Manual on the proper use of the 211At-labeled PSMA ligand ([211At]PSMA-5) for clinical trials of targeted alpha therapy (1st edition).

Recently, an astatine-labeled prostate-specific membrane antigen (PSMA) ligand ([211At]PSMA-5) has been developed for the targeted alpha therapy of patients with prostate cancer. This manual delineates its physicochemical characteristics to assist healthcare professionals in understanding the α-ray-emitting drug of [211At]PSMA-5 when administered to patients. The safety considerations regarding the handling and use of this drug in clinical trials are outlined, based on the proper usage manual of previous studies. The dose limits, as defined by the guidelines of the International Commission on Radiological Protection (ICRP) and the International Atomic Energy Agency (IAEA), are assessed for patients' caregivers and the general public. According to the calculations provided in this manual, clinical trials involving [211At]PSMA-5 can be safely conducted for these populations even if patients are released after its administration. Moreover, this manual provides comprehensive guidance on the handling of [211At]PSMA-5 for healthcare facilities, and compiles a list of precautionary measures to be distributed among patients and their caregivers. While this manual was created by a research team supported by Ministry of Health, Labour, and Welfare in Japan and approved by Japanese Society of Nuclear Medicine, its applicability extends to healthcare providers in other countries. This manual aims to facilitate conducting clinical trials using [211At]PSMA-5 in patients with prostate cancer.

Manual on the proper use of meta-[211At] astato-benzylguanidine ([211At] MABG) injections in clinical trials for targeted alpha therapy (1st edition).

In this manuscript, we present the guideline for use of meta-[211At] astatobenzylguanidine ([211At] MABG), a newly introduced alpha emitting radiopharmaceutical to the up-coming World's first clinical trial for targeted alpha therapy (TAT) at Fukushima Medical University in Japan, focusing on radiation safety issues in Japan. This guideline was prepared based on a study supported by the Ministry of Health, Labour, and Welfare, and approved by the Japanese Society of Nuclear Medicine on Oct. 5th, 2021. The study showed that patients receiving [211At] MABG do not need to be admitted to a radiotherapy room and that TAT using [211At] MABG is possible on an outpatient basis. The radiation exposure from the patient is within the safety standards of the ICRP and IAEA recommendations for the general public and caregivers or patient's family members. In this guideline, the following contents are also included: precautions for patients and their families, safety management associated with the use of [211At] MABG, education and training, and disposal of medical radioactive contaminants. TAT using [211At] MABG in Japan should be carried out according to this guideline. Although this guideline is based on the medical environment and laws and regulations in Japan, the issues for radiation protection and evaluation methodology presented in this guideline are useful and internationally acceptable as well.

Manual on the proper use of sodium astatide ([211At]NaAt) injections in clinical trials for targeted alpha therapy (1st edition).

We present the guideline for use of [211At] sodium astatide (NaAt) for targeted alpha therapy in clinical trials on the basis of radiation safety issues in Japan. This guideline was prepared by a study supported by the Ministry of Health, Labour, and Welfare, and approved by the Japanese Society of Nuclear Medicine on 8th Feb, 2021. The study showed that patients receiving [211At]NaAt do not need to be admitted to a radiotherapy room and outpatient treatment is possible. The radiation exposure from the patient is within the safety standards of the ICRP and IAEA recommendations for the general public and caregivers. Precautions for patients and their families, safety management associated with the use of [211At]NaAt, education and training, and disposal of medical radioactive contaminants are also included in this guideline. Treatment using [211At]NaAt in Japan should be carried out according to this guideline. Although this guideline is applied in Japan, the issues for radiation protection and evaluation methodology shown here are considered internationally useful as well.

Manual on the proper use of yttrium-90-labeled anti-P-cadherin antibody injection for radionuclide therapy in clinical trials.

We present the guideline for use of yttrium-90-labeled anti-P-cadherin antibody injection for radionuclide therapy in clinical trials on the basis of radiation safety issues in Japan. This guideline was prepared by a study supported by the Ministry of Health, Labour, and Welfare, and approved by the Japanese Society of Nuclear Medicine. Treatment using yttrium-90-labeled anti-P-cadherin antibody injection in Japan should be carried out according to this guideline. Although this guideline is applied in Japan, the issues for radiation protection shown here are considered internationally useful as well. Only the original Japanese version is the formal document.

Introduction of the targeted alpha therapy (with Radium-223) into clinical practice in Japan: learnings and implementation.

Radium-223 dichloride (Ra-223) is the first targeted alpha therapy approved for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastasis. Ra-223 improved overall survival in the international Phase III ALSYMPCA (ALpharadin in SYMPtomatic Prostate Cancer) study. Ra-223 was also demonstrated to be efficacious and safe in Japanese patients in Phase I and Phase II clinical trials. Ra-223 was approved in Japan for the treatment of patients with CRPC with bone metastasis in 2016. The conduct of clinical studies with radionuclides in Japan involves mandatory compliance with local and international regulations pertaining to radiation protection. Without an existing Japanese framework for the handling of α-emitters in clinical practice, we encountered many challenges to initiate the clinical studies. Therefore, we started on a project to determine best practice on the use of Ra-223 in clinical studies. For this project, we evaluated all applicable laws and regulations on the use of radionuclides in medicine, then examined whether and how the α-emitter Ra-223 could meet these legal and regulatory requirements. This included how to approach the matter of discharging patients administered Ra-223 from hospital and radiation protection for caregivers, general public and medical care professionals. Subsequently, we published Manual on the proper use of radium-223 dichloride injection in clinical trials that summarized the essential requirements necessary to allow the safe use of Ra-223 in clinical trials in Japan. As the result, we succeeded in demonstrating that clinical trials of an α-emitter, Ra-223, could be implemented safely in Japan. Our experience in Japan highlights the importance of a multidisciplinary team-based approach and continued professional training in a clinical setting. This article summarizes the rationale behind the development of this manual. We hope that by sharing our experience and information, we can help other countries considering the introduction of radionuclides for clinical use, and support the future development of radionuclide therapies in a safe and effective manner.

Manual on the proper use of lutetium-177-labeled somatostatin analogue (Lu-177-DOTA-TATE) injectable in radionuclide therapy (2nd ed.).

Here we present the guideline for the treatment of neuroendocrine tumors using Lu-177-DOTA-TATE on the basis of radiation safety aspects in Japan. This guideline was prepared by a study supported by Ministry of Health, Labour, and Welfare, and approved by Japanese Society of Nuclear Medicine. Lu-177-DOTA-TATE treatment in Japan should be carried out according to this guideline. Although this guideline is applied in Japan, the issues for radiation protection shown in this guideline are considered internationally useful as well. Only the original Japanese version is the formal document.

Thyroid remnant ablation using 1,110 MBq of I-131 after total thyroidectomy: regulatory considerations on release of patients after unsealed radioiodine therapy.

OBJECTIVES: This study was undertaken to measure the radiation exposure level of caregivers following outpatient NaI (I-131) 1,110 MBq therapy for remnant thyroid ablation after total thyroidectomy in patients with differentiated thyroid cancer, and to evaluate the influence of activities of daily living on radiation exposure level, with the goal of proposing an optimum method of I-131 therapy. METHODS: The study included 37 patients with differentiated thyroid cancer, who had undergone total thyroidectomy and received outpatient based remnant thyroid ablation using NaI (I-131) 1,110 MBq, who were satisfying the following requirements: (1) patients who have no evidence of distant metastases, (2) whose living environments were appropriate for outpatient I-131 (1,110 MBq) therapy, and (3) patients who gave written informed consent. The dose rate at a distance of 1 m from the body surface of the patient at the moment of release was measured using survey meters of the GM type or ionization chamber type. The dose level for the caregiver was measured with a personal dosimeter in all cases. RESULTS: The dose rate at a distance of 1 m from the patient's body surface 1 h after I-131 administration was in the range of 29-115 µSv/h (mean 63.8 µSv/h). The 7-day cumulative effective dose of caregivers was 0.11 ± 0.08 mSv, on an average, in 34 dosimeters. In 31 of 34 dosimeters, cumulative effective dose of caregivers was below 0.2 mSv. Dose levels exceeding 0.2 mSv were recorded in 3 cases (0.21, 0.35 and 0.43 mSv in one case each). These results suggest that the exposure level of family members (caregiver and others) was minimal and is lower than the radiation levels affecting human environments. CONCLUSION: Outpatient-based remnant thyroid ablation with I-131 (1,110 MBq) performed after total thyroidectomy in patients with differentiated thyroid cancer is safe if applied in accordance with the appropriate supervision and guidance by experts with certain qualifications.