title: Second- and third-line systemic therapy in patients with advanced esophagogastric cancer: a systematic review of the literature.
abstract: The optimal second- and third-line chemotherapy and targeted therapy for patients with advanced esophagogastric cancer is still a matter of debate. Therefore, a literature search was carried out in Medline, EMBASE, CENTRAL, and oncology conferences until January 2016 for randomized controlled trials that compared second- or third-line therapy. We included 28 studies with 4810 patients. Second-line, single-agent taxane/irinotecan showed increased survival compared to best supportive care (BSC) (hazard ratio 0.65, 95 % confidence interval 0.53-0.79). Median survival gain ranged from 1.4 to 2.7 months among individual studies. Taxane- and irinotecan-based regimens showed equal survival benefit. Doublet chemotherapy taxane/irinotecan plus platinum and fluoropyrimidine was not different in survival, but showed increased toxicity vs. taxane/irinotecan monotherapy. Compared to BSC, second-line ramucirumab and second- or third-line everolimus and regorafenib showed limited median survival gain ranging from 1.1 to 1.4 months, and progression-free survival gain, ranging from 0.3 to 1.6 months. Third- or later-line apatinib showed increased survival benefit over BSC (HR 0.50, 0.32-0.79). Median survival gain ranged from 1.8 to 2.3 months. Compared to taxane-alone, survival was superior for second-line ramucirumab plus taxane (HR 0.81, 0.68-0.96), and olaparib plus taxane (HR 0.56, 0.35-0.87), with median survival gains of 2.2 and 4.8 months respectively. Targeted agents, either in monotherapy or combined with chemotherapy showed increased toxicity compared to BSC and chemotherapy-alone. This review indicates that, given the survival benefit in a phase III study setting, ramucirumab plus taxane is the preferred second-line treatment. Taxane or irinotecan monotherapy are alternatives, although the absolute survival benefit was limited. In third-line setting, apatinib monotherapy is preferred.
authors.affiliation: Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Emil
authors.initials: E
authors.lastname: Ter Veer
authors.affiliation: Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Nadia
authors.initials: N
authors.lastname: Haj Mohammad
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: van Valkenhoef
authors.affiliation: Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Lok Lam
authors.initials: LL
authors.lastname: Ngai
authors.affiliation: Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rosa M A
authors.initials: RM
authors.lastname: Mali
authors.affiliation: Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Martijn G H
authors.initials: MG
authors.lastname: van Oijen
authors.affiliation: Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. h.vanlaarhoven@amc.uva.nl.
authors.forename: Hanneke W M
authors.initials: HW
authors.lastname: van Laarhoven
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D019233:Retreatment; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents
keywords: Advanced esophagogastric cancer; Chemotherapy; Meta-analysis; Second-line; Targeted therapy; Third-line