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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