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Calculation of radium-223 and actinium-225 α-emitter radiopharmaceuticals dose rates in treatment of metastatic castration-resistant prostate cancer


1 Department of Electrical and Electronic Engineering, Faculty of Engineering, University of Kyrenia, Girne, TRNC, Via Mersin 10, Turkey
2 Department of Medical Biotechnology, Faculty of Advanced Medical Sciences; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3 Center of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, Vienna, Austria; School of Pharmacy, Faculty of Sciences, University of Rome Tor Vergata, Via Della Ricerca Scientifica, 00133, Rome, Italy

Date of Submission26-Dec-2018
Date of Decision11-Feb-2019
Date of Acceptance19-May-2019
Date of Web Publication06-Feb-2020

Correspondence Address:
Akbar Abbasi,
Faculty of Engineering, University of Kyrenia, Girne, TRNC, Via Mersin 10
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_892_18

 > Abstract 


Aim of Study: There is limited information regarding the α-emitter radiopharmaceuticals dose calculation used in the setting of men with prostate cancer (PCa). The present study investigates the α-emitter radiopharmaceuticals absorbed dose distribution in the body organs.
Materials and Methods: The α-emitter radiopharmaceuticals dose coefficient and absorbed doses biokinetics distribution, which are used for the treatment of PCa in all over the world, were performed using the “Internal Dose Assessed by Computer” (IDAC-Dose 2.1) program. The results of absorbed dose distribution in any organ of the body, were compared in studied α-emitter radiopharmaceuticals.
Results: The absorbed dose value of 223Ra radiopharmaceutical in the prostate organ was evaluated 9.47E-9 Gy/Bq. The maximum and minimum absorbed doses due to biokinetics distribution of 223Ra were found in the thymus (9.53E-8 Gy/Bq) and eye lenses (1.30E-10 Gy/Bq) organs, respectively. Furthermore, the 225Ac absorbed dose in the prostate organ was obtained 1.91E-9 Gy/Bq, where this value is 1% of total body dose. While the absorbed dose distribution of 225Ac in body organs shows the highest concentration in the spleen (1.47E-8 Gy/Bq) and lowest in the eye lenses (7.93E-12 Gy/Bq).
Conclusion: The absorbed dose in the body organs due to 223Ra and 225Ac α-emitter radiopharmaceuticals which are used in metastasized castration-resistant prostate cancer (mCRPC), calculated in this study. The results of this study will assist in evaluating and analyzing human body organ doses from application of 223Ra and 225Ac that used in mCRPC patients.

Keywords: Absorbed dose, body organ, prostate cancer, radiopharmaceutical, α-emitter



How to cite this URL:
Abbasi A, Dadashpour M, Alipourfard I. Calculation of radium-223 and actinium-225 α-emitter radiopharmaceuticals dose rates in treatment of metastatic castration-resistant prostate cancer. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 27]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=277839




 > Introduction Top


An investigation in the United States shows that 241,740 men were diagnosed with prostate cancer (PCa) in 2012, contributing to a number of 28,170 deaths.[1] In 2017, approximately 160,000 men will be diagnosed with PCa in the USA.[2] Although it often has an indolent course, PCa remains the third-leading cause of cancer death in men. Since 2011, meaningful progress has been obtained in identifying therapeutic options and characterizing disease risk.[3]

Skeleton is the most common place for metastasis in PCa, and skeleton metastases happen in nearly 80% of final prostate carcinoma patients. The average survival of PCa patients with skeleton metastasis is 2–3 years, and the 5-year probability of survival is 30%.[4] Furthermore, an international randomized controlled test, within 921 patients from over 100 clinics placed in 19 countries, indicated an increase in life expectancy in patients treated with 223RaCl2 than that of patients in the placebo group, with overall survival of 14.9 months compared to 11.3 months.[5]

Skeletal metastases from PCa are mainly osteoblastic lesions or bone forming, and also in the rare cause, the osteolytic lesions have also been observed. PCa cells stimulate osteoblastic proliferation to produce specific growth factors for osteoblasts, which results in increased bone matrix deposition in the bone and tumor microenvironment.[6]

The routine treatments for skeleton metastases in the world include systemic chemotherapy, hormonal therapies, and bone-targeted radiopharmaceuticals such as radium-223 dichloride (Ra-223) and actinium-225 (Ac-225).[7]

The increased availability and improved radiochemistry techniques of α-emitter radionuclides for targeted therapy have offered modern feasibility for their use in radiotherapy. The α-emitter radionuclides offer good advantages over β-emitter radionuclides, in particular, the main advantages of α-emitter radionuclides are the high linear energy transfer (LET) and the limited range in tissue. The range of LET in α-particle is approximately 100 keV/μm and can produce substantially more lethal double-strand DNA breaks per radiation track than β-particles when transversing a cell nucleus.[8]

In recent decades, multiple radiopharmaceutical conjugates have been tested and shown to be efficacious in the treatment of metastasized castration-resistant prostate cancer (mCRPC). Several studies have been published on the therapeutic use of α-emitter radiopharmaceuticals and several authors suggested their treatment superiority.[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19] Targeted alpha-therapy delivers alpha-radiation to cancer cells and to the tumor microenvironment while minimizing toxicity to surrounding tissues.[20]

In this study, the internal absorbed radiation dose in castration-resistant PCa patients was investigated. Hence, we calculated the 223Ra and 225Ac α-emitter radiopharmaceutical distribution throughout human body organs.


 > Materials and Methods Top


Radiopharmaceuticals are unique medicinal formulations containing radioisotopes which are used in major clinical areas for diagnosis and therapy purposes. The main α-emitter radiopharmaceuticals which commonly used in the treatment of PCa are 223Ra and 225Ac radionuclides.

The LET due to the moving of α-particle in tissue causes damage to the cell DNA, whereas the short range of the α-particle confines the damage to the tumor, thus reducing the damage to nearby healthy cells. External bodily exposure of α-particle is negligible, however, if inhaled or ingested, α-particles can cause severe damage at both the cellular and genetic level. This makes α-particles possibly the most damaging form of radiation.

223Ra (T1/2= 11.43 day) is an α-emitter radiopharmaceutical with average α energy 5.78 Mev, (accounts for 93.5% of emitted energy); <4% as β particles; <2% as γ radiation which used in bone metastases of PCa. The dichloride- 223Ra is a targeted α-emitter that selectively binds to areas of increased bone turnover in bone metastases and emits high-energy alpha-particles of short range (<100 μm).[21],[22] Targeted α-emitter 223Ra therapy delivers radiation energy to cancer cells and to the tumor tissue while minimizing toxicity to surrounding tissues.[20] The energy bonds of 223Ra are shown in [Figure 1]a.
Figure 1: The decay scheme for 223Ra (a), and 225Ac (b) radiopharmaceuticals

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225Ac (T1/2= 10 days), like 223Ra, is an α-emitter radiopharmaceutical with six predominant radionuclides in the decay cascade to stable209 Bi.[23] 225Ac radioelement is a targeted alpha-therapy that prolongs survival in patients with castration-resistant metastatic PCa. 225Ac singly emits α particle of Eα= 6 MeV energy, with decay yields net four α-particles and three β-particles disintegrations, most of high energy and useful gamma emissions of which the213 Bi (T1/2= 45.6 m; Eα = 6 MeV, Emax(β)= 444 keV, and Eγ = 440 keV), where this γ-line has been used in imaging drug distribution.[23] The other daughters are221 Fr (T1/2= 4.8 min; Eα= 6 MeV and 218 keV γ energy line emission),217 At (T1/2= 32.3 ms; Eα= 7 MeV),213 Po (T1/2= 4.2 μs; Eα= 8 MeV),209 Tl (T1/2= 2.2 m; Emax(β)= 659 keV),209 Pb (T1/2= 3.25 h; Emax(β)= 198 keV), and209 Bi (stable). Given the 10.0-day half-life of 225Ac, the large alpha-particle emission energies, and the favorable rapid decay chain to s[table 209]Bi. This radionuclide is known as a good potential for use in cancer therapy.[24],[25] The decay scheme for 225Ac is shown in [Figure 1]b. Furthermore, the characteristics of 223Ra and 225Ac radiopharmaceuticals are shown in [Table 1].{table 209}
Table 1: The properties of 223Ra and 225Ac radiopharmaceuticals in the treatment of bone metastases prostate cancer

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According to clinical trial reports, six injections of 223Ra-chloride (0.05 MBq/kg) every 4 weeks schedule was recommended.[26] Furthermore, the treatment activity of 225Ac-PSMA-617 in 0.01 MBq/kg administered every 2 months was recommended with respect for tolerable side effects[27] To avoid complication, we only compute a dose of one injection.

The dose calculations were performed using the “Internal Dose Assessed by Computer” (IDAC-Dose 2.1) program. This program has used by the International Commission on Radiological Protection (ICRP) to calculate the dose coefficients for patients undergoing examinations with radiopharmaceuticals in nuclear medicine. In addition, the IDAC-Dose 2.1 program base is dose calculations on the same ICRP computational framework for internal dose assessment.

The mean absorbed dose (D) to a target region (rT) for a time-independent system as following equation:[28]

(1)

Whereis the cumulated activity (Bq) in source region rs, over the integration period TD, and S (rrrs) is the mean absorbed dose (Gy/Bq) in the target tissue per nuclear transformation in the source region and defined by this equation:

(2)

Where φ (rTrS, Ei) is the specific absorbed fractions value,[29] and Δi= EiYi(where Ei is the yield and Yi is the mean energy or part of the energy distribution for β-decay) of the ith the nuclear transition of the radionuclide in joules.[30]


 > Results Top


The absorbed dose and dose coefficients of 223Ra and 225Ac radiopharmaceuticals were calculated with IDAC-Dose 2.1 in 28 human body organs and shown in [Table 2]. The results was calculated within one intravenous injection during 1 h. The absorbed dose of 223Ra and 225Ac radiopharmaceuticals in the prostate organ was calculated 9.47E-9 Gy/Bq and 1.91E-9 Gy/Bq, respectively, where these values are 1% of total body dose, which absorbed in whole body. The absorbed dose results of 223Ra radiopharmaceutical are approximately five times more than 225Ac radiopharmaceutical. This difference can be caused by the energy of the alpha particle and its intensity. The maximum and minimum absorbed dose due to biokinetics distribution of 223Ra was found in the thymus (9.53E-8 Gy/Bq) and eye lenses (1.30E-10 Gy/Bq) organs, respectively. In addition, the 225Ac distribution in body organs shows the highest concentration absorbed dose in the spleen (1.47E-8 Gy/Bq) and lowest in the eye lenses (7.93E-12 Gy/Bq).
Table 2: Dose coefficients and absorbed dose (Gy/Bq) per intravenous injections of 223Ra and 225Ac radiopharmaceuticals calculated with Internal Dose Assessed by Computer-Dose 2.1 in human body organs

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[Figure 2] and [Figure 3] show the 223Ra and 225Ac radiopharmaceuticals absorbed doses in some human body organs. As observed in histogram, the 50% of absorbed dose in both radiopharmaceuticals are accumulated in six organs. Those six organs are the thymus, spleen, lung, kidneys, colon wall, and small intestine wall for 223Ra radiopharmaceutical and the spleen, lung, kidneys, colon wall, small intestine wall, and liver for 225Ac radiopharmaceutical.
Figure 2: The absorbed dose distribution of 223Ra radiopharmaceutical in some body organs

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Figure 3: The absorbed dose distribution of 225Ac radiopharmaceutical in some body organs

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 > Discussion Top


The comprehensive list of absorbed dose in body organs due to 223Ra and 225Ac α-emitter radiopharmaceutical, which are used in mCRPC, presented in this research was comparable with other researchers reports.

Lassmann et al. calculated the maximum dose of bone endosteum (7.5E-07 Gy/Bq) organ in six treatments of a 70 kg person with an administered activity of 0.05 MBq/kg 223Ra-chloride.[27] Where our results for one treatment in bone endosteum was 6.60E-9. Other administration protocols consist of 50 kBq 223Ra per kg body weight every 4 weeks administrations, with a total of six injections, the mean absorbed dose value was reported 8.99E-7 Gy/Bq.[28] Therefore, the results of this research have good agreement with reported data.

Kratochwil et al. have reported for 225Ac-PSMA-617, salivary glands (4.6E-7 Gy/Bq), kidneys (14E-8 Gy/Bq), and red marrow (1.0E-8 Gy/Bq).[23] Whereas, we find 1.91E-9 Gy/Bq, 1.13E-8 Gy/Bq, and 6.87E-9 Gy/Bq for the salivary glands, kidneys, and red marrow, respectively.

The range of absorbed doses delivered to the bone surfaces from 223Ra was 2.33 E-9 to 13.118E-9 Gy/Bq has been indicated by Chittenden et al.[12]

Due to the newness of 225Ac radiopharmaceutical, there are very few absorbed dose calculations related to 225Ac radiopharmaceutical.


 > Conclusion Top


Estimation of adsorbed dose is main parameter in cancer therapy by radionuclides.[31] Total body absorbed dose value (Gy/Bq) per intravenous injections of 223Ra was higher than 225Ac radiopharmaceuticals. This difference is related to the energy of alpha particles and the half-life of the radiopharmaceuticals.

The results of this study will assist in evaluating and analyzing human body organ doses from application of 223Ra and 225Ac that used in mCRPC patients.

Acknowledgment

The authors would like to thank Prof. M Andersson from the Department of Translational Medicine, Malmö, for permission of using computer code.

Financial support and sponsorship

Kyrenia University.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 2012;62:220-41.  Back to cited text no. 1
    
2.
Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 2016;66:271-89.  Back to cited text no. 2
    
3.
Litwin MS, Tan HJ. The diagnosis and treatment of prostate cancer: A review. JAMA 2017;317:2532-42.  Back to cited text no. 3
    
4.
Kuroda I. Strontium-89 for prostate cancer with bone metastases: The potential of cancer control and improvement of overall survival. Ann Nucl Med 2014;28:11-6.  Back to cited text no. 4
    
5.
Mangano AM, Pacilio M, Ialongo P, Semprebene A, Ventroni G, Mango L. Dosimetry-based consideration on remission and relapse after therapy with 223Ra-dichloride in castration-resistant prostate cancer (CRPC) with bone metastases. A case report. Diagnostics (Basel) 2018;8. pii: E18.  Back to cited text no. 5
    
6.
Saylor PJ, Smith MR. Bone health and prostate cancer. Prostate Cancer Prostatic Dis 2010;13:20-7.  Back to cited text no. 6
    
7.
Anido Herranz U, Fernández Calvo O, Afonso Afonso FJ, Rodríguez Martínez de Llano S, Lázaro Quintela M, León Mateos L, et al. Radium-223 dichloride: A new paradigm in the treatment of prostate cancer. Expert Rev Anticancer Ther 2015;15:339-48.  Back to cited text no. 7
    
8.
Miederer M, Scheinberg DA, McDevitt MR. Realizing the potential of the actinium-225 radionuclide generator in targeted alpha particle therapy applications. Adv Drug Deliv Rev 2008;60:1371-82.  Back to cited text no. 8
    
9.
Parker CC, Pascoe S, Chodacki A, O'Sullivan JM, Germá JR, O'Bryan-Tear CG, et al. A randomized, double-blind, dose-finding, multicenter, phase 2 study of radium chloride (Ra 223) in patients with bone metastases and castration-resistant prostate cancer. Eur Urol 2013;63:189-97.  Back to cited text no. 9
    
10.
Batra JS, Liu H, Kim S, Navarro VN, Vallabhajosula S, Tagawa ST, et al. PSMA-Targeted Alpha Radioimmunotherapy for Prostate Cancer with 225 Ac-J591. AACR; 2017.  Back to cited text no. 10
    
11.
Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: Results from a phase 3, double-blind, randomised trial. Lancet Oncol 2014;15:738-46.  Back to cited text no. 11
    
12.
Chittenden SJ, Hindorf C, Parker CC, Lewington VJ, Pratt BE, Johnson B, et al. A phase 1, open-label study of the biodistribution, pharmacokinetics, and dosimetry of 223Ra-dichloride in patients with hormone-refractory prostate cancer and skeletal metastases. J Nucl Med 2015;56:1304-9.  Back to cited text no. 12
    
13.
Hague C, Logue JP. Clinical experience with radium-223 in the treatment of patients with advanced castrate-resistant prostate cancer and symptomatic bone metastases. Ther Adv Urol 2016;8:175-80.  Back to cited text no. 13
    
14.
Julian RA, Kang CS, Sun X, Song HA, Revskaya E, Chong HS, et al. Optimizing Radioimmunotherapy Techniques for the Alpha-Emitter 225Actinium. AACR; 2015.  Back to cited text no. 14
    
15.
Nilsson S. Radionuclide therapies in prostate cancer: Integrating radium-223 in the treatment of patients with metastatic castration-resistant prostate cancer. Curr Oncol Rep 2016;18:14.  Back to cited text no. 15
    
16.
Tagawa ST, Vallabhajosula S, Jhanwar Y, Ballman KV, Hackett A, Emmerich L, et al. Phase I Dose-Escalation Study of 225Ac-J591 for Progressive Metastatic Castration Resistant Prostate Cancer (mCRPC). American Society of Clinical Oncology; 2018.  Back to cited text no. 16
    
17.
Wenter V, Herlemann A, Fendler WP, Ilhan H, Tirichter N, Bartenstein P, et al. Radium-223 for primary bone metastases in patients with hormone-sensitive prostate cancer after radical prostatectomy. Oncotarget 2017;8:44131-40.  Back to cited text no. 17
    
18.
Kulkarni HR, Singh A, Schuchardt C, Niepsch K, Sayeg M, Leshch Y, et al. PSMA-based radioligand therapy for metastatic castration-resistant prostate cancer: The Bad Berka experience since 2013. J Nucl Med 2016;57:97S-104S.  Back to cited text no. 18
    
19.
Pacilio M, Ventroni G, Frantellizzi V, Cassano B, Montesano T, Borrazzo C, et al. 330. 223Ra therapy of bone metastases for castration-resistant prostate cancer (CRPC): Lesion dosimetry and follow-up for a large group of patients. Phys Med Eurean J Med Phys 2018;56:262-3.  Back to cited text no. 19
    
20.
Du Y, Carrio I, De Vincentis G, Fanti S, Ilhan H, Mommsen C, et al. Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging 2017;44:1671-8.  Back to cited text no. 20
    
21.
Bruland ØS, Nilsson S, Fisher DR, Larsen RH. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: Adjuvant or alternative to conventional modalities? Clin Cancer Res 2006;12:6250s-6257s.  Back to cited text no. 21
    
22.
Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369:213-23.  Back to cited text no. 22
    
23.
Jurcic JG, Larson SM, Sgouros G, McDevitt MR, Finn RD, Divgi CR, et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood 2002;100:1233-9.  Back to cited text no. 23
    
24.
Geerlings MW, Kaspersen FM, Apostolidis C, van der Hout R. The feasibility of 225Ac as a source of alpha-particles in radioimmunotherapy. Nucl Med Commun 1993;14:121-5.  Back to cited text no. 24
    
25.
Elgqvist J, Timmermand OV, Larsson E, Strand SE. Radiosensitivity of prostate cancer cell lines for irradiation from beta particle-emitting radionuclide177 Lu compared to alpha particles and gamma rays. Anticancer Res 2016;36:103-9.  Back to cited text no. 25
    
26.
Lewington V, Lamey R, Staudacher K, Vogelzang N. Radium-223 chloride: Radiation safety, tolerability, and survival gain in patients with castration-resistant prostate cancer (CRPC) and bone metastases. J Nucl Med 2012;53 Suppl 1:222.  Back to cited text no. 26
    
27.
Lassmann M, Nosske D. Dosimetry of 223 Ra-chloride: Dose to normal organs and tissues. Eur J Nucl Med Mol Imaging 2013;40:207-12.  Back to cited text no. 27
    
28.
Andersson M, Johansson L, Eckerman K, Mattsson S. IDAC-dose 2.1, an internal dosimetry program for diagnostic nuclear medicine based on the ICRP adult reference voxel phantoms. EJNMMI Res 2017;7:88.  Back to cited text no. 28
    
29.
Bolch WE, Jokisch D, Zankl M, Eckerman KF, Fell T, Manger R, et al. ICRP publication 133: The ICRP computational framework for internal dose assessment for reference adults: Specific absorbed fractions. Ann ICRP 2016;45:5-73.  Back to cited text no. 29
    
30.
Eckerman K, Endo A. ICRP publication 107. Nuclear decay data for dosimetric calculations. Ann ICRP 2008;38:7-96.  Back to cited text no. 30
    
31.
Abbasi A, Sadikoglu F, Hassanzadeh M. Effect of Au-197 nanoparticles along with Sm-153 radiopharmaceutical in prostate cancer from simulation method. J Cancer Res Ther 2019;15:42.  Back to cited text no. 31
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

 
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