Affiliations of authors: R. García-Carbonero, M. V. Tornamira, A. Arcediano, C. Gómez, J. L. Pérez-Gracia, J. Hornedo, H. Cortés-Funes, L. Paz-Ares, Division of Medical Oncology, Hospital Universitario Doce de Octubre, Madrid, Spain; J. I. Mayordomo, A. Yubero, A. Trés, Division of Medical Oncology, Hospital Clínico, Zaragoza, Spain; M. López-Brea, F. Rivera, Division of Medical Oncology, Hospital M. Valdecilla, Santander, Spain; A. Rueda, Division of Medical Oncology, Hospital Clinico, Malaga, Spain; V. Guillem, Division of Medical Oncology, Instituto Valenciano de Oncologia, Valencia, Spain; C. Lumbreras, Division of Infectious Diseases, Hospital Universitario Doce de Octubre, Madrid.
Correspondence to: Luis Paz-Ares, M.D., Servicio de Oncologia Medica, Hospital Universitario Doce de Octubre, Avenida de Cordoba Km 5,4, Madrid 28041, Spain (e-mail: lpaz{at}hdoc.insalud.es).
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ABSTRACT |
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INTRODUCTION |
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Hematopoietic colony-stimulating factors (CSFs), such as granulocyte CSF (G-CSF) and granulocytemacrophage CSF, have been shown to promote proliferation, differentiation, and function of progenitor and mature cells of the myeloid lineage (3). These cytokines also stimulate the bactericidal functions of mature neutrophils (4). When administered as a preventive adjunct to chemotherapy, CSFs have shown in clinical trials to shorten the neutropenic period and to reduce by 50% the incidence of febrile neutropenia in high-risk patients (5,6). However, the role of CSFs in the treatment of febrile neutropenia remains uncertain, despite several randomized studies that have attempted to address this issue (712).
Patients with fever and neutropenia are not a homogeneous group, and not all such patients have the same risk of developing infections or serious complications or of dying during a febrile episode. Talcott et al. (13,14) developed a risk-assessment model for episode outcome by use of clinical variables that could be assessed within 24 hours of presentation with fever and neutropenia. Patients with risk factors, including prior inpatient status, serious independent comorbidity, or uncontrolled cancer, had a higher incidence of prolonged neutropenia, serious medical complications, and death than patients with no risk factors. Some of the studies evaluating the role of CSFs in the treatment of febrile neutropenia (79) showed a reduced incidence of episodes of prolonged neutropenia or protracted hospitalization among the cytokine-treated patients. Subset analysis in two of the trials showed the greatest benefit in patients with profound neutropenia (absolute neutrophil count [ANC] <100/mm3) and/or documented infection (7,10). These observations suggest that patients at higher risk of delayed hematologic recovery or with severe infection are probably the most likely to benefit from the therapeutic use of CSFs.
The purpose of this study was to evaluate in a prospective multicenter randomized clinical trial the efficacy and cost-effectiveness of G-CSF in the treatment of patients with solid tumors and high-risk febrile neutropenia.
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PATIENTS AND METHODS |
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From January 1997 through March 1999, a total of 210 patients from five Spanish University Hospitals were enrolled on the study. Adult patients with solid tumors (including lymphomas) were eligible for enrollment if they presented with chemotherapy-induced neutropenic fever, defined as axillary temperature above 38 °C with an ANC below 500/mm3, and met at least one of the high-risk criteria. High-risk criteria were defined as follows: profound neutropenia (ANC <100/mm3), short latency from previous chemotherapy cycle (<10 days), sepsis or clinically documented infection at presentation, severe comorbidity, performance status greater than or equal to 3 [Eastern Cooperative Oncology Group ECOGscale (15)], prior inpatient status, and failure of ambulatory management of low-risk febrile neutropenia (persistence of fever and grade IV (16) neutropenia for >72 hours despite ambulatory treatment with quinolones). Severe comorbid conditions included the following: respiratory failure (partial pressure of oxygen <60 millimeters of mercury, adjusted for hyperventilation), congestive heart failure (New York Heart Association class IIIIV), uncontrolled arrhythmia despite adequate therapy, renal failure (creatinine level greater than two times the upper limit of normal [ULN]), liver dysfunction (bilirubin level >2.5 times ULN or aspartate aminotransferase/alanine aminotransferase greater than four times the ULN), grade IIIIV emesis (16), grade IIIIV mucositis (16), grade IIIIV diarrhea (16), symptomatic hypercalcemia, and uncontrolled bleeding. Patients were considered to be ineligible if they had a history of allergic reactions to the study drug (G-CSF) or to -lactams or aminoglucosides, if they had been treated with hematopoietic growth factors in the preceding 7 days, if they were already receiving intravenous antibiotic therapy, if they were undergoing treatment with myeloablative chemotherapy that required progenitor-cell support, or if they were pregnant or breast-feeding. The study was approved by the Institutional Review Board of each hospital.
Study Design
All potentially eligible patients were evaluated by an internist and/or a medical oncologist at the emergency room or clinic. Baseline investigations included full medical history, physical examination, blood cell counts with differential leukocyte counts, blood and urine chemistries, chest radiograph, cultures of blood and urine, and investigation of other clinically suspicious sites. Once the diagnosis of febrile neutropenia was established and eligibility for study entry was confirmed, written informed consent was obtained from the patient. Subsequently, patients were admitted to the hospital and were randomly assigned by the consecutive drawing of sequentially numbered, opaque, sealed envelopes to receive or not G-CSF, in addition to broad-spectrum intravenous (i.v.) antibiotics. The allocation sequence was computer generated.
Empiric antibiotic treatment was immediately started with ceftazidime (2 g every 8 hours, i.v.) and amikacin (1 g every 24 hours, i.v., adjusted according to renal function). The addition of vancomycin (1 g every 12 hours as a 4-hour i.v. infusion, adjusted for renal function) was allowed if clinical evidence of catheter-related infection or suspicion of other gram-positive infection was present. For patients with dental or intra-abdominal infections or aspiration pneumonia, imipenem (500 mg every 6 hours, i.v.) was substituted for ceftazidime.
Antibiotic therapy was changed according to the following guidelines: 1) For relevant positive microbiologic findings, antibiotics were modified according to culture and antibiogram; 2) if new infectious foci became apparent after admission and if the patient remained febrile, antibiotics were modified accordingly; and 3) for patients with no new focality and persisting fever and neutropenia for 3 days, vancomycin was added. If fever and neutropenia persisted for 7 days, amphotericin B was added.
Treatment with antibiotics was maintained until the patient remained without fever for 2 consecutive days and had an ANC of 1000/mm3 or higher, provided that he or she had been on antibiotics for at least 5 days. Patients were to be discharged as soon as antibiotic therapy was discontinued, unless medically contraindicated. For patients randomly assigned to receive G-CSF, the growth factor was initiated within 12 hours of the diagnosis of neutropenic fever, at a dose of 5 µg/kg per day given subcutaneously. Treatment with G-CSF was discontinued as soon as the ANC rose above 1000/mm3.
The overall cost per episode was calculated on the basis of the expenses concerning the treatment of each patient with fever and neutropenia, including days of hospital stay, antibiotics, G-CSF, blood transfusions, and total parenteral nutrition. The average cost of 1 hospital day at an Adult Oncology Unit of a Spanish National Public Health Service Hospital is 560 U.S. dollars (USD). The cost of a hospital stay included all activities concerning professional staffing (doctors, nurses, etc.) and materials (laboratory tests, diagnostic procedures, supportive patient care, etc.). The antibiotic drug prices used were wholesale prices. The cost of a 300-µg G-CSF vial was 85 USD and of a 480-µg vial was 110 USD. The cost of a blood transfusion was 433 USD for 2 U of packed red blood cells and 383 USD for 6 U of platelets. One day of total parenteral nutrition cost 110 USD.
Study End Points
The primary end point of the study was the duration of hospital stay. Secondary end points were days on antibiotic therapy, time to resolution of fever, number of days during which the neutrophil count was less than 500/mm3 and less than 1000/mm3, changes in antibiotic therapy, incidence of clinical complications, mortality rate, and costs.
Statistical Analysis
The median hospital stay of patients with febrile neutropenia and high-risk criteria treated without CSFs, according to our historic data, was 7 days (9,17). The number of episodes per branch necessary to detect a 2-day reduction in hospital stay, with a power of 80% ( = 0.2) and a significance level of 95% (
= 0.05), was estimated to be 100. Assuming that approximately 5% of the patients would be ineligible, the total sample size of the study population was calculated to be 210. All eligible patients have been analyzed on an "intention-to-treat" basis.
Differences between the G-CSF and control groups regarding days of neutropenia, time to resolution of fever, days on antibiotic therapy, days of hospital stay, and costs were evaluated with the MannWhitney U test (18). The distribution of categorical variables among the two treatment groups was compared by the chi-square test (19,20) or Fisher's exact test (21) when appropriate. The Cox proportional hazards model (22) was used for adjusted analysis of prognostic factors for number of days to resolution of neutropenia, antibiotic discontinuation, and hospital discharge. All P values were two-sided and were considered to be statistically significant at P<.05.
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RESULTS |
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The median number of days of G-CSF treatment for patients randomly assigned to receive this cytokine in addition to antibiotics was 3 days (range, 113 days), and 95% of these patients required fewer than 6 days of G-CSF therapy. The median duration of grade IV neutropenia (ANC <500/mm3) was significantly shorter in patients treated with G-CSF (2 days) than in the control patients (3 days) (P = .0004) (Table 2). Recovery of the neutrophil count to 1000/mm3 occurred at a median of 3 versus 4 days for G-CSF and control patients, respectively (P<.0001) (Fig. 2
). The duration of antibiotic therapy was statistically significantly reduced in the G-CSF-treated group compared with the control group (median, 5 days versus 6 days; P = .013). The median hospital stay was 5 days for patients treated with G-CSF, which was significantly shorter than the 7-day median hospital stay observed in the control group (P = .015) (Fig. 3
). None of the study main end points were significantly different between sexes. G-CSF also reduced the incidence of prolonged antibiotic therapy or hospitalization. Forty-three patients (43%) in the control group required antibiotic treatment for at least 7 days versus 30 patients (29%) in the G-CSF group (P = .04). The number of patients with a hospital stay of 7 days or longer was 49 (49%) and 35 (34%) for the control and G-CSF groups, respectively (P = .03). Despite the resolution of the febrile neutropenia episode (end of antibiotic treatment), nine patients in the G-CSF group (9%) and 16 in the control group (16%) could not be discharged from the hospital (P = .1). The reasons for the prolonged hospitalization despite episode resolution included medical complications (six patients in the G-CSF group and 12 in the control group) and nonmedical reasons (three patients in the G-CSF arm and four in the control arm).
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The time to resolution of fever was similar in both study groups, with a median of 1 day for patients treated with G-CSF (25%75% interquartile range, 13) and 1 day for patients in the control arm (25%75% interquartile range, 13). The treatment was successful without the need for modifications in the antibiotic therapy in 50% of the episodes in the G-CSF group and in 52% of the episodes in the control group (P = .78) (Table 4). The need for antibiotic therapy modifications (G-CSF = 45% versus control = 43%; P = .78), vancomycin treatment (G-CSF = 32% versus control = 22%; P = .23), or amphotericin B treatment (G-CSF = 5% versus control = 2%; P = .12) was also not statistically significantly different between the study groups.
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Cost Analysis
The median cost of a hospital stay was reduced by 17% (G-CSF groupmedian = 2875 USD, 95% confidence interval [CI] = 2645 to 3105; control groupmedian = 3450 USD, 95% CI = 3164 to 3736) (P = .01). The median costs of antibiotics were 480 USD and 565 USD for the G-CSF and control arms, respectively (P = .1). The median cost of G-CSF was 255 USD. Other additional costs, including red blood cell and platelet transfusions (G-CSF groupmedian = 0 USD, mean = 165 USD; control groupmedian = 0 USD, mean = 152 USD; P = .75), and total parenteral nutrition (G-CSF groupmedian = 0 USD, mean = 46 USD; control groupmedian = 0 USD, mean = 30 USD; P = .36), were not statistically significantly different between the two treatment groups. Overall, the median total cost per patient admission was reduced by 11% (G-CSF groupmedian = 3960 USD, 95% CI = 3770 to 4150; control groupmedian = 4435 USD, 95% CI = 3933 to 4937; P = .07).
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DISCUSSION |
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Several randomized studies (712) have attempted to address the role of hematopoietic CSFs in the treatment of febrile neutropenia, with somewhat conflicting results. In fact, the evidence-based American Society for Clinical Oncology recommendations for the use of hematopoietic CSFs in patients with neutropenia and fever state that "the available data do not clearly support the routine initiation of CSFs as adjuncts to antibiotic therapy for the majority of patients" (5,23). They indicate, however, that "the use of CSFs together with antibiotics may be reasonable in certain high-risk patients (pneumonia, hypotension. . . .), even though the benefits of administration under these circumstances have not been definitively proved" (5,23). The lack of consistency in the results from previous CSF trials may be explained by several factors. First, the fact that patients with fever and neutropenia are a very heterogeneous population has not been taken into account in these trials to select the target population most likely to benefit from CSFs (712). Second, the criteria employed for CSF or antibiotic therapy duration or hospital discharge varied widely among the different studies (712). In addition, several of the studies were probably too small and had not enough power to detect the small, but still significant differences expected (811). Overall, all of the trials showed that the use of CSFs reduced the duration of neutropenia, but this benefit was not always associated with advantages in other more meaningful clinical end points (hospital stay, episode complications, cost, or mortality).
The eligibility criteria employed in our trial to select the target population were based on a medical risk predictive model described by Talcott et al. (13). This model considers a series of clinical variables that can be assessed within 24 hours of presentation in patients with fever and neutropenia and has been validated in 444 consecutive cancer patients from two different institutions (14). In these studies, serious medical complications occurred in 34% of the patients with risk factors, including prior inpatient status, serious independent comorbidity, or uncontrolled cancer, compared with a 5% incidence among the patients with no risk factors. The incidence of prolonged neutropenia (>7 days) was higher among the high-risk patients (61%) than among the low-risk patients (33%), and the risk of medical complications was smaller for patients whose neutropenia resolved in 7 days or fewer. Other independent prognostic factors for an increased risk of medical complications were short latency from chemotherapy to fever and neutropenia (<10 days) and age over 40 years. Multiple complications (17%) and death (10%) were common among patients in the high-risk groups, but they did not occur in the low-risk population.
The low incidence of severe infections or of protracted hematologic recovery among patients with uncomplicated febrile neutropenia and the demonstration of the safety and efficacy of early hospital discharge (24) or ambulatory management (17,25) in this patient population suggest a limited chance for CSF benefit if these types of strategies are employed in low-risk patients. In our experience, most (58%) adult patients with solid tumors treated with conventional-dose chemotherapy belong to the low-risk category (17), which indicates that probably a high percentage of low-risk patients were included in the trials published to date (712). On the contrary, the observation in several trials that CSF therapy reduces the incidence of prolonged neutropenia (9), protracted antibiotic therapy (8), or hospitalization (7) suggests that patients at higher risk for a delayed hematologic recovery are the most likely to benefit from CSF therapy. The present study, which is the first randomized trial performed in patients with high-risk febrile neutropenia according to previously defined risk criteria that have been associated with prolonged hematologic recovery and/or with severe infection (13,14), has proven prospectively this hypothesis. It should be pointed out, nevertheless, that our patient population, in comparison with that of Talcott's studies, excluded patients with leukemia or those undergoing treatment with myeloablative chemotherapy that required progenitor-cell support. In addition, patients with lymphoma or those hospitalized previously are minimally represented. These patient populations are at higher risk for a delayed hematologic recovery and for subsequent complications (13,14). In fact, the incidence of serious medical complications (17%) and death (5%) in our study control arm, although greater than that observed in Talcott's low-risk group (5% and 0%, respectively), was considerably lower than that encountered among Talcott's high-risk patients (34% and 10%, respectively).
The current study was an open-label, non-placebo-controlled trial, since we did not have financial support to accomplish a double-blinded, placebo-controlled study design. Acknowledging this caveat and to minimize potential physicians' bias in the assessment of outcome since the treatment group was known, CSF therapy duration, antibiotic discontinuation, and hospital discharge decisions were all based on clear-cut objective criteria (temperature, ANC, and number of days on therapy). Treatment with antibiotics was maintained until the patient remained without fever for 2 consecutive days and had an ANC of 1000/mm3 or higher, provided that he or she had been on antibiotics for at least 5 days. Patients were to be discharged as soon as antibiotic therapy was discontinued, unless medically contraindicated. These criteria have been used for more than a decade by our group and have proved to be safe and not associated with complications following patient discharge (9,17); they are among the least stringent reported in the literature. The duration of antibiotic treatment or hospital stay was, indeed, remarkably shorter in our trial than in most other published studies (712,26,27), even though some of them were performed in low-risk populations (26,27). This indicates that it is unlikely that the mentioned discharge rules may have substantially extended the duration of hospitalization in a substantial number of patients. In any case, more conservative policies for antibiotic treatment duration or hospital discharge are most likely to diminish the clinical impact of an earlier neutrophil recovery. Therefore, if the use of these rules mandated by the protocol were to have had any influence on the study outcome, this would have tended to minimize the benefit of G-CSF therapy. Indeed, the median duration of hospitalization was 5 days among the G-CSF-treated patients, the minimum required per protocol. One could argue that some of these patients may have been discharged earlier had this decision been based on resolution of fever and return of neutrophil count alone.
Besides treatment with G-CSF, other factors, such as WBC, lymphocyte, and monocyte counts at presentation, were found in our trial to have a substantial impact on time to resolution of grade IV neutropenia. No CSF therapy, a low WBC count at presentation, and the presence of an indwelling catheter were also independently associated with a longer hospital stay. Of interest, none of the different risk criteria employed for patient selection, whether associated with protracted hematologic recovery or with severe infection, were found to have an independent prognostic value in terms of neutropenia duration, time on antibiotics, or hospitalization.
The cost of CSFs combined with their current wide-scale application has raised some economic concern among caregivers and payers. The main issue to be defined in the febrile neutropenia setting is the threshold risk at which the added cost of the growth factor would be offset by the reduction in cost associated with a decrease in the duration of hospitalization and/or resources utilized. In the high-risk population included in this study, which represents about 30%40% of the solid tumor patients with fever and neutropenia, G-CSF therapy significantly reduced the cost of hospital stay, which is the major economic-driving factor of the episode cost estimate. We believe that the observed 17% reduction in the median hospital cost per patient in the G-CSF group could have been greater if this had been calculated from the actual resources utilized by each individual patient, since G-CSF reduced the most expensive episodes, such as those associated with long hospital stays or with medical complications. Unfortunately, the hospitals of the Spanish National Public Health Service Program do not provide data on individual expenses per specific patient admission but rather average day-cost estimates according to type and complexity of admission episode, type of admission unit, and length of hospital stay. In addition, the modest decrease of 475 USD in median overall cost per patient admission would be of a greater magnitude in settings where the febrile neutropenia costs are higher [e.g., 7736 USD in the study by Rubenstein et al. (28) or 8836 USD in the study by Cantor et al. (29), in contrast with 4435 USD in the present series]. Finally, our cost estimates did not include direct costs incurred by the patient and family while receiving medical care (transportation, etc.) or indirect costs related to the loss of income for days of work lost by patients and relatives due to hospitalization or early death.
The role of CSFs in other settings of febrile neutropenia remains undefined. In our opinion, G-CSF treatment has a limited chance to be cost-effective in low-risk patients, in whom alternative management approaches (early discharge and/or outpatient care) are safe and inexpensive (17,24,25). On the other hand, in very high-risk populations, such as leukemia patients or patients hospitalized previously or undergoing myeloablative chemotherapy with stem cell support, who were excluded or minimally represented in our trial, it is unlikely that G-CSF therapy could decrease costs, since early hospital discharge is rarely feasible. Whether this cytokine effectively reduces the morbidity and mortality of this last subset of patients also remains uncertain. Therefore, it is probably an intermediate- to high-risk population, such as that defined in our study, that is the most likely to benefit from cytokine therapy. Our study was not designed for or powered enough to do further subgroup analysis. Future studies should aim to define better whether different subsets of patients with different high-risk criteria may benefit more than others from this intervention.
In conclusion, the study presented here demonstrates that the use of G-CSF, in addition to antibiotics, in the treatment of an appropriately chosen, high-risk subset of patients with chemotherapy-induced febrile neutropenia accelerates neutrophil recovery, shortens antibiotic therapy and hospitalization, and may reduce costs. Thus, G-CSF should be used as part of the standard therapy in the management of febrile neutropenic patients with solid tumors meeting these risk criteria.
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NOTES |
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Presented in part at the 35th American Society of Clinical Oncology meeting. Atlanta (GA); 1999.
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Manuscript received April 14, 2000; revised September 29, 2000; accepted October 26, 2000.
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