Molecular-targeted first-line therapy for advanced gastric cancer.
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ABSTRACT:
SUBMITTER: Song H
PROVIDER: S-EPMC6457914 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundSystemic therapy is the standard treatment against advanced gastric cancer. Fluoropyrimidine plus platinum doublet has been recommended as the preferred first-line strategy. However, there is still a lack of a comprehensive and hierarchical evidence that compares all eligible literature simultaneously.MethodsRecord retrieval was conducted in PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, ASCO, and ESMO meeting library from inception to October 2018. Randomized controlled trials featuring comparisons between different first-line systemic treatments against advanced gastric cancer were eligible. Overall survival was utilized as the primary endpoint. Pairwise and network calculations were based on a random-effects model and the hierarchical ranking was numerically indicated by P-score. All procedures were conducted according to Cochrane Handbook 5.1 and PRISMA for Network Meta-analysis (Registration identifier: CRD42018084951).ResultsA total of 119 studies were eligible for our pooled analysis. Concerning general analysis, 'fluoropyrimidine plus platinum-based triplet' topped the overall survival hierarchy (HR 0.91 [0.83-0.99], P-score = 0.903, p = 0.04) while it ranked in second place for progression-free survival and objective response rate. However, it displayed worse tolerability against 'fluoropyrimidine plus platinum doublet'. More specifically, 'Capecitabine plus cisplatin-based triplet plus targeted medication' topped the ranking among all fluoropyrimidine plus platinum-based regimens in additional analysis. Nevertheless, it did not reach statistical advantage against fluoropyrimidine plus oxaliplatin doublet in terms of survival benefits, while still displaying significantly worse safety profile.ConclusionsTaken together, fluoropyrimidine plus oxaliplatin doublet (especially capecitabine or S-1) should still be considered as the preferred first-line regimen owing to its comparable survival benefits and lower toxicity.
| S-EPMC6767753 | biostudies-literature
Project description:The systemic treatment options for advanced gastric cancer (GC) have evolved rapidly in recent years. We have reviewed the recent data of clinical trial incorporating targeted agents, including inhibitors of angiogenesis, human epidermal growth factor receptor 2 (HER2), mesenchymal-epithelial transition, epidermal growth factor receptor, mammalian target of rapamycin, claudin-18.2, programmed death-1 and DNA. Addition of trastuzumab to platinum-based chemotherapy has become standard of care as front-line therapy in advanced GC overexpressing HER2. In the second-line setting, ramucirumab with paclitaxel significantly improves overall survival compared to paclitaxel alone. For patients with refractory disease, apatinib, nivolumab, ramucirumab and TAS-102 have demonstrated single-agent activity with improved overall survival compared to placebo alone. Pembrolizumab has demonstrated more than 50% response rate in microsatellite instability-high tumors, 15% response rate in tumors expressing programmed death ligand 1, and non-inferior outcome in first-line treatment compared to chemotherapy. This review summarizes the current state and progress of research on targeted therapy for advanced GC.
| S-EPMC6788003 | biostudies-literature
Project description:Gastric cancer is the third leading cause of malignant tumor-related mortality worldwide. Traditional cytotoxic agents prolong the overall survival and progression-free survival of patients with advanced gastric cancer (AGC) compared to that with best supportive care. Due to the occurrence of serious adverse drug reactions that result in discontinued treatment, the survival benefit in AGC remains unsatisfactory. Systemic chemotherapy regimens have changed greatly, especially since the introduction of trastuzumab. Nevertheless, HER2 positivity is present in only approximately 20% of tumors. Due to the genetic heterogeneity and complexity of patients, there are many studies in progress that are exploring novel targeted drugs as an alternative to chemotherapy or adjuvant treatment in early-stage, progressive, and advanced gastric cancer. On the basis of the differences in gene expression profiles among patients, searching for specific and sensitive predictive biomarkers is important for identifying patients who will benefit from a specific targeted drug. With the development of targeted therapies and available chemotherapeutic drugs, there is no doubt that, over time, more patients will achieve better survival outcomes. Recently, immune checkpoint blockade has been well developed as a promising anticancer strategy. This review outlines the currently available information on clinically tested molecular targeted drugs and immune checkpoint inhibitors for AGC to provide support for decision-making in clinical practice.
| S-EPMC7229784 | biostudies-literature
Project description:Although palliative chemotherapy has been shown to prolong survival and improve quality of life, the survival of advanced gastric cancer (AGC) patients remains poor. With the advent of targeted therapy, many molecular targeted agents have been evaluated in clinical studies. Trastuzumab, an anti-HER2 monoclonal antibody, has shown activity against HER2-positive AGC and becomes the first targeted agent approved in AGC. Drugs that target epidermal growth factor receptor, including monoclonal antibody and tyrosine kinase inhibitor, do not bring survival benefit to patients with AGC. Additionally, vascular endothelial growth factor inhibitors are also under investigation. Ramucirumab has shown promising result. Other targeted agents are in preclinical or early clinical development, such as mammalian target of rapamycinm inhibitors and c-MET inhibitors.
| S-EPMC3878836 | biostudies-literature
Project description:Gastric carcinoma (GC) is a common gastrointestinal malignancy with high incidence and mortality worldwide, and most patients are diagnosed in the late stages of disease. Palliative chemotherapy provides a survival benefit for patients with inoperable advanced GC. However, elderly patients who are unable to tolerate chemotherapy had worse prognosis due to lack of effective treatment. Herein we reported a Chinese elderly GC patient using next generation sequencing (NGS)-based tumor DNA analysis. Valuable gene variants of vascular endothelial growth factor (VEGF) A gene amplification were detected. Additionally, a novel NOTCH1-BPHL fusion has been identified. He received antiangiogenic drug apatinib and showed both good clinical and radiographic response, but eventually died of non-cancer related cause, with progression free survival time (PFS) and overall survival time (OS) up to 9.53 months. This was the first GC case with apatinib usage as first-line treatment under the guidance of NGS gene profiling.
| S-EPMC5915029 | biostudies-literature
Project description:Colorectal cancer is common and deadly. First-line treatments for patients with metastatic disease include FOLFIRI and FOLFOX, which have been combined with anti-EGFR or anti-VEGF antibodies to achieve benefit in selected populations. However, optimal therapy remains unclear.Fifteen publications on 10 trials were identified. There was a lack of decisive evidence that FOLFIRI or FOLFOX impact efficacy of either anti-EGFR or anti-VEGF, across mutational status groups. On the other hand, evidence suggests both anti-EGFR and anti-VEGF may be more effective for KRAS WT than MT patients. KRAS WT results provided evidence that anti-EGFR treatments may be more effective than anti-VEGF treatments when combined with FOLFIRI or FOLFOX. Further, evidence suggests that both anti-EGFR and anti-VEGF therapies, when combined with FOLFIRI or FOLFOX, may be harmful as compared to chemotherapy for KRAS MT patients.Literature was searched for randomized trials comparing anti-EGFR or anti-VEGF antibodies, paired with FOLFIRI or FOLFOX, as first-line therapy for advanced colorectal cancer. Meta-estimates were generated via Bayesian hierarchical log-linear model. The primary endpoint was overall survival.Further studies examining impact of all-RAS mutation status, left or right side location of primary tumor, and combination anti-VEGF with modern bolus fluoropyrimidine are needed.
| S-EPMC5630427 | biostudies-literature
Project description:It is increasingly recognized that gastric cancer is a heterogeneous disease which may be divided into subgroups based on histological, anatomical, epidemiological and molecular classifications. Distinct molecular drivers and tumor biology, and thus different treatment targets and predictive biomarkers, may be implicated in each subtype. However, there is little evidence in the literature regarding the correlation among these different classifications, and particularly the molecular aberrations present in each subtype. In this review, we approach advanced gastric cancer (AGC) by presenting aberrant molecular pathways and their potential therapeutic targets in gastric cancer according to histological and anatomical classification, dividing gastric cancer into proximal nondiffuse, distal nondiffuse and diffuse disease. Several pathways are involved predominantly, although not exclusively, in different subtypes. This may help to explain the disappointing results of many published AGC trials in which study populations were heterogeneous regardless of clinicopathological characteristics of the primary tumor. Histological and anatomical classification may provide insights into tumor biology and facilitate selection of an enriched patient population for targeted agents in future studies and in the clinic. However, some molecular pathways implicated in gastric cancer have not been studied in correlation with histological or anatomical subtypes. Further studies are necessary to confirm the suggestion that such classification may predict tumor biology and facilitate selection of an enriched patient population for targeted agents in future studies and in the clinic.
| S-EPMC3539290 | biostudies-literature
Project description:Gastric cancer is the fourth most common cancer worldwide. Surgery in combination with multimodal therapy provides the only curative therapy until now. The importance of targeted therapy became clear over the last few years. Due to the implication of HER2 and angiogenesis-directed targeted therapies major advances in the treatment of gastric cancer could be reached. Nevertheless, benefits in survival remain unsatisfactory and the development of resistance to monoclonal antibodies is arising.A comprehensive and comparative literature research was performed to evaluate the status of HER2 and angiogenesis-directed targeted therapy in gastric cancer.Up to now, trastuzumab and ramucirumab are the only agents showing remarkable benefits in the therapy for the patients suffering from gastric cancer. The limitations of targeted therapies in gastric cancer are mainly associated with the development of secondary resistance.Addition of targeted therapy in second-line treatment is beneficial when compared with chemotherapy alone. Nevertheless, results in first-line treatment remain modest. Therefore, new therapeutic agents and combinations in the first-line treatment of gastric cancer are urgently needed and remain to be validated in clinical trials.
| S-EPMC5065582 | biostudies-other
Project description:Niraparib (Zejula™) is a PARP inhibitor which is approved for maintenance therapy in adults with advanced ovarian cancer in complete or partial response to platinum-based chemotherapy. In a placebo-controlled phase III trial in patients with newly diagnosed advanced ovarian cancer, niraparib significantly extended progression free survival in two predefined populations, namely a patient population with altered homologous-recombination DNA repair pathways [i.e. homologous-recombination deficiency positive (HRd)] and the overall trial population. A prespecified exploratory subgroup analysis indicated that niraparib was also efficacious in patients who were homologous recombination deficiency negative or homologous recombination proficient (HRp). Niraparib has a manageable tolerability profile with myelosuppression as the main safety concern. Haematological reactions were managed with monitoring and dose reduction or interruption. A weight- and platelet count-based individualised dosage regimen introduced during the trial (and subsequently approved) appeared to improve haematological tolerability. Niraparib is a useful option for first-line maintenance therapy for advanced ovarian cancer in adults who responded to platinum-based chemotherapy, regardless of homologous-recombination deficiency status and is a promising option for HRp patients, for whom maintenance treatment options are limited.
| S-EPMC8613118 | biostudies-literature
Project description:Targeted therapy and immunotherapy have revolutionized treatment of various cancers in the past decade. Despite targeted therapy with trastuzumab in Her2-positive gastric cancer patients, survival has been dismal, mostly due to disease progression and toxicity related to the treatments. One area of active development is looking for ideal monoclonal antibodies (IMAB) specific to the proteins only on the tumor and hence avoiding unnecessary side effects. Claudin proteins with isoform 2 are one such protein, specific for several cancers, particularly gastric cancer and its metastases, leading to the development of anti-claudin 18.2 specific antibody, claudiximab. This review will highlight the latest development of claudiximab as first in class IMAB for the treatment of gastric cancer.
| S-EPMC5427576 | biostudies-literature