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1.  Intensification of chemotherapy for the treatment of solid tumours: feasibility of a 3-fold increase in dose intensity with peripheral blood progenitor cells and granulocyte colony-stimulating factor. 
British Journal of Cancer  1995;72(1):178-182.
Dose intensity may be an important determinant of the outcome in cancer chemotherapy, but is often limited by cumulative haematological toxicity. The availability of haematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and of peripheral blood progenitor cell (PBPC) transplantation has allowed the development of a new treatment strategy in which several courses of high-dose combination chemotherapy are administered for the treatment of solid tumours. PBPCs were mobilised before chemotherapy using 12 or 30 micrograms kg-1 day-1 G-CSF (Filgrastim) for 10 days, and were collected by 2-5 leucaphereses. The yields of mononuclear cells, colony-forming units and CD34-positive cells were similar at the two dose levels of Filgrastim, and the numbers of PBPCs were sufficient for rescue following multiple cycles of chemotherapy. High-dose chemotherapy (cyclophosphamide 2.5 g m-2 for 2 days, etoposide 300 mg m-2 for 3 days and cisplatin 50 mg m-2 for 3 days) was administered sequentially for a median of three cycles (range 1-4) to ten patients. Following the 30 evaluable cycles, the median duration of leucopenia < or = 0.5 x 10(9) l-1 and < or = 1.0 x 10(9) l-1 was 7 and 8 days respectively. The median time of thrombopenia < or = 20 x 10(9) l-1 was 6 days. There was no cumulative haematological toxicity. The duration of leucopenia, but not of thrombopenia, was inversely related to the number of reinfused CFU-GM (granulocyte-macrophage colony-forming units). In the majority of patients, neurotoxicity and ototoxicity became dose limiting after three cycles of therapy. However, the average dose intensity delivered was about three times higher than in a standard regimen. The complete response rate in patients with small-cell lung cancers was 66% (95% CI 30-92%) and the median progression-free survival and overall survival were 13 months and 17 months respectively. These results are encouraging and should be compared, in a randomised fashion, with standard dose chemotherapy.
PMCID: PMC2034125  PMID: 7541235
2.  Effective mobilisation of peripheral blood progenitor cells with 'Dexa-BEAM' and G-CSF: timing of harvesting and composition of the leukapheresis product. 
British Journal of Cancer  1993;68(5):950-957.
The mini-BEAM regimen (BCNU, etoposide, cytarabine, melphalan) and its modification 'Dexa-BEAM' are effective salvage protocols for relapsed Hodgkin's disease and non-Hodgkin's lymphoma. Since many patients with relapsed lymphoma are eligible for high-dose chemotherapy with autologous stem cell rescue, we were interested in the suitability of these second line regimens for mobilising peripheral blood progenitor cells (PBPC). The kinetics of PBPC were studied in 15 patients treated with Dexa-BEAM and granulocyte colony-stimulating factor (G-CSF). Leukocytes started to rise from < 0.5 nL-1 on day 18 (16-22) after Dexa-BEAM, and exceeded 10 nL-1 on day 20 (18-28). Peripheral blood CFU-GM peaked on day 21 (19-28) and declined slowly thereafter; the median leukocyte count was 18.7 nL-1 (12.2-60) on the day of CFU-GM-peak. The maximum number of CFU-GM circulating in peripheral blood was inversely correlated to the duration of leukopenia after Dexa-BEAM. Measurement of CD34+ cells with the monoclonal antibody 8G12-PE (HPCA-2) predicted the number of CFU-GM precisely in both peripheral blood and leukapheresis products (r = 0.90-0.95). Two to six leukapheresis procedures yielded 6.39 x 10(8) mononuclear cells kg-1 (1.82-13.49) containing 44.4 x 10(4) CFU-GM kg-1 (2.2-213.8). Immunophenotypical analysis revealed that the percentage of CD19+ B cells was very low in all collection products (less than 1%). Nine patients were autografted with PBPC (15.4-213.8 x 10(4) CFU-GM kg-1) after myeloablative chemotherapy and experienced rapid and sustained engraftment (Platelets > 50 nL-1 on day +13 [9-22]). We conclude that PBPC can be mobilised effectively by Dexa-BEAM plus G-CSF. An adequate timing of PBPC collection (when the leukocyte count has exceeded 10 nL-1) and evaluation of the progenitor content of the leukapheresis products with 8G12-PE will allow to minimise the number of leukaphereses.
PMCID: PMC1968738  PMID: 7692921
3.  High-dose mitoxantrone with peripheral blood progenitor cell rescue: toxicity, pharmacokinetics and implications for dosage and schedule. 
British Journal of Cancer  1997;76(6):797-804.
The optimal use of mitoxantrone (NOV) in the high-dose range requires elucidation of its maximum tolerated dose with peripheral blood progenitor cell (PBPC) support and the time interval needed between drug administration and PBPC reinfusion in order to avoid graft toxicity. The aims of this study were: (1) to verify the feasibility and haematological toxicity of escalating NOV up to 90 mg m(-2) with PBPC support; and (2) to verify the safeness of a short (96 h) interval between NOV administration and PBPC reinfusion. Three cohorts of ten patients with breast cancer (BC) or non-Hodgkin's lymphoma (NHL) received escalating doses of NOV, 60, 75 and 90 mg m(-2) plus melphalan (L-PAM), 140-180 mg m(-2), with PBPC rescue 96 h after NOV. Haematological toxicity was evaluated daily (WHO criteria). NOV plasma pharmacokinetics was also evaluated, as well as NOV cytotoxicity against PBPCs. Haematological recovery was rapid and complete at each NOV dose level without statistically significant differences, and there were no major toxicities. NOV plasma concentrations at the time of PBPC reinfusion were below the toxicity threshold against haemopoietic progenitors. It is concluded that, when adequately supported with PBPCs, NOV can be escalated up to 90 mg m(-2) with acceptable haematological toxicity. PBPCs can be safely reinfused as early as 96 h after NOV administration.
PMCID: PMC2228044  PMID: 9310249
4.  Transanal endoscopic microsurgery--impact on the practice of a colorectal surgeon in a district general hospital. 
INTRODUCTION: The objective was to assess the impact on the management of colorectal patients treated in a district general hospital within the first year after the introduction of transanal endoscopic microsurgery (TEM). PATIENTS AND METHODS: Data were collected for consecutive unselected patients who underwent TEM. Comparative data were derived from a matched group of patients who underwent anterior resection, peranal procedures (PAR) or transanal resection (TAR) in this unit. RESULTS: Twenty-two patients underwent TEM (11 men and 11 women; aged, 29-87 years; median, 75 years). Eighteen patients had a pre-operative diagnosis of benign rectal neoplasms; three were found to have invasive carcinoma, which might have been missed during TAR. Four patients had a pre-operative diagnosis of rectal cancer and TEM provided local tumour control in three cases. The operating time ranged between 20-150 min (mean, 65 min; median, 57 min). Hospital stay ranged between 0-10 days (mean, 3.7 days; median, 3 days), with a total of 97 in-patient days for the entire group of patients. Twenty-four operations were performed (22 TEM and two salvage anterior resections), with an estimated cost of 1544 pounds sterling for consumables used. Alternative treatments in the absence of TEM were considered to involve 10 anterior resections, 5 closures of ileostomy, 30 TAR procedures and one PAR procedure, with an estimated 306 days of in-patient admission, 46 operations and 6245 pounds sterling spent on consumables. CONCLUSIONS: Availability of TEM allows more efficient treatment for a significant number of patients with rectal tumours. The cost of the equipment is offset by a significant decrease in the length of in-patient admissions.
PMCID: PMC1964132  PMID: 16263010
5.  High-dose chemotherapy supported by peripheral blood progenitor cells in poor prognosis metastatic breast cancer--phase I/II study. Edinburgh Breast Group. 
British Journal of Cancer  1996;74(12):2013-2017.
Current treatments for metastatic breast cancer are not associated with significant survival benefits despite response rates of over 50%. High-dose therapy with autologous bone marrow transplantation (ABMT) has been investigated, particularly in North America, and prolonged survival in up to 25% of women has been reported, but with a significant treatment-related mortality. However, in patients with haematological malignancies undergoing autologous transplantation, haematopoietic reconstruction is significantly quicker and mortality lower than with ABMT, when peripheral blood progenitor cells (PBPCs) are used. In 32 women with metastatic breast cancer, we investigated the feasibility of PBPC mobilisation with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) after 12 weeks' infusional induction chemotherapy and the subsequent efficacy of the haematopoietic reconstitution after conditioning with melphalan and either etoposide or thiotepa. PBPC mobilisation was successful in 28/32 (88%) patients, and there was a rapid post-transplantation haematopoietic recovery: median time to neutrophils > 0.5 x 10(9) l-1 was 14 days and to platelets > 20 x 10(9) l-1 was 10 days. There was no procedure-related mortality, and the major morbidity was mucositis (WHO grade 3-4) in 18/32 patients (56%). In a patient group of which the majority had very poor prognostic features, the median survival from start of induction chemotherapy was 15 months. Thus, PBPC mobilisation and support of high-dose chemotherapy is feasible after infusional induction chemotherapy for patients with metastatic breast cancer, although the optimum drug combination has not yet been determined.
PMCID: PMC2074804  PMID: 8980406
6.  Patient costs in anticoagulation management: a comparison of primary and secondary care. 
BACKGROUND: The demand for anticoagulation management is increasing. This has led to care being provided in non-hospital settings. While clinical studies have similarly demonstrated good clinical care in these settings, it is still unclear as to which alternative is the most efficient. AIM: To determine the costs borne by patients when attending an anticoagulation management clinic in either primary or secondary care and to use this information to consider the cost-effectiveness of anticoagulation management in primary and secondary care, both from the National Health Service and patient perspectives. DESIGN OF STUDY: Observational study comparing two cohorts of patients currently attending anticoagulation management clinics. SETTING: Four primary care clinics in Birmingham and one in Warwickshire, and the haematology clinics at the University of Birmingham Hospitals Trust and the City Hospital NHS Trust. METHOD: The survey of patients attending the clinics was used to ascertain patient costs. This information was then used in conjunction with the findings of a recent randomised controlled trial to establish cost-effectiveness. RESULTS: Patient costs were lower in primary care than in secondary care settings; the mean (standard deviation) costs per visit were Pound Sterling6.78 (Pound Sterling5.04) versus Pound Sterling14.58 (Pound Sterling9.08). While a previous cost-effectiveness analysis from a health sector perspective alone found a higher cost for primary care, the adoption of the societal perspective lead to a marked change in the result: a similar total cost per patient in both sectors. CONCLUSION: There are significantly higher costs borne by patients attending secondary care anticoagulation management clinics than similar patients attending primary care clinics. This study also demonstrates that the perspective adopted in an economic evaluation can influence the final result.
PMCID: PMC1314189  PMID: 11766869
7.  Filgrastim XM02 (Tevagrastim®) after autologous stem cell transplantation compared to lenograstim: favourable cost-efficacy analysis 
ecancermedicalscience  2013;7:327.
Granulocyte colony-stimulating factors (G-CSFs), filgrastim and lenograstim, are recognised to be useful in accelerating engraftment after autologous stem cell transplantation. Several forms of biosimilar non-glycosylated G-CSF have been approved by the European Medicines Agency, with limited published data supporting the clinical equivalence in peripheral blood stem cell mobilisation and recovery after autologous stem cell transplantation.
With the aim of comparing cost-effective strategies in the use of G-CSF after autologous stem cell transplantation, we retrospectively evaluated 32 patients consecutively treated with biosimilar filgrastim XM02 (Tevagrastim) and 26 with lenograstim. All patients received G-CSF (biosimilar or lenograstim) at a dosage of 5 mcg/kg/day subcutaneously from day 5 to absolute neutrophil count of 1500/mmc for three days.
The median time to absolute neutrophil count engraftment was 11 days for the filgrastim XM02 group and 12 days for the lenograstim group. As for platelets recovery, the median time was 12 days in both groups. The median number of G-CSF vials used for patients was 9.5 for Tevagrastim and 10.5 for lenograstim, reflecting a mean estimated cost of about 556.1 euros for Tevagrastim versus 932.2 euros for lenograstim (p< 0.001). The median days of febrile neutropenia were 1.5 and 1 for filgrastim XM02 and lenograstim, respectively. No adverse event related to the use of XM02 filgrastim was recorded.
In our experience, filgrastim XM02 and lenograstim showed comparable efficacy in shortening the period of neutropenia after cytoreduction and autologous stem cell transplantation, with a favourable cost effect for filgrastim XM02.
PMCID: PMC3694838  PMID: 23818939
biosimilar G-CSF; autologous bone marrow transplantation; engraftment; filgrastim; lenograstim
8.  A Phase 3, Randomized, Placebo-controlled Trial of Filgrastim in Patients with Haematological Malignancies Undergoing Matched-related Allogeneic Bone Marrow Transplantation 
Archives of Drug Information  2008;1(3):89-96.
Recombinant granulocyte colony-stimulating factor (G-CSF) may aid engraftment post high-dose chemo-/radiotherapy in patients with haematological malignancies undergoing allogeneic bone marrow transplantation (BMT); however, the effects of G-CSF on graft-versus-host disease (GvHD), relapse, and survival are not well defined.
In this double-blind, randomized, placebo-controlled, multicentre, phase 3 study, the effects of the G-CSF Filgrastim on neutrophil and platelet recovery, and on clinical outcomes were evaluated. Patients (12–55 years) receiving an allogeneic BMT for a haematological malignancy were randomized to receive Filgrastim 5 µg/kg or placebo. Study treatment was continued until patients achieved an absolute neutrophil count (ANC) ≥0.5 × 109/L, or until day 42.
Fifty-one patients (Filgrastim, N = 25; placebo, N = 26) were evaluable. Patients treated with Filgrastim had significantly faster engraftment with ANC ≥0.5 × 109/L being achieved after a median (range) of 15.0 (1.0–22.0) days vs. 19.0 (15.0–28.0) days for placebo (P< 0.0001). The incidence of GvHD was comparable for both groups. During the limited follow-up (2 years), Filgrastim had no adverse effect on mortality and possibly reduced the rate of relapse.
PMCID: PMC2710993  PMID: 19639030
Allogeneic Bone Marrow Transplant; Filgrastim; Neutrophils; Graft-versus Host Disease; Randomized Clinical Trial; Survival
9.  The impact of a general practice group intervention on prescribing costs and patterns. 
BACKGROUND: The formation of primary care groups (PCGs) and trusts (PCTs) has shifted the emphasis from individual practice initiatives to group-based efforts to control rising prescribing costs. However, there is a paucity of literature describing such group initiatives. We report the results of a multilevel group initiative, involving input from a pharmaceutical adviser, practice comparison feedback, and peer review meetings. AIM: To determine the impact of a prescribing initiative on the prescribing patterns of a group of general practices. DESIGN OF STUDY: A comparative study with non-matched controls. SETTING: Nine semi-rural/rural practices forming a commissioning group pilot, later a PCG, in Southern Derbyshire with nine practices as controls. METHOD: Practice data were collated for overall prescribing and for therapeutic categories, between the years 1997/1998 and 1998/1999 and analysed statistically. Prescribing expenditure trends were also collated. RESULTS: Although both groups came well within their prescribing budgets, in the study group this was for the first time in five years. Their rate of increase in expenditure slowed significantly following the initiative compared with that of the comparison group, which continued to rise (median practice net ingredient cost/patient unit (nic/PU) increase: Pound Sterling0.69 and Pound Sterling3.80 respectively; P = 0.03). The study group's nic/PU dropped below, and stayed below, that of the comparison group one month after the start of the initiative. For most therapeutic categories the study group had lower increases in costs and higher increases in percentage of generic items than the comparison group. Quality markers were unaffected. CONCLUSION: We suggest that practices with diverse prescribing patterns can work together effectively within a PCT locality to control prescribing costs.
PMCID: PMC1314236  PMID: 12030659
10.  High-dose carboplatin, etoposide and melphalan (CEM) with peripheral blood progenitor cell support as late intensification for high-risk cancer: non-haematological, haematological toxicities and role of growth factor administration. 
British Journal of Cancer  1997;75(8):1205-1212.
The present report describes the non-haematological toxicity and the influence of growth factor administration on haematological toxicity and haematopoietic recovery observed after high-dose carboplatin (1200 mg m(-2)), etoposide (900 mg m(-2)) and melphalan (100 mg m(-2)) (CEM) followed by peripheral blood progenitor cell transplantation (PBPCT) in 40 patients with high-risk cancer during their first-line treatment. PBPCs were collected during the previous outpatient induction chemotherapy programme by leukaphereses. CEM administration with PBPCT was associated with low non-haematological toxicity and the only significant toxicity consisted of a reversible grade III/IV increase in liver enzymes in 32% of the patients. Haematopoietic recovery was very fast in all patients and the administration of granulocyte colony-stimulating factor (G-CSF) plus erythropoietin (EPO) or granulocyte-macrophage colony-stimulating factor (GM-CSF) plus EPO after PBPCT significantly reduced haematological toxicity, abrogated antibiotic administration during neutropenia and significantly reduced hospital stay and patient's hospital charge compared with patients treated with PBPCT only. None of the patients died early of CEM plus PBPCT-related complications. Low non-haematological toxicity and accelerated haematopoietic recovery renders CEM with PBPC/growth factor support an acceptable therapeutic approach in an adjuvant or neoadjuvant setting.
PMCID: PMC2222783  PMID: 9099971
11.  Cost effectiveness of a mass media-led anti-smoking campaign in Scotland 
Tobacco Control  1997;6(2):104-110.
OBJECTIVE: To evaluate the costs and outcomes associated with the Health Education Board for Scotland's general public anti-smoking campaign during the developmental stage and its first year of operation. DESIGN: Cost information collected retrospectively was combined with prospectively collected effectiveness data. SUBJECTS: A panel of 970 adults were recruited from a 1-in-10 random sample of adult callers to the telephone helpline (Smokeline). Those who smoked were subsequently interviewed at three weeks, six months, and one year follow up. Information on smoking status at one year and time spent as a non-smoker was available for 587 members of the panel. MAIN OUTCOME MEASURES: Intermediate outcomes in the follow-up sample included a point prevalence and period prevalence measure of smoking cessation. Long-term outcomes were measured in terms of predicted reductions in mortality as a consequence of smoking cessation. RESULTS: At the 12- month point, 9.88% of individuals in the follow-up sample reported themselves as non-smokers and as having given up for at least six months in the previous year. Estimates of the cost per life-year saved as a result of the campaign range from 304 pounds sterling to 656 pounds sterling. CONCLUSIONS: Provided that the benefits of smoking cessation are broadly accurate, and the assumed level of quitting can be directly attributed to Smokeline, then this mass media-led anti- smoking campaign appears to have been cost effective. 

PMCID: PMC1759546  PMID: 9291218
12.  Cost benefit analysis of early thrombolytic treatment with intracoronary streptokinase. Twelve month follow up report of the randomised multicentre trial conducted by the Interuniversity Cardiology Institute of The Netherlands. 
British Heart Journal  1988;59(5):527-534.
The costs and benefits of early thrombolytic treatment with intracoronary streptokinase in acute myocardial infarction were compared in a randomised trial. All hospital admissions were recorded and the functional class was assessed at visits to the outpatient clinic during a 12 month follow up of 269 patients allocated to thrombolytic treatment and of 264 allocated to conventional treatment. Mean survival during the first year was calculated for patients with inferior and with anterior infarction and adjusted for impaired quality of life in cases where there were symptoms or hospital admission. In patients with inferior infarction mean survival was 337 days (out of a total follow up of 365 days) for patients allocated to thrombolytic treatment and 327 days for controls. Quality adjusted survival was seven days longer in the thrombolysis group (307 vs 300 days in controls). In patients with anterior infarction mean survival was significantly longer (35 days) in the thrombolysis group than in the control group as was quality adjusted survival (38 days) (304 vs 266 days in controls). The gain in life expectancy with thrombolytic treatment was 0.7 years for patients with inferior infarction, 2.4 years for patients with anterior infarction, and 3.6 years for the subset of patients with large anterior infarction who were admitted within two hours of the onset of symptoms. The costs of medical treatment, including medication, hospital stay, cardiac catheterisation, coronary angioplasty, and bypass surgery, in the first year follow up were higher inpatients allocated to thrombolytic treatment (an additional cost ofDfl 7000 in inferior and Dfl 9000in anterior infarction (1 pounds sterling approximately Dfl 3.3.)) than in conventionally treated patients. The additional costs per year of life gained were Dfl 10 000 in inferior infarction, Dfl 3 800 in anterior infarction, and only Dfl 1 900 in patients with large anterior infarction admitted within two hours of onset of symptoms.Intracoronary thrombolysis can be recommended as a cost effective treatment in patients with extensive anteroseptal infarction.
PMCID: PMC1276892  PMID: 3132962
13.  Use of biosimilar filgrastim compared with lenograstim in autologous haematopoietic stem-cell transplant and in sibling allogeneic transplant 
Biosimilar filgrastim was compared with lenograstim for autologous haematopoietic stem-cell transplant (HSCT) in patients with haematological malignancies. Data from a separate group of sibling donors who underwent allogeneic HSCT are also reported.
Patients with lymphoma or multiple myeloma (MM) who underwent autologous HSCT with biosimilar filgrastim were compared with a historical control group of patients who received lenograstim. Peripheral blood (PB) cells counts were monitored after 7–8 consecutive days of granulocyte-colony stimulating factor (G-CSF) injection and apheresis was performed on day 8 if PB CD34+ cell count was ⩾10 cells/µl. The target PB CD34+ cell doses were ⩾2.0 × 106/kg (lymphoma), ⩾4.0 × 106/kg (MM ⩾60 years old) or ⩾8.0 × 106/kg (MM <60 years old).
A total of 259 patients were included in the autologous HSCT comparison (biosimilar filgrastim, n = 104; lenograstim, n = 155). In patients with lymphoma and older MM patients (⩾60 years old), no significant differences were observed between groups with regard to stem-cell mobilization parameters. However, in MM patients <60 years old, all parameters were significantly superior in the biosimilar filgrastim group, including the need for 1 rather than 2 apheresis procedures. No significant differences were observed between groups in median number of days to absolute neutrophil count (ANC) or platelet recovery. In the allogeneic setting, 47 sibling donors received biosimilar filgrastim. Mean CD34+ count at the first apheresis was 6.1 × 106/kg. A total of 13 donors needed a second apheresis and 4 required a third. Among recipients, median days to ANC recovery was 16 (10–28) and to platelet recovery was 13 (9–54).
Biosimilar filgrastim is as effective as lenograstim for autologous HSCT in patients with lymphoma or MM patients ⩾60 years old. However, mobilization with biosimilar filgrastim appeared to be superior to that with lenograstim in younger MM patients.
PMCID: PMC4365052  PMID: 25830013
biosimilar; filgrastim; G-CSF; haematopoietic stem-cell transplant; lenograstim
14.  Chemotherapy-induced neutropenia among pediatric cancer patients in Egypt: Risks and consequences 
Molecular and Clinical Oncology  2016;5(3):300-306.
Chemotherapy-induced neutropenia (CIN) is the major dose-limiting toxicity of systemic chemotherapy and it is associated with significant morbidity, mortality and treatment cost. The aim of the present study was to identify the risk factors that may predispose pediatric cancer patients who receive myelosuppressive chemotherapy to CIN and associated sequelae. A total of 113 neutropenia episodes were analyzed and the risk factors for CIN were classified as patient-specific, disease-specific and regimen-specific, while the consequences of CIN were divided into infectious and dose-modifying sequelae. The risks and consequences were analyzed to target high-risk patients with appropriate preventive strategies. Among our patients, 28% presented with a single neutropenia attack, while 72% experienced recurrent attacks during their treatment cycles. The mean absolute neutrophil count was 225.5±128.5 ×109/l (range, 10–497 ×109/l), starting 14.2±16.3 days (range, 2–100 days) after the onset of chemotherapy and resolving within 11.2±7.3 days, either with (45.1%) or without (54.9%) granulocyte colony-stimulating factor (G-CSF). No significant association was observed between any patient characteristics or disease stage and the risk for CIN. However, certain malignancies, such as acute lymphocytic leukemia (ALL), neuroblastoma and Burkitt's lymphoma, and certain regimens, such as induction block for ALL and acute myelocytic leukemia, exerted the most potent myelotoxic effect, with severe and prolonged episodes of neutropenia. G-CSF significantly shortened the duration of the episodes and enhanced bone marrow recovery. Febrile neutropenia was the leading complication among our cases (73.5%) and was associated with several documented infections, particularly mucositis (54.9%), respiratory (45.1%), gastrointestinal tract (38.9%) and skin (23.9%) infections. A total of 6% of our patients succumbed to infection-related complications. Neutropenia was responsible for treatment discontinuation (13.3%), dose delay (13.3%) and dose reduction (5.3%) in our patients. The mean cost for each episode in our institution was 9,386.5±6,688.9 Egyptian pounds, which represented a significant burden on health care providers.
PMCID: PMC4998081  PMID: 27588196
neutropenia; chemotherapy; risks; consequences
15.  Double high-dose chemotherapy with autologous stem cell transplantation in patients with high-risk neuroblastoma: a pilot study in a single center. 
Journal of Korean Medical Science  2002;17(4):537-543.
Double high-dose chemotherapy (HDCT) was applied to 18 patients with highrisk neuroblastoma including 14 patients who could not achieve complete response (CR) even after the first HDCT. In 12 patients, successive double HDCT was rescued with peripheral blood stem cells collected during a single round of leukaphereses and in 6 patients, second or more rounds of leukaphereses were necessary after the first HDCT to rescue the second HDCT. The median interval between the first and second HDCT (76 days; range, 47-112) in the single harvest group was shorter than that (274.5 days; range, 83-329) in the double harvest group (p<0.01). Hematologic recovery was slow in the second HDCT. Six (33.3%) treatment-related mortalities (TRM) occurred during the second HDCT but were not related to the shorter interval. Disease-free survival rates at 2 years with a median follow-up of 24 months (range, 6-46) in the single and double harvest group were 57.1% and 33.3%, respectively. These results suggest that successive double HDCT using the single harvest approach may improve the survival of high-risk patients, especially who could not achieve CR after the first HDCT despite delayed hematologic recovery and high rate of TRM during the second HDCT.
PMCID: PMC3054907  PMID: 12172052
16.  A randomized trial of amifostine in patients with high-dose VIC chemotherapy plus autologous blood stem cell transplanation 
British Journal of Cancer  2001;84(3):313-320.
This pilot study evaluates the degree of side effects during high-dose chemotherapy (HD-VIC) plus autologous bone marrow transplant (HDCT) and its possible prevention by the cytoprotective thiol-derivate amifostine. Additionally, the in-patient medical costs of both treatment arms were compared. 40 patients with solid tumours were randomized to receive HD-VIC chemotherapy with or without amifostine (910 mg/m2 at day 1–3) given as a short infusion prior to carboplatin and ifosfamide. Patients were stratified according to pretreatment. HDCT consisted of an 18 h infusion of carboplatin (500 mg/m2/d over 18 h), ifosfamide (4 g/m2/d over 4 h) and etoposide (500 mg/m2/d) all given for 3 consecutive days. All patients received prophylactic application of G-CSF (5 μg kg−1 subcutaneously) to ameliorate neutropenia after treatment. Patients were monitored for nephrotoxicity, gastrointestinal side effects, haematopoietic recovery, as well as frequency of fever and infections. The median fall of the glomerular filtration rate (GFR) was 10% from baseline in the amifostine group (105 to 95 ml min−1) and 37% in the control patient group (107 to 67 ml min−1) (P< 0.01). Amifostine-treated patients revealed a less pronounced increase in albumine and low molecular weight protein urinary excretion. Stomatitis grade III/IV occurred in 25% without versus 0% of patients with amifostine (P = 0.01). Acute nausea/vomiting was frequently observed immediately during or after the application of amifostine despite intensive antiemetic prophylaxis consisting of 5-HT3-receptor antagonists/dexamethasone/trifluorpromazine. However, delayed emesis occurred more often in the control patients. Engraftment of neutrophil (> 500 μl−1) and thrombocytes (> 25 000 μl−1)were observed at days 9 versus 10 and 10 versus 12, respectively, both slightly in favour of the amifostine arm. In addition, a lower number of days with fever and a shortened duration of hospital stay were observed in the amifostine arm. The reduction of acute toxicity observed in the amifostine arm resulted in 30% savings in costs for supportive care (Euro 4396 versus Euro 3153 per patient). Taking into account the drug costs of amifostine, calculation of in-patient treatment costs from the start of chemotherapy to discharge revealed additional costs of Euro 540 per patient in the amifostine arm. This randomized pilot study indicates that both organ and haematotoxicity of HD-VIC chemotherapy can be ameliorated by the use of amifostine. Additionally, a nearly complete preservation of GFR was observed in amifostine-treated patients which may be advantageous if repetitive cycles of HDCT are planned. Larger randomized trials evaluating amifostine cytoprotection during high-dose chemotherapy are warranted. © 2001 Cancer Research Campaign
PMCID: PMC2363753  PMID: 11161394
toxicity; high-dose chemotherapy; PBSC transplantation; cytoprotection; amifostine; pharmacoeconomics
17.  Stem Cell Mobilization with G-CSF versus Cyclophosphamide plus G-CSF in Mexican Children 
Stem Cells International  2016;2016:4078215.
Fifty-six aphaereses were performed in 23 pediatric patients with malignant hematological and solid tumors, following three different protocols for PBPC mobilization and distributed as follows: A: seventeen mobilized with 4 g/m2 of cyclophosphamide (CFA) and 10 μg/kg/day of granulocyte colony stimulating factor (G-CSF), B: nineteen with CFA + G-CSF, and C: twenty only with G-CSF when the WBC count exceeded 10 × 109/L. The average number of MNC/kg body weight (BW)/aphaeresis was 0.4 × 108 (0.1–1.4), 2.25 × 108 (0.56–6.28), and 1.02 × 108 (0.34–2.5) whereas the average number of CD34+ cells/kg BW/aphaeresis was 0.18 × 106/kg (0.09–0.34), 1.04 × 106 (0.19–9.3), and 0.59 × 106 (0.17–0.87) and the count of CFU/kg BW/aphaeresis was 1.11 × 105 (0.31–2.12), 1.16 × 105 (0.64–2.97), and 1.12 × 105 (0.3–6.63) in groups A, B, and C, respectively. The collection was better in group B versus group A (p = 0.007 and p = 0.05, resp.) and in group C versus group A (p = 0.08 and p = 0.05, resp.). The collection of PBPCs was more effective in the group mobilized with CFM + G-CSF when the WBC exceeded 10 × 103/μL in terms of MNC and CD34+ cells and there was no toxicity of the chemotherapy.
PMCID: PMC4736431  PMID: 26880960
18.  Use and delivery of granulocyte colony–stimulating factor in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy—single-centre experience 
Current Oncology  2012;19(4):e239-e243.
Use of granulocyte colony-stimulating factor (g-csf) as primary prophylaxis against chemotherapy-induced neutropenia has significant cost implications. We examined use of g-csf for early-stage breast cancer patients at our centre. The study also examined the pattern of nurse-led patient teaching with respect to drug self-administration.
Patients who received g-csf between November 2009 and October 2010 were identified from pharmacy records. After consent had been obtained, electronic charts were examined to extract data on chemotherapy and use of g-csf. Patients were contacted by telephone to obtain information on the utilization of home-care nursing visits for g-csf administration.
The study analyzed 36 patients. Median age was 58 years (range: 31–78 years). Of the 36 patients, 30 (83%) had received adjuvant treatment, and 6 (17%), neoadjuvant treatment. Most patients (71%) received 10 days (range: 7–10 days) of filgrastim. Of the 36 patients, 29 (81%) received g-csf as primary prophylaxis. In 90% of those patients, primary prophylaxis commenced with the taxane component of treatment. Of the 36 patients, 7 (19%) received g-csf after neutropenia, including 2 who had febrile neutropenia. In 96% of the patients, injections were received at home with the help of a nurse; those patients were subsequently taught self-injection techniques. The median number of nursing visits was 2 (range: 1–3 visits). Most patients were satisfied with the home care and g-csf teaching they received.
Most of the g-csf used in breast cancer treatment during the study period was given for primary prophylaxis. A major reason for the decision to use g-csf appears to have been physician-perceived risk of febrile neutropenia. Delivery of g-csf by home-care nurses was well received by patients.
PMCID: PMC3410835  PMID: 22876152
Growth factor; breast cancer; chemotherapy; neutropenia; febrile neutropenia; prophylaxis; drug administration
19.  Pharmacokinetic and -dynamic modelling of G-CSF derivatives in humans 
The human granulocyte colony-stimulating factor (G-CSF) is routinely applied to support recovery of granulopoiesis during the course of cytotoxic chemotherapies. However, optimal use of the drug is largely unknown. We showed in the past that a biomathematical compartment model of human granulopoiesis can be used to make clinically relevant predictions regarding new, yet untested chemotherapy regimen. In the present paper, we aim to extend this model by a detailed pharmacokinetic and -dynamic modelling of two commonly used G-CSF derivatives Filgrastim and Pegfilgrastim.
Model equations are based on our physiological understanding of the drugs which are delayed absorption of G-CSF when applied to the subcutaneous tissue, dose-dependent bioavailability, unspecific first order elimination, specific elimination in dependence on granulocyte counts and reversible protein binding. Pharmacokinetic differences between Filgrastim and Pegfilgrastim were modelled as different parameter sets. Our former cell-kinetic model of granulopoiesis was essentially preserved, except for a few additional assumptions and simplifications. We assumed a delayed action of G-CSF on the bone marrow, a delayed action of chemotherapy and differences between Filgrastim and Pegfilgrastim with respect to stimulation potency of the bone marrow. Additionally, we incorporated a model of combined action of Pegfilgrastim and Filgrastim or endogenous G-CSF which interact via concurrent receptor binding. Unknown pharmacokinetic or cell-kinetic parameters were determined by fitting the predictions of the model to available datasets of G-CSF applications, chemotherapy applications or combinations of it. Data were either extracted from the literature or were received from cooperating clinical study groups. Model predictions fitted well to both, datasets used for parameter estimation and validation scenarios as well. A unique set of parameters was identified which is valid for all scenarios considered. Differences in pharmacokinetic parameter estimates between Filgrastim and Pegfilgrastim were biologically plausible throughout.
We conclude that we established a comprehensive biomathematical model to explain the dynamics of granulopoiesis under chemotherapy and applications of two different G-CSF derivatives. We aim to apply the model to a large variety of chemotherapy regimen in the future in order to optimize corresponding G-CSF schedules or to individualize G-CSF treatment according to the granulotoxic risk of a patient.
PMCID: PMC3507764  PMID: 22846180
Chemotherapy; Filgrastim; Granulopoiesis; Haematotoxicity; Leucopenia; Pegfilgrastim
20.  Effects and safety of granulocyte colony-stimulating factor in healthy volunteers 
Current opinion in hematology  2009;16(1):35-40.
Purpose of Review
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is now widely used in normal donors for collection of peripheral blood progenitor cells (PBPCs) for allogeneic transplantation and granulocytes for transfusion. Currently available data on biologic and molecular effects, and safety of rhG-CSF in normal healthy volunteers are reviewed.
Recent Findings
In addition to its known activating role on neutrophil kinetics and functional status, rhG-CSF administration can affect monocytes, lymphocytes and the hemostatic system. G-CSF receptors were identified in a variety of non-myeloid tissues, although their role and functional activity have not always been well defined. Moreover, rhG-CSF is capable of modulating complex cytokine networks and can impact the inflammatory response. In addition to its known mobilizing role for PBPCs, rhG-CSF can mobilize dendritic and endothelial progenitor cells as well. On a clinical level, serious rhG-CSF-related adverse events are well described (e.g. splenic rupture) but remain rare.
rhG-CSF effects in healthy volunteers, while normally transient and self-limiting, are now believed to be more complex and heterogeneous that previously thought. While rhG-CSF administration to healthy volunteers continues to have a favorable risk-benefit profile, these new findings have implications for safeguarding the safety of normal individuals.
PMCID: PMC4454362  PMID: 19057203
Normal donors; granulocyte colony-stimulating factor; G-CSF; filgrastim
21.  Filgrastim, lenograstim and pegfilgrastim in the mobilization of peripheral blood progenitor cells in patients with lymphoproliferative malignancies 
Patients with lymphoproliferative disorders, candidate to autologous stem cell transplantation (ASCT), require mobilization with chemotherapy and granulocyte colony -stimulating factor (G-CSF). This study looked for differences in hematopoietic peripheral stem cells (HPSCs) mobilization in response to the three available G-CSFs, namely lenograstim, filgrastim, and pegfilgrastim. Between 2000 and 2012, 146 patients (66 M and 80 F) who underwent ASCT for multiple myeloma, non-Hodgkin’s lymphoma or Hodgkin’s lymphoma were studied. All patients received induction therapy and then a mobilization regimen with cyclophosphamide plus lenograstim, or filgrastim, or pegfilgrastim. From days 12 to 14, HPSCs were collected by two to three daily leukaphereses. Our results show that high-dose cyclophosphamide plus lenograstim achieved adequate mobilization and the collection target more quickly and with fewer leukaphereses as compared to filgrastim and pegfilgrastim. No differences between the three regimens were observed regarding toxicity and days to WBC and platelet recovery. Thus, lenograstim may represent the ideal G-CSF for PBSC mobilization in patients with lymphoproliferative diseases. Further studies are needed to confirm these results and better understand the biological bases of these differences.
PMCID: PMC4412650  PMID: 24722996
Cell mobilization; Granulocyte colony-stimulating factor; Pegylated G-CSF; Peripheral blood progenitor cells; Recombinant human glycosylated G-CSF; Recombinant non-glycosylated G-CSF
22.  Randomized Trial of Two Dosages of Prophylactic Granulocyte Colony-Stimulating Factor after Induction Chemotherapy in Pediatric Acute Myeloid Leukemia 
Cancer  2010;117(6):10.1002/cncr.25536.
Granulocyte colony-stimulating factor (G-CSF) is effective in accelerating neutrophil recovery after intensive chemotherapy for acute myeloid leukemia (AML). However, the optimal G-CSF dosage for patients with AML has not been determined. To our knowledge, G-CSF dosages have not been compared in a randomized AML study.
Patients enrolled on the St. Jude AML97 protocol who remained on study after window therapy were eligible to participate. The effect of the dosage of G-CSF given after induction chemotherapy courses 1 and 2 was analyzed in 46 patients randomly assigned in a double-blinded manner to receive 5 or 10 μg/kg/day of G-CSF. The number of days of G-CSF treatment, neutropenia (absolute neutrophil count < 0.5 × 109/L), and hospitalization; the number of episodes of febrile neutropenia, grade 2-4 infection, and antimicrobial therapy; transfusion requirements; the cost of supportive care; and survival were compared between the two study arms.
We found no statistically significant difference between the two arms in any of the endpoints measured.
The higher G-CSF dosage (10 μg/kg/day) offers no greater benefit than the lower dosage (5 μg/kg/day) in patients undergoing intensive chemotherapy for AML.
PMCID: PMC3116094  PMID: 21381017
acute myeloid leukemia; granulocyte colony-stimulating factor; dosage; children; randomized trial
23.  Granulocyte-macrophage colony stimulating factor (GM-CSF) after high-dose melphalan in patients with advanced colon cancer. 
British Journal of Cancer  1990;61(5):749-754.
Nine patients with progressive, metastatic disease from primary carcinoma of the colon were entered into a phase I/II study using continuous intravenous infusions of granulocyte-macrophage colony-stimulating factor (GM-CSF) and high dose melphalan (120 mg m-2). GM-CSF was given alone to six patients during the first part of the study to determine a dose that would produce a peripheral leucocyte count (WCC) greater than or equal to 50 X 10(9) 1(-1) and was initially given at 3 micrograms kg-1 day-1 and escalated to 10 micrograms kg-1 day-1 after 10 days. The infusion was discontinued when the WCC exceeded 50 X 10(9) 1(-1) and after a gap of one week, melphalan was given over 30 min. GM-CSF was recommenced 8 h later and was continued until the neutrophil count had exceeded 0.5 X 10(9) 1(-1) for greater than 1 week. One patient achieved a WCC greater than 50 X 10(9) 1(-1) with GM-CSF 3 micrograms kg-1 day-1, but the other five who entered this phase of the study required dose escalation to 10 micrograms kg-1. No toxicity attributed to GM-CSF was seen. After melphalan, the median times to severe neutropenia (less than 0.5 X 10(9) 1(-1] and thrombocytopenia (greater than 20 X 10(9) 1(-1] were 6 and 9 days respectively. The median durations of neutropenia and thrombocytopenia were 14 and 10 days respectively. All patients required intensive support with a median duration of inpatient stay of 24 days. There was one treatment related death due to renal failure. One complete and two partial remissions (33% response rate) were seen but these were of short duration (median of 10 weeks). This study demonstrates that GM-CSF given by continuous intravenous infusion produces significant increments of peripheral granulocyte counts at 3 and 10 micrograms kg-1 day-1 and is not associated with any toxicity. The duration of neutropenia and thrombocytopenia induced by high-dose melphalan appears to be reduced by the subsequent administration of GM-CSF to times which are at least as short as have been reported in historical series which have used autologous bone marrow rescue.
PMCID: PMC1971606  PMID: 1692472
24.  Small bowel obstruction due to postoperative adhesions: treatment patterns and associated costs in 110 hospital admissions. 
The workload and costs of the emergency admissions and treatment of adhesive small bowel obstruction (ASBO) are unclear. This review details and costs the admission workload of ASBO. All admissions over a 2-year period for ASBO at two district general hospitals were identified through ICD10 diagnostic codes. Diagnostic investigations, treatment patterns, ward stay and outcome information for admissions were detailed from clinical records to develop mean cost estimates and assess the associated workload. Of the 298 admissions identified, 188 were not due to ASBO and were excluded from analysis. Of the 110 admissions detailed, 41 (37%) were treated surgically and 69 (63%) conservatively. Most admissions occurred through general practitioner referral (86.4%) to accident and emergency (90.0%). Mean (SD) length of stay was 16.3 days (11.0 days) for surgical treatment and 7.0 days (4.6 days) for conservative treatment. In-patient mortality was 9.8% for the surgical group and 7.2% for the conservative group. Costs were based on the mean values from both centres for surgical and conservative admissions and detailed according to the cost of referral and follow-up (100.98 Pounds surgical versus 102.61 Pounds conservative), hospital ward and ICU stay (3,327.48 Pounds versus 1,267.92 Pounds), theatre time (832.32 Pounds surgical only), investigations (282.73 Pounds versus 207.33 Pounds) and drug costs (133.90 Pounds versus 28.29 Pounds). Total treatment cost per admission for ASBO was 4,677.41 Pounds for surgically treated admissions and 1,606.15 Pounds for conservatively treated admissions. The impact of admissions for ASBO is considerable in terms of both costs and workload. Bed stay for these admissions represents the equivalent of almost one surgical bed per year and at least 2 days theatre time, impacting on surgical capacity and waiting lists. Adhesion prevention strategies may reduce the workload associated with ASBO. The review provides useful information for planning resource allocation.
PMCID: PMC2503561  PMID: 11212449
25.  Filgrastim fails to improve haemopoietic reconstitution following myeloablative chemotherapy and peripheral blood stem cell rescue. 
British Journal of Cancer  1994;70(5):943-945.
The morbidity of high-dose chemotherapy has been considerably reduced by the use of autologous peripheral blood progenitor cell reinfusion. Most studies have used myeloid colony-stimulating factors after stem cell reinfusion, making it difficult to determine the relative contribution of each of these variables to the early recovery of blood cells. The financial implications of colony-stimulating factor use are an area of concern as dose intensification in chemosensitive malignancies is increasingly employed. We have studied 19 consecutive patients receiving high-dose chemotherapy with and without filgrastim (Amgen, granulocyte colony-stimulating factor, G-CSF) after stem cell infusion to examine its effect on the kinetics of blood cell recovery, the complications of myelosuppression and the associated costs. Analysis of the two treatment groups reveals that administration of filgrastim 10 micrograms kg-1 day-1 following stem cell reinfusion does not further accelerate haemopoietic recovery, fails to reduce the incidence of neutropenic fever or antibiotic usage and significantly increases the cost of the procedure. The results of this study do not support the routine use of filgrastim after high-dose chemotherapy and peripheral blood stem cell reinfusion.
PMCID: PMC2033565  PMID: 7524605

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