJ, Kindler HL, D Catenacci DVT, Bekaii-Saab TB, Tahiri S, Janjigian YY, Gibson MK, Chan E, Rajdev L. Vismodegib (V), a hedgehog (HH) pathway inhibitor, combined with FOLFOX for first-line therapy of patients (pts) with advanced gastric and gastroesophageal junction (GEJ) carcinoma: A New York Cancer Consortium led phase II randomized study. ASCO Meet Abstr 2013; 31:4011
   Google Scholar
• Bang Y-J, Im S-A, Lee K-W, Cho JY, Song E-K, Kyung Hee Lee KH, Kim YH, Park JO, Chun HG, Zang DY. Olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer: A randomized, double-blind phase II study. ASCO Meet Abstr 2013; 31:4013
   Google Scholar
• Moehler MH, Hartmann JT, Lordick F, Al-Batran S, Reimer P, Trarbach T, Ebert MP, Daum S, Weihrauch M, Galle PR. An open-label, multicenter phase II trial of sunitinib for patients with chemorefractory metastatic gastric cancer. ASCO Meet Abstr 2010; 28:e14503
   Google Scholar
• Yoon HH, Bendell JC, Braiteh FS, Firdaus I, Philip PA, Cohn AL, Lewis N, Anderson DM, Arrowsmith E, Schwartz JD. Ramucirumab (RAM) plus FOLFOX as front-line therapy (Rx) for advanced gastric or esophageal adenocarcinoma (GE-AC): Randomized, double-blind, multicenter phase 2 trial. ASCO Meet Abstr 2014; 32:4004
   Google Scholar
• Qin S. Phase III study of apatinib in advanced gastric cancer: A randomized, double-blind, placebo-controlled trial. ASCO Meet Abstr 2014; 32:4003
   Google Scholar
• Iveson T, Donehower RC, Davidenko I, Tjulandin S, Deptala A, Harrison M, Nirni S, Lakshmaiah K, Thomas A, Jiang Y, et al. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol 2014; 15:1007-18; PMID:24965569; http://dx.doi.org/10.1016/S1470-2045(14)70023-3
   PubMed Web of Science ®Google Scholar
• Fonsatti E, Sigalotti L, Arslan P, Altomonte M, Maio M. Emerging role of endoglin (CD105) as a marker of angiogenesis with clinical potential in human malignancies. Curr Cancer Drug Targets 2003; 3:427-32; PMID:14683500; http://dx.doi.org/10.2174/1568009033481741
   PubMed Web of Science ®Google Scholar
• Chechlinska M, Kowalska M, Kaminska J. Cytokines as potential tumour markers. Expert Opin Med Diagn 2008; 2:691-711; PMID:23495779; http://dx.doi.org/10.1517/17530059.2.6.691
   PubMedGoogle Scholar
• Fondevila C, Metges JP, Fuster J, Grau JJ, Palacin A, Castells A, Volant A, Pera M. p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer 2004; 90:206-15; PMID:14710231; http://dx.doi.org/10.1038/sj.bjc.6601455
   PubMed Web of Science ®Google Scholar
• Takiuchi H, Hirata I, Kawabe S, Egashira Y, Katsu K. Immunohistochemical expression of vascular endothelial growth factor can predict response to 5-fluorouracil and cisplatin in patients with gastric adenocarcinoma. Oncol Rep 2000; 7:841-6; PMID:10854555
   PubMed Web of Science ®Google Scholar
• Boku N, Chin K, Hosokawa K, Ohtsu A, Tajiri H, Yoshida S, Yamao T, Kondo H, Shirao K, Shimada Y, et al. Biological markers as a predictor for response and prognosis of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum. Clin Cancer Res 1998; 4:1469-74; PMID:9626464
   PubMed Web of Science ®Google Scholar
• Brink M, de Goeij AF, Weijenberg MP, Roemen GM, Lentjes MH, Pachen MM, Smits KM, de Bruïne AP, Goldbohm RA, van den Brandt PA. K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study. Carcinogenesis 2003; 24:703-10; PMID:12727799; http://dx.doi.org/10.1093/carcin/bgg009
   PubMed Web of Science ®Google Scholar
• Chiang JM. Role of K-ras mutations in colorectal carcinoma. Cancer Lett 1998; 126:179-85; PMID:9585064; http://dx.doi.org/10.1016/S0304-3835(98)00008-1
   PubMed Web of Science ®Google Scholar
• Hutchins G, Southward K, Handley K, Magill L, Beaumont C, Stahlschmidt J, Richman S, Chambers P, Seymour M, Kerr D, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 2011; 29:1261-70; PMID:21383284; http://dx.doi.org/10.1200/JCO.2010.30.1366
   PubMed Web of Science ®Google Scholar
• Fukahori M. Analysis of gene mutations in KRAS, NRAS, BRAF, and PIK3CA in patients who received systemic chemotherapy with metastatic gastric cancer. ASCO Meet Abstr 2013; 31:27
   Google Scholar
• Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 2012; 9:16-32; PMID:22124364; http://dx.doi.org/10.1038/nrclinonc.2011.177
   PubMed Web of Science ®Google Scholar
• Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13:25-32; PMID:22153890; http://dx.doi.org/10.1016/S1470-2045(11)70336-9
   PubMed Web of Science ®Google Scholar
• Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012; 379:633-40; PMID:22257673; http://dx.doi.org/10.1016/S0140-6736(11)61847-3
   PubMed Web of Science ®Google Scholar
• Pierga JY, Petit T, Delozier T, Ferrero JM, Campone M, Gligorov J, Lerebours F, Roché H, Bachelot T, Charafe-Jauffret E, et al. Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study. Lancet Oncol 2012; 13:375-84; PMID:22377126; http://dx.doi.org/10.1016/S1470-2045(12)70049-9
   PubMed Web of Science ®Google Scholar
• Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357:2666-76; PMID:18160686; http://dx.doi.org/10.1056/NEJMoa072113
   PubMed Web of Science ®Google Scholar
• Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011; 377:2103-14; PMID:21641636; http://dx.doi.org/10.1016/S0140-6736(11)60613-2
   PubMed Web of Science ®Google Scholar
• Reguart N, Cardona AF, Rosell R. Role of erlotinib in first-line and maintenance treatment of advanced non-small-cell lung cancer. Cancer Manag Res 2010; 2:143-56; PMID:21188105; http://dx.doi.org/10.2147/CMAR.S5398
   PubMedGoogle Scholar
• Stinchcombe TE, Socinski MA. Maintenance therapy in advanced non-small cell lung cancer: current status and future implications. J Thorac Oncol 2011; 6:174-82; PMID:21127437; http://dx.doi.org/10.1097/JTO.0b013e318200f9c5
   PubMed Web of Science ®Google Scholar
• Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, Esteban E, Molinier O, Brugger W, Melezínek I, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010; 11:521-9; PMID:20493771; http://dx.doi.org/10.1016/S1470-2045(10)70112-1
   PubMed Web of Science ®Google Scholar
• Mok TS, Ramalingam SS. Maintenance therapy in nonsmall-cell lung cancer: a new treatment paradigm. Cancer 2009; 115:5143-54; PMID:19658185; http://dx.doi.org/10.1002/cncr.24563
   PubMed Web of Science ®Google Scholar
• Correale P, Cusi MG, Tagliaferri P. Immunomodulatory properties of anticancer monoclonal antibodies: is the 'magic bullet' still a reliable paradigm? Immunotherapy 2011; 3:1-4; PMID:21174549; http://dx.doi.org/10.2217/imt.10.92
   PubMed Web of Science ®Google Scholar
• Hahm KB, Kim WH, Lee SI, Kang JK, Park IS. Comparison of immunomodulative effects of the histamine-2 receptor antagonists cimetidine, ranitidine, and famotidine on peripheral blood mononuclear cells in gastric cancer patients. Scand J Gastroenterol 1995; 30:265-71; PMID:7770717; http://dx.doi.org/10.3109/00365529509093275
   PubMed Web of Science ®Google Scholar
• Nio Y, Shiraishi T, Tsubono M, Morimoto H, Tseng CC, Imai S, Tobe T. In vitro immunomodulating effect of protein-bound polysaccharide, PSK on peripheral blood, regional nodes, and spleen lymphocytes in patients with gastric cancer. Cancer Immunol Pmmunother 1991; 32:335-41; PMID:1901030; http://dx.doi.org/10.1007/BF01741328
   PubMed Web of Science ®Google Scholar
• Botta C, Barbieri V, Ciliberto D, Rossi A, Rocco D, Addeo R, Staropoli N, Pastina P, Marvaso G, Martellucci I, et al. Systemic inflammatory status at baseline predicts bevacizumab benefit in advanced non-small cell lung cancer patients. Cancer Biol Ther 2013; 14:469-75; PMID:23760488; http://dx.doi.org/10.4161/cbt.24425
   PubMed Web of Science ®Google Scholar
• Botta C, Bestoso E, Apollinari S, Cusi MG, Pastina P, Abbruzzese A, Sperlongano P, Misso G, Caraglia M, Tassone P, et al. Immune-modulating effects of the newest cetuximab-based chemoimmunotherapy regimen in advanced colorectal cancer patients. J Immunother 2012; 35:440-7; PMID:22576349; http://dx.doi.org/10.1097/CJI.0b013e31825943aa
   PubMed Web of Science ®Google Scholar
• Correale P, Botta C, Basile A, Pagliuchi M, Licchetta A, Martellucci I, Bestoso E, Apollinari S, Addeo R, Misso G, et al. Phase II trial of bevacizumab and dose/dense chemotherapy with cisplatin and metronomic daily oral etoposide in advanced non-small-cell-lung cancer patients. Cancer Biol Ther 2011; 12:112-8; PMID:21525780; http://dx.doi.org/10.4161/cbt.12.2.15722
   PubMed Web of Science ®Google Scholar
• Correale P, Rotundo MS, Botta C, Del Vecchio MT, Ginanneschi C, Licchetta A, Conca R, Apollinari S, De Luca F, Tassone P, et al. Tumor infiltration by T lymphocytes expressing chemokine receptor 7 (CCR7) is predictive of favorable outcome in patients with advanced colorectal carcinoma. Clin Cancer Res 2012; 18:850-7; PMID:22142823; http://dx.doi.org/10.1158/1078-0432.CCR-10-3186
   PubMed Web of Science ®Google Scholar
• Mortenson ED, Fu YX. Adaptive immune responses and HER2/neu positive breast cancer. Curr Pathobiol Rep 2013; 1:37-42; PMID:23420038; http://dx.doi.org/10.1007/s40139-012-0001-8
   PubMedGoogle Scholar
• Manning EA, Ullman JG, Leatherman JM, Asquith JM, Hansen TR, Armstrong TD, Hicklin DJ, Jaffee EM, Emens LA. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin Cancer Res 2007; 13:3951-9; PMID:17606729; http://dx.doi.org/10.1158/1078-0432.CCR-07-0374
   PubMed Web of Science ®Google Scholar
• Adamcic U, Skowronski K, Peters C, Morrison J, Coomber BL. The effect of bevacizumab on human malignant melanoma cells with functional VEGF/VEGFR2 autocrine and intracrine signaling loops. Neoplasia 2012; 14:612-23; PMID:22904678; http://dx.doi.org/10.1593/neo.11948
   PubMed Web of Science ®Google Scholar
• Ren S, Fengyu  , Zuo S, Zhao M, Wang X, Wang X, Chen Y, Wu Z, Ren Z. Inhibition of tumor angiogenesis in lung cancer by T4 phage surface displaying mVEGFR2 vaccine. Vaccine 2011; 29:5802-11; PMID:21482223; http://dx.doi.org/10.1016/j.vaccine.2011.03.051
   PubMed Web of Science ®Google Scholar
• Block MS, Nevala WK, Leontovich AA, Markovic SN. Differential response of human and mouse dendritic cells to VEGF determines interspecies discrepancies in tumor-mediated TH1/TH2 polarity shift. Clin Cancer Res 2011; 17:1776-83; PMID:21349994; http://dx.doi.org/10.1158/1078-0432.CCR-10-2836
   PubMed Web of Science ®Google Scholar
• Yan J, Jia R, Song H, Liu Y, Zhang L, Zhang W, Wang Y, Zhu Y, Yu J. A promising new approach of VEGFR2-based DNA vaccine for tumor immunotherapy. Immunol Lett 2009; 126:60-6; PMID:19665480; http://dx.doi.org/10.1016/j.imlet.2009.07.013
   PubMed Web of Science ®Google Scholar
• Seavey MM, Paterson Y. Anti-Angiogenesis immunotherapy induces epitope spreading to Her-2/neu resulting in breast tumor immunoediting. Breast Cancer (Dove Med Press) 2009; 1:19-30; PMID:24367160
   PubMedGoogle Scholar
• Wada S, Tsunoda T, Baba T, Primus FJ, Kuwano H, Shibuya M, Tahara H. Rationale for antiangiogenic cancer therapy with vaccination using epitope peptides derived from human vascular endothelial growth factor receptor 2. Cancer Res 2005; 65:4939-46; PMID:15930316; http://dx.doi.org/10.1158/0008-5472.CAN-04-3759
   PubMed Web of Science ®Google Scholar
• Wang W, Liu H, Song Z, Wang Y, Wang J, Li Y, Li Y, Wang M, Chen J, Zhou Q. [Identification of the offspring of Vegfr2-luc transgenic mouse]. Zhongguo Fei Ai Za Zhi 2011; 14:391-5; PMID:21569642
   PubMedGoogle Scholar
• Suzuki H, Onishi H, Wada J, Yamasaki A, Tanaka H, Nakano K, Morisaki T, Katano M. VEGFR2 is selectively expressed by FOXP3high CD4+ Treg. Eur J Immunol 2010; 40:197-203; PMID:19902430; http://dx.doi.org/10.1002/eji.200939887
   PubMed Web of Science ®Google Scholar
• Ozdemir F, Akdogan R, Aydin F, Reis A, Kavgaci H, Gul S, Akdogan E. The effects of VEGF and VEGFR-2 on survival in patients with gastric cancer. J Exp Clin Cancer Res 2006; 25:83-8; PMID:16761623
   PubMed Web of Science ®Google Scholar
• Wang X, Chen X, Fang J, Yang C. Overexpression of both VEGF-A and VEGF-C in gastric cancer correlates with prognosis, and silencing of both is effective to inhibit cancer growth. Int J Clin Exp Pathol 2013; 6:586-97; PMID:23573305
   PubMed Web of Science ®Google Scholar
• Feng Y, Hu J, Ma J, Feng K, Zhang X, Yang S, Wang W, Zhang J, Zhang Y. RNAi-mediated silencing of VEGF-C inhibits non-small cell lung cancer progression by simultaneously down-regulating the CXCR4, CCR7, VEGFR-2 and VEGFR-3-dependent axes-induced ERK, p38 and AKT signalling pathways. Eur J Cancer 2011; 47:2353-63; PMID:21680174; http://dx.doi.org/10.1016/j.ejca.2011.05.006
   PubMed Web of Science ®Google Scholar
• Lieu CH, Tran H, Jiang ZQ, Mao M, Overman MJ, Lin E, Eng C, Morris J, Ellis L, Heymach JV, et al. The association of alternate VEGF ligands with resistance to anti-VEGF therapy in metastatic colorectal cancer. PloS One 2013; 8:e77117; PMID:24143206; http://dx.doi.org/10.1371/journal.pone.0077117
   PubMed Web of Science ®Google Scholar
• Manfredi GI, Dicitore A, Gaudenzi G, Caraglia M, Persani L, Vitale G. PI3K/Akt/mTOR signaling in medullary thyroid cancer: a promising molecular target for cancer therapy. Endocrine 2015; 48:363-70; PMID:25115638; http://dx.doi.org/10.1007/s12020-014-0380-1
   PubMed Web of Science ®Google Scholar
• Faggiano A, Ramundo V, Dicitore A, Castiglioni S, Borghi MO, Severino R, Ferolla P, Crin∫ L, Abbruzzese A, Sperlongano P, et al. Everolimus is an active agent in medullary thyroid cancer: a clinical and in vitro study. J Cell Mol Med 2012; 16:1563-72; PMID:21883896; http://dx.doi.org/10.1111/j.1582-4934.2011.01438.x
   PubMed Web of Science ®Google Scholar
• Zhong XB, Leeder JS. Epigenetic regulation of ADME-related genes: focus on drug metabolism and transport. Drug Metab Dispos 2013; 41:1721-4; PMID:23935066; http://dx.doi.org/10.1124/dmd.113.053942
   PubMed Web of Science ®Google Scholar
• Stewart LA, Parmar MK, Tierney JF. Meta-analyses and large randomized, controlled trials. N Engl J Med 1998; 338:61; author reply −2; PMID:9424569; http://dx.doi.org/10.1056/NEJM199802053380603
   PubMed Web of Science ®Google Scholar
• Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998; 17:2815-34; PMID:9921604; http://dx.doi.org/10.1002/(SICI)1097-0258(19981230)17:24%3c2815::AID-SIM110%3e3.0.CO;2-8
   PubMed Web of Science ®Google Scholar
• Parmar MK, Stewart LA, Altman DG. Meta-analyses of randomised trials: when the whole is more than just the sum of the parts. Br J Cancer 1996; 74:496-501; PMID:8761361; http://dx.doi.org/10.1038/bjc.1996.392
   PubMed Web of Science ®Google Scholar
• Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339:b2700; PMID:19622552; http://dx.doi.org/10.1136/bmj.b2700
   PubMed Web of Science ®Google Scholar
• Moher D, Altman DG, Liberati A, Tetzlaff J. PRISMA statement. Epidemiology 2011; 22:128; author reply; PMID:21150360; http://dx.doi.org/10.1097/EDE.0b013e3181fe7825
   PubMed Web of Science ®Google Scholar
• Armijo-Olivo S, Stiles CR, Hagen NA, Biondo PD, Cummings GG. Assessment of study quality for systematic reviews: a comparison of the cochrane collaboration risk of bias tool and the effective public health practice project quality assessment tool: methodological research. J Eval Clin Pract 2012; 18:12-8; PMID:20698919; http://dx.doi.org/10.1111/j.1365-2753.2010.01516.x
   PubMed Web of Science ®Google Scholar
• Detsky AS, Naylor CD, O'Rourke K, McGeer AJ, L'Abbe KA. Incorporating variations in the quality of individual randomized trials into meta-analysis. J Clin Epidemiol 1992; 45:255-65; PMID:1569422; http://dx.doi.org/10.1016/0895-4356(92)90085-2
   PubMed Web of Science ®Google Scholar
• Crowther M, Lim W, Crowther MA. Systematic review and meta-analysis methodology. Blood 2010; 116:3140-6; PMID:20656933; http://dx.doi.org/10.1182/blood-2010-05-280883
   PubMed Web of Science ®Google Scholar
• Wang D, Mou ZY, Zhai JX, Zong HX, Zhao XD. [Application of Stata software to test heterogeneity in meta-analysis method]. Zhonghua Liu Xing Bing Xue Za Zhi 2008; 29:726-9; PMID:19031771
   PubMedGoogle Scholar
• DerSimonian R, Levine RJ. Resolving discrepancies between a meta-analysis and a subsequent large controlled trial. JAMA 1999; 282:664-70; PMID:10517720; http://dx.doi.org/10.1001/jama.282.7.664
   PubMed Web of Science ®Google Scholar
• DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials 2007; 28:105-14; PMID:16807131; http://dx.doi.org/10.1016/j.cct.2006.04.004
   PubMed Web of Science ®Google Scholar
• Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, Carpenter J, Rücker G, Harbord RM, Schmid CH, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011; 343:d4002; PMID:21784880; http://dx.doi.org/10.1136/bmj.d4002
   PubMed Web of Science ®Google Scholar
• Boston RC, Sumner AE. STATA: a statistical analysis system for examining biomedical data. Adv Exp Med Biol 2003; 537:353-69; PMID:14995047
   PubMed Web of Science ®Google Scholar