29
Doentes com carcinoma da prstata metastizado castrao resistente Fatores preditivos de resposta ao retratamento com docetaxel Estudo Retrospetivo Artigo de Investigação Médica Catarina Dantas Rodrigues Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores Professor Doutor Rui Henrique, Anatomia Patolgica IPO Porto Drª Joaquina Maurício, Oncologia Mdica IPO Porto

Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

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Page 1: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Doentes com carcinoma da prostata metastizado

castracao resistente

Fatores preditivos de resposta ao retratamento com docetaxel

Estudo Retrospetivo

Artigo de Investigaccedilatildeo Meacutedica

Catarina Dantas Rodrigues

Interna do Ano Comum

Centro Hospitalar do Hospital Satildeo Joatildeo

Co-Autores

Professor Doutor Rui Henrique Anatomia Patologica IPO Porto

Drordf Joaquina Mauriacutecio Oncologia Medica IPO Porto

Catarina Dantas Rodrigues

Problema Sauacutede Puacuteblica Mundial

2

Cancro da Proacutestata

Referecircncias Bibliograacuteficas [1-2]

PortugalNeoplasia mais frequente

4ordf causa de morte

Catarina Dantas Rodrigues

3

Cancro da Proacutestata Metastizado

Referecircncias Bibliograacuteficas [7-9]

Melhoria dorMelhor

qualidadevida

Diminuiccedilatildeo[PSA] seacuterico

Melhor

SG

Docetaxel + PrednisolonaDocetaxel + Prednisolona

Standard of Care 2004 (TAX 327 e SWOG)

Catarina Dantas Rodrigues

4

Resistecircnciatotal

Resistecircnciatotal

Resistecircnciaparcial

Resistecircnciaparcial

Referecircncias Bibliograacuteficas [10-14]

Contudohellip

Catarina Dantas Rodrigues

5

Agentes aprovados pela FDA

Preacute-Quimioterapia1ordf Linha

QuimioterapiaPoacutes-Quimioterapia

Castraccedilatildeo-Resistente Metastizado

Enzalutamida

2014

Radium 223

2013

Abiraterona

2012

Sipuleucel-T

2010

Docetaxel

2004

Radium 223

2013

Abiraterona

2011

Cabazitaxel

2010

Enzalutamida

2012

From Bastos DA Dzik C Rathkop D Scher H Expanding Androgen- and Androgen Receptor SignalingndashDirected Therapies for Castration-Resistant Prostate Cancer Oncology Journal Aug 2014

Catarina Dantas Rodrigues

6

Melhor sequecircncia dos

novos faacutermacos

Resistecircncias

cruzadas

Resistecircnciaparcial

Referecircncias Bibliograacuteficas [23-28]

Catarina Dantas Rodrigues

7

Problema em Estudo

Fatores preditivos de resposta ao retratamento com

docetaxel

Catarina Dantas Rodrigues

Fatores com impacto

Sobrevivecircncia GlobalSobrevivecircncia Livre de

Progressatildeo

8

Dormoderada

severa

Dormoderada

severa

FosfataseAlcalina

gt130 UL

FosfataseAlcalina

gt130 UL

Progressatildeo PSA e DorProgressatildeo PSA e Dor

apoacutes 1ordf QTantes 1ordf QT

Catarina Dantas Rodrigues

9

Futuro ndash estratificar terapecircutica com base em

fatores preditivos

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Maior resistecircnciaFatores preditivos de

resposta desfavoraacutevel aoretratamento

Tratamento com mecanismo de accedilatildeo

diferente do docetaxel

Catarina Dantas Rodrigues

Dor

fator cliacutenico com grande impacto no prognoacutestico e progressatildeo

Procurar objetivaacute-lo e valorizaacute-lo para a tomada de decisotildees terapecircuticas

10

Conclusatildeo

Referecircncias Bibliograacuteficas [28]

Doentes com carcinoma da prostata metastizado

castracao resistente

Fatores preditivos de resposta ao retratamento com docetaxel

Estudo Retrospetivo

Artigo de Investigaccedilatildeo Meacutedica

Catarina Dantas Rodrigues

Interna do Ano Comum

Centro Hospitalar do Hospital Satildeo Joatildeo

Co-Autores

Professor Doutor Rui Henrique Anatomia Patologica IPO Porto

Drordf Joaquina Mauriacutecio Oncologia Medica IPO Porto

Anexos - Resultados

12

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 2: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

Problema Sauacutede Puacuteblica Mundial

2

Cancro da Proacutestata

Referecircncias Bibliograacuteficas [1-2]

PortugalNeoplasia mais frequente

4ordf causa de morte

Catarina Dantas Rodrigues

3

Cancro da Proacutestata Metastizado

Referecircncias Bibliograacuteficas [7-9]

Melhoria dorMelhor

qualidadevida

Diminuiccedilatildeo[PSA] seacuterico

Melhor

SG

Docetaxel + PrednisolonaDocetaxel + Prednisolona

Standard of Care 2004 (TAX 327 e SWOG)

Catarina Dantas Rodrigues

4

Resistecircnciatotal

Resistecircnciatotal

Resistecircnciaparcial

Resistecircnciaparcial

Referecircncias Bibliograacuteficas [10-14]

Contudohellip

Catarina Dantas Rodrigues

5

Agentes aprovados pela FDA

Preacute-Quimioterapia1ordf Linha

QuimioterapiaPoacutes-Quimioterapia

Castraccedilatildeo-Resistente Metastizado

Enzalutamida

2014

Radium 223

2013

Abiraterona

2012

Sipuleucel-T

2010

Docetaxel

2004

Radium 223

2013

Abiraterona

2011

Cabazitaxel

2010

Enzalutamida

2012

From Bastos DA Dzik C Rathkop D Scher H Expanding Androgen- and Androgen Receptor SignalingndashDirected Therapies for Castration-Resistant Prostate Cancer Oncology Journal Aug 2014

Catarina Dantas Rodrigues

6

Melhor sequecircncia dos

novos faacutermacos

Resistecircncias

cruzadas

Resistecircnciaparcial

Referecircncias Bibliograacuteficas [23-28]

Catarina Dantas Rodrigues

7

Problema em Estudo

Fatores preditivos de resposta ao retratamento com

docetaxel

Catarina Dantas Rodrigues

Fatores com impacto

Sobrevivecircncia GlobalSobrevivecircncia Livre de

Progressatildeo

8

Dormoderada

severa

Dormoderada

severa

FosfataseAlcalina

gt130 UL

FosfataseAlcalina

gt130 UL

Progressatildeo PSA e DorProgressatildeo PSA e Dor

apoacutes 1ordf QTantes 1ordf QT

Catarina Dantas Rodrigues

9

Futuro ndash estratificar terapecircutica com base em

fatores preditivos

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Maior resistecircnciaFatores preditivos de

resposta desfavoraacutevel aoretratamento

Tratamento com mecanismo de accedilatildeo

diferente do docetaxel

Catarina Dantas Rodrigues

Dor

fator cliacutenico com grande impacto no prognoacutestico e progressatildeo

Procurar objetivaacute-lo e valorizaacute-lo para a tomada de decisotildees terapecircuticas

10

Conclusatildeo

Referecircncias Bibliograacuteficas [28]

Doentes com carcinoma da prostata metastizado

castracao resistente

Fatores preditivos de resposta ao retratamento com docetaxel

Estudo Retrospetivo

Artigo de Investigaccedilatildeo Meacutedica

Catarina Dantas Rodrigues

Interna do Ano Comum

Centro Hospitalar do Hospital Satildeo Joatildeo

Co-Autores

Professor Doutor Rui Henrique Anatomia Patologica IPO Porto

Drordf Joaquina Mauriacutecio Oncologia Medica IPO Porto

Anexos - Resultados

12

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 3: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

3

Cancro da Proacutestata Metastizado

Referecircncias Bibliograacuteficas [7-9]

Melhoria dorMelhor

qualidadevida

Diminuiccedilatildeo[PSA] seacuterico

Melhor

SG

Docetaxel + PrednisolonaDocetaxel + Prednisolona

Standard of Care 2004 (TAX 327 e SWOG)

Catarina Dantas Rodrigues

4

Resistecircnciatotal

Resistecircnciatotal

Resistecircnciaparcial

Resistecircnciaparcial

Referecircncias Bibliograacuteficas [10-14]

Contudohellip

Catarina Dantas Rodrigues

5

Agentes aprovados pela FDA

Preacute-Quimioterapia1ordf Linha

QuimioterapiaPoacutes-Quimioterapia

Castraccedilatildeo-Resistente Metastizado

Enzalutamida

2014

Radium 223

2013

Abiraterona

2012

Sipuleucel-T

2010

Docetaxel

2004

Radium 223

2013

Abiraterona

2011

Cabazitaxel

2010

Enzalutamida

2012

From Bastos DA Dzik C Rathkop D Scher H Expanding Androgen- and Androgen Receptor SignalingndashDirected Therapies for Castration-Resistant Prostate Cancer Oncology Journal Aug 2014

Catarina Dantas Rodrigues

6

Melhor sequecircncia dos

novos faacutermacos

Resistecircncias

cruzadas

Resistecircnciaparcial

Referecircncias Bibliograacuteficas [23-28]

Catarina Dantas Rodrigues

7

Problema em Estudo

Fatores preditivos de resposta ao retratamento com

docetaxel

Catarina Dantas Rodrigues

Fatores com impacto

Sobrevivecircncia GlobalSobrevivecircncia Livre de

Progressatildeo

8

Dormoderada

severa

Dormoderada

severa

FosfataseAlcalina

gt130 UL

FosfataseAlcalina

gt130 UL

Progressatildeo PSA e DorProgressatildeo PSA e Dor

apoacutes 1ordf QTantes 1ordf QT

Catarina Dantas Rodrigues

9

Futuro ndash estratificar terapecircutica com base em

fatores preditivos

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Maior resistecircnciaFatores preditivos de

resposta desfavoraacutevel aoretratamento

Tratamento com mecanismo de accedilatildeo

diferente do docetaxel

Catarina Dantas Rodrigues

Dor

fator cliacutenico com grande impacto no prognoacutestico e progressatildeo

Procurar objetivaacute-lo e valorizaacute-lo para a tomada de decisotildees terapecircuticas

10

Conclusatildeo

Referecircncias Bibliograacuteficas [28]

Doentes com carcinoma da prostata metastizado

castracao resistente

Fatores preditivos de resposta ao retratamento com docetaxel

Estudo Retrospetivo

Artigo de Investigaccedilatildeo Meacutedica

Catarina Dantas Rodrigues

Interna do Ano Comum

Centro Hospitalar do Hospital Satildeo Joatildeo

Co-Autores

Professor Doutor Rui Henrique Anatomia Patologica IPO Porto

Drordf Joaquina Mauriacutecio Oncologia Medica IPO Porto

Anexos - Resultados

12

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 4: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

4

Resistecircnciatotal

Resistecircnciatotal

Resistecircnciaparcial

Resistecircnciaparcial

Referecircncias Bibliograacuteficas [10-14]

Contudohellip

Catarina Dantas Rodrigues

5

Agentes aprovados pela FDA

Preacute-Quimioterapia1ordf Linha

QuimioterapiaPoacutes-Quimioterapia

Castraccedilatildeo-Resistente Metastizado

Enzalutamida

2014

Radium 223

2013

Abiraterona

2012

Sipuleucel-T

2010

Docetaxel

2004

Radium 223

2013

Abiraterona

2011

Cabazitaxel

2010

Enzalutamida

2012

From Bastos DA Dzik C Rathkop D Scher H Expanding Androgen- and Androgen Receptor SignalingndashDirected Therapies for Castration-Resistant Prostate Cancer Oncology Journal Aug 2014

Catarina Dantas Rodrigues

6

Melhor sequecircncia dos

novos faacutermacos

Resistecircncias

cruzadas

Resistecircnciaparcial

Referecircncias Bibliograacuteficas [23-28]

Catarina Dantas Rodrigues

7

Problema em Estudo

Fatores preditivos de resposta ao retratamento com

docetaxel

Catarina Dantas Rodrigues

Fatores com impacto

Sobrevivecircncia GlobalSobrevivecircncia Livre de

Progressatildeo

8

Dormoderada

severa

Dormoderada

severa

FosfataseAlcalina

gt130 UL

FosfataseAlcalina

gt130 UL

Progressatildeo PSA e DorProgressatildeo PSA e Dor

apoacutes 1ordf QTantes 1ordf QT

Catarina Dantas Rodrigues

9

Futuro ndash estratificar terapecircutica com base em

fatores preditivos

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Maior resistecircnciaFatores preditivos de

resposta desfavoraacutevel aoretratamento

Tratamento com mecanismo de accedilatildeo

diferente do docetaxel

Catarina Dantas Rodrigues

Dor

fator cliacutenico com grande impacto no prognoacutestico e progressatildeo

Procurar objetivaacute-lo e valorizaacute-lo para a tomada de decisotildees terapecircuticas

10

Conclusatildeo

Referecircncias Bibliograacuteficas [28]

Doentes com carcinoma da prostata metastizado

castracao resistente

Fatores preditivos de resposta ao retratamento com docetaxel

Estudo Retrospetivo

Artigo de Investigaccedilatildeo Meacutedica

Catarina Dantas Rodrigues

Interna do Ano Comum

Centro Hospitalar do Hospital Satildeo Joatildeo

Co-Autores

Professor Doutor Rui Henrique Anatomia Patologica IPO Porto

Drordf Joaquina Mauriacutecio Oncologia Medica IPO Porto

Anexos - Resultados

12

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 5: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

5

Agentes aprovados pela FDA

Preacute-Quimioterapia1ordf Linha

QuimioterapiaPoacutes-Quimioterapia

Castraccedilatildeo-Resistente Metastizado

Enzalutamida

2014

Radium 223

2013

Abiraterona

2012

Sipuleucel-T

2010

Docetaxel

2004

Radium 223

2013

Abiraterona

2011

Cabazitaxel

2010

Enzalutamida

2012

From Bastos DA Dzik C Rathkop D Scher H Expanding Androgen- and Androgen Receptor SignalingndashDirected Therapies for Castration-Resistant Prostate Cancer Oncology Journal Aug 2014

Catarina Dantas Rodrigues

6

Melhor sequecircncia dos

novos faacutermacos

Resistecircncias

cruzadas

Resistecircnciaparcial

Referecircncias Bibliograacuteficas [23-28]

Catarina Dantas Rodrigues

7

Problema em Estudo

Fatores preditivos de resposta ao retratamento com

docetaxel

Catarina Dantas Rodrigues

Fatores com impacto

Sobrevivecircncia GlobalSobrevivecircncia Livre de

Progressatildeo

8

Dormoderada

severa

Dormoderada

severa

FosfataseAlcalina

gt130 UL

FosfataseAlcalina

gt130 UL

Progressatildeo PSA e DorProgressatildeo PSA e Dor

apoacutes 1ordf QTantes 1ordf QT

Catarina Dantas Rodrigues

9

Futuro ndash estratificar terapecircutica com base em

fatores preditivos

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Maior resistecircnciaFatores preditivos de

resposta desfavoraacutevel aoretratamento

Tratamento com mecanismo de accedilatildeo

diferente do docetaxel

Catarina Dantas Rodrigues

Dor

fator cliacutenico com grande impacto no prognoacutestico e progressatildeo

Procurar objetivaacute-lo e valorizaacute-lo para a tomada de decisotildees terapecircuticas

10

Conclusatildeo

Referecircncias Bibliograacuteficas [28]

Doentes com carcinoma da prostata metastizado

castracao resistente

Fatores preditivos de resposta ao retratamento com docetaxel

Estudo Retrospetivo

Artigo de Investigaccedilatildeo Meacutedica

Catarina Dantas Rodrigues

Interna do Ano Comum

Centro Hospitalar do Hospital Satildeo Joatildeo

Co-Autores

Professor Doutor Rui Henrique Anatomia Patologica IPO Porto

Drordf Joaquina Mauriacutecio Oncologia Medica IPO Porto

Anexos - Resultados

12

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 6: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

6

Melhor sequecircncia dos

novos faacutermacos

Resistecircncias

cruzadas

Resistecircnciaparcial

Referecircncias Bibliograacuteficas [23-28]

Catarina Dantas Rodrigues

7

Problema em Estudo

Fatores preditivos de resposta ao retratamento com

docetaxel

Catarina Dantas Rodrigues

Fatores com impacto

Sobrevivecircncia GlobalSobrevivecircncia Livre de

Progressatildeo

8

Dormoderada

severa

Dormoderada

severa

FosfataseAlcalina

gt130 UL

FosfataseAlcalina

gt130 UL

Progressatildeo PSA e DorProgressatildeo PSA e Dor

apoacutes 1ordf QTantes 1ordf QT

Catarina Dantas Rodrigues

9

Futuro ndash estratificar terapecircutica com base em

fatores preditivos

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Maior resistecircnciaFatores preditivos de

resposta desfavoraacutevel aoretratamento

Tratamento com mecanismo de accedilatildeo

diferente do docetaxel

Catarina Dantas Rodrigues

Dor

fator cliacutenico com grande impacto no prognoacutestico e progressatildeo

Procurar objetivaacute-lo e valorizaacute-lo para a tomada de decisotildees terapecircuticas

10

Conclusatildeo

Referecircncias Bibliograacuteficas [28]

Doentes com carcinoma da prostata metastizado

castracao resistente

Fatores preditivos de resposta ao retratamento com docetaxel

Estudo Retrospetivo

Artigo de Investigaccedilatildeo Meacutedica

Catarina Dantas Rodrigues

Interna do Ano Comum

Centro Hospitalar do Hospital Satildeo Joatildeo

Co-Autores

Professor Doutor Rui Henrique Anatomia Patologica IPO Porto

Drordf Joaquina Mauriacutecio Oncologia Medica IPO Porto

Anexos - Resultados

12

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 7: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

7

Problema em Estudo

Fatores preditivos de resposta ao retratamento com

docetaxel

Catarina Dantas Rodrigues

Fatores com impacto

Sobrevivecircncia GlobalSobrevivecircncia Livre de

Progressatildeo

8

Dormoderada

severa

Dormoderada

severa

FosfataseAlcalina

gt130 UL

FosfataseAlcalina

gt130 UL

Progressatildeo PSA e DorProgressatildeo PSA e Dor

apoacutes 1ordf QTantes 1ordf QT

Catarina Dantas Rodrigues

9

Futuro ndash estratificar terapecircutica com base em

fatores preditivos

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Maior resistecircnciaFatores preditivos de

resposta desfavoraacutevel aoretratamento

Tratamento com mecanismo de accedilatildeo

diferente do docetaxel

Catarina Dantas Rodrigues

Dor

fator cliacutenico com grande impacto no prognoacutestico e progressatildeo

Procurar objetivaacute-lo e valorizaacute-lo para a tomada de decisotildees terapecircuticas

10

Conclusatildeo

Referecircncias Bibliograacuteficas [28]

Doentes com carcinoma da prostata metastizado

castracao resistente

Fatores preditivos de resposta ao retratamento com docetaxel

Estudo Retrospetivo

Artigo de Investigaccedilatildeo Meacutedica

Catarina Dantas Rodrigues

Interna do Ano Comum

Centro Hospitalar do Hospital Satildeo Joatildeo

Co-Autores

Professor Doutor Rui Henrique Anatomia Patologica IPO Porto

Drordf Joaquina Mauriacutecio Oncologia Medica IPO Porto

Anexos - Resultados

12

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 8: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

Fatores com impacto

Sobrevivecircncia GlobalSobrevivecircncia Livre de

Progressatildeo

8

Dormoderada

severa

Dormoderada

severa

FosfataseAlcalina

gt130 UL

FosfataseAlcalina

gt130 UL

Progressatildeo PSA e DorProgressatildeo PSA e Dor

apoacutes 1ordf QTantes 1ordf QT

Catarina Dantas Rodrigues

9

Futuro ndash estratificar terapecircutica com base em

fatores preditivos

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Maior resistecircnciaFatores preditivos de

resposta desfavoraacutevel aoretratamento

Tratamento com mecanismo de accedilatildeo

diferente do docetaxel

Catarina Dantas Rodrigues

Dor

fator cliacutenico com grande impacto no prognoacutestico e progressatildeo

Procurar objetivaacute-lo e valorizaacute-lo para a tomada de decisotildees terapecircuticas

10

Conclusatildeo

Referecircncias Bibliograacuteficas [28]

Doentes com carcinoma da prostata metastizado

castracao resistente

Fatores preditivos de resposta ao retratamento com docetaxel

Estudo Retrospetivo

Artigo de Investigaccedilatildeo Meacutedica

Catarina Dantas Rodrigues

Interna do Ano Comum

Centro Hospitalar do Hospital Satildeo Joatildeo

Co-Autores

Professor Doutor Rui Henrique Anatomia Patologica IPO Porto

Drordf Joaquina Mauriacutecio Oncologia Medica IPO Porto

Anexos - Resultados

12

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 9: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

9

Futuro ndash estratificar terapecircutica com base em

fatores preditivos

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Dor moderadasevera

Fosfatase Alcalina elevada

Progressatildeo PSA e cliacutenica

Maior resistecircnciaFatores preditivos de

resposta desfavoraacutevel aoretratamento

Tratamento com mecanismo de accedilatildeo

diferente do docetaxel

Catarina Dantas Rodrigues

Dor

fator cliacutenico com grande impacto no prognoacutestico e progressatildeo

Procurar objetivaacute-lo e valorizaacute-lo para a tomada de decisotildees terapecircuticas

10

Conclusatildeo

Referecircncias Bibliograacuteficas [28]

Doentes com carcinoma da prostata metastizado

castracao resistente

Fatores preditivos de resposta ao retratamento com docetaxel

Estudo Retrospetivo

Artigo de Investigaccedilatildeo Meacutedica

Catarina Dantas Rodrigues

Interna do Ano Comum

Centro Hospitalar do Hospital Satildeo Joatildeo

Co-Autores

Professor Doutor Rui Henrique Anatomia Patologica IPO Porto

Drordf Joaquina Mauriacutecio Oncologia Medica IPO Porto

Anexos - Resultados

12

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 10: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

Dor

fator cliacutenico com grande impacto no prognoacutestico e progressatildeo

Procurar objetivaacute-lo e valorizaacute-lo para a tomada de decisotildees terapecircuticas

10

Conclusatildeo

Referecircncias Bibliograacuteficas [28]

Doentes com carcinoma da prostata metastizado

castracao resistente

Fatores preditivos de resposta ao retratamento com docetaxel

Estudo Retrospetivo

Artigo de Investigaccedilatildeo Meacutedica

Catarina Dantas Rodrigues

Interna do Ano Comum

Centro Hospitalar do Hospital Satildeo Joatildeo

Co-Autores

Professor Doutor Rui Henrique Anatomia Patologica IPO Porto

Drordf Joaquina Mauriacutecio Oncologia Medica IPO Porto

Anexos - Resultados

12

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 11: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Doentes com carcinoma da prostata metastizado

castracao resistente

Fatores preditivos de resposta ao retratamento com docetaxel

Estudo Retrospetivo

Artigo de Investigaccedilatildeo Meacutedica

Catarina Dantas Rodrigues

Interna do Ano Comum

Centro Hospitalar do Hospital Satildeo Joatildeo

Co-Autores

Professor Doutor Rui Henrique Anatomia Patologica IPO Porto

Drordf Joaquina Mauriacutecio Oncologia Medica IPO Porto

Anexos - Resultados

12

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 12: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Anexos - Resultados

12

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 13: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

Diagnoacutestico

13

Populaccedilatildeo n = 58

Idade ao diagnoacutestico mediana 64 [49-76]

PSA ao diagnoacutestico mediana (ngmL) 662 [300 - 135200]

Score Gleason

4-5

6

7

8-10

Desconhecido

n = 4 (69)

n = 8 (138)

n = 12 (207)

n = 26 (448)

n = 8 (138)

Estadio ao diagnoacutestico

Natildeo metastizado

Metastizado

Desconhecido

n = 30 (517)

n = 27 (466)

n = 1 (17)

Aacutecido Zoledroacutenico n = 50 (862)

Follow-up vivos e falecidos (mediana) 19 e 165 meses

Referecircncias Bibliograacuteficas [31-32]

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 14: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

Tratamento QT

1ordf Linha

Tempo diagnoacutestico - 1ordf QT mediana (anos) 328

Idade 1ordf QT mediana 70 [56-82]

Metaacutestases

sem metaacutestases castraccedilatildeo-resistente

metaacutestases oacutesseas

apenas oacutesseas

oacutesseas + linfaacuteticas

oacutesseas + linfaacuteticas eou viscerais

apenas linfaacuteticas

linfaacuteticas + viscerais

n = 1 (17)

n = 55 (948)

n = 38 (655)

n = 14 (241)

n = 3 (52)

n = 1 (17)

n = 1 (17)

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Desconhecido

n = 21 (362)

n = 18 (310)

n = 10 (172)

n = 3 (52)

n = 6 (103)

Fosfatase Alcalina gt130 UL n = 28 (483)

[PSA] seacuterico antes da 1ordm QT mediana (ngmL) 592 [175 - 80700]

14

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 15: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

Resposta

agrave 1ordf QT

[PSA] nadir mediana e intervalo (ngmL) 782 [0126 - 3685]

Tempo ateacute atingir [PSA] nadir semanas

le 20

gt 20

Desconhecido

1864 [10 - 486]

n = 23 (397)

n = 32 (552)

n = 3 (52)

Decliacutenio [PSA]

le 50

gt 50

Progressatildeo

Desconhecido

n = 6 (103)

n = 32 (552)

n = 13 (224)

n = 7 (121)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 16 (276)

n = 34 (586)

n = 6 (103)

n = 2 (34)

Tipo de progressatildeo durante o seguimento

PSA

PSA e dor oacutessea

PSA e cintigrafia oacutessea

Desconhecido

n = 15 (259)

n = 16 (276)

n = 23 (397)

n = 4 (69)

SLP (meses) 139 [95 IC 119 - 159]

SG (meses) 375 [95 IC 309 - 441]

15

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 16: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

Intervalo 1ordf QT - retratamento (meses) 9 [079 - 8261]

Idade ao retratamento mediana (anos) 71 [58-83]

Dor

Assintomaacutetico

Ligeira sem interferecircncia com AVD

Moderada interfere com AVD

Severa interfere com AVD

Natildeo aplicaacutevel

n = 16 (276)

n = 15 (259)

n = 23 (397)

n = 3 (52)

n = 1 (17)

Fosfatase Alcalina gt130 UL n = 36 (621)

[PSA] seacuterico mediana (ngmL) 1198 [062 - 191800]

16

Retratamento

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 17: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

[PSA] nadir mediana e intervalo (ngmL) 589 [0155 - 1736]

Tempo [PSA] nadir (semanas)

le 20

gt 20

Desconhecido

1771 [100 - 4671]

n = 28 (483)

n = 25 (431)

n = 5 (86)

Decliacutenio [PSA]

le 50

gt 50

50 - 90

90 - 95

gt 95

Progressatildeo

Desconhecido

n = 14 (241)

n = 21 (362)

n = 12 (207)

n = 3 (52)

n = 6 (103)

n = 17 (293)

n = 6 (103)

Resposta imediata ndash 1 mecircs apoacutes QT

Estaacutevel

Parcial

Progressatildeo

Desconhecido

n = 17 (293)

n = 15 (259)

n = 22 (379)

n = 1 (17)

Tipo de progressatildeo durante o seguimento

PSA

PSA e Dor oacutessea

PSA e Cintigrafia oacutessea

Desconhecido

n = 14 (241)

n = 23 (397)

n = 18 (310)

n = 3 (52)

17

Resposta

ao

Retratamento

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 18: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

18

Curva de SG e SLP

SG - mediana de 175 meses SLP - mediana de 105 meses

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 19: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

19

Fatores com impacto na SG

p = 94times10-8

Assintomaacuteticos

Ligeira

ModeradaSe

vera

p = 41times10-5

Dor antes da 1ordf QT FA antes 1ordf QT

le130

gt 130

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 20: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

20

Fatores com impacto na SG

p = 0046

gt329 anos

le328 anos

Tempo entre diagnoacutestico e 1ordf QT

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 21: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

21

Anaacutelise univariada - fatores com impacto na SG

Regressatildeo de Cox Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira 306 135 - 691 0007

ModeradaSevera 1008 411 - 2472 45x10-7

FA 392 195 - 788 125x10-4

RETRATAMENTO

Dor Ligeira - - 0132

ModeradaSevera 427 198 - 919 20x10-4

FA 222 112 - 440 0023

Decliacutenio [PSA] le50 043 020 - 096 41x10-2

50-90 018 007 - 050 10x10-2

90-95 - - 0110

gt95 010 002 - 044 30x10-3

Tempo ateacute [PSA] nadir gt 20 semanas 033 017 ndash 064 10x10-3

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 22: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

22

Anaacutelise multivariada - fatores com impacto na SG

Regressatildeo de Cox

Variaacuteveis SG

HR IC 95 p

1ordf QT

Dor Ligeira - - 0217

ModeradaSevera 673 255 - 1776 12x10-4

FA 272 121 - 610 15x10-2

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 23: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

23

Fatores com impacto na SLP

p = 0002

Tipo de progressatildeo apoacutes 1ordf QT

PSA

PSA + Novas lesotildees cintigrafia

PSA + Dor

p = 0002

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 24: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

24

Anaacutelise univariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

1ordf QT

Tipo de Progressatildeo PSA e dor 420 180 - 982 10x10-3

PSA e cintigrafia oacutessea - - -

RETRATAMENTO

Tempo ateacute [PSA] Nadir gt20 semanas 034 019 - 062 39x10-4

Resposta imediata Doenccedila estaacutevel 545 247 - 1200 26x10-5

Resposta parcial - - -

Progressatildeo - - -

Decliacutenio da [PSA] le50 041 018 - 094 35x10-2

50-90 020 008 - 048 37x10-4

90-95 012 002 - 055 60x10-3

gt95 027 009 - 076 13x10-2

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 25: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

25

Anaacutelise multivariada - fatores com impacto na SLP

Regressatildeo de Cox

Variaacuteveis SLP

HR IC 95 p

Tempo ateacute [PSA] nadir apoacutes

retratamento

024 011 - 049 12x10-4

Tipo de Progressatildeo apoacutes a 1ordf

QT

PSA e dor 397 161 - 979 30x10-3

PSA e cintigrafia oacutessea 280 121 - 646 16x10-2

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 26: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

Sobrevivecircncia Global

variaacuteveis p

Dor 17x10-2

FA 22x10-4

Decliacutenio da [PSA] 10x10-3

Tempo ateacute [PSA] nadir 40x10-3

Sobrevivecircncia Livre de

Progressatildeo

26

Fatores com impacto apoacutes retratamento

variaacuteveis p

Tempo ateacute [PSA] Nadir 23x10-4

Decliacutenio da [PSA] 10x10-3

Resposta imediata 50x10-6

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 27: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Bibliografia

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 28: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

[1] Center MM Jemal A Lortet-Tieulent J Ward E Ferlay J Brawley O et al International Variation in Prostate Cancer Incidence and

Mortality Rates Eur Urol 2012 Jun61(6)1079-92

[2] Palma dos Reis J Prostate Cancer Are We Able to Diagnose Those in Need And Are Those That Are Diagnosed and Treated Those

that Are Effectively in Need Acta Med Port 2014 Jan-Feb27(1)12-14

[3] Gupta E Guthrie T Tan W Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC) BMC

Urol 2014 Jul 251455

[4] Heidenreich A Bastian PJ Bellmunt J Bolla M Joniau S van der Kwast T et al EAU Guidelines on Prostate Cancer Part II Treatment

of Advanced Relapsing and Castration-Resistant Prostate Cancer Eur Urol 2014 Feb65(2)467-79

[5] Halabi S Vogelzang NJ Kornblith AB Ou SS Kantoff PW Dawson NA et al Pain predicts overall survival in men with metastatic

castration-refractory prostate cancer J Clin Oncol 2008 May 2026(15)2544-9

[6] Fizazi K Massard C Smith MR Rader ME Brown JE Milecki P et al Baseline covariates impacting overall survival (OS) in a phase III

study of men with bone metastases from castration-resistant prostate cancer J Clin Oncol 30312s 2012 (suppl abstr 4642)

[7] Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN et al Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer N Engl J Med 2004 3511502-12

[8] Petrylak DP Tangen CM Hussain MH Lara PN Jr Jones JA Taplin ME et al Docetaxel and estramustine compared with mitoxantrone

and prednisone for advanced refractory prostate cancer N Engl J Med 2004 Oct 7351(15)1513-20

[9] Berthold DR Pond GR Soban F de Wit R Eisenberger M Tannock IF Docetaxel plus prednisone or mitoxantrone plus prednisone for

advanced prostate cancer updated survival in the TAX 327 study J Clin Oncol 2008 Jan 1026(2)242-5

[10] Ganju A Yallapu MM Khan S Behrman SW Chauhan SC Jaggi M Nanoways to overcome docetaxel resistance in prostate cancer

Drug Resist Updat 2014 Apr17(1-2)13-23

[11] Darshan MS Loftus MS Thadani-Mulero M Levy BP Escuin D Zhou XK et al Taxane-induced blockade to nuclear accumulation of

the androgen receptor predicts clinical responses in metastatic prostate cancer Cancer Res2011 Sep 1571(18)6019-29

[12] Antonarakis ES Armstrong AJ Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer Prostate

Cancer Prostatic Dis 2011 Sep14(3)192-205

[13] Mahon KL Henshall SM Sutherland RL Horvath LG Pathways of chemotherapy resistance in castration-resistant prostate cancer

Endocr Relat Cancer 2011 Jul 418(4)R103-23

[14] Seruga B Ocana A Tannock IF Drug resistance in metastatic castration resistant prostate cancer Nat Rev Clin Oncol 2011

Jan8(1)12-23

[15] Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I et al Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial Lancet 2010 Oct

2376(9747)1147-54

[16] Kantoff PW Higano CS Shore ND Berger R Small EJ Penson DF et al Sipuleucel-T Immunotherapy for castration-resistant prostate

cancer N Engl J Med 2010 363 411ndash22

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70

Page 29: Doentescom carcinoma da próstatametastizado castraçã ... · Interna do Ano Comum Centro Hospitalar do Hospital São João Co-Autores ... Resposta imediata Doença estável 5.45

Catarina Dantas Rodrigues

[17] Fizazi K Scher H Molina A Logothetis CJ Chi KN Jones RJ et al Abiraterone acetate for treatment of metastatic castration-resistant

prostate cancer final overall survival analysis of the COU-AA-301 randomized double-blind placebo-controlled phase 3 study Lancet

Oncol 2012 Oct13(10)983-92

[18] Scher H Fizazi K Saad F Taplin ME Sternberg CN Miller K et al Increased survival with enzalutamide in prostate cancer after

chemotherapy N Engl J Med 2012 3671187-1197

[19] Parker C Nilsson S Heinrich D Helle SI OSullivan JM Fossaring SD et al Alpha emitter radium-223 and survival in metastatic prostate cancer

N Engl J Med 2013 Jul 18369(3)213-23

[20] Fizazi K Albiges L Massard C Escudier B Loriot Y Novel and bone-targeted agents for CRPC Ann Oncol 2012 Sep23 Suppl 10x264-7

[21] Suzman DL Antonarakis ES Castration-resistant prostate cancer latest evidence and therapeutic implications Ther Adv Med Oncol 2014

Jul 6(4) 167ndash179

[22] Bahl A Masson S Birtle A Chowdhury S de Bono J Second-line treatment options in metastatic castration-resistant prostate cancer a

comparison of key trials with recently approved agents Cancer Treat Rev 2014 Feb40(1)170-7

[23] Ansari J Hussain SA Zarkar A Tanguay JS Bliss J Glaholm J Docetaxel chemotherapy for metastatic hormone refractory prostate cancer

as first-line palliative chemotherapy and subsequent re-treatment Birmingham experience Oncol Rep 2008 Oct20(4)891-6

[24] Heck MM Thalgott M Retz M Wolf P Maurer T Nawroth R et al Rational indication for docetaxel rechallenge in metastatic castration-

resistant prostate cancer BJU Int 2012 Dec110(11 Pt B)E635-40

[25] Loriot Y Massard C Gross-Goupil M Di-Palma M Escudier B Bossi A et al The interval from the last cycle of docetaxel-based

chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer Eur J Cancer 2010

Jul46(10)1770-2

[26] Caffo O Pappagallo G Brugnara S Caldara A di Pasquale MC Ferro A et al Multiple rechallenges for castration-resistant prostate cancer

patients responding to first-line docetaxel assessment of clinical outcomes and predictive factors Urology 2012 Mar79(3)644-9

[27] Di Lorenzo G Buonerba C Faiella A Rescigno P Rizzo M Autorino R et al Phase II study of docetaxel retreatment in docetaxel-pretreated

castration-resistant prostate cancer BJU Int 2011 Jan107(2)234-9

[28] Oudard S Kramer G Caffo O Creppy L Loriot Y Hansen S et al Docetaxel rechallenge after an initial good response in patients with

metastatic castration-resistant prostate cancer BJU Int 2015 May115(5)744-52

[29] Scher HI Halabi S Tannock I Morris M Sternberg CN Carducci MA et al Design and End Points of Clinical Trials for Patients With

Progressive Prostate Cancer and Castrate Levels of Testosterone Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin

Oncol 2008 Mar 126(7)1148-59

[30] Scher HI Morris MJ Basch E Heller G End Points and Outcomes in Castration-Resistant Prostate Cancer From Clinical Trials to Clinical

Practice J Clin Oncol 2011 Sep 2029(27)3695-704

[31] Altman DG McShane LM Sauerbrei W Taube SE Reporting recommendations for tumor marker prognostic studies (REMARK) explanation

and elaboration PLoS Med 20129(5)e1001216

[32] Egevad L Granfors T Karlberg L Bergh A Stattin P Prognostic value of the Gleason score in prostate cancer BJU Int 2002 Apr89(6)538-

42

[33] Beer TM Garzotto M Henner WD Eilers KM Wersinger EM Intermittent chemotherapy in metastatic androgen- independent prostate cancer

Br J Cancer 2003 89 968ndash70