3Granulocyte Colony StimulatingFactor• Endogenous G-CSF is produced in Marrowstromal cells, Neutrophils, Monocytes, T cells,Endothelial cells etc.• It regulates the production, maturation, andfunction of the neutrophil lineage.• G-CSF in blood ranges from 20 to 100 pg/mL inhealthy individuals and rises inversely withneutrophil concentration.• Patients who are bacteremic and neutropeniccan have serum levels of G-CSF exceeding2,000 pg/mL
4rHu-G-CSF• Recombinant Human Granulocyte Colony-stimulating Factor.• "Filgrastim, a recombinant proteinproduced in Escherichia coli, has anamino acid sequence identical toendogenous G-CSF, with a littlealteration*."• Other forms available are, Pegfilgastrim,lenograstim& nartograstim.*the exception of the addition of an N-terminal methionine and absence of glycosylation
5Filgastrim• A single, non-glycosylated, polypeptidechain that contains 175 amino acids andhas a molecular mass of 18.8 KD.• Half-life ~ 3.5 hrs (IV or SC)• Clearance increases as blood neutrophilconcentration increases.(negative feedback mechanism)Pegfilgrastim is a polyethylene glycol-conjugated version of filgrastim designed forlonger half-life, thereby necessitating fewer injections. ~33 hours
6Effects of Filgastrim• Accelerates production through reductionof transit time from stem cell to matureneutrophil.• Inhibition of neutrophil apoptosis.• Stimulates the entry of quiescent stem andprogenitor cells into cell cycle.
7Side Effects of Filgastrim• Most common is mild to moderate bonepain.• Splenomegaly is reported in chronic use.• Transient Dyspnea, pulmonary infiltrates.• Transient neutropenia in iv administration.
9• Highlights:– Primary Prophylaxis– Secondary Prophylaxis– To enable delivery of dose dense chemotherapy– Adjunct to stem cell Transplant– Delayed engraftment graft failure– AML / ALL– Myelodysplastic Syndromes
10Primary Prophylaxis• Administered in first cycle of treatment.– Regimen with more than 20% incidence of FN– A decrease in dose intensity compromisingsurvival/cure– Patient at risk of serious complications fromFN (age, low PS, Infection, prior large RT field)• Primary prophylaxis results in relative riskreduction of FN by 50 - 90%FN, febrile neutropenia
11Secondary Prophylaxis• "Secondary prophylaxis with CSFs isrecommended for patients whoexperienced a neutropenic complicationfrom a prior cycle of chemotherapy (forwhich primary prophylaxis was notreceived), in which a reduced dose maycompromise disease-free or overallsurvival or treatment outcome. In manyclinical situations, dose reduction or delaymay be a reasonable alternative."
12Secondary Prophylaxis• "Secondary prophylaxis with CSFs isrecommended for patients whoexperienced a neutropenic complicationfrom a prior cycle of chemotherapy (forwhich primary prophylaxis was notreceived), in which a reduced dose maycompromise disease-free or overallsurvival or treatment outcome. In manyclinical situations, dose reduction or delaymay be a reasonable alternative."
13Secondary Prophylaxis• "No definitive conclusions can be drawnregarding the benefits of secondaryprophylaxis on survival, quality of life, orcost. Randomized trials to properly test thehypothesis are required."
14Therapy for febrile Neutropenia• CSFs should not be routinely used asadjunctive treatment with antibiotic therapy.• Should be only considered in:– Expected prolonged (> 10 days) and profound(<100/cmm) neutropenia,– Age greater than 65 years,– Uncontrolled primary disease,– Pneumonia, hypotension and multiorgandysfunction, sepsis, invasive fungal infection,– Being hospitalized at the time of thedevelopment of fever.
15To Increase ChemotherapyDose-Density• Survival benefit shown in a few specificsettings (eg, node-positive breast cancer)• 2,005 patients randomly assigned to receive one of the following:(I) sequential A × 4 → T × 4 → C × 4,doses 3 wkly,(II) sequential A × 4 → T × 4 → C × 4 doses 2 wkly with filgrastim,(III) concurrent AC × 4 → T × 4 every 3 weeks,(IV) concurrent AC × 4 → T × 4 every 2 weeks with filgrastim.Four-year DFS was 82% for the dose-dense regimens and 75% for theothersCitron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versusconventionally scheduled and sequential versus concurrent combinationchemotherapy as postoperative adjuvant treatment of node-positive primarybreast cancer: First report of Intergroup Trial C9741
16Not Recommened in• Treatment of established neutropenia inafebrile patients.• Use of CSF to increase dose intensity.• Concurrent administration of CSFs withchemotherapy and radiation therapyshould be avoided.
17Initiation, Duration, Dosing, andAdministration• Should be given 24 to 72 hours after theadministration of myelotoxic chemotherapy.• CSF should be continued ANC reachesat least 2,000/mmc.• In adults, the recommended : 5μg/kg/d
18• Recommendations:– Patient with increased risk of FN.– Regimen with increased risk of FN.– To support intensive chemotherapy regimens.– In patients with existing FN. (marginallyimproves the time spent in hospital and timeto recover from neutropenia)## J Clin Oncol. 2005 Jun 20;23(18):4198-214.Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis ofrandomized controlled trials.Clark OA, Lyman GH, Castro AA, Clark LG, Djulbegovic B.Hospital Celso Pierro/PUC-Campinas, Sao Paulo, Brazil.