Extrahepatic Applications of Yttrium-90 Radioembolization

Abstract

While initially described and now accepted as treatment for primary and secondary malignancies in the liver, radioembolization therapy has expanded to include treatment for other disease pathologies and other organ systems. Advantages and limitations for these treatments exist and must be compared against more traditional treatments for these processes. This article provides an overview of the current applications for radioembolization outside of the liver, for both malignant and nonmalignant disease.

Intra-arterial locoregional therapies have evolved into mainstay therapies for unresectable liver cancers. ¹ Locoregional liver cancer treatments include transarterial chemoembolization (TACE), ablation using various forms of energy, and radioembolization, the intra-arterial delivery of yttrium-90 (Y90)-containing radioactive microspheres. ¹ Here, we will discuss potential future extrahepatic applications of Y90 radioembolization.

Examining the history of Y90 in hepatic malignancies can serve as a guideline for how to bring extrahepatic radioembolization into clinical practice. Y90 was first described in the 1960s with nonselective administration of radioactive particles from the celiac artery. ^{2 3} In the 1980s and 1990s, phase I trials demonstrated the safety and efficacy of resin (SIR-Spheres, Sirtex Medical Ltd., New South Wales, Australia) and glass microspheres (TheraSphere, BTG International Group, London, UK). ^{2 4 5} In 2002, a phase III trial demonstrated increased progression-free survival in patients with chemotherapy and resin microsphere radioembolization when compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of Y90 in colorectal liver metastases. ⁶ When applied to hepatocellular carcinoma (HCC), Y90 was demonstrated to be safe in patients with portal vein thrombosis, was well tolerated in multiple sessions, and could be administered in combination with other locoregional treatments and systemic therapy. ^{7 8 9} In 2016, the landmark phase II PREMIERE study randomized Barcelona Clinic Liver Cancer A and B patients to TACE or Y90. Though no survival differences were observed, the Y90 cohort had a longer median time to progression when compared with TACE (26 vs. 6.8 months). ¹⁰ Improved local control after Y90 can downstage tumors to bridge patients to transplant. ¹¹ The LEGACY trial demonstrated that patients with both early and advanced HCC showed high response rates to Y90 (72.2% at 4 weeks and 76.1% at 6 months), leading to the FDA approval of TheraSphere Y90 Glass Microspheres for unresectable HCC in March 2021. ¹²

Contemporary Evidence

Today, Y90 is used both in primary and metastatic liver tumors as a solitary treatment, an adjunct with chemotherapies and immunotherapies, and as a bridge to surgical resection and transplantation. ¹ Y90 can also be potentially curative in patients with early-stage HCC. ¹³ In patients with anatomic factors precluding ablation, selective administration of higher dose particles is safe and effective in patients with lesions confined to two or fewer liver segments—a treatment modality now referred to as radiation segmentectomy. ^{13 14} In patients who would be candidates for surgical resection if not for reduced future liver remnant volumes, Y90 can be administered to an entire hepatic lobe (radiation lobectomy). ¹⁵ Similar to portal vein embolization, radiation lobectomy causes contralateral lobe hypertrophy. Unlike portal vein embolization, radiation lobectomy provides simultaneous local tumor control, which can more effectively bridge patients to curative surgery in the correct patient population.

These nuanced treatment strategies of Y90, ranging from supraselective to less specific radiation delivery, reflect the advantages of intra-arterial delivery of radiation that could be translated to other vascular tumor types outside of the liver. Unlike stereotactic body radiation therapy (SBRT), arterial delivery of radiation is not susceptible to respiratory or patient motion. Intraprocedural cone-beam CT and angiography facilitate clear visibility of where treatment will be delivered and provide real-time monitoring during treatments. Ultimately, the increased operator control of intra-arterial radioembolization limits nontarget tissue treatment and toxicity, mitigates risk of injury to adjacent structures, and facilitates safer delivery of higher radiation doses. The arterial route of administration, mitigating the earlier-mentioned challenges with radiotherapy, arguably imparts to Y90 the most efficient method of radiotherapy delivery.

Extrahepatic Y90

Extrahepatic applications of Y90 are early in the research process. In 2020, Pasciak et al examined whether intra-arterial Y90 can be safely applied to axial brain malignancies in a canine model. ¹⁶ In their study, Y90 was successfully performed on healthy research dogs and dogs with spontaneous intra-axial brain cancers. Absorbed doses ranging from 45.4 to 76.7 Gy were delivered to intra-axial lesions in patient dogs, while healthy research dog models received doses up to 73.2 Gy to large volumes of brain tissue with no detectable permanent neurological sequelae in either group. ¹⁶ Their results suggest that neurologic toxicity in Y90 may be tolerable and merit further study.

In 2013, Hamoui et al reported a case of successful treatment of metastatic renal cell carcinoma treated with Y90 in a 76-year-old woman presenting with abdominal pain. ¹⁷ The goal of treatment was palliative, as her large left renal tumor had signs of local invasion, and she had distant hepatic metastases. Y90 was favored in this case, as renal cell carcinoma tumor biology is considered to be relatively radioresistant (and therefore a poor candidate for SBRT), and her tumor had high proximity to colon (preventing safe ablation). The patient tolerated the treatment well. Her tumor remained grossly stable on subsequent imaging with areas of decreased tumor enhancement. Her disease eventually progressed and she died 23 months after treatment. Further investigation is necessary to determine whether a subset of renal cancers not amenable to cryoablation, such as those larger than 6 cm, may be good candidates for treatment with Y90.

A case report by Ricke et al describes similar palliative treatment of lung metastases. ¹⁸ Two patients with diffuse colorectal and renal cancer metastases to the lung were treated with Y90. The resin microspheres were delivered via the bronchial artery, with confirmation of deposition within the tumor by SPECT-CT. Selective treatment was chosen to limit the risk of radiation-induced pneumonitis. Though radiation-induced pneumonitis is a feared complication of patients with high lung shunt fractions in Y90, neither patient developed nontarget radiation-related lung injury. It should be noted that time to follow up pulmonary function tests in this study was short (4 weeks), while radiation lung injury can manifest months after treatment. In these two cases, follow-up imaging demonstrated targeted lesions were stable or showed partial response. Both patients died within 1 year of treatment due to high disease burden. This case report suggests that Y90 may have a role to play in the locoregional treatment of lung tumors when thermal ablation is not desirable. For example, Y90 may be considered when lesions are hypervascular, large (>3 cm), or numerous.

Another area of intense interest is radioembolization of the prostate gland. In April 2021, Mouli et al reported a canine cohort successfully treated with Y90. ¹⁹ A cohort of 14 dogs received dihydroandrosterone/estradiol to induce prostatic hyperplasia. Each dog underwent fluoroscopic prostatic artery catheterization with delivery of glass Y90 microspheres to one prostatic-hemigland (dose escalation from 60 to 200 Gy), with the contralateral side serving as the control. The animals tolerated the procedure well without adverse events. PET-MRI demonstrated dose-dependent decrease in treated hemigland size at 40 days (25–60%, p  < 0.001). While bland embolization of the prostatic artery is already emerging as a growing treatment for patients with benign prostatic hyperplasia, radioembolization may serve a potential role in the treatment of prostate cancer in select subgroups. ²⁰

Nononcologic Extrahepatic Y90

Y90 is also being investigated in treatments outside of oncologic applications. The FDA has approved an investigational device exemption to study whether splenic artery–directed glass microsphere Y90 is a safe and effective treatment for patients with refractory thrombocytopenia secondary to cirrhosis. ²¹ The rationale for such a study is based on the unacceptably high adverse event profile of splenic artery embolization, a treatment used for treating thrombocytopenia. Primary endpoints for the clinical trial include safety. Secondary outcomes include platelet counts, postprocedural splenic volume, and hospital length of stay. The clinical trial (NCT03059030) began in 2017 and is ongoing.

Conclusion

The extrahepatic potential of Y90 is largely unexplored. To bring the potential of Y90 to fruition, more rigorous investigation is indicated. Harnessing the full potential of Y90 will require a sustained level of dedication to producing level I and II evidence, similar to the efforts behind the body of work that has established the clinical role of radioembolization within hepatic malignancies. As the field of interventional radiology reimagines its role as a clinically focused specialty, we must invest in robust concurrent research to not only invent the future of Y90 beyond the liver but also produce the science proving its efficacy in improving patient outcomes.