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Original Contribution
Safety of Beta Radiation Exposure to the Non-Target Segment:
An Intravascular Ultrasound Dosimetric Analysis
July 2006
Although catheter-based brachytherapy has been demonstrated to effectively treat in-stent restenosis, a technique-dependent issue known as “geographic miss” has evolved as a potential limitation contributing to long-term treatment failures. The mechanism responsible for the unfavorable edge effects may include the combination of low-dose radiation and mechanical injury during the interventional procedure.1,2 To ensure full coverage of radiation over the entire injured segment, longer radioactive seed trains have been recently introduced to interventional laboratories. This strategy, however, potentially leads to excessive radiation exposure to adjacent normal vasculature, especially the distal segment, due to the natural tapering of coronary arteries.
A recent IVUS study has demonstrated that gamma radiation showed no evidence of deleterious effects on angiographically normal, noninjured reference segments at 6 months.3 Potential effects of beta radiation, however, still remain unknown. Importantly, dose prescriptions for beta radiation trials are often higher than those using gamma-emitters, due to the rapid dose fall-off and the potential shielding of beta radiation by the stent struts.4 Furthermore, several retrospective dosimetric analyses have revealed a considerable discrepancy between the prescribed and “actual delivered” dose, demanding detailed investigations of vascular responses based upon quantitative dose evaluation methods. Thus, the aim of this study was to evaluate the effect of beta radiation on normal, noninjured distal segments using IVUS-based three-dimensional dosimetric analysis.
Methods
Patient population. The study population consisted of patients who underwent successful three-dimensional IVUS immediately post-procedure and at follow up in the STent And Restenosis Therapy (START) 40/20 trial. In this trial, a 40 mm, .90Strontium/Yttrium (90Sr/Y), noncentered radioactive source train (Novoste Corporation, Norcross, Georgia) was exclusively used for treatment of in-stent restenosis. The prescribed dose, 2 mm from the centerline of the source axis, was either 18.4 Gray (Gy; 9 patients) or 23 Gy (8 patients), based on visual assessment of the reference diameter, measuring ? 3.3 mm or > 3.3 mm, respectively.
IVUS imaging. All patients received aspirin and heparin (100 U/kg) prior to the procedures. Both baseline (preradiation) and follow up ultrasound studies were performed using a 3.2 Fr, 30 MHz mechanical ultrasound catheter (Boston Scientific Corporation, Natick, Massachusetts). IVUS studies were performed after intracoronary nitroglycerin (0.2 mg) administration. Using 0.5 mm/second automated pullback, ultrasound images were obtained and recorded on 0.5 inch S-VHS videotape for offline quantitative analysis.
Qualitative and quantitative intravascular ultrasound analysis. Atheroma morphology was defined according to American College of Cardiology clinical expert consensus.5 Three-dimensional reconstruction of IVUS images was performed at an independent IVUS core laboratory (Cardiovascular Core Analysis Laboratory, Stanford, California) using a commercially available quantitative analysis system (echoPlaque, Indec Systems, Inc. Mountain View, California). After digitization of IVUS recordings, lumen and external elastic membrane areas were manually traced at 16-frame intervals, and the interpolated measurements of the remaining frames were automatically generated.6 Using Simpson’s method, lumen volume and vessel volume inside the external elastic membrane were calculated, and the following volumetric parameters were defined for analysis: plaque volume = vessel volume - lumen volume. The percent change of each parameter was calculated as follow up minus post-treatment measurements, divided by post-treatment measurements. For this analysis, the computed volume of the irradiated segment was divided into 2 mm length subsegments, with mean areas calculated as volumes divided by axial length (2 mm). The longitudinal positions of the radioactive source train and injury zones relative to the stents were determined by an independent angiographic core laboratory (Cardiovascular Research Foundation, New York, New York). These angiographic data sets were converted and correlated with IVUS for correct geographic matching, as previously described in detail.6 Noninjured, but fully radiated, distal references were used for this IVUS substudy, with each divided into 2 mm-long subsegments (Figure 1) (average distance from stent edge = 6.3 mm).
Retrospective IVUS-based dosimetry. The actual dose received by the vessel was retrospectively calculated by means of dose-volume histograms7 using a PC-based dose calculation system (iPlanTM, Atlanta, Georgia).8 A detailed methodology and validation of this IVUS-based dosimetry in vascular brachytherapy has been previously reported.9 In short, the IVUS catheter was used to estimate the radiation source position in the vessel. Using the prescribed dose and the detailed geometric data obtained by three-dimensional IVUS, the cumulative curve of the dose-volume histogram for a predefined volume (i.e., plaque between the lumen and the external elastic membrane) was obtained. Based on this curve, the minimum dose received by 90% of the vessel wall (D.v90) was calculated for each 2 mm length subsegment in all patients.
Statistical analysis. Statistical analysis was performed using StatView 5.0.1 (SAS Institute). Data are presented as mean ± 1 SD. Continuous variables were compared using a paired Student’s t-test; p-values Results
A total of 52 segments in 17 patients (11 men and 6 women, aged 62 ± 15 years) were identified as noninjured, but fully radiated, distal reference subsegments (3.1 ± 1.9 subsegments from each patient). Baseline clinical characteristics included diabetes mellitus (12%), hypertension (65%), hypercholesterolemia (65%), current smoking (12%), prior myocardial infarction (47%) and prior CABG surgery (18%). Target vessels were left anterior descending, left circumflex and right coronary arteries in 64%, 18% and 18%, respectively. None of them had angiographic restenosis; in-stent diameter stenosis was 24 ± 14% (range 2–49%) at follow up.
Four patients had fibrocalcific plaque, 5 patients had fibrous plaque and 8 patients had fibrofatty plaque at baseline. All patients had the same plaque type at follow up, except 1 fibrofatty plaque changed to fibrocalcific plaque.
On average, no significant serial change was observed in mean plaque area (5.0 ± 2.5 mm3/mm post-treatment to 5.6 ± 3.1 mm3/mm at follow up; p = 0.09), mean vessel area (10.2 ± 3.7 to 10.3 ± 4.0 mm3/mm; p = 0.84), or mean lumen area (5.2 ± 2.0 to 4.7 ± 1.8 mm3/mm; p = 0.19).
As expected, due to vessel tapering, detailed dosimetric analysis revealed higher radiation doses received by the distal reference segments than the in-stent, fully radiated segments (D.v90: 37.8 ± 8.4 vs. 23.5 ± 5.8 Gy; p = 0.16), with a wide range of dose distribution among the subsegments in both regions (distal: 19.9 to 61.2 Gy; in-stent: 12.3 to 41.7 Gy) (Figure 2).
At the distal reference segments, a weak but significant positive correlation was found between the delivered dose (D.v90) and plaque change during follow up (r = 0.366; p = 0.008) (Figure 3A). On the other hand, D.v90 correlated positively with vessel change (r = 0.446; p Discussion
Elimination of geographic miss is considered a critical step toward optimization of clinical outcomes associated with catheter-based vascular brachytherapy. Although the use of longer radioactive seed trains is a potential solution, published long-term safety data on this approach are limited to a single IVUS study with gamma radiation.3 Importantly, since biological effects of ionizing radiation are often dose-dependent, the pattern and degree of vessel response at noninjured, but irradiated, reference segments can vary depending on the actual delivered dose to the arterial wall. In theory, due to the short range of low-energy electrons, beta radiation can be associated with greater dose heterogeneity than gammas. Therefore, the present study first used a recently developed IVUS-based three-dimensional dosimetric model to properly understand the relationship between the vascular response of noninjured reference segments and the actual delivered dose with a current beta radiation strategy.
In this study, despite no statistically significant change in overall vessel dimensions, more detailed analysis demonstrated large variability in vessel response at individual subsegments, corresponding to a wide range of radiation dose actually delivered to the tapering distal vasculature with the fixed-dose long source train. Beta radiation appeared to facilitate positive vessel remodeling in a dose-dependent fashion, preventing late lumen loss despite a mild increase in plaque mass. The additional information available from IVUS-derived dosimetry parameters can improve our understanding of the mechanisms of action of brachytherapy, and may be helpful for the comparison of the trials with different radiation strategies.
Although few studies have revealed the dose-effect relationship, the phenomenon of favorable vessel remodeling observed in this study is consistent with the result of the previous gamma radiation study noted above,3 as well as those seen at the nonstented, target segment treated with beta radiation.10–13 On the other hand, the exact reasons of the mild plaque mass increase after high dose radiation exposure at the normal, noninjured segments remain unclear. However, normal human cell lines, in response to radiation, have been shown to secrete factors that may influence the delayed response of the vascular system. By exposing smooth muscle cells to gamma radiation, Martin et al14 revealed an extensive accumulation of extracellular matrix containing elastin between the cell layers. Farb et al15 also found thickened adventitia in the presence of an increased inflammatory response and matrix-rich intima in rabbit iliac arteries treated with radioactive stents. Further studies will be needed to determine exact histopathologic mechanisms underlying these observations.
Study limitations. First, this study is based on a relatively small, retrospectively selected patient population (only patients with in-stent restenosis), raising the possibility of selection bias. Second, the obtained dose was based on the assumption that both the IVUS and delivery catheters were lying in the same position within the target coronary segment. However, these two catheters may not have occupied the exact position because of variations in size and stiffness between the two catheters, as well as variable axial and longitudinal movements during the cardiac cycle and during radiation. Third, this study was designed to examine the dose-response relationship in the adjacent vessel segment and had no “control” group to completely exclude the possible influence of natural disease progression. However, the correlations between the increase in plaque-vessel areas and radiation dose are difficult to explain by natural disease progression. Fourth, follow up was limited to 8 months. Finally, there are several inherent limitations in three-dimensional analysis techniques, including the effects of movement artifacts and distortion due to curvature of the vessels.16
In conclusion, detailed IVUS-based dosimetric analysis demonstrated that beta radiation promoted positive remodeling, preventing lumen loss despite a mild increase in plaque mass. The treatment of in-stent restenosis with long radioactive seed trains appears safe, with no deleterious overall effect on normal, noninjured distal segments at 8-month follow up.
Acknowledgement. The authors wish to thank Heidi N. Bonneau, RN, MS, for her expert review of the manuscript.
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