Empiric therapy for the febrile neutropenic patient. Design bias

Empiric therapy is practical and must be begun promptly; the specific regimen chosen must be based upon local conditions and epidemiology. It must be recalled that subgroups of patients are not necessarily equivalent to the majority, i.e., there are low-risk patients for whom ambulatory and/or oral therapy is appropriate and, conversely, there are high-risk patients who have a potential for a high mortality and who, while perhaps few in number, are of critical importance. Further, many of these patients are very complex, and this leads to a high level of physician concern and insecurity. This physician concern, in turn, leads to a tendency to modify regimens, given that the physician all too often is dealing with inadequate diagnostic information owing to the patient situation. The physician's choice of modification is highly dependent upon knowledge of the regimen the patient is already receiving. There is a need for clear definition of endpoints, and these must be established before the study is initiated. All too many published studies are too small to evaluate the endpoint that has been defined, and many others, although sufficient in size, have all of the problems inherent in studies conducted at multiple sites by multiple individuals with differing degrees of commitment or enthusiasm toward the study at hand. A few implications for study design and evaluation seem evident: it is critical to define endpoints and execute the study accordingly. This means determining the size of the population needed and determining the presence or absence of risk groups. Patients to be excluded e.g., those in whom infection is doubted must be selected on the basis of objective data by an observer blinded to both the outcome and the treatment. Similarly, the classification of response should preferably be done by an observer not influenced by knowledge of the therapy being given. Finally, and similarly, the decision to modify therapy (especially if modification is equivalent to defining failure with the regimen) should not be influenced by knowledge of the therapy being administered.