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      Association between ramucirumab-related hypertension and response to treatment in patients with metastatic gastric cancer

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          Abstract

          Purpose

          Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway, such as ramucirumab. The aim of this study was to retrospectively evaluate if occurrence of HTN is correlated with response to second line treatment with ramucirumab+paclitaxel for metastatic gastric cancer.

          Methods

          Treatment consisted of ramucirumab 8 mg/kg intravenously (iv) on days 1 and 15, plus paclitaxel 80 mg/m 2 iv on days 1, 8, and 15 of a 28-day cycle. Patients received study treatment until disease progression, unacceptable toxicity, or withdrawal of consent.

          Results

          Thirty-four patients were retrospectively evaluated. Among these, 6 (17.6%) developed grade 3 ramucirumab-induced HTN. These patients had a better outcome than those with lesser grades events, with a progression-free survival (PFS) of 7.8 months (95% CI 4.4-not reached) versus 4.2 months (95% CI 3.1-5.2) (p=0.001). overall survival (OS) was 11.9 months (95% CI 9.3-not reached) in the grade 3 HTN group, versus 7.2 months (95% CI 5.9-10.1).

          Conclusions

          Despite the small number of patients and the retrospective nature of the data, our analysis showed that occurrence of ramucirumab-related HTN, in particular G3 HTN, predicts response to treatment with ramucirumab+paclitaxel in patients with metastatic gastric cancer.

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          Most cited references20

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          Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100.

          No biomarkers have been identified to predict outcome with the use of an antiangiogenesis agent for cancer. Vascular endothelial growth factor (VEGF) genetic variability has been associated with altered risk of breast cancer and variable promoter activity. Therefore, we evaluated the association of VEGF genotype with efficacy and toxicity in E2100, a phase III study comparing paclitaxel versus paclitaxel plus bevacizumab as initial chemotherapy for metastatic breast cancer. DNA was extracted from tumor blocks of patients from E2100. Three hundred sixty-three samples were available to evaluate associations between genotype and outcome. Genotyping was performed for selected polymorphisms in VEGF and VEGF receptor 2. Testing for associations between each polymorphism and efficacy and toxicity was performed. The VEGF-2578 AA genotype was associated with a superior median overall survival (OS) in the combination arm when compared with the alternate genotypes combined (hazard ratio = 0.58; 95% CI, 0.36 to 0.93; P = .023). The VEGF-1154 A allele also demonstrated a superior median OS with an additive effect of each active allele in the combination arm but not the control arm (hazard ratio = 0.62; 95% CI, 0.46 to 0.83; P = .001). Two additional genotypes, VEGF-634 CC and VEGF-1498 TT, were associated with significantly less grade 3 or 4 hypertension in the combination arm when compared with the alternate genotypes combined (P = .005 and P = .022, respectively). Our data support an association between VEGF genotype and median OS as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer.
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            Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab.

            Arterial hypertension occurring during antiangiogenic therapy has been correlated with the biological inhibition of the vascular endothelial growth factor-related pathway and may represent a possible clinical marker for treatment efficacy. The aim of our study was to retrospectively assess if grades 2-3 hypertension were associated with response to bevacizumab, progression-free survival (PFS) and survival in metastatic colorectal cancer patients treated with first-line bevacizumab. Patients with histologically proven, metastatic colorectal cancer receiving bevacizumab as first-line therapy in combination with irinotecan and 5-fluorouracil were eligible for our analysis. Thirty-nine metastatic colorectal cancer patients were eligible. Eight patients (20%) developed grades 2-3 hypertension. A partial remission was observed in six of eight cases with bevacizumab-related hypertension (75%) and in 10 of 31 (32%) patients with no hypertension (P = 0.04). Median PFS was 14.5 months for patients showing bevacizumab-related hypertension, while it was 3.1 months in those without hypertension (P = 0.04). Median overall survival was not reached in patients with hypertension while it was 15.1 months in the remaining cases (P = 0.11). Our data indicate that bevacizumab-induced hypertension may represent an interesting prognostic factor for clinical outcome in advanced colorectal cancer patients receiving first-line bevacizumab.
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              Unmet needs and challenges in gastric cancer: the way forward.

              Although the incidence of gastric cancer has fallen steadily in developed countries over the past 50 years, outcomes in Western countries remain poor, primarily due to the advanced stage of the disease at presentation. While earlier diagnosis would help to improve outcomes for patients with gastric cancer, better understanding of the biology of the disease is also needed, along with advances in therapy. Indeed, progress in the treatment of gastric cancer has been limited, mainly because of its genetic complexity and heterogeneity. As a result, there is an urgent need to apply precision medicine to the management of the disease in order to ensure that individuals receive the most appropriate treatment. This article suggests a number of strategies that may help to accelerate progress in treating patients with gastric cancer. Incorporation of some of these approaches could help to improve the quality of life and survival for patients diagnosed with the disease. Standardisation of care across Europe through expansion of the European Registration of Cancer Care (EURECCA) registry - a European cancer audit that aims to improve quality and decrease variation in care across the region - may also be expected to lead to improved outcomes for those suffering from this common malignancy. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                27 April 2018
                27 April 2018
                : 9
                : 32
                : 22332-22339
                Affiliations
                1 Division of Medical Oncology, Department of Onco-Hematology, IRCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero, Vulture (PZ), Italy
                2 Peter MacCallum Cancer Centre, Radiation Oncology Department, Moorabbin Campus, East Bentleigh, Victoria 3165, Australia
                3 Unit of Medical Oncology, Department of Oncology, Ospedale San Donato, 52100, Arezzo, Italy
                4 Unit of general medicine, Azienda Ospedaliera “C. Poma” Presidio ospedaliero di Pieve di Coriano, ASST Mantova, Italy
                5 Medical Oncology Unit, Department of Oncology, ASST del Garda, 25015 Desenzano del Garda (BS), Italy
                6 Department of Medicine, Surgery and Neurosciences, Medical Oncology Unit, University of Siena, Viale Bracci - Policlinico “Le Scotte”, 53100, Siena, Italy
                7 Department of Medical, Surgery and Health Sciences, University of Trieste, 34129 Trieste, Italy
                8 Breast Cancer and Translational Research Unit, ASST Cremona, 26100 Cremona, Italy
                Author notes
                Correspondence to: Giandomenico Roviello, giandomenicoroviello@ 123456hotmail.it
                Article
                24900
                10.18632/oncotarget.24900
                5976467
                a2a100e8-50ff-4c1b-8646-5f1093b8b14e
                Copyright: © 2018 Roviello et al.

                This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 15 January 2018
                : 11 March 2018
                Categories
                Research Paper

                Oncology & Radiotherapy
                gastric cancer,ramucirumab,hypertension
                Oncology & Radiotherapy
                gastric cancer, ramucirumab, hypertension

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