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Originally published as JCO Early Release 10.1200/JCO.2009.21.2084 on March 2 2009 © 2009 American Society of Clinical Oncology.
Hidden Biases in an Observational Study of Bevacizumab Beyond ProgressionDepartment of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX To the Editor: Grothey et al1 recently reported a prospective observational study that monitored oncologists' use of bevacizumab after patients experienced disease progression while receiving a prior bevacizumab-containing regimen. The conclusion formed on the basis of this study was that there was a suggested survival benefit from continuing bevacizumab after failure of a first-line bevacizumab-containing regimen, with a hazard ratio (HR) of 0.46 on multivariate analysis. Generally, observational studies can provide important data on toxicities and practice patterns, but these types of studies have significant limitations when they are used to answer comparative questions of efficacy. Grothey et al1 clearly acknowledge the potential bias with this study design and attempt to adjust for several factors. Unfortunately, it is impossible to quantify the extent to which this bias formed or altered the outcome of the trial. Several important sources of bias cannot be controlled for in the absence of randomization to treatment in this study, as will undoubtedly be delineated in this space by other readers of this journal. As a result, factors that are correlated with survival also affect the oncologist's decision to continue bevacizumab. Several poor prognosis factors that may decrease an oncologist's enthusiasm to continue bevacizumab include poor performance status at progression, higher vascular comorbidities, rapid tumor growth while receiving the prior bevacizumab-containing regimen, or peritoneal disease. Each of these factors would generally have predicted shorter survival in patients in whom bevacizumab was discontinued. However, in lieu of enumerating the number and reasoning for such biases in greater detail, we conducted similar analyses that may help to highlight the extent to which the conclusions in this observational trial may have been formed by these unseen biases. Since the US Food and Drug Administration's approval of bevacizumab in 2004, most previously untreated metastatic colorectal patients at our institution have been treated with a bevacizumab-containing regimen. We chose to retrospectively examine these sequential patients to determine if patients treated again with bevacizumab as part of a later-line regimen had improved outcomes than those who did not receive a later-line bevacizumab-containing regimen. Indeed, we were able to demonstrate a similar HR of 0.62 (P = .01) in favor of patients receiving bevacizumab after failing a prior bevacizumab-containing regimen. As the most commonly utilized regimens for previously untreated patients include a potentially emetogenic combination of fluorouracil, irinotecan, and/or oxaliplatin, our practice is to prophylactically administer the antiemetic ondansetron before chemotherapy infusion. Therefore, we also evaluated patients with metastatic colorectal cancer since 2004 to see if there was a benefit in continuing intravenous administration of ondansetron after failing a prior chemotherapy regimen that included intravenous ondansetron. Indeed, as shown in the Figure 1, we found that patients who continued intravenous ondansetron for nausea prophylaxis in a second-line regimen had significantly improved survival (HR, 0.65; P = .02) compared to those who received further treatment without intravenous ondansetron. Similarly, fluorouracil is administered as part of first-line regimens and variably continued with second-line regimens, and we saw a similar trend in favor of continuation of intravenous fluorouracil (HR, 0.72, P = .06).
Instead of the conclusion posited by Grothey et al,1 we suggest that continuation of agents such as bevacizumab, fluorouracil, or ondansetron reflects the administration of more intense (and emetogenic) regimens to refractory patients with a better performance status and fewer comorbidities. Both patient-related factors are among the strongest determinants of patient outcome. Thus, we suggest that it is not the agents themselves from which the benefit derives, but instead the assessment by the oncologist of the suitability for such treatment that separates the patients into two groups with different prognoses. Unfortunately, in the Grothey et al1 study, these factors (the regimens used for the refractory patients and the performance status and comorbidities of these patients at the time of progression) were not collected, and therefore cannot be controlled during subsequent analyses. We suggest that these and other unknown factors may have flawed this analysis. We agree with the hypothesis that bevacizumab may provide benefit after disease progression following treatment with a first-line bevacizumab-containing regimen. However, we feel that observational studies are poorly suited for answering such questions and harbor unseen and unquantifiable biases. Like Grothey et al,1 we encourage further evaluation of this hypothesis by proceeding with a properly designed randomized study, as represented by Southwest Oncology Group 0600, that formally evaluates the benefit of bevacizumab continuation. Until these data demonstrate a benefit, we feel that "judicious use of the current best evidence"2 dictates limiting the administration of bevacizumab beyond disease progression to a research setting. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Scott Kopetz, Genentech (C) Stock Ownership: None Honoraria: None Research Funding: Scott Kopetz, Genentech Expert Testimony: None Other Remuneration: None REFERENCES
1. Grothey A, Sugrue M, Purdie D, et al: Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: Results from a large observational cohort study (BRiTE). J Clin Oncol 26:5326–5334, 2008. 2. Sackett DL, Rosenberg WM, Gray JA, et al: Evidence-based medicine: What it is and what it isn't. BMJ 312:71–72, 1996.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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