By Jacob Poliskey & Joseph McFarland

A small village lay nestled on an island on the western side of Sweden. Carl Arrhenius, a lieutenant from the nearby city of Stockholm, was indulging his interest in gunpowder in search of new combustible elements near a mine. He noticed a most unusual band of dark, heavy metal running in the rock. This “new earth,” as he called it, was named Yttria after this small Swedish village of Ytterby.1 Little did the lieutenant know that his discovery would later serve as the foundation of one of the most fashionable and fascinating procedures in Interventional Radiology: Y-90 Radioembolization.

The liver is an incredible metabolizer of nutrients, as well as a filter of toxins, that come directly from the gut. Normal hepatic parenchyma actually receives most of its blood supply from the very gastrointestinal system that it is designed to filter. A key discovery about the liver that paved the way towards Selective Internal Radiation Therapy (SIRT) or Radioembolization, was that hepatocellular carcinomas (HCC) do not have the same dominant portal blood supply as the rest of the liver. HCC receives 80% of its blood from the hepatic artery (Figure 1).

Figure 1. Y-90 Radioembolization can successfully ablate an HCC tumor, while mostly sparing the normal hepatic parenchyma, because the HCC’s vasculature primarily comes from the hepatic artery. A catheter is guided into the supplying arteries of the tumor, and then radioactive Y-90 ceramic or glass beads are deployed at carefully dosed amounts. The beads are manufactured at such a size that they can lodge in the tumor’s capillaries without stopping blood flow. The proximity of the tumor to the lodged radioactive beads allows for selective destruction of the tumor.

Shortly after angiographers discovered the blood supply of HCC, early reports of radioembolization with Y-90 appeared. Several small studies over the 1960s-1980s demonstrated feasibility in humans, but the adverse effects outweighed the benefits of the therapy. This was often due to the toxic effects of radiation such as pneumonitis, liver disease, and gastrointestinal ulceration. Some patients even developed the most serious adverse effect of myelosuppression, attributed to yttrium leaching from the spheres and into the bone marrow. The yttrium leaching problem greatly lessened interest in and use of SIRT technology.

TheraSphere, developed in 1988, was the first technology to overcome the leaching problem. Melting aluminum oxide and silicon dioxide at 1,500°C in the presence of Y-89 forms a glass matrix with embedded non-radioactive yttrium. Neutron bombardment then transforms the Y-89 into the radioactive Y-90. As Y-90 is completely embedded within the glass, there is virtually no possibility of leakage. However, this glass-based approach came with the limitation that the glass particles were denser than blood, possibly limiting the even distribution in the tumor.1

SIR-Spheres, developed about a decade later, solved this seeping difficulty in a different way. The SIR-Spheres are composed of a cation-exchange resin. Pure radioactive Y-90 is exchanged for sodium and then precipitated with phosphate, immobilizing it within the resin. This technique leaves no room for radioactive impurities and has a theoretical benefit of better tumor distribution due to their density. To minimize Y-90 leakage, however, the SIR-Spheres were initially suspended and dosed in a non-ionic solution: pure water. This led to arterial stasis and intra-procedural pain. Subsequently, this changed to 5% dextrose in water, which helps alleviate these issues.2

Both TheraSphere and SIR-Spheres have effectively solved the leaching problem and are widely used today. There have been no trials demonstrating superiority of either method, so the platform used is simply a matter of physician or institutional preference.2

From advancements in sphere size for optimal tumor deposition to intraprocedural affirmation of tumor targeting with radio-opaque glass microspheres, this promising technology continues to forge ahead. Even now, Y-90 radioablation therapy is being explored as a curative option when historically, it has been considered only a palliative therapy3. It will be exciting to see what advances are made in the future.

Sources
1. Marshall JL, Eta B. Yttrium and Johan Gadolin. Unt.edu. Accessed November 26, 2020. http://www.chem.unt.edu/~jimm/REDISCOVERY%207-09-2018/Hexagon%20Articles/gadolin.pdf

2. Westcott MA, Coldwell DM, Liu DM, Zikria JF. The development, commercialization, and clinical context of yttrium-90 radiolabeled resin and glass microspheres. Adv Radiat Oncol. 2016;1(4):351-364.

3. What’s new in Y-90? – endovascular today. Accessed November 26, 2020. https://evtoday.com/articles/2019-oct/whats-new-in-y-90