Page 49 - Towards personalized therapy for metastatic prostate cancer: technical validation of [18F]fluoromethylcholine
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[18F]FCH as chemotherapy response read-out
INTRODUCTION
Prostate cancer (PC) is the second most common cancer in males worldwide [1]. The disease presents itself mostly in men above the age of 50 and the incidence increases with age. The clinical behavior of PC is very diverse. Some tumors are indolent, do not cause any symptoms and arise as microscopic, well-differentiated foci that may never become clinically manifest. However, a significant proportion of PC patients presents with or will develop aggressive tumors that lead to morbidity, metastases and ultimately to death.
The initial systemic treatment in metastatic PC is based on androgen deprivation. 3 Nevertheless, the majority of PC patients will ultimately progress and reach a
castration resistant PC (CRPC) status after starting the anti-hormone treatment.
Therapeutic options against CRPC include agents that interfere with androgenic
stimulation of tumor growth (e.g., abiraterone, enzalutamide) [2–4], immunotherapy (sipuleucel-T) [5], chemotherapy (docetaxel, cabazitaxel) [6, 7] and bone-seeking radiopharmaceuticals (e.g., Radium-223) [8]. Abiraterone acetate inhibits androgen biosynthesis by irreversibly blocking the CYP17, an essential enzyme in testosterone and estrogen synthesis [2]. When combined with low-dose prednisone, Abiraterone improves survival of patients with CRPC [3]. Enzalutamide is an antiandrogen agent with demonstrated potential to inhibit nuclear translocation of the androgen receptor and DNA binding, inducing tumor volume reduction in xenograft models [4]. Sipuleucel-T is an active cellular immunotherapeutic which prolongs survival among men with asymptomatic or minimally symptomatic metastatic CRPC [5]. Docetaxel and cabazitaxel are chemotherapeutic drugs from the Taxane class. Their principal mechanism of action is disruption of microtubule function, resulting in cell death [6, 7]. Radium-223 dichloride (radium-223) is an alpha emitter which selectively binds to areas of increased bone turnover in metastatic lesions. The emitted high-energy alpha particles with short range radiation induce double-stranded DNA breaks, resulting in a highly localized cytotoxic effect in the target areas [8].
However, despite the variety of therapeutic options available, the proper sequencing (e.g., modality, timing) in individual patients is unclear. When chemotherapy is indicated the initial regimen is docetaxel combined with prednisone [9, 10]. It has been shown that this combination significantly prolongs overall survival, compared to mitoxantrone [6]. For patients progressing after docetaxel, treatment with another
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