Filgrastim. A reappraisal of pharmacoeconomic considerations in the prophylaxis and treatment of chemotherapy-induced neutropenia

Neutropenia is a frequent and often dose-limiting complication of chemotherapy and is associated with considerable patient morbidity and mortality. Standard treatment in patients who become febrile includes hospitalisation and empirical antibiotic therapy. Filgrastim is a recombinant human granulocyte colony-stimulating factor (rHuG-CSF). It significantly decreases the incidence of febrile neutropenia in patients receiving standard-dose chemotherapy, and shortens the duration of febrile neutropenia in patients undergoing autologous bone marrow transplantation (BMT) or peripheral blood progenitor cell (PBPC) infusion after myeloablative chemotherapy regimens. These effects are usually associated with a decrease in hospitalisation and antibiotic requirements. The contribution of filgrastim therapy to beneficial effects on other clinically important end-points (e.g. quality of life, tumour relapse rate, and short and long term survival) remains to be accurately determined. Pharmacoeconomic data concerning the use of filgrastim as an adjunct to standard-dose chemotherapy are derived largely from the results of phase III trials. Cost analyses based on hospital charges suggest that the cost of providing filgrastim therapy can be fully recouped if the drug is used as primary prophylaxis in previously untreated patients, for whom the risk of developing febrile neutropenia is at least 40%. Reserving filgrastim for use in patients who have developed febrile neutropenia in a previous chemotherapy cycle may result in further cost savings. However, careful patient selection is required, since potential cost savings will vary depending upon the risk of hospitalisation in the absence of filgrastim treatment. Infusion of filgrastim-mobilised PBPCs is emerging as a preferred strategy in patients receiving myeloablative chemotherapy, and promising results have been obtained from cost analyses. From a pharmacoeconomic viewpoint, future research should be directed towards defining optimum dosage regimens and hence improving the cost-effective use of filgrastim. Data evaluating patient quality of life and treatment preferences would help define the cost utility of filgrastim therapy. In the meantime, available pharmacoeconomic data support the use of filgrastim as an adjunct to chemotherapy in selected clinical situations.     

Economic evaluations of granulocyte colony-stimulating factor: in the prevention and treatment of chemotherapy-induced neutropenia

The prevailing uncertainty about the pharmacoeconomic positioning of granulocyte colony-stimulating factor (G-CSF) in the prevention and treatment of chemotherapy-induced febrile neutropenia has resulted in a number of pharmacoeconomic evaluations published in the past 10 years. These studies vary considerably regarding the approaches used and the results presented. In order to contribute to a clearer pharmacoeconomic positioning of G-CSF, a systematic review of economic evaluations was carried out.The focus of the review was prophylaxis and therapy of chemotherapy-induced neutropenia in patients with cancer. A computerised bibliography search of several databases was conducted yielding 33 studies.The findings demonstrated the cost-saving potential of G-CSF in standard-dose chemotherapy to be limited, with lower costs often seen in the control group. The results of these studies were too heterogeneous to extract a clear recommendation from a cost-saving point of view. The administration of G-CSF after high-dose chemotherapy with stem cell support resulted more often in cost savings in the G-CSF group as compared with standard-dose chemotherapy, illustrating a possible cost-saving potential of G-CSF. In the treatment of established chemotherapy-induced febrile neutropenia, cost savings were found in all studies. This result is surprising but hampered by the small number of studies (n = 5) and remains to be confirmed by more rigourously designed prospective economic analyses.Despite the substantial research on this topic, the economic evaluation of G-CSF is far from being settled and needs further investigation.     

Granulocytic growth factors and cancer-related neutropenia: limited effects

(1) Cancer chemotherapy often causes haematological complications, in particular neutropenia, which can have grave consequences in terms of the risk of infections (increasing with the degree and duration of neutropenia) and the need for modifications in chemotherapy protocols (longer intervals between cycles or dose reductions). (2) In France, three haematopoietic growth factors are licensed to stimulate leukocyte production: filgrastim (unglycosylated granulocyte colony-stimulating factor (G-CSF)), pegfilgrastim (pegylated filgrastim), and lenograstim (glycosylated G-CSF). (3) The main adverse effects of these three growth factors are joint and bone pain, a flu-like syndrome, and reactions at the injection site. (4) G-CSF has provided disappointing results in primary prevention, and its use is only justified for patients receiving chemotherapy that causes febrile neutropenia in at least 40% of cases: patients with acute leukaemia, elderly patients, and patients with cancer-related neutropenia or poor general status, etc. In these patients, G-CSF reduces the incidence of febrile neutropenia and, possibly, the risk of hospitalisation. A meta-analysis of 11 comparative trials involving about 1500 patients with non Hodgkin's lymphoma showed only a reduction in the incidence of febrile neutropenia and infections. (5) In the prevention of recurrences of neutropenia on continuing chemotherapy, only one trial, involving patients aged over 60 with high-grade non Hodgkin's lymphoma, showed an improvement in survival time with filgrastim (survival rate: 64.3% with filgrastim versus 49% with placebo, after a median follow-up of 40 months). Until these results are confirmed in other clinical trials, reduction in the intensity of chemotherapy (dosage, frequency) is generally recommended. (6) Curative treatment of neutropenia with G-CSF is only warranted for febrile patients with a high risk of severe infections requiring lengthy hospitalisation. Two meta-analyses, one including 8 trials and the other including 13 trials, involving a total of about 1500 patients, only showed a reduction in the length of hospitalisation.     

Granulocyte colony--stimulating factor for chemotherapy-induced neutropenia in patients with small cell lung cancer : the 40% rule revisited

Recombinant granulocyte colony-stimulating factor (G-CSF) [filgrastim and lenograstim] and pegylated G-CSF (pegfilgrastim) have been shown to reduce the severity and duration of chemotherapy-associated febrile neutropenia (FN) when administered prophylactically to cancer patients receiving chemotherapeutic regimens. The American Society of Clinical Oncology (ASCO) evidence-based clinical guidelines published in 1994, 1996 and 1997 recommended primary prophylaxis with G-CSF for cancer patients. The 2000 ASCO update, with the same recommendation, highlights the importance of economic considerations in decision making for CSFs. This paper reviews the available cost-effectiveness evidence on the use of G-CSF as primary prophylaxis against FN in patients with small cell lung cancer (SCLC).Cost-effectiveness ratios from a healthcare payer perspective supported the use of filgrastim as primary prophylaxis for people with SCLC, on the basis of both clinical and economic benefits, treated with chemotherapeutic regimens that have an FN rate in the range of 40-60%. However, when indirect and patient out-of-pocket costs attributable to severe FN are included, available evidence suggests that the risk threshold may be reduced by more than half.Given that FN rates associated with chemotherapeutic regimens for SCLC are generally <40%, then few circumstances would warrant the use of G-CSFs (filgrastim and lenograstim) under the current rule. However, inclusion of indirect costs would lower the cost-effectiveness threshold. Future cost-effectiveness studies of medications such as pegfilgrastim should attempt to capture the societal perspective by incorporating productivity-related costs and using base-case rates of FN reported in the literature.     

Cost effectiveness of cephalosporin monotherapy and aminoglycoside/ureidopenicillin combination therapy. For the treatment of febrile episodes in neutropenic patients

OBJECTIVE: To assess the relative cost effectiveness of cephalosporin monotherapy options and aminoglycoside/ureidopenicillin combination therapy for the treatment of febrile episodes in adult patients with neutropenia. DESIGN AND SETTING: This was a retrospective cost-effectiveness analysis conducted from the institutional perspective. METHODS: The analysis was based on 741 febrile episodes in adult patients with neutropenia enrolled in 5 randomised trials: 3 comparing monotherapy with ceftazidime or cefepime, and 2 comparing cefepime monotherapy versus aminoglycoside/ureidopenicillin combination therapy. Resource utilisation included costs for study antibacterials, treatment of adverse effects and failures, and hospitalisation. The primary end-point was the overall cost of treatment per patient. Cost-effectiveness ratios were also analysed. RESULTS: No significant differences in clinical success rates were detected. Median per-patient costs in the monotherapy comparisons were $US7849 for cefepime and $US7788 for ceftazidime [1997 values; not significantly different (NS)]. Corresponding costs for the monotherapy versus combination therapy comparisons were $US9780 for cefepime and $US10 159 for gentamicin/ureidopenicillin (NS). Despite a higher acquisition cost for cefepime, there were no statistically significant differences in cost effectiveness compared with either ceftazidime monotherapy or gentamicin/ureidopenicillin combination therapy. Sensitivity analyses revealed that monotherapy can be cost effective compared with combination therapy in many situations. CONCLUSION: There were no economic differences between the 3 regimens tested. Therefore drug cost should not be a deciding factor when choosing antibacterial therapy for the treatment of febrile episodes in adult patients with neutropenia.     

Economic analysis of filgrastim use for patients with acute myeloid leukaemia in the UK: a comparison of collection methods of resource use data

BACKGROUND: A clinical trial of patients with de novo acute myeloid leukaemia (AML) showed that haematopoietic support with filgrastim (granulocyte colony-stimulating factor, G-CSF) following induction and consolidation chemotherapy accelerated recovery from neutropenia. The clinical benefits included reductions in infections, anti-infective therapy and length of hospital stay. OBJECTIVE: The objective of this economic analysis is 2-fold. First, it aims to determine if the observed clinical benefits from the use of filgrastim would lead to cost savings from the perspective of a healthcare institution in the UK. Second, the analysis compares the results of two methods on collection of resource use data. DESIGN: A retrospective cost-minimisation analysis was undertaken based on the clinical results of all UK patients enrolled in the trial. Two cost models were developed: a model based only on the medical resource use collected in the case report forms (the CRF model); and a model based on all medical resources collected from patient medical files (the PF Model). Treatment costs of AML between filgrastim and the placebo arm were compared for the first induction cycle as well as the first induction and the first consolidation cycles combined. Results from the two models were compared. SETTING AND PATIENTS: The CRF model was applied to two samples of patients: all UK patients (n = 82) and patients enrolled at one centre [the Manchester Royal Infirmary (MRI) (n = 30)], whereas the PF model was applied to the MRI patient sample only. RESULTS: For all UK patients, using the CRF model, the filgrastim-treated arm produced cost savings of 747 pounds sterling (9.0%) and 2135 pounds sterling (14.4%) [1998 values] per patient in the first induction cycle and in the induction and consolidation cycles combined, respectively. For the patients at MRI the CRF model resulted in cost savings with filgrastim of 177 pounds sterling (2.2%) and 414 pounds sterling (3.2%) per patient respectively. Using the PF model the savings at MRI were 910 pounds sterling (8.6%) and 1285 pounds sterling (8.0%) per patient, respectively. CONCLUSION: Use of filgrastim in the treatment of AML in the UK may result in net cost savings. A retrospective analysis using total resources obtained through patient files produced higher cost savings estimates than that obtained by resources noted in the CRFs. The models based on PF resource data may be more reliable because they are more comprehensive. However, the cost estimates in this study may have been impacted by sample size, site characteristics, disease and treatment settings. Therefore, further evaluation on the methods for collecting resource use data in larger, multicentred studies is warranted.     

The role of colony-stimulating factors and granulocyte transfusion in treatment options for neutropenia in children with cancer

Children with cancer receiving anticancer therapy always experience neutropenia, and as a result often develop serious neutropenic infections that cause morbidity and/or mortality. Intensive chemotherapy with improved supportive care for neutropenia contribute to the recent advances in treatment outcome in children with cancer. Recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) can shorten the duration and decrease the severity of neutropenia, and thus support intensive chemotherapy. Both G-CSF and GM-CSF stimulate proliferation and maturation of myeloid progenitor cells and are thus used to help mobilization of peripheral blood progenitor cells, and after stem-cell transplantation. The American Society of Clinical Oncology 2000 Guidelines recommended that colony-stimulating factors (CSFs) can be administered as a primary prophylaxis with a chemotherapy regimen if previous experiences with chemotherapy regimens have shown that the incidence of febrile neutropenia (neutropenic fever) is > or =40%. The routine use of CSFs for secondary prophylaxis or for patients with afebrile neutropenia is not recommended in order to avoid the overuse of CSFs. The use of a CSF may be considered in children with febrile neutropenia with a neutrophil count <100/microL, uncontrolled primary disease, pneumonia, hypotension, multiorgan dysfunction (sepsis syndrome), or invasive fungal infection. Although these guidelines are generally applicable to children with cancer, further studies on CSFs are certainly needed in pediatric oncology. The recent advances in granulocyte collection, using healthy volunteer donor stimulation with G-CSF and/or dexamethasone to yield large numbers of granulocytes has made granulocyte transfusion a more realistic option. Granulocyte transfusion has shown promising results in treating children with severe neutropenic infection; however, controlled trials are warranted to clarify the efficacy and cost-effectiveness of this procedure.     

Outpatient therapy for febrile neutropenia: clinical and economic implications

Although febrile episodes in neutropenic patients remain a potentially life-threatening complication of anticancer chemotherapy, considerable progress has been achieved in understanding this issue. Febrile neutropenic patients represent a heterogeneous population that displays a very variable risk for serious medical complications. It has also been ascertained that in low-risk patients, the standard of care can be safely and effectively shifted from traditional hospital-based, parenteral, empiric, broad-spectrum antibacterial therapy to outpatient treatment, even for the entire duration of the febrile episode. Furthermore, in the last years some risk assessment models have been developed to identify, at the onset of febrile episodes, low-risk neutropenic patients who are most likely to have a favourable outcome (and who can effectively and safely be treated on an outpatient basis). With respect to traditional hospital-based therapy, the outpatient treatment of low-risk patients is associated with several advantages, including a conspicuous cost saving. Some strategies for inpatient therapy, such as switching from intravenous to oral antibacterials and early discharge, can allow some cost containment; however, the most substantial decrease in costs can be obtained by using outpatient treatment over the entire febrile episode, especially by using oral antibacterials. In spite of the considerable number of clinical studies published over the past 20 years, only limited pharmacoeconomic data on this issue are available. Future comparative studies between outpatient and inpatient treatment of febrile neutropenia, in addition to clinical outcomes (e.g. survival, time to clinical response), should therefore include the following: (i) a detailed analysis of total costs, specifying the setting of outpatient treatment and the method of administration of antimicrobial agents (home nursing, self administration or treatment at infusion centres or at a low-care unit of the hospital); (ii) cost of inpatient treatment if outpatient therapy fails; and (iii) out-of-pocket expenses incurred by the patients.     

Paclitaxel: a pharmacoeconomic review of its use in non-small cell lung cancer.

A number of first-line chemotherapy options for patients with advanced non-small cell lung cancer (NSCLC) are advocated in treatment guidelines and/or by various clinical investigators. Platinum-based chemotherapy has clearly demonstrated efficacy in patients with advanced NSCLC and is generally recommended as first-line therapy, although there is increasing interest in the use of non-platinum chemotherapy regimens. Among the platinum-based combinations currently used in clinical practice are regimens such as cisplatin or carboplatin combined with paclitaxel, vinorelbine, gemcitabine, docetaxel or irinotecan. The particular combinations employed may vary between institutions and geographical regions. Several pharmacoeconomic analyses have been conducted on paclitaxel in NSCLC and most have focused on its use in combination with cisplatin. In terms of clinical efficacy, paclitaxel-cisplatin combinations achieved significantly higher response rates than teniposide plus cisplatin or etoposide plus cisplatin (previously thought to be among the more effective regimens available) in two large randomised trials. One of these studies showed a survival advantage for paclitaxel plus cisplatin [with or without a granulocyte colony-stimulating factor (G-CSF)] compared with etoposide plus cisplatin. A Canadian cost-effectiveness analysis incorporated data from one of the large randomised comparative trials and showed that the incremental cost per life-year saved for outpatient administration of paclitaxel plus cisplatin versus etoposide plus cisplatin was $US 22181 (30619 Canadian dollars; $Can) [1997 costs]. A European analysis incorporated data from the other large randomised study and showed slightly higher costs per responder for paclitaxel plus cisplatin than for teniposide plus cisplatin in The Netherlands ($US 30769 vs $US 29592) and Spain ($US 19 923 vs $US 19724) but lower costs per responder in Belgium ($US 22852 vs $US 25000) and France ($US28 080 vs $US 34747) [1995/96 costs]. In other cost-effectiveness analyses, paclitaxel plus cisplatin was associated with a cost per life-year saved relative to best supportive care of approximately $US 10000 in a US study (year of costing not reported) or $US 11200 in a Canadian analysis ($Can 15400; 1995 costs). Results were less favourable when combining paclitaxel with carboplatin instead of cisplatin and particularly when G-CSF was added to paclitaxel plus cisplatin. The Canadian study incorporated the concept of extended dominance in a threshold analysis and ranked paclitaxel plus cisplatin first among several comparator regimens (including vinorelbine plus cisplatin) when the threshold level was $Can 75000 ($US 54526) per life-year saved or per quality-adjusted life-year gained (1995 values). CONCLUSION: Current treatment guidelines for advanced NSCLC recognise paclitaxel-platinum combinations as one of the first-line chemotherapy treatment options. In two large head-to-head comparative clinical trials, paclitaxel plus cisplatin was associated with significantly greater response rates than cisplatin in combination with either teniposide or etoposide, and a survival advantage was shown for paclitaxel plus cisplatin (with or without G-CSF) over etoposide plus cisplatin. There are limitations to the currently available pharmacoeconomic data and further economic analyses of paclitaxel-carboplatin regimens are warranted, as this combination is widely used in NSCLC and appears to have some clinical advantages over paclitaxel plus cisplatin in terms of ease of administration and tolerability profile. Nevertheless, results of various cost-effectiveness studies support the use of paclitaxel-platinum combinations, particularly paclitaxel plus cisplatin, as a first-line chemotherapy treatment option in patients with advanced NSCLC.     

Effects of a formulary change from granulocyte colony-stimulating factor to granulocyte-macrophage colony-stimulating factor on outcomes in patients treated with myelosuppressive chemotherapy

STUDY OBJECTIVE: To evaluate the effects on efficacy and safety of a formulary change from granulocyte colony-stimulating factor (G-CSF) to granulocyte-macrophage CSF (GM-CSF). DESIGN: Retrospective chart review. SETTING: Single-center academic institution. PATIENTS: Fifty-six patients aged 18 years or older with breast cancer, lung cancer, melanoma, Hodgkin's lymphoma, or non-Hodgkin's lymphoma who developed neutropenia within 4 weeks after treatment with myelosuppressive chemotherapy and who had been given five or more doses of CSF as primary or secondary prophylaxis from January 1995-March 2002. Twenty-nine patients treated before January 2000 were given G-CSF; after the formulary change in January 2000, 27 patients were primarily given GM-CSF. MEASUREMENTS AND MAIN RESULTS: The primary efficacy end point was time to an absolute neutrophil count of 1.5x10(3)/mm3 or greater after treatment with CSF. Second and third efficacy end points, respectively, were frequency of febrile neutropenia and effect of CSF treatment on schedule and dose intensity of subsequent chemotherapy cycles. Primary and secondary safety end points, respectively, were frequency of adverse events and use of resources used to manage these events. The time to neutrophil recovery was similar with G-CSF and GM-CSF. Febrile neutropenia was more common in the patients given GM-CSF. Chemotherapy dose delays also were more common in patients treated with GM-CSF, as was the frequency of fever. Use of resources (platelet and red blood cell transfusions, intravenous antibiotics, and hospitalizations) was greater in the patients treated with GM-CSF. CONCLUSION: The formulary change to GM-CSF was associated with a higher frequency of febrile neutropenia, resultant chemotherapy dose delays, more adverse events, and greater use of resources to manage the adverse events. These results suggest that G-CSF and GM-CSF are not therapeutically equivalent, with G-CSF having a superior safety and efficacy profile for the prevention of chemotherapy-induced neutropenic events.     

Optimized granulocyte colony-stimulating factor prophylaxis in adult cancer patients: from biological principles to clinical guidelines

INTRODUCTION: Chemotherapy-induced neutropenia, the depth and length of which are correlated to the risk of febrile neutropenia (FN) and neutropenia sepsis, remains a serious problem in medical oncology. Granulocyte colony-stimulating factors (G-CSF) stimulate the proliferation and survival of neutrophils and their precursors, thereby reducing the incidence, duration and severity of neutropenic events across a broad range of malignancies and regimens, often enabling the delivery of full chemotherapy dose intensity. AREAS COVERED: In this review, areas covered include the physiologic role of G-CSF in granulopoiesis, as well as a related biological model of bone marrow kinetics after chemotherapy. Information relating to the application of clinical guidelines for optimization of prophylaxis of FN in adult cancer patients was critically summarized. The literature and pharmacological data were obtained through an electronic search. EXPERT OPINION: There are relevant physiological and clinical evidences for the use of G-CSF to prevent FN and to ameliorate the myelotoxicities of cancer chemotherapy. In particular, biological models are in favor of the prophylactic rather than therapeutic use of G-CSF therapy. Use of a single dose of pegfilgrastim per cycle in appropriate patients provides a more convenient and potentially more effective strategy for assisting neutrophil recovery. While biosimilars may cost less, future developments in their regulation will need to address multiple issues. In the interim, physicians should remember that small differences in biochemical and biophysical characteristics might translate into differences in potency and immunogenic potential.     

Prediction of neutropenia

Newer treatment strategies for the management of febrile neutropenic patients are being developed. These include: (a) hospital based oral therapy; (b) early discharge after initial stabilization in-hospital, and (c) out-patient therapy. All strategies are likely to be more successful in patients with short-lived neutropenia (< or = 7 days) than in those with more prolonged neutropenia. Although risk-prediction rules and clinical criteria can help clinicians identify 'low-risk' neutropenic patients, the overall ability of clinicians to accurately predict the subsequent duration of neutropenia once a neutropenic patient becomes febrile needs to be improved upon considerably. One attempt to do so is the survey being conducted by the Infection Study Section of the Multinational Association of Supportive Care in Cancer (MASCC). Development of an accurate rule for the prediction of neutropenia will enable more appropriate, risk-based therapy to be administered to febrile neutropenic patients, and will represent a significant advance in the management of such patients.     

Risks and consequences of travel burden on prophylactic granulocyte colony-stimulating factor administration and incidence of febrile neutropenia in an aged Medicare population

Objective: Granulocyte colony-stimulating factors (G-CSFs) decrease the incidence of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy. This study examines the impact patient travel burden has on administration of prophylactic G-CSFs and the subsequent impact on FN incidence.

Methods: Medicare claims data were used to identify a cohort of beneficiaries age 65+ with non-myeloid cancers at high risk for FN between January 2012 and December 2014. Driving distance and time were calculated from patient residence ZIP code to the location of G-CSF and/or chemotherapy administration. Regression models were used to estimate the odds of G-CSF prophylaxis relative to patient driving distance and time, and odds of FN incidence relative to timing of G-CSF administration (optimal [days 2–4 after chemotherapy], sub-optimal [same day], or none).

Results: The 52,389 study patients had a mean age of 73.5 years, and were 82% female and 89% white race; 49% had female breast cancer, 12% lung cancer, 15% ovarian cancer, and 24% non-Hodgkin’s lymphoma. Of these high FN risk patients, 69% had at least one prophylactic G-CSF administration within at least one chemotherapy cycle. The percentage of patients receiving prophylactic G-CSFs in the first cycle was 56%. Median travel time was slightly longer for patients who did not receive G-CSFs and patients receiving short-acting vs long-acting G-CSFs. The odds of receiving no G-CSFs were 26–52% higher (depending on cancer type) for patients with a?>80-min one-way travel time, compared to patients traveling <20-min. Concurrently, the odds of FN (using a “narrow” definition) were 18–93% higher for patients who did not receive G-CSFs in the first cycle of chemotherapy.

Conclusions: Travel burden, linked to clinic visits for G-CSF administration following myelosuppressive chemotherapy, is associated with sub-optimal use of G-CSF prophylaxis, which may result in a higher incidence of FN.     

Travel burden associated with granulocyte colony-stimulating factor administration in a Medicare aged population: a geospatial analysis

Objective: Prophylaxis with granulocyte colony-stimulating factors (G-CSFs) is recommended for patients receiving myelosuppressive chemotherapy regimens with a high risk of febrile neutropenia (FN). G-CSFs should be administered starting the day after chemotherapy, necessitating return trips to the oncology clinic at the end of each cycle. We examined the travel burden related to prophylactic G-CSF injections after chemotherapy in the US.

Methods: We used 2012–2014 Medicare claims data to identify a national cohort of beneficiaries age 65+ with non-myeloid cancers who received both chemotherapy and prophylactic G-CSFs. Patient travel origin was based on residence ZIP code. Oncologist practice locations and hospital addresses were obtained from the Medicare Physician Compare and Hospital Compare websites and geocoded using the Google Maps Application Programming Interface (API). Driving distance and time to the care site from each patient ZIP code tabulation area (ZCTA) were calculated using Open Street Maps road networks. Geographic and socio-economic characteristics of each ZCTA from the US Census Bureau’s American Community Survey were used to stratify and analyze travel estimates.

Results: The mean one-way driving distance to the G-CSF provider was 23.8 (SD 30.1) miles and the mean one-way driving time was 33.3 (SD 37.8) minutes. When stratified by population density, the mean one-way travel time varied from 12.1 (SD 10.1) minutes in Very Dense Urban areas to 76.7 (SD 72.1) minutes in Super Rural areas. About 48% of patients had one-way travel times of <20?minutes, but 19% of patients traveled ≥50?minutes one way for G-CSF prophylaxis. Patients in areas with above average concentrations of aged, poor or disabled residents were more likely to experience longer travel.

Conclusions: Administration of G-CSF therapy after chemotherapy can present a significant travel burden for cancer patients. Technological improvements in the form and methods of drug delivery for G-CSFs might significantly reduce this travel burden.     

Safe and effective outpatient treatment of adults with chemotherapy-induced neutropenic fever.

PURPOSE: The safe and effective outpatient treatment of adults with chemotherapy- induced neutropenic fever is reviewed. SUMMARY: Chemotherapy-induced neutropenic fever is a potentially life-threatening circumstance in high-risk patients. The standard of care for neutropenic fever is inpatient treatment with i.v. broad-spectrum antibiotics. Within the past 5-10 years, there has been growing interest in oral therapy and outpatient treatment for carefully selected low-risk patients. Outpatient treatment has the potential to avoid patient exposure to multidrug-resistant organisms found in the hospital, provide a more comfortable environment for the patient and his or her family, and achieve significant cost savings. Two risk-assessment tools have been developed to identify patients with a low risk of developing complications from neutropenic fever. A limited number of clinical trials have been conducted to evaluate outpatient treatment of low-risk patients. The evidence from well-designed randomized controlled trials comparing the safety and efficacy of outpatient therapy with standard therapy is not extensive. However, some centers have reported successful outpatient therapy in low-risk patients with febrile neutropenia. The greatest amount of evidence for outpatient treatment of neutropenic fever is available for the combination regimen of ciprofloxacin plus amoxicillin-clavulanate. Clinical practice guidelines are available to guide patient evaluation, antibiotic selection, monitoring, and follow-up. CONCLUSION: The accepted standard for treatment of neutropenic fever remains inpatient therapy with i.v. broad-spectrum antibiotics. However, some centers have had success treating selected low-risk patients with neutropenic fever as outpatients.     

Cost-benefit analysis of prophylactic granulocyte colony-stimulating factor during CHOP antineoplastic therapy for non-Hodgkin's lymphoma

Several randomised comparative trials have shown that granulocyte colony-stimulating factor (G-CSF) reduces the duration of neutropenia, hospitalisation and intravenous antibacterial use in patients with cancer who are receiving high-dosage antineoplastic therapy. However, one area that has received less attention is the role of G-CSF in standard-dosage antineoplastic regimens. One such treatment that is considered to have a low potential for inducing fever and neutropenia is the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) for non-Hodgkin's lymphoma. We conducted a cost-benefit analysis from a societal perspective in order to estimate the net cost or benefit of prophylactic G-CSF in this patient population. This included direct costs for hospitalisation with antibacterial support, as well as indirect societal costs, such as time off work and antineoplastic therapy delays secondary to neutropenia. The findings were then tested by a comprehensive sensitivity analysis. The administration of G-CSF at a dosage of 5 micrograms/kg/day for 11 doses following CHOP resulted in an overall net cost of $Can1257. In the sensitivity analysis, lowering the G-CSF dosage to 2 micrograms/kg/day generated a net benefit of $Can6564, indicating a situation that was cost saving to society. The results of the current study suggest that the use of G-CSF in patients receiving CHOP antineoplastic therapy produces a situation that is close to achieving cost neutrality. However, low-dosage (2 micrograms/kg/day) G-CSF is an economically attractive treatment strategy because it may result in overall savings to society.     

The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta)

Recombinant protein technology produces drugs for human therapy in unprecedented quantity and quality. Research is now focusing on the relationship between pharmacokinetic and pharmacodynamic properties of molecules, with the aim of engineering proteins that possess enhanced therapeutic characteristics in contrast to being used as simple replacements for the natural equivalent. The addition of a polyethylene glycol (PEG) moiety to filgrastim (rmetHu-G-CSF, Neupogen) resulted in the development of pegfilgrastim. Pegfilgrastim is a long-acting form of filgrastim that requires only once-per-cycle administration for the management of chemotherapy-induced neutropenia. The covalent attachment of PEG to the N-terminal amine group of the parent molecule was attained using site-directed reductive alkylation. Pegylation increases the size of filgrastim so that it becomes too large for renal clearance. Consequently, neutrophil-mediated clearance predominates in elimination of the drug. This extends the median serum half-life of pegfilgrastim to 42 hours, compared with between 3.5 and 3.8 hours for Filgrastim, though in fact the half-life is variable, depending on the absolute neutrophil count, which in turn reflects of the ability of pegfilgrastim to sustain production of those same cells. The clearance of the molecule is thus dominated by a self-regulating mechanism. Pegfilgrastim retains the same biological activity as filgrastim, and binds to the same G-CSF receptor, stimulating the proliferation, differentiation and activation of neutrophils. Once-per-chemotherapy cycle administration of pegfilgrastim reduces the duration of severe neutropenia as effectively as daily treatment with filgrastim. In clinical trials, patients receiving pegfilgrastim also had a lower observed incidence of febrile neutropenia than patients receiving filgrastim.     

Piperacillin/tazobactam: a pharmacoeconomic review of its use in moderate to severe bacterial infections.

Piperacillin/tazobactam is a beta-lactam/beta-lactamase inhibitor combination with a broad spectrum of antibacterial activity against most Gram-positive and Gram-negative aerobic bacteria and anaerobic bacteria. Piperacillin/tazobactam is effective and well-tolerated in patients with lower respiratory tract infections (LRTI), intra-abdominal infections, skin and soft tissue infections, and febrile neutropenia. In comparative clinical trials against various other antibacterial regimens, piperacillin/tazobactam has shown higher clinical success rates, particularly in the treatment of patients with intra-abdominal infections and febrile neutropenia. Cost analyses of piperacillin/tazobactam have been variable, in part, because of differences in specific costs included. Three US cost analyses found that piperacillin/tazobactam had lower total medical costs than clindamycin plus gentamicin or imipenem/cilastatin in intra-abdominal infections, and ticarcillin/ clavulanic acid in community-acquired pneumonia. Piperacillin/tazobactam plus amikacin had lower total costs than ceftazidime plus amikacin in another cost analysis of patients with febrile neutropenic episodes modelled in nine European countries. However, piperacillin/tazobactam plus tobramycin was more costly than ceftazidime plus tobramycin in hospital-acquired pneumonia in a US cost analysis. In cost-effectiveness analyses, all studies of intra-abdominal infections, pneumonia and febrile neutropenic episodes consistently reported lower costs per unit of effectiveness versus comparators. Piperacillin/tazobactam was dominant (greater efficacy and lower costs) versus imipenem/cilastatin in intra-abdominal infections and ceftriaxone, ciprofloxacin or meropenem in pneumonia. Piperacillin/tazobactam plus amikacin was dominant over ceftazidime plus amikacin in the treatment of febrile neutropenic episodes. In a cost-effectiveness analysis of skin and soft tissue infection, piperacillin/tazobactam had lower costs per successfully treated patient than ceftriaxone or cefotaxime, but a slightly higher cost-effectiveness ratio than amoxicillin/clavulanic acid. All cost-effectiveness analyses were based on decision-analytical models. CONCLUSIONS: Piperacillin/tazobactam is likely to reduce overall treatment costs of moderate to severe bacterial infections by increasing initial treatment success, thereby reducing the length of hospital stay and the use of additional antibacterials. Piperacillin/tazobactam has shown clinical and economic advantages over standard antibacterial regimens in the treatment of intra-abdominal infections, LRTIs, febrile episodes in patients with neutropenia, and skin and soft tissue infections, although more complete published data are needed to confirm these results. Present data regarding clinical efficacy, bacterial resistance and costs would support the use of piperacillin/tazobactam as an empirical first-line option in moderate to severe bacterial infections.     

Mobilization of peripheral blood stem cells by granulocyte-colony stimulating factors: comparison of a standard dose of glycosylated and mutated granulocyte-colony stimulating factor in non-Hodgkin's lymphoma patients following CHOP therapy

The effects of granulocyte-colony stimulating factor (G-CSF) have been studied in several clinical settings. G-CSFs are widely used to stimulate the production of granulocytes and are well known to mobilize peripheral blood stem cells (PBSCs). However, very few studies have examined differences among G-CSFs. The aim of this study was to compare the mobilization of PBSCs induced by a standard dose of two G-CSFs following biweekly cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) therapy. Using a standard dose of G-CSF, we conducted a randomized, crossover trial that compared the efficacy of two kinds of G-CSF, glycosylated [lenograstim (2 micrograms/kg)] and mutated [nartograstim (1 microgram/kg)], on PBSC mobilization in 10 patients with non-Hodgkin's lymphoma after biweekly CHOP chemotherapy. Lenograstim (2 micrograms/kg) was more effective in shortening the duration of neutropenia than nartograstim (1 microgram/kg) (3.8 days vs. 5.0 days, p < 0.05, the number of days for the neutrophil count to reach 5 x 10(9)/l from nadir). The number of CD34+ cells and granulocyte-macrophage colony forming units (GM-CFU) was higher for lenograstim but no statistically significant difference between the two groups was found. Glycosylated G-CSF is more effective than mutated G-CSF in shortening the duration of neutropenia. As for the mobilization of CD34+ cells and the number of CFU-GM, there was a tendency to increase in the lenograstim group but no statistically significant differences were found.     

Cost effectiveness of riluzole in amyotrophic lateral sclerosis. Italian Cooperative Group for the Study of Meta-Analysis and the Osservatorio SIFO sui Farmaci.

OBJECTIVE: In patients with amyotrophic lateral sclerosis, long term treatment with riluzole has been reported to improve survival or tracheostomy-free survival in comparison with placebo. We conducted a pharmacoeconomic analysis for estimating the cost per life-year gained using this drug. DESIGN: This study was an incremental cost-effectiveness lifetime analysis. SETTING: The clinical material was derived from 2 placebo-controlled randomised controlled trials comparing riluzole versus usual care without riluzole, which were identified through a literature search based on the IOWA and the Medline systems. PATIENTS AND INTERVENTIONS: The study included 633 patients with amyotrophic lateral sclerosis. Patient-level information was retrieved from 313 patients treated with riluzole and 320 patients assigned to placebo. Survival after randomisation was compared between the 2 groups using standard statistics (log-rank test and Cox analysis), whereas the lifetime survival gain was estimated using Gompertz extrapolation. Cost data relative to the expenditure for healthcare resources were obtained from published information (using the US average wholesale price for the acquisition cost of riluzole). Sensitivity testing assessed the impact of different cost-of-illness assumptions for treated and untreated patients. MAIN OUTCOME MEASURES AND RESULTS: Our primary analysis showed that treatment with riluzole significantly prolonged survival [death risk = 0.77; 95% confidence interval (CI): 0.62 to 0.96; p = 0.022]. The lifetime survival gain (including 3% annual discounting) was, on average, 2.3 months per patient, while the incremental cost was around $US12,000 per patient. Hence, the cost-effectiveness ratio of riluzole versus usual care without riluzole was $US62,609 per life-year gained (discounted dollars per discounted years; 95% CI: $US13,458 to $US205,714). The sensitivity analysis, considering different values of national cost for riluzole, suggested an interval for this parameter ranging from $US45,048 to $US62,609. CONCLUSIONS: Our study indicates that in patients with amyotrophic lateral sclerosis, riluzole has an unfavourable cost-effectiveness ratio or, at best, a borderline pharmacoeconomic profile.