Editorial

Radium-223 Therapy in the Set of Patients Affected by Bone Metastases

Alessandro Sindoni*
Department of Biomedical and Dental Sciences, and of Morphological and Functional Images, University of Messina, Italy


*Corresponding author: Alessandro Sindoni, Department of Biomedical and Dental Sciences and of Morphological and Functional Images, University of Messina, Italy AOU Policlinico G. Martino Via Consolare Valeria, 198125 Messina, Italy


Published: 22 Nov, 2016
Cite this article as: Sindoni A. Radium-223 Therapy in the Set of Patients Affected by Bone Metastases. Clin Oncol. 2016; 1: 1138.

Keywords

Radium-223 therapy; Bone metastases; Prostate cancers


Editorial

Bone-seeking radiopharmaceuticals permit targeted radiation treatment of the metastatic bone disease. Among bone-seeking radiopharmaceuticals, The beta- (β-) emitting Samarium-153- ethylene diamine tetramethylene phosphonate (153Sm-EDTMP) has been used for palliation of pain from bone metastases with interesting results [1]: namely, a trial has found that patients who received 153Sm experienced significant improvement in pain scores compared with those receiving placebo [2]. However, even if these agents allowed to reach palliative benefits, they showed no impact on survival [1,3]. Additionally, because of tissue penetration and track lengths, surrounding tissues can be damaged resulting in important adverse effects, in particular bone marrow toxicity. The new bone-seeking Radium-223 dichloride (223Ra) is an alpha (α) emitting and calcium mimetic which selectively targets increased areas of turnover in bone metastases: it has demonstrated to reach not only bone pain relief but also improved survival in the set of patients affected by metastatic castration-resistant prostate cancer (mCRPC), receiving FDA approval in 2013.
223Ra has a half-life of 11.4 days and decays to 207Pb with the emission of four α-particles: these are heavy and highly ionizing particles which are able to deposit a large amount of energy over a short range in tissue (50–100 μm) due to the high linear energy transfer (100 keV/μm), rendering α-radiation more cytotoxic than that of β-emitters, but at the same time sparing the normal structures [1,3]. The penetration of alpha particles is approximately 40–100 μm (2–10 tumor cell diameters), while 89Sr and 153Sm show a tissue penetration of approximately 2.4 and 0.6 mm, respectively [4]. Alpha emission induces predominantly non-repairable DNA double-strand breaks in cells, with respect to DNA single breaks of other bone-seeking radiopharmaceuticals, allowing the antitumor peculiar features of 223Ra [5].
After intravenous injection, 223Ra is rapidly cleared from the blood: in fact, after 15 minutes, only about 20% of the injected activity is present in the blood. At 4 and 24 hours, about 4% and 1% of the injected activity remains in the blood; oppositely, the activity in bone at 4 hours ranges between 44 and 77%. Fecal excretion is the major way of elimination and only 5% is excreted through the urine.
223Ra is indicated for the treatment of adult men with CRPC with symptomatic bone metastases and without known visceral metastases. 223Ra is administered by intravenous injection at the therapeutic activity of 50 kBq/kg body weight, at four week intervals, for a total of six injections.
The ALSYMPCA trial was a randomized, double blind, phase III study that compared six injections of 223Ra against placebo in men with CRPC and bone metastases who had received, were not eligible to receive, or had declined docetaxel chemotherapy [8]. In their study, Parker et al. [8] evaluated 921 patients with or without previous docetaxel administration, in a 2:1 ratio, to receive 223Ra or matching placebo. All patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points were the time to an increase in the total alkaline phosphatase level, total alkaline phosphatase response and normalization of the total alkaline phosphatase, the time to the first Symptomatic Skeletal Event (SSE) and the time to an increase in the Prostatic Specific Antigen (PSA) level. 223Ra showed survival benefit and significantly improved overall survival. Evaluation of all main secondary efficacy end points also showed a benefit of 233Ra with respect to placebo. Detailed analyses of SSEs were evaluated subsequently and the administration of 223Ra demonstrated to prolong significantly the time to first SSE and reduce the need of external beam radiation therapy for bone pain and spinal cord compression, regardless of prior docetaxel therapy, baseline ALP level, or use of bisphosphonates [9]. The safety profile of 223Ra can be obtained from data of more than 1000 patients treated in phase II and III studies [8,10,11].
223Ra was well tolerated and associated with few adverse events. Although the difference was not significant, a slightly higher rate of diarrhea (25% v 15%) was seen with radium with respect to placebo. Other reported side effects were nausea, vomiting, peripheral edema, and hematologic abnormalities (mainly anemia, leukopenia, thrombocytopenia, neutropenia). An improvement in quality of life was also observed for 223Ra with respect to placebo [8].
Unfortunately, there are no established data to support 223Ra use in combination with other agents. Additional studies that combine 223Ra with docetaxel, abiraterone, or enzalutamide are ongoing. Denosumab and zoledronic acid may not compete with 223Ra for uptake in the bone and therefore may be used concomitantly [12-14].
Further studies could evaluate the efficacy of 223Ra in patients with bone metastases from other tumor types and trials evaluating breast, thyroid and renal cancers metastatic to bone are ongoing. Recently, Takalkar et al. [15] reported a case of breast cancer with bone metastases and without visceral metastases who underwent surgery, chemotherapy, radiation and hormonal therapy, but still had extensive symptomatic secondary bone disease. She received 223Ra, reporting an excellent response with significant pain relief and tumor markers decrease. Follow-up 18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) and 18F-sodium fluoride bone PET/CT scans confirmed improvement in the lesions.
PET/CT imaging (with choline or other radiotracers) can have an important impact on the management of mCRPC. Recently, Ahmadzadehfar H et al. [16] retrospectively evaluated the utility of 68Ga-PSMA-11 PET for the management of 223Ra therapy in patients affected by metastatic prostate cancer. They observed a significant correlation between the PSA changes and the therapeutic response according to follow-up PSMA-PET. They concluded that, considering PSMA-PET as the gatekeeper, radionuclide therapy with 223Ra may be more effective and have more success regarding changes in the PSA. These new imaging modalities could certainly lead to more tailored and personalized therapy, especially in the set of patients with reduced PSA levels but with progression of disease on imaging. Namely, these patients may be conducted to a second line of systemic therapy, to radiotherapy on the non-responding lesions, or even to 223Ra therapy.


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