Short Range Of Alpha Particles Research Articles

Abstract 6034: PSMA targeted alpha radiopharmaceutical [211At]PSAt-3 inhibits tumor growth in a preclinical model of prostate cancer

Abstract Introduction: Prostate cancer continues to be a highly prevalent cancer diagnosis among men and a leading cause of cancer related deaths worldwide. With the introduction[177Lu]Lu-PSMA-617, targeted radionuclide therapy has proven successful in increasing survival time for patients with metastasized castration resistant prostate cancer. However, despite encouraging results, such patients tend to develop progressive disease, and thus, enhanced efficacy is warranted. To this end, the use of radiopharmaceuticals harnessing alpha-emitters is a promising venue due to the potent energy deposition and short range of alpha particles in tissue. Here, we employ the PSMA targeting vector, [211At]PSAt-3, for targeted alpha radionuclide therapy in a preclinical prostate cancer model. Methods: [211At]PSAt-3, a structural derivative of PSMA-617, in which the L-2-naphtylalanine was replaced by L-3-[211At]astato-phenylalanine, was obtained by electrophilic [211At]astatodesilylation. Evaluation of [211At]PSAt-3 was conducted in male inbred nude mice of Balb/c background xenografted subcutaneously with human prostate cancer cells (LNCaP). Prior biodistribution studies were carried out with approximately 100 kBq intravenous injections, and subsequent biodistribution 2, 6 and 24h post injection (P.I.). For establishment of therapeutic effect, a single intravenous dose of [211At]PSAt-3 was administered. To asses hematological toxicity, blood cell composition was assessed weekly. Results: Favorable tumor uptake of 15.2±6 %ID/g was observed 2h after injection of [211At]PSAt-3 in LNCaP xenografted nude mice, with subsequent 9±5.1% ID/g and 6.4±2.4% ID/g 6 and 24h P.I., respectively. [211At]PSAt-3 cleared mainly by the kidneys, in which uptake was 72, 38 and 6% ID/g at 2, 6 and 24h P.I., respectively. Thyroid/throat uptake remained low at ~0.1% ID for all timepoints investigated, indicating a low degree of de-astatination. Initial efficacy studies using a single intravenous dose of 0.5 MBq (~20 MBq/kg) demonstrated significant growth delay and tumor volume reduction compared with control mice (saline). Blood platelet count was reduced after administration of [211At]PSAt-3 and subsequently recovered. No signs of severe toxicity, and no significant weight loss between control and treated mice was observed, suggesting that the treatment is well tolerated. Conclusion: 0.5 MBq [211At]PSAt-3 was well tolerated in mice and demonstrated tumor volume reduction and significant delay of tumor growth. These findings suggest [211At]PSAt-3 as a promising candidate for clinical translation. Citation Format: Lars Hvass, Marius Müller, Anne Clausen, Matthias Herth, Andreas Kjaer. PSMA targeted alpha radiopharmaceutical [211At]PSAt-3 inhibits tumor growth in a preclinical model of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6034.

The Mapping of Alpha-Emitting Radionuclides in the Environment Using an Unmanned Aircraft System

The protection of first responders from radioactive contamination with alpha emitters that may result from a radiological accident is of great complexity due to the short range of alpha particles in the air of a few centimeters. To overcome this issue, for the first time, a system mounted on a UAS for the near-real-time remote measurement of alpha particles has been developed, tested, and calibrated. The new system, based on an optical system adapted to be installed on a UAS in order to measure the UV-C fluorescence emitted by alpha particles in the air, has been tested and calibrated, carried out in the laboratory and in field experiments using UV-C LEDs and 241Am sources. In experimental flights, the probability of detecting a point source was determined to be approximately 60%. In the case of a surface extended source, a detection efficiency per unit surface activity of 10 counts per second per MBq cm−2 was calculated. A background count rate of UV-C of around 26 ± 28 s−1 for an integration time of 0.1 s was measured during flights, which led to a decision threshold surface activity of 5 MBq cm−2.

Development and evaluation of a standard for absorbed dose to water from alpha-particle-emitting radionuclides

Targeted radionuclide therapy and brachytherapy with alpha particles has gained significant clinical relevance recently. Absorbed dose traceability to a standard is currently lacking in the dosimetry chain. The short range of alpha particles in water of <100 μm complicates the absorbed dose measurements in the form of significant attenuation and perturbation effects. The aim of this work was to develop and validate a standard for absorbed dose to water from alpha-particle-emitting radionuclides. A dosimetric formalism to realize surface absorbed dose to water per unit activity using a windowless cylindrical parallel-plate ion chamber (IC) was introduced. IC-based and Monte Carlo (MC)-based correction factors were calculated for a planar circular 210Po alpha-particle emitter. The measured absorbed dose to air was compared to the MC-calculated absorbed dose. A parallel-plate IC with a nominal 4 mm collector diameter composed of polystyrene-equivalent material was utilized as a standard. MC simulations were performed using the TOPAS MC code and finite source size, backscatter, and emission angle divergence correction factors were calculated by modeling the IC and the source. Multiple measurement trials were performed to measure ionization current at air gaps in the 0.3 mm to 0.525 mm range. The proposed dosimetric formalism was employed to calculate the surface absorbed dose to water from a point-like 210Po source. The recombination and polarity correction factors were measured to be <0.50% when a 150 V mm−1 electric field strength was applied. The MC-calculated and measured absorbed dose to air agreed within 2.05%. The finite source size and backscatter corrections were <10% with the emission angle divergence correction being in the 93%–239% range. The surface absorbed dose to water was measured to be 2.8913 × 10−6 Gy s−1 Bq−1 with a combined uncertainty of 4.23% at k = 1. This work demonstrated the ability of a windowless parallel-plate IC as a standard for absorbed dose from alpha-particle-emitting radionuclides.

Macroscopic and microscopic investigation of maximum effectiveness of proton-boron capture therapy using Monte Carlo simulation

Proton-boron capture therapy (PBCT) has been proposed as a new method to enhance effectiveness of proton therapy. There is, however, no consensus on its potential effectiveness. Most theoretical studies have been done at a macroscopic level. At cellular dimensions, however, the dose ratio with PBCT can be strongly favourable due to proton-boron reactions. The goal of this study was to investigate the theoretical maximum dose enhancement with PBCT, and its radiation physics mechanisms, through both macroscopic and microscopic simulations. The Monte Carlo simulations involved two stages due to model limitations. In the macroscopic calculations, variations in Bragg-peak height and depth caused by a 10 mm thick boron region were examined for different proton energies (62, 80 and 100 MeV) using MCNPX. Percentage depth doses and energy spectra of protons, alpha particles, neutrons and photons were also computed. The second stage used Geant4 for dose calculation in cellular dimensions. Macroscopically, the energy deposition peak shifted towards the surface by about 3.1 mm and the Bragg peak dose increased by up to 53.1%, 53.4%, 53.9% for proton energies 62, 80 and 100 MeV, respectively, compared to the proton-only (no boron) case. Microscopically, the calculated total equivalent doses for these energies showed 5%, 23% and 50% enhancements, respectively. The results suggest increased effectiveness with PBCT due to production of short-range alpha-particles, especially at higher incident proton energies. Also, by adding boron, the mean proton energy is reduced thereby increasing the probability of local dose deposition. The theoretical maximum possible improvement in dose equivalent in the target region at the cellular scale was shown to slightly increase with beam energy, reaching about 54% at the highest studied energy. This combined approach has provided further insight into the potential of PBCT. Further studies, particularly at higher proton energies, are indicated.

Comparing absorbed doses and radiation risk of the α-emitting bone-seekers [223Ra]RaCl2 and [224Ra]RaCl2.

[223Ra]RaCl2 and [224Ra]RaCl2 are bone seekers, emitting high LET, and short range (< 100 μm) alpha-particles. Both radionuclides show similar decay properties; the total alpha energies are comparable (223Ra: ≈28 MeV, 224Ra: ≈26 MeV). [224Ra]RaCl2 has been used from the mid-1940s until 1990 for treating different bone and joint diseases with activities of up to approximately 50 MBq [224Ra]RaCl2. In 2013 [223Ra]RaCl2 obtained marketing authorization by the FDA and by the European Union for the treatment of metastatic prostate cancer with an activity to administer of 0.055 MBq per kg body weight for six cycles. For intravenous injections in humans a model calculation using the biokinetic model of ICRP67 shows a ratio of organ absorbed dose coefficients (224Ra:223Ra) between 0.37 (liver) and 0.97 except for the kidneys (2.27) and blood (1.57). For the red marrow as primary organ-at-risk, the ratio is 0.57. The differences are mainly caused be the differing half-lives of the decay products of both radium isotopes. Both radionuclides show comparable DNA damage patterns in peripheral blood mononuclear cells after internal ex-vivo irradiation. Data on the long-term radiation-associated side effects are only available for treatment with [224Ra]RaCl2. Two epidemiological studies followed two patient groups treated with [224Ra]RaCl2 for more than 25 years. One of them was the "Spiess study", a cohort of 899 juvenile patients who received several injections of [224Ra]RaCl2 with a mean specific activity of 0.66 MBq/kg. Another patient group of ankylosing spondylitis patients was treated with 10 repeated intravenous injections of [224Ra]RaCl2, 1 MBq each, 1 week apart. In total 1,471 of these patients were followed-up in the "Wick study". In both studies, an increased cancer mortality by leukemia and solid cancers was observed. Similar considerations on long-term effects likely apply to [223Ra]RaCl2 as well since the biokinetics are similar and the absorbed doses in the same range. However, this increased risk will most likely not be observed due to the much shorter life expectancy of prostate cancer patients treated with [223Ra]RaCl2.

A phase IB and randomised phase IIA trial of CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases: CARBON trial results

BackgroundApproximately 70% of patients with metastatic breast cancer (MBC) develop bone metastases. Despite advances in systemic treatment options and the use of bone targeted agents in the management of bone metastases to reduce skeletal morbidity, there remains an unmet need for further treatment options. Radium-223 (Ra223) is an alpha-emitting radiopharmaceutical that is preferentially taken up into bone at sites of increased osteoblastic activity where it emits high-energy, short-range alpha-particles that could provide a targeted anti-tumour effect on bone metastases. Here we evaluate the safety, feasibility and efficacy findings of the combination of Ra223 with capecitabine chemotherapy in patients with MBC with bone involvement. MethodsCARBON is a multi-centre, open-label phase IB/IIA study evaluating the combination of Ra223 (55 kBq/kg day 1 given on 6 weekly schedule) and capecitabine (1000 mg/m2 bd days 4–17 every 21 days) in patients with bone metastases from MBC (± other disease sites). Other eligibility criteria included ECOG performance status 0–2, ≤2 lines of chemotherapy for MBC and current bisphosphonate or denosumab use for ≥ 6 weeks. The phase IB part of the trial (6 patients) was conducted to provide preliminary feasibility and safety of capecitabine + Ra223. Thereafter, 28 patients were randomised (2:1) to capecitabine + Ra223 or capecitabine alone to further characterise the safety profile and evaluate efficacy, the primary efficacy endpoint being the bone turnover marker (urinary n-telopeptide of type I collagen) change from baseline to end of cycle 5 and secondary endpoints of time to first symptomatic skeletal event, and disease progression at extra-skeletal and bone disease. ResultsIn addition to bone metastases, 10/23 [44%] and 13/23 [57%] capecitabine + Ra223 and 2/11 [18%] and 9/11 [82%] capecitabine alone patients had soft tissue and visceral disease sites respectively. More capecitabine + Ra223 patients had received prior chemotherapy for MBC: 11/23 [48%] vs 2/11 [18%]. The analysis populations comprise 34 patients (23 capecitabine + Ra223, 11 capecitabine); 2 patients randomised to capecitabine + Ra223 received capecitabine alone and are included in the capecitabine arm. Median number of cycles received was 8.5 in capecitabine + Ra223 (range 3–12) and 12 in the capecitabine arm (range 1–12). 94/95 prescribed Ra223 cycles were administered. No dose limiting toxicities were seen in phase IB and no patients developed grade ≥ III diarrhoea. Gastrointestinal, haematological and palmer-planter erthyrodysesthesia adverse events were similar in both arms. Although formal statistical comparisons were not made, changes in bone turnover markers, the times to extra-skeletal progression and bone disease progression, and the frequency of symptomatic skeletal events were similar across the two treatment arms. ConclusionCapecitabine + Ra223 at the planned dose was safe and feasible in MBC patients with bone metastases. However, no efficacy signals were seen that might suggest greater efficacy of the combination over capecitabine alone clinically or biochemically.

Factors Influencing the Therapeutic Efficacy of the PSMA Targeting Radioligand 212Pb-NG001.

Simple SummaryProstate-specific membrane antigen (PSMA) is a protein overexpressed in metastatic castration-resistant prostate cancer and a promising target for targeted radionuclide therapy. PSMA-targeted alpha therapy is of growing interest due to the high-emission energy and short range of alpha particles, resulting in a prominent cytotoxic potency. This study assesses the influence of various factors on the in vitro and in vivo therapeutic efficacy of the alpha particle generating PSMA-targeting radioligand 212Pb-NG001.This study aimed to determine the influence of cellular PSMA expression, radioligand binding and internalization, and repeated administrations on the therapeutic effects of the PSMA-targeting radioligand 212Pb-NG001. Cellular binding and internalization, cytotoxicity, biodistribution, and the therapeutic efficacy of 212Pb-NG001 were investigated in two human prostate cancer cell lines with different PSMA levels: C4-2 (PSMA+) and PC-3 PIP (PSMA+++). Despite 10-fold higher PSMA expression on PC-3 PIP cells, cytotoxicity and therapeutic efficacy of the radioligand was only 1.8-fold better than for the C4-2 model, possibly explained by lower cellular internalization and less blood-rich stroma in PC-3 PIP xenografts. Mice bearing subcutaneous PC-3 PIP xenografts were treated with 0.2, 0.4, and 0.8 MBq of 212Pb-NG001 that resulted in therapeutic indexes of 2.7, 3.0, and 3.5, respectively. A significant increase in treatment response was observed in mice that received repeated injections compared to the corresponding single dose (therapeutic indexes of 3.6 for 2 × 0.2 MBq and 4.4 for 2 × 0.4 MBq). The results indicate that 212Pb-NG001 can induce therapeutic effects at clinically transferrable doses, both in the C4-2 model that resembles solid tumors and micrometastases with natural PSMA expression and in the PC-3 PIP model that mimics poorly vascularized metastases.

Abstract PS14-02: A randomised phase IB/IIA study of CApecitabine plus Radium-223 in breast cancer patients with BONe metastases (CARBON) - Safety and preliminary efficacy findings

Abstract Background: Bone metastases (BMs) occur in approximately 70% of patients (pts) with metastatic breast cancer (MBC). Despite significant advances in the management of BMs with bone-targeted agents and the associated reduction in skeletal-related events, there remains an unmet need for further treatment options to improve median overall survival beyond 2-3 years. Radium-223 [R] dichloride is an alpha-emitting radiopharmaceutical that is avidly taken up, like calcium, into the bone where it emits high-energy, short-range alpha-particles resulting in a targeted anti-tumour effect on BMs. Combining R with current systemic therapy could potentially enhance efficacy in MBC with BMs. Methods: CARBON is a UK, open-label, multi-centre phase IB/IIA study evaluating the combination of capecitabine [C] (1000mg/m2 bd days 4-17, 12x21 day cycles) with R 55kBq/kg day 1 given on a 6-weekly schedule in pts with BMs from MBC (+/- other sites of disease) with ≥2 bone lesions on radionuclide bone scan and/or ≥1 lesion confirmed on plain radiographs, CT or MRI. Other eligibility criteria included ECOG PS 0-2, ≤ 2 lines of chemotherapy for MBC and current use of a bisphosphonate / denosumab for ≥6 weeks. To establish the feasibility and safety of C+R the phase IB opened in August 2016 registering 6 pts; the primary endpoint was dose-limiting toxicities (DLTs), defined as ≥grade 3 gastrointestinal toxicity lasting &amp;gt;48 hours or ≥grade 4 haematological toxicity lasting &amp;gt;7 days. Subsequently, between April 2017 and March 2019 28 pts were randomised (2:1) to C+R vs C in phase IIa to further characterise the safety profile, with frequency of CTC grade 3-4 toxicities and diarrhoea as primary endpoints. Preliminary evaluation of efficacy through assessment of bone turnover marker changes from baseline to end of cycle 5 and time to progression in bone and overall was made. Results: Baseline clinico-pathologic characteristics and prior treatments were well balanced between the arms; 13 C+R and 9 C pts had visceral metastases. There were 0 DLTs in the 6 phase IB pts, therefore the same C+R dose and schedule was studied in phase IIA. 2 pts randomised to C+R received C alone and are included in the C arm. The safety population consists of 34 pts (23 C+R, 11 C). Median number of cycles received was 8.5 (range 3-12) in C+R arm and 12 (range 1-12) in C arm. 38/307 (12%) treatment cycles were delayed (25 [13%] C+R arm, 13 [12%] C arm). 11 (48%) C+R and 6 (55%) C pts had a permanent C dose reduction. 94/95 (99%) prescribed R cycles were administered. 9 (39%) C+R and 9 (82%) C pts completed all 12 cycles. Other reasons for discontinuation were: progressive disease in 12 (52%) C+R and 0 in C pts; toxicity in 1 (4%) C+R and 1 (9%) C pt; clinician decision in 1 (9%) C pt; progressive disease and toxicity in 1 (4%) C+R pt. Only 25/575 (4%) reported AEs were grade 3-4 (n=21 in 11 [48%] C+R pts, n=4 in 4 [36%] C pts) with 0 episodes of grade 3-4 diarrhoea. Table 1 shows maximum grades of diarrhoea and haematological AEs experienced by arm. 18 SAEs occurred (n=11 in 8 C+R pts, n=7 in 2 C pts). 8 (44%) SAEs were grade 3 (C+R: 6, C: 2); none were related to diarrhoea. There were 0 SUSARs. Conclusion: In the first completed trial evaluating R with chemotherapy in MBC pts, the combination of C+R is safe and well-tolerated. Preliminary efficacy analyses including bone markers are ongoing and will be presented at the meeting. The creation of the data was supported in part by Bayer Plc and Yorkshire Cancer Research. Table 1: Maximum CTCAE grade (G) experienced - diarrhoea and haematological AEs.C+R (n=23)C (n=11)Not experiencedG1G2G3G4Not experiencedG1G2G3G4Diarrhoea7 (30%)14 (61%)2 (9%)006 (55%)4 (36%)1 (9%)00Neutropenia18 (78%)02 (9%)3 (13%)010 (91%)01 (9%)00Thrombocytopenia21 (91%)1 (4%)1 (4%)009 (82%)1 (9%)1 (9%)00Anaemia21 (91%)2 (9%)0008 (73%)1 (9%)2 (18%)00 Citation Format: Matthew Winter, Jessica Kendall, Sarah Brown, Emma Rathbone, Caroline Wilson, Sacha Howell, Chris Twelves, Carlo Palmieri, Anjana Anand, Iain MacPherson, Rob Coleman, Janet Brown. A randomised phase IB/IIA study of CApecitabine plus Radium-223 in breast cancer patients with BONe metastases (CARBON) - Safety and preliminary efficacy findings [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-02.

Enhanced extraction via surface asperities of light generated around the boundary plane in poly (ethylene naphthalate)

Applications of poly (ethylene naphthalate) (PEN) in radiation safety are attractive. However, for worker safety at nuclear power reactors, further enhancements of undoped scintillation materials are required for alpha particle detection. Here, we show that restrictions on the maximum light extraction from PEN can be lifted by controlling its surface conditions. Specifically, 1 mm-thick PEN plates with various degrees of surface asperities were examined. Emission and transmission spectra indicated little effect on the emission wavelengths of the generated light, but large effect on the propagation directions. These features resulted in excellent instrument efficiency for short-range alpha particles in radioactive contamination inspection devices that incorporated PEN having several tens of μm deep surface scratches. We modelled the relationship between surface asperities and instrument efficiencies for alpha particles by imaging the surface conditions with scanning electron microscopy. Surface asperities led to a quasi-decrease in the critical angle of the light generated around the surface boundary plane, which then resulted in an increase in total internal reflections at the plane. This knowledge should initiate general interest in PEN for radiological management devices.

Alpha Particle Detection Using Alpha-Induced Air Radioluminescence: A Review and Future Prospects for Preliminary Radiological Characterisation for Nuclear Facilities Decommissioning.

The United Kingdom (UK) has a significant legacy of nuclear installations to be decommissioned over the next 100 years and a thorough characterisation is required prior to the development of a detailed decommissioning plan. Alpha radiation detection is notoriously time consuming and difficult to carry out due to the short range of alpha particles in air. Long-range detection of alpha particles is therefore highly desirable and this has been attempted through the detection of secondary effects from alpha radiation, most notably the air-radioluminescence caused by ionisation. This paper evaluates alpha induced air radioluminescence detectors developed to date and looks at their potential to develop a stand-off, alpha radiation detector which can be used in the nuclear decommissioning field in daylight conditions to detect alpha contaminated materials.

Application of CR-39 Microfilm for Rapid Discrimination Between Alpha-Particle Sources

Abstract This work presents a new technique for discriminating between alpha particles of different energy levels. In a first study, two groups of alpha particles emitted from radium-226 and americium-241 sources were successfully separated using a CR-39 microfilm of appropriate thickness. This thickness was adjusted by chemical etching before and after irradiation so that lower-energy particles were stopped within the detector, while higher-energy particles were revealed on the back side of the detector. The number of tracks on the front side of the microfilm represented all alpha particles incident on that side from the two sources. However, the number of tracks on the back side of the microfilm represented only the long-range alpha particles of higher energy that arrived at that side. Therefore, by subtracting the number of tracks on the back side from the number of tracks on the front side, one could easily determine the number of tracks for the short-range alpha particles of lower energy that remained embedded in the microfilm. Discrimination of the two energy levels is thus achieved in a simple, fast, and reliable process.

Nursing management of patients with castration-resistant prostate cancer undergoing radium-223 dichloride treatment.

Radium-223 dichloride, or radium-223, is a first-in-class alpha emitter that selectively targets bone metastases with high-energy, short-range alpha particles and is approved for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease. Nurses are essential in educating patients about radium-223. This article provides oncology nurses with information from the randomized phase III Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, as well as important handling, administration, and safety details unique to radium-223. Data from the ALSYMPCA trial and related published information on radium-223 were reviewed. Radium-223 is the only alpha-emitting radiopharmaceutical that has been shown to improve overall survival in patients with CRPC, as demonstrated in the ALSYMPCA trial. In addition, radium-223 delays time to first symptomatic skeletal event, and it is well tolerated with a low incidence of myelosuppression and gastrointestinal adverse events. Delivered on an outpatient basis, radium-223 requires universal precautions for handling and administration. Because of the potential for additive myelosuppression, the concomitant use of radium-223 with chemotherapy, other systemic radioisotopes, or hemibody external radiation therapy is not recommended.

Alpha-emitter radium-223 in the management of solid tumors: current status and future directions.

Bone metastases, which are commonly seen in patients with advanced cancers, are a major cause of skeletal events, disability, and death. Radium-223 dichloride (radium-223; Xofigo, formerly Alpharadin), a first-in-class, alpha-emitting radiopharmaceutical that selectively targets bone metastases with high-energy short-range alpha-particles, has been approved for the treatment of patients with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastases. Approval is based on results of the randomized phase III trial Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA), in which radium-223 prolonged overall survival and time to first symptomatic skeletal event versus placebo among patients with CRPC with symptomatic bone metastases and was generally well tolerated, with low myelosuppression rates and manageable gastrointestinal adverse events. Long-term follow-up of the ALSYMPCA safety population showed that the incidence of myelosuppression remained low among patients treated with radium-223, with no additional safety issues of acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, or primary bone cancer within approximately 1.5 years after treatment. The radium-223 overall survival benefit and low toxicity make it an effective, well-tolerated, and novel treatment option for CRPC and symptomatic bone metastases and opens the possibility of exploring radium-223 in the treatment of bone metastases from other cancers. A phase I clinical trial of patients with breast and prostate cancer with skeletal metastases demonstrated that radium-223 was safe and well tolerated at all therapeutically relevant dosages. Moreover, a phase IIa trial of patients with advanced breast cancer and progressive bone-dominant disease demonstrated that radium-223 targeted areas of increased bone metabolism and showed biologic activity.

A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease

Radium-223 dichloride (radium-223) mimics calcium and emits high-energy, short-range alpha-particles resulting in an antitumor effect on bone metastases. This open-label, phase IIa nonrandomized study investigated safety and short-term efficacy of radium-223 in breast cancer patients with bone-dominant disease. Twenty-three advanced breast cancer patients with progressive bone-dominant disease, and no longer candidates for further endocrine therapy, were to receive radium-223 (50 kBq/kg IV) every 4 weeks for 4 cycles. The coprimary end points were change in urinary N-telopeptide of type 1 (uNTX-1) and serum bone alkaline phosphatase (bALP) after 16 weeks of treatment. Exploratory end points included sequential 18F-fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT) to assess metabolic changes in osteoblastic bone metastases. Safety data were collected for all patients. Radium-223 significantly reduced uNTX-1 and bALP from baseline to end of treatment. Median uNTX-1 change was −10.1 nmol bone collagen equivalents/mmol creatinine (−32.8 %; P = 0.0124); median bALP change was −16.7 ng/mL (−42.0 %; P = 0.0045). Twenty of twenty-three patients had FDG PET/CT identifying 155 hypermetabolic osteoblastic bone lesions at baseline: 50 lesions showed metabolic decrease (≥25 % reduction of maximum standardized uptake value from baseline) after 2 radium-223 injections [32.3 % metabolic response rate (mRR) at week 9], persisting after the treatment period (41.5 % mRR at week 17). Radium-223 was safe and well tolerated. Radium-223 targets areas of increased bone metabolism and shows biological activity in advanced breast cancer patients with bone-dominant disease.

Updated analysis of radium-223 dichloride (Ra-223) impact on skeletal-related events (SRE) in patients with castration-resistant prostate cancer (CRPC) and bone metastases from the phase III randomized trial (ALSYMPCA).

11 Background: Ra-223 is a first-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy, short-range (&lt; 100 μm) alpha-particles. In the phase 3, double-blind, randomized, multinational ALSYMPCA study, Ra-223 significantly improved OS in CRPC patients (pts) with bone mets by a median increase of 3.6 months compared with placebo (median OS: 14.9 vs 11.3 mo; P &lt; 0.001; HR = 0.69; 95% CI: 0.58-0.83). An updated analysis of the SRE secondary endpoint is presented. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving best standard of care (BSoC); and either previously received docetaxel, or did not because they were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra‑223 (50 kBq/kg IV) q4wk or matching placebo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. Results: 921 pts were randomized (Ra-223, n = 614; placebo, n = 307); 40% had &gt;20 mets. Ra-223 significantly delayed time to first SRE versus placebo by a median increase of 5.8 months (median time to SRE: 15.6 vs 9.8 mo; P &lt; 0.001; HR = 0.66; 95% CI: 0.52-0.83). Ra-223 also reduced the risk of time to first event for all 4 SRE components versus placebo. Conclusions: Ra-223 significantly delayed time to first SRE with a reduction in risk observed for all 4 SRE components. Despite the longer time at risk, Ra-223 patients had an approximately 50% reduction in risk for SCC. Ra-223 is an effective therapy with a highly favorable safety profile and may provide a new standard of care for treatment of CRPC pts with bone mets. Clinical trial information: NCT00699751. [Table: see text]

Dosimetry of 223Ra-chloride: dose to normal organs and tissues

(223)Ra-Chloride (also called Alpharadin®) targets bone metastases with short range alpha particles. In recent years several clinical trials have been carried out showing, in particular, the safety and efficacy of palliation of painful bone metastases in patients with castration-resistant prostate cancer using (223)Ra-chloride. The purpose of this work was to provide a comprehensive dosimetric calculation of organ doses after intravenous administration of (223)Ra-chloride according to the present International Commission on Radiological Protection (ICRP) model for radium. Absorbed doses were calculated for 25 organs or tissues. Bone endosteum and red bone marrow show the highest dose coefficients followed by liver, colon and intestines. After a treatment schedule of six intravenous injections with 0.05 MBq/kg of (223)Ra-chloride each, corresponding to 21 MBq for a 70 kg patient, the absorbed alpha dose to the bone endosteal cells is about 16 Gy and the corresponding absorbed dose to the red bone marrow is approximately 1.5 Gy. The comprehensive list of dose coefficients presented in this work will assist in comparing and evaluating organ doses from various therapy modalities used in nuclear medicine and will provide a base for further development of patient-specific dosimetry.

Poster - Thur Eve - 15: Production and assessment of astatine-211 for targeted alpha therapy.

Biologically-targeted alpha-particle radiation is the basis of new and promising treatments for eliminating disseminated micrometastases and the residual microscopic malignancies that remain after surgery or radiation therapy. The short-range alpha-particles are highly cytotoxic and capable of inactivating single, isolated cancer cells which may otherwise cause recurrence. Astatine-211 is a promising alpha emitter for therapy; the 7.2 hour half-life of 211 At provides sufficient time for biological-targeting to take place. However, this radionuclide is in short supply and future treatment strategies still require extensive preclinical evaluation. The present work aims to develop technologies that (1) increase the world-wide availability of 211 At for clinical use, and (2) assess the risks of 211 At-based therapies by quantifying the activity distributions in animal models. At TRIUMF (Vancouver, BC), the feasibility of a novel generator system for 211 At is under investigation which would allow distribution of 211 At across Canada and internationally. Briefly, a longer-lived parent radionuclide of 211 At, radon-211, would be produced and allowed to decay in containment to yield 211 At in solution. Additionally, a supplementary study is underway in collaboration with the University of Washington to evaluate the sub-organ biodistributions of astatinated targeting biomolecules, with cell-level resolution. These measurements involve high resolution quantitative alpha-particle imaging in thin tissue samples and can be done for a selection of applications (eg. lymphoma, metastatic prostate cancer, etc) using animal models. The planned alpha-camera measurements are primarily designed to predict and assess the risk of toxicity associated with 211 At-based therapies and aid in developing the future clinical applications.

Modelling and dosimetry for alpha-particle therapy.

As a consequence of the high potency and short range of alpha-particles, radiopharmaceutical therapy with alpha- particle emitting radionuclides is a promising treatment approach that is under active pre-clinical and clinical investigation. To understand and predict the biological effects of alpha-particle radiopharmaceuticals, dosimetry is required at the micro or multi-cellular scale level. At such a scale, highly non-uniform irradiation of the target volume may be expected and the utility of a single absorbed dose value to predict biological effects comes into question. It is not currently possible to measure the pharmacokinetic input required for micro scale dosimetry in humans. Accordingly, pre-clinical studies are required to provide the pharmacokinetic data for dosimetry calculations. The translation of animal data to the human requires a pharmacokinetic model that links macro- and micro-scale pharmacokinetics thereby enabling the extrapolation of micro-scale kinetics from macroscopic measurements. These considerations along with a discussion of the appropriate physical quantity and related units for alpha-particle radiopharmaceutical therapy are examined in this review.

Alpha dosimetry for the skeletal model of the reference adult male

Introduction: Dosimetry of bone marrow is challenging due to the complex histology of the skeleton and to the fact that the segmentation is not possible on the macroscopic level. In this context, calculation of absorbed fractions (AFs) of energy from alpha particles is of particular interest. Indeed, the high ionizing power and the short range of alpha particles makes them toxic in the case of internal contaminations or beneficial for radioimmunotherapy applications. Materials and methods: A reference voxelized adult model of the human skeleton, developed at the University of Florida using 3-D microCT images of a 40 year-old male, is used for the calculation of AFs for alpha particles with initial energy ranging from 4 to 10 MeV. The MCNPX Monte Carlo code associated to OEDIPE software will be used to simulate the transport of alphas in 32 skeletal microstructures for the following source regions: trabecular bone volume, active marrow, inactive marrow and endosteum. Radiosensitive skeletal target regions are the active marrow (risk of leukemia) and endosteum (risk for bone cancer). Siteand agespecific percentage of marrow cellularity will be considered. The Monte Carlo calculations will be benchmarked with the GEANT4 Monte Carlo code, which generates secondary electrons in addition of alpha particles. Results: Significant variations in absorbed fractions between different skeletal sites were observed. The parietal bone demonstrates the greatest difference as this particular bone site is characterized by relatively small marrow cavities and thick bone trabeculae. Differences were also observed between this model and the absorbed fractions given in ICRP Publication 30. In fact, the energy deposition in the active marrow is overestimated in the ICRP 30. On the contrary, the AFs are underestimated for the endosteum. Calculation of the AFs as a function of the marrow cellularity shows that the energy deposition decrease with the cellularity and increase with the energy of alpha particles. Conclusion: Results presented here provide a firmer basis for a more realistic dosimetry in alpha emitter radionuclide therapies through the explicit consideration of absorbed fraction variations with particle energy, skeletal site, and marrow cellularity.

Radium-223 chloride, a first-in-class alpha-pharmaceutical for patients with castration-resistant prostate cancer (CRPC) and bone metastases: Biodistribution/dosimetry compared to overall safety profile.

e15009 Background: Radium-223 chloride (Alpharadin) is a first-in-class targeted alpha-pharmaceutical with a potent and highly targeted antitumor effect on bone metastases. It has shown a promising survival benefit, a benign safety profile and pain improvement in patients (pts) with bone metastatic CRPC. Biodistribution/dosimetry was evaluated in the context of safety. Methods: 6 pts with bone-metastatic CRPC received 2 radium-223 doses, 100 kBq/kg, 6 weeks apart. Blood, urine and feces were collected before and at regular intervals after injection. Whole body gamma camera imaging determined biodistribution. Radiation dose was calculated with adjustments for GI tract, heart wall, red marrow (RM) and osteogenic cells (OC). It was also taken into consideration that the product emits short range, high energy alpha particles. Overall safety and tolerability were evaluated in 292 pts across all Phase I/II trials. Results: Radium-223 wasrapidly eliminated from blood and taken up in bone (∼60% at 4hr) or excreted into the small intestine. There was <5% urinary and no hepato-biliary excretion. Highest calculated absorbed doses were to OC, RM and lower large intestine wall. In separate studies of 292 pts who had received range administered activities, <1% had CTC grade 4 hematological toxicity, 2-4% had grade 3 toxicity for HB, platelets, neutrophils, WBC. Mainly mild to moderate and reversible AEs were seen in the GI tract. Conclusions: Radium-223 was rapidly sequestered to bone/bone metastases and excreted in the GI tract. Due to the very short range of alpha particles (2-10 cell diameters), only a small volume of RM would have received a significant radiation dose, possibly accounting for the favorable hematologic safety profile. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Algeta ASA Algeta ASA Algeta ASA