Clinical Best Practices for Radiation Safety During an Alpha DaRT Treatment

Abstract

Alpha DaRT is a new alpha radiation treatment for treating solid tumors and is currently being evaluated through clinical trials worldwide. Being a novel radiation treatment, it is important to discuss the safety considerations and procedures that are needed to ensure safe use of this unique approach. The objective of this article is to provide a set of recommendations—radiation safety best practices that were developed based on operational and clinical experience.

INTRODUCTION

Diffusing alpha-emitters Radiation Therapy (“Alpha DaRT”) is a new method for treating solid tumors with alpha particles. The method relies on the release of the short-lived alpha-emitting radioactive-decay-product (progeny) atoms of radium-224 (²²⁴Ra) from interstitial sources inserted into the tumor.

Alpha DaRT was, and still is, extensively investigated in in vitro and in vivo preclinical studies on a large number of cancer types, as a stand-alone treatment, in combination with chemotherapy, immunotherapy (Mare et al. 2023), and other standard cancer treatments, as well as a stimulant of a local and systemic anti-tumor immune response (Domankevich et al. 2019).

Since 2017, Alpha DaRT has been under clinical investigations (https://www.alphatau.com/alpha-dart-clinical-trials), starting with locally advanced and recurrent squamous cell carcinoma (SCC) of the skin and head and neck. Results of the first-in-human trial were highly promising in terms of both efficacy and safety: all treated tumors (28/28) shrank noticeably (by ∼30 − 100%), beginning in the first few days after the treatment, with ∼80% of the tumors exhibiting complete response (the rest of the tumors exhibiting partial response). Adverse effects were mild to moderate, with no observable local or systemic radiation-induced damage to healthy tissue (Popovtzer et al. 2020).

Alpha DaRT treatments have been used both in large research hospitals around the world as well as in smaller clinics. The simplicity inherent in the method with respect to implementation and mode of radiation delivery, with no requirement of any capital equipment, allows for it to be used in rural and community-based clinics, with a good degree of ease and confidence, as well. While smaller sites may offer nuclear medicine services limited to diagnostic purposes only, there are different regulatory requirements and radiation safety actions that may be addressed with the correct guidance and support.

Alpha DaRT harnesses the DNA double strand break potential of alpha particles for the treatment of solid tumors. In Alpha DaRT, tumors are treated with sources carrying a few microcuries (1 μCi equals to 37 kBq) of ²²⁴Ra activity on their surface (with a typical treatment consisting of a total of ~10 MBq of ²²⁴Ra, highly dependent on tumor’s volume and shape). The sources are designed to continuously release from their surface the short-lived progeny atoms of ²²⁴Ra, namely: radon-220 (²²⁰Rn), polonium-216 (²¹⁶Po), lead-212 (²¹²Pb), bismuth-212 (²¹²Bi), polonium-212 (²¹²Po), and thallium-208 (²⁰⁸Tl). Once inside the tumor, these isotopes spread by diffusion (with possible contribution by convective effects), creating, primarily through their alpha decays, a high-dose region dense in alpha particles, measuring several millimeters in diameter around each source, due to the sharp fall-off of the alpha dose.

Biokinetic model studies showed that the alpha dose to all organs, resulting from ²¹²Pb leaving the tumor through the blood, was calculated to be on the centigray (cGy) level, with blood and urine activity measurements consistent with the predictions of an ICRP-based biokinetic model (Heger et al. 2023).

The radiation safety challenges associated with external dose rates from Alpha DaRT treatments are less than that of other clinically used therapeutic radiopharmaceuticals; primarily due to the very short range of alpha particles and the low required activity for a single treatment (order of hundreds of micro curies of ²²⁴Ra on average), possibly making special radiation safety measurements redundant. The development of a radiation safety program to support the addition of a new therapeutic isotope may require investing some time and research on this new technology that might be challenging for medical Radiation Safety Officers (RSOs) or their equivalent. A panel of medical physicists and RSOs from Israel, Europe and the US have worked on this document outlining operational best practices, to act as a reference for RSOs tasked with or interested in expanding their radiation safety program to support Alpha DaRT treatments. The notion of writing this document and its template were based on the Lutetium-177 best practices document (Cappon et al. 2023).

The target audience for this set of guidelines are radiation safety professionals, medical physicists and Alpha DaRT authorized users looking to start ²²⁴Ra-based treatments at their institutions.

The goal is that with this guide as a reference, more radiation safety professionals will be able to support the implementation of Alpha DaRT treatments at their institutions, thus expanding the availability of this modality and improving outcomes for cancer patients while ensuring the safety of the medical staff and the compliance with regulation.

The authors thus believe that the themes of this paper are relevant in any country; notwithstanding, local licensing and regulatory requirements must be reviewed and considered during the implementation of any program.

PRODUCT DESCRIPTION

The Alpha DaRT technology consists of two main components: the Alpha DaRT sources and an applicator for their deployment into tumors. Several types of applicators have been developed: Needle, Flex, Template, Plant and Loading Device, as presented on Fig. 1.

Fig. 1.

Alpha Tau’s main applicators. From left to right: loading device, template, flex (140 mm), flex (240 mm), plant, needle.

The objective is to treat a wide variety of solid tumors based on a radiation therapy modality which relies on the release of short-lived alpha-emitting atoms from the source surface into the tumor. The merits of Alpha DaRT are its observed effectiveness against radiation-resistant or recurrent tumors, where its high-LET dose can lead, with a high probability, to tumor control with minimal collateral radiation damage to surrounding healthy tissue. In addition, it was shown that alpha radiation results in more direct strand breaks compared to indirect ones (de la Fuente Rosales et al. 2018).

The sources are made of biocompatible metal tubes and are embedded with ²²⁴Ra atoms, which are well-fixed in place through baking and coating methods. The sources are encapsulated within an applicator containing glycerin, minimizing the likelihood of contamination. During the Alpha DaRT treatment, several Alpha DaRT sources are inserted into the tumor according to a pre-determined treatment plan. Every applicator comes loaded with sources in a ready-to-use state.

Because the therapeutic dose is delivered by the diffusion of ²²⁰Rn and its progeny inside the tumor, the sources themselves are not sealed. Fig. 2 shows the decay chain of ²²⁴Ra, along with the half-lives and the principal alpha emission energies of the isotopes. Alpha DaRT applicators are categorized as “sealed devices”, as they are packed in Alpha Tau manufacturing facility, such that no radioactive atoms are released to the environment until the packaging is opened at the treatment site, for sources insertion into the tumor.

Fig. 2.

Decay chain of ²²⁴Ra (embedded on a source) with data on half-lives and energy deposition per transition.

Alpha Tau has developed specific training tools to help teams to hone their skills in product utilization, backed by comprehensive support, until they attain technical proficiency, and offers support and training across a number of key topics, summarized in Fig. 3.

Fig. 3.

Diagram of the key training topics provided by Alpha Tau.

MATERIALS AND METHODS

Thoughts, questions and ideas from a group consisting of seven RSOs and medical physicists from six different institutions in Israel, Europe, and the US were assembled for making this report; all of these individuals have experience of implementing and/or developing the Alpha DaRT technology at their sites. Experience level varied, but each individual had been involved with the implementation or ongoing support of Alpha DaRT treatments at the clinic or hospital they represented. The panelists actively participated in the review of this summary to ensure their perspectives were accurately represented. The following three main categories were deemed most important for discussion for purposes of this report: (1) facility layout and design, (2) radiation safety, and (3) device management and patient care.

FACILITY LAYOUT AND DESIGN

Due to its primarily alpha dose, Alpha DaRT treatments offer significant practical advantages over other isotopes emitting beta and/or gamma radiation. The practicing sites did not have to install special shielding in the treatment room specifically for Alpha DaRT treatments. At most of the sites, Alpha DaRT treatments are routinely performed in a non-dedicated space; typically, a standard procedure room or a general-purpose room using local anesthetic. There are also instances where Alpha DaRT treatments are performed in an operation room (OR) or surgical suite, but primarily limited to the cases when patients are required to be fully anesthetized. Although sub-therapeutic, ²²⁴Ra decay chain also includes beta and gamma emissions, with various energies and intensities. These can be easily accounted for in terms of external exposure assessment.

Reducing the effect of low-level gamma emissions can be achieved by storing the applicators inside steel/lead boxes. It is possible/recommended to use the galvanized ST37 casks that are provided by the manufacturer (relevant only for the excepted package-type deliveries). These casks have a wall thickness of 26 mm at their thickest part (when the applicators face down inside the cask, most of the emissions will traverse such distance). With a half-value layer of about 16 mm lead and 39 mm steel for ²²⁴Ra (Daw 2023), it is up to the institutes’ discretion whether to use such shielding or to add more. It is advised to store the applicators inside casks during the treatment itself and to take them out from them one by one as needed.

During treatment, a possible route for contamination may arise from the interaction of glycerin coming out the applicators with the surroundings. The glycerin contains ²¹²Pb atoms that might spread during the treatment. In order to minimize this potential contamination, personnel with direct contact with the patient and the applicators should wear double gloves and change them often; all personnel should wear disposable shoe covers and gowns and the patient should be covered with a disposable mat. An absorbent mat can be used to mark off the immediate ground area around the patient. Personnel must wear overshoe covers and refrain from stepping off the mat until their feet have been monitored. Area around the treatment site should be taped, especially if the fluid from the treatment site can flow into an organ at risk like eye, ear, mouth, etc. Frequent wiping of fluid/blood through the site using gauze and gloved hands is advisable.

Furthermore, waste that comes in contact with the implantation site, such as gauze, used applicators, absorbent pads, etc., should be treated as contaminated material and be disposed of inside a designated waste container that can be provided by the manufacturer. Tools such as scissors and forceps must be handled with care and treated according to the decontamination procedures of the center. On average, a single treatment will generate waste that can be accommodated inside a ~ 5-L vessel.

Due to the relatively short half-life (3.63 days) of ²²⁴Ra, waste can be stored for decay for 60 days. Prior to disposal as an inert bio-hazard waste, it can be surveyed to ensure it is indistinguishable from background.

RADIATION SAFETY

If not already authorized/licensed for ²²⁴Ra, an institution must typically apply to a local regulator to authorize its use. The application process and type of authorization required will vary depending on local regulations, but this will often require amendments to the radiation safety program. General guidance for development of a radioactive material license or permit is presented in this section. These recommendations are based on Israeli and American experience, but the general concepts should be relevant globally. Organizations applying for a radioactive material license will generally need to identify an authorized user for ²²⁴Ra to supervise the use of radioactive materials at the site. This is a physician who has been certified in a relevant specialty by a medical board recognized by the US NRC or who meets a specific combination of training and work experience for this specialty.

In many radiation safety programs, the approval by an internal radiation safety committee is required before major changes can be made to the program or license. The timeframe required to add a new radionuclide or radiopharmaceutical to a license or commence a new treatment or clinical trial varies widely (weeks to months). While the details of the radiation safety review process are unique to every site, the following topics are almost entirely shared between all sites: the amount of activity to be used per treatment and stored on site; exposure to staff; patient release instructions; and waste management planning, which has been discussed above.

The activity possession limit on the license should be carefully considered at this stage. The limit applies to the total activity a site has on hand, including activity from ordered spares, from cancelled patients, and waste. The minimal possession activity of ²²⁴Ra that institutions should ask for is 111 MBq. The licensee must have sufficient room to accommodate the accumulated quantities of ²²⁴Ra in the facility.

Depending on the trial at hand, Alpha DaRT packages are shipped either as excepted radioactive material (UN2910) or as a radioactive labeled: Yellow II category (type A) box. A contamination survey upon receipt is not mandatory for excepted packages unless there is evidence of degradation of package integrity, such as packages that are crushed, wet, or damaged; however, sites may optionally choose to use a wipe-test upon receipt as their practice (US NRC 2024). It is recommended to verify that the measured dose rate of the package prior to opening does not exceed the allowed limit of 5 μSv h⁻¹ at any point on the packaging box in case of an excepted package, or 10 μSv h⁻¹ at 1 m from the outer sides of the box in case of a Yellow II labeled box. The US NRC Materials License Toolkit is a valuable resource (nrc.gov/materials/miau/mat-toolkits.html).

During the medical procedure, it is advised that all personnel interacting with the applicators should wear dosimeters (ring and chest badges). Ensure proper radiation warning signage is posted at room entrance(s). In case any of the personnel has left the room during the procedure, they should remove their gloves, gown, and shoe covers and wear new ones before re-entering the room and survey themselves for possible contamination. It is advised to minimize the frequency of walking in and out of the treatment room.

An Alpha DaRT procedure may lead to local contamination, due to glycerin being pushed out of the applicators at insertion. This glycerin is radioactive (mainly contains ²¹²Pb) and may come in contact with the patient’s blood and surroundings. This can lead to contamination transferred to gauze and pads, gloves, working counters, and the procedure room’s floor. At the end of the procedure, the authorized user should conduct the following measurements: (a) Use an alpha detector to measure the hands and shoe soles (without gloves and shoe covers) of all involved personnel. Any calibrated alpha detector with known efficiency can be used, and the manufacturer may be able to assist with providing/lending an alpha scintillator detector to be used during a procedure; and (b) Scan both the patient and the room with an alpha detector and a Geiger Muller counter for any possible contamination. These measurements should be documented in a radiation contamination form (can be supplied by the vendor).

In case of contamination found on a person’s hands, one must wash their hands thoroughly. The physicist should then re-survey the hands to ensure full decontamination. In case of contamination found at any area in the room, the physicist should make sure the area is cleaned appropriately until the contamination has been removed completely or is no longer removable. Because glycerin is highly soluble in water, the cleaning procedure can be done promptly and swiftly via repeated washing and wiping with water.

The overall risk of ²²⁰Rn dispersion into the air is minimal, due to (1) the low half-life of the isotope (56 seconds), (2) the initial activity to begin with is typically on the order of 3,700 kBq, reducing almost by half considering the desorption probability of ²²⁰Rn from the source, (3) the sources are encapsulated within tubes filled with glycerin, thus preventing the release of ²²⁰Rn into the air, (4) at the manufacturer’s production facility, every applicator undergoes a leak test to ensure that no more than one thousandth of the ²²⁰Rn produced in the decay of ²²⁴Ra is released to the environment, and (5) in the unlikely event of an exposed source falling to the ground, the exposure to personnel standing at a 60-cm radius sphere from the source for an hour equals to roughly 0.005 annual limit on intake (ALI).

On Alpha DaRT implant removal date, handling the sources should be done only with tongs/tweezers. The sources must be placed inside a sealed cup/bag and stored inside a waste container. Ensure the notation of date, activity, type of radionuclide, and the recorder's name or initials on the container for decay or disposal tracking purposes.

Doses to staff delivered during Alpha DaRT treatments are minimal relative to other nuclear medicine programs. Gamma dose measurements taken during treatments at different places across the treatment room ranged between 0.9 μSv (a 50-minute treatment with dozens of sources inserted to the patient) to 5.2 μSv (a 2-hour treatment, with more than 200 sources inserted to the patient while the wearer of the dosimeter stood close (~30 cm) to the patient throughout the entire treatment). These findings coincide with the theoretical calculations considering the gamma exposure constants (Peplow 2020).

Because dose exposure is relatively minimal, patients are released from the institute right after the treatment with instructions on wound-care and material handling if source(s) come lose. In order to comply with the as low as reasonably achievable (ALARA) concept, it is advised to minimize interactions with infants and children for the first week after the treatment, and if possible, to sleep in a separate bed alone for the same duration.

For further information, it is advised to go over the US NRC “Alpha Tau Alpha DaRT Manual Brachytherapy Licensing Guidance” (Tapp 2022).

DEVICE MANAGEMENT AND PATIENT CARE

Panelists recommended scheduling delivery of the activity for the day before treatment, allowing a buffer in the event of manufacturing or shipping delays. Before treatment, the treatment room should be prepared by papering surfaces to protect them from contamination.

All patients participating in the Alpha DaRT trial receive a document with instructions regarding several possible scenarios that can occur at home.

To allay any potential concerns about a patient treated with Alpha DaRT having the potential to set off radiation detectors at public areas, notwithstanding the rapid isotope decay compared to other nuclear medicine therapies, a clinical site has suggested a written patient card, which can be provided by the manufacturer, containing information about the therapy the patient received (with date, radionuclide and total activity administered) and radiation safety contact information.

Patients’ blood and urine will contain trace amounts of ²¹²Pb, as ²¹²Pb leaks with a certain probability from the tumor. An overall number of 57 urine samples and 59 blood samples, with patients’ inserted activity varying from 473 kBq to 14,467 kBq, were measured for ²¹²Pb. The specific activity range of ²¹²Pb that was measured at the earliest follow up point (day 4 or day 6, depending on the protocol) in the trials is 0.85 to 98.5 kBq L⁻¹ for urine and 9.3 to 193 kBq L⁻ for blood, with the mean equal to 11.6 kBq L⁻¹ for urine and 47.3 kBq L⁻¹ for blood.

Clinical data of blood and urine radioactivity measurements in patients are largely consistent with the model prediction. The dose to all organs in treated patients has so far been ~1-2 orders of magnitude below the tolerance levels. Appropriate instructions are included in the self-care discharge sheet for safe usage of home bathrooms (double-flushing) and wipe-cleaning any visible spills.

CONCLUSION

Establishment of a safe, effective Alpha DaRT program at an institution with no prior experience in alpha-radiation based treatment is feasible and can be done without physical changes to a facility. Local regulations vary from place to place, and radiation staff must be aware of their regulatory requirements before pursuing this venture. Collective operational radiation therapy experience and best practices presented in this report will provide a starting point into outlining steps needed for an Alpha DaRT program initiation at one’s center to benefit from this novel radiation therapy, offering much needed access to quality care in community settings. Adopting Alpha DaRT technology in clinics and hospitals is picking up and will only continue to expand as more cancer types are researched at the vendor’s headquarters.