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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
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