BY lecturer / Hend Hamdey Rashed Clinical oncology & Nuclear medicine

 The treatment of many tumors with chemotherapy is associated with a high rate of infection due to neutropenia.  This will lead to increased costs due to hospitalization, IV antibiotics and reduced quality of life for the patient and reduced intensity of chemotherapy.  Reduction or delays to chemotherapy dosing may impact the success of treatment especially when treatment intent is curative.

 G-CSF is a cytokine normally produced by the human body itself.  They act like hormones and neuro-transmitters and are involved in a series of variety of immunological, inflammatory, and infectious diseases.  The type of G-CSF which is given as treatment is not from human beings but is safely made by genetic engineering to produce an identical substance which acts like the naturally occurring cytokine.

 Primary prophylaxis.  Secondary prophylaxis.  Supportive measurments.  To mobilise Peripheral Blood Progenitor Cells.  Acute myeloid leukaemia.

1. Primary Prophylaxis: not G-CSF is not recommended with most first line therapies. It is used in: risk patients dose reduction or delays  Reducing and preventing chemotherapy- associated neutropenia in at risk patients and/or where dose reduction or delays would compromise outcomes. curative 2 categories:  Primary prophylaxis should only be given to patients receiving chemotherapy with curative intent. so it is recommended in 2 categories:

 Patients receiving myelotoxic chemotherapy with curative intent and which has a documented incidence rate of Febrile neutropenia (FN) of > 20%.  Patients receiving myelotoxic chemotherapy with curative intent and which has a documented incidence rate of FN of 10 – 20% AND one or more of the following pre- disposing patient risk factors:

1) Pre-existing neutropenia due to disease infiltration of bone marrow or other aetiology. 2) Age > 65 years. 3) Advanced disease stage. 4) Poor performance status. 5) Previous episodes of febrile neutropenia whilst receiving earlier chemotherapy of a similar or lower dose intensity. 6) Poor renal function. 7) liver dysfunction, esp. elevated billirubin level.

8) Previous irradiation to large volume of bone marrow. 9) Poor nutritional status. 10) Active infections or increased risk of infections (e.g. presence of open wounds). N.B If a neutropenic complication occurs when using primary prophylaxis a dose reduction or a change in treatment should be considered.

Myelotoxic Chemotherapy  ESHAP, DHAP. FN > 20%  Regimens for AML. FN > 20%  FEC-T.  Carboplatin & Etoposide; CAV; ECX; EOX.  Folfiri.  R-CHOP.  Topotecan; Vinorelbine & Cisplatin  BEB 360, BEB 500.  TPF. FN 10-20% FN 10-20%

2. Secondary prophylaxis:  Reducing and preventing future neutropenia in patients with a prior sever neutropenic event, prolonged neutropenia or febrile neutropenia, with or without dose delay where dose reduction or delays would compromise outcomes.  Secondary prophylaxis should NOT be used in the case of palliative chemotherapy unless neutropenic sepsis occurs after a suitable dose reduction has been made.

Possible clinical contexts for secondary prevention might include:-  Adjuvant chemotherapy.  Chemotherapy for germ cell tumours.  Elderly patients with high grade NHL.  Dose escalated or intensive schedules for Hodgkin’s and NHL.  AML following consolidation treatment.  AML following induction treatment if appropriate to reduce hospital stay and antibiotic use.  ALL following intensive phases of therapy.  In patients who have previously experienced episodes of complicated neutropenia.

3. Supportive management(therpeutic use) 3. Supportive management (therpeutic use) of prolonged neutropenia or severe neutropenic sepsis. G-CSF should not be routinely prescribed for the treatment of patients with uncomplicated febrile (duration of fever< 10 dayes) neutropenia or afebrile neutropenia. only for the following :

a. Profound febrile neutropenia: Patient is febrile and has absolute neutrophil count (ANC) < 0.1 x10 ^9/L. b. one of the following prognostic factors predictive of poor clinical outcome:  Clinically unwell with signs such as hypotension, organ dysfunction etc indicating potential risk of septic shock.  Expected prolonged duration of neutropenia ( > 10 days)

 Persistent pyrexia despite appropriate antibiotics/antifungals.  Pneumonia.  Proven or suspected invasive fungal infection.

4. To mobilise Peripheral Blood Progenitor Cells : (PBPCs) in donors (allogeneic stem cell transplantations) or patients (autologous stem cell transplantations) before collection and to stimulate stem cell proliferation after PBPC infusion or Bone Marrow Transplantation (BMT). 5. Acute myeloid leukaemia: acute lymphocytic leukaemia and some cases of myelodysplastic syndromes.

 Doses should be rounded to the nearest vial or pre- filled syringe size.  G-CSF should not be administered within 24 hours of cytotoxic chemotherapy. The recommended start date is 3 days after the administration of chemotherapy.  Treatment should be continued for 7-10 days or until neutrophils >1.0 x 10 9 /L.

A. Filgrastim: ( category 1) treatmentprophylaxis  1st line for treatment and prophylaxis of chemotherapy induced neutropenia.  5mcg/kg once daily by subcutaneous injection. Doses should be rounded up or down to the most appropriate vial / syringe size (300mcg or 480mcg).  It is common practice for a daily dose of 300mcg to be given. However, patients with weight > 90kg may be given the 480mcg vial/syringe either initially or if they have an inadequate response to the standard dose.  Started h after completion of chemotherapy untill post-nadir ANC recovery to normal or near normal. N.B. ADMINISTRATION of G.CSF on same day as CTH is not recommended.

B. Peg-filgrastim (Neulasta®) : ( category 1) prophylaxis only  For prophylaxis only (primary and secondary prophylaxis).  One dose S/C 6 mg (Pre-filled syringes 6 mg in 0.6ml).  Started hr after chemotherapy.  The drug acquisition cost of pegylated G-CSF (pegfilgrastim) is considerably higher than daily G- CSF.  Use of pegfilgrastim should be restricted to patients where the risk of neutropenia from chemotherapy is likely to be prolonged (TAC, FEC-T, and TIP)

C. Lenograstim: (category 2B)  150 mcg/m2 once daily by S.C.  Doses should be rounded up or down to the most appropriate vial / syringe size (105 mcg and 263 mcg).  It is common practice for a daily dose of 263mcg to be given, but patients with BSA > 1.8 m2 may be given an additional 105 micrograms (i.e. 368 micrograms total) daily, either initially or if they have an inadequate response to the standard daily dose.

G-CSF is not recommended within 24 hours of chemotherapy.  G-CSF is not recommended within 24 hours of chemotherapy.  A reasonable starting point for lenograstim and filgrastim is to start not less than 24 hours and not more than 72 hours after cytotoxic treatment is completed.  G-CSF injections should continue until the neutrophil count has recovered to > 1.0 x 10^9 /L on two consecutive days.  This will normally require a minimum of 5 days of treatment, although consideration should be given to a minimum of 7 days for more myelosuppressive regimens.

G-CSF is usually well tolerated  localized reactions may be observed at the injection site.  Musculo-skeletal pain  Headaches may be in some patients. Patients should be warned of these effects. This can be minimised by the use of mild analgesia e.g. Paracetamol, Non-Steroidal Anti-Inflammatory Drugs. Patients should be warned of these effects. This can be minimised by the use of mild analgesia e.g. Paracetamol, Non-Steroidal Anti-Inflammatory Drugs.  Rare side effects: transient hypotension, thrombocytopenia, disturbances in liver enzymes and serum uric acid, splenic enlargement.

 G.CSF is used as 1ry,2ry prophylaxis and for supportive ttt of FN.  Primary prophylaxis should only be given to patients receiving chemotherapy with curative intent.  G-CSF is not recommended with most first line therapies.  If a neutropenic complication occurs when using primary prophylaxis a dose reduction or a change in treatment should be considered.  Secondary prophylaxis should NOT be used in the case of palliative chemotherapy unless neutropenic sepsis occurs after a suitable dose reduction has been made.  G-CSF is not recommended within 24 hours of chemotherapy.  Started h after completion of chemotherapy untill post-nadir ANC recovery to normal or near normal.  Treatment should be continued for 7-10 days or until neutrophils >1.0 x 10 9 /L.  Peg-filgrastim (Neulasta®) is used For prophylaxis only (primary and secondary prophylaxis).  G-CSF is usually well tolerated with less side effects.