The Outpatient Management of Febrile Neutropenia in Cancer Patients

The discussion by Freifeld and Pizzo is a comprehensive summaryof an important recent trend: the attempt to identify low-riskpatients with fever and neutropenia and relax their therapy appropriately.It is not surprising that a summary from these authors would bedefinitive. Dr. Pizzo and his colleagues have defined many centralelements of the therapy of fever and neutropenia: that broad-spectrumantibiotics should be continued after patients become afebrilewhile they remain neutropenic [1]; that an antifungal agent, amphotericin,should be added to prevent potentially serious fungal superinfectionwhen patients remain febrile and neutropenic after 7 days [2];and that monotherapy using ceftazidime alone is as effective ascombination therapy with a semisynthetic penicillin and an aminoglycoside,particularly for low-risk patients [3]. Their current review catalogsrecent attempts to define less aggressive, costly, and restrictivetherapy for low-risk patients with fever and neutropenia. I wouldadd only a few comments based on our work at the Dana-Farber CancerInstitute.

My belief that there exist low-risk patients with fever and neutropeniaappropriate for less aggressive therapy stems from: (1) the clinicalimpression that some patients have predictably benign coursesand (2) the hypothesis that "uncomplicated" fever andneutropenia is a self-limited condition, assuming that the patientis appropriately supported with broad-spectrum antibiotics, sinceadequate production of granulocytes and re-establishment of thegastrointestinal integument soon restore the patient's usual barriersto infection. Unless interrupted by additional problems, suchas an unusually serious infection, a structural problem with thegut mucosa (eg, a locally invasive tumor), or a myelophthisictumor interfering with production of bone marrow elements, patientrecovery proceeds smoothly and promptly.

Of course, patients receiving cytotoxic chemotherapy for cancerhave, by definition, other medical problems besides the effectsof cytotoxic chemotherapy. If nothing else, they have the cancerthat the chemotherapy was initiated to combat, the cumulativeeffects of prior therapy, or other comorbid illnesses common inthe older age groups in which cancer is most common. Therefore,the goal of risk assessment, as I see it, is to use clinical informationto distinguish uncomplicated patients with febrile neutropeniafrom those with additional problems that place them at higherrisk of medical complications.

Is Expected Duration of Neutropenia an Independent Predictorof Risk?

Our goal was to assess risk in febrile neutropenic patients asearly as possible after presentation using clinical characteristicsavailable to the treating clinician, in order to help guide managementdecisions. Therefore, we evaluated only risk factors that couldbe determined within 24 hours of presentation [4,5]. While thework of Pizzo and colleagues [6] and of Bodey and colleagues [7]has consistently affirmed the prognostic impact of longer vs shorterperiods of neutropenia, the duration of neutropenia can be determinedwith certainty only when the episode of febrile neutropenia isover, when management decisions have already been made.

Whether the predicted duration of neutropenia is also an independentpredictor of patient risk is an empirically answerable question:Simply add the pretreatment prediction of neutropenia durationto variables assessed and enter it into a multiple regressionmodel. When they identified brief neutropenia as a marker of goodrisk, Pizzo and colleagues reported that they were unable to findclinical predictors of it [6], although Freifeld and Pizzo nowstate that they can predict duration of neutropenia more accurately.However, when we retrospectively applied the actual duration ofneutropenia to our patient population, we found that patientswith neutropenia of < 7 days indeed had a lower risk, but theiroverall risk of major medical complications was 16%, as comparedwith 5% for the patients in our own low-risk group [5].

Medical Risk: The Fundamental Issue in Outpatient Therapy

Freifeld and Pizzo correctly point out that, absent a randomizedtrial showing equivalence between standard IV antibiotic regimensgiven in the hospital and the same regimen given at home, outpatienttherapy per se has not been assessed and thus cannot be consideredthe standard of care. Other approaches to simplifying care, includingthe use of oral regimens, simplified intravenous (IV) regimens,and early discontinuation of antibiotics, may ultimately contributeelements to a safe, easy-to-administer outpatient regimen, butnow represent additional experimental variables, in addition tothe site at which care is delivered.

The primary characteristic of home care, as compared with standardin-hospital care, is the necessarily lower level of surveillancepossible for patients at home. Therefore, if patients are at toohigh a risk of serious medical problems requiring immediate intervention,treating them at home would be unwise and potentially harmful.To alter both the site of care and some other element of care,such as the route of antibiotic administration, changes two variablesin a single trial, making the effect of treatment at home perse on any outcome difference difficult to identify.

The outcome used to compare efficacy is also important. Deathis unarguably important but is too uncommon among low-risk patientsfor a trial with death as the primary end point to have both adequatepower and manageably low patient numbers. The problem that deathis important but uncommon has led to the troubling finding insome trials of an extra death in the outpatient group-a statisticallyinsignificant outcome that, nevertheless, substantially underminesthe conclusion that the two approaches are equally safe and efficacious[8,9]. In our ongoing Cancer and Leukemia Group B randomized trialof in-hospital IV antibiotic therapy vs early discharge to homeIV antibiotic care for low-risk patients, we use the occurrenceof major medical complications, defined as serious problems forwhich an emergent intervention is necessary, as the primary endpoint. While this is a more ambiguous outcome than death, it ismore common and is, we believe, logically linked to the issueof medical risk, the fundamental issue in home therapy of febrileneutropenia.

These technical points aside, Freifeld and Pizzo have done anexcellent job of summarizing the changing approach to identifyingand treating low-risk patients with fever and neutropenia.

References:

1. Pizzo PA, Robichaud KJ, Gill FA, et al: Duration of empiricantibiotic therapy in granulocytopenic patients with cancer. AmJ Med 67(2):194-200.1979

2. Pizzo PA, Robichaud KJ, Gill FA, et al: Empiric antibioticand antifungal therapy for cancer patients with prolonged feverand granulocytopenia. Am J Med 72(1):101-11, 1982.

3. Pizzo PA, Hathorn JW, Hiemenz J, et al: A randomized trialcomparing ceftazidime alone with combination antibiotic therapyin cancer patients with fever and neutropenia. N Engl J Med 315(9):552-558,1986.

4. Talcott JA, Finberg R, Mayer RJ, et al: The medical courseof cancer patients with fever and neutropenia: Clinical identificationof a low-risk subgroup at presentation. Arch Intern Med 148(12):2561-2568,1988.

5. Talcott JA, Siegel RD, Finberg R, et al: Risk assessment incancer patients with fever and neutropenia: A prospective, two-centervalidation of a prediction rule. J Clin Oncol 10(2):316-322, 1992.

6. Pizzo PA, Robichaud KJ, Wesley R, et al: Fever in the pediatricand young adult patient with cancer: A prospective study of 1001episodes. Medicine 61(3):153-165, 1982.

7. Bodey GP, Buckley M, Sathe YS, et al: Quantitative relationshipsbetween circulating leukocytes and infection in patients withacute leukemia. Ann Intern Med 64:328-340, 1966.

8. Gardembas-Pain M, Desablens B, Sensebe L, et al: Home treatmentof febrile neutropenia: An empirical oral antibiotic regimen.Ann Oncol 2:485-487, 1991.

9. Malik IA, Khan WA, Karim M, et al: Feasibility of outpatientmanagement of fever in cancer patients with low-risk neutropenia:Results of a prospective randomized trial. Am J Med 98(3):224-231,1995.