Final Yttrium-90 Microsphere Brachytherapy Medical Events Analysis 

June 18, 2013 

Subcommittee members: Sue Langhorst, Steve Mattmuller, John Suh, Orhan Suleiman, Bruce 

Thomadsen, James Welsh (chair) 

Charge: To investigate the apparent trend in medical events involving yttrium-90 (Y-90) 

microsphere brachytherapy over the past 6 years, including the greater rate of medical events with 

glass microspheres than with resin microspheres. 

Introduction: 

At the April 15-16, 2013 Spring Meeting of the Advisory Committee for the Medical Uses of 

Isotopes (ACMUI), a subcommittee was charged with investigating the apparent increase in 

medical events involving Y-90 microsphere brachytherapy. 

Over the past several years, the use of yttrium-90 (Y-90) microsphere brachytherapy has grown in 

popularity as a treatment option for hepatic malignancies but has also experienced an increase in 

the number of reported medical events (MEs). The subcommittee has been asked to explore the 

apparent increase in MEs over the past few years and ascertain if the trend is real, and if real what 

might be the underlying causes. The subcommittee has been asked to compare the two existing 

commercially available systems (TheraSphere® glass microspheres (Nordion Inc.) and SIRSpheres® resin microspheres (Sirtex Medical Limited)) for ease of use, potential design flaws, 

and related aspects that might explain the apparent trend. 

To begin, we present a table provided by NRC staff: 

FY % Incidence 

TheraSphere®

% Incidence 

SIR-Spheres® Total % 

Incidence

2007 2.34% 0.21% 0.53%

2008 unknown Unknown 0.13%

2009 0.30% 0.17% 0.23%

2010 0.10% 0.08% 0.09%

2011 0.29% 0.13% 0.20%

2012 0.36% 0.18% 0.26%

TOTAL 0.29% 0.13% 0.26%

A few points and comments can be made about the data presented: 

1. Aside from 2007, neither type of microsphere demonstrated a medical event rate exceeding 

0.36% in any given year. 

2. For TheraSphere®, the ME rate has gone from 0.10% to 0.29% to 0.36% during the interval 

from 2010-2012. During the same period, the ME rate for SIR-Spheres® has gone from 0.08% to 

0.13% to 0.18%. Thus one might conclude that in the period from 2010 to 2012, there appears to 

be an upward trend in ME incidence for both glass and resin microspheres. However, when 
including data available from 2007 and 2009, this upward trend appears questionable since 2007 

was the highest year for both glass and resin microspheres. 

3. For TheraSphere® glass microspheres, 2009, at 0.30% was essentially the same as 2011 at 

0.29%; for SIR-Spheres resin microspheres, 2009, at 0.17% was essentially the same as 2012 at 

0.18%. For both microspheres, 2007 demonstrated the highest ME rate on record. Specific data 

from 2008 were not available because the type of microsphere used was not provided in the event 

report in NRC’s Nuclear Material Events Database (NMED). 

4. Given the available data, it may be impossible to state with certainty that there is a statistically 

significant increased number of MEs during the past six years. 

General observations: 

Focusing on 2011-2012 (the two years in which there appeared to be an increased incidence of 

MEs compared to years prior and the years that largely have prompted this investigation), if one 

ignores the unenlightening miscalculations and wrong lobe injections, the vast majority of 

medical events were underdoses due to flow problems. 

The causes of the flow problems were varied with no single cause predominating. This would 

appear to indicate a process that is complex and somewhat susceptible to error. The 

TheraSphere® process appears to fit this description, with many things required to go right for it 

to work properly. TheraSphere® employs an excellent checklist approach, without which one 

might speculate that there would be more MEs. The equipment is delicate, and perhaps not 

ideally designed, but to change any of it might require an FDA process. The SIR-Spheres®

apparatus, however, is no more robust and one could argue that the set-up and procedure may be 

even more involved. It could be that with no assessment of residual activity for SIR-Spheres®, the 

users are unaware of problems. Alternatively, as SIR-Spheres® users are more accustomed to 

reaching stasis and stopping the procedure prematurely, this could also lead to users being 

unaware of technical problems. 

Because SIR-Spheres® and TheraSphere® went through different FDA approval pathways, 

initially TheraSphere® was only used for primary liver cancer (hepatocellular carcinoma (HCC)). 

Now, like SIR-Spheres®, it is being used to treat colorectal (and other) hepatic metastases, which 

typically includes patients that have previously received chemotherapy and other treatments. The 

number of MEs reported prior to 2011 was nearly the same for each manufacturer; however, the 

discrepancy between the two is more pronounced in 2011 and 2012. The subcommittee is aware 

that up to two TheraSphere® vials can be used for one patient. Thus, mathematically, the 

TheraSphere® ME denominator has the potential to be up to half of the number provided by the 

manufacturers to NRC staff, which would thereby double the incidence rate of MEs and causes an 

even larger discrepancy for TheraSphere®. A substantial change in the numbers, however, is 

unlikely. 

Specific observations: 

There are challenging aspects of the TheraSphere® system, such as the clamp used on the delivery 

tube before the administration that crimps the line (often requiring re-rounding before delivery) 

and a somewhat complicated delivery apparatus. Much of the complexity in the device is there 

specifically to prevent problems during delivery. 
Over the last two years, the most common problem was microsphere settling due to low flow 

rates. This has occasionally happened due to a crimped line, but not often. The reported reasons 

for the slow flow were: 

* Low flow due to pause 

* Clumping 

* Leaking of priming line and reduced pressure 

* Needles inserted at an angle 

* Possible defective catheter 

* Hemostat caused deformation of tube and limited flow 

* Slow flush due to small arteries 

* "Dose seemed harder to push" 

* Low flow rate NOS 

* Piece of septum within vial impeded flow 

* Clamp not fully opened 

* Stasis due to vascular spasm, small/fragile vessels slowed delivery or malfunction of delivery 

system 

The question of training was raised in several of these MEs but the subcommittee is aware that 

training is often used as an explanation when other explanations are not found. It should again be 

noted that Nordion Inc. provides an excellent training program. 

SIR-Spheres® likewise has a complicated delivery apparatus, with three-way stopcocks and 

switching between the delivery and flush/arteriogram modes. Their reasons for incomplete 

delivery in the past two years were: 

* Occlusion of catheter due to microcatheter (catheters < 2.8 French) 

* Procedure halted because of patient pain (this should not be listed as a ME) 

* Slow delivery that led to settling 

* Microspheres stuck to septum because the bottle was shipped upside down 

For neither type of microsphere was simple stasis (which should not be reported as an ME 

anyway) an issue. There were typical human errors, such as wrong patient, wrong lobe or misread 

prescriptions with both devices. 

In several cases (low flow due to pause; leaking of priming line and reduced pressure; hemostatdeformed tube and limited flow; low flow rate NOS; not using appropriately sized catheters), the 

licensees indicated that inadequate training might be at the root of the problem. 

Regarding the microspheres sticking to the septum due to an inverted bottle during shipping, the 

vendor was made aware and has agreed not to ship them where microspheres could settle on the 

septum of the vial. 

One subcommittee member pointed out that compared with a permanent implant prostate seed 

brachytherapy procedure or a high-dose-rate brachytherapy cervical treatment, Y-90 microsphere 

brachytherapy is no more complex nor patient-dependent. However, another subcommittee 

member has pointed out that the precision of microsphere brachytherapy dosimetry is severely 

limited by the fact that unlike macrobrachytherapy, this procedure (which is more akin to 

radiopharmaceutical therapy) suffers from gross imprecision and comparisons to 

macrobrachytherapy and external beam radiation therapy are meaningless. None of this 

dosimetric uncertainty has anything to do with the events. However, the technical aspects of Y90 microsphere brachytherapy are also far more complex and involved than simple parenteral 
radiopharmaceutical therapy. Y-90 microsphere brachytherapy is considered "manual 

brachytherapy" but is licensed under 10 Code of Federal Regulations (CFR) 35.1000. 

In 2011, in addition to Authorized Users (AUs) with traditional 10 CFR 35.300 and 400 training 

and experience, interventional radiologists with appropriate training, education and experience 

became eligible to serve as AUs. 

Conclusions: 

In summary, the subcommittee was not able to conclusively identify an obvious root cause for the 

apparent trend towards the increased incidence of MEs with Y-90 microsphere brachytherapy nor 

was it obvious why one product has been involved in more MEs than the other. 

Recommendations such as different clamps and different syringes can be made, but the 

subcommittee is aware that making significant changes could entail a significant change in the 

overall approach. Such radical recommendations, which could potentially introduce additional 

failures, do not appear warranted at this time. It remains possible that the apparent trend is, in 

fact, simply a non-statistically significant deviation from background in a procedure that has a 

low baseline medical event rate. Another observation is that the particular MEs reported (mostly 

underdoses) have generally not had serious clinical consequences, especially in cases where 

repeat treatment has been offered to provide full final dose to the patients. Rather than being of 

major clinical significance, these MEs appear to be of the type that serves the purpose of alerting 

NRC of a possible trend that someday could become clinically important, and provoking action, 

as in the form of this report. The subcommittee will continue to monitor the reported events and 

make recommendations, as appropriate. 

The ACMUI unanimously approved this report on June 18, 2013.