Complications Following Radioembolization with Yttrium-90 Microspheres: A Comprehensive Literature Review

doi:10.1016/j.jvir.2009.05.030

Journal of Vascular and Interventional Radiology

Volume 20, Issue 9, September 2009, Pages 1121-1130

https://doi.org/10.1016/j.jvir.2009.05.030 Get rights and content

The past decade has seen significant advancement in the locoregional management of liver tumors; novel and promising therapies such as transarterial chemoembolization, radioembolization, and radiofrequency ablation are now available. The development of new techniques and devices has led to the improved safety and efficacy profiles of external-beam radiation. Radioembolization with yttrium-90 (⁹⁰Y) microspheres has emerged as a safe and efficacious treatment modality for liver malignancies. The purpose of this article is to present a comprehensive evidence-based review of the complications and adverse events that may be associated with radioembolization with ⁹⁰Y microspheres. Strategies to mitigate these adverse events are also discussed.

Section snippets

Primary Tumors

THE most common primary malignancy of the liver is hepatocellular carcinoma (HCC); its incidence is increasing worldwide. It ranks as the sixth most common malignancy and third most common cause of cancer-related mortality (1, 2). The management of liver tumors has seen significant advancement in the past decade with the development of new screening, diagnostic, and therapeutic modalities. Primary liver tumors include HCC and intrahepatic cholangiocarcinoma. Surgical resection is considered

Pretreatment Evaluation

HCC is diagnosed on imaging if there is a lesion greater than 2 cm with arterial-phase enhancement and venous washout (17). Biopsy is performed in lesions that do not have the typical radiologic findings as defined by the European Association for the Study of the Liver and American Association for the Study of Liver Diseases guidelines (18). The role of α-fetoprotein in diagnosis of HCC is not yet established. Secondary liver tumors are diagnosed by imaging with fluorodeoxyglucose positron

Yttrium-90

⁹⁰Y is a pure β-emitter. It has an average β-energy emission of 0.9367 MeV and a maximum of 2.1 MeV. The mean tissue penetration is 2.5 mm with a maximum of 10 mm.

TheraSphere

TheraSphere particles (MDS Nordion, Ottawa, ON, Canada) are glass microspheres 20–30 μm in size with ⁹⁰Y as anintegral constituent (26). One 3-GBq vial contains 1.2 million particles. Given the low particle number, the particles impart a minimal embolic effect (27). This device was approved by the Food and Drug Administration for use

Complications of Radioembolization

The complications occurring after radioembolization can be broadly classified into the following groups: postradioembolization syndrome (PRS), hepatic dysfunction, biliary sequelae, portal hypertension, radiation pneumonitis, GI ulceration, vascular injury, lymphopenia, and a miscellaneous category. These will be discussed in the following evidence-based review of the published literature.

PRS

Patients may experience a mild PRS that consists of the following clinical symptoms: fatigue, nausea, vomiting, anorexia, fever, abdominal discomfort, and cachexia. Hospitalization is usually not required. PRS is less severe than the posttreatment syndromes observed after other embolic therapies in which fatigue and constitutional symptoms predominate (11, 27, 32, 33). Mild abdominal pain may be experienced after radioembolization (21, 33). As a result of the lack of macroscopic embolization

Conclusion

The mild adverse events and constitutional symptoms after radioembolization rarely require hospitalization. Serious adverse events can be mitigated if proper patients are selected, accepted dosimetry models used, and meticulous technique employed (Table 2). Patients with poor liver function before treatment are more prone to develop RILD. Derangement in liver function can be prevented by lobar or segmental injection and avoidance of whole-liver treatment (35). Biliary sequelae occur mostly

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Temporary Vascular Occlusion with Retrievable Microvascular Plugs to Protect Normal Liver during Yttrium-90 Radioembolization
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This case series describes a technique to protect nondiseased liver parenchyma during transarterial radioembolization (TARE) using microvascular plugs to occlude nontarget vessels temporarily and protect normal liver. This technique, defined as temporary vascular occlusion, was performed in 6 patients, with complete vessel occlusion obtained in 5 of the 6 patients and partial occlusion with flow reduction in 1 of the 6 patients. A statistically significant (P = .001) dose decrease of 5.7 ± 3.1 times was measured using postadministration yttrium-90 positron emission tomography/computed tomography in the protected zone compared with that in the treated zone.
Long-term Clinical Outcomes of Yttrium-90 Transarterial Radioembolization for Hepatocellular Carcinoma: A 5-Year Institutional Experience
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To examine the clinical outcomes of yttrium-90 (Y90) transarterial radioembolization (TARE) for primary hepatocellular carcinoma (HCC) through the evaluation of a 5-year institutional experience.
This retrospective study evaluated 88 consecutive patients with primary HCC receiving Y90 TARE treatment at an academic medical center from 2017 to 2021. Disease distribution was bilobar in 60.2% of patients with an average lesion diameter of 5.0 ± 3.4 cm and Barcelona Clinic Liver Cancer stage B or C in 77% of the participants. Clinical outcomes were elucidated by examination of complications, liver function tests, biochemical response, and radiographic response. Objective response ratio (ORR) and progression-free survival (PFS) were also calculated.
The mean administered Y90 radiation dose was 127.8 ± 20.2 Gy. No significant complications or LFT elevations occurred post-therapy. Of the 73.9% of patients with α-fetoprotein-producing tumors, 67.8% experienced a complete or partial biochemical response 1 month post-treatment. The ORR was 83.3% on 6-month imaging and PFS was 9.6 ± 8.5 months. Functional outcomes (Eastern Cooperative Oncology Group) were maintained or improved in 79.6% and 76.1% of patients by 6 months and 1 year post-treatment, respectively. The mean survival was 14.7 ± 12.1 months. At 6 months post-treatment, 77.3% of patients were downstaged to or maintained Milan criteria, which was sustained for 74.4% and 70.0% of patients 1 year and 2 years after treatment, respectively.
Y90-TARE is a safe and effective therapy for primary HCC. Enduring outcomes further act as a realistic bridge to liver transplantation, with a majority of patients maintaining Milan criteria and preserving their functional status long term.
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Physical properties and biological impact of <sup>90</sup>Y microspheres prepared by sol-gel method for liver radioembolization
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Microspheres for liver radioembolization for human use have high requirements in terms of their toxicity and biocompatibility on the one hand, but also typical properties such as physical and chemical durability or specific activity on the other hand. Developed manufacturing process based on the sol-gel method allowed to obtain spherical, yttrium trioxide grains of fully polycrystalline structure with diameters between 20 μm and 100 μm. The work is focused on a further investigation concerning the Y₂O₃ microspheres including physical, radiometric, dosimetric, and biological experiments. Neutron activation analysis confirmed a high concentration of radioactive ⁹⁰Y in the sample. The developed procedure for determining the specific activity of a single microsphere showed that at the time of administration, the activity can be specified at the level of 2600–3200 Bq per microsphere. FLUKA Monte Carlo code was used to prepare model for the calculation of dose distributions at the microscopic level, indicating that locally occurring heterogeneities can lead to cold spots during radioembolization. The data obtained from the simulation enabled analysis of the absorbed dose delivered by gel ⁹⁰Y₂O₃ microspheres as a function of radioactivity concentration, initial specific activity, or microsphere concentration in the sample. The reduction in colorectal cancer cell proliferation in vitro confirms the significant influence of beta ray radiation from yttrium-90 trioxide microspheres. Histopathological examination of the distribution of microspheres in the porcine model confirmed the proper location of yttrium trioxide microspheres inside blood vessels in a porcine model. Gel Y₂O₃ microspheres manufactured using the sol-gel method showed relevant properties, indicating the possible use of microspheres for further biological and preclinical studies.
Intrahepatic flow diversion prior to segmental Yttrium-90 radioembolization for challenging tumor vasculature
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Hepatic tumors with complex vascular supply or poor relative perfusion are prone to decreased rates of objective response. This is compounded in the setting of Yttrium-90 (Y90) transarterial radioembolization (TARE), which is minimally embolic and flow-dependent, relying on high threshold dose for complete response.
We describe our experience with intrahepatic flow diversion (FD) prior to TARE of hepatocellular carcinoma (HCC) with challenging vascular supply.
Between April 2014 and January 2020, 886 cases of coinciding MAA or TARE and bland embolization or temporary occlusion were identified. Intraprocedural embolizations performed for more routine purposes were excluded. FD was performed by bland embolization or temporary occlusion of vessels supplying non-malignant parenchyma in cases where flow was not preferential to target tumor. Lesion characteristics, vascular supply, treatment approach, angiography, and adverse events (AEs) were reviewed. Radiographic response was assessed using mRECIST criteria.
22 cases of FD of focal HCC were identified. Embolics included calibrated microspheres (n = 11), microcoils (n = 4), gelfoam (n = 3), temporary balloon occlusion (n = 2) and temporary deployment of a microvascular plug (n = 1). Post-treatment SPECT-CT dosimetry coverage was concordant with target lesions in all cases. Mean follow-up was 16.7 months (1.4–45 mos). Tumor-specific response per mRECIST was 41% complete response, 50% objective response, and 59% disease control rate. No major adverse events or grade 3/4 hepatotoxicity were reported.
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: R.S. is a paid consultant for MDS Nordion (Ottawa, Ontario, Canada) and has served on advisory boards for Sirtex Medical (Lane Cove, Australia). None of the other authors have identified a conflict of interest.

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Review articleComplications Following Radioembolization with Yttrium-90 Microspheres: A Comprehensive Literature Review

Section snippets

Primary Tumors

Pretreatment Evaluation

Yttrium-90

TheraSphere

Complications of Radioembolization

PRS

Conclusion

Gastroenterology

J Hepatol

Tech Vasc Interv Radiol

Gastroenterology

J Vasc Interv Radiol

J Vasc Interv Radiol

Ann Oncol

J Hepatol

J Vasc Interv Radiol

J Vasc Interv Radiol

Tech Vasc Interv Radiol

J Vasc Interv Radiol

J Vasc Interv Radiol

Int J Radiat Oncol Biol Phys

J Vasc Interv Radiol

J Vasc Interv Radiol

J Vasc Interv Radiol

J Vasc Interv Radiol

J Vasc Interv Radiol

Int J Radiat Oncol Biol Phys

J Vasc Interv Radiol

J Vasc Interv Radiol

J Vasc Interv Radiol

Ann Vasc Surg

Global cancer statistics, 2002

CA Cancer J Clin

Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis

N Engl J Med

Yttrium-90 microspheres (TheraSphere(R)) treatment of unresectable hepatocellular carcinoma: downstaging to resection, RFA and bridge to transplantation

J Surg Oncol

Radiofrequency ablation of hepatocellular carcinoma: treatment success as defined by histologic examination of the explanted liver

Radiology

Drop-out rates of patients with hepatocellular cancer listed for liver transplantation: outcome with chemoembolization

Liver Transpl

Review article
Complications Following Radioembolization with Yttrium-90 Microspheres: A Comprehensive Literature Review