Personalized dosimetry of internal exposure to foci and organs at risk of patients: development and implementation of a methodological basis for dosimetric support of clinical trials of therapeutic radiopharmaceuticals

«Radiation and Risk», 2023, vol. 32, No. 1, pp.156-167

DOI: 10.21870/0131-3878-2023-32-1-156-167

Authors

Stepanenko V.F. – Head of Lab., D. Sc., Biol., Prof. Contacts: 4 Korolyov str., Obninsk, Kaluga region, Russia, 249035. Tel.: (484) 399-70-02; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. .
Petriev V.M. – Head of Lab., D. Sc., Biol.
Ivanov S.A. – Director, Corr. Member of RAS, MD, Prof. of PFUR Dep.
Bogacheva V.V. – Sen. Researcher, C. Sc., Biol.
Kolyzhenkov T.V. – Lead. Researcher, C. Sc., Biol.
Petukhov A.D. – Re-searcher, C. Sc., Biol.
Krylov V.V. – Head of Dep., MD
Kucherov V.V. – Head of Dep., C. Sc., Med.
Sigov M.A. – Head of Dep.
Vlasova O.P. – Head of Dep., C. Sc., Biol
Petrosyan A.P. – Doctor, C. Sc., Med.
Petrosyan К.М. – Researcher
Spichenkova O.N. – Lead. Engineer
Ivannikov A.I. – Lead. Researcher, C. Sc., Phys.-Math.
Khailov A.M. – Sen. Researcher, C. Sc., Biol.
Korotkov V.A. – Head of Dep., C. Sc., Med.
Eremeev M.P. – Engineer. A. Tsyb MRRC.
Kaprin A.D. – General Director of NMRRC, Director of P. Hertsen MORI, Head of PFUR Dep., Academician of RAS, MD, Prof.
Shegay P.V. – Deputy General Director, C. Sc., Med.
Zharova E.P. – Researcher, Scien. Secretary. NMRRC.
¹ A. Tsyb MRRC, Obninsk
² NMRRC, Obninsk
³ Peoples' Friendship University of Russia, Moscow
⁴ P. Hertsen MORI, Moscow

Abstract

The cluster of calculational and instrumental methods for estimation of personalized internal radiation doses to foci and organs at risk among patients undergoing to therapy by radiopharmaceuticals has been developed. The developed set of methods was used for dosimetrical support of clinical trials of therapeutic radiopharmaceuticals: a) ¹⁷⁷Lu-DOTA-PSMA (or "Lutaprost") targeted for radioligand therapy of metastatic castrate-resistant prostate cancer; b) ¹⁸⁸Re albumin microspheres 5-10 μm (or "Artroren") targeted for radiosynovectomy in the local treatment of chronic inflammatory diseases of the joints and c) ¹⁸⁸Re albumin microspheres 20-40 μm (or "Gepatoren") targeted for intra-arterial radionuclide embolization in the treatment of inoperable liver cancer. The results of estimations absolute activities of radiopharmaceuticals and their dynamics during SPECT/CT scanning of radio-pharmaceuticals in the body of patients were verified by measurements using physical phantoms of humans with different body weights and various standard activities of radionuclides distributed inside the phantoms. The developed cluster of programs (for calculating the absorbed fraction of energy in biostructures), relevant databases and instrumental methods were used as the basis for estimations personalized internal radiation doses in foci and organs at risk among patients included in clinical trials of the studied radiopharmaceuticals. Individual internal radiation doses in foci among 39 patients, included in the first phase of clinical trials of the three studied radiopharmaceuticals, were estimated. The analysis of the distribution of estimated doses shows that absorbed doses in foci are very differing not only in different patients, but also in different foci in the same patient. Irradiation doses in foci increase with an increasing in the administered activities of radiopharmaceuticals and, depending on the volume of foci, are within the following ranges: 1) in a case of “Lutaprost” – from 1.4 to 32 Gy (planned administered activity – 5 GBq), from 5.1 to 59 Gy (planned activity – 7.5 GBq), from 13 to 94 Gy (planned activity – 10 GBq); 2) in a case of "Arthroren" – from 17.5 to 74 Gy (planned administered activities – from 0.37 to 0.925 GBq); 3) in a case of “Gepatoren” – from 10.7 to 43 Gy (planned administered activities – from 1 to 3 GBq). Individual absorbed doses in organs at risk were estimated as well. Dose values in organs at risk also vary greatly between different patients and between different critical organs. These doses ranged from 0.01 to 7.4 Gy (39 patients), which is many times less than “commonly applied dose constraints” in radiotherapy.

Key words
internal dosimetry, individual absorbed doses, radiopharmaceuticals, radionuclide therapy, clinical trials, nuclear medicine.

References

1. Lawrence J.H. Nuclear physics and therapy: preliminary report of a new method for the treatment of leukemia and polycythemia. Radiology, 1940, vol. 35, no. 1, pp. 51-60.

2. Hertz S., Roberts A. Radioactive iodine in the study of thyroid physiology; the use of radioactive iodine therapy in hyperthyroidism. J. Am. Med. Assoc., 1946, vol. 131, no. 2, pp. 81-86.

3. Kaprin A.D., Mardynskiy Yu.S. Terapevticheskaya radiologiya: natsional’noye rukovodstvo [Therapeutic radiology: National guidelines]. Moscow, GEOTAR-Media, 2018. 704 p.

4. Treatment planning for molecular radiotherapy: potential and prospects. European Association of Nuclear Medicine. Vienna, 2017. 68 p. Available at: https://www.eanm.org/content-eanm/uploads/documents/EANM_2017_iDTF-Report_online.pdf (Accessed 06.01.2022).

5. Flux G.D., Sjogreen Gleisner K., Chiesa C., Lassmann M., Chouin N., Gear J., Bardiès M., Walrand S., Bacher K., Eberlein U., Ljungberg M., Strigari L., Visser E., Konijnenberg M.W. From fixed activities to personalized treatments in radionuclide therapy: lost in translation? Eur. J. Nucl. Med. Mol. Imaging, 2018, vol. 45, no. 1, pp. 152-154.

6. Aerts A., Eberlein U., Holm S., Hustinx R., Konijnenberg M., Strigari L., van Leeuwen F.W.B., Glatting G., Lassmann M. EANM position paper on the role of radiobiology in nuclear medicine. Eur. J. Nucl. Med. Mol. Imaging, 2021, vol. 48, no. 11, pp. 3365-3377.

7. Brans B., Bodei L., Giammarile F., Linden O., Luster M., Oyen W.J.G, Tennvall J. Clinical radionuclide therapy dosimetry: the quest for the “Holy Gray”. Eur. J. Nucl. Med. Mol. Imaging, 2007, vol. 34, no. 5, pp. 772-786.

8. Gear J., McGowan D., Rojas B., Craig A.J., Smith A.-L., Scott C.J., Scuffam J., Aldridge M., Tipping J. The internal dosimetry user group position statement on molecular radiotherapy. Br. J. Radiol., 2021, vol. 94, no. 1126, pp. 20210547. DOI: 10.1259/bjr.20210547.

9. Sudprasert W., Belyakov O.V., Tashiro S. Biological and internal dosimetry for radiation medicine: current status and future perspectives. J. Radiat. Res., 2022, vol. 63, no. 2, pp. 247-254.

10. Li W.B. Internal dosimetry. A review of progress. Hoken Butsuri, 2018, vol. 53, no. 2, pp. 72-99.

11. Stepanenko V.F., Yaskova E.K., Belukha I.G., Petriev V.M., Skvortsov V.G., Kolyzhenkov T.V., Petukhov A.D., Dubov D.V. The calculation of internal irradiation of nano-, micro- and macro-biostructures by electrons, beta particles and quantum radiation of different energy for the development and research of new radiopharmaceuticals in nuclear medicine. Radiatsia i risk – Radiation and Risk, 2015, vol. 24, no. 1, pp. 35-60. (In Russian).

12. Stepanenko V., Kaprin A., Ivanov S., Shegay P., Bogacheva V., Sato H., Shichijo K., Toyoda Sh., Kawano N., Ohtaki M., Fujimoto N., Endo S., Chaizhunusova N., Shabdarbaeva D., Zhumadilov K., Hoshi M. Microdistribution of internal radiation dose in biological tissues exposed to 56Mn dioxide microparti-cles. J. Radiat. Res., 2022, vol. 63, no. S1, pp. i21-i25.

13. Kurth J., Heuschkel M., Tonn A., Schildt A., Hakenberg O.W., Krause B.J., Schwarzenböck S.M. Stream-lined schemes for dosimetry of 177Lu-labeled PSMA targeting radioligands in therapy of prostate cancer. Cancers, 2021, vol. 13, no. 15, pp. 3884. DOI: 10.3390/cancers13153884.

14. Okamoto S., Thieme A., Allmann J., D’Alessandria C., Maurer T., Retz M., Tauber R., Heck M.M., Wester H.-J., Tamaki N., Fendler W.P., Herrmann K., Pfob C.H., Scheidhauer K., Schwaiger M., Ziegler S., Eiber M. Radiation dosimetry for 177Lu-PSMA I&T in metastatic castration-resistant prostate cancer: absorbed dose in normal organs and tumor lesions. J. Nucl. Med., 2017, vol. 58, no. 3, pp. 445-450.

15. Torres M., Ayra E., Albuerne O., Montano Delgado M.A. Absorbed dose profiles for (32)P, (90)Y, (188)Re, (177)Lu, (153)Sm and (169)Er: radionuclides used in radiosynoviortheses treatment. Rev. Esp. Med. Nucl., 2009, vol. 28, no. 4, pp. 188-192.

16. ICRP, 2019. Radiological protection in therapy with radiopharmaceuticals. ICRP Publication 140. Ann. ICRP, 2019, vol. 48, no. 1, pp. 5-95.

17. Bolch W.E., Eckerman K.F., Sgouros G., Thomas R. MIRD pamphlet No. 21: a generalized schema for radiopharmaceutical dosimetry – standardization of nomenclature. J. Nucl. Med., 2009, vol. 50, no. 3, pp. 477-484.

18. Briesmeister F. MCNP – A General Monte Carlo N-Particle Transport Code. Version 4C. Los-Alamos, LANL, 2000.

19. Zhumadilov K., Ivannikov A., Apsalikov K., Zhumadilov Zh., Zharlyganova D., Stepanenko V., Skvortsov V., Berekenova S., Toyoda S., Endo S., Tanaka K., Miyazawa C., Hoshi M. Results of tooth enamel EPR dosimetry for population living in the vicinity of the Semipalatinsk nuclear test site. Radiat. Meas., 2007, vol. 42, no. 6-7, pp. 1049-1052.

20. Stepanenko V.F., Biryukov V.A., Karyakin O.B., Kaprin A.D., Galkin V.N., Ivanov S.A., Mardynskiy Yu.S., Kolyzhenkov T.V., Petukhov A.D., Bogacheva V.V., Akhmedova U.A., Yas’kova E.K., Lepilina O.G., Sanin D.B., Skvortsov V.G., Ivannikov A.I., Khaylov A.M., Anokhin Yu.N. Local absorbed doses of irradi-ation of medical personnel at brachytherapy of prostate cancer using 125I microsources of Russian production. Radiatsia and risk – Radiation and Risk, 2017, vol. 26, no. 1, pp. 44-59. (In Russian).

21. Stepanenko V.F., Kaprin A.D., Ivanov S.A., Shegay P.V., Petriyev V.M., Davydov G.A., Krylov V.V., Ku-cherov V.V., Bogacheva V.V., Kolyzhenkov T.V., Petukhov A.D., Spichenkova O.N., Sigov M.A., Petrosyan A.P., Biryukov V.A., Vlasova O.P. Determination of personalized doses of internal radiation of tumor formations and organs at risk of patients with the use of new therapeutic radiopharmaceuticals. Evraziyskiy onkologicheskiy zhurnal – Eurasian Journal of Oncology, 2022, vol. 10, no. 2 (Application (online)), pp. 969-970. (In Russian).

22. Stepanenko V.F., Petriyev V.M., Davydov G.A., Krylov V.V., Kucherov V.V., Karyakin O.B., Borysheva N.B., Kolyzhenkov T.V., Bogacheva V.V., Petukhov A.D., Yaskova E.K., Spichenkova O.N., Sigov M.A., Garbuzov P.I., Kochetova T.Yu., Shurinov A.Yu., Petrosyan K.M., Petrosyan A.P., Biryukov V.A., Ere-meyev M.R., Vlasova O.P., Ivanov S.A., Shegay P.V., Kaprin A.D. Development and implementation of a set of methods for determining personalized doses of internal radiation of tumor formations and organs at risk of patients in clinical trials and the use of new therapeutic radiopharmaceuticals. Radiation and the organism 2021, materials of the final scientific and practical conference. Obninsk, A. Tsyb MRRC, 2021, pp. 69-71. (In Russian).

23. Deasy J.O., Moiseenko V., Marks L., Chao K.S., Nam J., Eisbruch A. Radiotherapy dose-volume effects on salivary gland function. Int. J. Radiat. Oncol. Biol. Phys., 2010, vol. 76, no. 3 (Suppl.), pp. S58-S63.

24. Grundmann O., Mitchell G.C., Limesand K.H. Sensitivity of salivary glands to radiation: from animal models to therapies. J. Dent. Res., 2009, vol. 88, no. 10, pp. 894-903.

25. Jeong S.Y., Kim H.W., Lee S.W., Ahn B.C., Lee J. Salivary gland function 5 years after radioactive iodine ablation in patients with differentiated thyroid cancer: direct comparison of pre- and postablation scintigraphies and their relation to xerostomia symptoms. Thyroid, 2013, vol. 23, no. 5, pp. 609-616.

26. Sandström M., Garske-Román U., Granberg D., Johansson S., Widström C., Eriksson B., Sundin A., Lundqvist H., Lubberink M. Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment. J. Nucl. Med., 2013, vol. 54, no. 1, pp. 33-41.

27. ICRU, 2022. ICRU Report 96, Dosimetry-guided radiopharmaceutical therapy. J. ICRU, 2022, vol. 21, no. 1, pp. 1-212.

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