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Proposal 1075

Title of the Proposed Research

Efficacy and Safety of Bevacizumab in the Elderly Cancer Patients: Pooled Analysis of Ten Randomized Clinical Trials

Lead Researcher

Xiaofei Wang

Affiliation

Department of Biostatistics & Bioinformatics
Duke University

Funding Source

None

Potential Conflicts of Interest

None

Data Sharing Agreement Date

28 Oct 2015

Lay Summary

The cancer incidence and the number of deaths due to cancer among elderly patients are increasing in recent years due to the improvement of cancer diagnosis and treatment and the increase of life expectancy (Yancik 2005). Angiogenesis inhibitors such as bevacizumab have been used to effectively treat cancer, such as metastatic breast, colon and lung cancer, that involve a proliferation of blood vessels. The problems of geriatric cancer treatment and management using angiogenesis inhibitors are compounded because older patients are a heterogeneous population with comorbid illnesses and often taking multiple drugs. Moreover, the evidence-based decision as to whether or not to use angiogenesis inhibitors is challenging because elderly cancer patients are often under-represented in clinical trials. Among the most frequently reported adverse events after receiving angiogenesis inhibitors are hand-foot syndrome, stomatitis, diarrhea, fatigue, hypothyroidism and hypertension (Boehm et al. 2009). The safety of antiangiogenic drugs is of concern especially when taking these agents for longer-term adjuvant or maintenance treatment. It was reported that elderly patients were at increased risk of thromboembolic events when receiving bevacizumab, and potentially for cardiac dysfunction when receiving sunitinib or sorafenib (Choueiri et al 2010). Overall, to date there are a limited number of studies focusing on systematic and evidence-based assessments on the short-term and long-term safety of angiogenesis inhibitors for treating elderly patients, and how the treatment-related adverse events interplay with cancer prognosis and comorbidity. The patient-level trial data provided through the data sharing mechanism at ClinicalStudyDataRequest.com provide an excellent opportunity to systematically address this issue through a pooled analysis of multiple bevacizumab-based phase II and III clinical trials.

The specific aims of the project are (1) to conduct a pooled-analysis of safety and efficacy of elderly cancer patients treated with bevacizumab, and (2) to develop a prognostic index to predict treatment-related adverse events of interest. The data elements required to address these aims are adverse events, overall survival, baseline patient characteristics, clinical/pathological characteristics, and treatment information.

The pooled analysis will provide a deep understanding of angiogenesis inhibitors related adverse events among elderly breast, colon and lung cancer patients. Elderly patients are defined as 70 years or older and the benefit-risk ratio of the treatment will be evaluated on this important patient population. The baseline clinical and pathological variables will also be used to develop a predictive tool for severe adverse event sensitivity for elderly cancer patients. The findings of this research will greatly enhance the understanding and the practice of using angiogenesis inhibitors to treatment elderly cancer patients.

Study Data Provided

Study ROCHE-APM4074g: A randomized, double-blind, phase ii trial of paclitaxel plus carboplatin plus bevacizumab with or without apomab in patients with previously untreated, advanced-stage non-small cell lung cancer
Study ROCHE-AVF2119G A multicenter, open-label, phase III, randomized, active-controlled trial evaluating the efficacy, safety, and pharmacokinetics of rhuMAb VEGF (bevacizumab), in combination with capecitabine chemotherapy, in subjects with previously treated metastatic breast cancer
Study ROCHE-BO17708 A randomized, double-blind study of the effect of first line treatment with Avastin (bevacizumab) in combination with docetaxel on progression-free survival and disease response in patients with HER2 negative metastatic breast cancer
Study ROCHE-AVF3694G A multicenter, phase III, randomized, placebo-controlled trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy regimens in subjects with previously untreated metastatic breast cancer
Study ROCHE-ML18147A randomized, open-label phase III Intergroup study: Effect of adding Bevacizumab to cross over fluoropyrimidine based chemotherapy in patients with mCRC and disease progression under first-line standard CTx/Bevacizumab combination
Study ROCHE-AVF2107g A phase III, multicenter, randomized, active-controlled clinical trial to evaluate the efficacy and safety of rhumab vegf (bevacizumab) in combination with standard chemotherapy in subjects with metastatic colorectal cancer
Study ROCHE-AVF2192g A phase II, multicenter, double-blind, randomized, active-controlled clinical trial to evaluate the efficacy and safety of rhumab vegf (bevacizumab), a recombinant humanized monoclonal antibody to vascular endothelial growth factor, in combination with 5-fluorouracil and leucovorin chemotherapy in subjects with metastatic colorectal cancer who are not optimal candidates for first-line cpt-11
Study ROCHE-BO17704 (AVAIL) A randomized, double-blind multicenter 2-stage phase III study of bevacizumab in combination with cisplatin and gemcitabine versus placebo, cisplatin and gemcitabine in patients with advanced or recurrent non-squamous non-small cell lung cancer, who have not received prior chemotherapy
Study ROCHE-BO17705 (AVOREN) A randomised, double-blind phase III study to evaluate the efficacy and safety of bevacizumab in combination with interferon alfa-2a (roferon) versus interferon alfa-2a and placebo as first line treatment administered to nephrectomized patients with metastatic clear cell renal cell carcinoma
Study ROCHE-NO16966 2 x 2 Factorial randomized phase III study of intermittent oral capecitabine in combination with intravenous oxaliplatin (q3w) ("XELOX") with/without intravenous bevacizumab (q3w) versus bolus and continuous infusion fluorouracil/intravenous leucovorin with intravenous oxaliplatin (q2w) ("FOLFOX-4") with/without intravenous bevacizumab (q2w) as first-line treatment for patients with metastatic colorectal cancer.

Statistical Analysis Plan

The statistical analysis plan will be added after the research is published.

Publication Citation

The publication citation will be added after the research is published.