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J Am Coll Cardiol, 2002; 39:1937-1942
© 2002 by the American College of Cardiology Foundation
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CLINICAL STUDY

Dose heterogeneity may not affect the neointimal proliferation after gamma radiation for in-stent restenosis

A volumetric intravascular ultrasound dosimetric study

Akiko Maehara, MD*, Neil S. Patel, MS{dagger}, Louis B. Harrison, MD{dagger}, Neil J. Weissman, MD, FACC*,*, Anh B. Bui, MD*, Han-Soo Kim, MD*, Andrew E. Ajani, MD*, Marco T. Castagna, MD*, Taya L. McMillan, MS*, Nathan Yang, PhD*, Rosanna Chan, PhD*, Julliana Pisch, MD{dagger}, Harry Quan, MD{dagger}, Sou-Tung Chiu-Tsao, PhD{dagger}, Ron Waksman, MD, FACC* and Gary S. Mintz, MD, FACC{ddagger}

* Cardiovascular Research Institute, Washington Hospital Center, Washington DC, USA
{dagger} Beth Israel Medical Center and St. Luke’s-Roosevelt Hospital Center, New York, New York, USA
{ddagger} Cardiovascular Research Foundation, New York, New York, USA

Manuscript received September 10, 2001; revised manuscript received February 28, 2002, accepted March 14, 2002.

* Reprint requests and correspondence: Dr. Neil J. Weissman, Cardiovascular Research Institute, 110 Irving Street, Northwest, Suite 4B-1, Washington, DC 20010, USA.
Neil.J.Weissman{at}medstar.net


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: The goal of this study was to use serial (postirradiation and follow-up) volumetric intravascular ultrasound (IVUS): 1) to evaluate the actual distribution of gamma radiation in human in-stent restenosis (ISR) lesions, and 2) to analyze the relationship between neointimal regrowth and the delivered radiation dose.

BACKGROUND: The relationship between the neointimal regrowth and delivered dose during the treatment of ISR remains unknown.

METHODS: We analyzed 20 actively (gamma emitter) treated, native artery ISR patients from the Washington Radiation for In-Stent restenosis Trial (WRIST) that met the following criteria: on both postirradiation and six-month follow-up IVUS imaging, ≥80% of the external elastic membrane circumference could be identified throughout the treated length including the lesion and proximal and distal reference segments. Intravascular ultrasound images were digitized every 1 mm. Proximal and distal reference and stented segment luminal and adventitial contours were imported and reconstructed. The source was placed circumferentially at the site of the IVUS catheter and longitudinally according to the relationship between the radioactive seeds and stent edges. Using Monte Carlo simulations, dose volume histograms for the adventitia and intima were calculated. The relationship between the neointimal regrowth and calculated doses were evaluated.

RESULTS: There was large dose heterogeneity at both the intimal and adventitial levels. Most of the sites (93%) received >4 Gy at the adventitia, and all of the sites received >4 Gy at the intima. There was no relationship between neointimal regrowth and radiation dose.

CONCLUSIONS: Although there may be large dose heterogeneity, gamma irradiation (using a fixed dose prescription) appears to deliver a sufficient dose to prevent neointimal regrowth.

Abbreviations and Acronyms
  CSA
  cross-sectional area
  DV
  dose volume
  DVH
  dose volume histogram
  EEM
  external elastic membrane
  ISR
  in-stent restenosis
  IVUS
  intravascular ultrasound
  TG-60
  Task Group-60 of the American Association of Physicists in Medicine
  WRIST
  Washington Radiation for In-Stent restenosis Trial

Intravascular brachytherapy has been evaluated in a number of clinical settings including de novo lesions, restenotic lesions, newly stented lesions and in-stent restenosis (ISR) lesions in both native arteries and saphenous vein grafts (1–3). As a result of randomized, placebo controlled clinical trials, the Food and Drug Administration has approved brachytherapy for the treatment of ISR. The purpose of the current study was to use serial (postirradiation and follow-up) volumetric intravascular ultrasound (IVUS) analysis: 1) to evaluate the actual distribution of gamma radiation to the intima and adventitia in native artery ISR lesions, and 2) to analyze the relationship between the neointimal regrowth and the calculated dose.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patient population.   We analyzed 20 actively treated, native artery ISR patients from Washington Radiation for In-Stent restenosis Trial (WRIST), a randomized, placebo-controlled trial of gamma-irradiation for the treatment of ISR. The WRIST study enrolled 50 patients with native artery ISR. Thirty-six of these patients had postirradiation and follow-up IVUS imaging. The 20 patients in the current analysis were selected because ≥80% of the external elastic membrane (EEM) circumference could be identified throughout the treated length (including the lesion and proximal and distal reference segments) on both postirradiation and six-month follow-up IVUS imaging and because they were treated with the same dose prescription.

Radiation procedure.   The details of the radiation procedure have been reported previously (3). A closed end-lumen 5.0F noncentered catheter (Medtronic Vascular Interventional, Minneapolis, Minnesota) was inserted into the vessel and positioned at the ISR lesion. The radiation source—192Ir (Best Medical International, Beuningen, The Netherlands)—was hand-loaded into the closed end-lumen catheter. The prescribed dose was 15 Gy to a distance of 2 mm from the surface of the source.

Angiographic analysis.   All cineangiograms were analyzed using CMS-GFT system (Medis, Maastricht, Netherlands) by an independent angiographic core laboratory (Washington Hospital Center) that was blinded to the IVUS findings. With the outer diameter of the contrast-filled catheter used for calibration, minimum lumen diameter in diastole was measured from multiple projections, and results from the "worst" view were recorded. Reference segment diameter was averaged from user-defined 5-mm-long angiographically normal segments proximal and distal to the lesion, but between any major side branches. The diameter stenosis was calculated as reference diameter minus minimum lumen diameter divided by reference lumen diameter. Lesion length was measured as the distance from the proximal shoulder to the distal shoulder in the projection with the least amount foreshortening. Angiography was used to compare the final source placement to the stented segment.

IVUS imaging protocol and analysis.   All IVUS studies were performed after intracoronary administration of 200 µg nitroglycerin using a commercially available IVUS system (Boston Scientific Corporation/SciMed, Maple Grove, Minnesota). The IVUS catheter was advanced distal to the lesion and imaging performed retrograde back to the aorto-ostial junction at an automatic pullback speed at 0.5 mm/s.

We selected the following seven specific cross-sectional images to represent the anatomic and dose heterogeneity throughout the length of the treated segment: the sites of the 1) minimum and 2) maximum distances from the IVUS catheter to the leading edge of the intima; the sites of the 3) minimum and 4) maximum distances from the IVUS catheter to the leading edge of the adventitia (EEM); 5) the proximal stent edge; 6) the center of the stent; and 7) the distal stent edge. The IVUS catheter was assumed to represent the location of the radiation source.

Using planimetry software (TapeMeasure, INDEC Systems Inc., Capitola, California), EEM cross-sectional area (CSA), stent CSA and lumen CSA were measured every 1 mm including the seven cross-sections of interest according to the Standards for the Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents (4). Neointima CSA was calculated as stent CSA minus lumen CSA within the stented segment. Using perivascular landmarks and the known transducer pullback speed, the cross-sections at postirradiation and follow-up were matched, analyzed and compared. The change in neointima CSA within the stent was calculated as follow-up minus postirradiation neointima CSA. The change in neointima CSA was also averaged over the length of the stented segment.

In addition, the proximal and distal reference sites and the minimum lumen CSA site postirradiation and follow-up were identified and measured. The reference sites were the most normal looking sections within 5 mm of the ends of the stents, but before major side branches. Qualitative analyses included dissections and incomplete stent apposition.

Dosimetry analysis.   Three-dimensional dosimetric analysis was performed with software developed for intravascular brachytherapy. We digitized the IVUS images every 1 mm throughout the stent and reference segments and drew both luminal and adventitial contours. Intravascular ultrasound images were imported, and intimal and adventitial contours were digitally reconstructed. The assumption was made that the cross-sectional location of the source within the artery was at the site of the IVUS catheter. The longitudinal location of the source was determined angiographically by comparing the radiodense seeds with the stent edges.

Dosimetry calculations were performed by the method recommended by Task Group-60 (TG-60) of the American Association of Physicists in Medicine (5), and it was validated in vitro (6,7). Dose is decomposed into the product of multiple parameters that describe the source characteristics. Source information was provided by data generated from Monte Carlo simulations of a single 192Ir seed. Gamma, characteristic X-ray, beta, conversion electron and Auger electron radiations were tracked from the source and were used to generate pertinent TG-60 dosimetric parameters.

For the seven cross-sections of interest as well as for the entire stented segment, dose volume histograms (DVH) were calculated. We assumed that intimal thickness measured 0.1 mm and adventitial thickness measured 0.5 mm (8).

Statistics.   Statistical analysis was performed using Statview 5.0 (SAS Institute, Cary, North Carolina). Continuous variables are presented as mean value ± 1 SD, and categorical variables are presented as frequencies. Continuous variables were compared using paired Student t test or simple regression analysis. A p value of <0.05 was considered significant.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Patient demographics and procedural and angiographic variables are shown in Tables 1 and 2. The minimum lumen diameter decreased and the diameter stenosis increased slightly, but significantly, from postirradiation to follow-up (p = 0.036 and p = 0.006, respectively). Four patients required target vessel revascularization; however, there were no deaths, no Q-wave myocardial infarctions and no episodes of late thrombosis in these 20 patients.


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  		Table 1 Patient Demographics (n = 20)

 

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  		Table 2 Procedural and Angiographic Variables

 
Intravascular ultrasound measurements are shown in Table 3. There was a decrease in lumen CSA and an increase in neointima CSA both at the minimum lumen CSA site and throughout the length of the stent. However, overall, these changes were modest. The DVHs at the both intima and adventitia of individual cases are shown in Figures 1 and 2.


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  		Table 3 Intravascular Ultrasound Findings

 


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  		Figure 1 Individual dose (D) volume (V) histograms at the adventitia for the entire stent.

 


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  		Figure 2 Individual dose (D) volume (V) histograms at the intima for the entire stent.

 
Most of the sites (93%) received a dose of >4 Gy at adventitia, and all sites received a dose of >4 Gy at intima (Dv90). To find the best parameter to predict neointimal regrowth, we compared the increase in neointima CSA to the Dv5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 at both the adventitia and intima at each of the seven preselected cross-sections of interest. Although there was a weak correlation between neointimal regrowth and Dv50 at the intima (p = 0.003, r = 0.32), in general, there were no significant relationships between neointimal regrowth and dosimetric calculations (Table 4, Figs. 3 and 4). When the entire stented segment was evaluated, there was also no significant relationship with either Dv at intima or Dv at adventitia (Figs. 5 and 6).


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  		Table 4 Correlation Between Neointimal Regrowth and Calculated Dose

 


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  		Figure 3 The relationship between the neointimal regrowth and Dv90 at adventitia. DV90 = dose delivered to at least 90% of the volume.

 


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  		Figure 4 The relationship between the neointimal regrowth and Dv50 intima. DV50 = dose delivered to at least 50% of the volume.

 


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  		Figure 5 The relationship between the average neointimal regrowth and entire Dv90 at adventitia.

 


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  		Figure 6 The relationship between the average neointimal regrowth and entire Dv50 at intima.

 
Intravascular ultrasound detected three postintervention distal edge dissections to the media, one dissection to the media between two stents and five dissections within the neointima. All were healed at the follow-up. There was no late stent malapposition at follow-up.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Dose heterogeneity and effectiveness.   Previous studies in pig models showed that the effective prescribed dose for brachytherapy using a gamma source was 3.5 to 14 Gy at 2 mm (9) or 15 to 20 Gy at 1.5 mm (10–12) from the center of the lumen. Ideally, treatment protocols should be designed to deliver a uniform dose to the target; however, the source is rarely centered within the lumen, and the lumen and stent are rarely centered within the artery. This precludes centering the source within the artery and delivering a uniform dose to the adventitia.

Human ISR treatment protocols using gamma irradiation have selected either a fixed prescription (e.g., 15 Gy at 2 mm from the center of the source [3]) or a calculated and variable dose prescription (minimum of 8 Gy as long as the maximum dose is limited to 30 Gy [2,13]). However, in these ISR protocols, there have been little attempts to calculate the actual delivered dose and the affect of the delivered dose on the biologic process—neointimal regrowth. As shown in Figures 1 and 2, the actual dose ranged from 4 to 30 Gy at adventitial level and from 8 to 80 Gy at the intimal level with large dose variability.

In native artery lesions treated with balloon angioplasty and beta-irradiation, Sabate et al. (14) suggested that 4 Gy (Dv90 at adventitia) was the threshold to inhibit the neointimal growth (14). However, the dose that inhibits neointimal hyperplasia may be different in normal animal tissue versus human atherosclerotic tissue and in de novo human atherosclerotic tissue versus in-stent neointima. Therefore, we attempted to relate neointimal regrowth and various DVH values to either the adventitia or intima. In general, there was no correlation with any specific value of DVH. However, most (93%) of the cross-sections of interest received a dose >4 Gy at adventitia. Therefore, we suspect that using a fixed dose prescription, the overall delivered dose was enough to prevent the neointimal regrowth even though there was large dose heterogeneity. However, as shown in Figures 3 to 6, there were some cross-sections that received a high dose yet still exhibited a large neointimal regrowth. Therefore, it is possible that the biological variability among the patients or along the length of the ISR site affected neointimal regrowth more than the actual delivered dose. Finally, gamma-irradiation using an 192Ir source is considered to be unaffected by the presence of stent struts and lesion calcium (15).

Target of radiation for ISR.   The mechanism of radiation in preventing recurrent ISR is assumed to be the inactivation of cells that proliferate, migrate and synthesize matrix after intervention (16–18). Animal injury models of normal arteries show that the medial smooth muscle cell and/or adventitial myofibroblast are the source of the neointima (19–21). However, when the neointima created by the first injury is injured again (double-injury model), cell proliferation occurs in the intima as well as in the media or adventitia (22,23). Therefore, in treating ISR lesions, the target may be both the intima as well as the media and adventitia. For this reason, we evaluated the delivered dose to both the intimal and the medial-adventitial interface. This finding may also be part of the explanation for our inability to relate neointimal recurrence to actual dose delivery. The intima uniformly received at least 4 Gy.

Clinical implications.   We simulated the actual dose distribution in the clinical setting of gamma-irradiation brachytherapy using a fixed dose prescription. Although there was large dose heterogeneity, most of the artery appeared to receive an acceptable minimum dose. Therefore, IVUS-guided dose calculations and prescription may not be necessary. However, we detected cases in which the intima received very high doses (80 Gy). Caution may be necessary to avoid adverse effect of radiation (e.g., necrosis of the vessel) in these patients.

Study limitations.   The number of patients was small, and the recurrence rate was low. Total occlusion cases were excluded from our analysis. Although we assumed that the radiation source was located at the same position within the artery as the IVUS catheter, this might not be correct because the radiation catheter (5F) was bigger than IVUS catheter (3.2F). The current analysis assumes the ability to "align" cross-sections on serial studies.

Conclusions.   In patients undergoing brachytherapy using a gamma emitter and a fixed dose prescription, we were able to demonstrate a wide variability in actual dose delivered to the intima and to the adventitia. Nevertheless, there was little correlation between neointimal reaccumulation and actual delivered dose, suggesting that a minimum threshold was achieved in most patients. Other trials, specifically Scripps Coronary Radiation to Inhibit Proliferation Post Stenting I and GAMMA I, used a "variable" dose prescription (based on IVUS measurements) that resulted in a wide spectrum of doses received. In the WRIST trial, the dose was limited to one or two doses based on vessel diameter only, and this dose prescription appears to be adequate.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

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