Anti-angiogenic treatment in breast cancer: Facts,successes, failures and future perspectives

Angiogenesis is one of the hallmarks of cancer and a crucial requisite in the development of tumors. Interrupting this process by blocking the vascular endothelial growth factor (VEGF) with the monoclonal antibody bevacizumab has been considered a possible breakthrough in the treatment of various types of cancer, especially for advanced disease. However in breast cancer, studies have shown ambivalent results causing debate about the value of this drug. In this article, we review the evidence for anti-angiogenic treatment options for breast cancer, as well as discuss the possible factors limiting the effectiveness of anti-angiogenic agents and offer a recommendation regarding the future research on these therapies for the treatment of breast cancer.     

Tumor Response and Symptom Palliation from RAINBOW,a Phase III Trial of Ramucirumab Plus Paclitaxel in Previously Treated Advanced Gastric Cancer

BackgroundIn the intent‐to‐treat (ITT) population of the RAINBOW study, objective response rate (ORR) was 28% and 16% in the ramucirumab and control arms, respectively. To further characterize tumor response, we present details on timing and extent of tumor shrinkage, as well as associations with symptom palliation.Materials and MethodsTumor response was assessed with RECIST v1.1, and quality of life (QoL) was assessed with the European Organization for Research and Treatment of Cancer Quality‐of‐Life Questionnaire‐Core 30 (EORTC QLQ‐C30) v3.0. Prespecified and post hoc analyses were conducted in the ITT population, patients with measurable disease, or responders, and included best overall response (BOR), ORR, disease control rate (DCR), duration of response, time to response (TtR), change in tumor size, and associations of QoL with tumor shrinkage and BOR.ResultsIn both treatment arms, median TtR was 1.5 months. Responses were more durable in the ramucirumab versus control arm (median 4.4 vs. 2.8 months). In patients with measurable disease (78% of ITT), ORR was 36% versus 20%; DCR was 81% versus 61% in the ramucirumab versus control arms. Waterfall plots demonstrated more tumor shrinkage in the ramucirumab versus control arm. Regardless of treatment, tumor response and stable disease were associated with improved or stable QoL, with more tumor shrinkage associated with greater symptom palliation.ConclusionTreatment with ramucirumab plus paclitaxel yielded the highest ORR reported to date for patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma. Additional details demonstrate robustness of tumor response results. The extent of tumor shrinkage is directly associated with symptom palliation and should be considered when evaluating patient needs and treatment selection. Clinical trial identification number. {"type":"clinical-trial","attrs":{"text":"NCT01170663","term_id":"NCT01170663"}}NCT01170663.Implications for PracticeRamucirumab plus paclitaxel is a recognized standard of care as it improves survival for patients with advanced gastric or gastroesophageal junction adenocarcinoma who have been previously treated with recommended first‐line therapy. These additional data on tumor response demonstrate a positive association between tumor shrinkage and symptom palliation in a patient population that is often symptomatic. These observations included patients with nonmeasurable disease, a group of patients often underrepresented in clinical trials. This knowledge can inform treatment decisions, which align individual patient characteristics and needs with demonstrated benefits.     

Ramucirumab in the treatment of non-small cell lung cancer

Introduction: Therapeutic options for treating Non-Small Cell Lung Cancer (NSCLC) have recently increased. Ramucirumab (Cyramza), an anti-angionenic agent was approved in 2014 for treatment of several malignancies, including second-line treatment of patients with NSCLC with disease progression on or after platinum-based chemotherapy.

Areas covered: We performed a comprehensive search of the literature focused on clinical trials with use of ramucirumab, targeting its evolution in the treatment of NSCLC. This review summarizes the results regarding its safety and efficacy.

Expert opinion: Angiogenesis has been widely recognized as a quintessential feature in cancer, intrinsically mediating tumor survival and progression. Ramucirumab, an anti-VEGFR2 agent, combined with docetaxel, was FDA-approved for NSCLC patients. Results from a phase III trial have demonstrated the usefulness of this combination, with benefits in progression free survival and overall survival for NSCLC patients. A greater magnitude of benefit is seen in patients with aggressive tumor behavior. Treatment with ramucirumab is generally tolerable, however, there is potential for severe toxicity. Adverse events reported with this combination include neutropenia, febrile neutropenia and hypertension. Also, there is the intrinsic risk of bleeding resulting from the mechanism of action. As such, adverse events should be identified timely, so drug-related complications can be prevented.     

Second-line treatments for advanced gastric cancer: Interpreting outcomes by network meta-analysis

AIM: To study the effectiveness of second-line treatments for advancer gastric cancer by application of Bayesian network meta-analysis.METHODS: Our search covered the literature up to February 2015. The following 6 treatments were evaluated: (1) irinotecan (camptothecins); (2) paclitaxel (taxanes class); (3) docetaxel (taxanes); (4) everolimus (mammalian target of rapamycin inhibitors); (5) ramucirumab (vascular endothelial growth factor receptor 2 inhibitors); (6) ramucirumab + paclitaxel. Our methodology was based on standard models of Bayesian network meta-analysis. The reference treatment was best supportive care (BSC). The end-point was overall survival. Median survival was the outcome measure along with 95% credible intervals.RESULTS: Our search identified a total of 7 randomized controlled trials. These trials included 2298 patients (in 15 treatment arms) in whom a total of 6 active treatments were evaluated as well as BSC. There were 21 head-to-head comparisons (6 direct, 15 indirect). The difference in survival between each of two active treatments (paclitaxel and ramucirumab + paclitaxel) vs BSC was statistically significant, while the other 4 showed no statistical difference. In the 6 head-to-head comparisons between active treatments, no significant survival difference was demonstrated.CONCLUSION: Our results indicate that both paclitaxel monotherapy and ramucirumab + paclitaxel determine a significant prolongation in survival as compared with BSC.     

雷莫卢单抗致肿瘤患者出血风险的荟萃分析

目的:系统评价雷莫卢单抗(Ramucirumab)对肿瘤患者出血风险的影响。方法:全面检索PubMed、ASCO Abstracts、ESMO Abstracts、Embase、ClinicalTrials.gov、CNKI以及万方数据库,查找雷莫卢单抗所有相关的前瞻性随机对照试验(RCTs),采用Revman5.2软件进行Meta分析。结果:纳入13篇随机对照试验,包含6307例肿瘤患者。结果显示与对照组相比,雷莫卢单抗增加了肿瘤患者所有级别出血风险(RR:1.95,95%CI:1.79–2.13,P<0.00001),但没有增加高级别(≥3级)出血风险(RR:1.04,95%CI:0.78–1.39,P=0.79)。在亚组分析中,雷莫卢单抗没有增加非小细胞肺癌患者所有级别(RR:1.28,95%CI:0.95–1.74,P=0.11)以及高级别肺出血风险(RR:1.37,95%CI:0.46–4.09,P=0.57)。此外,在雷莫卢单抗不同剂量组,发生高级别和所有级别的出血风险未见差异。结论:雷莫卢单抗致严重出血的风险较小,由于本研究存在一定的局限性,仍需更多高水平、大样本、多中心的临床随机对照试验加以验证。