Nuevos conceptos y alternativas en el tratamiento hormonal para la enfermedad avanzada

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