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.

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


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


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

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

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.

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


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


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

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.

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..

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



• 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

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


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)


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)


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

advancing the management of chemotherapy-induced … e p06.pdf · cancer-related anaemia z20%–60%...

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