ERITROPOIETINA EN ONCOLOGIA: ERITROPOIETINA EN ONCOLOGIA: USO CLINICO Y NIVELES DE USO CLINICO Y NIVELES DE

EVIDENCIAEVIDENCIA

ALBERT BIETEALBERT BIETE

HOSPITAL CLINIC I PROVINCIALHOSPITAL CLINIC I PROVINCIAL

UNIVERSITATUNIVERSITAT DE BARCELONADE BARCELONA

LA ANEMIA EN ONCOLOGIALA ANEMIA EN ONCOLOGIA

Relative increase of mortality in Relative increase of mortality in anaemic patients with canceranaemic patients with cancer150

100

50

0

Mean increase in

mortality risk (%)

Lung

125

75

25

Prostate Lymphoma Head & neck

Overall

19%

47%

67%75%

65%

Systematic review of 60 studies Caro et al. Cancer 2001; 91: 2214–21

7653 421

Low Hb

100

0

20

40

60

80

Years after randomisation

High Hb

37%

22%

51%

36%

5-year survival rate: p=0.0016

Patients with advanced head and neck cancer

Lee et al. Int J Radiat Oncol Biol Phys 1998; 42: 1069–75

LA ANEMIA ES UN FACTOR LA ANEMIA ES UN FACTOR NEGATIVO PARA SUPERVIVENCIANEGATIVO PARA SUPERVIVENCIA

High Hb: ≥14.5 g/dl (men), ≥13 g/dl (women)Low Hb: <14.5 g/dl (men), <13 g/dl (women)

Probability of survival (%

)

0

La La anemiaanemia se se asociaasocia a a menormenorcontrol control locoregionallocoregional

p=0.003

Not anaemic (n=231)

Time after surgery (years)

0

20

40

60

80

100

0 51 2 3 4

Anaemic* (n=27)

*Hb <13 g/dl (men) <12 g/dl (women) Lutterbach and Guttenberger. Int J Radiat Oncol Biol Phys 2000; 48: 1345–50

Fisiopatología de la Hipoxia Fisiopatología de la Hipoxia Anémica en CáncerAnémica en CáncerAsteniaAstenia

“Feelings of tiredness and weakness despite adequate amounts of sleep and rest”

Cella D, et al. J Clin Oncol 2001

MermaMerma de CDVde CDVLind M, et al. Br J Cancer 2002

PeorPeor SupervivenciaSupervivenciaFactor predictivo independiente

Caro JJ, et al. Cancer 2001Watine J, Bouarioua N. Cancer 2002

NeoangiogénesisNeoangiogénesisDunst J, et al. Strahlenther Onkol 2002

ResistenciaResistencia al al TratamientoTratamientoObermair A, et al. Int J Gynecol Cancer 2003Prosnitz RG, et al. IJROBP 2005; 61: 1087-95

Anaemia is a predictive factor for poor Anaemia is a predictive factor for poor prognosis in patients with cancerprognosis in patients with cancer

Poor prognosis

Anaemia

Selection pressureApoptotic deficiency

Chemo- and radio-resistance

Geneticinstability

Angio-genesis

Tumour hypoxia

Accelerated progressionIncreased rate of distant metastases

Algunos datos sobre Algunos datos sobre EpoEpo y y EpoEpo--RR

EritropoyetinaEritropoyetina

� Hormona de 165 aa, codificada en el cr. 7, con 56 kDa

� Regulación compleja

(+): HIF-1, HNF-4 (“Hepatocyte nuclear factor”), insulina e IGF

(-): IL-1 beta, IL-6 y FNT alfa

� EPO sérica 6-32 U/L, puede ser > 10.000 U/L en hipoxia

Receptor de Receptor de EritropoyetinaEritropoyetina

� Glicoproteína de 484 aa, de la superfamilia “receptores de citokinas”, presente en eritroblastos, sistema nervioso, corazón, endotelio, hígado, riñón y gónadas

� 1 molécula de EPO se une a un dímero e induce activación de Jak-2 (tirosina kinasa)

� El dominio intracelular EPO se fosforila y adquiere capacidad para activar varias rutas de señalización:

� Stat-5

� PI3-K / Akt

� Ras - MAPK

Anti-apoptosis (Bcl-X)Mitogénesis

Además de en

los progenitores

hemopoyéticos el

receptor de

eritropoyetina se

expresa otras

células normales

y neoplásicas

EPO: EPO: funciónfunción hemopoyéticahemopoyética

1996: Yoshimura, The Oncologist 1, 337-339

EFECTOS CLINICOS DE LA EPOEFECTOS CLINICOS DE LA EPO

•• Corrección de la anemiaCorrección de la anemia

•• Disminución de las transfusionesDisminución de las transfusiones

•• Disminución de la fatiga y la asteniaDisminución de la fatiga y la astenia

•• Mejora en la calidad de vida globalMejora en la calidad de vida global

•• Efecto protector en SNC y corazónEfecto protector en SNC y corazón

• Epoetina alfa • Darbepoetina• Epoetina beta

EORTC 2004

Epoetina / DarbepoetinaNCCN 2004

EpoetinaASCO / ASH 2002

EPOEPOGuíaGuía

Una Guía de Uso Clínico

¿Existe un EPO de elección?¿Existe un EPO de elección?

Epoetina alfa: - 10.000 UI tres veces por semana - 40.000 UI una vez por semana

Epoetina beta:- 10.000 UI tres veces por semana - 30.000 UI una vez por semana

Darbepoetina alfa:- 150-300 microg una vez por semana - 500 microg cada 3 semanas

Edad y peso del paciente no relevantes

80

Epoetin increases Hb levels and improves prognosis in anaemic

patients* with head and neck cancer

100

Months after treatment

Overall survival (%

)

Hb <14.5 g/dl + epoetin

Hb <14.5 g/dl + no epoetin

00

20

40

60

366 12 18 24 30

Hb ≥≥≥≥14.5 g/dl

Glaser et al. Int J Radiat Oncol Biol Phys 2001; 50: 705–15

Hb ≥≥≥≥14.5 vs Hb <14.5 + no epoetin p=0.04Hb <14.5 no epoetin vs Hb <14.5 + epoetin p=0.001Hb ≥≥≥≥14.5 vs Hb <14.5 + epoetin p=0.7

*Treated with chemoradiotherapy

BRAVEBRAVEBreast cancer Breast cancer –– AnaemiaAnaemia and the Value of and the Value of

Erythropoietin Erythropoietin

•• MulticentreMulticentre study (18 countries), open label designstudy (18 countries), open label design

•• RandomisationRandomisation 1:1 to 1:1 to NeoRecormonNeoRecormon®® versus standard versus standard treatment (transfusion per standard of care)treatment (transfusion per standard of care)

•• Patients with Patients with metastaticmetastatic breast cancer with breast cancer with HbHb <12.9 g/dl<12.9 g/dl and scheduled to start and scheduled to start anthracyclineanthracycline-- and/or and/or taxanetaxane--based chemotherapybased chemotherapy

•• Recruitment target: 460 patientsRecruitment target: 460 patients�� Primary Endpoint Overall SurvivalPrimary Endpoint Overall Survival

BRAVE study designBRAVE study design

24 weeks

Followup

Followup

Chemotherapy

NeoRecormon® 30 000 IU once weekly

18 months

Hb target 13–15 g/dlEpoetin treatment interrupted if Hb >15 g/dl

*Transfusion as per standard practice (Hb <8g/dl)

Metastatic breast cancer scheduled for chemotherapy

2 weeks screeningStandard treatment*

Chemotherapy

IDMC at > 6 months fup: no issue…!

BRAVEBRAVEIncrease in Increase in HbHb with Once Weekly with Once Weekly NeoRecormonNeoRecormon®®

30 000 IU compared with control30 000 IU compared with control

0 4 8 12 16 20 240

1.0

2.0

3.0

Weeks

Mean Hbchange relative

to control (g/dl)

ESMO 2004

DoubleDouble--blind, placeboblind, placebo--controlled study of controlled study of

quality of life, quality of life, hematologichematologic endpoints and endpoints and

safety of weekly safety of weekly EpoEpo--alfaalfa in children with in children with

cancer receiving cancer receiving myelosuppressivemyelosuppressive QTQT

100 EPO x 16 s. 600-900 u./Kg/semana211

(5-18 a.) 111 Placebo x 16 s. 1 x semanaAnemia

ResultadosResultados y y conclusionesconclusiones::

�� Menor número de transfusiones en grupo Epo� Efectos adversos idénticos en ambos grupos� Mejoria leve en los índices de calidad de vida� Aumento significativo de Hb en el grupo Epo

Razzouk et al.

St. Jude Children’s Hosp. MemphisJ. Clin Oncol 2006 24 (22): 3583

DoubleDouble--blind, placeboblind, placebo--controlled study of controlled study of

quality of life, quality of life, hematologichematologic endpoints and endpoints and

safety of weekly safety of weekly EpoEpo--alfaalfa in children with in children with

cancer receiving cancer receiving myelosuppressivemyelosuppressive QTQT

ReducciónReducción de de transfusionestransfusiones en en pacientespacientes neoplásicosneoplásicos

Weeks 4–12

22%

43%

*

Weeks 1–12

32%

52%

*

Patients requiring

transfusion (%)

50

0

20

10

30

Standard therapy (n=129)

Epoetin beta (n=133)

40

60

*p≤0.001 vs standard therapy Boogaerts et al. Br J Cancer 2003; 88: 988–95

La La AnemiaAnemia decrecedecrece la la calidadcalidad dede vidavida

AnaemiaCapacidadde trabajodisminuida

Depresion

Relacionessociales

dificultadas

Fatiga

Alteracionessexuales

Menorconcentración

Capacidad de ejercicioreducida

EpoEpo mejoramejora la la calidadcalidad de de vidavidaen en pacientespacientes con cancercon cancer

-10

-5

0

5

10n=227

n=108

n=227

n=108

n=227

n=107

Energía p<0.001Actividad diaria

p<0.01Calidad de vida global

p<0.01

Change in score

Epoetin alfa Placebo

7.84

-5.81

7.28

-5.99

4.55

-5.97

Littlewood et al. J Clin Oncol 2001; 19: 2865–74

Hay alguna relación entre Hay alguna relación entre EpoEpo y y supervivencia y/o control local en los supervivencia y/o control local en los pacientes con cáncer?pacientes con cáncer?

Placebo

100

0

20

40

60

80

Months

Survival (%

)

Epoetin

0 406 12 18 24 30 36

Study not originally designed or powered to evaluate survival Littlewood et al. J Clin Oncol 2001; 19: 2865–74

EpoetinPlacebo

60%49%

17 months11 months

12-monthsurvival

Mediansurvival

EpoEpo puedepuede mejorarmejorar la la supervivenciasupervivenciade de pacientespacientes con con cáncercáncer

EpoEpo puedepuede aumentaraumentar la la supervivenciasupervivencia de de pacientespacientes con con cáncercáncer de de pulmónpulmón y QTy QT--PtPt100

90

80

70

60

50

40

30

20

10

0

Percentage of patients surviving

1 6 11 16 21 26 31 36 41 46 51 56 61 66 71 76 81 86 91 96Study week

n= 159 149 137 123 104 87 75 66 55 51 45 36 28 21 14 6 4 2n= 155 149 139 125 99 92 85 78 71 60 51 39 25 19 12 8 4 3

0 01 0

PlaceboDarbepoetin alpha

Vansteenkiste et al. J Natl Cancer Inst 2002; 94: 1211–20

Leyland-Jones et al. FDA ODAC hearing May 4. 2004

Time to deaths of all causes within Time to deaths of all causes within 12 months after randomisation12 months after randomisation

Month

xx

1.0

0.9

0.8

0.7

0.6

0.5

Proportion of subjects alive

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Group n Died KM estimatePlacebo 470 78 79%Epoetin 469 101 74%

(EPO-INT-76: All subjects)

EpoetinEpoetin alfaalfa: : Survival in combined analysisSurvival in combined analysis

0.990.99

1.171.17

0.810.81

1.561.56

0.150.15

1.581.58

0.420.42

1.681.68

0.860.86

1.081.08

0.890.89

HazardHazardratioratio

OVERALLOVERALL

Mixed (PR98Mixed (PR98--2727--008)008)

Mixed (EPOMixed (EPO--INTINT--10)10)

Mixed (EPOMixed (EPO--INTINT--3)3)

MM (EPOMM (EPO--INTINT--2)2)

Ovarian (EPOOvarian (EPO--INTINT--1)1)

CLL (PCLL (P--174)174)

CLL (J89CLL (J89--040)040)

Mixed (Mixed (cisplatincisplatin))

Mixed (nonMixed (non--cisplatincisplatin))

Mixed (nonMixed (non--chemo)chemo)

Tumor type/studyTumor type/study

Mortality, n/N (%)Mortality, n/N (%)

31/168 (19)31/168 (19)

41/251 (16)41/251 (16)

9/135 (7)9/135 (7)

1/69 (1)1/69 (1)

6/164 (4)6/164 (4)

1/33 (3)1/33 (3)

16/142 (11)16/142 (11)

8/67 (12)8/67 (12)

10/81 (12)10/81 (12)

13/65 (20)13/65 (20)

EpoetinEpoetin alfaalfa

26/165 (16)26/165 (16)

22/124 (18)22/124 (18)

3/65 (5)3/65 (5)

7/76 (9)7/76 (9)

2/80 (3)2/80 (3)

1/12 (8)1/12 (8)

6/79 (8)6/79 (8)

9/65 (14)9/65 (14)

9/76 (12)9/76 (12)

13/59(22)13/59(22)

PlaceboPlacebo

(0.76, 1.28)

0.1 1 10

Favoursepoetin alfa

Favoursplacebo

HR (95% CI) log scaleTest for heterogeneity, P = .66 J&J FDA ODAC May 04

EpoEpo--beta shows a trend towards beta shows a trend towards slowing tumour progressionslowing tumour progression

1 3 40.2 0.40.6 2 56 10 20 30

Risk ratio

0.79

0.78

0.72

1.43

0.55

0.36

0.69

0.83

0.97

0.84

Ten Bokkel Huinink 1998

Österborg 1996

Rau 1998*

Kettelhack 1998

Data on file*

Cazzola 1995

Oberhoff 1998

Boogaerts 2003

Österborg 2002

Solid

Haematological

TOTAL

120

144

54

109

20

146

218

259

343

617

791

1413

nStudy

Favours Epo beta Favours control

*Inadequate no. of events to calculate HR Aapro et al. ESMO 2004

EpoEpo--beta y SV globalbeta y SV global

Overall survival

n at risk

Epo beta Control

0 3 6 9 12

800 509 137 3 2613 388 60 4 0

p=0.87

Months since treatment

1.0

0.8

0.6

0.4

0.2

0.0

Epo beta

Control

Aapro et al. ESMO 2004;

MetanálisisMetanálisis de de EpoEpo--beta y beta y supervivenciasupervivencia globalglobal

Aapro et al. Ann Oncol 2004; 15(Suppl 3): 841P

1.0

0.8

0.6

0.4

0.2

0

n at risk

NeoRecormon®

Control

Overall survival

800 509 137613 388 60

NeoRecormon®

Control

p=0.87

0 1 2 3 4 5 6 Months since treatment

Bohlius et al. Cochrane Database Syst Rev. 2004; (3): CD003407 Also JNCI 2005

Outcomes of Outcomes of epoetinepoetin--treated cancer treated cancer patients: independent metapatients: independent meta--analysisanalysis•• A total of 27 randomised trials included 3287 A total of 27 randomised trials included 3287 patientspatients

•• EpoetinEpoetin significantly reduced risk of RBC significantly reduced risk of RBC transfusions (relative risk = 0.67, 95% CI 0.62transfusions (relative risk = 0.67, 95% CI 0.62––0.73)0.73)

•• EpoetinEpoetin significantly improved haematological significantly improved haematological response (relative risk = 3.60, 95% CI 3.07response (relative risk = 3.60, 95% CI 3.07––4.23)4.23)

•• EpoetinEpoetin shows a trend towards improved overall shows a trend towards improved overall survival (hazard ratio = survival (hazard ratio = 0.81; 95% CI 0.670.81; 95% CI 0.67––0.99)0.99)

El El tratamientotratamiento con EPO con EPO muestramuestra unauna tendenciatendenciaal al incrementoincremento de la de la supervivenciasupervivencia globalglobal

10.01 100Risk ratio

Abels 1993Cascinu 1994

Case 1993Cazzola 1995Coiffier 2001

Dammacco 2001Del Maestro 1997

Dunphy 1999Henry 1995

TOTAL (OR = 0.81)

Study

Favours epoetin Favours control

Kurz 1997Littlewood 2001Oberhoff 1998

Rose 1994Ten Bokkel Huinink 1998

Thatcher 1999aThatcher 1999bThompson 2000Throuvalas 2000Österborg 1996Österborg 1996Österborg 2002

100.1

Odds ratio (OR) (95% CI)

Test for heterogeneity chi-square=14.49: df=18 p=0.6966

Test for overall effect= –2.07 p=0.04

Bohlius et al. Cochrane Database Syst Rev. 2004; (3): CD003407

Also JNCI 2005

Not includingHedenus 2002,Hedenus 2003, Kotasek 2003, Vansteenkiste 2002,Lleyland-Jones 2003,and Henke 2003

Survival with Survival with epoetinepoetin

Studies inconclusive asStudies inconclusive as

•• Most not designed for survivalMost not designed for survival

•• Most not powered for survivalMost not powered for survival

•• Some have methodological issuesSome have methodological issues

USO DE EPOUSO DE EPO

�� ASCO / ASHASCO / ASH

Rizzo JD, et al. Blood 2002, J Rizzo JD, et al. Blood 2002, J ClinClin OncolOncol 20022002

�� NCCN, NCCN, PracticePractice GuidelineGuideline 20042004

http://http://www.nccn.orgwww.nccn.org

�� EORTCEORTC

BokemeyerBokemeyer C, C, AaproAapro MS, MS, CourdiCourdi A, et al. A, et al. EurEur J Cancer J Cancer 20042004

Recomendaciones de SociedadesCientíficas basadas en sólida

bibliografía

B12-13 g/dL

A, B, D< 11 g/dLHbEORTC 2004

2A11-12 g/dL

2A1

< 11 g/dL < 10 g/dL

Síntomas

NCCN 2004

D12 g/dLBD

< 10 g/dL10-12 g/dL

HbASCO/ASH 2002

GradoGradoLlegar a…Llegar a…GradoGradoEmpezar Empezar con…con…

Criterio Criterio principalprincipalGuíaGuía

Uso Clínico de EPORecomendaciones según cifras de Hemoglobina

1º Considerar Epo en pacientes sintomáticos, con o sin tratamiento oncológico activo

No a título profiláctico2º Comenzar con Hb < 11g/dL y llevarla al entorno de 12 g/dL

Aparte del efecto Aparte del efecto antianémicoantianémico, tiene , tiene EpoEpootros efectos?otros efectos?

CONOCIMIENTOS RECIENTESCONOCIMIENTOS RECIENTES

Evidencia de la presencia de Epo, Epo-R y vías de

señales intracelulares en tejidos no hemopoyéticos:

• Sistema nervioso

• Tejido cardiovascular (endotelio, músculo liso,

cardiomiocitos)

• Hígado, intestino y páncreas

• Riñón

• Testículos, útero

• Tejido tumoral

¿Ejerce este sistema alguna función fisiológica ?

Estudios in vitro demuestran una actividad anti-apoptótica

del sistema EPO/EPO-R, ej:

� pro angiogénica

� protección frente a daño de isquemia-reperfusion

¿Es este sistema realmente necesario?

Los ratones mutantes que expresan exlusivamente EPO-R en el

tejido hematopoyético se desarrollan normalmente y son fértiles

(2002 Sasaki et al. Blood, 100, 2279-2288)

Estos hallazgos cuestionan el papel de la EPO-R/EPO más allá del sistema

hematopoyético al menos en lo que se refiere al desarrollo y fertilidad

Expresión de EPO y EPO-R en cerebro

Producción de EPO por astrocitos y neuronas

Expresión de EPO-R por neuronas

Modelo de acción paracrina: prevención de apoptosis

1992: Tan et al. Am. J. Physiol 263(3 PT 2), F474-F481

1993: Masuda et al. J. Biol. Chem. 268, 11208-11216

1994: Masuda et al. J. Biol. Chem. 269, 19488-19493

1999: Juul et al. Pediatric & Developmental Pathology 2, 148-158

La inyección intraperitoneal de Epo reduce el volumen del infarto cerebral en ratas cuando se administra 24 h antes (*p < 0.01) o hasta 6 horas después de oclusión (*p < 0.05).

EPO: actividad protectora de isquemia cerebral

EPO-R células endotelialesEPO como factor angiogénico

control

EPO 1U/ml

Ribatti et al. 1999: Blood, 93, 2627-2636

EPO 10 U/ml

control

Células endoteliales inmortalizadas Embrión de pollo

EPO: función cardioprotectoraModelos animales

Cardiomiocitos: Rata, conejo Descenso de necrosis,

Isquemia/reperfusión apoptosis y caspasas

mejora función cardíaca

Infarto miocardio Rata, conejo Descenso de necrosis y

apoptosis. Mejora de la

función VI

Insuficiencia cardíaca Humanos Mejora de función cardiaca y fracción de eyección

Condición clínica Modelo animal Función

Modelo de infarto experimental en ratones. Volumen del área infartada en el grupo control (MI+ s. salina) frente a MI+EPO. Confirmación de las diferentes áreas infartadas en cortes de tejido miocárdico

EPO: función cardioprotectora

EPO: función anticaquexia (?)Modelo experimental Intervención Resultados/Comentarios

Adenocarcinoma rHuEpo vs Reducción de la pérdida de

C26-B, ratones1 no tratamiento peso. Relación probable con

menor glicolisis anaerobia

Modelo humano Intervención Resultados/Comentarios

Diversos tumores Indometacina vs Menor pérdida de peso y

avanzados con indometacina+Epo mejor capacidad funcional

pérdida de peso2 con Epo.

Tumores sólidos en Epo vs no Tendencia a menor pérdida

niños con pérdida de tratamiento de peso con Epo.

Peso3

1.- van Halteren. Cancer Res Clin Oncol 20042.-Daneryd. Cancer Res 19983.-Csàki. Eur J Cancer 1998

¿El ¿El sistemasistema EPO/EPOEPO/EPO--R R juegajuega algúnalgún

papelpapel vital en el vital en el crecimientocrecimiento tumoraltumoral??

EPO-R EPO200U/ml for 30mins.

Receptor-EPO

Expresión de EPO-R y ligando de EPO en células

HELA

Roche data, 2003

EPO-R en carcinoma de mamaEPO-R expresión en el carcinoma ductal invasor

Carcinoma intraductalHiperplasia ductal

benigna

Acs et al. 2002: Immunohistochemical Expression of EPO and EPOR in Breast Carcinoma, Cancer, 95, 969-981

Hiperplasia vs

carcinoma

EPO stimulates growth and STAT % EPO stimulates growth and STAT %

phosphorilationphosphorilation in human prostate in human prostate

epithelial and cancer cellsepithelial and cancer cells

Estudio de laboratorio que investiga la presencia de EpoR y su funcionalidad mediante ensayos de proliferación celular y STAT5 fosforilización.

CONCLUSIÓN: Las células humanas epiteliales normales y cancerosas de la próstata expresan receptoresfuncionantes de Epo y ésta última sirve como factor de crecimiento para las mismas. Estos resultados tienen implicaciones para nuestro conocimiento del crecimiento prostático y el desarrollo del cáncer.

Feldman et al.Beth Israel Med. C. BostonProstate 2006 66(2): 135

EPOEPO--R Transcription is not predictive of R Transcription is not predictive of

surface expression in Human Tumour Cellssurface expression in Human Tumour Cells

��A survey of 1000 tumour samples found no evidence for A survey of 1000 tumour samples found no evidence for amplification, suggesting the EPOR gene is not amplified in amplification, suggesting the EPOR gene is not amplified in there tumoursthere tumours

��EPOEPO--R transcript levels are R transcript levels are not elevatednot elevated in tumours in tumours compared with normal tissuescompared with normal tissues

��Even though EPOEven though EPO--R protein may be synthesized in some R protein may be synthesized in some tumour lines, they have tumour lines, they have undetectable levels of surface EPOR.undetectable levels of surface EPOR.

��These data suggest that These data suggest that EpoREpoR expression is not a driver of expression is not a driver of tumour formation or progressiontumour formation or progression

Sinclair et al.Sinclair et al.Abstract on AACR meeting, (2004)Abstract on AACR meeting, (2004)

AntiAnti--EPOEPO--R antibodies do not predict R antibodies do not predict EpoEpo

receptor expressionreceptor expression

��The four commercially available antiThe four commercially available anti--EpoREpoR antibodies (Hantibodies (H--194, C194, C--20, M20, M--20 and 0720 and 07--311) detected proteins of 66 to 78 311) detected proteins of 66 to 78 kDakDa, significantly larger than the predicted molecular , significantly larger than the predicted molecular weight of weight of EpoEpo--R (56R (56--57 57 kDakDa))

��Only MOnly M--20 identify a 5920 identify a 59--kDa EPOkDa EPO--R protein by R protein by immuneblottingimmuneblotting, but is not suitable for , but is not suitable for immunehistochemistryimmunehistochemistry detectiondetection

��These antibodies have limited utility for detection These antibodies have limited utility for detection ofEpoRofEpoR

��Reports of Reports of EpoEpo--R expression in tumour cells using these R expression in tumour cells using these antibodies should be viewed with cautionantibodies should be viewed with caution

Elliot S. et al.Elliot S. et al.

Blood, 107, 5, 1892 (2006)Blood, 107, 5, 1892 (2006)

Ensayos “de alerta” con AREEnsayos “de alerta” con AREBEST (EPO-INT-76)

QT

Hb < 13

EPO alfa, 40.000 UI/semana

Placebo (dob le ciego)

N = 939, ccááncerncer de mamade mama, en 139 centros de 20 países

Objetiv oprimario: superv ivencia1 año

Leyland-Jones, Lancet 2003

• EPO empeora la supervivencia• Disbalance pronóstico

Henke M, et al. Lancet 2003

• EPO acorta el ILP• Graves defectos de método

�Multicéntrico, aleatorizado, doble ciego, en cabezacabeza y y cuellocuello

� N = 351, con RT + placebo ó + EPO beta

EpoetinEpoetin treatment to prevent anaemia in patients treatment to prevent anaemia in patients with with metastaticmetastatic breast cancer: (BEST study)breast cancer: (BEST study)

•• EpoetinEpoetin alfaalfa in nonin non--anaemic patients (n=939) receiving anaemic patients (n=939) receiving firstfirst--line chemotherapy for line chemotherapy for metastaticmetastatic breast cancerbreast cancer((HbHb: 13 g/dl): 13 g/dl)

•• Study terminated earlyStudy terminated early

––0.20.211ThromboticThrombotic and vascular events and vascular events (%)(%)

––3366Disease progression (%)Disease progression (%)

––1616414144--month mortality (no. of month mortality (no. of deaths)deaths)

0.01170.0117767670701212--month survival (%)month survival (%)

p valuep valuePlaceboPlaceboEpoetinEpoetin alfaalfa

Leyland-Jones et al. Lancet Oncol 2003; 4: 459–60BEST, Breast Cancer Erythropoietin Trial

Unless indicated, p values not specified in publication

Results from the BEST study should Results from the BEST study should be interpreted with cautionbe interpreted with caution•• Imbalance of risk factorsImbalance of risk factors

–– epoetinepoetin alfaalfa patients were older, had lower PS, more advanced patients were older, had lower PS, more advanced disease and more disease and more thromboticthrombotic risk factorsrisk factors

•• Mortality imbalance mostly caused by disease progression within Mortality imbalance mostly caused by disease progression within first first 4 months 4 months –– unlikely to be related to unlikely to be related to epoetinepoetin

•• Unusual features of the study population Unusual features of the study population

–– a high number of early deaths in both groups a high number of early deaths in both groups

–– small difference in small difference in HbHb levels between groupslevels between groups

–– a high proportion of patients in the placebo group did not a high proportion of patients in the placebo group did not become anaemicbecome anaemic

•• Problems in design, conduct and analysis complicate interpretatiProblems in design, conduct and analysis complicate interpretationon

Leyland-Jones et al. Lancet Oncol 2003; 4: 459–60

ENHANCE study results: LPFS ENHANCE study results: LPFS –– overall overall ITT populationITT population

Henke et al. Lancet 2003;362:1255–60

1.0

0.8

0.6

0.4

0.2

0

n at riskNeoRecormon 180 133 94 71 54 37 24 19 15 12 6 0Placebo 171 134 104 89 69 49 32 23 18 10 4 0

0 6 12 18 24 30 36 42 48 54 60 66

Study month

Progression-free survival NeoRecormon

p=0.04

Placebo

PACIENTES NO EVALUABLESPACIENTES NO EVALUABLES

Global

39%

Grupo placebo

34%

Grupo EPO

44%

El % estándar aceptado para considerar metodológicamente

válidas las conclusiones de un estudio es del 15%.

(Redmon, 2001)

CONTROVERSIAS RECIENTES DEL USO DE EPO.

Henke et al. Lancet 2003; 362:1255-1260.

Supervivencia libre de progresión

Tiempo (meses)

Probabilidad de SLP-LR

0 12 24 36 48 60 72

Disminución estadísticamente significativa del control local en el grupo tratado con EPO.

CONTROVERSIAS RECIENTES DEL USO DE EPO.

Henke et al. Lancet

2003; 362:1255-1260.

Implicaciones de la hipoxia tumoral en la respuesta clínica a la radioterapia

LPFS by LPFS by TumourTumour Location Location –– Difference in Difference in effect is limited to effect is limited to hypopharynxhypopharynx populationpopulation

Hypoharyngeal Tumours All Other Tumours

““ TheThe characteristicscharacteristics of of thethe patients patients in in thethe intentionintention--to to treattreat population population werewere similarsimilar in in thethe twotwo treatmenttreatmentgroups groups atat baselinebaseline, , withwith thetheexception of a exception of a higherhigher proportion in proportion in thethe epoetinepoetin betabeta group of group of smokerssmokersandand of patients of patients withwith relapsedrelapsed cancercancer””

Henke et al. Lancet 2003; 362: 1255–60

18

16

14

12

10

Hb(g/dL)

0 2 4 6 8 10Time (weeks)

Placebo

EPO

Henke (2003)H & N

Becker (2000)Vaupel (2002)SCC

Median pO2 (mm Hg)0 4 8 12 16 20

18

16

14

12

10

La La OxigenaciónOxigenación MáximaMáxima TumoralTumoral se se encuentraencuentraentreentre unauna HbHb de 12.2 de 12.2 -- 14.4 14.4 g/dLg/dL

Do Do EpoEpo--R R onon CancerCancer CellsCells UnexpectedUnexpectedClinicalClinical FindingsFindings??

ObjetivoObjetivo: Determinar si el efecto de la : Determinar si el efecto de la EpoEpo en SVen SV--NED se correlaciona NED se correlaciona con la expresión de con la expresión de EpoEpo--RR

ResultadosResultados: n: 154 (104+ 50: n: 154 (104+ 50--). En los casos ). En los casos EpoEpo--R + tratados con R + tratados con EpoEpoLa SV libre de progresión LLa SV libre de progresión L--R era significativamente peor que en los R era significativamente peor que en los que recibieron placebo (RR:2.07 CI:1.27que recibieron placebo (RR:2.07 CI:1.27--3.36 p<0.01). Por el 3.36 p<0.01). Por el contrario contrario EpoEpo no empeoró el pronóstico de los casos no empeoró el pronóstico de los casos EpoEpo--R R –– en los en los que se administró (RR:0.94). Pero la diferencia entre ambos RR nque se administró (RR:0.94). Pero la diferencia entre ambos RR no o alcanza la significación estadística (p:0.08)alcanza la significación estadística (p:0.08)

ConclusiónConclusión:Epo:Epo puede afectar de forma adversa el pronóstico de los puede afectar de forma adversa el pronóstico de los pacientes con pacientes con cancercancer de cabeza y cuello si las células malignas de cabeza y cuello si las células malignas expresan receptores de expresan receptores de EpoEpo..

HenkeHenke M et alM et al

JCO 24:4708 oct 2006JCO 24:4708 oct 2006

Phase III, Phase III, randomizedrandomized, , doubledouble--blindblind studystudy of of epoetinepoetin alfa alfa comparedcompared withwith placebo in placebo in anaemicanaemic patients patients receivingreceiving

chemotherapychemotherapy

Overall survival of the 330 patients by treatment group. EPO,

From Witzig TE JCO, Vol 23, No 12 (April 20), 2005: pp. 2606-2617

Cervical cancer Phase III trialCervical cancer Phase III trial

EPO EPO betabeta

30 000 IU 30 000 IU weeklyweekly

RadiochemotherapyRadiochemotherapy RR

n=74n=74 Standard Standard supportivesupportive carecare

No No significantsignificant differencesdifferences

-- in time to progression or in time to progression or deathdeath (RR : 1,00 ; CI : 0,57(RR : 1,00 ; CI : 0,57––1,75, p=0,99)1,75, p=0,99)

-- in in overalloverall survivalsurvival (RR : 1,16 ; CI : 0,69(RR : 1,16 ; CI : 0,69––1,94 ; p=0,57)1,94 ; p=0,57)

-- or or diseasedisease progression (RR : 1,08 ; CI : 0,62progression (RR : 1,08 ; CI : 0,62––1,87 ; 1,87 ; p=0,79)p=0,79)

From STRAUSS HG, abst 5121, ASCO 2005

BreastBreast cancer Phase III trialcancer Phase III trial

EPO alpaEPO alpa

Adjuvant Adjuvant chemotherapychemotherapy RR

((highhigh dose or dose or conventionalconventional)) --

n=1284n=1284

EpoietinEpoietin αα significantlysignificantly reducedreduced thethe numbernumber of RBC of RBC transfusion transfusion andand preventedprevented a a declinedecline of of thethe medianmedianHbHb value value withoutwithout influence or DFS influence or DFS andand OSOS

From MICHAEL U, abst 613, ASCO 2005

High dose recombinant human erythropoietin use is associated with increased overall survival in

patients with mutipe myeloma

•• HighHigh dose, long dose, long termterm erythropoietinerythropoietin use use isisassociatedassociated withwith longer longer survivalsurvival in patients in patients withwithmultiple multiple myelomamyeloma andand anemiaanemia..

•• TheThe findingsfindings cancan bebe explainedexplained by a direct or by a direct or indirect antiindirect anti--myelomamyeloma effecteffect of of humanhumanerythropoietinerythropoietin..

•• A A randomizedrandomized controlledcontrolled trials trials isis neededneeded to to corroboratecorroborate thesethese findingsfindings..

From BAZ R, abst 6621, ASCO 2005

DarbopoetinDarbopoetin for the treatment of for the treatment of ChtCht--Induced Induced AnemiaAnemia: : Disease Progression and SV analysis from four randomized, Disease Progression and SV analysis from four randomized, double blind, placebodouble blind, placebo--controlled trialscontrolled trials

1. Lung cancer:1. Lung cancer: n = 314n = 3142. Lymphoma:2. Lymphoma: n = 344n = 3443. Multiple tumour types:3. Multiple tumour types: n = 405n = 4054. Lymphoma:4. Lymphoma: n = 66n = 66

Conclusion:Conclusion: Treatment with DA Treatment with DA does not seemdoes not seem to influence to influence DFS or OS in patients with chemotherapyDFS or OS in patients with chemotherapy--induced induced anemiaanemia

HedenusHedenus et al.et al.JCO 23:6941 (2005JCO 23:6941 (2005))

EfectosEfectos tromoembólicostromoembólicos

Bohlius et al. Proc ASH 2003

ErythropoetinErythropoetin: Adverse events: Adverse eventsRR (fixed)95% CI

RR (fixed)95% CI

Pooled results for Hypertension(15 Trials) p=0.06 1.25 (0.99, 1.56)

Pooled results for Thromboticevents(12 Trials) p=0.09 1.55 (0.93, 2.59)

Pooled results for Hemorrhage/Thrombosytopenia (9 Trials) p=0.30 1.27(0.80, 2.01)

Pooled results for Rash/Irritation/Pruritis (9 Trials) p=0.62 1.17 (0.63, 2.10)

Pooled results for Seizure(2 Trials) p=0.79 1.19 (0.33, 4.35)

0.1 0.2 0.5 1 2 5 10

Control Epoetin

Cochrane metaCochrane meta--analysis: analysis: erythropoieticerythropoietictherapy adverse eventstherapy adverse events

1.171.17(0.63(0.63––2.18)2.18)

11/28011/28021/39521/39567567588Rash, irritation, Rash, irritation, itchingitching

1.261.26(0.85(0.85––1.86)1.86)

32/41232/41274/67074/6701,0821,08288Haemorrhage, Haemorrhage, thrombocytopeniathrombocytopenia

1.19 1.19 (0.96(0.96––1.49)1.49)

64/64764/647138/1,009138/1,0091,6561,6561212HypertensionHypertension

1.581.58(0.94(0.94––2.66)2.66)

14/71914/71943/1,01943/1,0191,7381,7381212ThromboembolicThromboemboliceventsevents

Pooled RR Pooled RR (95% CI)(95% CI)

Control Control groupgroup

EPOEPOgroupgroup

No. of No. of patientspatients

No. of No. of trialstrialsOutcomeOutcome

Bohlius et al. J Natl Cancer Inst 2005;97:489–98

NeoRecormonNeoRecormon metameta--analysis shows analysis shows similar similar TEEsTEEs

0.140.140.190.19No. of events per No. of events per

patient yearpatient year**

1.1% (n=7)1.1% (n=7)1.1% (n=9)1.1% (n=9)Patients with serious Patients with serious

AEsAEs leading to deathleading to death

4.2% (n=26)4.2% (n=26)5.9% (n=47)5.9% (n=47)Patients with at least Patients with at least

one AEone AE

Control(n=613)

NeoRecormon®

(n=800)

*Total patient years = 252.1 with NeoRecormon vs 181.4 with control

Coiffier et al. Ann Oncol 2004;15(Suppl 3):840P

Cochrane Review. Period: 1985-2005 57 Trials. 9.353 patients

ConclusionsConclusions

� There is consistent evidence that Epo/Darbepo reduces the R Risk for blood transfusions and the number of units transfused

� For patients with baselines Hb<12 gr./dl. There is strong evidence that Epo/Darbepo improves haematological response

� There is suggestive evidence that Epo/Darbepo may unprofe quality of life

� There is strong evidence that Epo/Darbepo increases the R Risk (1.67) for thrombo embolic events

� Whether and how Epo/Darbepo effects tumour response and overall survival remains uncertain

Cochrane Database Sys Rev 2006 19,3: 3407

EPO OR DARBEPOETIN FOR EPO OR DARBEPOETIN FOR

PATIENTS WITH CANCERPATIENTS WITH CANCER