CSFs

1

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2
CSFs

• Therapeutic benefits.
• Side effects.
• Guidelines.

3
Therapeutic benefits of CSFs

• Reduces the risk of febrile neutropenia?

4
Reduced risk of febrile neutropenia

• Administration of CSFs result in a 50 risk
  reduction of developing febrile neutropenia
  (NCCN Practice Guidelines in Oncology v.2.2005
  (Overview).

5
Chemotherapy Induced Neutropenia
Planned DI G-CSF
Primary prophylaxis
Crawford J. et al. N Engl J Med 1991325164-170.
Purpose
Testing the hypothesis and clinical implications
of chemotherapy-related neutropenia reduction in
patients with cancer.
Patients and methods
211 SCLC patients participated a double-blind,
randomized, placebo-controlled trial of G-CSF
support to 6 cycles of Cyclophosphamide,
Doxorubicin, and Etoposide.
P lt 0.001
6
Risk of febrile neutropenia with and without
GCSF-results of a meta-analysis

• Kuderer NM et al. J Clin Oncol 25 3158-67,
  2007 (a meta-analysis of 15 controlled trials
  (n3182 pts) using GCSF before the onset of fever
  or neutropenia following systemic chemotherapy
  for solid tumors or lymphomas)

Mean risk for FN
RR0.54---Plt,0001
7
Therapeutic benefit of CSFs

• Shortens the length of neutropenia and febrile
  neutropenic episode, and reduces the period of
  hospitalization and IV antibiotics?

8
(CDE Cyclophosphamide, Doxorubicin, Etoposide)
Trillet-Lenoir V. et al. Eur J Cancer
199329A(3)319-324.
9
Neupogen reduces the duration of
hospitalizationand i.v. antibiotic use in
patients with AML
p0.0001
30 20 10 0
p0.0001
Median duration (days)
Hospitalisation i.v. antibiotics
Placebo
Neupogen
Adapted from Heil G et al. Blood 1997
10
Therapeutic benefit of CSFs

• Reduces the risk of documented infection?

11
Risk of documented infection-results of a
meta-analysis

• Lyman GH et al. Am J Med 112 406-11, 2002 (a
  meta-analysis of 8 controlled trials (n1144
  pts)7 trials reported information on the
  documented infection

• Odds ratio 0.51 (p 0.001)

12
Therapeutic benefit of CSFs

• Reduces the risk of documented infection-related
  mortality?

13
Risk of documented infection-related mortality-
results of a meta-analysis

• Kuderer NM et al. J Clin Oncol 25 3158-67,
  2007 (a meta-analysis of 12 controlled trials
  (n3122 pts) using GCSF before the onset of fever
  or neutropenia following systemic chemotherapy
  for solid tumors or lymphomas)

(RR0.55 P0.018) reduction in
infection-related mortality was significant
among studies of filgrastim but did not reach
statistical significance with lenograstim or
pegfilgrastim.
14
Therapeutic benefit of CSFs

• Reduces the need for dose reductions and
  treatment delays ( reduced dose-intensity)?

15
Relative Dose Intensity (RDI)

• Kuderer NM et al. J Clin Oncol 25 3158-67, 2007
  (a meta-analysis of 10 controlled trials using
  GCSF before the onset of fever or neutropenia
  following systemic chemotherapy for solid tumors
  or lymphomas)

P 0.001
16
Therapeutic benefit of CSFs

• Enables full-dose following a prior cycle with
  febrile neutropenia?

17
Full-dose chemotherapy following a prior cycle
with febrile neutropenia

• Metastatic small cell lung cancer treated with a
  combination of cyclophosphamide, doxorubicin, and
  etoposide
• Patients who developed neutropenic fever during
  the first cycle received the second cycle with
  full dose G-CSF
• Only 23 of these patients developed neutropenic
  fever during the second cycle.
• (Crawford J et al. N Engl J Med 1991 325
  164-170)

18
Full-dose chemotherapy with GCS-F support
following a prior cycle with febrile neutropenia-
Dept Oncology, Rambam Medical Center experience

• Since September 1995, a standard policy in
  patients treated with an intent for cure or for
  durable complete remission.
• filgrastim (neupogen)300 or 480 mcg/day for
  10 days

19
Eligibility Criteria

• Neutropenic fever was not associated with
  life-threatening infection.
• There were no other dose-limiting toxicities.
• Age 75 or less performance status (WHO) 0-2

20
Diagnosis in 51 patients who developed
neutropenic fever (without GCSF)(age22-75,media
n 47)
21
Chemotherapy protocols (n51)
CHOP/CHOP-like 14
CAF 6
Other ADM-cont 4
MOPP/ABV 4
CMF 9
BEP 8
Cisplatin/Etoposide 6
22
Next cycle (n1) (full dose with GCSF support in
all pts)

• Number of pts51
• Neutropenic fever..8/51(16)
• Days of IV antibiotics..4.5 (median),(3-7)
• Evidence of bacterial infectionnone

23
Next cycle (n2) (full dose with GCSF support in
all pts)

• Number of pts41
• Neutropenic fever..4/41 (10)
• There was no drug-related death associated with
  either cycle.

24

• A policy of full-dose chemotherapy with
  secondary G-CSF support in pts who develop
  febrile neutropenia following moderately
  myelotoxic chemotherapy is relatively safe and
  feasible.
• Haim N, Shulman K, Goldberg H, Tsalic M. Med
  Oncol 22 229-32, 2005

25
Therapeutic benefit of CSFs

• Enables administration of dose-dense therapy?

26
Dose-intensity Dose-density

• 90 mg/m2 every 3 wks vs.
• 30 mg/m2/week
• Both regimens have the same dose intensity.
• 30 mg/m2/week gives a greater dose
• density than the 3-weekly administration.

27
Tolerability of dose-dense chemotherapy with
GCSF-breast cancer

• Citron ML et al. J Clin Oncol 21 1431-39,
  2003
• AC (doxorubicin 60 mg/m2 cyclophosphamide 600
  mg/m2)
• q 3 wks or q 2 weeks filgrastim days 3-10 at
  5 mcg/kg rounded to either 300 or 480 mcg.
• Treatment was well tolerated. Severe neutropenia
  was less frequent in patients who received the
  dose-dense regimens (6 vs. 33).

28
Dose-dense CHOP (CHOP-14)

• Cyclophosphamide 750 mg/m2 IV, day 1
• Adriamycin 50 mg/m2 IV , day 1
• Vincristine 1.4 mg/ m2 IV , day 1
• Dexamethasone 20 mg IV, day 1
• Prednisone 100 mg PO, days 2-5
• Cycles are repeated every 2 weeks.
• GCSF is given on days 4-13.
• Pfreundschuh M et al. Blood 104 626-33, 2004
  (young pts)
• Pfreundschuh M et al. Blood 104 634-41, 2004
  (elderly pts)

29
Therapeutic benefit of CSFs

• Enables administration of high-dose
  chemotherapy (without peripheral blood stem cell
  support)?

30
CHOP Mega CHOP in aggressive non Hodgkins
lymphomas

• CHOP
• Cyclophosphamide 750 mg/m2 IV, day 1
• Adriamycin 50 mg/m2 IV , day 1
• Vincristine 1.4 mg/ m2 IV , day 1
• Prednisone 100 mg PO, days 1-5
• (cycles repeated every 3 weeks)
• Mega CHOP
• Cyclophosphamide 1500mg/m2 IV (1hr), days
• 1 and 2
• Mesna 200 mg/m2 X 4, IV, day 1 200 mg/m2 X 8,IV
  day 2
• Adriamycin 50 mg/m2 IV , day 1
• Vincristine 1.4mg/m2 (max. 2mg) IV, day 1
• Prednisone 100 mg PO , days 1-5
• (cycles repeated every 3 weeks)

31
Therapeutic benefit of CSFs

• Improves the outcome of febrile neutropenia
  when started at the time of established
  neutropenia?

32
ASCO 2000 Guidelines for GCSF Therapy- Febrile
Patients with neutropenia (2000)

• The results of 8 randomized trials provide
  strong and consistent support for the
  recommendation that G-CSFs should not be
  routinely used as adjunct therapy for the
  treatment of uncomplicated fever and
  neutropenia.
• GCSF should be considered in pts with complicated
  neutropenia and fever.

33
CSFs for chemotherapy-induced febrile
neutropenia a meta-analysis (Clark OAC et al. J
Clin Oncol 23 4198-4214, 2005) (13 trials with
a total of 1,518 pts)

• Significantly reduces the length of
  hospitalization (HR0.63P0.006)
• Significantly reduces the time to neutrophil
  recovery (HR0.32Plt0.0001).
• A marginally significant result was obtained for
  the use of CSF in reducing infection-related
  mortality (3.1 VS. 5.7 HR0.51 p0.05).

34
Therapeutic benefit of CSFs

• Improves treatment outcome?

35

• ESMO recommendations for the application of
  haematopoietic growth factors (hGFs). Ann Oncol
  12 1219-20, 2001
• No high level evidence for increase in
  survival

36
CSFs in lymphoma-meta-analysis

• Bohlius J et al. Cochrane Database Syst Rev.
  3 CD003189, 2004
• (12 eligible randomized controlled trials with
  1823 pts)
• -----reduced the risk of neutropenia, febrile
  neutropenia and infection.
• However, there is no evidence that CSFs provide a
  significant advantage in terms of CR, freedom
  from treatment failure or overall survival.

37
Therapeutic benefit of CSFs

• Enables stem cell
• mobilization ?

38

• Side effects

39
Adverse Events Bone pain

• In bone marrow bearing locations
• Usually of mild/moderate severity (15)
• Transient - controlled with oral analgesics
• Med Oncol 22 229-32, 2005
  20/51(39)severe in 8 (16)

40
Adverse Events Transient elevations in LDH,
uric acid, and alkaline phosphatase

• In LDH, and uric acid attributed to the
  proliferative effects of G-CSF on neutrophil
  precursors in the bone marrow, with increased
  cell turnover
• In alkaline phosphatase potentially secondary
  effects on bone.

41
GCSF and lung toxicity

• Pulmonary complications of GCSF are very rare
  and include cough, dyspnea, and interstitial or
  alveolar pulmonary edema. Few cases of acute
  respiratory distress syndrome have been reported.
  

42
A possible interaction between bleomycin and GCSF

• Martin WG et al. J Clin Oncol 23 7614-20,
  2005
• GCSF was associated with increased lung
  toxicity in Hodgkins disease patients treated
  with bleomycin containing drug combinations).
• (GCSF may enhance bleomycin-induced lung
  toxicity by a mechanism that probably involved
  neutrophils).
• On the other hand
• Saxman SB et al. Chest 111 657-60, 1997
• There is no increase in pulmonary toxicity
  with co-administration of G-CSF and bleomycin
  compared to bleomycin alone in pts with advanced
  germ cell tumors.

43
GCSF effect on spleen

• Spleen enlargement (Picardi M et al.
  Haematologica 88 794, 2003),
• Splenic rupture (Falzetti F et al. Lancet 353
  555, 1999 Dincer AP et al. J Pediatr Hematol
  Oncol 26 761, 2004).

44

• Guidelines for the
• use of CSFs
• guidelines cannot always account for
  individual variations among patients. They are
  not intended to supplant physician judgement with
  respect to to particular patients or special
  clinical situations.(ASCO guidelines-2006)

45
ASCO (American Society for Clinical Oncology)
Guidelines

• 2006 Update of recommendations for the use
  of white blood cell growth factors an
  evidence-based, clinical practice guidelines.
  Smith TJ et al. for the American Society of
  Clinical Oncology Growth Factor Expert Panel.
  Published ahead of print on J Clin Oncol May 8,
  2006

46
ESMO (European Society of Medical Oncology)
Guidelines

• ESMO recommendations for the application of
  haematopoietic growth factors (hGFs). Ann Oncol
  12 1219-20, 2001

47
Clinical Practice Guidelines in Oncology
Myeloid Growth Factors in Cancer Treatment,
Version 1. 2007 http//www.nccn.org
48
EORTC (European Organization for Research and
Treatment of Cancer) Guidelines

• EORTC guidelines for the use of
  granulocyte-colony stimulating factor to reduce
  the incidence of chemotherapy-induced febrile
  neutropenia adult patients with lymphomas and
  solid tumors. Aapro MS et al. Published ahead of
  print, Europ J Cancer , 2006

49

• Types of CSFs, Dosage Administration

50
Dosage and administration

• Filgrastim (Neupogen) (category 1)
• Daily dose of 5mcg/kg (rounding to the nearest
  vial size) (300 mcg/day for pts lt 78 kg and 480
  mcr/day for pts gt 78 kg)
• Pegfilgrastim (Neulasta Neulastim) (category
  1)
• One dose of 6mg per cycle of treatment
• (There is evidence to support use for
  chemotherapy regimens given every 3weeks/2 weeks)
• Category 1 There is uniform NCCN consensus,
  based on high-level evidence, that the
  recommendation is appropriate.

51
GM-CSF

• NCCN
• Sargramostim (GM-CSF) (category 2B)
• Category 2B ununiform NCCN consensus (but
  no major disagreement)
• ASCO
• .GM-CSF has been licensed specifically for use
  after autologous or allogeneic BMT and for AML

52
Pegfilgrastim NCCN ASCO

• NCCN (2005)
• The safety data appears to be similar between
  filgrastim and pegfilgrastim.
• ASCO (2006)
• Not currently indicated for stem cell
  mobilization.
• The safety and efficacy has not been fully
  established in the setting of dose-dense
  chemotherapy.
• Should not be used in children or small
  adolescents (lt 45 kg).
• The long-term effects of long acting growth
  factors are unknown---need for long-term safety
  data.

53
Lenograstim (Granocyte)

• Glycosylated G-CSF produced in culture by
  mammalian cells identical to the natural
  molecule.
• Recommended dose 1 Amp 263 mcg/day.

54
EORTC guidelines for choice of formulation

• Filgrastim, lenograstim and pegfilgrastim
  have clinical efficacy and we recommend the use
  of any of these agents to prevent FN and
  FN-related complications, where indicated.

55
Dosage Administration (contd)

• ASCO, ESMO NCCN
• Start 24-72 h after completion of chemotherapy.
• Treat through post-nadir ANC recovery.
• The package insert suggests to continue until
  the occurrence of ANC-10,000 /microL after the
  neutrophil nadir. However, a shorter duration is
  sufficient (ASCO 2006 until reaching ANC of at
  least 2000-3000/mm3).

56
Non continuous (less intensive) G-CSF therapy

• Papaldo P et al. J Clin Oncol
  236908-18, 2005
• The study was designed to evaluate the
  comparative efficacy of varying intensity
  schedules of recombinant human granulocyte
  colony-stimulating factor (G-CSF filgrastim)
  support in preventing febrile neutropenia in
  early breast cancer patients treated with
  relatively high-dose epirubicin plus
  cyclophosphamide (EC).
• CONCLUSION In the adjuvant setting, the
  frequency of prophylactic G-CSF administration
  during EC could be curtailed to only two
  administrations (days 8 and 12) without altering
  outcome. This nonrandomized trial design provides
  support for evaluating alternative, less intense
  G-CSF schedules for women with early breast
  cancer.
• Kuderer NM et al. J Clin Oncol 253158-67, 2007
  (a systematic review) a nonrandomized post hoc
  analysis of different interrupted G-CSF
  strategies in pts with low risk of febrile
  neutropenia. Interruption of growth factor
  administration before adequate neutrophil
  recovery seems not to be effective in higher risk
  settingswhereas trials using uninterrupted
  treatment according to current guidelines have
  clearly demonstrated the efficacy of G-CSF in
  this setting

57

• For peripheral blood stem cell collection
  (PBPC) the filgrastim dose is 10/mcg/kg/day.

58

• Primary secondary prophylaxis

59
ASCO guidelines for primary prophylaxis

• When the risk of febrile neutropenia is
  approximately 20 or more (notgt40 as in 2000
  guidelines) and no other equally effective
  regimen that does not require GCSF is available.

60
Prophylactic use of CSFs

• Over the last decade, the costs of inpatient
• hospitalization have escalated, changing the risk
  threshold on a pure cost basis from 40 to
• approximately 20.
• More importantly, several randomized studies have
  documented clinical benefits of CSFs in lower
  risk populations.

61
Pegfilgrastim is effective in preventing febrile
neutropenia resulting from moderately
myelosuppressive chemotherapy

• Vogel CL et al. J Clin Oncol 23 1178-84,
  2005
• Docetaxel (taxotere) 100 mg/m2 q 3wks in breast
  cancer
• Randomized pegfilgratim administered 24 hrs
  after chemotherapy vs. placebo
• Overall incidence of febrile neutropenia1 vs.
  17 (plt 0.001).
• Overall incidence of hospitalization 1 vs. 14
  (plt 0.001).

62
ASCO/primary prophylaxis (contd)

• For dose-dense regimens CSFs are required and
  recommended.

63
ASCO/primary prophylaxis Special Circumstances

• Age gt 65,
• Poor PS,
• Previuos episodes of FN,
• Pre-existing neutropenia due to disease,
• Extensive prior therapy, including large
  radiation ports,
• Cytopenias due to BM involvement,
• Poor nutritional status,
• Open wounds or active infections,
• More advanced cancer serious comorbidities.
• Consider even with regimens with FN rates
  of lt 20.

64
ASCO EORTC guidelines/ CSFs in older patients

• ASCO Prophylactic CSF for patients with
  diffuse aggressive NHL aged gt 65 treated with
  curative chemo (CHOP or more aggressive regimens)
  should be given to reduce the incidence of FN and
  infections.
• EORTC In assessing patient-related risk
  factors, particular consideration should be given
  to the elevated risk of FN in elderely pts (aged
  65 or older).

65
ASCO recommendations for Secondary Prophylaxis

• After a documented febrile neutropenia in an
  earlier cycle.
• Even if febrile neutropenia has not occurred, the
  use of CSFs may be considered if prolonged
  neutropenia is causing excessive dose reduction
  or a delay in chemotherapy.

66
Prophylactic use of CSFs

• Re-evaluate patient every cycle for treatment
  intent and risk categorization.

67
Prophylactic use of CSFs

• The decision to use prophylactic CSFs is based on
  the
• Type of chemotherapy,
• patient's risk factors,
• Treatment intent
• -curative/adjuvant
• -prolong survival
• -symptom management

68
NCCN Indications for prophylactic CSF according
to type of chemotherapy treatment intent and risk
of febrile neutropenia (applies to the first and
all subsequent cycles)
69
NCCN-high risk (gt20 probability of febrile
neutropenia or a neutropenic event compromising
treatment)

• Curative/adjuvant prolong survival and
• Quality of life
• Routine use is recommended (category 1).
• Category 1 There is uniform NCCN consensus,
  based on high-level evidence, that the
  recommendation is appropriate.
• Symptom management/quality of life
• The use of high dose chemotherapy in this
  setting is a difficult decision and requires
  careful discussion between the physician and the
  patient

70
NCCN- intermediate risk (10-20 probability of
febrile neutropenia or a neutropenic event
compromising treatment)

• Curative/adjuvant
• Consider CSF
• Individualized consideration based on
  physician-patient discussion
• Symptom management/quality of life
• Consider CSF
• The use of high dose chemotherapy in this
  setting is a difficult decision and requires
  careful discussion between the physician and the
  patient.

71
NCCN-low risk (lt10 probability of febrile
neutropenia)

• Routine use of CSFs is not recommended unless
  the patient is receiving curative or adjuvant
  treatment and is at significant risk for serious
  medical consequences of febrile neutropenia,
  including death.

72
NCCN Examples of chemotherapy regimens with a
high risk of febrile neutropenia (gt20) (1 of 2)
73
NCCN Examples of chemotherapy regimens with a
high risk of febrile neutropenia (gt20) (2 of 2)
74
NCCN Examples of chemotherapy regimens with an
intermediate risk of febrile neutropenia (10-20)
(1 of 2)
75
NCCN Examples of chemotherapy regimens with an
intermediate risk of febrile neutropenia
(10-20) (2 of 2)
76
NCCN Patient risk factors for developing febrile
neutropenia (1 of 2)
77
NCCN Patient risk factors for developing febrile
neutropenia (2 of 2)
78
NCCN Risk factors that compromise ability to
deliver full-dose chemotherapy (1 of 2)
79
NCCN Risk factors that compromise ability to
deliver full-dose chemotherapy (2 of 2)
80
CSFs in dose-dense or dose-intense chemotherapy

• ASCO EORTC Use if such strategy has
  therapeutic benefit.

81

• CSFs in established febrile neutropenia

82
CSFs for chemotherapy-induced febrile
neutropenia a meta-analysis (Clark OA et al. J
Clin Oncol 23 4198-4214, 2005)

• Significantly reduces the length of
  hospitalization and the time to neutrophil
  recovery.
• A marginally significant result was obtained for
  the use of CSF in reducing infection-related
  mortality.

83
ASCO Guidelines for G-CSF Therapy- Febrile
Patients with neutropenia

• High-risk patients in whom G-CSF may be
  considered
• Expected prolonged (gt 10 d) and profound
  neutropenia (ANC lt 100/microliter)
• Age gt 65
• Fever of gt 10 days in duration
• Pneumia, hypotension and multiple organ failure
  (sepsis syndrome)
• Multi-organ dysfunction
• Invasive fungal infection
• Uncontrolled malignancy
• Being hospitalized at the time of the development
  of fever

84
ESMO Guidelines for G-CSF Therapy- Febrile
Patients with neutropenia

• Protracted febrile neutropenia (gt 7 days)
• OR hypotension or sepsis
• OR pneumonia or fungal infection

85
EORTC Guidelines for G-CSF Therapy- Febrile
Patients with neutropenia

• limited to those pts who are not responding
  to appropriate antibiotic management and who are
  developing life-threatening infections (such as
  severe sepsis or septic shock).

86
ASCO/ CSF in patients with afebrile neutropenia

• .should not routinely be used.

87
ASCO/Use of CSF in patients receiving radiotherapy

• Avoids in pts receiving concomitant chemo and
  radiotherapy, particularly involving the
  mediastinum.
• Consider in pts receiving radiotherapy alone if
  prolonged delays, secondary to neutropenia, are
  expected.