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Alpha Particles as Radiopharmaceuticals in the Treatment of Bone Metastases: Mechanism of Action of Radium-223 Chloride (Alpharadin) and Radiation

Alpha Particles as Radiopharmaceuticals in the Treatment of Bone Metastases: Mechanism of Action of Radium-223 Chloride (Alpharadin) and Radiation

Approximately 85% to 90% of men with castration-resistant prostate cancer (CRPC) have radiological evidence of bone metastases. To date, however, therapies to manage bone metastases have been primarily palliative. Among CRPC patients with bone metastases, there is a significant unmet need for active antitumor treatment options that are highly efficacious and have a favorable safety profile. This article will present current information about alpha-pharmaceuticals, a new class of targeted cancer therapy for the treatment of patients with CRPC and bone metastases. It will review preclinical and clinical studies of the experimental radiopharmaceutical radium-223 chloride (Alpharadin), a first-in-class, highly targeted and well-tolerated alpha-pharmaceutical under development to improve survival in patients with bone metastases from advanced prostate cancer. Alpharadin kills cancer cells via alpha radiation from the decay of radium-223, a calcium mimetic that naturally self-targets to bone metastases. The mechanism of action of Alpharadin and specifics of administration, radiation protection, and patient management will be discussed.


Prostate cancer is the most common cancer among men living in the United States and Europe.[1,2] An estimated 240,890 new cases of prostate cancer occurred in the US in 2011—making it the most frequently diagnosed of all new cancers (25%), and about 33,720 men died from the disease.[3] Currently, approximately 2 million American men are living with prostate cancer.[4] Management considerations include individualizing therapy with clearly defined goals that focus on specific treatments, adverse events (AEs), and quality of life (QoL).


Radium-223 Physical Properties

Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer characterized by disease progression following surgical or pharmaceutical (androgen deprivation) castration. The process by which prostate cancer cells become castrate-resistant is unclear, but it has been proposed that androgen ablation provides a selective advantage to androgen-independent cells, which grow and eventually repopulate the tumor.[5] Compared with castration-sensitive prostate cancer, the prognosis for patients with CRPC is poor, and survival is reduced. Treatment options for metastases to bone have, until very recently, been limited mainly to symptomatic relief of pain, which occurs more frequently in progressive CRPC than in castration-sensitive disease.[6,7]

Bone metastases in CRPC

Bone metastases cause morbidity and mortality in a wide range of cancers, including CRPC, breast, renal, lung, thyroid, and others. Approximately 85% to 90% of men with CRPC have radiological evidence of bone metastases.[8-10]


Radium-223 Decay Chain

Bone metastases occur in almost all prostate cancer patients during the natural course of the disease, typically appearing in the lumbar spine, vertebrae, and pelvis. Bone metastases have several clinical consequences in patients with CRPC. In particular, metastatic bone may be more susceptible to pathologic fractures and spinal cord compression, and patients may require surgery or radiation therapy. Skeletal-related events (SREs), including pathologic fracture, spinal cord compression, and the need for bone surgery and/or radiation therapy to the bone, also present a significant challenge in the management of prostate cancer.

Kaplan-Meier survival analyses of patients with prostate cancer who have no bone metastases vs one or more bone metastases confirm that the development of bone metastases (and subsequent SREs) negatively impacts the overall survival (OS) of these patients, compared with patients who do not develop bone metastases.[11] Indeed, fewer than 50% of patients with CRPC and bone metastases are alive 5 years after diagnosis.[12] Furthermore, bone metastases and SREs often result in bone pain that is a main cause of disability, and these can have a significant impact on QoL[13,14] and result in increased treatment costs.[15]

The underlying mechanisms of bone metastases in patients with prostate cancer[16-19] include (1) factors released by tumor cells that stimulate both osteoclast and osteoblast activity; (2) excessive new bone formation occurring around tumor cell deposits, resulting in low bone strength and potential vertebral collapse; and (3) osteoclastic and osteoblastic activity, releasing growth factors that stimulate tumor cell growth, perpetuating the cycle of bone resorption and abnormal bone growth.

Current therapies for bone metastases

Currently, other therapies for bone metastases are considered to be primarily palliative and are mainly used for symptom relief or to prevent serious complications, such as those caused by fractures, hypercalcemia, and spinal cord compression.

Despite pain palliation, external beam radiation therapy (EBRT) and beta-emitting radiopharmaceuticals have not demonstrated improved OS in patients with advanced prostate cancer. With EBRT, normal cells and cancer cells receive the same amount of radiation within the target field. Beta-emitting radiopharmaceuticals palliate pain, but they have not demonstrated a survival benefit. Agents such as 90Sr have been associated with significant thrombocytopenia.[20] Bisphosphonates are used to reduce the incidence of bone fractures and other SREs, but they do not have much effect on pain and do not affect survival.[21,22] The new agent denosumab (Xgeva),[23] targeted to treat pain and SREs, has been demonstrated to delay development of the first skeletal metastases by 4 months in initially nonmetastatic patients.[24]

Chemotherapy in CRPC with bone metastases

Chemotherapy with docetaxel and prednisone improves survival in metastatic CPRC, compared with mitoxantrone and prednisone. Cabazitaxel (Jevtana), a new chemotherapy agent, was recently approved for second-line use in men with advanced hormone-refractory prostate cancer already treated with docetaxel. Sipuleucel-T (Provenge), an autologous cellular immunotherapy, is now also approved by the US Food and Drug Administration (FDA) for the treatment of metastatic CRPC.

Pain relief has been demonstrated in patients treated with docetaxel-based chemotherapy, and a pain response has been correlated with an improved survival.[25] However, docetaxel chemotherapy may not be appropriate for all patients, and it can be associated with significant neutropenia and asthenia. Thus, a significant unmet medical need in the treatment of patients with CRPC and bone metastases is for active antitumor treatment options that are highly efficacious and have a favorable safety profile.[10]


The rationale for use of alpha-pharmaceuticals in metastastic CRPC

Alpha-pharmaceuticals, radionuclides that emit alpha particles, are of increasing interest in CRPC.[26] They represent a new class of targeted cancer therapy for patients with bone metastases. Targeted alpha therapy has the potential to inhibit the growth of micrometastases by selectively killing cancer cells.[27-29]

Alpha particles differ from beta particles in energy (MeV), tissue range, linear-energy transfer (LET), and number of DNA hits needed to kill a cell.[30] Radionuclides of interest in alpha-radionuclide therapy[31,32] include 225Ac, 213Bi, 211At, and 223Ra, or Alpharadin. Radium-223 is one of the most promising candidates for high- LET alpha-particle irradiation of cancer cells on bone surfaces. Unlike beta-emitting radiopharmaceuticals, alpha-pharmaceuticals deliver an intense and highly localized radiation dose (with a range of 2 to 10 cell diameters) to bone surfaces.[30] Radium-223 and its daughter radionuclides are thus much more potent, causing double-stranded DNA breaks leading to cell death,[33] but with substantially less irradiation of healthy bone marrow than standard bone-seeking beta-emitters. Thus, 223Ra does not require cells to cycle in order to achieve its antitumor effect. This distinct advantage is of particular benefit in the treatment of prostate cancer, which has a low proliferative rate.

Radium-223 is a first-in-class, highly targeted, alpha-pharmaceutical under clinical development to improve survival in patients with bone metastases from advanced prostate cancer. Phase I and II efficacy and safety trials are now complete for 223Ra, and a phase III trial in patients with CRPC and bone metastases is under way. 213Bi and 225Ac are both in preclinical development for use in prostate cancer.[34-37]

Radionuclide selection criteria

Treatment success depends on matching the physiologic characteristics of the target tissue to a specific pharmaceutical carrier and optimal radionuclide.[38] Radium-223 is a natural bone-seeking radionuclide. Using an alpha-pharmaceutical like 223Ra to treat bone metastases has the potential to spare surrounding healthy bone tissue[30,39] and result in a highly tolerable side effect profile.[40] Furthermore, any 223Ra not taken up by the bone metastases is rapidly cleared to the gut and excreted. Alpha-pharmaceuticals are easy to handle and do not require complex shielding during shipping or administration.[39]

Alpharadin Mechanism of Action


Bone-Targeted Localized Mechanism of Action of α-Pharmaceuticals

Alpharadin, radium-223 chloride (223RaCl2) in solution, is classified as an alpha-pharmaceutical or alpha-particle–emitting nuclide.[39,41,42] Radium-223, an alkaline earth metal (Figure 1), is a calcium mimetic and thus a natural bone-seeking agent.[41] Bone mineral hydroxyapatite, which forms 50% of the bone matrix, is its target. Alpharadin has preferential uptake in areas of new bone formation, targeting tumor cells in close proximity to areas of new bone growth in and around metastases.[39,43] Alpharadin forms complexes with hydroxyapatite, thus it subsequently gets incorporated into the bony matrix. Alpharadin has a half-life of 11.4 days (Figure 2).[39]

The localized action of Alpharadin’s alpha emission (with a short path length only in the 40- to 100-μm range in tissue) helps to preserve the surrounding healthy bone tissue and bone marrow[39] and limits distribution of the agent to soft tissue, thus also minimizing the risk of systemic side effects (Figure 3). Alpharadin thus has potentially better efficacy and tolerability when compared with beta-emitters.

Preclinical Studies of Alpharadin

Three key preclinical studies[30,39,44] with Alpharadin reveal its targeted mechanism of action in bone and provide the efficacy and safety rationales for proceeding to clinical development and trials in patients with CRPC and bone metastases.

The becquerel (Bq) is the International System of Units (SI)-derived unit of radioactivity. One Bq is defined as the activity of a quantity of radioactive material in which one nucleus decays per second. A measurement in becquerels is proportional to activity, so a more dangerous source of radiation gives a higher reading.


Effect of 223Ra in Prolonging Symptom-Free Survival of Rats

Henriksen et al addressed the therapeutic efficacy of alpharadin in the treatment of experimental skeletal (human breast cancer) metastases in nude rats (Figure 4).[39] All of the tumor-bearing control animals had to be sacrificed because of tumor-induced paralysis 20 to 30 days after injection with tumor cells, whereas the rats treated with a dose of 10 kBq or higher of 223Ra had a significantly increased rate of symptom-free survival (P < .05). A total of 36% of rats (5 of 14) treated with 11 kBq and 20% of rats (1 of 5) treated with 6 kBq were alive beyond the 50-day follow-up period.

Biodistribution studies, involving measurement of 223Ra in rat bone marrow samples after IV injection, were also performed in this study. The investigators demonstrated that 223Ra was selectively concentrated in bone as compared with soft tissues, after analysis of 223Ra levels in the femur vs in the kidney, spleen, and bone marrow. No signs of bone marrow toxicity or body weight loss were observed in the groups of treated animals.

The authors concluded that the significant antitumor effect of 223Ra at doses that do not induce significant neutropenia or thrombocytopenia were linked to the intense and highly localized radiation dose from alpha particles at the bone surfaces. The results of this study indicated that 223Ra should be investigated further as a potential bone marrow–sparing treatment of skeletal metastases.

In a later study, Henriksen et al compared the bone-seeking properties of, and potential exposure of red marrow to, 223Ra vs the beta-emitter 89Sr.[30] In this study, the biodistribution of both agents was assessed in mice. Tissue uptake was determined at various time intervals after IV administration of each agent. Both 223Ra and 89Sr were found to be selectively concentrated on bone surfaces relative to soft tissues. However, the measured bone uptake of 223Ra was higher than that of 89Sr. After 24 hours, the percentage of injected dose of 223Ra per gram of femur tissue was 40.1 ± 7.7. For 89Sr, the corresponding value was 17.7 ± 2.8. At 14 days, the values for 223Ra and 89Sr were 31.1 ± 2.6 and 21.1 ± 2.7, respectively.

Furthermore, estimates of the dose to marrow cavities showed that the 223Ra alpha-emitter might have a marrow-sparing advantage, with substantially less irradiation of healthy bone marrow compared with standard bone-seeking beta-emitters for targeting osteoid surfaces. This effect was substantiated from data obtained from marrow-cavity spheres. For 223Ra, the estimated absorbed dose in a 250-µm marrow-cavity sphere decreased steeply from approximately 65 Gy at 5 µm from the surface to 0 Gy at about 70 µm, the energy-range cutoff distance. For a 150-µm sphere, the absorbed dose decreased steeply with distance from 75 Gy at 3 µm to 0 Gy at 69 µm. For a 50-µm sphere, the absorbed dose decreased from 97 Gy near the bone surface to about 60 Gy in the least exposed volume.

By comparison, only small changes in the absorbed dose from 89Sr, with increasing distance from the surface, were observed from the dose calculations. The implications of this dosimetry are clearly important to understanding the potential differences between 223Ra and 89Sr with respect to marrow toxicity, with short-range alpha-particles of 223Ra irradiating a significantly lower fraction of the marrow volumes. At the same time, the bone surfaces received a therapeutically effective radiation dose. The results of this study thus indicated that 223Ra was a promising candidate for high-LET alpha-particle irradiation of cancer cells on bone surfaces, and together with its daughter radionuclides, 223Ra delivered an intense and highly localized radiation dose to the bone surfaces. That 223Ra has a mar row-sparing advantage theoretically makes it a better isotope to combine with other cytotoxic agents.

The third preclinical study, by Larsen et al, investigated adverse effects in mice receiving IV doses of either 1250, 2500, or 3750 kBq/kg of dissolved 223Ra who were followed in the initial toxicity phase.[44] This resulted in a dose-related minimal-to-moderate depletion of osteocytes and osteoblasts in the bones. Furthermore, the investigators observed a dose-related minimal-to-marked depletion of the bone marrow hematopoietic cells, and a minimal-to-slight extramedullary hematopoiesis in the spleen and in the mandibular and mesenteric lymph nodes.

The LD50 (lethal dose that kills 50% of study animals) for acute toxicity, defined as death within 4 weeks of receiving the substance, was not reached. This study demonstrated that high doses of 223Ra did not completely inactivate the blood-producing cells. The relatively high tolerance to skeletal alpha doses was probably caused by the surviving pockets of red bone marrow cells beyond the range of alpha particles from the bone surfaces, and the recruitment of peripheral stem cells.


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