The New England Journal of Medicine -- July 29, 1999 -- Vol. 341, No. 5  (Editorial)

Fever and Neutropenia -- How to Use a New Treatment Strategy

The first effective treatment for patients with fever and neutropenia was the combination of an antipseudomonal penicillin, carbenicillin, and gentamicin in a strategy of early empirical therapy triggered by fever alone. (2) The studies of Pizzo and colleagues refined this approach. Small, randomized trials showed that terminating antibiotics before the resolution of neutropenia often led quickly to septic shock and that adding amphotericin B for persistent neutropenia and fever prevented fungal superinfection. (3,4) Even with these innovations, the death rates for patients with fever and neutropenia remained fearsome, and all treatment was given in the hospital.

In the 1980s, the options for antibiotic treatment improved. A large, randomized study (5) demonstrated that a single broad-spectrum drug, ceftazidime, could safely replace the standard combination of an antipseudomonal penicillin and an aminoglycoside. Despite this finding, because of their previous experience with rapidly fatal pseudomonas infections, wary clinicians were reluctant to use ceftazidime alone in patients who often were very ill from intensive chemotherapy.

However, risk-assessment studies began to refine clinicians' intuitions about the medical instability of their patients. A retrospective study by Talcott et al. (6) of 261 episodes of fever and neutropenia treated in the hospital provided justification, in part, for the anxiety of clinicians. In one of five episodes, serious, potentially life-threatening medical complications developed, such as hypotension, respiratory failure, and altered mental status. However, not all patients were at similarly high risk.
Within 24 hours of hospitalization, three high-risk groups could be identified:

• patients who were already inpatients when fever and neutropenia developed;
• outpatients who needed acute hospital care for problems in addition to the fever and neutropenia; and
• clinically stable outpatients with uncontrolled cancer (those with acute leukemia not in complete remission or those with another tumor that was progressing during anticancer therapy).
  * For patients in the three high-risk groups, the rate of medical complications was 36 percent, and 20 percent of such patients died.

• All the remaining patients -- a group that comprised 70 percent of the outpatients -- were by default at low risk. For the low-risk patients, the complication rate was 2 percent, and none died.

The ability to make distinctions about risk offered new possibilities for treatment. If fever and neutropenia do not always have the same clinical significance, then the strategy for treating them may vary according to circumstance.

This issue of the Journal includes reports on two large, prospective, randomized studies of low-risk patients (defined variously by the investigators) that expand our options for the management of fever and neutropenia in patients with cancer. (8,9) The results of these studies show that oral antibiotics may be safely substituted for intravenous antibiotics in low-risk patients with fever and neutropenia.

As reported by Kern et al., (8) the International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer conducted an open-label, randomized trial at 25 hospitals, comparing intravenous ceftriaxone plus amikacin with oral amoxicillin-clavulanate plus ciprofloxacin in patients with cancer and granulocytopenia (defined as <1000 granulocytes per cubic millimeter) that was expected to last 10 days or less. Patients were eligible if their condition was judged to be clinically stable and if they had no clinical evidence of any specific infection. Patients with allogeneic bone marrow transplants, recent treatment with antibiotics, renal failure, respiratory insufficiency, or a high probability of death within 48 hours were excluded. Most of the patients had fever that developed at home after they received treatment for solid tumors, although approximately 30 percent had hematologic cancers. All patients were hospitalized until their fevers resolved; the median duration of granulocytopenia was six to seven days. Success was defined as the resolution of fever and infection and any manifestation of infection, and the success rates were similar in the two treatment groups. In this study of 353 patients, there were six deaths from primary infection.

The trial conducted by Freifeld et al. (9) compared oral amoxicillin-clavulanate plus ciprofloxacin with intravenous ceftazidime alone in 232 episodes of neutropenia (defined as <500 neutrophils per cubic millimeter) that were projected by the patients' physicians to last no more than 10 days and that occurred in patients without important coexisting illness. The use of a double-blind design (with a dummy intravenous or oral treatment, as appropriate) eliminated any bias toward modifying therapy earlier in the oral-therapy group.   In this study, as in the study by Kern et al., most of the patients had solid tumors, but the average duration of neutropenia was shorter (3.4 days in the oral-therapy group and 3.8 days in the intravenous-therapy group).   The patients were hospitalized for the duration of fever and neutropenia, and there were no deaths. There were no significant differences between the treatment groups in the frequency of the need to change the antibiotic regimen or in drug-related toxic effects.

Now that these studies have provided us with more convenient, versatile antibiotic strategies for treating low-risk patients with fever and neutropenia, when should we use them? Do these studies of oral therapy justify our using outpatient treatment? The authors of both of these rigorous, careful studies, which were designed to assess the relative efficacy of antibiotic regimens given to inpatients, caution that they do not. We agree. Although clinical experience with the treatment of patients with fever and neutropenia on an outpatient basis has grown in the past decade, (10,11) this approach has yet to be validated in large, randomized studies designed to assess this critical question: Is outpatient treatment of fever and neutropenia, away from the watchful eyes and readily available emergency equipment of the hospital, as safe as inpatient treatment, or at least safe enough?

In the largest study conducted to date, Malik and colleagues (12) examined 169 episodes of fever and neutropenia and found that inpatients and outpatients treated with ofloxacin alone were equally likely to have their fever and neutropenia resolve without requiring a change in their antibiotic regimen. Although this finding indicates that identical regimens have equal efficacy in inpatients and outpatients, it says little about the safety of outpatient treatment. Three patients in the outpatient group died; at least one of these deaths was apparently preventable. In comparison, two patients in the inpatient group died. The power of this study to find a 100 percent increase in mortality in the outpatient group (from 2 percent to 4 percent) was only 8 percent, which is evidence of the difficulty of designing trials with serious but uncommon end points that are of a practical size. Was the additional death in the outpatient group a fluke that could be averted by better surveillance of outpatients in the future? Or was it a signal that outpatient care is inherently less safe and could be shown to be so if measured by more sensitive indicators? What clinical outcomes will we accept as evidence of the safety of an innovation designed primarily to reduce costs? The answer is not yet clear.

The two studies in this issue of the Journal provide data about convenient new ways of treating fever and neutropenia in patients with cancer. But the challenge remains how to use these new approaches most appropriately. Given the ever-increasing pressure to reduce costs, there is every reason for some to cheer the decreasing lengths of hospital stays and to bank on the savings possible through greater outpatient treatment.

But in making treatment decisions, we should remain clear about what we know and what we do not. That oral antibiotics will have an increasing role in the empirical treatment of fever and neutropenia is something we know. That we can, with confidence, identify and safely treat some of the patients with this condition on an outpatient basis is something we do not know.

Robert W. Finberg, M.D., James A. Talcott, M.D. -  Harvard Medical School ,  Boston, MA 02115

A Double-Blind Comparison of Empirical Oral and Intravenous Antibiotic Therapy for Low-Risk Febrile Patients With Neutropenia during Cancer Chemotherapy

Alison Freifeld, Donna Marchigiani, Thomas Walsh, Stephen Chanock, Linda Lewis, John Hiemenz, Sharon Hiemenz, Jeanne E. Hicks, Vee Gill, Seth M. Steinberg, Philip A. Pizzo

Background.
Among patients with fever and neutropenia during cancer chemotherapy who have a low risk of complications, oral administration of empirical broad-spectrum antibiotics may be an acceptable alternative to intravenous treatment.

Methods.
We conducted a randomized, double-blind, placebo-controlled study of patients (age, 5 to 74 years) who had fever and neutropenia during chemotherapy for cancer. Neutropenia was expected to be present for no more than 10 days in these patients, and they had to have no other underlying conditions. Patients were assigned to receive either oral ciprofloxacin plus amoxicillin-clavulanate or intravenous ceftazidime. They were hospitalized until fever and neutropenia resolved.

Results.
A total of 116 episodes were included in each group (84 patients in the oral-therapy group and 79 patients in the intravenous-therapy group). The mean neutrophil counts at admission were 81 per cubic millimeter and 84 per cubic millimeter, respectively; the mean duration of neutropenia was 3.4 and 3.8 days, respectively. Treatment was successful without the need for modifications in 71 percent of episodes in the oral-therapy group and 67 percent of episodes in the intravenous-therapy group (difference between groups, 3 percent; 95 percent confidence interval, -8 percent to 15 percent; P=0.48). Treatment was considered to have failed because of the need for modifications in the regimen in 13 percent and 32 percent of episodes, respectively (P<0.001) and because of the patient's inability to tolerate the regimen in 16 percent and 1 percent of episodes, respectively (P<0.001). There were no deaths. The incidence of intolerance of the oral antibiotics was 16 percent, as compared with 8 percent for placebo (P=0.07).

Conclusions.
In hospitalized low-risk patients who have fever and neutropenia during cancer chemotherapy, empirical therapy with oral ciprofloxacin and amoxicillin-clavulanate is safe and effective. (N Engl J Med 1999;341:305-11.)                

Oral versus Intravenous Empirical Antimicrobial Therapy for Fever in Patients with Granulocytopenia Who Are Receiving Cancer Chemotherapy

Winfried V. Kern, Alain Cometta, Robrecht de Bock, John Langenaeken, Marianne Paesmans, Harold Gaya, Giorgio Zanetti, Thierry Calandra, Michel P. Glauser, Francoise Crokaert, Jean Klastersky, Athanasios Skoutelis, Harry Bassaris, Stephen H. Zinner, Claudio Viscoli, Dan Engelhard, Andrew Padmos, for the International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer

Background.
Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost.

Methods.
In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less.  

Results.
Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency.

Conclusions.
In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy. (N Engl J Med 1999;341:312-8.)