ADVANCING THE MANAGEMENT OF CHEMOTHERAPY-INDUCED … E p06.pdf · Cancer-Related Anaemia z20%–60%...
Transcript of ADVANCING THE MANAGEMENT OF CHEMOTHERAPY-INDUCED … E p06.pdf · Cancer-Related Anaemia z20%–60%...
ADVANCING THE MANAGEMENT OF
CHEMOTHERAPY-INDUCED ANAEMIA AND NEUTROPENIA
E. Ulsperger
KH Hietzing, 5th Med. Department, OncologyHead: 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 Reticulocytes correspondwith grade of anaemia with grade of anaemia
MCV MCV MCV reduced normal increasedMicro- Normo- Macro-
cytic anaemia
Iron BM Vit. B12 BLEEDING, HAEMOLYSIS defici., insuff. Folic-acidThalass-aemia
DEFINITION ANAEMIAWHO EORTC NCI, ECOG, COG,
SWOG, CALGB
Grade 0 >11 >12 female: 12-15male: 14-16
Grade 1 9,5-10,9 10-12 10- grad 0Grade 2 8-9,4 8-9.9 8-9,9Grade 3 6,5-7,9 6,5-7,9 6,5-7,9Grade 4 <6,5 <6,5 <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
RBCs
Activatedimmune system
MacrophagesTNF
Anaemia
IFN-α,β IFN-γ IFN-γIL-1 IL-1 IL-1TNF TNF TNF
α1-antitrypsin
Reduced Impaired SuppressedEPO iron BFU-e
production utilisation CFU-e
Erythrophagocytosis
Dyserythropoiesis
Shortenedsurvival
Nowrousian MR. Med Oncol.1998;15(suppl 1):S19-S28.
IFN = interferon; TNF = tumour necrosis factor;IL = interleukin
Negative Impact of Fatigue on Aspects of Daily Life in Patients with Cancer (N = 419)
Ability to work
Physical well-being
Ability to enjoy life in the moment
Emotional well-being
Intimacy with partner
Ability to take care of family
Relationships with family and friends
Concerns about mortality and survival
0 10 20 30 40 50 60 70Patients (%)
Vogelzang NJ, et al. Semin Hematol. 1997;34(suppl 2):4-12.
61
60
57
51
44
42
38
33
Evaluation of FATIGUE in USA
What is the major symptom reducing „quality-of live“ in cancer patients daily life?
Patient / Onkologist
Fatigue
Pain
Both
61%37%
19%61%
5%2%
Anaemia is an Adverse Prognostic Factor in Patients with Head and Neck Cancer
1.0
0.8
0.6
0.4
0.2
0Prop
ortio
n of
pat
ient
s w
ith
loco
regi
onal
tum
ourc
ontr
ol
0 1 2 3 4 5Years
NonanaemicAnaemic
Patients treated with radiotherapy and stratified for anaemia (N = 889)
P < 0.0001
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 European Cancer AnaemiaAnaemia Survey (ECAS)Survey (ECAS)DefinitionsDefinitions
Prospective survey conducted in 2001Prospective survey conducted in 2001
Anaemia (NCI and EORTC)Anaemia (NCI and EORTC)–– MildMild 11.9 11.9 –– 10.0 g/dl10.0 g/dl–– ModerateModerate 9.9 9.9 –– 8.0 g/dl8.0 g/dl–– SevereSevere < 8.0 g/dl< 8.0 g/dl–– No gender or age differentiationNo gender or age differentiation
““Ever anemicEver anemic””–– If If HbHb dropped below 12 dropped below 12 g/dLg/dL during surveyduring survey
Ludwig H, et al.Eur J Cancer. 2004;40:2293-2306.
ECASECASHbHb of cancer patients at enrollment (n=14.912)of cancer patients at enrollment (n=14.912)
0
10
20
30
40
50
60
Breast
Lung
GI/Colo
rectal H&N
GynLy
mphom
a/Mye
loma
Leuk
aemia
Urogenit
al%
Pat
ient
s
< 8 8 - 9.9 10 - 11.9
Ludwig H, et al.Eur J Cancer. 2004;40:2293-2306.
ECASECASChemo patients Chemo patients ““ever ever anaemicanaemic”” (n = 8.470)(n = 8.470)
0
20
40
60
80
100
Breast
Lung
GI/Colo
rectal
H&N
GynLy
mph/M
yelom
aLe
ukem
iaUrog
enita
l
Other
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: 60%• Range: 8 - 86%• median time until
response: 4-6 wks• Median increase of Hb: 2-2,2 g/dl
(Demetri et al 1998)
rHuEPO Improves QOL in Anaemic Patients with Cancer
14121086420
–2–4
Cha
nge
in s
core
*
Energy level Daily activities Overall QOL
rHuEPO 100–150 IU/kg TIW (n = 83)
Placebo (n = 143)†
††
Abels RI, et al. Proceedings of theBeijing symposium. Dayton, OH: AlphaMed Press. 1991.
*Based on 100 mm visual scale; †P < 0.05QOL = quality of life;TIW = three times per week
rHuEPO responders: haematocrit (Hct) increase ≥ 6 percentage points
CancerCancer--Related AnaemiaRelated Anaemia
20%20%––60% of patients with cancer will have anaemia 60% of patients with cancer will have anaemia at presentationat presentationChemotherapy, radiotherapy and the disease itself can all Chemotherapy, radiotherapy and the disease itself can all worsen the incidence of anaemiaworsen the incidence of anaemiaOften underOften under--diagnosed and underdiagnosed and under--recognised recognised by physiciansby physiciansTreatment involves Treatment involves ‘‘watchful waitingwatchful waiting’’, red blood cell (RBC) , red blood cell (RBC) transfusion or transfusion or erythropoiesiserythropoiesis stimulating protein (ESP) therapystimulating protein (ESP) therapy
Guidelines needed*Ludwig H et al. The European cancer anaemia survey (ECAS): a large, multinational, prospective survey definingthe 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 GuidelinesExisting Guidelines
• US Guidelines recomend use of ESPs for patientswith a Hb < 10 g/dl (ASCO/ASH1) or < 11 g/dl(NCCN2)
• Under corresponding clinical facts use of ESPsshould be considered at Hb 10-12 g/dl(ASCO/ASH)
• Target -Hb:11–12 g/dl (NCCN)~ 12 g/dl (ASCO/ASH)
• US Guidelines recomend use of ESPs for patientswith a Hb < 10 g/dl (ASCO/ASH1) or < 11 g/dl(NCCN2)
• Under corresponding clinical facts use of ESPsshould 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 OncologyASH = American Society of HematologyNCCN = National Comprehensive Cancer Network
1Rizzo JD, et al. J Clin Oncol. 2002;20:4083-4107;
2NCCN. Version 1. 2004.
EORTC Anaemia GuidelinesEORTC Anaemia GuidelinesDevelopmentDevelopment
EORTC TaskforceEORTC Taskforce
BokemeyerBokemeyer C (Germany)C (Germany)
AaproAapro MS (Switzerland)MS (Switzerland)
CourdiCourdi A (France)A (France)
FoubertFoubert J (Belgium)J (Belgium)
Link H (Germany)Link H (Germany)
ÖÖsterborgsterborg A (Sweden)A (Sweden)
RepettoRepetto L (Italy)L (Italy)
SoubeyranSoubeyran P (FranceP (France))EORTC = European Organization for Research and Treatment of Cancer
EORTC Anaemia GuidelinesEORTC Anaemia GuidelinesSearch Strategy and ResultsSearch Strategy and Results
StrategyStrategy–– MEDLINE (1996MEDLINE (1996––2003)2003)–– PreMEDLINEPreMEDLINE–– Abstract search (2000Abstract search (2000––2003;2003;
AACR, ASCO, ASH, ECCO, EHA, ESMO)AACR, ASCO, ASH, ECCO, EHA, ESMO)ResultsResults–– A total of 78 published studies relating to the administration A total of 78 published studies relating to the administration
of of ESPsESPs to anaemic patients with cancer were considered to to anaemic patients with cancer were considered to be relevant (from a total of 235 studies identified by the be relevant (from a total of 235 studies identified by the search)search)
–– An additional 50 relevant abstracts were identifiedAn 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 EORTC AnaemiaAnaemia GuidelinesGuidelinesTreatment GoalTreatment Goal
The two major goals of The two major goals of erythropoieticerythropoietic protein protein therapy should be (grade A)therapy should be (grade A)
–– to improve QOLto improve QOL
–– to prevent RBC transfusionsto prevent RBC transfusions
EORTC EORTC AnaemiaAnaemia Guidelines Guidelines When to start ESPWhen to start ESP
in cancer patients receiving chemo-therapy and/or radiotherapy at a Hb of 9-11 g/dL, based on anaemia-related symptoms (grade A).
In cancer patients with tumor-induced anaemia (withoutchemo or radiotherapy) at a Hb of 9–11 g/dl based on anaemic symptoms (grade B).
EORTC EORTC AnaemiaAnaemia GuidelinesGuidelinesTargetTarget
The target Hbshould be12–13 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
Receptor 1
rHuEPO
Receptor 2
Carbohydrate side chains
New carbohydrate side chains
Receptor 1
Aranesp®
Receptor 2
Three N-linked carbohydrate chainsMaximum 14 sialic acidsMW ~ 30,400 daltons40% carbohydrate
Five N-linked carbohydrate chainsMaximum 22 sialic acidsMW ~ 37,100 daltons51% carbohydrate
MW = molecular weight
100
10
1
0.1
0.010 25 50 75 100
Time post-intravenous injection (hours)
Mea
n (S
D) b
asel
ine-
corre
cted
seru
m c
once
ntra
tion
(ng/
mL)
*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.
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
t1/2 = 25.3 hours
t1/2 = 8.5 hours
Pharmacokinetic Profile:Pharmacokinetic Profile:AranespAranespTMTM ((darbepoetindarbepoetin alfaalfa) Has a Longer Half) Has a Longer Half--Life Than Life Than rHuEPOrHuEPO
SingleSingle--Dose Pharmacokinetics of Intravenous Dose Pharmacokinetics of Intravenous darbepoetindarbepoetin alfaalfa
t1/2 = 38.8 hours
KaplanKaplan--Meier proportions of patients Meier proportions of patients achieving a achieving a HbHb response*response*
*Defined as an increase of ≥2 g/dL from baselinein the absence of any red blood cell transfusion within the preceding 28 daysCI = confidence interval
P <0.001 P <0.001 P <0.001Darbepoetin alfaPlacebo
n = 174
n = 170
Overall
n = 86
n = 84
n = 88
n = 86
Lymphoma Myeloma0
20
40
60
80
Perc
enta
ge (9
5% C
I) of
pat
ient
s re
spon
ding
64
13
56
23
60
18
Hedenus M, et al. Br J Haematol. 2003;122:394-403.
Summary of adverse eventsSummary of adverse eventsAdverse events occurring in at least 15% of patients
Fatigue
Fever
Nausea
Diarrhoea
Vomiting
Dyspnoea
Constipation
Darbepoetin alfaPlacebo
0 10 20 30 40Patients (%)
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 (non-inferiority) .
• 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
0
0.1
0.2
0.3
0.4
Prob
abilit
y of T
rans
fusion
(Upp
er 95
% C
I)
23%
0.5
Week 5 to EOTP Week 1 to EOTP
30%36%
29%
Difference: Q3W-QWa
-6.8 (95% CI: -13.6 to 0.1)Percentage Points
Difference: Q3W-QWa
-6.9 (95% CI: -14.0 to 0.2)Percentage Points
DA 2.25 mcg/kg QWDA 500 mcg Q3W
J-L Canon, et al.; JNCI, 98, 4, 273, 2006
Incidence of TransfusionsExternal Validity - Comparison With Previous DA Trials
9. Vansteenkiste J, et al. J Natl Cancer Inst. 2002;94:1211-122010. Hedenus M, et al. Br J Haematol. 2003;122:394-403.11. Kotasek D, et al. Proc Am Soc Clin Oncol. 2002;21:356a.
Prob
abilit
y of T
rans
fusio
n (9
5% C
I)(W
eek 5
to E
OTP)
Vansteenkiste, et al9 Hedenus, et al10 Kotasek, et al11 Canon, et al (present study)
0.2
0.4
0.3
0.5
n = 149 n = 148 n = 165 n = 167 n = 345 n = 334 n = 337 n = 335
0.6 PlaceboDA 2.25 mcg/kg QWDA 4.5 mcg/kg front-loadDA 500 mcg Q3W
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
ChemotherapyChemotherapy--Induced Induced NeutropeniaNeutropenia
MildMild((<< 2,000)2,000)
Grade 1Grade 1
ModerateModerate((<< 1,500)1,500)
Grade 2Grade 2
SevereSevere((<< 1,000)1,000)
Grade 3Grade 3
Severe/LifeSevere/Life--threateningthreatening
((<< 500)500)
Grade 4Grade 4
Common Toxicity CriteriaCommon Toxicity Criteria. Version 2.0 [electronic document]. Bethesda, . Version 2.0 [electronic document]. Bethesda, MdMd: National Cancer : National Cancer Institute; 1999. Available at: Institute; 1999. Available at: http://http://ctep.info.nih.gov/reporting/ctc.htmctep.info.nih.gov/reporting/ctc.htmll. Accessed January 8, 2003.. Accessed January 8, 2003.
Neutropenia and Risk of Febrile Neutropenia (FN)
0% 3%11%
19%
39%
0
10
20
30
40
50
0 1 2 3 >=4
Duration of Severe Neutropenia (Days)
Perc
ent F
N (%
)
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
23%
0%10%20%30%40%50%60%70%80%
Mamman=6935
NSCLCn=3721
SCLCn=1728
Ovarn=2467
NHLn=4431
HDn=1628
AMLn=1437
Gesamt
Febrile Neutropenia (FN): absolut Neutrophilecount (ANC) < 1,0 x 109/l and orale temperature > 38.2°C1… Adelphi Databank: 1997-2002, n = 30753 Pat; Germany, Italy, Spain, France
10,9% (8,5-18%) Mortality at FN
8,5%10,1%
18,0%
10,9%
0%2%4%6%8%
10%12%14%16%18%20%
solide Tumore Lymphome Leukämien Gesamtn = 41.779 Pat. hospitalised with FN; 1995-2000; excapt Transplantations Kuderer N, et al. Proc ASCO 2002;21: Abstract 998
ChemotherapyChemotherapy--Induced Induced NeutropeniaNeutropeniaHas Significant ConsequencesHas Significant Consequences
•• Grade 3 or 4 Grade 3 or 4 neutropenianeutropenia is commonis common
–– ↑↑ risk of liferisk of life--threatening infections, threatening infections, hospitalization, and IV antibioticshospitalization, and IV antibiotics
•• Primary dosePrimary dose--limiting toxicitylimiting toxicity
–– Chemotherapy dose delays and reductions Chemotherapy dose delays and reductions compromise treatment effectivenesscompromise treatment effectiveness
•• Additional impacts: Additional impacts: economic, quality of lifeeconomic, quality of life
OzerOzer H, et al. H, et al. J J ClinClin OncolOncol. 2000;18:3558. 2000;18:3558--353585. Lyman G, et al. 85. Lyman G, et al. EurEur J Cancer. J Cancer. 11998;34:1857998;34:1857--181864. 64. Lyman G, et al. Lyman G, et al. BloodBlood. 2001;98:432a. . 2001;98:432a. Calhoun E, et al. Calhoun E, et al. Blood.Blood. 2001;98:427a. Fortner, et al. 2001;98:427a. Fortner, et al. Ann Ann OncolOncol.. 20022002--13(suppl 5):640 p.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
GG--CSF Decreases CSF Decreases SeveritySeverity and and DurationDuration of Chemotherapyof Chemotherapy--Induced Induced
NeutropeniaNeutropeniaMedian ANC during cycle 1,Median ANC during cycle 1,
CAE chemotherapy in smallCAE chemotherapy in small--cell lung cancercell lung cancer
0.010.01
0.10.1
0.50.51.01.0
10.010.0
100.0100.0
00 44 88 1212 1616 2020 2424
Start Start NeupogenNeupogen®®/Placebo/Placebo Placebo (n = 110)Placebo (n = 110)NeupogenNeupogen®® (n = 101)(n = 101)
ANC ANC ((×× 101099/L)/L)
Severe Severe neutropenianeutropenia (ANC (ANC << 500)500)
Study dayStudy dayCrawford J, et al. Crawford J, et al. N N EnglEngl J Med.J Med. 1991;325:1641991;325:164--170.170.
FilgrastimFilgrastim Decreases Decreases IncidenceIncidence of FNof FN
0
20
40
60
80
100
FN Cycle 1 FNCumulative
Culture-ConfirmedInfection
FN Cycle 1 FNCumulative
Culture-ConfirmedInfection
% P
atie
nts
Placebo NEUPOGEN
PP < 0.001< 0.001
NR*NR*
PP < 0.001< 0.001
PP < 0.012< 0.012PP < 0.012< 0.012
PP = 0.101= 0.101
®
Crawford J, et al. Crawford J, et al. N N EnglEngl J Med.J Med. 1991;325:1641991;325:164--170.170. TrilletTrillet--Lenoir V, et al. Lenoir V, et al. EurEur J Cancer.J Cancer. 1993;29A:3191993;29A:319--324.324.
* NR = Not Reported* NR = Not Reported
FilgrastimFilgrastim Reduces Need for Reduces Need for Antibiotic Antibiotic TherapyTherapy and and HospitalizationHospitalization for Infectionfor Infection
5858 5858
3737 3939
Placebo (n = 64)Placebo (n = 64)NeupogenNeupogen®® (n = 65)(n = 65)
Antibiotic useAntibiotic use HospitalizationHospitalization
7070
6060P P << 0.040.04P P << 0.020.025050
4040IncidenceIncidence(%)(%)
3030
2020
1010
00
TrilletTrillet--Lenoir V, et al. Lenoir V, et al. EurEur J Cancer.J Cancer. 1993;29A:3191993;29A:319--324.324.
Oncology Practice Pattern Study Shows Oncology Practice Pattern Study Shows Lower FN Rates With Lower FN Rates With Optimal DaysOptimal Days of of
FilgrastimFilgrastim•• FN rates were 12% when an average of 5 days of FN rates were 12% when an average of 5 days of NeupogenNeupogen®® was usedwas used•• FN rates were 5% when an average of 10 days of FN rates were 5% when an average of 10 days of NeupogenNeupogen®® was usedwas used
Scott SD, et al. Scott SD, et al. SupplSuppl J Man Care J Man Care PharmPharm.. 2003;9(2):152003;9(2):15--21.21.
n = 73 n = 73 cycles1414 cycles
n = 579 n = 579 cycles
1212 Group A(mean 4.7 days)
cycles1010
88 Group B(mean 10.1 days)
n = 579 n = 579 cyclescycles
n = 73 n = 73 cycles66 cycles
44
P P = 0.02= 0.0222
00AvgAvg NeupogenNeupogen®®
Use (days)FN RateFN Rate
(percentage)(percentage)Use (days)
Delayed InitiationDelayed Initiation of Gof G--CSF May CSF May Compromise Clinical OutcomesCompromise Clinical Outcomes
Impact of Timing of GImpact of Timing of G--CSF Administration After HighCSF Administration After High--Dose Dose CyclophosphamideCyclophosphamide
KoumakisKoumakis, et al. , et al. OncologyOncology. 1999;56:28. 1999;56:28--35.35.
Group A Group A
(24 hrs) (24 hrs) n = 13n = 13
Group BGroup B
(48 hrs) (48 hrs) n = 11n = 11
Group CGroup C
(72 hrs) (72 hrs) n = 10n = 10
Group D Group D
(96 hrs) (96 hrs) n = 12n = 12
No Growth No Growth Factor Factor n = 14n = 14
Incidence of FN Incidence of FN 16%16% 33%33% 25%25% 66%66% 75%75%
Duration of Duration of NeupogenNeupogen®®
((filgrastimfilgrastim) ) Administration (Days)Administration (Days)
11.511.5 1212 13.513.5 15.515.5 ––
Note: Patients in this study were dosed through grade 1 Note: Patients in this study were dosed through grade 1 neutropenianeutropenia..
• 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
PegylatingPegylating filgrastimfilgrastim Makes OnceMakes Once--PerPer--ChemotherapyChemotherapy--Cycle Dosing PossibleCycle Dosing Possible
FilgrastimFilgrastimDaily dosingDaily dosing
HelicalHelicalbundlebundle
PegfilgrastimPegfilgrastim1 dose per cycle of
chemotherapy
HelicalHelicalbundlebundle
Polyethylene glycolPolyethylene glycol(PEG)(PEG)
Pegfilgrastim- stabil serumconcentrationANC-nadir less decreased
Tag0
ANC
5 10 15 20 25
1000
100
10
1
0.1
0.01
Pegfilgrastim 100 µg/kg (n = 3)
Med
ian e
r AN
C(×
109 /L
)
ANC
Tag
Filgrastim 5 µg/kg/d (n = 3)100
10
1
0.1
0.010 5 10 15 20
Mediane S
erum-
konzentration(µg/L)
25
sustained plasma concentrationssustained plasma concentrationsSerum halfSerum half--life 46life 46––62 hours62 hours
Serum halfSerum half--life ~3 hourslife ~3 hours
Adapted from Johnston E, et al. J Clin Oncol. 2000;18:2522–2528.
Single Dose of Single Dose of NeulastaNeulasta®® Stimulates Stimulates NeutrophilNeutrophilRecovery as Recovery as EffectivelyEffectively as 11 Daily Injections of as 11 Daily Injections of
NeupogenNeupogen®®
0.01
0.10
1.00
10.00
100.00
1000.00
Cycle day1 2 3 4 5 6 7 8 99 10 11 12 13 14 15 16 17 18 19 20 21
AN
C (x
109 /L
)In
terq
uart
ilera
nge
Study drug
Chemo-therapy
Neupogen® 5 µg/kg/day (n = 75)Neulasta® fixed, 6 mg (n = 77)
Neulasta®
Neupogen® Injections
Adapted from Green M, et al.Adapted from Green M, et al. Ann Ann OncolOncol. 2003;14:29. 2003;14:29--3535..
DurationDuration of Severe of Severe NeutropeniaNeutropenia (DSN) in Cycle 1(DSN) in Cycle 1
NeupogenNeupogen®® ((filgrastimfilgrastim))NeulastaNeulasta®® ((pegfilgrastimpegfilgrastim))No Growth FactorNo Growth Factor
1.61.61.81.8Green et al Green et al
(n = 130)(n = 130)
00 11 22 33 44 55
1.81.81.71.7Holmes et alHolmes et al
(n = 296)(n = 296)
00 11 22 33 44 55
5
0 1 2 3 4 5
Misset et al* (n = 42)(n = 42)
DAYSDAYS*In patients who received a similar *In patients who received a similar myelosuppressivemyelosuppressive regimen, but did not receive growth factor, the median regimen, but did not receive growth factor, the median DSN was 5 days.DSN was 5 days.Holmes FA, et al. Holmes FA, et al. J J ClinClin OncolOncol.. 2002;20:7272002;20:727--731. 731. Green M, et al.Green M, et al. Ann Ann OncolOncol. . 2003;14:292003;14:29--3535.. MissetMisset, et al. , et al. Ann Ann OncolOncol. 1999; . 1999; 10:55310:553--560.560.
PegfilgrastimPegfilgrastim Led to a Led to a Lower Rate of FNLower Rate of FN
Green et alGreen et al(n = 152) (n = 152)
Holmes et alHolmes et al(n = 296) (n = 296)
NeulastaNeulasta®® NeupogenNeupogen®® NeulastaNeulasta®® NeupogenNeupogen®®
13%13% 20%20% 9%9% 18%
MissetMisset et al* et al* (n = 42)(n = 42)
No Growth No Growth FactorFactor
38%18% 38%
Febrile Febrile neutropenianeutropenia defined as defined as ANC < 500 (0.5 ANC < 500 (0.5 ×× 101099/L) and fever/L) and fever ((≥≥ 38.238.2°°C).C).
Note:Note: These trials comparing These trials comparing NeupogenNeupogen®® ((filgrastimfilgrastim) and) andNeulastaNeulasta®® were designed as nonwere designed as non--inferiority studies.inferiority studies.
** In patients who received a similar In patients who received a similar myelosuppressivemyelosuppressive regimen, but did not receive regimen, but did not receive growth factor, the rate of febrile growth factor, the rate of febrile neutropenianeutropenia was 38%.was 38%.
Holmes FA, et al. J Holmes FA, et al. J ClinClin OncolOncol. 2002;20:727. 2002;20:727--731; 731; Green M, et al. Ann Green M, et al. Ann OncolOncol. 2003;14:29. 2003;14:29--35; 35; MissetMisset JL, et al. Ann JL, et al. Ann OncolOncol. 1999;10:553. 1999;10:553--560.560.
PegfilgrastimPegfilgrastim shows a 71% relative shows a 71% relative reduction reduction in FN incidencein FN incidence
19*
38†
11*
0
10
20
30
40
Pegfilgrastim Filgrastim No G-CSF
*Siena S, et al. *Siena S, et al. OncolOncol Rep. Rep. 2003;10:7152003;10:715--724724;;††MissetMisset J, et al. Ann J, et al. Ann OncolOncol. 1999;10:553. 1999;10:553--560.560.
42
50
71
Inci
denc
e of
FN
(%)
Pegfilgrastim 6-mg Fixed Dose Is Effective Across a Broad Range of Body Weights
PegfilgrastimPegfilgrastim 66--mg Fixed Dosemg Fixed Dose Is Effective Is Effective Across a Broad Range of Body WeightsAcross a Broad Range of Body Weights
Mean DSN in cycle 1 by body weight group in quartilesMean DSN in cycle 1 by body weight group in quartiles
Mea
n D
urat
ion
of S
ever
e M
ean
Dur
atio
n of
Sev
ere
Neu
trop
enia
Neu
trop
enia
(day
s)(d
ays)
0
1
2
3
4
4646--62 kg62 kg >71>71--80 kg80 kg>62>62--71 kg71 kg >80>80--125125 kgkg
PegfilgrastimPegfilgrastim 66--mg fixed dosemg fixed dose
FilgrastimFilgrastim 5 5 mcmcg/kg/dg/kg/d
Data on file, Amgen.Data on file, Amgen.
First and First and Subsequent CySubsequent Cyccle Usele Use of Pegfilgrastim of Pegfilgrastim in in PaPatients tients wwith Breast Cancer: A Multicenter, Doubleith Breast Cancer: A Multicenter, Double--BlBliind, nd,
Placebo Controlled Phase III StudyPlacebo Controlled Phase III Study;;
SCREENING
SCREENING
PlaceboPlacebo
PegfilgrastimPegfilgrastim
Double-Blind Phase
FN Docetaxel + PegfilgrastimDocetaxel + Pegfilgrastim
Open-Label Phase
RANDOMIZATION
RANDOMIZATION
CHEMOTHERAPY
CHEMOTHERAPY
N=928
Docetaxel 100mg/m2 IV + blinded product Q3wk x 4 cycles
Charles L. Vogel et al; JCO 2005, vol 23
NeulastaNeulasta shows 94 % relative reduction in FN shows 94 % relative reduction in FN incidence comparing to placeboincidence comparing to placebo
1%*
0
5
10
15
20
Neulasta Placebo
P < 0,05
RR 94 %
Inci
denc
e of
FN
*(%
)
17%*
*FN = febrile neutropenia
Charles L. Vogel et al; JCO 2005, vol 23
• 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
Patients Frequently Experience Patients Frequently Experience Chemotherapy Dose Delays and Dose Chemotherapy Dose Delays and Dose
ReductionsReductions
0
24 24
5
26 26
6
2728
9
28 30
10
36
43
8
36
46
25
37
56
0
10
20
30
40
50
60
Patie
nts
(%)
1(n=19,898)
2(n=19,824)
3(n=19,781)
4(n=19,243)
5(n=11,648)
6(n=11,027)
Overall(n=19,898)
Delay ≥ 7 daysReduction ≥ 15%
RDI <85%
CyclesLyman GL et al. J Clin Oncol. 2003;21:4524-4531.
Delivery of Chemotherapy Delivery of Chemotherapy Planned Dose Planned Dose Improves Outcomes in Adjuvant Breast Cancer Improves Outcomes in Adjuvant Breast Cancer
ChemotherapyChemotherapy
The Milan Study: relapseThe Milan Study: relapse--free and overall survivalfree and overall survivalwith CMF: 20with CMF: 20--year followyear follow--up (n = 386)up (n = 386)
Prob
abilit
y of
Prob
abilit
y of
relap
sere
lapse
-- free
survi
val
free s
urviv
al
55 1010 1515 202000
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0
Prob
abilit
y of
Prob
abilit
y of
over
all su
rviva
lov
erall
survi
val
55 1010 1515 202000
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0
Years after mastectomyYears after mastectomy0000
≥≥ 85 (n = 42) 85 (n = 42) 6565––84 (n = 94) 84 (n = 94) << 65 (n = 71)65 (n = 71)Control (n = 179)Control (n = 179)
% of planned dose% of planned dose
BonadonnaBonadonna G, et al. G, et al. N N EnglEngl J MedJ Med. 1995;332:901. 1995;332:901--906906..
Delivery of Chemotherapy Delivery of Chemotherapy Planned Dose Improves Planned Dose Improves SurvivalSurvival in Nonin Non--HodgkinHodgkin’’s Lymphomas Lymphoma
RDI = relative dose intensity.RDI = relative dose intensity.KwakKwak LW, et al. LW, et al. J J ClinClin OncolOncol. . 1990;8:9631990;8:963--977.977.
Retrospective survival analysis with CHOP, Retrospective survival analysis with CHOP, mm--BACOD, or MACOPBACOD, or MACOP--B (n = 115)B (n = 115)
100100
Years after treatmentYears after treatment00
8080
6060
4040
2020
0011 22 33 44 55 66 77
P P = 0.001= 0.001
RDI doxorubicin RDI doxorubicin >> 75%75%
n = 92n = 92
RDI doxorubicin RDI doxorubicin ≤≤ 75%75%
n = 23n = 23
SurvivalSurvivalprobabilityprobability
(%)(%)
NeupogenNeupogen®® support in Elderly Patients (> 60 support in Elderly Patients (> 60 years) with NHL,years) with NHL, Dose Dense ChemotherapyDose Dense Chemotherapy
58.658.6
47.047.0
9797
44.644.639.239.2
9393
00
2525
5050
7575
100100CHOPCHOP--14 + G14 + G--CSF (n = 181)CSF (n = 181)CHOPCHOP--21 (n = 189)21 (n = 189)
P P = 0.002= 0.002
P P = 0.024= 0.024
PatientsPatients(%)(%)
Time to treatment failureTime to treatment failure(median 49 months)
RDIRDI(median)
Overall survivalOverall survival(median 49 months)(median 49 months)(median) (median 49 months)
PfreundschuhPfreundschuh M, et al. M, et al. Blood.Blood. 2002;100:774a. Abstract 3060.2002;100:774a. Abstract 3060.
Dose Dense CT at Breastcancerwith Neupogen® Prophylaxis* : CALGB 9741Dose Dense CT at Breastcancerwith Neupogen® Prophylaxis* : CALGB 9741
Doxorubicin 60 mg/m2
Cyclophosphamid 600 mg/m2Paclitaxel (Taxol) 175 mg/m2 über 3 hNeupogen® 5 µg/kg, Tag 3-10
* Filgrastim-Administartion in Q2W primärprophylactic, in Q3W according ASCO-GuidelinesCitron M et al. J Clin Oncol 2003, Vol 21: 1431-1439
26% reduced Risk of Relaps26% reduced Risk of Relaps
1 10,93
0,74
1.0
0.8
0.6
0.4
0.2
0sequential alternating 3-wek 2-wek
P = 0.058 P = 0.010
-26 % RR*
n = 1973R
iskr
ate
* Multivariates, proportionell Cox RiskmodelCitron M et al. J Clin Oncol 2003, Vol 21: 1431-1439
31% reduced Risk of Mortality31% reduced Risk of Mortality
1 10,89
0,69
1.0
0.8
0.6
0.4
0.2
0
P = 0.48 P = 0.013
-31 % RR*
sequential alternating 3-wek 2-wek
n = 1973R
iskr
ate
* 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
GuidelinesGuidelinesNCCN 2005 NCCN 2005 vs vs ASCO 2000ASCO 2000
NCCN 2005NCCN 2005 ASCO 2000ASCO 2000
First cycle GFirst cycle G--CSF useCSF use
Consider GConsider G--CSF forCSF for
Patient risk factorsPatient risk factors
Relevance of CT dose Relevance of CT dose intensityintensity
Intervention for subsequent Intervention for subsequent cyclescycles
Recommended productsRecommended products
riskrisk FN > 20%FN > 20%
risk FN risk FN 1010––20%20%
riskrisk FN > 40%FN > 40%
<< 40% 40% ““watch and waitwatch and wait””
Extensive listExtensive list Limited listLimited list
Include dose intensity in risk Include dose intensity in risk assessmentassessment
No endoresement of GNo endoresement of G--CSFCSF
Review FN risk and use of Review FN risk and use of GG--CSFCSF
at each cycleat each cycle
Consider dose reduction Consider dose reduction before use of Gbefore use of G--CSFCSF
Category 1 for Category 1 for filgrastimfilgrastim or or pegfilgrastimpegfilgrastim**
NANA
Ref. NCCN MGF Guidelines – v1 2005; pdf - accessed 20th April 2005 http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.
Patient risk factorsPatient risk factors for developing for developing febrile neutropeniafebrile neutropenia
(examples, NCCN 2005)(examples, NCCN 2005)
Age(> 65 years)Age(> 65 years)
Female genderFemale gender
Poor performance status (ECOG Poor performance status (ECOG ≥≥ 2)2)
Neutropenia in the historyNeutropenia in the history
Comorbidities ( COPD, cardiovascular disease, diabetes Comorbidities ( COPD, cardiovascular disease, diabetes mellitus, etc.)mellitus, etc.)
Bone marrow involvement with tumorBone 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.
ChemoChemo--regimensregimens with FN with FN risk > 20%risk > 20%(examples, NCCN 2005)(examples, NCCN 2005)
BreaBreasst cancert cancer•• ACAC -- T (doxorubicin, cyclophosphamid, docetaxel)T (doxorubicin, cyclophosphamid, docetaxel)
•• AT (doxorubicin, paclitaxel)AT (doxorubicin, paclitaxel)
•• TAC (docetaxel, doxorubicin, cyTAC (docetaxel, doxorubicin, cycclofosfamid)lofosfamid)
Ovarian cancerOvarian cancer•• PaclitaxelPaclitaxel
•• DocetaxelDocetaxel
NHLNHL•• DHAP (dexamethason, cisplatin, cytarabin)DHAP (dexamethason, cisplatin, cytarabin)
•• ESHAP (etoposid, methylprednison, cisplatin, cytarabin)ESHAP (etoposid, methylprednison, cisplatin, cytarabin)
Testicular Cancer Testicular Cancer •• VIP (vinblastin, ifosfamid, cisplatin)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.
ChemoChemo--regimensregimens with FN with FN risk 10% risk 10% -- 20%20%(examples, NCCN 2005)(examples, NCCN 2005)
Breast carcinomaBreast carcinoma•• DocetaxelDocetaxel
•• AC (doxorubicin, cyAC (doxorubicin, cycclofosfamid)lofosfamid)
NonNon--small Cell Lung Carcinoma small Cell Lung Carcinoma •• TC (cisplatina, paclitaxel)TC (cisplatina, paclitaxel)
NHLNHL•• RR--CHOP (cyCHOP (cycclofosfamid, doxorubicin, vinlofosfamid, doxorubicin, vinccristin, prednison, rituximab)ristin, prednison, rituximab)
•• FM (fludarabin, mitoxantron)FM (fludarabin, mitoxantron)
Testicular carcinomaTesticular carcinoma•• EC (etoposid, cisplatin)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 TreeNCCN 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