title: 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?
abstract: It is still uncertain if targeted therapy-based regimens in advanced gastric cancer actually produce survival benefit. To shed light on this important question, we performed a systematic review and meta-analyses on each relevant targeted-pathway. By searching literature databases and proceedings of major cancer meetings in the time-frame 2005-2014, 22 randomized clinical trials exploring targeted therapy for a total of 7022 advanced gastric cancer patients were selected and included in the final analysis. Benefit was demonstrated for antiangiogenic agents in terms of overall survival (HR 0.759; 95%CI 0.655-0.880; p < 0.001). Conversely no benefit was found for EGFR pathway (HR 1.077; 95%CI 0.847-1.370; p = 0.543). Meta-analysis of HER-2 pathway confirmed improvement in terms of survival outcome, already known for this class of drugs (HR 0.823; 95%CI 0.722-0.939; p = 0.004). Pooled analysis demonstrated a significant survival benefit (OS: HR 0.823; PFS: HR 0.762) with acceptable tolerability profile for targeted-based therapies as compared to conventional treatments. This finding conflicts with the outcome of most individual studies, probably due to poor trial design or patients selection. In conclusion, our findings demonstrate a significant survival benefit for targeted therapy in its whole, which can be ascribed to anti-angiogenic and anti-HER2 agents.
authors.affiliation: a Department of Experimental and Clinical Medicine ; Magna Græcia University ; Campus Salvatore Venuta ; Catanzaro , Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Ciliberto
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Staropoli
authors.forename: Francesca
authors.initials: F
authors.lastname: Caglioti
authors.forename: Simona
authors.initials: S
authors.lastname: Gualtieri
authors.forename: Lucia
authors.initials: L
authors.lastname: Fiorillo
authors.forename: Silvia
authors.initials: S
authors.lastname: Chiellino
authors.forename: Antonina Maria
authors.initials: AM
authors.lastname: De Angelis
authors.forename: Francesco
authors.initials: F
authors.lastname: Mendicino
authors.forename: Cirino
authors.initials: C
authors.lastname: Botta
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000401:mortality; D016019:Survival Analysis
chemical_list: D020533:Angiogenesis Inhibitors; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: ADME, absorption, distribution, metabolism, and excretion; Ab, monoclonal antibody; BSC, best supportive care; CHT, chemotherapy; EGFR, epidermal growth factor receptor; GC, gastric cancer; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; MET, mesenchymal epithelial transition factor; NGS, next generation sequencing; NSCLC, non-small cell lung cancer; OR, odds-ratio; OS, overall survival; PARP, poly ADP ribose polymerase; PFS, progression free survival; PI3K, phosphatidylinositide 3-kinases; PRISMA, preferred reporting items for systematic reviews and meta-analyses; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma viral oncogene homolog; RCTs, randomized clinical trials; RR, response rate; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR: VEGF receptor; aGC, advanced gastric cancer; angiogenesis; gastric cancer; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; meta-analysis; randomized clinical trials; systemic chemotherapy; targeted pathways; targeted therapy