Radium-223: Insight and Perspectives in Bone-metastatic Castration-resistant Prostate Cancer

Abstract

Abstract. 223 Prostate cancer (PCa) is the most common malignancy in men (1). In patients affected by advanced PCa, defined as hormonesensitive disease since the tumor still requires androgen for growth, androgen deprivation therapy (ADT), including luteinizing hormone-releasing hormone (LHRH) agonists, antagonists and anti-androgens, represents the first-line treatment. Unfortunately some cancer cells develop resistance to ADT, indicating the progression of the disease to metastatic castration-resistant prostate cancer (mCRPCa). Such resistance to castration occurs in most patients (2) and, despite the approval of new therapeutic agents, mCRPCa remains a lethal disease (3). Nowadays the new therapeutic landscape for patients affected by mCRPCa aims to extend overall survival (OS) and includes cytotoxic, new-generation anti-androgens, immunotherapeutics and radiopharmaceuticals (4, 5).Bones are the preferred site of metastasis. Almost 90% of men who die from PCa have bone-metastatic disease (6), with a 5-year OS rate of 20%. Due to the fragility of bone with metastases, with the related risk of pain, fractures, spinal cord compression and hematological consequences, several drugs have been developed to treat the osseous involvement of this disease. In previous years, the optimal treatment aimed to relieve pain and reduce skeletal morbidity.Besides systemic therapies, bone-targeted agents that focus their activity on bone, such as bisphosphonates, monoclonal antibody and radiopharmaceuticals, have become available. The bisphosphonate zoledronic acid, the antibody to receptor activator of nuclear factor kappa-B ligand (RANKL) denosumab and radiopharmaceuticals [such as 89 Sr and 153 Sm-ethylene diamine tetramethylene phosphonate ( 153 Sm-EDTMP)], were approved for delaying skeletal-related events (SREs) and for the palliation of bone pain from mCRPCa. Radionuclide TherapyRadionuclide therapy is known to deliver ionizing radiation to tumor sites, thereby killing cancer cells (7). Bone-targeted radiopharmaceuticals localize their radiation to sites of high bone remodeling. 5719

Application of the HTA Core Model for complex evaluation of the effectiveness and quality of Radium-223 treatment in patients with metastatic castration resistant prostate cancer

“…It is recommended to indicate the Radium-223 treatment especially in patients with less advanced prostate cancer, who are more likely to undergo the complete treatment and thus benefit more from it. However, the PSA, skeleton scintigraphy, or FDG PET/CT scan are not suitable methods for patient selection or Radium-223 monitoring, as small visceral or other metastases might not be found [4, 7]. Thus, a more precise selection is desirable for selecting suitable patients with mCRPC; a new 68Ge/68Ga generator should help.…”

“…The therapeutic options for their treatment are bisphosphonates, denosumab, beta-emitting radionuclide palliative therapy, external radiotherapy, surgery, and, last but not least, new specific radionuclide therapy with an alpha emitter, Radium-223 ( 223 Ra) or its dichloride, 223 RaCl 2 [32]. Radium-223 is an alpha emitter with a half-life of 11.4 days that is selectively targeted to bone metastases, and, as the only one of the therapeutic options, it has a positive effect on patient survival [4]. The combination of targeted Radium-223 accumulation in the bones, high energy, and short-range alpha particles allows to kill target tumor cells, as it causes deoxyribonucleic acid (DNA) double-strand breaks.…”

“…Alpharadin was the working name of the therapeutic substance containing Radium-223 that is currently registered under the trade name of Xofigo. Men with mCRPC with symptomatic bone metastases (at least two) and no present visceral metastases are indicated for treatment with Radium-223 [4]. Bone metastases are normally displayed by the skeletal scintigraphy examination that should not be older than 6 months at the time of Radium-223 therapy indication.…”

“…It is also recommended that the patients also had lower levels of the prostate-specific antigen (PSA) [17] and the alkaline phosphatase (ALP) [7] in the serum. Taking into account all the facts, the prostate-specific membrane antigen (PSMA) is the best diagnostic method for selecting suitable patients with mCRPC for the treatment with Radium-223; for PET/CT imaging, it can be labeled by the 68 Ga or 18 F positron emitter ( 68 Ga/ 18 F-PSMA-PET/CT), while 68 Ga is more suitable for better imaging of as many as possible small metastases [4]. In 2018 the INMM plans to purchase a 68 Ge/ 68 Ga generator to produce gallium-68 necessary for 68 Ga-PMSA-PET/CT metastases imaging in patients with mCRPC.…”

Clinical Factors Asssociated with Treatment Outcomes following Whole-brain Irradiation in Patients with Prostate Cancer

“…Since prostate cancer is the most common type of cancer in men, considerable research is performed in order to improve the outcomes of these patients, including preclinical studies and clinical investigations of new systemic treatments, surgical approaches and radiation techniques (8)(9)(10)(11)(12)(13). In contrast to metastatic spread to the bone, metastases to the brain are very rare.…”