Statistical considerations in clinical trials testing empiric antibiotic regimens in patients with febrile neutropenia

The Chalmers scoring system for assessing the quality of randomized controlled trials was applied to 19 papers (published in 1976–1984) reporting the results of trials of antibiotics in febrile neutropenic patients; it was found at the time of this survey (publication 1986) that statistical issues were inadequately addressed in the papers and that the scoring system was a measure of the quality of reporting in the papers rather than the quality of the actual trials. Some new items have been added to the system to improve the validity of results, and 15 more recent papers have been reviewed with reference to the updated scoring procedure, to find whether the quality of trials and of their reporting has improved since 1986. Further discussion of statistical issues in clinical trials is recommended.     

Empirical therapy for bacterial infections in neutropenic patients

Infection in neutropenic patients remains a continuing challenge as the modalities of cancer treatment evolve and new pathogens appear. Although the concept of empirical therapy remains valid, there is a need for adaptation of our therapeutic approaches to new clinical and microbiological evidence.Presented as an invited lecture at the 6th International Symposium: Supportive Care in Cancer, New Orleans, La., USA, 2–5 March 1994     

The treatment of febrile neutropenia: from the Dark Ages to the present

 Developments in the treatment of infection in neutropenic patients are traced from the 1950s up to the present. In addition to the various antobiotics applied at different times, the varying predominance of different groups of pathogens is discussed. Finally, future prospects are considered.     

Treatment of neutropenic infection: trends towards monotherapy?

 Febrile neutropenia has been a changing syndrome over the last 20 years. The perspectives and goals that we face today are mainly the constant adaptation of antibacterial prophylactic and therapeutic regimens to the emergence of resistant strains; the definition of prognostic factors influencing the outcome of febrile neutropenia; the introduction of pragmatic algorithms for adaptation of therapy; ambulatory and/or home therapy for certain categories of patients; the definition of indications for the use of cytokines to restore earlier bone marrow function and to help with home management of febrile neutropenia, and, finally, the recognition of risk factors for fungal infections and the improvement of our diagnostic as well as therapeutic anti-fungal strategies.     

Candidemia in acute leukemia patients

 Fungal infections are an important cause of morbidity and mortality in patients with acute leukemia (AL). Candidemia, once rare, is now a common nosocomial infection because of the intensity of chemotherapy, prolonged neutropenia, administration of broad-spectrum antibiotics and use of central venous catheters (CVC). We retrospectively identified patients treated for AL from 6/86 to 6/95 who also had candidemia. We describe 28 patients (incidence 6.3%) with a median age of 39 years, 24 of whom were on remission induction and 4 on postremission chemotherapy. All patients had CVC and empiric antimicrobial therapy, 4 had been given prophylactic antifungal drugs, and 2 had parenteral nutrition. Neutropenia was profound (median leukocyte nadir 200/μl, median duration 19 days). Candida was isolated in blood cultures 10 days (median) after the start of neutropenia. The clinical presentation included fever (100%), respiratory symptoms (71.4%), skin lesions (39.2%) and septic shock (17.8%). Amphotericin B was given to 17 patients and liposomal amphotericin to 5 patients. Infection resolved in 18 patients (64.2%), 10 of whom were in complete remission. Mortality from candidemia was 17.8% (5/28). In conclusion, fungal infections are responsible for death in a significant number of patients. In our series treatment success was related to its rapid onset and to the recovery of neutropenia.     

Ceftriaxone versus β-lactams with antipseudomonal activity for empirical, combined antibiotic therapy in febrile neutropenia: a meta-analysis

 The object of this work was to compare the efficacy of antibiotic combinations including ceftriaxone with that of combinations including an antipseudomonal β-lactam for the empirical treatment of febrile neutropenia in cancer patients. We identified all published randomised trials comparing two antibiotic combinations differing only in the β-lactam, being ceftriaxone in one treatment group and an antipseudomonal β-lactam in the other. The quality of individual trials was formally evaluated. A meta-analysis was performed using the Peto-modified Mantel-Haenszel method for combining binary data. Primary analysis was done, for both febrile episodes and bacteraemic episodes, using failure of empirical antibiotic treatment defined as modification of the initial allocated regimen or death during treatment. Secondary analysis was done using death from any cause in the two treatment groups. Data relating to 1,537 febrile neutropenic episodes recorded in eight randomised clinical trial were pooled s. Overall, there were 256 treatment failures out of 782 febrile episodes treated with ceftriaxone-containing combinations (32.7%), and 243 out of 755 treated with antipseudomonal β-lactam regimens (32.1%). The pooled odds ratio of failure for ceftriaxone-containing combinations for febrile episodes was 1.04, with the 95% confidence interval ranging from 0.84 to 1.29, and that for bacteraemic episodes was 0.93 (95% confidence interval 0.58–1.49). With regard to overall mortality, there were 54 deaths among 782 febrile episodes treated with ceftriaxone-containing combinations (6.9%) and 62 deaths among 755 febrile episodes treated with antipseudomonal β-lactam-containing regimens (8.2%). The pooled odds ratio of death for ceftriaxone regimens was 0.84 (95% confidence interval 0.57–1.24). Results of this meta-analysis show that in the empirical treatment of febrile neutropenia, antibiotic combinations containing ceftriaxone are as effective as those in which the β-lactam has specific activity against Pseudomonas aeruginosa, such as ureidopenicillin or ceftazidime. Published online: 5 October 1999     

Monotherapy with piperacillin/tazobactam versus combination therapy with ceftazidime plus amikacin as an empiric therapy for fever in neutropenic cancer patients

Between July 1993 and September 1996, 107 consecutive febrile episodes in 83 neutropenic cancer patients with a median age of 41 years were randomized to treatment either with piperacillin/tazobactam 4.5 g every 8 h i.v. or ceftazidime 2 g every 8 h plus amikacin 15 mg/kg i.v. per day. In the case of fever >38° C 48 h after initiation of the antibiotic therapy, vancomycin 500 mg every 6 h i.v. was added. The study population was at serious risk of a poor outcome, since 67% of the patients had leukemia or lymphoma, 19% of the febrile events occurred after autologous bone marrow or blood stem cell transplantation, the median total duration of neutropenia was 16 days, and the median neutrophil count at study inclusion was 0.09 × 10⁹/l. The two patient groups were comparable in terms of risk factors. Bacteremia was found in 37%, other microscopically documented infections in 16%, and clinically documented infections in 26% of the febrile episodes. Most (96) febrile episodes were evaluable for response. No significant difference was found between piperacillin/ tazobactam and ceftazidime plus amikacin in terms of success rate (81% versus 83%), empirical addition of vancomycin (42% versus 38%), median time to fever defervescence (3.3 versus 2.9 days) or median duration of antibiotic therapy (7.2 versus 7.4 days). No patient died from the infection. Both antibiotic regimens were well tolerated, the study treatment being stopped only in 1 patient because of toxicity (cutaneous allergy to piperacillin/tazobactam). On the basis of the 107 febrile events encountered, we conclude that piperacillin/tazobactam is a safe and effective monotherapy. To define the definitive value of piperacillin/ tazobactam as a monotherapy for febrile neutropenic patients a large randomized trial is warranted.     

Fatigue in patients with cancer: results with National Cancer Institute of Canada Clinical Trials Group studies employing the EORTC QLQ-C30

 The purpose of this study was to examine the factors which affect the level of fatigue among patients participating in clinical trials in which this symptom had been assessed with the EORTC QLQ-C30. Data were assembled from 2390 patients in ten clinical trials in which the QLQ-C30 had been used to assess baseline and on-study quality of life. The relationship between the level of fatigue reported by the patients on the fatigue scale of this questionnaire and patient and disease characteristics was assessed in univariate and multivariate cross-sectional analyses. In addition, changes in fatigue scores were compared in a longitudinal analysis among patients on two arms of an anti-emetic trial whose emesis control was markedly different. Baseline fatigue levels differed substantially among patients taking part in the different trials. Factors associated with greater fatigue severity on univariate analysis included: female gender, presence of metastatic disease, and poorer performance status. In addition, on multivariate analyses the oldest patients were found to have less fatigue, as were patients with breast cancer, while patients with ovarian and lung cancer experienced greater fatigue. Patients on the arm of the anti-emetic trial in which emesis was better controlled showed significantly less increase in fatigue after receiving chemotherapy. The fatigue scale of the QLQ-C30 appears to provide a useful approach to assessing this important symptom. The relationships found between fatigue and patient and disease characteristics need further exploration as does the degree to which the QLQ-C30 fully captures this dimension of quality of life.     

Infections in cancer patients: some controversial issues

Despite more than two decades of clinical research into the management of infections in the neutropenic cancer patient, many patients still develop serious morbidity from infection and all too many still die. A number of controversies surround (a) the use of combination versus monotherapy for initial empiric administration; (b) the use of vancomycin as part of the initial regimen; (c) the origin ofStaphylococcus epidermidis infections (i.e., mostly from vascular catheters or mostly from the alimentary canal); (d) the use of acyclovir for herpes simplex prophylaxis during remission induction for acute leukemia patients not undergoing bone marrow transplantation; (e) the use of alimentary canal microbial suppression or reverse isolation in a room with laminar air flow, or both, as infection pevention techniques. Current recommendations and observations include the following. (a) Monotherapy with ceftazidime or imipenem is effective and appropriate for patients with moderate granulocytopenia at limited risk for infection with a resistant organism. Combination therapy is recommended for patients with profound, persistent granulocytopenia who are at high risk for gram-negative bacteremia; such bacteremic patients have a better prognosis with combined-modality therapy. (b) Vancomycin need not be included in the initial regimen although some centers may choose to do so because of the high prevalence of gram-positive bacteremias. (c) Despite the ubiquitous presence of indwelling vascular catheters, mostS. epidermidis infections among neutropenic patients originate from along the alimentary canal. (d) Herpes simplex infection is much more common following standard remission induction chemotherapy than previously recognized. Acyclovir will reduce these infections and concurrently probably reduce the likelihood of resultant bacterial/fungal co-infections and superinfections. (e) Selective microbial suppression is appropriate for patients expected to experience prolonged (more than 2 weeks) or profound (below 100 granulocytes/l) granulocytopenia. Agents chosen should suppress aerobic but not anaerobic flora (maintain colonization resistance) and need to have an effect on both the oral cavity and esophagus as well as the intestines.Presented as an invited lecture at the 4th International Symposium: Supportive Care in Cancer, St. Gallen, Switzerland, 24–27 February 1993     

Ceftazidime in combination with glycopeptide antibiotic is an effective first-line therapy for patients undergoing high-dose therapy with autologous peripheral blood stem cell support

 It was the objective of this study to evaluate the efficacy and toxicity of an empirical antibiotic therapy consisting in ceftazidime and a glycopeptide antibiotic. All patients enrolled in the study had hematological malignancies and underwent high-dose therapy with peripheral blood stem cell (PBSC) support. In this retrospective study, 183 of 207 patients who had received a PBSC-supported high-dose therapy were evaluable. Any patients who had fever higher than 38.5  °C received ceftazidime in combination with vancomycin (105 patients) or teicoplanin (69 patients). In 80 of 174 patients with fever (45%) the fever resolved within 72 h as a result of the treatment with ceftazidime and the glycopeptide antibiotic. In nonresponding patients, the changes included the replacement of ceftazidime by imipenem/cilastin (94 patients) and the addition of erythromycin (12 patients) or metronidazole (3 patients). Amphotericin B was administered in 29 patients. Following hematological reconstitution, the fever and clinical signs, including radiographic findings, resolved in 20 primarily nonresponding patients. In blood cultures, a significantly higher incidence of gram-positive than of gram-negative bacteria was observed (26 vs 7). The toxicity of the first-line antibiotic therapy was limited to allergic skin reactions in 12 patients. Ceftazidime in combination with a glycopeptide antibiotic provides an effective and safe first-line therapy for patients with neutropenic fever following PBSC-supported high-dose therapy.     

A circadian distribution to febrile episodes in neutropenic patients

Four-hourly temperature charts relating to 63 febrile neutropenic episodes in 32 patients were assessed for a circadian distribution to the onset of fever (>37.5°C) using the Edward's test. A highly significant distribution was found with the maximum incidence of febrile events between the hours of 5 p.m. and midnight (acrophase 9.30 p.m.). Patients were 5.53 times more likely to develop fever at 9.30 p.m. that 9.30 a.m.     

Clinical and methodological issues in antiemetic therapy: a worldwide survey of experts' opinions

 During the 1995 Multinational Association of Supportive Care in Cancer (MASCC) Congress, a consensus conference was planned by the Subcommittee for Antiemetics. To define the topics to be discussed, a questionnaire containing both clinical and methodological issues was sent to 118 experts in 31 countries. The questionnaire contained 33 items on clinical and 19 items on methodological issues, and each response was rated on a 4-level categorical scale. The clinical issues were evaluated for interest, that is clinical importance, and feasibility, that is availability of sufficient data to make them suitable topics for the consensus conference. About 60% of questionnaires were returned, with a small number of missing responses. The responses to the items of clinical interest showed that about two-thirds of the issues identified by the Subcommittee were found by the experts to be of at least high interest, but often the availability of data was found to be insufficient for their discussion. Prevention of acute emesis induced by cisplatin and by moderately emetogenic chemotherapy and the optimal intravenous dose and schedule of the 5-HT₃ receptor antagonists were the items with the highest interest and feasibility. The issues in the methodological section were also mostly found to be of at least high interest. The distinction between acute and delayed emesis, the evaluation of the persistence of antiemetic efficacy in subsequent cycles of chemotherapy and the statistical analysis of delayed emesis were the methodological issues in which the highest interest was recorded. Data collected will be used to define the main topics to be discussed during the planned consensus conference.     

Febrile neutropenia in cancer patients in Kuwait: microbial spectrum and outcome

A sample of 100 consecutive febrile neutropenic episodes in cancer patients in Kuwait was studied. Acute leukaemias (44%) and lymphomas (29%) were the most frequent underlying cancers; 21 bacteraemias (gram-positive 10, gram-negative 9, polymicrobial 2) were encountered. Staphylococcous epidermidis and Escherichia coli were the commonest organisms. Urinary tract infection occurred in 30% of the microbiologically documented cases. A total of 84 episodes responded to therapy and 9 of the 14 deaths were secondary to infection.     

Performance of a modified MASCC index score for identifying low-risk febrile neutropenic cancer patients

GOALS OF WORK: This is a prospective and observational study comparing the efficacy of risk-assessment models in patients with neutropenic fever in a reference treatment center. The meaning of the complex infection was evaluated. MATERIALS AND METHODS: Patients were recruited throughout a 9-month period. Inclusion criteria were histologic diagnosis of malignancy, neutropenic febrile secondary to chemotherapy and/or radiotherapy (absolute neutrophil count of <500/microl and axillary temperature > or = 38 degrees C), and > or = 18 years of age. MAIN RESULTS: Fifty-three febrile neutropenic patients were included. Twenty one of them were classified as low risk by the Multinational Association of Supportive Care in Cancer (MASCC) risk-index score. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of the MASCC risk-index scores were, respectively 87.9, 85.0, 90.6, 80.9, and 86.8%. None of the low-risk patients died, but four patients classified as low risk by the MASCC model developed serious medical complications during febrile neutropenic episodes. When we subtracted patients with complex infections from the group of patients with the MASCC risk-index score of > or = 21, we got 15 patients that were classified as low risk by a proposed adjustment by complex infection (PACI) model. None of them developed serious medical complications. The sensitivity, specificity, PPV, NPV, and the accuracy of this new model were, respectively, 100, 75.0, 86.8, 100, and 90.6%. CONCLUSION: The MASCC risk-index score had high sensitivity and specificity to predict the absence of complications, but the PACI model was better than MASCC for predicting the absence of complications in this febrile neutropenic patients.     

Pharmacological treatment of cachexia: any progress?

 In view of the renewed interest in pharmacological treatment of anorexia-cachexia in cancer patients over the past 3 years, both the established drugs used in its treatment and the emerging new drugs still being tested for it are reviewed. Results of trials that have already been evaluated are reported, and possible areas for further research are indicated.     

Causes of fever in cancer patients (prospective study over 477 episodes)

Goals of work The aim of this study was to determine the causes of fever among cancer patients.Methods All febrile cancer patients were followed up prospectively. Clinical, microbiological and radiological documentations were performed. Aetiologies of fever, type of tumour, site of infection, type of microorganism and outcome were assessed and compared between neutropenics and non-neutropenics.Results Four hundred and seventy-seven episodes were evaluated. Infection, non-infectious causes and fever of unknown origin represented 67, 23 and 10%, respectively. The respiratory tract is the most frequently involved site in infection (29%), and in microbiologically documented infections, Gram-negative bacilli were predominant. The tumour itself (27%) or an invasive procedure (17%) were the main causes of non-infectious febrile episodes. Mortality from infection was higher among non-neutropenic (11.1%) than neutropenic patients (4.3%).Conclusion Fever in cancer patients remains a challenge, and the differentiation between infectious and non-infectious causes at onset of fever is very difficult. Despite all the prophylactic measures, infection is still the principal cause. However, the infection-related mortality is low either in neutropenic or non-neutropenic patients.     

Progress in fighting systemic fungal infections in haematological neoplasia

 Considering the limited data available, there is clearly a need for thorough, well-designed clinical research on the epidemiology, diagnosis, treatment and prevention of invasive fungal infection in patients who are treated for cancer. Our knowledge has increased, but the information obtained so far is patchy and not generally applicable, as it is influenced by local problems and circumstances. New diagnostic tools have become available, but they are still insufficient in many cases. Until the value of the presently available chemoprophylaxis has been established beyond doubt, the strategy should be one of wait-and-see for patients with a low or moderate risk of developing infection. In bone marrow transplant recipients fluconazole has shown favourable results in eliminating yeast infections, but in patients at high risk of mould infections early initiation of intravenous treatment with amphotericin B at a therapeutic dose remains the best approach. The question of the optimal time point to start empirical antifungal treatment remains and has even been extended by the dispute about what antifungal drugs should be used for this purpose. Amphotericin B is still the drug of choice for the treatment of disseminated fungal infection, but its lipid formulations seem to offer a safer, though far more expensive, alternative. Head-to-head comparisons between the different formulations are required before a final conclusion on their respective efficacies and toxicities can be drawn, and it is questionable whether a higher dose will produce better results. Fluconazole appears very useful against the majority of Candida infections, whereas itraconazole is effective against both yeast and moulds, providing that adequate resorption can be ensured. The results of the first clinical trial of voriconazole in pulmonary aspergillosis have proved very promising.     

Lipopolysaccharide-binding protein: a possible diagnostic marker for Gram-negative bacteremia in neutropenic cancer patients

Objective Cancer patients with febrile neutropenia after chemotherapy have a variable risk of bacterial infection. Especially Gram-negative bacteremia is associated with high mortality and/or morbidity. Early diagnosis of patients with Gram-negative bacteremia at the onset of febrile neutropenia is potentially useful in tailoring therapy.Design and setting Prospective study at the Department of Pediatric Oncology and Internal Medicine of a university hospital.Patients Were analyzed 66 febrile neutropenic episodes in 57 adults and children. Patients were divided into four groups: those with Gram-negative bacteremia, Gram-positive bacteremia, clinical sepsis, or fever of unknown origin.Measurements and results Plasma lipopolysaccharide-binding protein (LBP) and C-reactive protein (CRP) concentrations were determined. LBP at the onset of febrile neutropenia was significantly higher in patients with Gram-negative bacteremia than those with fever of unknown origin and those with Gram-positive bacteremia. Using a cutoff value for LBP proved to have much greater sensitivity, specificity, and positive and negative predictive value for Gram-negative bacteremia than the best cutoff value for CRP.Conclusions An initial high LBP level might predict Gram-negative bacteremia in cancer patients with febrile neutropenia. These results may have potential clinical impact by allowing therapy to be initiated for these patients at a very early stage.This study was supported by a grant from the University Hospital Groningen, The Netherlands     

Change of procalcitonin predicts clinical outcome of febrile episodes in patients with hematological malignancies

Background Procalcitonin (PCT) was widely investigated in febrile neutropenia as an indirect marker of infection. Many institutions also use PCT as a tool to monitor the course of a febrile episode because increases in PCT values during the febrile episode were associated with development of complications. However, to date, no study systematically evaluated the accuracy of decreasing PCT values in predicting favorable outcomes of a febrile episode. The aim of this study was to evaluate the changes in PCT values after resolution of fever with regard to their predictive value of stable defervescence.Materials and methods PCT was studied prospectively in 94 febrile episodes of 35 patients with hematological malignancies.Results Sixty-seven episodes were associated with an increased level of PCT at the beginning. In these episodes, stable resolution of fever was significantly correlated with a decrease in PCT values. The best cut-off level to predict freedom from recurrence of fever for at least 5 days was <70% of the maximum PCT value on the second afebrile day. Out of 44 patient episodes with a subsequent decrease to <70%, only two patients had recurrent fever within the next 5 days, revealing a negative predictive value of 95%, p<0.001.Conclusion Our study supports the value of PCT as a reliable tool to predict clinical outcome in febrile neutropenia.     

The magic bullet in the new millennium – Cause for optimism

K. Fukuoka (♪) GlaxoSmithKline, GSK Bldg., 4-6-15 Sendagaya, Shibuya-ku, Tokyo 151-8566, Japan?Tel. +81-3-5786-5048; Fax +81-3-5786-5233?e-mail: kf11259@glaxowellcome.co.uk Received: October 9, 2001