Progress in clinical trials for coronary arterial restenosis using beta radiation sources

Cardiovascular Radiation Medicine 1:3 (1999) 220–226

CLINICAL ORIGINAL ARTICLE

PROGRESS IN CLINICAL TRIALS FOR CORONARY ARTERIAL RESTENOSIS USING BETA RADIATION SOURCES Ron Waksman, M.D., F.A.C.C.a,b,* a

Experimental Angioplasty and Cardiovascular Brachytherapy Program, Washington Hospital Center, Washington, DC, USA bDepartment of Medicine (Cardiology), Georgetown University, Washington, DC, USA Received 9 September 1999; accepted 14 September 1999

Vascular brachytherapy has yet taken the leap into progression from emerging technology to standard of care dependent on the outcome of clinical trials. Data collected from early pilot trials and on-going clinical trials indicate that such a progression is achievable. Three-year follow-up data from patients treated with intracoronary radiation for the prevention of restenosis are now available. Data from larger trials are being assessed using angiographic and intravascular ultrasound analysis. The beta radiation studies are demonstrating different levels of efficacy, raising new issues regarding dosimetry and potential complications. Past trials have examined the use of vascular brachytherapy for recurrence prevention of restenosis in patients with in-stent restenosis. New data related to the use of liquid-filled balloon systems and radioactive stent are also being collected. This article updates the current status of clinical trials in vascular brachytherapy utilizing beta emitters, highlighting preliminary results and assessing their implications for the development of this field. © 1999 Elsevier Science Inc. Keywords: Beta radiation; Restenosis; Clinical trials.

Introduction The merits of introducing beta emitters to the field of vascular brachytherapy were to provide cardiologists with a user-friendly system compatible with the catheterization laboratory environment with minimum radiation exposure to the operator and to the patient. In addition, the limited penetration of beta emitters would localize the radiation to the treatment site and minimize the adverse effects of radiation to the heart. Over the past 7 years, engineers and technologies adapted beta emitters and calculated the right dosimetry, designed sources, catheters, and afterloader to deliver beta radiation into the coronary arteries to be used clinically for * Correspondence to: Ron Waksman, M.D., Vascular Brachytherapy Institute, Washington Hospital Center, 100 Irving St. NW, Suite 4B-1, Washington, DC 20010, USA; E-mail: [email protected]. 1522-1865/99/$–see front matter. © 1999 Elsevier Science Inc. PII S1522-1865(99)0 0027- X

the application of restenosis prevention. However, the ultimate test for any of these emerging technologies before becoming a standard of care depends on performance and outcome of the clinical trials. At the end of 1999, we have completed the feasibility studies utilizing beta sources and are currently testing the efficacy of these devices in multicenter, randomized, clinical trials. During the feasibility trials we have identified two major complications of the technology: edge effect and late thrombosis. As a result of these findings, the treatment strategies in the pivotal studies have been implemented (longer coverage of the lesion and prolonged antiplatelet therapy). Despite the differences in the initial trial designs, in the last year more trials have focused on examining the effectiveness of vascular brachytherapy for the prevention of recurrences in patients with in-stent restenosis. The controversy of beta vs. gamma, centering vs. noncentering de-

R. Waksman / Cardiovascular Radiation Medicine 1:3 (1999) 220–226

livery systems, and manual vs. automatic afterloader is ongoing. Meanwhile, new data related to the use of liquid-filled balloon systems and radioactive stent as platforms for beta emitters are being collected. This overview is an update on the current status of the clinical trials in vascular brachytherapy using beta emitters, and an attempt to discuss the preliminary results of these studies and their implications for the progress of this field. Beta Isotopes and Systems Utilized in the Coronary System A variety of beta isotopes, catheter delivery systems, and afterloaders are being tested in clinical trials of vascular brachytherapy. A list of the beta isotopes and systems is provided in Table 1. Different configurations of beta sources are available, among them are wire or seed solid sources, liquid sources, and the radioactive stent. Different types of delivery radiation catheters are available; the noncentered catheter (Novoste, Norcross, GA) vs. centered catheter designs either by helical (Guidant, Santa Clara, CA) or segmented balloon (Boston Scientific, Namic, MA). Among the afterloaders there are the manual hydraulic device of the BetaCath system (Novoste) vs. the automatic afterloaders (Guidant and Boston Scientific). The liquid-filled balloons use a sealed syringe and the radioactive stent is mounted on a balloon catheter. Beta trials for de novo lesions The clinical trials (Table 2) using beta emitters have been designed to examine the feasibility, safety, and efficacy of beta-radiation therapy for prevention of restenosis initially for de novo lesions in native coronaries and later for the treatment or prevention of restenosis. The Geneva experience. In this study, the safety of

221

Yttrium 90 source and a centering balloon following percutaneous transluminal coronary angioplasty (PTCA) in de novo lesions were examined in a small cohort of 15 patients. The prescribed dose in this trial was 9 Gy at 1 mm from the surface of the centering balloon to the vessel wall. The investigators demonstrated feasibility and safety of the radiation system. However, the outcome of this study was disappointing because 5 of 15 patients in this trial experienced angiographic and clinical restenosis [1]. The investigators related their results to insufficient dose delivered to the adventitia (,5 Gy). Importantly, patients from this study who presented with a patent artery at follow-up were studied at 2 years after radiation and found to be free of adverse clinical and angiographic events related to the radiation treatment. The dose-finding study. A multicenter study in Europe to determine the effective dose using the Y-90, the centering balloon, and the automatic afteloader was initiated in 1997. Doses of 9, 12, 15, and 18 Gy at 1 mm from the surface of the balloon were examined in 160 patients. The patients and the investigators were blinded to the dose, the patients underwent 6 months of angiographic follow-up, and the results were presented in the European Heart Congress in Barcelona in August 1999. A dose response was demonstrated from 8.3% angiographic restenosis with the highest dose of 18 Gy to a 28% restenosis rate in the lowest dose of 9 GY. The intermediate doses of 12 and 15 Gy were associated with similar restenosis rates of 15.8% and 17.5%. The late thrombosis rate in this study was about 10% and angiographic edge effect was not demonstrated. Beta energy restenosis trial (BERT). BERT is a feasibility study approved by the FDA limited to 23 patients in two centers (Emory and Brown Universities). The study was designed to test the 90Sr/Y source delivered by hydraulic system (Novoste). The prescribed doses

Table 1. Beat emitters and systems used for catheter-based vascular brachytherapy Energy maximum (MeV)

Energy average (MeV)

29 yr

2.28

0.93

50 mCi

Y-90

64 h

2.28

0.93

50 mCi

P-32

14 days

1.71

0.69

40 mCi

Re-186

90 h

1.08

0.38

300 mCi

Re-188

17 h

2.12*

0.77*

100 mCi

P32

14 days

1.71

0.69

Isotype

Half-life

Sr/Y-90

*Beta energy only.

Activity required

1–20 mCi

Delivery/catheter

Afterloader

Noncentered/ Novoste Segmented balloon/ Boston Scientific Helical balloon/ Guidant Galileo Balloon (liquid) Mallinckrodt Balloon (liquid) Guidant Saber BX-stent/ Isostent

Manual Betacath Automatic Betamed Automatic Manual MARS Manual Manual Isostent

222

R. Waksman / Cardiovascular Radiation Medicine 1:3 (1999) 220–226

Table 2. Clinical trials using catheter-based systems with beta emitters in coronaries Principal investigator/ sponsor

Study name and design

Radiation system

Isotope and dose

Verin/ Schneider

Geneva Open label in 15 patients after PTCA in de novo lesions

King Novoste

BERT Open label in 23 patients post PTCA in de novo lesions

Mechanical loading of 0.014” 29-mm fixed wire via a segmented, centered 30mm balloon (2.5–4 mm) Hydraulic hand delivery of a train of 12 radioactive seeds (30 mm) in a noncentered 5.0 F catheter

90-Y 18 Gy to the surface of balloon 90-Sr/Y 12, 14, 16 Gy to 2 mm from source

Serruys/ Novoste

BRIE European registry in 150 patients after PTCA up to 2 vessels BETACATH Multicenter, randomized, blinded study in 1,100 patients after PTCA and provisional stenting Dose findings European, multicenter, open-label study in 160 patients after PTCA

Novoste BetaCath system

90-Sr/Y 14, 18 Gy to 2 mm from the source 90-Sr/Y 14, 18 Gy to 2 mm from the source

Automatic afterloader (ITS) of 0.014” 29-mm fixed wire via a centered balloon (Schneider)

Raizner/ Guidant

PREVENT Multinational, open-label feasibility study in 80 patients after PTCA or stenting

Automatic afterloader (Nucletron) if 0.018” 27mm fixed wire via a helical centering balloon 2.5–4.0 mm 30-mm length

Weinberger/ Columbia University

CURE Registry open label in 30 patients post-PTCA and 30 before stenting

Liquid 188-Re from a generator (Oak Ridge) fills a perfusion coronary balloon Lifestream™

Waksman/ CRF

BETA WRIST Registry for 50 patients with in-stent restenosis

Schneider System 90-Y source centering balloon and an afterloader

Waksman*/ Guidant

INHIBIT Multicenter for 320 patients with in-stent restenosis

Hueser*/ Novoste

START Multicenter for patients with in-stent restenosis

Automatic afterloader (Nucletron) 0.018” 27-mm fixed wire via a helical centering balloon Novoste BetaCath system lesions up to 30 mm in length

De Schreder*/ Mallinckrodt

MARS Two centers registry for nonstented lesions

Kuntz*/ Novoste

Verin*/ Boston Scientific

Novoste BetaCath system

Liquid-filled balloon; delivered manually

90-Y 9, 12, 15, 18 Gy at 1 mm from balloon 32-P 16-20-24 Gy to 1.0 mm from balloon surface 188-Re 20 Gy on the vessel wall 90-Y 20.6 Gy to 1.0 mm distance 32-P 20 Gy to 1.00 mm from source Sr/Y90 18–20 Gy at 2 mm 186-Re

Results and status Completed. Demonstrated feasibility & safety, with no apparent effectiveness, restenosis rate (45%). Completed. Demonstrated feasibility & safety, restenosis rate of 15% with late loss of 0.05 mm and loss index of 4%. Interim results: reported target vessel restenosis of 30%, late loss index for the total population 5 13%. Study initiated in July 1997, currently conducted in 35 centers in the US and enrollment completed in September of 1999. Restenosis rate of 28% in the low dose of 9 Gy, 15% in the intermediate doses of 12 and 15 Gy, and 8.3% in the high dose of 18 Gy. Enrollment completed in May 1998, demonstrated safety at 30 days, lower late loss and TLR in the irradiated group. Multicenter, randomized, blinded study to follow. Initiated in October 1997, enrollment of 30 patients was completed, demonstrating safety with TLR rate of 17% at 6 months. Enrollment completed in June of 1998, demonstrated safety at 30 days, restenosis of 22% at 6 months. Initiated in June 1998, safety was demonstrated at 30 days. Enrollment will be completed by December 1999. Initiated in September 1998, enrollment is complete. Results will be available March 2000. Initiated in December 1998, terminated after 30 patients. Results will be available March 2000.

BERT 5 Beta Energy Restenosis Trial; PTCA 5 percutaneous transluminal coronary angioplasty; BRIE 5 Beta Radiation in Europe; PREVENT 5 Proliferation Reduction with Vascular Energy Trial; CURE 5 Columbia University radiation energy; BETA WRIST 5 Beta Washington Radiation for In-Stent Restenosis Trial; INHIBIT 5 Intimal Hyperplasia Inhibition with Beta In-Stent Trial; START 5 Stents and Radiation Therapy; MARS 5 Mallinckrodt Angioplasty Radiation study. *Data are not available

in this study were 12, 14, or 16 Gy and the treatment time did not exceed 3.5 min. The radiation was delivered successfully to 21 of 23 patients following conventional PTCA without any complications or

adverse events at 30 days. At follow-up two patients at 6 months and one patient at 9 months underwent repeat revascularization to the target lesion [2]. The Canadian arm of this study was included 30 patients

R. Waksman / Cardiovascular Radiation Medicine 1:3 (1999) 220–226

from the Montreal Heart Institute and included intravascular ultrasound analysis [3, 4]. The European arm BERT 1.5 was conducted at the Thoraxcenter in Rotterdam in an additional 30 patients utilizing the same system under the same protocol; the reported restenosis rate was 26% [5]. At 6 months follow-up, the angiographic restenosis for the entire cohort of 84 patients was 17% with a late loss rate of 9%. However, 6 more patients required revascularization due to edge effect. BETACATH. The BETACATH trial was initiated in July 1997 as a prospective , randomized, placebocontrolled trial to evaluate the safety and effectiveness of the 90Sr/Y BetaCath system vs. placebo in de novo or restenotic lesions of native coronary arteries. A total of 1,100 patients undergoing elective PTCA or provisional stent placement have been enrolled in more than 35 centers and the angiographic follow-up at 8 months will be available by the spring of 2000. An additional 300 patients were added to the stent arm of the study due to higher rates of late thrombosis that were observed in one of the treated groups and that required a change in the antiplatelet protocol. The results of this study will determine the use of this technology for prevention of restenosis for de novo lesions. Beta radiation in Europe (BRIE). BRIE is a registry of 180 patients who were enrolled in nine sites in Europe. In this trial, treatment of up to two vessels was allowed with the BetaCath system using the 90 Sr/Y source doses 14 and 16 Gy. The primary angiographic endpoints of the BRIE registry were target lesion revascularization, and late loss index measured at 6 months. An interim report of the first 90 patients with 98 lesions who returned for angiographic follow-up evaluation was reported in the European Heart Congress in Barcelona in August of 1999. Target vessel revascularization for the entire cohort of patients was 30%, with 19% in the PTCA subgroup and 35% in the stent group. The late loss index for the total population was 12%, with 3% in the PTCA subgroup and 17% in the stent group. The main problem in this study was incomplete coverage of the treated area subjected to trauma “geographical miss,” which was found in 40% of the treated lesions. Proliferation reduction with vascular energy trial (PREVENT). PREVENT is a prospective, randomized, blinded, multinational, multicenter study. Its objective is to demonstrate the safety of the Guidant beta radiation system in human coronaries immediately following PTCA or a stent placement. The system consists of 32P isotope, 27 mm in length delivered into a centering helical balloon delivery

223

catheter via an automatic afterloader apparatus. The doses used in this open-label phase are 16, 20, and 24 Gy prescribed to 1 mm from the source. The feasibility phase of the study was completed in May 1998. The preliminary results suggested low rates of late loss in the irradiated group: 4.8% compared with control 51.3% with significant reduction for the need for target lesion revascularization (4% vs. 18%). However, due to an increase of edge effect the target lesion revascularization rates were similar in the treated vessels (24% vs. control 29%) [6]. Subanalysis of patients with in-stent restenosis treated with P-32 demonstrated lower rates of recurrences (20%) compared with a matched control group from the Washington Radiation for In-Stent Restenosis Trial (WRIST) (66%). Columbia University radiation energy (CURE). CURE is the first liquid-filled balloon system used in a feasibility clinical trial for 30 patients after balloon angioplasty or 30 patients who undergoing intracoronary stenting. The study was initiated in Columbia University (New York, NY) under an institutional investigational device exemption (IDE). The isotope in the liquid form is 188-Re retrieved from a 188-tungsten generator injected via syringe into a perfusion balloon (Lifestream™ Guidant) to allow dwell times of up to 10 min. No data on the feasibility and the safety of this system have been reported yet. Target lesion revascularization was reported in 5 of the 30 patients treated in this cohort (17%) [7]. Mallinckrodt angioplasty radiation study (MARS). MARS is a multicenter feasibility study using a liquid Re-186 beta-emitter source for prevention of restenosis in de novo and restenotic lesions. The study was initiated in two centers in Europe. Enrollment was stopped after 30 patients and angiographic follow-up will be completed by February 2000. Beta trials for in-stent restenosis lesions Studies to examine the effectiveness of beta-radiation systems to prevent recurrence of in-stent restenosis has been launched, among them BETA WRIST (90Y), INHIBIT (32P), and Stents and Radiation Therapy (START) (90Sr/Y). These studies are similar in design and aim to address the efficacy of beta emitters for the treatment of restenosis. It is hoped that approval for marketing in the US can be expedited. BETA WRIST. BETA WRIST is the first study to report about the efficacy of beta radiation for prevention of in-stent restenosis. This is a registry of 50 patients undergoing treatment for in-stent resteno-

224

R. Waksman / Cardiovascular Radiation Medicine 1:3 (1999) 220–226

Figure 1. Candy wrapper edge effect of a radioactive stent 4 months following implantation. Courtesy of Antonio Colombo, M.D., Columbus Hospital, Milan, Italy.

sis in native coronaries and treated with a beta radiation system using the Yttrium-90 source, a centering catheter, and an afterloader system. The clinical outcome of these patients was compared with the control group of the original cohort of WRIST who were randomized to placebo vs. Ir-192. In BETA WRIST, the reported angiographic restenosis rate at 6 months was 22%; about 10% of the patients had late thrombosis. The overall the use of beta radiation for the treatment of in-stent restenosis demonstrated a more than 50% reduction in the need for target lesion or vessel revascularization compared with the historical control of WRIST. A comparison of the outcome of the irradiated beta with the gamma group did not detect major differences between these two groups [8]. This study suggested that treatment with beta emitters for in-stent restenosis may have a similar outcome as shown with gamma emitters. An example of a patient from the BETA WRIST study is presented in Fig. 1. Stents and radiation therapy trial (START). This is an FDA pivotal, multicenter, randomized trial in more than 55 centers in the US and Europe that will determine the efficacy and safety of the BetaCath system for the treatment of in-stent restenosis. The dose in this trial is 16 or 20 Gy at 2 mm from the center of the source depending on vessel diameter. The enrollment of 385 patients was completed and results will be available in the spring of 2000. START 40/20. START 40/20 is a registry of 200 patients in the US to determine the efficacy of longer

source trains for the treatment lesions up to 20 mm. Inclusion/exclusion criteria for this study are similar to that for the START study. INHIBIT. INHIBIT is a multicenter, randomized study in the US and Europe for patients with in-stent restenosis to test the efficacy of the GALILEO system using a P-32 source with a dose of 20 Gy at 1 mm from the surface of the balloon. The antiplatlet therapy for this study is prescribed for 3–6 months and all patients will undergo angiographic followup at 8 months. The study was initiated in July of 1998 and enrollment will be completed by December 1999. So far, the lessons from the beta feasibility studies have been that (1) the radiation effect is confined to the length of the source and (2) longer beta sources are required to cover the entire segment undergoing intervention to eliminate the edge effect phenomenon. Radioactive b-emitting stents The clinical trials with radioactive stent have demonstrated safety but were disappointing in efficacy. The isotope examined on this radioactive stent is P-32 and the platform was either the Palmaz-Schatz PS 153 or the BX stent. Isostent for restenosis intervention study (IRIS). IRIS was the first feasibility study using the radioactive 32-P Palmaz Schatz stent (Isostent, San Carlos, CA). In this study, 30 patients with stenosis in de novo or restenotic lesions of native coronaries underwent radioactive stent implantation (activity between 0.5

R. Waksman / Cardiovascular Radiation Medicine 1:3 (1999) 220–226

and 1.0 mCi) with a mean stent activity of 0.69 mCi. There were no adverse effects at 30 days in any of the treated patients; however, at the 6-month angiographic follow-up there was a binary restenosis rate of 31% and clinical-driven target lesion revascularization of 21%. Late loss data by segment was 0.94 mm for de novo and 0.70 mm for restenosis lesions. Intravascular ultrasound detected significant amount of diffuse disease with a mean cross-sectional area (CSA) stenosis of 41% in the reference vessel at the time of the stent implantation [8–11]. The IRIS trial was expanded for additional 25 patients who underwent intracoronary stent implanta-

225

tion with a higher activity stent (0.75–1.5 mCi, mean 1.14 mCi). This cohort demonstrated safety of the radioactive stent without evidence of thrombus or subacute closure, but the overall restenosis rate was higher than reported with nonradioactive stents. A small registry from Rotterdam with implantation of 31 radioactive stents (activity ranged 0.75– 1.5 mCi) in 26 patients reported safety with a late loss index of 0.5310.35 and a restenosis rate of 17%. Studies with higher activities of emitting stents (1.5–3.0 mCi) in Heidelberg were associated with higher rates of restenosis and target vessel revascularization of 36% [12].

Figure 2. Representative angiogram from a patient treated in the BETA WRIST trial using the 90-Y source centering balloon and afterloader. (A) Preintervention. (B) Centering balloon catheter during radiation. (C) Postintervention and radiation therapy. (D) Six-month angiographic follow-up.

226

R. Waksman / Cardiovascular Radiation Medicine 1:3 (1999) 220–226

In a dose-finding study conducted in Milan, higher activities above 6 mCi detected nearly complete neointima formation in the body of the stent, but were associated with high degrees of restenosis at the edges of the stent (range 36–44%) with a unique angiographic pattern of stenosis at the edges, termed the “candy wrapper” effect [13]. Studies with activities of up to 20 mCi are being conducted to evaluate whether higher activities will minimize the edge effect phenomenon as seen in Fig. 2. Other approaches to improve the results with the radioactive stent are to change the geometry of the stent to replace the isotope or the activity level at the edges of the stent. Conclusions and Future Perspective Initial data from the preclinical work and the clinical experience from the feasibility clinical trials with beta emitters leads to the conclusion that beta emitters will be effective as gamma emitters for the prevention of restenosis if the right dose is provided to the right target. The beta trials, although they have enrolled more patients than the gamma trials, do not have randomization to placebo to prove the efficacy yet. Dosimetry still seems to play a major role in the success of the technology and although not proven by head-to-head study, delivery systems with centering capability should provide more a homogenous dose to the target area. The latest data from the clinical trials identified two major complications that require a solution. The edge effect phenomenon, which is seen primarily with the radioactive stent, has also been reported to occur with catheter-based systems, with both beta and gamma emitters especially when the treated area is not covered with wide margins. Late thrombosis is reported in any radiation trial with rates up to 10%. This phenomenon of late thrombosis was associated with additional stent implantation, probably due to the delayed healing associated with radiation. A potential solution to the late thrombosis is to prolong treatment with antiplatelet therapy. Antiplatelet therapy to prevent late thrombosis is currently in all protocols, mostly prescribed to patients for 3 months and lately prescribed up to 6

months. Hopefully, with the continuation of positive results from the ongoing clinical trials, this technology will have a permanent role in the field of interventional cardiology and radiology for the prevention of restenosis.

References [1] Verin V, Urban P, Popowski Y, et al. Feasibility of intracoronary beta-irradiation to reduce restenosis after balloon angioplasty. A clinical pilot study. Circulation 1997;95:1138–1144. [2] King SB, Williams DO, Chougule P, et al. Endovascular betaradiation to reduce restenosis after coronary balloon angioplasty. Results of the beta energy restenosis trial (BERT). Circulation.1998;97:2025–2030. [3] Meerkin D, Tardif JC, Crocker IR, et al. Effects of intracoronary beta-radiation therapy after coronary angioplasty: an intravascular ultrasound study. Circulation 1999;99:1660–1665. [4] Bonan R, Arsenault A, Tardif JC, et al. Beta energy restenosis trial, Canadian arm [abstract]. Circulation 1997;96:I-219. [5] Gijzel AL, Wardeh AJ, van der Giessen WJ, et al. b-Energy to prevent restenosis: the Rotterdam contribution to the BERT1.5 trial—1 year follow-up [abstract 1945]. Eur. Heart J. 1999;370. [6] Raizner ER, Osterle S, Waksman R, et al. The PREVENT trial, a feasibility study of intracoronary brachytherapy in the prevention of restenosis: an interim report [abstract 3423]. Circulation 1998;17;I-651. [7] Amols HI, Reinstein LE, Weinberger J. Dosimetry of a radioactive coronary balloon dilatation catheter for treatment of neointimal hyperplasia. Med. Phys. 1996;23:1783–1788. [8] Weinberger J. Clinical experience with the liquid-filled balloon: the CURE study [abstract]. In: Advances in Cardiovascular Radiation Therapy III; February 17–19, 1999; Washington, DC. [9] Waksman R, White RL, Chan RC, et al. Intracoronary beta radiation therapy for in-stent restenosis: preliminary report from a single center clinical study [abstract]. J. Am. Coll. Cardiol. 1999;33:19A. [10] Fischell TA, Carter AJ, Laird JR. The beta-particle-emitting radioisotope stent (Isostent): animal studies and planned clinical trials [abstract]. Am. J. Cardiol. 1996;78(3A):45–50. [11] Baim DS, Fischell T, Weissman NJ, et al. Short term (1 month) results of the IRIS feasibility study of a beta particle emitting radioisotope stent [abstract]. Circulation 1997;96: I-218. [12] Hehrlein C. European moderate-activity 32P stent [abstract]. In: Advances in Cardiovascular Radiation Therapy III; February 17–19, 1999; Washington, DC. [13] Colombo A. European high-activity 32P stent [abstract]. In: Advances in Cardiovascular Radiation Therapy III; February 17–19, 1999; Washington, DC.