Title Early dissemination of bevacizumab for advanced colorectal cancer : a prospective cohort study Permalink

Background: We describe early dissemination patterns for first-line bevacizumab given for metastatic colorectal cancer treatment. Methods: We analyzed patient surveys and medical records for a population-based cohort with metastatic colorectal cancer treated in multiple regions and health systems in the United States (US). Eligible patients were diagnosed with metastatic colorectal cancer and initiated first-line chemotherapy after US Food & Drug Administration (FDA) bevacizumab approval in February 2004. First-line bevacizumab therapy was defined as receiving bevacizumab within 8 weeks of starting chemotherapy for metastatic colorectal cancer. We evaluated factors associated with first-line bevacizumab treatment using logistic regression. Results: Among 355 patients, 31% received first-line bevacizumab in the two years after FDA approval, including 26% of men, 41% of women, and 16% of those ≥ 75 years. Use rose sharply within 6 months after FDA approval, then plateaued. 20% of patients received bevacizumab in combination with irinotecan; 53% received it with oxaliplatin. Men were less likely than women to receive bevacizumab (adjusted OR 0.55; 95% CI 0.32-0.93; p = 0.026). Patients ≥ 75 years were less likely to receive bevacizumab than patients < 55 years (adjusted OR 0.13; 95% CI 0.04-0.46; p = 0.001). Conclusions: One-third of eligible metastatic colorectal cancer patients received first-line bevacizumab shortly after FDA approval. Most patients did not receive bevacizumab as part of the regimen used in the pivotal study leading to FDA approval. Background Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, was the first biologic agent shown to improve median overall survival (by 4.7 months) in patients with metastatic colorectal cancer, when given with cytotoxic chemotherapy [1]. Results of the first phase III study demonstrating this benefit were released publically in June, 2003, and published in June, 2004. The United States (US) Food and Drug Administration (FDA) approved bevacizumab for first-line treatment of metastatic colorectal cancer in February, 2004. The drug was approved by the European Union a year later in January, 2005. Although effective in prolonging survival, bevacizumab is expensive,[2] can cause hypertension, cardiovascular events, and in rare instances, severe hemorrhage or gastrointestinal tract perforation [1,3]. Little is known about the early uptake of new biologic therapies such as bevacizumab for advanced cancer. Specifically, 1) what is the initial dissemination pattern of biologic agents? ; and 2) how do clinicians interpret clinical trial results for biologic agents, especially since selective trial eligibility might not represent the broad spectrum of patients treated in the community setting? [4] Registry studies for bevacizumab have examined postmarketing safety and efficacy, but these studies cannot * Correspondence: yousuf.zafar@duke.edu Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA Full list of author information is available at the end of the article Zafar et al. BMC Cancer 2011, 11:354 http://www.biomedcentral. com/1471-2407/11/354 © 2011 Zafar et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. answer our two questions since all enrolled patients received bevacizumab [5,6]. Answering these questions is critically important in light of recent regulatory decisions related to bevacizumab. At the end of 2010, the FDA recommended removing bevacizumab’s breast cancer indication due to lack of survival benefit; the European Medicines Agency has maintained its indication but only in combination with paclitaxel. In light of the high drug cost, we must understand how novel agents are used in standard care since in certain instances, rapid dissemination occurs despite lack of long-term, phase IV data. We used data from the Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium, a US populationand healthcare systems-based study of newly-diagnosed patients with colorectal cancer, to describe the uptake of bevacizumab and to identify factors associated with its use. Comprehensive medical record abstraction enabled us to evaluate bevacizumab use in relationship to comorbidity and other patient characteristics not typically available in cancer registry data [7]. Thus, we were able to examine dissemination of this new therapy in a broad range of community settings. Methods Cancer Care Outcomes Research and Surveillance Consortium CanCORS is a prospective, observational, populationand healthcare systems-based cohort study designed to determine how characteristics of cancer patients, providers, and health care organizations influence treatments and outcomes in newly diagnosed lung or colorectal cancer patients [8]. The full CanCORS cohort appears representative of the US Surveillance, Epidemiology, and End Results (SEER) registry sample: CanCORS participants did not differ from their corresponding SEER population by more than 8 percentage points in any important demographic characteristics such as gender, race, age, and stage [9]. Patients with colorectal cancer were nationally enrolled from geographically diverse populations and health care systems, including five integrated health care systems in the NCI-funded Cancer Research Network, and fifteen Veterans Administration Hospitals [8]. Primary data were collected from patient surveys and medical records. Human subject committees approved the study protocol at each participating site. Patients Eligible patients were at least 21 years old and were identified within 3 months of diagnosis of colorectal cancer. Three thousand six hundred sixty-four incident cases of colorectal cancer (Figure 1) were enrolled in the CanCORS cohort between September, 2003 to January, 2006, including 742 patients (20%) with advanced colorectal cancer (677 with stage IV cancer at diagnosis, and 65 with a metastatic or regional recurrence within the 15month post-diagnosis follow-up period of the study). Of note, this stage distribution (20% with advanced cancer) is consistent with that seen in the SEER registry, where patients with advanced colorectal cancer comprise 19% of all patients [10]. Of the 742 patients in our cohort with stage IV or recurrent disease, 355 initiated first-line treatment after the bevacizumab approval date in February, 2004 and were included in this analysis. Hence, the subcohort of interest for this analysis began treatment from March, 2004-January, 2006. All patients or their surrogates provided informed consent at enrollment. Recruitment materials and patient surveys were translated into Spanish and Chinese. Data Collection Medical records data were abstracted by trained abstractors at each of the data-collection sites. The time window for records abstraction was three months before diagnosis to fifteen months after diagnosis. Data abstractors had professional experience as cancer registrars or nurses and underwent an intensive four-day training course on data collection processes and standards in CanCORS. Quality assurance was monitored by completion of up to six goldstandard reference chart abstractions per abstractor. Presence of comorbid illness was collected as part of the medical record abstraction. The degree of comorbidity was scored using the Adult Comorbidity Evaluation 27 (ACE-27), a 27-item index developed to provide prognostic information for cancer patients [11]. Primary data were collected from patients via computerassisted telephone interviews 4-7 months after diagnosis. For patients who had died or were too ill to be interviewed, a surrogate (relative or household member) familiar with their cancer care was interviewed. The surveys (available at http://www.cancors.org/public) assessed patients’ sociodemographic characteristics (age, race/ethnicity, annual income), insurance coverage, comorbid conditions, and beliefs about cancer care (see Additional file 1) [12]. Surveys were the primary source of insurance information; medical records provided a secondary source. We categorized patients by whether or not they received care in an integrated health system, defined as one of the 5 participating health maintenance organizations, a California Kaiser Permanente plan, or one of the participating Veterans Administration hospitals [8]. Patients were also classified by US region (South, including sites in Alabama, Mississippi, Tennessee, Texas, Georgia; Atlantic, including sites in Massachusetts, Maryland, New York, and North Carolina; and West/Midwest, including sites in Arizona, California, Oregon, Washington, Iowa, Illinois, Indiana, Michigan, Minneapolis, Indiana). Zafar et al. BMC Cancer 2011, 11:354 http://www.biomedcentral. com/1471-2407/11/354 Page 2 of 12