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ADVANCING THE
MANAGEMENT OF
CHEMOTHERAPY-INDUCED
ANAEMIA AND NEUTROPENIA
E. Ulsperger
th
KH Hietzing, 5 Med. Department, Oncology
Head: Univ.Prof.Dr.K.Geissler
• Anaemia
– European Cancer Anaemia Survey (ECAS)
– rHuEPO
– Guidelines
• EORTC
– Darbepoetin-alfa
– Q3W Darbepoetin-alfa 500 mcg
• Neutropenia
–
–
–
–
Filgrastim
Pegfilgrastim
Dose Dense Chemotherapy
NCCN 2005 Guidelines
DIFFERENTIAL DIAGNOSIS
IN ANAEMIA
Reticulocytes correspond not
with grade of anaemia
MCV
reduced
Micro-
Reticulocytes correspond
with grade of anaemia
MCV
MCV
normal
increased
NormoMacrocytic anaemia
Iron
defici.,
Thalassaemia
BM
insuff.
Vit. B12
Folic-acid
BLEEDING, HAEMOLYSIS
DEFINITION ANAEMIA
WHO
EORTC
NCI, ECOG, COG,
SWOG, CALGB
Grade 0
>11
>12
Grade 1
Grade 2
Grade 3
Grade 4
9,5-10,9
8-9,4
6,5-7,9
<6,5
10-12
8-9.9
6,5-7,9
<6,5
female: 12-15
male: 14-16
10- grad 0
8-9,9
6,5-7,9
<6,5
EORTC: European Organization f.Research a.Treatment of Cancer; NCI: National Cancer Institute;
ECOG: Eastern Cooperative Oncology Group; SWOG: Southwest Oncology Group; CALGAB:
Cancer a. Leukemia Group B; GOC: Gynecologic Oncology Group
all values in g/dl
Factors in the Cause and Development of
Anaemia in Cancer
Tumour cells
Activated
immune system
RBCs
Erythrophagocytosis
Dyserythropoiesis
Shortened
survival
Anaemia
Macrophages
TNF
IFN-α,β
IL-1
TNF
IFN-γ
IL-1
TNF
α1-antitrypsin
IFN-γ
IL-1
TNF
Reduced
EPO
production
Impaired
iron
utilisation
Suppressed
BFU-e
CFU-e
IFN = interferon; TNF = tumour necrosis factor;
IL = interleukin
Nowrousian MR. Med Oncol.
1998;15(suppl 1):S19-S28.
Negative Impact of Fatigue on Aspects of
Daily Life in Patients with Cancer (N = 419)
61
Ability to work
60
Physical well-being
57
Ability to enjoy life in the moment
Emotional well-being
51
Intimacy with partner
44
Ability to take care of family
42
Relationships with family and friends
38
Concerns about mortality and survival
33
0
10
20
30
40
Patients (%)
50
60
70
Vogelzang NJ, et al. Semin Hematol. 1997;34(suppl 2):4-12.
Evaluation of FATIGUE in USA
What is the major symptom reducing „quality-of live“ in
cancer patients daily life?
Patient / Onkologist
61%
Fatigue
37%
19%
Pain
Both
61%
5%
2%
Anaemia is an Adverse Prognostic Factor
in Patients with Head and Neck Cancer
Proportion of patients with
locoregional tumour control
Patients treated with radiotherapy and stratified for anaemia (N = 889)
1.0
0.8
0.6
Nonanaemic
Anaemic
0.4
P < 0.0001
0.2
0
0
1
2
3
4
5
Years
Frommhold H, et al. Strahlenther Onkol. 1998;174(suppl 4):31-34.
• Anaemia
– European Cancer Anaemia Survey (ECAS)
– rHuEPO
– Guidelines
• EORTC
– Darbepoetin-alfa
– Q3W Darbepoetin-alfa 500 mcg
• Neutropenia
–
–
–
–
Filgrastim
Pegfilgrastim
Dose Dense Chemotherapy
NCCN 2005 Guidelines
European Cancer Anaemia Survey (ECAS)
Definitions
z
Prospective survey conducted in 2001
z
Anaemia (NCI and EORTC)
–
–
–
–
z
Mild
11.9 – 10.0 g/dl
Moderate
9.9 – 8.0 g/dl
Severe < 8.0 g/dl
No gender or age differentiation
“Ever anemic”
– If Hb dropped below 12 g/dL during survey
Ludwig H, et al.
Eur J Cancer. 2004;40:2293-2306.
60
50
<8
8 - 9.9
10 - 11.9
40
30
20
10
Ly
m
G
Ur
og
en
ita
l
ae
m
ia
Le
uk
a
ph
om
a/
M
ye
lo
m
yn
G
H&
N
I/C
ol
o
re
ct
al
Lu
ng
t
0
Br
ea
s
% Patients
ECAS
Hb of cancer patients at enrollment (n=14.912)
Ludwig H, et al.
Eur J Cancer. 2004;40:2293-2306.
ECAS
Chemo patients “ever anaemic” (n = 8.470)
100
80
60
40
20
er
O
th
l
en
ita
ro
g
U
Le
uk
em
ia
lo
m
a
/M
ye
G
yn
m
ph
Ly
&N
H
al
ol
or
ec
t
ng
G
I/C
Lu
Br
ea
st
0
Ludwig H, et al.
Eur J Cancer. 2004;40:2293-2306.
• Anaemia
– European Cancer Anaemia Survey (ECAS)
– rHuEPO
– Guidelines
• EORTC
– Darbepoetin-alfa
– Q3W Darbepoetin-alfa 500 mcg
• Neutropenia
–
–
–
–
Filgrastim
Pegfilgrastim
Dose Dense Chemotherapy
NCCN 2005 Guidelines
rHuEPO – RESPONSE RATES
• Median response:
• Range:
• median time until
response:
• Median increase of Hb:
60%
8 - 86%
4-6 wks
2-2,2 g/dl
(Demetri et al 1998)
rHuEPO Improves QOL in Anaemic
Patients with Cancer
Change in score*
rHuEPO 100–150 IU/kg TIW (n = 83)
14
12
10
8
6
4
2
0
–2
–4
†
Placebo (n = 143)
†
Energy level
Daily activities
†
Overall QOL
rHuEPO responders: haematocrit (Hct) increase ≥ 6 percentage points
*Based on 100 mm visual scale; †P < 0.05
Abels RI, et al. Proceedings of the
QOL = quality of life;
Beijing symposium. Dayton, OH: AlphaMed Press. 1991.
TIW = three times per week
Cancer-Related Anaemia
z
20%–60% of patients with cancer will have anaemia
at presentation
z
Chemotherapy, radiotherapy and the disease itself can all
worsen the incidence of anaemia
z
Often under-diagnosed and under-recognised
by physicians
z
Treatment involves ‘watchful waiting’, red blood cell (RBC)
transfusion or erythropoiesis stimulating protein (ESP) therapy
Guidelines needed
*Ludwig H et al. The European cancer anaemia survey (ECAS): a large, multinational, prospective survey defining
the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 2004;40:2293-2306
• Anaemia
– European Cancer Anaemia Survey (ECAS)
– rHuEPO
– Guidelines
• EORTC
– Darbepoetin-alfa
– Q3W Darbepoetin-alfa 500 mcg
• Neutropenia
–
–
–
–
Filgrastim
Pegfilgrastim
Dose Dense Chemotherapy
NCCN 2005 Guidelines
Existing Guidelines
• US Guidelines recomend use of ESPs for patients
with a Hb < 10 g/dl (ASCO/ASH1) or < 11 g/dl
(NCCN2)
• Under corresponding clinical facts use of ESPs
should be considered at Hb 10-12 g/dl
(ASCO/ASH)
• Target -Hb:
11–12 g/dl (NCCN)
~ 12 g/dl (ASCO/ASH)
ASCO = American Society of Clinical Oncology
ASH = American Society of Hematology
NCCN = National Comprehensive Cancer Network
1
Rizzo JD, et al. J Clin Oncol.
2002;20:4083-4107;
2
NCCN. Version 1. 2004.
EORTC Anaemia Guidelines
Development
EORTC Taskforce
z
Bokemeyer C (Germany)
z
Aapro MS (Switzerland)
z
Courdi A (France)
z
Foubert J (Belgium)
z
Link H (Germany)
z
Österborg A (Sweden)
z
Repetto L (Italy)
z
Soubeyran P (France)
EORTC = European Organization for Research and Treatment of Cancer
EORTC Anaemia Guidelines
Search Strategy and Results
z
Strategy
–
–
–
z
MEDLINE (1996–2003)
PreMEDLINE
Abstract search (2000–2003;
AACR, ASCO, ASH, ECCO, EHA, ESMO)
Results
– A total of 78 published studies relating to the administration
of ESPs to anaemic patients with cancer were considered to
be relevant (from a total of 235 studies identified by the
search)
– An additional 50 relevant abstracts were identified
AACR = American Association for Cancer Research; ECCO = European Conference on Clinical
Oncology; EHA = European Hematology Association; ESMO = European Society for Medical Oncology
EORTC Anaemia Guidelines
Treatment Goal
z
The two major goals of erythropoietic protein
therapy should be (grade A)
– to improve QOL
– to prevent RBC transfusions
EORTC Anaemia Guidelines
When to start ESP
in cancer patients receiving chemo-therapy and/or
radiotherapy at a Hb of 9-11 g/dL, based on anaemiarelated symptoms (grade A).
In cancer patients with tumor-induced anaemia (without
chemo or radiotherapy) at a Hb of 9–11 g/dl based on
anaemic symptoms (grade B).
EORTC Anaemia Guidelines
Target
The target Hb
should be
12–13 g/dL
(grade B)
Treatment should
be continued as
long as Hb remains
≤ 12–13 g/dL and
patients show
symptomatic
improvement
• Anaemia
– European Cancer Anaemia Survey (ECAS)
– rHuEPO
– Guidelines
• EORTC
– Darbepoetin-alfa
– Q3W Darbepoetin-alfa 500 mcg
• Neutropenia
–
–
–
–
Filgrastim
Pegfilgrastim
Dose Dense Chemotherapy
NCCN 2005 Guidelines
Differences Between Aranesp and
rHuEPO Molecular Structures
®
rHuEPO
Carbohydrate
side chains
Receptor 1
New
carbohydrate
side chains
Receptor 1
Receptor 2
z Three N-linked carbohydrate
chains
z Maximum 14 sialic acids
z MW ~ 30,400 daltons
z 40% carbohydrate
MW = molecular weight
Aranesp®
Receptor 2
z Five N-linked carbohydrate
chains
z Maximum 22 sialic acids
z MW ~ 37,100 daltons
z 51% carbohydrate
Pharmacokinetic Profile:
AranespTM (darbepoetin alfa) Has a Longer Half-Life Than rHuEPO
Single-Dose Pharmacokinetics of Intravenous darbepoetin alfa
Mean (SD) baseline-corrected
serum concentration (ng/mL)
100
Darbepoetin alfa (oncology; 0.5 mcg/kg, n = 20)*1
Darbepoetin alfa (dialysis; 0.5 mcg/kg, n = 11)2
rHuEPO (dialysis; 100 U/kg, n = 10)2
10
t1/2 = 38.8 hours
1
t1/2 = 25.3 hours
0.1
0.01
t1/2 = 8.5 hours
0
25
50
75
Time post-intravenous injection (hours)
*Oncology patients received 2.25 mcg/kg; data shown is normalized for 0.5 mcg/kg.
1. Heatherington A, et al. Proc ASCO.2002.
2. Macdougall I, et al. J Am Soc Nephrol. 1999;10:2392–2395.
100
Kaplan-Meier proportions of patients
achieving a Hb response*
Darbepoetin alfa
Placebo
P <0.001
Percentage (95% CI)
of patients responding
80
n = 174
P <0.001
P <0.001
n = 86
n = 88
60
64
60
56
40
n = 86
n = 170
20
18
0
Overall
n = 84
23
13
Lymphoma
Myeloma
*Defined as an increase of ≥2 g/dL from baseline
in the absence of any red blood cell transfusion within the
preceding 28 days
Hedenus M, et al. Br J Haematol. 2003;122:394-403.
CI = confidence interval
Summary of adverse events
Adverse events occurring in at least 15% of patients
Fatigue
Fever
Nausea
Diarrhoea
Darbepoetin alfa
Vomiting
Placebo
Dyspnoea
Constipation
0
10
20
Patients (%)
30
40
Hedenus M, et al. Br J Haematol. 2003;122:394-403.
• Anaemia
– European Cancer Anaemia Survey (ECAS)
– rHuEPO
– Guidelines
• EORTC
– Darbepoetin-alfa
– Q3W Darbepoetin-alfa 500 mcg
• Neutropenia
–
–
–
–
Filgrastim
Pegfilgrastim
Dose Dense Chemotherapy
NCCN 2005 Guidelines
Darbepoetin alfa Once Every 3 Weeks for the Treatment
of Anaemia in Patients Receiving Multicycle
Chemotherapy
• This was a randomised, double-blind, double-dummy,
active-controlled phase 3 study in 110 centres across
Europe.
• Patients were randomised 1:1 to either 500 mcg Q3W
DA or 2.25 mcg/kg QW DA for up to 15 weeks (noninferiority) .
• Randomisation was stratified by tumour type
(lung/gynaecological vs other), screening haemoglobin
(Hb) (< 10 g/dL vs ≥ 10 g/dL), and geographic region
(Western vs Central/Eastern Europe).
J-L Canon, et al.; JNCI, 98, 4, 273, 2006
Incidence of Transfusions
Probability of Transfusion
(Upper 95% CI)
0.5
0.4
Difference: Q3W-QW a
-6.8 (95% CI: -13.6 to 0.1)
Percentage Points
Difference: Q3W-QW a
-6.9 (95% CI: -14.0 to 0.2)
Percentage Points
DA 2.25 mcg/kg QW
DA 500 mcg Q3W
36%
30%
0.3
29%
23%
0.2
0.1
0
Week 5 to EOTP
Week 1 to EOTP
J-L Canon, et al.; JNCI, 98, 4, 273, 2006
Incidence of Transfusions
Probability of Transfusion (95% CI)
(Week 5 to EOTP)
External Validity - Comparison With Previous DA Trials
Placebo
DA 2.25 mcg/kg QW
DA 4.5 mcg/kg front-load
DA 500 mcg Q3W
0.6
0.5
0.4
0.3
0.2
n = 149 n = 148
Vansteenkiste, et al9
n = 165 n = 167
Hedenus, et al10
9. Vansteenkiste J, et al. J Natl Cancer Inst. 2002;94:1211-1220
10. Hedenus M, et al. Br J Haematol. 2003;122:394-403.
11. Kotasek D, et al. Proc Am Soc Clin Oncol. 2002;21:356a.
n = 345
n = 334
Kotasek, et al11
n = 337 n = 335
Canon, et al
(present study)
J-L Canon, et al.; JNCI, 98, 4, 273, 2006
Aranesp® - Conclusion
•
Higher biological activity than rHuEPO
•
Mayor goal: prevent RBC transfusions and improve QoL
•
EORTC Giudeline Initiation: of therapy at Hb concentration
of 9-11g/dl based on anaemia-related symptoms
•
EORTC guideline Target: Hb concentration: 12-13g/dl
•
500µg Q3W non-inferior to weight-based 2.25 µg/kg
•
Less frequent administration offers patient benifits approved
by the EMEA in Sep 2004
• Anaemia
– European Cancer Anaemia Survey (ECAS)
– rHuEPO
– Guidelines
• EORTC
– Darbepoetin-alfa
– Q3W Darbepoetin-alfa 500 mcg
• Neutropenia
–
–
–
–
Filgrastim
Pegfilgrastim
Dose Dense Chemotherapy
NCCN 2005 Guidelines
Chemotherapy-Induced Neutropenia
Mild
(< 2,000)
Moderate
(< 1,500)
Severe
(< 1,000)
Grade 1
Grade 2
Grade 3
Severe/Lifethreatening
(< 500)
Grade 4
Common Toxicity Criteria. Version 2.0 [electronic document]. Bethesda, Md: National Cancer
Institute; 1999. Available at: http://ctep.info.nih.gov/reporting/ctc.html. Accessed January 8, 2003.
Percent FN (%)
Neutropenia and Risk of Febrile
Neutropenia (FN)
50
39%
40
30
19%
20
10
11%
0%
3%
0
0
1
2
3
>=4
Duration of Severe Neutropenia (Days)
Bodey GP et al. Ann Intern Med. 1966;64:328-340; Meza L et al. Proc Am Soc Clin Oncol. 2002;21:255b.Abstract 2840.
23% (12-76%) FN at standard-CT1
80%
70%
60%
50%
40%
30%
23%
20%
10%
0%
Mamma
n=6935
NSCLC
n=3721
SCLC
n=1728
Ovar
n=2467
NHL
n=4431
HD
n=1628
AML
n=1437
Gesamt
Febrile Neutropenia (FN): absolut Neutrophilecount (ANC) < 1,0 x 109/l and orale temperature
> 38.2°C
1… Adelphi Databank: 1997-2002, n = 30753 Pat; Germany, Italy, Spain, France
10,9% (8,5-18%) Mortality at FN
20%
18%
16%
14%
12%
10%
8%
6%
4%
2%
0%
18,0%
8,5%
solide Tumore
10,9%
10,1%
Lymphome
Leukämien
Gesamt
n = 41.779 Pat. hospitalised with FN; 1995-2000; excapt Transplantations
Kuderer N, et al. Proc ASCO 2002;21: Abstract 998
Chemotherapy-Induced Neutropenia
Has Significant Consequences
• Grade 3 or 4 neutropenia is common
– ↑ risk of life-threatening infections,
hospitalization, and IV antibiotics
• Primary dose-limiting toxicity
– Chemotherapy dose delays and reductions
compromise treatment effectiveness
• Additional impacts: economic, quality of life
Ozer H, et al. J Clin Oncol. 2000;18:3558-3585. Lyman G, et al. Eur J Cancer. 1998;34:1857-1864.
Lyman G, et al. Blood. 2001;98:432a. Calhoun E, et al. Blood. 2001;98:427a. Fortner, et al. Ann Oncol. 2002-13(suppl 5):640 p.
• Anaemia
– European Cancer Anaemia Survey (ECAS)
– rHuEPO
– Guidelines
• EORTC
– Darbepoetin-alfa
– Q3W Darbepoetin-alfa 500 mcg
• Neutropenia
–
–
–
–
Filgrastim
Pegfilgrastim
Dose Dense Chemotherapy
NCCN 2005 Guidelines
G-CSF Decreases Severity and
Duration of Chemotherapy-Induced
Neutropenia
Median ANC during cycle 1,
CAE chemotherapy in small-cell lung cancer
Start Neupogen®/Placebo
Placebo (n = 110)
Neupogen® (n = 101)
100.0
ANC
(× 109/L)
10.0
1.0
0.5
0.1
Severe neutropenia (ANC < 500)
0.01
0
4
8
Crawford J, et al. N Engl J Med. 1991;325:164-170.
12
Study day
16
20
24
Filgrastim Decreases Incidence of FN
100
P < 0.001
% Patients
80
60
Placebo
P < 0.001
NEUPOGEN®
P < 0.012
P < 0.012
40
P = 0.101
NR*
20
0
FN Cycle 1
FN
Culture- FN Cycle 1
FN
CultureCumulative Confirmed
Cumulative Confirmed
Infection
Infection
Crawford J, et al. N Engl J Med. 1991;325:164-170.
* NR = Not Reported
Trillet-Lenoir V, et al. Eur J Cancer. 1993;29A:319-324.
Filgrastim Reduces Need for Antibiotic
Therapy and Hospitalization for Infection
70
60
50
Placebo (n = 64)
Neupogen® (n = 65)
58
58
P < 0.02
P < 0.04
37
39
Incidence 40
(%)
30
20
10
0
Antibiotic use
Trillet-Lenoir V, et al. Eur J Cancer. 1993;29A:319-324.
Hospitalization
Oncology Practice Pattern Study Shows
Lower FN Rates With Optimal Days of
Filgrastim
• FN rates were 12% when an average of 5 days of Neupogen® was used
• FN rates were 5% when an average of 10 days of Neupogen® was used
n = 73
cycles
14
n = 579
cycles
12
10
8
6
Group A
(mean 4.7 days)
n = 579
cycles
n = 73
cycles
4
2
P = 0.02
0
Avg Neupogen®
Use (days)
FN Rate
(percentage)
Scott SD, et al. Suppl J Man Care Pharm. 2003;9(2):15-21.
Group B
(mean 10.1 days)
Delayed Initiation of G-CSF May
Compromise Clinical Outcomes
Impact of Timing of G-CSF Administration After High-Dose Cyclophosphamide
Group A
Group B
Group C
Group D
(24 hrs)
n = 13
(48 hrs)
n = 11
(72 hrs)
n = 10
(96 hrs)
n = 12
No Growth
Factor
n = 14
Incidence of FN
16%
33%
25%
66%
75%
Duration of Neupogen®
(filgrastim)
Administration (Days)
11.5
12
13.5
15.5
–
Note: Patients in this study were dosed through grade 1 neutropenia.
Koumakis, et al. Oncology. 1999;56:28-35.
• Anaemia
– European Cancer Anaemia Survey (ECAS)
– rHuEPO
– Guidelines
• EORTC
– Darbepoetin-alfa
– Q3W Darbepoetin-alfa 500 mcg
• Neutropenia
–
–
–
–
Filgrastim
Pegfilgrastim
Dose Dense Chemotherapy
NCCN 2005 Guidelines
Pegylating filgrastim Makes Once-PerChemotherapy-Cycle Dosing Possible
Filgrastim
Daily dosing
Helical
bundle
Pegfilgrastim
1 dose per cycle of
chemotherapy
Helical
bundle
Polyethylene glycol
(PEG)
Pegfilgrastim- stabil serumconcentration
ANC-nadir less decreased
ANC
ANC
Filgrastim 5 µg/kg/d (n = 3)
Pegfilgrastim 100 µg/kg (n = 3)
1000
100
10
10
1
1
0.1
0.01
0.1
0
5
10
15
Tag
Serum half-life ~3 hours
20
25
0
Mediane Serumkonzentration (µg/L)
Medianer ANC
(× 109/L)
100
0.01
10
15
20
25
Tag
sustained plasma concentrations
Serum half-life 46–62 hours
5
Adapted from Johnston E, et al. J Clin Oncol. 2000;18:2522–2528.
Single Dose of Neulasta® Stimulates Neutrophil
Recovery as Effectively as 11 Daily Injections of
Neupogen®
1000.00
Neupogen® 5 µg/kg/day (n = 75)
ANC (x109/L)
Interquartile range
Neulasta® fixed, 6 mg (n = 77)
100.00
10.00
1.00
0.10
Chemo- Study
therapy drug
0.01
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Cycle day
Neulasta®
Neupogen®
Adapted from Green M, et al. Ann Oncol. 2003;14:29-35.
Injections
Duration of Severe Neutropenia (DSN) in Cycle 1
Neupogen® (filgrastim)
Neulasta® (pegfilgrastim)
No Growth Factor
1.8
1.6
Green et al
(n = 130)
0
1
2
3
4
5
3
4
5
1.7
1.8
Holmes et al
(n = 296)
0
1
2
Misset et al*
(n = 42)
5
0
1
2
DAYS
3
4
5
*In patients who received a similar myelosuppressive regimen, but did not receive growth factor, the median
DSN was 5 days.
Holmes FA, et al. J Clin Oncol. 2002;20:727-731. Green M, et al. Ann Oncol. 2003;14:29-35. Misset, et al. Ann Oncol. 1999;
10:553-560.
Pegfilgrastim Led to a Lower Rate of FN
Green et al
(n = 152)
Holmes et al
(n = 296)
Misset et al*
(n = 42)
Neulasta®
Neupogen®
Neulasta®
Neupogen®
No Growth
Factor
13%
20%
9%
18%
38%
Febrile neutropenia defined as ANC < 500 (0.5 × 109/L) and fever (≥ 38.2°C).
Note: These trials comparing Neupogen® (filgrastim) and
Neulasta® were designed as non-inferiority studies.
* In patients who received a similar myelosuppressive regimen, but did not receive
growth factor, the rate of febrile neutropenia was 38%.
Holmes FA, et al. J Clin Oncol.
Oncol. 2002;20:7272002;20:727-731; Green M, et al. Ann Oncol.
Oncol. 2003;14:292003;14:29-35;
Misset JL, et al. Ann Oncol.
Oncol. 1999;10:5531999;10:553-560.
Pegfilgrastim shows a 71% relative reduction
in FN incidence
Incidence of FN (%)
40
38†
30
50
71
20
10
0
11*
42
Pegfilgrastim
*Siena S, et al. Oncol Rep. 2003;10:715-724;
J, et al. Ann Oncol. 1999;10:553-560.
†Misset
19*
Filgrastim
No G-CSF
Pegfilgrastim 66-mg
-mg Fixed Dose Is Effective
Across a Broad Range of Body Weights
Mean DSN in cycle 1 by body weight group in quartiles
Mean Duration of Severe
Neutropenia (days)
4
Pegfilgrastim 6-mg fixed dose
Filgrastim 5 mcg/kg/d
3
2
1
0
46-62 kg
Data on file, Amgen.
>62-71 kg
>71-80 kg
>80-125 kg
First and Subsequent Cycle Use of Pegfilgrastim in
Patients with Breast Cancer: A Multicenter, Double-Blind,
Placebo Controlled Phase III Study;
SS
CC
RR
EE
EE
NN
II
NN
GG
CC
HH
EE
M
M
OO
TT
HH
EE
RR
AA
PP
YY
RR
AA
NN
DD
OO
M
M
II
ZZ
AA
TT
II
OO
NN
N=928
Placebo
Placebo
FN
Docetaxel
Docetaxel ++ Pegfilgrastim
Pegfilgrastim
Pegfilgrastim
Pegfilgrastim
Double-Blind Phase
Open-Label Phase
Docetaxel 100mg/m2 IV + blinded product Q3wk x 4 cycles
Charles L. Vogel et al; JCO 2005, vol 23
Neulasta shows 94 % relative reduction in FN
incidence comparing to placebo
Incidence of FN* (%)
20
P < 0,05
15
10
RR 94 %
17%*
5
1%*
0
Neulasta
*FN = febrile neutropenia
Charles L. Vogel et al; JCO 2005, vol 23
Placebo
• Anaemia
– European Cancer Anaemia Survey (ECAS)
– rHuEPO
– Guidelines
• EORTC
– Darbepoetin-alfa
– Q3W Darbepoetin-alfa 500 mcg
• Neutropenia
–
–
–
–
Filgrastim
Pegfilgrastim
Dose Dense Chemotherapy
NCCN 2005 Guidelines
Patients Frequently Experience
Chemotherapy Dose Delays and Dose
Reductions
60
56
Delay ≥ 7 days
Patients (%)
50
≥ 15% Reduction
46
43
RDI <85%
40
30
28
27 28
26 26
24 24
36
37
36
30
25
20
9
10
5
10
8
6
0
0
1
2
3
4
5
6
Overall
(n=19,898) (n=19,824) (n=19,781) (n=19,243) (n=11,648) (n=11,027) (n=19,898)
Cycles
Lyman GL et al. J Clin Oncol. 2003;21:4524-4531.
Delivery of Chemotherapy Planned Dose
Improves Outcomes in Adjuvant Breast Cancer
Chemotherapy
The Milan Study: relapse-free and overall survival
with CMF: 20-year follow-up (n = 386)
% of planned dose
≥ 85 (n = 42)
1.0
65–84 (n = 94)
< 65 (n = 71)
0.8
Control (n = 179)
0.8
Probability of
overall survival
Probability of
relapse-free survival
1.0
0.6
0.4
0.2
0
0
5
10
15
0.6
0.4
0.2
0
0
20
Years after mastectomy
Bonadonna G, et al. N Engl J Med. 1995;332:901-906.
5
10
15
20
Delivery of Chemotherapy Planned Dose Improves
Survival in Non-Hodgkin’s Lymphoma
Retrospective survival analysis with CHOP,
m-BACOD, or MACOP-B (n = 115)
100
80
RDI doxorubicin > 75%
60
n = 92
Survival
probability
40
(%)
RDI doxorubicin ≤ 75%
P = 0.001
n = 23
20
0
0
1
2
RDI = relative dose intensity.
Kwak LW, et al. J Clin Oncol. 1990;8:963-977.
3
4
Years after treatment
5
6
7
Neupogen® support in Elderly Patients (> 60
years) with NHL, Dose Dense Chemotherapy
100
93
97
CHOP-14 + G-CSF (n = 181)
CHOP-21 (n = 189)
P = 0.002
75
P = 0.024
Patients
(%)
47.0
50
39.2
58.6
44.6
25
0
RDI
(median)
Time to treatment failure
(median 49 months)
Pfreundschuh M, et al. Blood. 2002;100:774a. Abstract 3060.
Overall survival
(median 49 months)
Dose Dense CT at Breastcancer
with Neupogen®® Prophylaxis* : CALGB 9741
Doxorubicin 60 mg/m2
Cyclophosphamid 600 mg/m2
Paclitaxel (Taxol) 175 mg/m2 über 3 h
Neupogen® 5 µg/kg, Tag 3-10
* Filgrastim-Administartion in Q2W primärprophylactic, in Q3W according ASCO-Guidelines
Citron M et al. J Clin Oncol 2003, Vol 21: 1431-1439
26% reduced Risk of Relaps
1.0
1
0,93
n = 1973
1
-26 % RR*
0,74
Riskrate
0.8
0.6
0.4
0.2
P = 0.058
P = 0.010
0
sequential alternating
3-wek
2-wek
* Multivariates, proportionell Cox Riskmodel
Citron M et al. J Clin Oncol 2003, Vol 21: 1431-1439
31% reduced Risk of Mortality
1.0
1
n = 1973
1
0,89
-31 % RR*
Riskrate
0.8
0,69
0.6
0.4
0.2
P = 0.48
P = 0.013
0
sequential alternating
3-wek
2-wek
* Multivariat, proportional Cox Riskmodel
Citron M et al. J Clin Oncol 2003, Vol 21: 1431-1439
• Anaemia
– European Cancer Anaemia Survey (ECAS)
– rHuEPO
– Guidelines
• EORTC
– Darbepoetin-alfa
– Q3W Darbepoetin-alfa 500 mcg
• Neutropenia
–
–
–
–
Filgrastim
Pegfilgrastim
Dose Dense Chemotherapy
NCCN 2005 Guidelines
Guidelines
NCCN 2005 vs ASCO 2000
First cycle G-CSF use
Consider G-CSF for
Patient risk factors
Relevance of CT dose
intensity
Intervention for subsequent
cycles
NCCN 2005
ASCO 2000
risk FN > 20%
risk FN > 40%
risk FN 10–20%
< 40% “watch and wait”
Extensive list
Limited list
Include dose intensity in risk
assessment
No endoresement of GCSF
Review FN risk and use of
G-CSF
Consider dose reduction
before use of G-CSF
at each cycle
Recommended products
Category 1 for filgrastim or
pegfilgrastim*
Ref. NCCN MGF Guidelines – v1 2005; pdf - accessed 20th April 2005
http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.
NA
Patient risk factors for developing
febrile neutropenia
(examples, NCCN 2005)
ƒ Age(> 65 years)
ƒ Female gender
ƒ Poor performance status (ECOG ≥ 2)
ƒ Neutropenia in the history
ƒ Comorbidities ( COPD, cardiovascular disease, diabetes
mellitus, etc.)
ƒ Bone marrow involvement with tumor
Ref. NCCN MGF Guidelines – v1 2005; pdf - accessed 20th April 2005
http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.
Chemo-regimens with FN risk > 20%
(examples, NCCN 2005)
ƒ Breast cancer
• AC - T (doxorubicin, cyclophosphamid, docetaxel)
• AT (doxorubicin, paclitaxel)
• TAC (docetaxel, doxorubicin, cyclofosfamid)
ƒ Ovarian cancer
• Paclitaxel
• Docetaxel
ƒ NHL
• DHAP (dexamethason, cisplatin, cytarabin)
• ESHAP (etoposid, methylprednison, cisplatin, cytarabin)
ƒ Testicular Cancer
• VIP (vinblastin, ifosfamid, cisplatin)
Ref. NCCN MGF Guidelines – v1 2005; pdf - accessed 20th April 2005
http://www.nccn.org/professionals/physician_gls/PDF/myeloid
_growth.
Chemo-regimens with FN risk 10% - 20%
(examples, NCCN 2005)
ƒ Breast carcinoma
• Docetaxel
• AC (doxorubicin, cyclofosfamid)
ƒ Non-small Cell Lung Carcinoma
• TC (cisplatina, paclitaxel)
ƒ NHL
• R-CHOP (cyclofosfamid, doxorubicin, vincristin, prednison, rituximab)
• FM (fludarabin, mitoxantron)
ƒ Testicular carcinoma
• EC (etoposid, cisplatin)
Ref. NCCN MGF Guidelines – v1 2005; pdf - accessed 20th April 2005
http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.
NCCN Decision Tree
Neulasta® - Conclusion
• one fixed dose per one chemo-cycle
• superior efficacy comparing to daily filgrastim
• significant risk reduction of FN incidence also in moderate
myelotoxic regimens
• single dose 6mg comparable to 11 days of Neupogen®
concerning efficacy
• improves survival saves dose density and planed doses
• primary prophylaxis at regimens with FN risk > 20%
recommended by NCCN guidelines