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Journal of Clinical Oncology, Vol 24, No 7 (March 1), 2006: pp. 1221-1222 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.7670
Withholding Antibiotics From Patients With Febrile NeutropeniaProfessor of Medicine and Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York To the Editor: I read with interest the recent article by Nijhuis et al1 in the October 20, 2005, issue of the Journal of Clinical Oncology. The authors address an important and timely issue related to the identification of patients with febrile neutropenia (FN) at low risk for serious medical complications including mortality. Although they are not the first to take on this challenge, they may be the first to select a management option for low-risk patients with FN that includes no empiric antibiotics for presumed infection. On the basis of a high mortality rate when early antibiotic therapy is withheld, the Infectious Diseases Society of America recommends a course of empiric therapy until recovery from the neutropenia and fever.2 However, patients with FN have a wide variation in the duration of neutropenia, time to defervescence, hospitalization length of stay, and mortality. Previous efforts to identify low-risk patients with FN who may be candidates for ambulatory treatment or oral antibiotics have been limited by high false-negative and false-positive rates.3 The authors of this study offer another approach to identifying low-risk patients with FN who might need less aggressive treatment or perhaps no treatment at all. Although interleukin-8 is not clinically available outside of a research setting, if the results of this study are confirmed and validated, this could offer a safe and less expensive approach to managing low-risk patients with FN. However, before there is a leap to this potentially risky approach to treating patients with FN, it is important to make note of the substantial methodologic limitations of this study. It is important to emphasize that half of the patients in this study were children, who experience significantly less morbidity and mortality than adults with FN.4,5 Therefore, the results may not be generalizable to an adult cancer population, including the elderly. In addition, the authors admit that the observed rate of bacteremia of 11% was considerably less than that reported by other authors. Importantly, the analysis focused on the 196 FN episodes rather than the 128 individual patients, with 40 patients entered onto this study more than once. The statistical methods used in the analysis are based on an assumption of independence between observations, which can never be assumed when the same patient is included more than once. The authors attempt to justify this approach using a method that does not negate the lack of independence between observations in the same patients. A lack of difference in risk classification, patient characteristics, or outcomes in patients across repeated observations does not represent evidence of independence, particularly in a study of low power. Therefore, the statistical measures and levels of statistical significance reported in this study are invalid. The authors evaluate the test performance of their approach based on the documentation of bacteremia in low-risk and high-risk episodes. However, the appropriate analysis based on the 24 low-risk patients provides a 95% CI on the estimated false-negative rate of 0% to 14%, leaving considerable uncertainty about the safety of this approach. In addition, the median age of the low-risk group was 19 years, with no patients older than 65 years of age. Therefore, the risk for low-risk patients seems to be based on no more than a dozen adult individuals. More appropriate risk outcomes would include recurrent fever, infectious complications, the need for hospitalization, and mortality. Although it is clear that such an approach to low-risk patients with FN could potentially save money, no clinical cost for interleukin-8 assays is available, and the cost analysis based on Dutch standard prices has little relevance to a US population. The proportion of patients identified as low risk in this study constituted less than 20% of the entire population, further limiting the potential economic impact. The authors' suggestion that medium-risk patients may be candidates for oral antibiotics according to their scheme goes beyond the results of this study. Clearly, validation of this approach is needed in separate adult cancer populations before any conclusions about its safety or efficacy can be drawn. Oncologists should have zero tolerance for false-negative risk classification for FN when considering withholding antibiotics in low-risk patients given the large associated regret accompanying a false-negative result.6 In the meantime, all patients receiving cancer chemotherapy presenting with FN should be evaluated and started on empiric broad-spectrum antibiotics. Author's Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Nijhuis CO, Kamps WA, Daenen SM, et al: Feasibility of withholding antibiotics in selected febrile neutropenic cancer patients. J Clin Oncol 23:7437-7444, 2005 2. Hughes WT, Armstrong D, Bodey GP, et al: 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 34:730-751, 2002[CrossRef][Medline] 3. Klastersky J, Paesmans M, Rubenstein EB, et al: The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 18:3038-3051, 2000 4. Basu SK, Fernandez ID, Fisher SG, et al: Length of stay and mortality associated with febrile neutropenia among children with cancer. J Clin Oncol 23:7958-7966, 2005 5. Kuderer NM, Dale DC, Crawford J, et al: Mortality, morbidity and cost associated with febrile neutropenia in adult cancer patients. Cancer (in press)[CrossRef][Medline] 6. Djulbegovic B, Frohlich A, Bennett CL: Acting on imperfect evidence: How much regret are we ready to accept? J Clin Oncol 23:6822-6825, 2005
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
