Colony-stimulating factors

Transcription

1 Colony stimulating factors page 1 APC/DTC Briefing Document Colony-stimulating factors Contents Conclusions from clinical evidence 1 Background 2 Clinical guidelines 2 Licensed indications 3 Clinical evidence 3 Filgrastim vs. lenograstim 3 Pegfilgrastim 8 Economic considerations 9 Safety 10 Summary 11 References 11 Appendix 1 13 Produced for the London Procurement Programme by Alexandra Denby Regional MI Manager London Medicines Information Service Northwick Park Hospital Middlesex HA1 3UJ Conclusions from clinical evidence The British Society for Haematology, the European Society for Medical Oncology and the American Society of Clinical Oncology all recommend in their guidelines that colony stimulation factors (CSFs) should be used for febrile neutropenia, leukaemias, lymphomas, peripheral blood progenitor cell mobilisation and transplants. They do not recommend a specific product. Most haematologists consider filgrastim and lenograstim to be equally efficacious and use pegfilgrastim only when this is thought to be cost effective, i.e. when the anticipated number of days of daily G-CSF is thought to be long more than 7-10 days of neutropenia. After chemotherapy lenograstim, filgrastim and pegfilgrastim are all effective in increasing neutrophil and leucocyte counts. Both lenograstim and filgrastim are effective (and licensed) for peripheral blood progenitor cell mobilisation. The potential benefits of pegfilgrastim over filgrastim and lenograstim relate to the convenience of a once-per-cycle administration fewer injections, potentially less injection site complications and better compliance. Pegfilgrastim has the fewest licensed indications at the time of writing (July 2007) whilst filgrastim has the widest range. The efficacy of G-CSF in reducing the risk of febrile neutropenia does not always result in cost-savings, as the costs of the drug may not be offset by the reduced incidence of febrile neutropenia and shorter stay in hospital. The routine use of pegfilgrastim is not recommended by the London Cancer New Drugs Group but in certain clinical settings its use may be cost-effective. Such indications should be defined and agreed locally. Tel: alexandra.denby@nwlh.nhs.uk Further copies of this document are available from URL:

2 Colony stimulating factors page 2 Background information The most common dose-limiting factor for the use of chemotherapy is neutropenia and its consequences. 1;2 Some chemotherapy is restricted to be given at 3-4 weekly intervals, because that is the time period required for the haematopoietic system, in particular white blood cells, to recover. The use of chemotherapy is limited by the high rate of proliferation of neutrophil precursors, the rapid turnover of neutrophils in the blood and the essential part that neutrophils play in protecting the body against bacterial and fungal infections. 2 Neutropenia is associated with morbidity, mortality and costs. 3 Patients with neutropenia are at risk of developing a fever (febrile neutropenia, FN) 1 ; about 40% of patients admitted to hospital with febrile neutropenia have documented infections. 2 Febrile neutropenia is defined as the occurrence of fever (>38.5 C) for more than 1 hour associated with an absolute neutrophil count (ANC) of <0.5x10 9 /L. 4 The risk of FN is greatest during the first cycle of chemotherapy, when approximately 60% of episodes occur, though it is unclear whether the risk diminishes in later cycles. 2 Patients with FN may require hospitalisation for evaluation and broad-spectrum antibiotics; such complications can result in dose reductions or treatment delays, which may compromise clinical outcomes. 3 Recombinant human granulocyte-colony stimulating factor (rhg-csf) is a glycoprotein which stimulates the production of neutrophils from bone marrow and may reduce the duration of chemotherapy-induced neutropenia and thereby reduce the incidence of associated sepsis. 5;6 There are currently three G- CSFs available: filgrastim (unglycosylated rhg-csf), lenograstim (glycosylated rh-g- CSF) and pegfilgrastim (pegylated derivative of filgrastim, pegylation increases the duration of activity). 5 G-CSFs are also used to shorten the duration of neutropenia in patients receiving high-dose chemotherapy for peripheral blood stem (progenitor) cell transplants (PBSC or PBPCs), and to mobilise PBSCs for collection by apheresis (see footer). 7 All three G-CSFs have identical modes of action, causing a marked increase in peripheral blood neutrophil counts within 24 hours. 6;8-10 The serum elimination half-lives of filgrastim and lenograstim are relatively short (3-4 hours) and they should be administered daily until the expected neutrophil nadir has passed and the neutrophil count has returned to within the normal range. This may take up to approximately one month depending on the type, dose and schedule of chemotherapy Pegfilgrastim is a covalent conjugate of filgrastim with a single polyethylene glycol (PEG) molecule which increases its size and decreases renal clearance. Only one dose of pegfilgrastim is required for each chemotherapy cycle. 6 Clearance of pegfilgrastim is dependent on the total body neutrophil mass, so when the neutrophil count is low (due to chemotherapy) the half-life of pegfilgrastim is increased. 2 The use of pegfilgrastim has the potential to simplify the management of neutropenia, as well as improving cancer patients quality of life by reducing the number of daily injections required. 1 Most haematologists consider filgrastim and lenograstim to be equally efficacious and use pegfilgrastim only when this is thought to be cost effective, i.e. when the anticipated number of days of daily G-CSF is thought to be long more than 7-10 days of neutropenia. Clinical Guidelines The British Society for Haematology (BSH) 11, the European Society for Medical Oncology (ESMO) 4 and the American Society of Clinical Oncology (ASCO) 12 all recommend in their guidelines that CSFs should be used when the incidence of FN is at least 40% (BSH) or at least 20% (ASCO and ESMO) [see Appendix 1 for examples of regimens with a high risk of neutropenia]. They also recommended CSFs after chemotherapy for leukaemias and lymphomas, autologous stem cell transplantation, allogeneic transplantation, for mobilisation of peripheral blood progenitor cells. None of the guidelines recommend a specific product, just when a CSF is indicated. Apheresis: The process of removing a specific component from the blood and returning the remaining components to the donor, in order to collect more of one particular part of the blood than could be separated from a unit of whole blood.

3 Colony stimulating factors page 3 Licensed Indications Filgrastim currently has the widest range of licensed indications (see table 1 for detailed indications). All three are licensed for the reduction of duration of severe neutropenia and the incidence of febrile neutropenia in patients undergoing established cytotoxic chemotherapy. Both lenograstim and filgrastim are licensed for the mobilisation of peripheral blood progenitor cells, and for reducing neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation who are at high risk of severe neutropenia. Filgrastim has two additional licensed indications: long-term administration in patients with severe congenital, cyclic, or idiopathic neutropenia with an ANC of 0.5 x 10 9 /L, and a history of severe or recurrent infections, and the treatment of persistent neutropenia in patients with advanced HIV infection, in order to reduce the risk of bacterial infections when other options to manage neutropenia are inappropriate. Clinical evidence Numerous studies have demonstrated that the administration of G-CSFs to patients undergoing myelosuppressive chemotherapy reduces the duration of severe neutropenia and the incidence of febrile neutropenia, and also facilitates on-time delivery of scheduled doses of chemotherapy in these patients. There is also substantial data on the benefits of using G- CSFs for PBPC mobilisation. 7 Filgrastim vs. lenograstim Filgrastim is non-glycosylated methionyl G-CSF and produced in culture by bacteria, whilst lenograstim is glycosylated G-CSF produced in culture by mammalian cells. Glycosylation confers molecular stability to the molecule and protects from variations in ph, temperature and proteolysis. This has practical implications - lenograstim does not have to be stored in a refrigerator. Glycosylated G-CSF (lenograstim) is a more rigid molecule and has higher receptor binding than non-glycosylated G-CSF (filgrastim): this accounts for the higher in vivo activity. One microgram (mcg) of filgrastim contains 100,000 biological units whereas 1mcg of lenograstim contains 127,750 units. 13 Bonig et al 14 compared blood counts, C- reactive protein and infection-related clinical events in 11 patients (age 3-29 years, median 14 years) receiving lenograstim or filgrastim after chemotherapy. The trial was of a prospective, randomised, cross-over design. Patients were included if they were considered to be at 50% risk of developing severe neutropenia, or they were to receive G-CSF as part of their chemotherapy regimen. G-CSF (paediatric dose 250mcg/m 2 /day) was started one day after the end of the chemotherapy block and continued until a white blood count of >1500/microlitre (ml) had been measured for 3 successive days after the end of the expected leucocyte nadir. Patients were treated alternately with lenograstim and filgrastim. The study was powered to detect a 25% advantage for lenograstim. Thirty-three cycles were given: 16 with lenograstim and 17 with filgrastim. Twenty-two cross over pairs were evaluated, of which 12 received lenograstim first. There appeared to be no carry-over effects so the order in which the growth factors were given did not have to be taken into consideration. Results are in table 2. In all patients the ANC dropped to below 1000/mL and in both groups day 11 was the first day on which over 50% of patients had returned to an ANC of 1000/ml. The incidence, severity and duration of leucopenia and neutropenia followed the same pattern in lenograstim- or filgrastim-treated patients. At the paediatric dose used in this study lenograstim and filgrastim did not differ in their effect on duration and severity of neutropenia and on the frequency and clinical course of infections. Patients treated with lenograstim did not differ from those treated with filgrastim in terms of any of the end-points measured.

4 Colony stimulating factors page 4 Table 1: G-CSF preparations Drug Filgrastim (Neupogen): 8;9 Lenograstim (Granocyte): 10 Pegfilgrastim (Neulasta): 6 Presentation Pre-filled syringes - 30 million units (MU) (300 micrograms) or 48 MU (480 micrograms) per 0.5ml. Vial - 30 MU in 1ml or 48 MU in 1.6mls. Powder for reconstitution (with water in a prefilled syringe) MU, (105 micrograms) and 33.6 MU, (263 micrograms), per ml after reconstitution Pre-filled syringe - 6mg in 0.6ml, (expressed as filgrastim) Administration route Intravenous infusion or subcutaneous injection Intravenous infusion or a subcutaneous injection Subcutaneous injection The reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with established cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia (CML) and myelodysplastic syndromes) The reduction in the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia. The reduction of duration of severe neutropenia and its associated complications in patients undergoing established cytotoxic chemotherapy associated with a significant incidence of febrile neutropenia. Reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with cytotoxic chemotherapy for malignancy (with the exception of CML and myelodysplastic syndromes). Indications Long term administration in patients, children or adults, with severe congenital, cyclic, or idiopathic neutropenia with an ANC of 0.5 x 10 9 /L, and a history of severe or recurrent infections, to increase neutrophil counts and to reduce the incidence and duration of infectionrelated events. The reduction in the duration of neutropenia in patients (with non-myeloid malignancy) undergoing myeloablative therapy followed by bone marrow transplantation (BMT) in patients considered to be at increased risk of prolonged severe neutropenia. The mobilisation of peripheral blood progenitor cells (PBPC). Mobilisation of peripheral blood progenitor cells (PBPCs). The treatment of persistent neutropenia (ANC 1.0 x10 9 /L) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections when other options to manage neutropenia are inappropriate. Storage Store in a refrigerator (+2 C - +8 C) Not above 30 C Store in a refrigerator (+2 C - +8 C). Neulasta may be exposed to room temp for a maximum single period of up to 72 hours.

5 Colony stimulating factors page 5 Table 2: Results of the prospective cross-over study comparing lenograstim with filgrastim. 14 Lenograstim (16 cycles) Filgrastim (17 cycles) WBC <1000/mL at day 0 69% (11) 76% (13) WBC 1000/mL by day % (10) 59% (10) Leucocyte nadir <500/mL 44% (7) 41% (7) Severe neutropenia 77% (10/13) 69% (11/16) (ANC<500/mL) (n=29) ANC ³500/mL by day 9 54% (7/13) 50% (8/16) (n=29) Comparison of pair differences for each endpoint WBC >500/mL WBC >1000/mL ANC >500/mL ANC >1000/mL 0 (-2.3, 1.3) days (median (95% confidence limits) 0 (-3.3, 0.9) days 0 (-2.0, 4.5) days 0 (-0.9, 2.7) days Median length of treatment 12.5 days (7-18) 12 days (3-17) Median difference 0 days (-4 7) Infections (CRP>5mg/dL) 33% (5/15) 35% (6/17) Median infection duration 5 (4-9) days 5.5 (3-12) days Median difference in length of infectious episode 0 days (-8-7) Antibiotic treatment 58% (7/12) 60% (9/15) Median antibiotic duration 9 (1-12) days 9 (2-17) days Median difference 0 days (-2-6) Mean infection-related hospital stay 11 (6-12) days 9 (3-14) days Median difference 0 (-5-6) Kopf et al 15 conducted a prospective, randomised study to compare the stem cell mobilising effects of filgrastim, lenograstim and molgramostim, (granulocyte-macrophage (GM)- CSF). The number of stem cells (CD34+) harvested and time to recovery of ANC >500/ml and platelets >20,000/ml after mobilising chemotherapy were evaluated. Doses used were 5mcg/kg/day. Peripheral blood progenitor cell (PBPCs) mobilisation is carried out after disease-specific mobilising chemotherapy followed by administration of a myeloid growth factor, such as G-CSF and the PBPC harvest is performed by apheresis. Studies have shown a possible advantage of glycosylated G-CSF (lenograstim) over nonglycosylated G-CSF (filgrastim) in terms of colony-forming units-granulocyte-macrophage harvested. Of the 103 patients assessed, 59 had received prior chemotherapy and 44 were chemonaive; 21 did not undergo apheresis. The minimum threshold value to guarantee safe haematological recovery of a high-dose chemotherapy treatment was 2x10 6 /kg CD34+ cells. Results are in table 3.

6 Colony stimulating factors page 6 A non-statistically significant trend in favour of filgrastim in relation to the median number of CD34+ cells collected was seen though there was a statistically significant advantage in favour of lenograstim for the median number of days until apheresis. Although there was a correlation between the WBC count on the day of apheresis and circulating CD34+ cells there was not a correlation between circulation and harvested CD34+ cells. This conflicts with reports from other authors who report that the CD34+ cell count in peripheral blood is a good indicator for estimating PBPC yield. In this study all three growth factors were efficacious with no significant difference between CD34+ yields achieved. Table 3: Lenograstim vs filgrastim for PBPC harvest. 15 Lenograstim (n=36) Filgrastim (n=38) Molgramostim (n=29) P value Grade 4 neutropenia 19 (53%) 28 (74%) 25 (85%) p=0.001 Median duration to recovery of ANC>0.5x10 9 /L 3 days (1-15) 4 days (1-18) 6 days (3-11) p= Difference among the three treatment arms was statistically in favour of lenograstim for frequency and duration of neutropenia. Patients undergoing apheresis 29 (80.5%) 29 (76.3%) 24 (82.7%) - CD34+ count³2x10 6 /kg 25 (86%) 28 (97%) 21 (87.5%) - Median duration of growth factor administration 12 days (11-16) 13 days (10-17) 14 days (12-20) p< Median number of apheresis performed* 1 (1-3) 1 (1-2) 1 (1-2) NS Median WBC count on day 1 of first apheresis, x10 3 /ml 14 ( ) 14.7 (4.1-43) 5.1 ( ) p< Median CD34+ cells in peripheral blood on day of apheresis /ml 81.2 ( ) ( ) 61.6 ( ) p<0.015 Median CD34+ cells x10 6 /kg NS 5.8 ( ) 8.4 ( ) 4.0 ( ) per apheresis, (range) (p=0.1) *No statistically significant difference among treatment groups were seen in terms of number of apheresis procedures needed to collect an adequate number of CD34+ cells.

7 Colony stimulating factors page 7 Kim et al 16 retrospectively compared the efficacy of lenograstim and filgrastim on haematological recovery following an autologous peripheral blood stem cell transplant (PBSCT) with high dose chemotherapy. Patients (n=85) were included for analysis if they had started G-CSF one day after transplantation. The primary efficacy parameter was to determine the number of days required to reach an ANC of 0.5x10 9 /L, a WBC count of 4x10 9 /L and a platelet count of 20x10 9 /L for 3 consecutive days. Secondary efficacy parameters included the number of days with neutropenic fever above 38.3 C or 38 C for more than 3 hours. The majority of patients had non-hodgkin s lymphoma or breast cancer. The average number of previous chemotherapy cycles were 4.1 ± 1.6 cycles in the lenograstim 250mcg/day group (n=49) and 5.1 ± 2.2 cycles in the filgrastim 300mcg/day group (n=36). Results are in table 4. Patients received a fixed dose of G-CSF in this study rather than a weight-based dose, which is more usual. This may have influenced the results although the authors conclude that a fixed dose offers a similar outcome. The mean treatment duration was statistically significantly shorter with filgrastim (12.5 ± 7.0 days) compared with lenograstim (18.6 ± 8.5 days, p=0.001). Blood cell recovery within 2 weeks of G-CSF therapy was achieved in 72% of patients on filgrastim compared with 39% on lenograstim. Neutropenic fever lasted for longer in the lenograstim group but the difference was not statistically significant. A larger prospective study is required to confirm and evaluate the efficacy of these G-CSFs in PBSCT. Table 4: Retrospective comparison of lenograstim vs. filgrastim. 16 Recovery (days ±SD) Lenograstim (n=49) Filgrastim (n=36) P value ANC >0.5x10 9 /L 19 ± ± WBC >4x10 9 /L 29.9 ± ± Platelets >20x10 9 /L 27.2 ± ± G-CSF admin (days ±SD) 18.6 ± ± Hospitalisation (days ±SD) 32 ± ± Febrile (days ±SD) 6.7 ± ± IV antimicrobials (days ±SD) 29.1 ± ±

8 Colony stimulating factors page 8 Pegfilgrastim The reviewed pegfilgrastim in October 2003 for the London Cancer New Drugs Group. The review concludes that studies comparing pegfilgrastim with filgrastim have found the two to be equally effective, therefore the most notable advantage of pegfilgrastim appears to be that it is given as a single dose rather than multiple daily injections. 20Viewing/viewRecord.aspx?id= The Cancer New Drug Groups recommendation (May 2007) is: The currently licensed pegfilgrastim presentation represents a longer duration of treatment than is common in current UK clinical practice. There is no robust evidence to suggest that it offers an advantage in terms of clinical outcomes over filgrastim and therefore, its routine replacement in place of filgrastim is not recommended. However, in certain clinical settings its use may be cost-effective. Such indications should be defined and agreed locally. 20Viewing/viewRecord.aspx?id= Schipppinger et al 17 compared the efficacy of filgrastim or lenograstim with pegfilgrastim in reducing FN in 118 patients treated for breast cancer with epirubicin and either docetaxel (n=107) or paclitaxel (n=11). The study was retrospective. Prophylactic G-CSF was administered to all patients. Filgrastim (30-48MU/ day) or lenograstim (34MU/day) was given to 82 patients and another 6 patients received both G-CSFs. Pegfilgrastim (6mg once per cycle) was administered to 30 patients. Each patient received a median 6 cycles of G-CSF. Results are in table 5. Eighty percent of FN occurred in the first 2 cycles. The rates of FN were not statistically different in the treatment groups, though there was a statistically nonsignificant trend towards a lower frequency of FN in chemotherapy cycles which had pegfilgrastim support. There was also a trend towards fewer delays in chemotherapy administration in treatment cycles with pegfilgrastim. A limitation of this study was that as the data was retrospectively evaluated, some patients with transient febrile temperatures without other symptoms may not have informed their oncologist. Lane et al 18 retrospectively analysed data from patients receiving hyper-cvad chemotherapy ( A cycles of cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with B cycles of high dose methotrexate and cytarabine). Patients receiving pegfilgrastim were matched with those receiving G-CSF (filgrastim or lenograstim) for chemotherapy cycle, prior chemotherapy, dose of cytarabine, age, diagnosis (acute lymphoblastic leukaemia (ALL) or non-hodgkins lymphoma (NHL)) and presence of bone marrow involvement. A single dose of pegfilgrastim 6mg was given on discharge 24 hours following completion of chemotherapy. Alternately G-CSF 5mcg/kg/day was started 24 hours following completion of chemotherapy and continued Table 5: Results of the retrospective study of filgrastim or lenograstim vs. pegfilgrastim. 17 Filgrastim/ lenograstim (n=88) Pegfilgrastim (n=30) P value Febrile neutropenia in cycle 1 8 pts (9.1%) 1 pt (3.3%) Febrile neutropenia episodes in total Dose reductions due to toxicity Delays in chemotherapy delivery 13 (2.7%) of 476 treatment cycles 5 treatment cycles (1%) 21 treatment cycles (4.3%) 2 (1.2%) of 172 treatment cycles treatment cycles (2.8%) treatment cycles (1.7%) 0.157

9 Colony stimulating factors page 9 daily until the ANC>2000/mL on two consecutive days or >5000/mL. The primary endpoint was the duration of grade IV neutropenia (ANC<500/mL). Secondary endpoints included time from starting chemotherapy to neutrophil recovery, incidence of FN, positive blood cultures and delay in subsequent chemotherapy. The authors hypothesised that there would be a significant difference between pegfilgrastim and other G-CSFs, and assuming 80% power, 126 cycles would be required to detect a 1 day difference in the duration of grade IV neutropenia. There were 124 pegfilgrastim-supported cycles in 43 patients and 124 G-CSF-supported cycles in 38 patients. Results are shown in table 6. There were no significant differences in the duration of grade IV neutropenia, time to neutrophil recovery, incidence of febrile neutropenia, positive blood cultures or delay in the next chemotherapy cycle. Although this study was not randomised, matched pairs analysis was used based on factors known to influence neutrophil recovery after chemotherapy. Potential bias could have been caused by funding restrictions for pegfilgrastim which was only administered at completion of chemotherapy, possibly selecting for a more robust patient population, and NHL patients were not matched for lymphoma sub-classification or stage. Economic considerations Esser et al carried out a systematic review of economic evaluations of the prophylaxis and therapy of chemotherapy-induced neutropenia in patients with cancer. 19 The following indications of G-CSF (filgrastim or lenograstim) were considered: prophylaxis of neutropenic complications in patients receiving standard dose chemotherapy post-transplant prophylaxis of neutropenic complications in patients receiving high dose chemotherapy followed by peripheral blood stem cell transplant Table 6: Results of the retrospective pegfilgrastim vs. G-CSF study. 18 Pegfilgrastim Filgrastim/ lenograstim P value Median duration of grade IV neutropenia (all cycles) 4 days 4 days cycle A 2 days 2 days cycle B 6 days 6 days 0.70 Median time to ANC>500/ ml, all cycles 13 days 14 days 0.75 Median time to ANC>2000/ ml, all cycles 14 days 14.5 days 0.27 Incidence of FN 29% 38% 0.16 Positive blood cultures 11% 12% 0.85 Incidence of grade IV neutropenia 84% 76% 0.13 Delays in subsequent chemo cycles 44% 47% 0.75

10 Colony stimulating factors page 10 (PBSCT) or bone marrow transplant (BMT) and treatment of patients with established chemotherapy-induced febrile neutropenia. At least one common parameter of effectiveness, such as incidence of FN or duration of neutropenia had to be reported. For all studies the predominating costs were the average total direct costs per patient, for both treatment and control groups. Fourteen studies of G-CSF for prophylaxis in patients with standard dose chemotherapy were identified and intermediate endpoints, e.g. duration of neutropenia, were used to determine the effectiveness of their treatment. Although the majority of the studies showed statistically significant decreases in duration or rate of neutropenia, time/duration of hospitalisation and/or rate of febrile neutropenia in the G-CSF groups (though not all reported significance tests), only six studies presented mean cost-savings in this group of 43% (range 3.3%- 50.3%). In the other eight studies the use of G-CSF increased costs by 10.3%-567.7%. The results are difficult to interpret due to the differences in study design and treatment protocols used. Seven studies of primary prophylaxis with G- CSF in patients undergoing BMT were identified. Most studies had patients with both solid and haematological tumours. Costs calculated covered the time period between BMT and discharge from hospital. Wide ranges in the incidences of neutropenia were less likely as all protocols were myeloablative. All studies reported decreased time of neutropenia and duration of hospitalisation; the reductions were statistically significant in four and three trials respectively but not in one other trial, and two did not report significance tests at all. Six studies demonstrated cost savings of between 2.9% and 14.5%. There were also seven studies in patients undergoing PBSCT. There were six studies with a statistically significant decrease in the time of neutropenia. Duration of hospitalisation was significantly reduced in all six, statistically significantly in three. The seventh study reported a non-statistically significant increase in both the time of neutropenia and duration of hospitalisation. Cost savings ranging from 2.7% % were seen in four of the studies. Costs were increased in the other three studies by 3.8% %. Neutropenia is more likely to be detected in randomised controlled trials (RCTs) because of the closer monitoring of body temperature and haematological paramaters, and these type of trials are recommended for economic evaluations. This evaluation used studies with a variety of methodologies, such as RCTs, chart reviews, meta-analysis, and prospective studies. In retrospective studies there may be potentially different conditions between the treatment and control groups which might influence the outcome and which are not related to the study question, such as better home care conditions resulting in early discharge from hospital. In most of the papers the economic evaluations were more of an appendix to the results rather than an independent analysis and did not evaluate definitive endpoints such as survival times/rates. Whilst it is clear that the use of G-CSF is effective in reducing the risk of febrile neutropenia there is no clear evidence that it benefits patients in terms of overall survival or diseasefree survival. 19 The efficacy of G-CSF when used for primary prophylaxis after standard dose chemotherapy did not always result in cost-savings as the costs of the drug were not offset by the reduced incidence of febrile neutropenia and shorter stay in hospital seen in most studies. In the post-transplant setting, after high dose chemotherapy, G-CSF can shorten the period of neutropenia and reduce associated complications. Cost-savings are possible but the results in this evaluation were hampered by the fact that in most studies the patient population was heterogenous, mixing patients with different haematological malignancies as well as solid tumours. Safety/tolerability The most common side effect reported is bone pain, which occurs in 20-30% of patients. 7 Other side effects include gastro-intestinal disturbances, headache, asthenia, fever and musculoskeletal pain. 5 Bone and musculoskeletal pain is attributed to the rapid proliferation of myeloid cells in the bone marrow. 20 CSFs should be used with caution in patients with pre-malignant or malignant myeloid conditions. 5

11 Colony stimulating factors page 11 Summary Myelosuppression with neutropenia is the most important dose limiting toxicity of chemotherapy and can compromise dose-intensity. The development of fever during neutropenia can represent a life-threatening condition requiring hospitalisation and broad-spectrum antibiotics. FN tends to occur early in the course of chemotherapy and is associated with a number of factors, including treatment intensity, age and disease. The economics of G-CSFs is determined mainly by the cost associated with the management of FN and its consequences, and is complicated by the fact that the length of hospitalisation can vary greatly. 21 Reference List (1) Dale DC. Colony-stimulating factors for the management of neutropenia in cancer patients. Drugs 2002; 62(Suppl 1):1-15. (2) Dale DC. Advances in the use of colony-stimulating factors for chemotherapy-induced neutropenia. Journal of Supportive Oncology 2005; 3(2 (Suppl 1)): (3) NCCN Clinical Practice Guidelines in Oncology: Myeloid growth factors. National Comprehensive Cancer Network myeloid_growth.pdf (4) European Society for Medical Oncology. Hematopoietic growth factors: ESMO recommendations for the application. Ann Oncol 2007; 18 (Suppl 2):ii89-ii91. (5) British National Formulary 53 March London: Martin J, editor British Medical Association & Royal Pharmaceutical Society of Great Britain., (6) Summary of Product Characteristics. NEULASTA. Date of revision of the text 3 January Amgen Ltd (7) Gabrilove JL. An analysis of current neutropenia therapies, including pegfilgrastim. Clinical Cornerstone 2006; 8(S5):S19-S28. (8) Summary of Product Characteristics. Neupogen 30MU and 48MU solution for injection. Date of revision of text 12 Jan Amgen Ltd (9) Summary of Product Characteristics. Neupogen Singleject 30MU and 48MU. Date of revision of the text 12 January Amgen Ltd (10) Summary of Product Characteristics. Granocyte 13 million IU, and 34 million IU. Date of revision of the text 29 October Chugai Pharma UK Ltd emc.medicines.org.uk (11) British Society for Haematology. Guidelines on the use of colony-stimulating factors in haematological malignancies. Br J Haematol 2003; 123(22):33.

12 Colony stimulating factors page 12 (12) Smith TJ, Khatcheressian J, Lyman GH Update of recommendations for the use of white blood cell growth factors: An evidence-based clinical practice guideline. J Clin Oncol 2006; 24(19):1-19. (13) Martin-Christin F. Granulocyte colony stimulating factors: How different are they? How to make a decision? Anticancer Drugs 2001; 12: (14) Bonig H, Silbermann S, Weller S et al. Haematopoietic growth factors. Glycosylated vs non-glycosylated granulocyte colony-stimulating factor (G-CSF) - results of a prospective randomised monocentre study. Bone Marrow Transplant 2001; 28: (15) Kopf B, De Giorgi U, Vertogen B et al. A randomized study comparing filgrastim versus lenograstim versus molgramostim plus chemotherapy for peripheral blood progenitor cell mobilization. Bone Marrow Transplant 2006; 38: (16) Kim IH, Park SK, Suh OK. Comparison of lenograstim and filgrastim on haematological effects after autologous peripheral blood stem cell transplanation with high-dose chemotherapy. Curr Med Res Opin 2003; 19(8): (17) Schippinger W, Holub R, Dandachi N et al. Frequency of febrile neutropenia in breast cancer patients receiving epirubicin and docetaxel/paclitaxel with colony-stimulating growth factors: A comparison of filgrastim or lenograstim with pegfilgrastim. Oncology 2006; 70: (18) Lane SW, Crawford J, Kenaly M. Safety and efficacy of pegfilgrastim compared to granulocyte colony stimulating factor (G-CSF) supporting a dose-intensive, rapidly cycling antimetabolite containing chemotherapy regimen (Hyper-CVAD) for lymphoid malignancy. Leuk Lymphoma 2006; 47(9): (19) Esser M, Brunner H. Economic evaluations of granulocyte colony-stimulating factor in the prevention and treatment of chemotherapy-induced neutropenia. Pharmacoeconomics 2003; 21(18): (20) Heuser M, Ganser A. Colony-stimulating factors in the management of neutropenia and its complications. Ann Hematol 2005; 84: (21) Lyman GH, Kuderer NM. The economics of the colony-stimulating factors in the prevention and treatment of febrile neutropenia. Crit Rev Oncol Hematol 2004; 50: Document written by Alexandra Denby, Regional MI Manager, London Medicines Information Service, Northwick Park Hospital, for the London Procurement Programme. The LNDG would like to thank Dr Stephen MacKinnon, Royal Free Hospital, for his comments on the review.

13 Colony stimulating factors page 13 Appendix 1. Examples of chemotherapy regimens with a high risk of febrile neutropenia (>20%) 3 [This list is not comprehensive there are other agents/regimens that have a high risk factor of febrile neutropenia.] Bladder TC: paclitaxel, cisplatin MVAC: methotrexate, vinblastine, doxorubicin, cisplatin Breast AT: doxorubicin, paclitaxel TAC: docetaxel, doxorubicin, cyclophosphamide Cervical TC: paclitaxel, cisplatin Gastric DCF: docetaxel, cisplatin, fluorouracil (5FU) Head and neck Paclitaxel, ifosfamide, mesna, cisplatin Non-Hodgkins Lymphoma CHOP-14: cyclophosphamide, doxorubicin, vincristine, prednisolone VAPEC-B: vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide, bleomycin A(N)CVB: doxorubicin (or mitozantrone), cyclophosphamdie, vindesine, bleomycin DHAP: dexamethasone, cisplatin, cytarabine ESHAP: etoposide, methylprednisolone, cisplatin, cytarabine Non-Small Cell Lung Cancer VIG: gemcitabine, ifosfamide, vinorelbine DP: docetaxel, carboplatin Ovarian Topotecan Paclitaxel Docetaxel Pancreatic Gemcitabine, docetaxel Prostate Docetaxel, prednisolone Mitozantrone, prednisolone Sarcoma MAID: mesna, doxorubicin, ifosfamide, dacarbazine Doxorubicin Doxorubicin, ifosfamide Small Cell Lung Cancer CAE: cyclophosphamide, doxorubicin, etoposide Topotecan Topotecan, paclitaxel Testicular VIP: vinblastine, ifosfamide, cisplatin