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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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