Side Effects of Yttrium-90 Radioembolization

Microsphere and particle technology represent the next-generation agents that have formed the basis of interventional oncology, an evolving subspecialty of interventional radiology. One of these platforms, yttrium-90 microspheres, is rapidly being adopted in the medical community as an adjunctive therapeutic tool in the management of primary and secondary liver malignancies. Given the complexity of the treatment algorithm of patients who may be candidates for this therapy and the need for clinical guidance, a comprehensive review of the methodologic and technical considerations was undertaken. This experience is based on more than 900 (90)Y infusions performed over a 5-year period.

SIR-Spheres are radioactive yttrium90 microspheres (SIR-Spheres, Sirtex Medical Limited, Australia) used to selectively target high levels of ionising radiation to tumors within the liver. This trial was designed to measure any increased patient benefit by adding a single administration of SIR-Spheres to a regimen of regional hepatic artery chemotherapy (HAC) administered as a 12 day infusion of floxuridine and repeated at monthly intervals, vs. the same chemotherapy alone. A phase III randomised clinical trial entering 74 patients was undertaken on patients with bi-lobar non-resectable liver metastases from primary adenocarcinoma of the large bowel. Patient benefit criteria assessed in the trial were tumor response, time to disease progression in the liver, overall survival, quality of life, and treatment related toxicity. Tumor response was measured by serial changes in both cross-sectional tumor areas and total tumor volumes, provided any response lasted not less than three months as well as changes in serum carcino-embryonic antigen (CEA). The partial and complete response rate (PR + CR) was significantly greater for patients receiving SIR-Spheres when measured by tumor areas (44%) vs. 17.6%, P = 0.01) tumor volumes (50% vs. 24%, P = 0.03) and CEA (72% vs. 47%, P = 0.004). The median time to disease progression in the liver was significantly longer for patients receiving SIR-Spheres in comparison to patients receiving HAC alone when measured by either tumor areas (9.7 vs. 15.9 months, P = 0.001), tumor volumes (7.6 vs. 12.0 months, P = 0.04) or CEA (5.7 vs. 6.7 months, P = 0.06). The one, two, three and five-year survival for patients receiving SIR-Spheres was 72%, 39%, 17% and 3.5%, compared to 68%, 29%, 6.5% and 0% for HAC alone. Cox regression analysis suggests an improvement in survival for patients treated with SIR-Spheres who survive more than 15 months (P = 0.06). There was no increase in grade 3-4 treatment related toxicity and no loss of quality of life for patients receiving SIR-Spheres in comparison to patients receiving HAC alone. The combination of a single injection of SIR-Spheres plus HAC is substantially more effective in increasing tumor responses and progression free survival than the same regimen of HAC alone.

The use of 90Y-microspheres to treat unresectable liver metastases originating from a variety of neuroendocrine tumors was reviewed. This is a retrospective review from 10 institutions of patients given 90Y-microsphere therapy for neuroendocrine hepatic metastases. Physical, radiographic, biochemical, and clinical factors associated with treatment and response were examined. All patients were followed with laboratory and imaging studies at regular intervals until death, or censured whether other therapy was given after brachytherapy. Toxicities (acute and late) were recorded, and survival of the group determined. A total of 148 patients were treated with 185 separate procedures. The median age was 58 years (26-95 years) at treatment with median performance status of Eastern Cooperative Oncology Group (0). The median activity delivered was 1.14 GBq (0.33-3.30 GBq) with a median of 99% of the planned activity able to be given (38.1%-147.4%). There were no acute or delayed toxicity of Common Terminology Criteria for Adverse Events v3.0 grade 3 in 67% of patients, with fatigue (6.5%) the most common side effect. Imaging response was stable in 22.7%, partial response in 60.5%, complete in 2.7% and progressive disease in 4.9%. No radiation liver failure occurred. The median survival is 70 months. Radioembolization with 90Y-microspheres to the whole liver, or lobe with single or multiple fractions are safe and produce high response rates, even with extensive tumor replacement of normal liver and/or heavy pretreatment. The acute and delayed toxicity was very low without a treatment related grade 4 acute event or radiation induced liver disease in this modest-sized cohort. The significant objective response suggests that further investigation of this approach is warranted.