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(Chest. 2003;124:1284-1293.)
© 2003 American College of Chest Physicians

Intracoronary ß-Irradiation With Liquid Rhenium-188*

Results of the Taiwan Radiation in Prevention of Post-Pure Balloon Angioplasty Restenosis Study

Chi-Ling Hang, MD; Morgan Fu, MD; Bor-Tsung Hsieh, PhD; Stephen Wan Leung, MD; Chiung-Jen Wu, MD; Hon-Kan Yip, MD and Gann Ting, PhD

* From the Section of Cardiology (Drs. Hang, Fu, Wu, and Yip), Department of Internal Medicine, and Department of Radiation Oncology (Dr. Leung), Chang Gung Memorial Hospital, Kaohsiung Hsien, Taiwan, Republic of China; Institute of Nuclear Energy Research (Drs. Hsieh and Ting), Taoyuan Hsien, Taiwan, Republic of China.

Correspondence to: Stephen Wan Leung, MD, Chang Gung Memorial Hospital, 123 Ta-Pei Rd, Niao-Sung Hsiang, Kaohsiung Hsien 833, Taiwan, Republic of China


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Study objective: To assess the feasibility and short-term outcome of intracoronary irradiation after pure balloon angioplasty (POBA) of de novo and post-POBA restenotic lesions with a liquid ß-emitter 188Re-filled balloon.

Design and setting: Nonrandomized prospective study with contemporaneous control group in a single medical center.

Patients and methods: In the Taiwan Radiation in Prevention of Post-Pure Balloon Angioplasty Restenosis study, 40 patients underwent 14-Gy irradiation and 15 patients underwent 20-Gy irradiation at a tissue depth of 0.5 mm after POBA. Thirty control patients received a 5-min inflation with a perfusion balloon catheter after POBA.

Results: No procedural or in-hospital complications, or 30-day major adverse cardiac events were noted. Six-month angiographic restenosis rates were 49% in the 14-Gy group, 20% in the 20-Gy group, and 57% in the control group (p = 0.05, 20-Gy group vs control group). In the lesions with an arc of calcification of < 180°, restenosis occurred in 15 of the 34 lesions (44%) in the 14-Gy group and in none of the 11 lesions (0%) in the 20-Gy group (p = 0.007). In a vessel with a reference diameter < 3.0 mm, restenosis occurred in 1 of the 8 lesions (13%) in the 20-Gy group, and in 8 of the 11 lesions (73%) in the control group (p = 0.02). In the post-POBA restenotic lesions, restenosis occurred in none of the six lesions (0%) in the 20-Gy group, and in five of the six lesions (83%) in the control group (p = 0.008).

Conclusions: Post-POBA, catheter-based brachytherapy in nonstented native coronary artery with a 188Re-filled balloon can effectively reduce target lesion restenosis with 20-Gy irradiation at a tissue depth of 0.5 mm and seems to be more effective in the treatment of lesions with an arc of calcification < 180°, in a vessel with a reference diameter of < 3.0 mm, and in post-POBA restenotic lesions.

Key Words: angioplasty • brachytherapy • coronary artery disease • restenosis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Intracoronary brachytherapy with {gamma}-emitters and ß-emitters has been shown to reduce restenosis rates both in animals and in clinical studies.1 2 3 4 5 6 7 8 9 10 11 12 13 14 The only available {gamma}-emitter for intracoronary brachytherapy, 192Ir, is deeply penetrating and is not effectively shielded by standard lead aprons. ß-emitters deliver the dose to the required tissue depth of 2 to 3 mm, and they are safer because little radiation goes beyond 1 cm from the source. However, deviation of the position of a catheter-based ß-source by as little as 0.5 mm from the center can lead to significant differences in dose distribution. Moreover, longitudinal source displacement of a catheter-based isotope during the cardiac cycle might cause underdosing of the margin of the target vessel and might lead to marginal failure.15 Because intracoronary brachytherapy with a liquid-filled balloon catheter provides accurate source positioning and uniform delivery of treatment to the vessel wall, we conducted this study to determine the feasibility and outcome of ß-irradiation using a liquid 188Re-filled balloon after pure balloon angioplasty (POBA) of de novo and post-POBA restenotic lesions in native coronary arteries.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
Study Design
This study, which was approved by the Ethics Committee of our institution and by the Ministry of Health, was initially designed to be a randomized prospective study enrolling 60 study patients and 60 control subjects. However, we could not randomize the patients because the 188Re isotope was produced only once every 1 to 2 weeks at the Institute of Nuclear Energy Research in Taiwan. Therefore, patient assignment to either irradiation or control groups depended on the availability of 188Re. There was no attempt to match the control group with the irradiation group. Forty study patients who received 14-Gy radiation to a tissue depth of 0.5 mm and 25 control patients were enrolled in the study between August 1999 and August 2000. By the end of August 2000, an interim analysis on 20 study patients who underwent repeat angiography showed a restenosis rate of 50%. The radiation dose then was increased to 20 Gy to a tissue depth of 0.5 mm. Fifteen patients were enrolled into the 20-Gy radiation study, and 5 additional control subjects were enrolled between September 1999 and March 2001. Due to the shortage of the 188W supply, from which the 188Re was generated, the enrollment was halted in March 2001. The National Health Insurance Scheme of Taiwan normally does not cover the cost of intracoronary stenting in most clinical situations. A coronary stent costs the patient about $1,300 to $1,500 (in US dollars), which is a considerable cost for the majority of Taiwanese. Hence, only about 55% of our percutaneous coronary intervention procedures were stent implantations between 1998 and 2002 (there are 1,000 to 1,200 percutaneous coronary intervention procedures performed per year in our 2,400-bed hospital). Most of the patients in our study declined to undergo stent implantation for financial reasons. There was no contraindication of stent placement in any of the patients who enrolled in this study. At the time of registration, patients were evaluated by a radiation oncologist and an interventional cardiologist. After the risks and benefits were discussed with the patients, patients who signed informed consent forms were enrolled in the study. The criteria for enrollment were that the patient had to be >= 50 years of age, had to be clinically required to undergo balloon angioplasty of a native coronary artery (ie, either a de novo or post-POBA restenotic lesion), and had to have a target lesion with a reference vessel between 2.5 and 3.5 mm in diameter and a lesion length of <= 25 mm. Patients were excluded from the study if the final angiographic residual stenosis was > 30% by online quantitative coronary analysis (QCA), if a stent had been implanted, if there was angiographic evidence of a thrombus in the target lesion, or if the patient was premenopausal, had received previously thoracic therapeutic irradiation, had advanced renal failure (ie, serum creatinine level, > 3.0), had a left ventricular ejection fraction of < 25%, had an evolving myocardial infarction currently or within 72 h, or had used thrombolytic or GpIIb/IIIa inhibitors within the previous 48 h. At 1 month and 6 months after the procedure, information with regard to recurrent ischemic symptoms, death, target vessel myocardial infarction, or requirement for revascularization of the treated vessel was collected by chart check, outpatient visit, or telephone contact with the patient. All patients were admitted to the hospital approximately 6 months after undergoing the procedure for repeat coronary angiography.

Procedure
Patients were pretreated with aspirin, 100 mg/d. An IV or intracoronary bolus of 10,000 IU heparin was administered prior to the placement of a 0.014-inch guidewire into the target coronary artery. The POBA balloon sizes were chosen by visual estimation or QCA of the reference vessel diameters. Gradual increments of the percutaneous transluminal coronary angioplasty (PTCA) balloon pressures or sizes were increased to achieve a < 30% residual stenosis by online QCA. The involved lesion was successfully treated if the residual stenosis was < 30% by online QCA. After the successful POBA, media-to-media measurements as an index study were obtained by intravascular ultrasonography (IVUS) for dosing the radiation. The IVUS study was intended only for vessel sizing but not for the determination of the adequacy of the POBA. No further intervention was performed for an unsatisfactory post-POBA result, like dissection or small minimal luminal diameter (MLD) by IVUS study. Irradiation and control procedures were carried out after successful POBA without stenting or the use of any other devices. A perfusion balloon dilatation catheter (Lifestream; Advanced Cardiovascular Systems; Santa Clara, CA) was used in both the 188Re-irradiation and control groups to deliver the radiation and the diluted contrast (placebo), respectively. The size of the perfusion balloon for the delivery of the 188Re isotope was within ± 0.5 mm of the reference vessel diameter by IVUS. The balloon was prepared by applying negative pressure with an empty 10-mL syringe via a three-way valve. The 188Re-filled leaded glass syringe was connected to the balloon by the three-way valve, and the entire proximal balloon inflation structure then was embedded in a leaded acrylic shield (Fig 1 ). The balloon was positioned to cover the target lesion and to match the approximate position of the original angioplasty site in the 14-Gy radiation study group, but the irradiation did not cover the precise length of the vessel exposed to barotrauma from the POBA balloon. In contrast, the irradiation extended at least 2 mm beyond the barotrauma site from the POBA balloon plus a proximal and distal edge zone to avoid a geographic miss in the 20-Gy irradiation study group. Geographic miss was defined as the segments of the target vessel that were injured or touched by the angioplasty balloon receiving a lower radiation dosage due to incomplete coverage of radiation. A tiny amount of 188Re solution (without contrast) was injected into the 10-mL empty syringe on the other side of the three-way valve in order to eliminate the small amount of air present in the system (Fig 1) . The balloon was manually inflated with the 188Re solution at an approximate inflation pressure of 3 atm. Cineangiograms were obtained with contrast injections to verify the position and the full expansion of the balloon. After irradiation, the balloon catheter, guidewire, 10-mL syringe, three-way valve, and 188Re-filled syringe were placed in a plastic bag and put into a lead-shielded container immediately for decay.



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  		Figure 1.. The delivery system consisting of a perfusion balloon catheter (1), a three-way valve (2), a 2.5-mL syringe filled with a 188Re-perrhenate solution shielded by leaded glass (3), an empty 10-mL syringe for receiving a tiny amount of the 188Re solution (without contrast) from the 2.5-mL syringe to eliminate the small amount of air present in the system (4), the base of the leaded acrylic shield (5), and the hatch of the leaded acrylic shield (6).

 
Radiation Source and Dosimetry
188Re is a ß emitter with a maximum transition energy of 2.13 MeV, a mean ß-ray energy of 0.77 MeV, and physical half-life of 17 h. Only 15% of the ß-ray decays are accompanied by 155-keV {gamma}-rays. The carrier-free liquid 188Re was obtained as sodium perrhenate prior to use by the elution of a 188W/188Re generator and was concentrated to 50 to 209 mCi/mL in this study. The 188W was provided by Oak Ridge National Laboratory (Oak Ridge, TN). The generators were prepared from 188W, which was produced by neutron irradiation of enriched 186W metal targets in the High Flux Isotope reactor. The eluted 188Re solution was filtered (Millipore; Billerica, MA), and was checked for sterility and pyrogenicity before use.

When liquid 188Re is used to inflate a balloon catheter, it allows both perfect source centering and intimate contact between the radioactive source and the inner arterial wall, and radial dose symmetry is assured. Because of this "automatic source centering" and the uniformity of a solution source, it is easy to predict the dose from the surface of the balloon, since the dose is only a function of the balloon diameter and specific activity. For a 3-mm diameter balloon, for example, the dose rate at the surface of the balloon for 188Re is approximately 0.14 cGy/s per mCi/mL (ie, 3.78E to 11 Gy/s per Bq/mL), with the dose decreasing to 53% at 0.5 mm. At a specific concentration of 100 mCi/mL (ie, 1.85 x 109 Bq/mL), one is able to deliver 20 Gy radiation at 0.5 mm tissue depth in < 5 min. Using this as a basis of calculation, we could derive the post-POBA 5-min inflation time of the perfusion balloon for the placebo control.

Using a 3.2F catheter, we could obtain the media-to-media measurements of the vessel size at different sites of the target vessel, approximately 5 mm proximal and distal to the lesion and at the lesion itself, by IVUS after the successful POBA. The vessel size data, the length and the nominal size of the perfusion balloon catheter, and the activity of the 188Re were used to calculate the radiation (dwell) times required to deliver 14 Gy or 20 Gy radiation to a tissue depth of 0.5 mm. This corresponded to doses of 26 and 38 Gy, respectively, at the surface of the balloon. The computer treatment-planning program was provided by Columbia University (New York, NY).

Quantitative Coronary Angiography
Angiographic measurements were done with the online QCA image system. Image calibration was performed with a contrast-filled catheter. The external diameter of the catheter was used as the calibration standard. The coronary MLD and the degree of stenosis (ie, the percentage of the diameter) were measured from coronary end-diastolic matched frames in the single worst view obtained before dilatation at the end of the procedure and during follow-up angiography 6 months later (or earlier if there were recurrent symptoms). Restenosis was defined as the presence of stenosis of > 50% of the luminal diameter by on-line QCA at follow-up in a vessel with < 30% residual stenosis immediately after POBA.

Statistical Analysis
Statistical analyses of frequency counts were performed with the use of the {chi}2 test or Fisher exact test for small samples. All tests were two-sided. Differences in numerical variables among the three groups were analyzed by Newman-Keuls multiple comparisons test. Values were reported as the mean ± SD. A p value of < 0.05 was considered to be significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
Between August 1999 and March 2001, 85 patients were enrolled in the study. The first 40 study patients were assigned to the 14-Gy 188Re group, the last 15 study patients were assigned to the 20-Gy 188Re group, and 30 patients were assigned to the control group. Except for patients in the 20-Gy radiation group who had significantly more two-vessel disease than the control group, the three groups had similar baseline clinical and angiographic characteristics (Tables 1 2 3 ). In the 188Re group, the prescribed radiation dose of 14 Gy or 20 Gy at 0.5-mm tissue depth was delivered successfully to all the patients with liquid 188Re via a perfusion dilatation balloon catheter (Lifestream; Advanced Cardiovascular Systems). The mean specific activity of the 188Re was 102 ± 44 mCi/mL (range, 50 to 209 mCi/mL). The mean dwell times were 440 ± 214 s and 823 ± 299 s, respectively, for the 14-Gy and 20-Gy irradiated groups. The dwell time for the control group was 300 s. The treatment was given in a single inflation cycle in all but one patient in the 20 Gy group. No adverse effects of delivering the radiation were observed. All the patients were maintained indefinitely on therapy with aspirin, 100 mg/d. Neither the 14-Gy irradiated patients nor the control patients received clopidogrel or ticlopidine in addition to aspirin after the procedure, but all of the 20-Gy irradiated patients received 250 to 500 mg/d ticlopidine for at least 3 months. No deaths, myocardial infarctions, or reinterventions were found at the 30-day follow-up.


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  		Table 1.. Baseline Clinical Characteristics*

 

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  		Table 2.. Baseline Cardiac Characteristics*

 

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  		Table 3.. Baseline Angiographic Characteristics*

 
The baseline, postprocedure, and 6-month QCA results for the 14-Gy radiation, 20-Gy radiation, and control groups were similar (Tables 4 and 5 ). Angiographic follow-up data were obtained at 6 months in all of the patients in the control group (100%), in 39 of the 40 patients in the 14-Gy 188Re group (98%), and in 14 of the 15 patients (93%) in the 20-Gy 188Re group. One patient in the 14-Gy radiation group refused follow-up angiography and remained asymptomatic 18 months after the procedure. One patient in the 20-Gy radiation group underwent amputation of his ischemic leg in another hospital, and did not come for repeat coronary angiography and remained asymptomatic 12 months after the procedure. The mean time to angiographic follow-up was 5.8 ± 2.0 months in the 14-Gy radiation group, 5.9 ± 0.6 months in the 20-Gy radiation group, and 6.4 ± 1.7 months in the control group. On follow-up angiographic examination, there was total occlusion of the vessel in 3 of the 39 patients (7.7%) who had received 14-Gy irradiation, in 1 of the 30 control patients (3.3%), but none in the 20-Gy irradiated group (0%). Of the three patients in the 14-Gy irradiated group with occlusion, two were found to have unstable angina, at 2 and 4 months after the procedure. One patient in the 14-Gy irradiated group and 1 patient in the control group had silent total occlusion of the target vessel, which was discovered at the 6-month angiographic examination. Angiographic restenosis (ie, >= 50% stenosis of the luminal diameter) either within the lesion or at its edge (5 mm beyond the proximal and distal approximate location of the previous angioplasty balloon) was observed in 49% of the 14-Gy irradiated patients, in 21% of the 20-Gy irradiated patients, and in 53% in the control groups (p = 0.05, 20-Gy radiation group vs control group). Restenosis limited to the edge occurred in only one patient in the 14-Gy radiation group.


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  		Table 4.. Baseline and Postprocedure Quantitative Angiographic Results*

 

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  		Table 5.. 6-Month Quantitative Angiographic Results*

 
Subgroup analyses were performed on the effect of the degree of calcification of the lesions on the 6-month angiographic restenosis rate (Table 6 ). Six-month target lesion angiographic restenosis of the lesions with an arc of calcification of >= 270° occurred in four of the four lesions (100%) in the 14-Gy radiation group and in three of the three lesions (100%) in the 20-Gy radiation group. Only one lesion with an arc of calcification of >= 180° and <270° in the 14-Gy radiation group had no restenosis. No lesions were found to have arc of calcification >= 180° and <270° in the 20-Gy radiation group. Six-month target lesion angiographic restenosis of the lesions with an arc of calcification of >= 90° and <180° occurred in one of the two lesions (50%) in the 14-Gy radiation group and in none of the four lesions (100%) in the 20-Gy radiation group (difference not significant). Six-month target lesion angiographic restenosis of the lesions with an arc of calcification of < 90° occurred in 14 of the 32 lesions (44%) in the 14-Gy radiation group and in none of the 7 lesions (0%) in the 20-Gy radiation group (p = 0.029). Six-month target lesion angiographic restenosis of the lesions with an arc of calcification < 180° occurred in 15 of the 34 lesions (44%) in the 14-Gy radiation group and in none of the 11 lesions (0%) in the 20-Gy radiation group (p = 0.007).


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  		Table 6.. Subgroup Analysis*

 
Subgroup analyses on a reference vessel diameter of < 3.0 mm and >= 3.0 mm were performed (Table 7 ). Six-month target lesion angiographic restenosis of a vessel with a reference diameter of < 3.0 mm occurred in 11 of the 24 lesions (46%) in the 14-Gy radiation group, in 1 of the 8 lesions (13%) in the 20-Gy radiation group, and in 8 of the 11 lesions (73%) in the control group (p = 0.02, 20-Gy radiation group vs control group). Six-month target lesion angiographic restenosis of a vessel with a reference diameter of >= 3.0 mm occurred in 8 of the 15 lesions (53%) in the 14-Gy radiation group, in 2 of the 6 lesions (33%) in the 20-Gy radiation group, and in 10 of the 19 lesions (53%) in the control group (difference not significant).


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  		Table 7.. Subgroups Analysis*

 
Subgroup analyses on the de novo lesions and post-POBA restenotic lesions were performed (Table 7) . Six-month target lesion angiographic restenosis of the de novo lesions occurred in 15 of the 32 lesions (47%) in the 14-Gy radiation group, in 3 of the 8 lesions (38%) in the 20-Gy radiation group, and in 13 of the 24 lesions (54%) in the control group (difference not significant). Six-month target lesion angiographic restenosis of the post-POBA restenotic lesions occurred in four of the seven lesions (57%) in the 14-Gy radiation group, in none of the six lesions (0%) in the 20-Gy radiation group, and in 5 of the 6 lesions (83%) in the control group (p = 0.008, 20-Gy radiation group vs control group; p = 0.027, 20-Gy radiation group vs 14-Gy radiation group).

Clinical Events
Six-month clinical follow-up data were obtained for all patients (Table 8 ). One patient in the 14-Gy radiation group sustained a myocardial infarction on day 46. After angiographic examination showed a tight stenosis at the target lesion, a stent was implanted. In the 14-Gy radiation group, two patients who had total occlusions of the vessel underwent subsequent bypass surgery. No other myocardial infarctions, bypass surgery, or deaths occurred. At the 6-month follow-up, 13 patients in the 14-Gy radiation group, 3 patients in the 20-Gy radiation group, and 13 patients in the control group underwent percutaneous interventions of the target lesion. In the 14-Gy radiation group, eight patients received stent implantations and five underwent POBA. In the 20-Gy radiation group, all three patients received stent implantations, and in the control group five patients received stent implantations, three patients underwent POBA, and five patients received post-POBA brachytherapy with 188Re. Four of the five patients in the control group who crossed over to intracoronary brachytherapy after post-POBA restenosis received 14-Gy irradiation, and the others received 20-Gy irradiation. Only one of the four patients receiving 14-Gy 188Re had angiographic restenosis at 6 months. The patient who received 20-Gy irradiation had no restenosis. Target vessel revascularization was required in 15 of the 39 patients in the 14-Gy radiation group (38%), 3 of the 14 patients in the 20-Gy radiation group (21%), and 13 of the 30 patients in the control group (43%). The composite clinical end points of the patients in the 14-Gy radiation group (40%), the 20-Gy radiation group (20%), and the control group (43%) had no significant difference.


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  		Table 8.. Clinical Events at 6-Month Follow-up*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
This intracoronary brachytherapy study included patients who had either de novo or post-POBA restenotic lesions and who were undergoing POBA of the native coronary artery without stent implantation or the use of any other devices. We also enrolled patients who had received 5-min perfusion balloon inflation after successfully undergoing POBA as a contemporaneous placebo-control group. True randomization was prohibited because the 188Re isotope was available only at certain times. The initial dose (14 Gy) prescribed in this study was derived from the animal studies conducted by Waksman et al4 and Makkar et al.5 In the study by Waksman et al,4 ß-irradiation doses between 7 and 56 Gy at a 2-mm tissue depth showed evidence of inhibition of neointima formation. Makkar et al5 demonstrated that measurable dose-dependent inhibition of intimal hyperplasia was achieved with a 188Re balloon that delivered 16 Gy radiation prior to stenting at a tissue depth of 0.5 mm in porcine coronary arteries. However, in the study by Makkar et al5 the effect of the radiation doses of < 16 Gy on neointimal formation was not investigated. The dose of 14 Gy at a 0.5-mm tissue depth in this study was cautiously selected to avoid possible pseudoaneurysm formation caused by excessive radiation. While we were conducting this study with the 14-Gy radiation dose, a clinical study by Hoher et al,16 using a 188Re-filled balloon, revealed a total restenosis rate of 46%, mainly due to edge stenoses. Likewise, our own interim analysis of 20 of the 40 study patients enrolled showed a 50% 6-month angiographic restenosis rate. Thus, a raise in the radiation dose to 20 Gy at a 0.5-mm tissue depth and the application of a longer balloon to prevent the geographic miss then was employed. At our 6-month follow-up, 95% and 100%, respectively, of the restenoses after irradiation with 14-Gy and 20-Gy were intralesion restenoses. In contrast, edge stenosis was the main cause (75%) of restenosis after irradiation in the study conducted by Hoher et al16 using the same isotope delivered at 15 Gy at a 0.5-mm tissue depth. Their study reported that 68% of their patients had undergone stent implantation and that the restenosis rate was lower in cases of stented de novo stenoses.1 The intralesion restenosis rate of 12% in the study by Hoher et al16 might have been due to the effect of the stent itself. The lack of effect on the total restenosis rate might be attributed to the low radiation dose used in both our 14-Gy radiation group and in the study by Hoher et al.16 When a dose of 20 Gy was used and the longer irradiation segment was used to cover the geographic miss, the 6-month target lesion restenosis rate in our study was significantly lower than that of the control subjects (20% vs 57%, respectively; p = 0.05). The reduction of the composite end points of death, myocardial infarction, and target-vessel revascularization with 20-Gy irradiation was not statistically significant and was found mainly in target-vessel revascularization.

Some studies have suggested that smooth muscle cells from the adventitia and the progenitor cells from the media play a role in the restenosis process.17 18 19 However, multiple factors like the dose gradient of the isotopes, the location and volume of the residual plaque, and the presence of calcification or stents might influence the homogeneity of dose distribution and the outcome of the irradiated lesions after balloon angioplasty. The heavy plaque-loaded lesions (mean stenosis, 80 ± 6%) of our patients’ coronary arteries rendered ineffective the predetermined effective dose of 14 Gy, which was derived from the overstretched normal porcine coronary artery without any plaque burden. One study20 has shown that the actual dose received by the adventitia varied considerably between coronary subsegments and the remnant plaque burden is a powerful predictor of outcome. All the severely calcified lesions with an arc of calcification of >= 270° in four of the 14-Gy radiation patients and in three of the 20-Gy radiation patients had restenosis. The ß-irradiation shielding effect of the calcium and the application of excessive barotrauma to dilate the severe calcified lesions (ie, arc of calcification, >= 270°) in our patients might have led to exuberant intimal hyperplasia without adequate inhibition by irradiation. The lesions with an arc of calcification of < 180° in our 20-Gy radiation patients were free of significant restenosis, a finding similar to that of Sabate et al,20 who found that the effects of the attenuation of irradiation induced by hard material (either containing calcium <= 90° of circumferential arc or mixed noncalcified tissue excluded the diffuse calcified lesions) may be negligible compared with that of soft tissue, because the degree of remodeling was similar between the different type of tissue. Although it is ideal to have a uniform dose delivered to the vessel wall, the eccentricity of the residual plaque in the vessel wall might render the various centering devices ineffective in providing real centering. Nevertheless, treating 10 patients with balloon angioplasty followed by intracoronary ß-irradiation, Carlier et al21 demonstrated that the prescribed dose was obtained in 60% of the adventitia after centering the source in the lumen compared to the 35% with the noncentering source. ß-emitters have more falloff, because of their shorter range of electrons, than does {gamma}-irradiation, so centering the ß-irradiation source in the lumen becomes crucial in the treatment process.

Smaller vessels have been associated with a high rate of restenosis. In our study, 6-month target lesion angiographic restenosis of the vessel with a reference diameter of >= 3.0 mm occurred in 8 of the 15 lesions (53%) in the 14-Gy radiation group, in 2 of the 6 lesions (33%) in the 20-Gy radiation group, and in 10 of the 19 lesions (53%) in the control group (difference not significant). Lesions with a reference vessel diameter of < 3.0 mm in the control group had a 73% (8 of 11 lesions) restenosis rate compared with a restenosis rate of 46% (11 of 24 lesions) in the 14-Gy radiation group and a restenosis rate of 13% (1 of 8 lesions) in the 20-Gy radiation group (difference not significant, control group vs 14-Gy radiation group, 37% reduction; p = 0.02, 20-Gy radiation group vs control group). Although the difference in the restenosis rate between the control group and the 14-Gy radiation group in vessels < 3.0 mm in diameter was not statistically significant, the decrease in the restenosis rate might have been due to the closer proximity of the intended target for irradiation in smaller vessels. The restenosis rate of the 20-Gy radiation group was 33% (two of the six lesions) in lesions with a reference vessel diameter of < 3.0 mm and was 13% (one of the eight lesions) in lesions with a reference vessel diameter of >= 3.0 mm. However, all three of the restenoses in the 20-Gy radiation group occurred in lesions with severe calcification (arc of calcification, >= 270°).

In our study, 6-month target lesion angiographic restenosis of de novo lesions occurred in 15 of the 32 lesions (47%) in the 14-Gy radiation group, in 3 of the 8 lesions (38%) in the 20-Gy radiation group, and in 13 of the 24 lesions (54%) in the control group (difference not significant). There was restenosis in three of the eight de novo lesions (38%) in the 20-Gy radiation group, and all three lesions had an arc of calcification of >= 270°. None of the five lesions (0%) without severe calcification among the de novo lesions in the 20-Gy radiation group had restenosis. In the balloon angioplasty-only group of the BetaCath trial, the largest brachytherapy trial on de novo lesions using the solid form of ß-emitter Sr/90Y was delivered via a noncentered 5F catheter.22 The 8-month angiographic analysis showed a statistically significant decrease in in-lesion restenosis (34.3% vs 21.4%, respectively; p = 0.003), but the edge failures erased any benefits from irradiation.22 No edge failure occurred in the 20-Gy radiation group of our study because the irradiation was extended at least 2 mm beyond the barotrauma site from the POBA balloon plus a proximal and distal edge zone to avoid a geographic miss. The system used for intraarterial ß-irradiation therapy in the Geneva randomized dose-finding study23 consisted of a solid 90Y coil, a centering balloon, and an automated delivery device. It randomized patients with de novo lesions to receive 9, 12, 15, and 18 Gy at 1 mm from the balloon surface.23 In 129 patients treated with balloon angioplasty without a stent, restenosis rates were 28%, 17%, 16%, and 4%, respectively (p = 0.02, 9 Gy vs 18 Gy).23 Our study also showed a dose-dependent decrease in the rate of restenosis in de novo lesions after angioplasty. Six-month target lesion angiographic restenosis of the de novo lesions without severe calcification (ie, an arc of calcification of >= 270°) occurred in 11 of the 28 lesions (39%) in the 14-Gy radiation group, and in none of the 5 lesions (0%) in the 20-Gy radiation group. The lower restenosis rates, compared with stent implantations, in patients with good angiographic results after balloon angioplasty alone in the GENEVA study and in our study, suggest that the possibility of ß-irradiation as a first-line adjunct to balloon angioplasty in the treatment of de novo disease must be explored further.

Restenotic lesions have been associated with a higher rate of restenosis. The post-POBA restenotic lesions in our control group had an 83% restenosis rate (five of six lesions) compared with a restenosis rate of 57% (four of seven lesions) in the 14-Gy radiation group. There was a restenosis rate of 0% in the six lesions in the 20-Gy radiation group (p = 0.027, 20-Gy radiation group vs 14-Gy radiation group; p = 0.008, 20-Gy radiation group vs control group). Our study has shown a remarkable reduction of restenosis in the non-in-stent restenotic lesions. Currently, the US Food and Drug Administration has approved two devices for the delivery of intracoronary irradiation after effective percutaneous intervention of in-stent restenosis, but none for nonstented restenotic lesions. Further investigations will be needed to define the value of intracoronary brachytherapy in patients with non-in-stent restenotic lesions.

The rate of late total occlusion (ie, > 30 days after the procedure) in patients undergoing intracoronary brachytherapy has been found to be relatively high, especially in patients with in-stent restenosis.24 25 This phenomenon is more pronounced after restenting. In our trial, 3 of the 39 188Re patients (7.7%) had late total occlusions. Two of these patients experienced unstable angina, and the other patient had silent occlusion. One patient in the 188Re group sustained an acute myocardial infarction at 46 days postprocedure due to target lesion thrombosis. The angiographic examination performed 12 h after the myocardial infarction showed a tight stenosis of the previous target lesion site with a flow of Thrombolysis in Myocardial Infarction grade III. This might represent a spontaneous reperfusion process. If the myocardial infarction case was considered to be a late total occlusion, then the late total occlusion rate in the 14-Gy 188Re group was 10%. Only one silent late occlusion occurred in 30 patients (3%) in the placebo group, and none occurred in the 20-Gy 188Re group. Although the late total occlusion was not statistically significant, the adjunct antiplatelet therapy with ticlopidine that was used in our 20-Gy irradiation patients might have prevented this potentially disastrous complication. Therefore, a double antiplatelet regimen (ie, aspirin plus ticlopidine or clopidogrel) also is recommended for nonstented postintracoronary brachytherapy lesions.

Compared to the solid ß-sources using expensive afterloading devices, the 188Re-filled balloon system can be used with the standard PTCA technology. However, it is vital to note the risk of leakage and spillage outside the target area in the use of the radioisotope-filled balloon system. In this study, no external spillage or internal leakage had occurred. Perfusion balloon catheters (Lifestream; Advanced Cardiovascular Systems) were used in all our patients to allow prolonged inflation of the balloon and to maintain distal perfusion of the coronary artery during the radiation treatment. All manufacturers currently submit data supporting a rated burst pressure, which is defined as a 95% confidence of maintaining 99% integrity at the rated burst pressure. Thus, an upper limit on burst frequency of < 1% is guaranteed. Since the target lesions in our study were successfully dilated prior to the radiation treatment, and since the balloon used to deliver the 188Re was only hand-inflated to approximately 3 atm pressure, the frequency of balloon rupture should be even lower.


   Conclusions
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
Catheter-based radiotherapy after POBA in nonstented native coronary artery with a 188Re-filled balloon is effective in reducing target lesion restenosis with 20-Gy radiation at 0.5-mm tissue depth and seems to be more effective in lesions with an arc of calcification of < 180°, in vessels with a reference diameter of < 3.0 mm, and in post-POBA restenotic lesions.


   Acknowledgements
 
The authors appreciate the efforts of the catheterization laboratory staff, Mr. Wei-Dih Chang and Ms.Yui-Jiao Liao. We thank Mr. Ching-Jen Liu and the personnel of the Institute of Nuclear Energy Research for their assistance with the delivery of the isotope and the procedures. We are indebted to Howard Amols, PhD, Cheng-ShinWuu, PhD, and Judith Weinberger, MD, PhD, for generously providing the computer software for dwell-time calculations and for enthusiastically offering technical assistance.


   Footnotes
 
Abbreviations: IVUS = intravascular ultrasonography; MLD = minimal luminal diameter; POBA = pure balloon angioplasty; PTCA = percutaneous transluminal coronary angioplasty; QCA = quantitative coronary analysis

This research was supported in part by a grant from the Chang Gung Memorial Hospital Medical Center and a grant from the Institute of Nuclear Energy Research, Taiwan, Republic of China.

Received for publication October 8, 2002. Accepted for publication February 26, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

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