Maarten van der Doelen

Chapter 1

patients with asymptomatic or minimally symptomatic mCRPC. (18) However, two years after approval, the drug was withdrawn from the European market at the request of the marketing authorization holder. Next, two second generation androgen-signaling inhibitors, enzalutamide and abiraterone acetate, were registered for the treatment of both chemotherapy-naïve mCRPC patients and mCRPC patients who underwent prior docetaxel chemotherapy. (19-22) Radium-223 dichloride (radium-223) therapy, an alpha particle emitting radionuclide, was added to the therapeutic landscape of mCRPC in 2013. (23) More recently, the poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitors rucaparib and olaparib were approved for treatment of pretreated mCRPC patients with a deleterious germline or somatic homologous recombination repair gene alteration. (24, 25) Furthermore, in 2015, the CHAARTED and STAMPEDE trials showed that the combination of continuous ADT plus six courses of docetaxel chemotherapy resulted in improved survival when compared to ADT alone in patients with an initial diagnosis of metastatic prostate cancer. (26, 27) Subsequently, the combination of ADT plus abiraterone and prednisone was also found to be life-prolonging in patients with metastatic hormone sensitive prostate cancer. (28, 29) The upfront use of docetaxel or abiraterone already in the hormone-sensitive setting has resulted in a change in the treatment paradigm of metastatic prostate cancer patients and the expanding number of treatment options has made the sequencing of life-prolonging agents more complex. Therefore, optimization of treatment strategies to improve survival and postpone disease-associated morbidity are of utmost importance. These strategies include combinatory therapy in patients with newly diagnosed metastatic hormone-sensitive prostate cancer, concomitant use of bone protective agents, and personalized medicine in patients with mCRPC. Targeted alpha-radionuclide therapy Radionuclides, also known as radioisotopes, are unstable atomswith excess of energy. By radioactive decay, the atoms lose their excess of energy in the form of energy particles. Based on the type of the emitted particles, radionuclides are classified as alpha, beta or gamma-emitting radionuclides. The therapeutic effectiveness of specific radionuclides is determined by their specificity of targeting and the innate characteristics of the particles emitted, including the range, effective travel distance in surrounding tissue, and the magnitude of emitted energy. (30) An alpha particle is identical to the nucleus of a Helium atom and consists of two protons and two neutrons. Alpha particles have a high linear energy transfer (50-230 keV/µm) and short radiation range in tissue (40-100 µm). In beta decay, an electron or

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