Nuevos conceptos y alternativas en el
tratamiento hormonal para la
enfermedad avanzada
María J. Ribal
Servicio de Urología.
Hospital Clínic. Universitat de Barcelona
• El tratamiento hormonal no está exento de efectos secundarios, debemos tener en cuenta la calidad de vida de nuestros pacientes.
• Podemos retrasar la castración-resistencia?– Tratamiento hormonal intermitente– Tratamiento hormonal diferido
• Los mecanismos moleculares de desarrollo del CPCR han abierto las puertas a nuevas alternativas terapéuticas.
– El RA es uno de los efectivos en el desarrollo del CPCR.– Las maniobras hormonales siguen siendo vigentes en el
CPCR.
•We performed a matched cohort study using linked administrative data at the Institute for Clinical Evaluative Sciences (ICES) in Ontario, Canada (population of approximately 11,000,000). •Men with prostate cancer were identified using the Ontario Cancer Registry (OCR). The OCR is a comprehensive provincial registry that captures more than 95% of cancer cases
Tratamiento inmediato o diferido
Selection Criteria
Results Intermittent versus Continous AD
(ASCO#4558)• Prospective study, N = 48 PCa pts treated with intermittent ADT
for biochemical relapse after RP or RT
Dynamics of bone mineral density (BMD) during intermittent ADT
ADT-induced loss of BMD was attenuated during the ‘off treatment’ period of an intermittent ADT regimen, suggesting less net BMD loss than during continuous ADT
Castración resistencia
Rising PSAHormone Naive
Monotherapy
Rising PSACRPC
Locally Advanced
Mets CRPC Symptomatic
Mets AsymptomaticHormone Naive
Mets Asymptomatic CRPC
CRPC Post-Docetaxel
Death From CRPC
Multimodality
NCCN, 2010.
Prostate Cancer Continuum
• Análisis secundario de la rama placebo de un estudio RCT (atrasentran vs placebo)
• N = 470 pts afectos CPRC M0
• Análisis multivariante:
Predictive factors for outcome*
Factor not predictive for outcome*
PSA BMI
PSA velocity
Time (mo)
Median time to disease progression 22.4
Median time to first bone metastasis 25.2
Median overall survival 46.8
Charles B. Huggins
“Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.”
CRPC: Adaptation or selection?Androgen-sensitive tumour cells
Androgen-independent tumour cells
Tumour hormone-dependent
Tumour hormone-
independent
Adaptation theory: genetic changes provide survival mechanisms that allow the cells to continue growing in the androgen depleted environment
Regression of
tumour
Hormonewithdrawal
Clonal selection pathway, androgenwithdrawal allows for the selection of androgen-independent cells to proliferate that existed at the time of initiation of therapy
Hormone-withdrawal
Testosterone
DHT
5a-R
RA (Inactive)
AR with DHT Ligand (Dimers)
Activated AR gets in the nucleus and binds DNA
Androgen Response Element (ARE)
Gene expression
Hsp 90
Hsp 70