***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: PURPOSE To determine whether macrophage colony-stimulating factor ( M-CSF ) reduces the incidence and duration of febrile neutropenia during three courses of intensive consolidation therapy and whether it shortens time to complete consolidation therapy . PATIENTS AND METHODS In 198 adult patients with acute myeloid leukemia ( AML ) in complete remission ( CR ) , M-CSF ( 8 x 10(6 ) U/d ) or placebo was administered from 1 day after the end of each consolidation chemotherapy for 14 days . RESULTS The duration and incidence of febrile neutropenia was significantly reduced by 34 % ( P = .00285 ) and 17 % ( P = .02065 ) , respectively , in 88 assessable patients in the M-CSF group compared with those in 94 assessable patients in the placebo group . Patients in the M-CSF group had 565 days and 133 episodes of febrile neutropenia during 7,901 days at risk , while patients in the placebo group had 977 days and 185 episodes during 9,077 days at risk . The median period required to finish the three courses of consolidation therapy was 93 days in the M-CSF group , which was significantly shorter than 110 days in placebo group ( P = .0050 ) . In the M-CSF group , the recovery of neutrophils and platelets was significantly faster ( P = .0348 and P = 0.0364 , respectively ) , the administration of systemic antimicrobial agents tended to be less ( P = .0839 ) , and the frequency of platelet transfusion ( P = .0259 ) and the total volume of transfused platelets ( P = .0292 ) were significantly less . However , there was no significant difference in the disease-free survival . CONCLUSION M-CSF significantly reduced the incidence and duration of febrile neutropenia during the intensive consolidation therapy , and shortened the time to complete consolidation chemotherapy in AML Sepsis associated with neutropenia remains a major cause of morbidity and mortality from many chemotherapy regimens . In a recent tabulation of commonly used chemotherapy agents [ 1 ] , 29 of 37 are listed as causing marked or moderate leukopenia . A known correlation exists between the degree and duration of neutropenia and the risk for sepsis [ 2 ] . In conjunction with neutropenia , infections with gram-negative organisms such as Pseudomonas spp . occur relatively frequently and have high morbidity and mortality rates if antibiotic therapy is not begun until infection is microbiologically confirmed [ 3 , 4 ] . Current recommended practice is to initiate empiric , broad-spectrum intravenous antibiotic therapy in all patients with febrile neutropenia at the onset of fever , despite clinical and microbiological evidence of infection being found in only 40 % to 60 % of cases [ 5 ] . In addition to antibiotic therapy , neutrophil recovery is an important factor for a successful treatment outcome in these patients [ 6 , 7 ] and has been identified as the most favorable prognostic factor in a recent multivariate logistic regression analysis of 14 variables analyzed in a study of antibiotic efficacy [ 7 ] . Granulocyte transfusions are logistically difficult , are associated with substantial toxicity , and are of uncertain efficacy [ 8 , 9 ] ; before the availability of the colony-stimulating factors , few pharmacologic agents had clinical utility in increasing neutrophil levels [ 10 ] . Filgrastim ( previously known as recombinant methionyl human granulocyte colony-stimulating factor [ r-metHuG-CSF ] ) is a hematopoietic growth factor that promotes the survival , proliferation , differentiation , and function of progenitor and mature cells of the neutrophil granulocyte lineage [ 11 ] . It has potent granulopoietic effects in vivo [ 12 - 14 ] , and its clinical pharmacology has been defined [ 15 ] . In two phase III studies [ 16 , 17 ] , filgrastim therapy that was started 1 day after chemotherapy reduced the severity and duration of neutropenia and decreased by nearly half the incidence of febrile neutropenic episodes and the average duration of hospitalization and antibiotic use per patient . The use of filgrastim to prevent febrile neutropenic episodes in patients with cancer who receive chemotherapy is now an approved indication in many countries . Not all patients with cancer who have had chemotherapy and who have been treated with  filgrastim receive it to reduce the risk for neutropenic sepsis . Approximately 14 % of filgrastim in the United States has been used to treat episodes of postchemotherapy febrile neutropenia after they occur rather than to prevent them ( unpublished market research data , Amgen , Inc. ) . To determine if filgrastim administered in addition to st and ard empiric inpatient antibiotic therapy was also beneficial in patients presenting with established fever and neutropenia , we conducted a multicenter , r and omized , double-blind , placebo-controlled study . This is the first report of a study assessing therapeutic intervention with filgrastim in this clinical setting . Methods We present the analysis of findings from 218 patients enrolled at four centers between October 1988 and February 1992 . The study drug was filgrastim , a recombinant human protein produced in Escherichia coli [ 18 ] and supplied by Amgen , Inc. , Thous and Oaks , California . Patients Eligible patients with febrile neutropenia were adults ( age 16 years ) receiving chemotherapy for histologically confirmed cancer other than myeloid leukemia who had an oral temperature of greater than 38.2 C and a neutrophil count less than 1.0 109/L. The neutrophil count included the number of b and s and polymorphonuclear forms counted in manual differentials from blood smears . Patients were ineligible if they were already receiving antibiotic therapy , if they had septic shock ( a systolic blood pressure of < 90 mm Hg , poor peripheral perfusion , and abnormal mentation ) , if they were receiving myeloablative chemotherapy with marrow transplantation support , if they had severe renal impairment ( serum creatinine level > 0.7 mM ) , abnormal liver function ( bilirubin > 5 times the upper limit of normal ) , were pregnant or breast-feeding , or had a history of allergic reactions to the study antibiotics . Patients could enter the r and omized trial only once . If subsequent episodes of fever and neutropenia developed , patients were offered open-label filgrastim therapy according to the same procedures described in the protocol . Data from these episodes are not included in this report . The study was approved by the relevant institutional review boards of each treatment center , and all patients gave signed informed consent . Study Design Our study was a r and omized , double-blind , placebo-controlled trial . Patients were r and omly assigned to receive either filgrastim or placebo from identically labeled vials . Stratification was not done before r and omization . The r and omization code was maintained by the Biostatistical Department of Amgen , Inc. , and was not broken until all collected data had been verified by Amgen and its design ee , Biomedicus ( Boronia , Australia ) , and had been audited by a separate department at Amgen . Enrolled patients were admitted to the hospital , and a full medical history was taken and physical examination done . Baseline investigations included full blood counts with differential leukocyte counts and chest radiographs . Cultures of blood ( in duplicate ) , urine , and other clinical ly suspicious sites were done . Empiric treatment was started with piperacillin ( 4 g intravenously every 6 hours ) and tobramycin ( 2 mg/kg of body weight intravenously for the loading dose and 80 mg intravenously every 8 hours thereafter ) . Antibiotic dose was adjusted for patient size , renal and hepatic impairment , and drug serum levels according to st and ard criteria . Therapy with filgrastim or placebo was initiated within 12 hours of the start of antibiotic therapy at a dose of 12 g/kg per day by continuous subcutaneous infusion with the use of a portable pump . Filgrastim ( supplied in 5- or 10-mL vials as a clear , colorless solution of 300 g/mL ) or placebo ( supplied in matching vials for double-blinding ) was diluted in a sterile solution of 5 % glucose in water to a volume of 50 mL. Patients remained in the study until 4 consecutive afebrile days ( peak daily temperature , < 37.5 C ) had passed and the blood neutrophil count was greater than 0.5 109/L or until 28 days had elapsed . Filgrastim or placebo doses were reduced or the drugs were withdrawn before study completion if the blood neutrophil count exceeded 10.0 109/L ( dose reduced to 6 g/kg per day ) , 15.0 109/L ( dose reduced to 3 g/kg per day ) , or 20.0 109/L ( drug withdrawn ) . Intravenous antibiotics were administered until study completion , although the actual drugs or doses could be altered at the investigators ' discretion within broad protocol guidelines . Study End Points Our study evaluated the effect of filgrastim on the number of days of fever and on the number of days of neutropenia associated with presumed or documented infection that was treated with antibiotics . Blood counts were done daily , and oral temperatures were recorded at least four times per day . Two end points were defined for days of neutropenia and are specified here as the number of days on which the neutrophil count was less than 0.5 109/L and less than 1.0 109/L. The days of fever end point was defined as the number of consecutive days ( after and including the day of presentation ) on which the maximum oral temperature was 37.5 C or greater , plus any subsequent periods beginning with a day of temperature peak of greater than 38.2 C and ensuing days with peaks of 37.5 C or greater . We also analyzed several related end points . The time to resolution of fever was defined as the number of days elapsed before the first complete day with a temperature less than 37.5 C ( subsequent fevers were not included in this definition ) . Late fever was defined as a temperature greater than 38.2 C occurring after the fever had initially resolved . The time to resolution of febrile neutropenia was defined as the number of days elapsed before the first day with both a temperature less than 37.5 C and a neutrophil count of 1.0 109/L or less ( subsequent days of fever or neutropenia were not included in this definition ) . The prospect ively defined secondary end points of the study were days on study ( hospitalization ) and the incidence of the change of antibiotics .  This was an inpatient study ; therefore , all days on study were spent in the hospital . Although some patients were in patients when fever and neutropenia developed and some remained in the hospital after completing the study , the days on study equalled the period of hospitalization for most patients . Patients who remained in the hospital after completing the study did so for reasons other than continued morbidity related to fever and neutropenia . Safety All adverse events were grade d according to World Health Organization criteria [ 19 ] . Data collected included daily clinical evaluation , toxicity grading , and blood examinations ; and urea , electrolytes , creatinine , liver function tests , clotting tests , and urinalysis , all of which were done every fifth day . The numbers of red blood cell and platelet transfusions were also recorded . Deaths that occurred during the study and within 30 days of study completion were recorded , and a blinded assessment was made of any possible contribution to the death by the study drug . Statistical Analyses We used a 1:1 ratio of patients treated with filgrastim to patients receiving placebo .  The sample size was chosen to detect a 25 % difference in the protocol -specified primary end points of days of fever and days of neutropenia with 80 % power at a significance level of 0.05 . However , an unplanned interim analysis was done for administrative purpose s , rather than with the intent of early study termination , when 87 patients had completed the study . Therefore , the A Phase I trial was conducted to determine the safety , biological activity , and hematopoietic recovery by the combination of interleukin 6 ( IL-6 ) and granulocyte-colony stimulating factor ( G-CSF ) after myelosuppressive chemotherapy in children . Patients < 22 years of age at diagnosis with either recurrent or refractory solid tumors received ifosfamide 1,800 mg/m2/day x 5 days , carboplatin 400 mg/m2/ day x 2 days , and etoposide 100 mg/m2/day x 5 days , followed by daily s.c . G-CSF ( 5 microg/kg/day ) and IL-6 ( 2.5 , 3.75 , or 5.0 microg/kg/day ) . Pharmacokinetic , proinflammatory mediator levels , hematopoietic colony assays , and cytokine receptor expression studies were performed during course one . Nineteen patients were evaluable for toxicity  and received  IL-6  at doses of 2.5 ( n = 8) , 3.75 ( n = 5 ) , or 5.0 ( n = 6 ) microg/kg/day . Dose-limiting constitutional toxicity occurred in two of six patients at 5.0 microg/kg/day , two of five patients at 3.75 microg/kg/day , and two of eight patients at 2.5 microg/kg/day . The maximum tolerated dose ( MTD ) exceeded the lowest dose tested . 
    Output:
    
Prophylactic CSFs significantly decrease the incidence of FN and the duration s of severe neutropenia , hospitalization , and antibiotic use in pediatric cancer patients , but they do not significantly decrease documented infections