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Beta emitter systems and results from clinical trials
Cardiovascular Radiation Medicine 4 (2003) 54 – 63
Beta emitter systems and results from clinical trials State of the art Ron Waksman a,*, Albert Raizner b, Jeffrey J. Popma c a
Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010, USA b Methodist Hospital, Houston, TX 77030, USA c Brigham & Women’s Hospital, Boston, MA 02215, USA
Received 1 August 2003; received in revised form 12 August 2003; accepted 12 August 2003
Abstract
Vascular brachytherapy has been established as the standard of care for the treatment of in-stent restenosis (ISR). Both beta and gamma emitters are currently in use for the prevention of ISR recurrence. The use of beta sources for vascular application is attractive from both the radiation exposure and safety points of view, and a wide variety of beta sources are available for this application. This review is intended to summarize the clinical trials utilizing beta emitter systems for the treatment of ISR and de novo lesions and their subsequent results. D 2003 Elsevier Inc. All rights reserved.
Keywords:
Radiation; Restenosis; Vascular brachytherapy
1. Introduction Vascular brachytherapy using beta and gamma radiation has revolutionized the treatment of restenosis following coronary stent placement and may also be useful in preventing the initial restenotic event in patients undergoing balloon angioplasty and stent placement. Annually, there are 900,000 coronary angioplasties performed on de novo and restenotic lesions in the United States alone [1]. Despite the widespread application (70 – 80%) of stent implantation to reduce restenosis, 15 – 35% of these patients still develop restenosis, usually within 6 –9 months after the procedure [1,2]. Accordingly, nearly 200,000 patients develop in-stent restenosis (ISR) in this country each year. Attempts to expand vascular brachytherapy for use in de novo lesions were initially encouraging but its use in this setting has lost momentum with the encouraging results of the drug-eluting stent technology. The question of vascular brachytherapy utilization for de novo lesions remains viable but unanswered, especially with the mixed results reported with
* Corresponding author. Tel.: +1-202-877-8575; fax: +1-202-8772715. E-mail address: [email protected] (R. Waksman). 1522-1865/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1522-1865(03)00169-0
drug-eluting stents on difficult subsets of patients and its associated costs. The beta isotopes currently in preclinical or clinical use include 90-Yttrium (90Y), 90-Strontium (90Sr/ Y), 32Phosphorus (32P), 106-Ruthenium (106Ru), 133-Xenon (133Xe), 186-Rhenium (186Re), and 188-Rhenium (188Re). The clinical implication is that beta emitters are very effective in smaller vessels ( < 4 mm) but may lose their ability to deliver adequate amounts of radiation in larger vessels ( z 4 mm), such as saphenous vein grafts of peripheral vessels. This review is intended to give an overview of beta emitter systems and summarize the current status of clinical trials utilizing beta radiation therapy.
2. Beta emitter systems in vascular brachytherapy There are three systems of beta emitters currently in use: the Beta-Cath System (Novoste, Norcross, GA), the Guidant GALILEO Intravascular Radiotherapy System (Guidant, Houston, TX), and the RDX Radiation Delivery System (Radiance Medical, San Diego, CA). The Beta-Cath System (Fig. 1) is a proprietary catheterbased delivery system that delivers localized beta radiation to a coronary artery at the site of coronary intervention. Used immediately after percutaneous transluminal coronary
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The Guidant GALILEO System (Fig. 2) consists of three components: a source wire containing 32P, a source delivery unit or afterloader, and a centering catheter, which has a perfusion balloon that centers the source wire within the artery and allows for side branch and distal perfusion during the active radiation treatment. The system allows for a short dwell time, the centering of the radiation source allows for a more controlled delivery, and the afterloader provides an automatic ‘‘hands-off’’ application to deliver and retrieve the source [4]. The RDX System (Fig. 3) uses a 32P isotope incorporated directly into the balloon material of a PTCA-type catheter using a trilayer sealed source design. The expanded balloon provides centering but at the expense of obstructing flow during the dwell time, thus mandating a sequential inflation/ deflation program. Additionally, direct vessel apposition of the source reduces the required activity to deliver
Fig. 1. Beta-Cath System (Novoste, Norcross, GA).
angioplasty (PTCA), the system is composed of two separate components: the transfer device, which contains a radiation source train, and the delivery catheter, which is a single-use, self-centering, multilumen catheter that is positioned at the coronary artery treatment site. The radiation source train is delivered to the treatment site and returned to the transfer device using a saline-injected hydraulic system. The system functions as a closed loop system in which the radioactive source is never directly in contact with the patient’s blood or tissue [3].
Fig. 2. Guidant GALILEO III Intravascular Radiotherapy System (Guidant, Corporation, Houston, TX).
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Fig. 3. RDX Radiation Delivery System (Radiance Medical, San Diego, CA).
therapeutic doses to the target tissue, allowing simplistic shielding and a disposable device design [5].
3. Beta radiation clinical trials for ISR 3.1. Beta WRIST Beta Washington Radiation for In-Stent Restenosis Trial (WRIST) examined the efficacy of beta radiation for prevention of ISR using a design similar to original WRIST [6]. This registry included 50 patients who were treated for ISR in native coronaries, 2.5 –4.0 mm in diameter with lesions < 50 mm in length. Beta radiation using a 90Y source was administered using a centering catheter and an afterloader system. Clinical outcomes of these patients were compared to those of the original WRIST cohort (randomized to either placebo or 192Ir). Angiographic restenosis at 6 months in Beta WRIST was 22% with a late total occlusion rate of 12%. In comparison to the historical control group of WRIST, Beta WRIST patients demonstrated a 58% reduction in the rate of target lesion revascularization (TLR) and 53% reduction in target vessel revascularization (TVR) at 6 months ( P < .001). No differences were detected in comparison to the gamma-radiated patients of WRIST. The clinical benefit was maintained at a 2-year follow-up with the beta radiation reducing TLR (42% vs. 66%; P = .016), TVR (46% vs. 72%; P = .009), and major adverse cardiac events (MACE) (46% vs. 72%; P = .008) compared to placebo. The efficacy of beta and gamma emitters for the treatment of ISR appeared similar at longer term follow-up. 3.2. START and START 40/20 A pivotal multicenter randomized trial, stents and radiation therapy (START), involved 476 patients in over 55 centers throughout the United States and Europe and was designed to determine the efficacy and safety of the Beta-
Cath System for the treatment of ISR [7]. Patients were randomized to either placebo or an active radiation train 30 mm in length. The inclusion criteria were single ISR lesions >50% (by visual assessment) in native coronary target vessels between 2.7 and 4.0 mm in diameter. The target lesion (V20 mm) required treatment with a 20-mm balloon and a 30mm source train. In the radiated patients, the mean lesion length was 16.3 mm in arteries and 2.8 mm in diameter. After successful angioplasty, these patients were treated with the Beta-Cath System containing 90Sr/ Y seeds, delivering beta radiation through a closed-end lumen catheter. The dose prescribed at a point 2 mm from the center of source axis was based on visual assessment of reference vessel diameter (RVD); 18.4 Gy in RVD z2.7 to V3.3 mm and 23 Gy in RVD >3.3 to V4.0 mm. The duration of the antiplatelet therapy was initially based on operator preference and was modified in early 1999 to at least 90 days of clopidogrel 75 mg/qd following recommendations from the Beta-Cath Trial Data Safety Monitoring Board, where late thrombosis as a complication of brachytherapy was first recognized. At 8 months, the angiographic restenosis rate in the irradiated segments was 24% versus 46% in the placebo group ( P < .001). In the irradiated group, TLR was 13% as compared to 22% in control ( P =.008), with similar reductions of TVR (16% vs. 24%; P =.028) and MACE (18% vs. 26%; P =.026). There were late thrombotic events in radiated patients. During multiple studies of radiation, including START, the medical community became aware of the mismatch between the interventional injury length and radiation length, the so-called ‘‘geographic miss’’ phenomenon, with its potential to compromise clinical outcome [8]. The START 40/20 trial was a 207-patient registry that mirrored START and ensured an adequate irradiation margin with 10 mm of radiation therapy applied proximal and distal to the injury zone (additional 5 mm each end) [9]. In comparison to the START population, START 40/20 patients were older, had more unstable angina, and more prior treatments for ISR, with similar angiographic indices including RVD and lesion length. Compared to the control arm of START, patients in START 40/20 had a 44% reduction in restenosis in the analysis segment compared to 36% in radiated arm of START; a 50% reduction in TLR ( P =.002) compared to 42% in radiated arm of START; a 34% reduction in TVR ( P =.03) compared to 34% in START, and a 26% reduction in MACE ( P =.10) compared to 31% in the irradiated arm of START. While the START 40/20 registry showed no deleterious effects of adding 10 mm of length to the source train, there was a lack of a relationship between ‘‘geographic miss’’ and clinical or angiographic outcomes for ISR. 3.3. Intimal Hyperplasia Inhibition with Beta In-stent Trial The Intimal Hyperplasia Inhibition with Beta In-stent Trial (INHIBIT) was a multicenter randomized study
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involving 332 patients in 29 U.S. and international sites, which examined the efficacy of the GALILEO System for the treatment of ISR [10]. The GALILEO System uses a 32 P source delivered in a centered delivery catheter with a dose of 20 Gy to a depth of 1 mm into the vessel wall. This system provides the potential advantage of a more homogenous dose distribution, reduced radiation exposure, and a perfusion balloon to ensure distal vessel flow during treatment dwell time. The study mandated at least 3 months of antiplatelet therapy and 307 patients completed 9 months of clinical follow-up. Radiation was delivered successfully in 315 patients, was tolerated well in all but 2 patients, and there were no adverse effects related to the radiation procedure. At 9 months, treatment with 32P reduced the primary angiographic endpoint of binary restenosis by 67% ( P =.0001) in the stented segment and by 50% ( P =.0003) in the analysis segment. There were no differences in the edge effect rates between the active and the control-treated groups. The radiated patients had reduced late loss (0.4 vs. 0.6 mm; P < .001) and improved minimal lumen diameter (MLD) (1.52 vs. 1.38 mm; P =.01). At 9 months, 32P significantly reduced rates of TLR (11% vs. 29%; P < .001) and MACE (14% vs. 31%; P < .001). Tandem positioning to cover more diffuse longer lesions >22 mm with 32P was safe and equally effective. 3.4. GALILEO INHIBIT GALILEO INHIBIT is an international multicentered registry of 120 patients with ISR treated with an automatic afterloader (Guidant GALILEO Radiotherapy System) via a helical centering balloon. 32P delivered at 20 Gy at 1 mm into vessel wall reduced the primary clinical endpoint defined as MACE TLR at 9 months by 49% ( P = .003). The thrombosis rate was low, 1.5%, and similar to the control group, 1.2%. Treatment with 32P reduced the primary angiographic endpoint of binary restenosis by 74% ( P < .0001) in the stented segment and by 27% ( P =.036) in the analysis segment [11]. 3.5. Beta Radiation to Prevent In-stent Restenosis Beta Radiation to Prevent In-stent Restenosis (BRITE) is a U.S. feasibility study to test the RDX Radiation System, which uses a balloon catheter encapsulating a 32P radioactive sleeve for the treatment of ISR. In the BRITE trial, 27 patients were treated with PTCA (26 balloon, 1 rotoblator) for lesions < 25 mm in length. Following intervention, the catheter was successfully delivered in all but 1 patient. The prescribed dose mean was 19.8 F 0.4 Gy at 1 mm from the inflated source surface and delivered in an average dwell time of 482 F 39 s. Seventy percent of the dose was administered when the balloon was inflated. The transit time was 8.5 s and no cases were interrupted. All patients were treated with clopidogrel, 75 mg daily for 3 months. There were no procedural complications or MACE at a
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30-day clinical follow-up. At 6 months, TVR (3.7%), MACE (3.7%), and angiographic binary restenosis rates (7.7%) were the lowest reported to date in any vascular brachytherapy series [12]. The specific dosimetry and source apposition characteristics of the RDX system may have contributed to these encouraging results. 3.6. BRITE II The objective of the BRITE II study was to evaluate the efficacy of beta radiation using the RDX System (‘‘hot balloon,’’ incorporating a solid 32P h-isotope into the balloon material using a tri-layer-sealed source design) versus placebo for the prevention of reintervention of instent restenotic lesions in native coronary arteries measured by clinically driven TVR at 9 months. Four hundred and twenty-nine patients were randomized to either radiation (n = 321) or placebo (n = 108). The RDX System demonstrated safety characterized by high technical success rates (>95%), low periprocedural complications ( < 1%), and low 30-day MACE ( < 1%). The most prevalent location of restenosis was within the radiated vessel outside of the injured zone despite lower rates of geographical miss (8.5%). Final analysis is not complete, but the RDX System met the study assumption of a 42% reduction in TVR with significant improvement over placebo. MACE in the irradiated group was lower compared to control 27% versus 45% ( P < .02). The RDX System demonstrated a very low ISR rate (10.9% vs. 46.1%) and proved to optimize the results when compared to historical studies. Although the system will probably not be released for marketing due to commercial considerations, the BRITE II study confirmed again in a randomized study the utility of vascular brachytherapy for the treatment of ISR [13]. 3.7. 4R 4R is a South Korean registry evaluating h-radiation therapy with a 188Re-MAG3-filled balloon following rotational atherectomy for diffuse ISR (length >10 mm). Radiation was delivered successfully to 50 patients with a dose of 15 Gy at 1.0 mm into the vessel wall. The mean irradiation time was 201.8 F 61.7 s. No adverse events occurred during the follow-up period (mean 10.3 F 3.7 months). Six-month binary angiographic restenosis rate was 10.4%. Two potential limitations of this technology include reduced dosing at the balloon margins (edge effect) and the risks of balloon rupture with radiation spill. In the event of balloon rupture using 188 Re, concomitant administration of potassium perchlorate may mitigate thyroid uptake [14]. 3.8. Columbia University Restenosis Elimination The Columbia University Restenosis Elimination (CURE) Study evaluated liquid 188Re injected into a perfusion
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with a 20-mm balloon) de novo or restenotic lesions in different vessels who have undergone stand-alone PTCA or who are candidates for provisional stent placement. In the initial 149 patients, 6-month and 1-year rates of TVR with PTCA were 22% and 31%, respectively [17] (for a summary of the studies performed, see Table 1).
balloon; 30 patients were treated with balloon alone and 30 patients were stented (with subsequent 188Re therapy). The delivered dose was 20 Gy to the balloon surface with a dwell time of 6.9 F 2.2 min. At 12 months follow-up in the first 37 patients, the rate of TLR-free survival was 75% [15]. 3.9. RENO AND BRIE Other studies assessing the efficacy of beta radiation are currently underway. Registry Novoste (RENO) is an active registry of 1098 consecutive patients treated in 46 centers in Europe and the Middle East with the Novoste Beta-Cath System. Six-month follow-up data were obtained for 1085 patients. Of 1174 target lesions, 94.1% were located in native vessels and 5.9% in a bypass graft; 17.7% were de novo lesions, 4.1% were restenotic, and 77.7% were in-stent restenotic lesions. Intravascular brachytherapy was technically successful in 95.9% of lesions. Angiographic followup was available for 70.4% of the patients. Nonocclusive restenosis was seen in 18.8% and total occlusion in 5.7% of patients [16]. The Beta Radiation in Europe (BRIE) Study was designed to evaluate the safety and efficacy of the BetaCath System in patients with up to two discrete (treatable
4. Beta radiation clinical trials for de novo lesions Large-scale clinical studies testing the effectiveness of beta radiation for de novo, restenotic, and in-stent restenotic lesions have paralleled the encouraging results of gamma radiation. Important early studies included the Geneva trial [18], which used 90Y, the dose-finding Beta Energy Restenosis Trial (BERT), which used 90Sr/ Y [19], and the Proliferation Reduction with Vascular Energy Trial (PREVENT) that utilized 32P emitter [20]. 4.1. Beta Energy Restenosis Trial BERT was a feasibility study limited to 23 patients enrolled at two centers (Emory and Brown Universities). The study was designed to test the 90Sr/ Y source delivered
Table 1 Clinical trials for ISR using catheter-based systems with beta radiation Study name
Design
Radiation system
Isotope and dose (Gy)
Results and status
90
Completed. Restenosis rate of 22% at 6 months. MACE 46% at two years. Similar results to the gamma wrist group. Completed. Demonstrated reduction of 50% in restenosis (analysis segment) and 55% in MACE. Completed. Showed reduction in TLR, TVR, and MACE (35%) in the irradiated group. No late thrombosis. Completed. 50%, 34%, and 26% reduction in TLR, TVR, and MACE, respectively. Completed. TVR, MACE, and restenosis rates were 3.7%, 3.7%, and 7.7%, respectively, at 6 months. ISR 10.9% and geographical miss 8.5% at 9 months. 10.4% restenosis rate at 6 months.
Beta WRIST
Registry for 50 patients with ISR in native coronaries.
A centering catheter and an afterloader system.
Y, 20.6 Gy at 1 mm from surface.
INHIBIT
Multicenter, double-blind, randomized trial involving 332 patients. Multicenter, randomized, double-blind design involving 476 patients. 207 patients with more prior treatments for ISR than in START. Feasibility study of 27 patients with ISR lesions <25 mm. Randomized study involving 429 patients. South Korean registry of 50 patients with ISR>10 mm.
GALILEO System using a centered delivery catheter.
32
P, 20 Gy at 1 mm into vessel wall.
Beta-Cath System — 30 mm source train.
90 Sr/ Y, 18 – 20 Gy at 2 mm from center of source axis.
Beta-Cath System — 40 mm source train.
90
RDX System with balloon catheter.
32 P, 20 Gy at 1.0 mm from the balloon surface.
RDX System.
32
Liquid-filled balloon following rotational atherectomy. Liquid injected into perfusion balloon. Guidant GALILEO System automatic afterloader via a helical centering balloon. Beta-Cath System.
188 Re-MAG3, 15 Gy at 1 mm into the vessel wall.
START
START 40/20 BRITE
BRITE II 4R
CURE GALILEO INHIBIT
Open-label registry of 60 patients. International multicenter registry of 120 patients.
BRIE
Registry of 149 patients.
SVG BRITE
Feasibility study. 49 patients enrolled; 25 with ISR.
RDX System using hot balloon.
Sr/ Y, 18 – 20 Gy at 2 mm.
P, 20 Gy at 1 mm.
188
Re, 20 Gy to balloon surface.
32
P, 20 Gy at 1 mm into vessel wall.
90
Sr/ Y, 14 – 18 Gy at 2 mm from the centerline of the source axis. 32 P, 20 Gy at 1 mm from balloon surface.
TLR-free survival was 75% in first 37 patients at 12 months. MACE TLR reduced by 49% with 1.5% thrombosis rate.
TVR rates with PTCA were 22% and 31% at 6 months and 1 year follow-up, respectively. 36% TVR and 26% restenosis rates at 1 year.
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by a prototype hydraulic delivery system (Novoste, Norcross, GA) [19]. The prescribed doses in this study were 12, 14, or 16 Gy and the treatment time did not exceed 3.5 min. The radiation was successfully delivered 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. One patient underwent stent implantation to a segment proximal to the irradiated site. Angiographic follow-up at 6 months assessed by QCA detected late loss of 10% with a late loss index of 5%. The Canadian arm of this study included 30 patients from the Montreal Heart Institute utilizing the same system under the same protocol [21]. At 6 months follow-up, the angiographic restenosis rate was 10% with negative late loss and late loss index. Intravascular ultrasound (IVUS) analysis of this cohort demonstrated larger lumen at 6 months follow-up with reduction of the wall area. The European arm of the BERT (BERT 1.5) was conducted at the Thoraxcenter in Rotterdam, The Netherlands, in an additional 30 patients who were treated successfully with balloon angioplasty. Angiographic restenosis in this cohort was higher than reported in the U.S. and Canadian trials. Overall, the restenosis rate based on 64 of the 80 patients in the BERT series was 17%, and the late loss and late loss index were below 5%. Over 50% of the patients had larger MLD at follow-up compared to control, and a substudy of IVUS demonstrated vessel remodeling at the irradiated site [22].
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wire and a centering catheter was safe and effective in reducing neointimal formation within the target site in patients undergoing PTCA. However, caution should be exercised so as to not injure the vessels proximal and distal to the radiation source (‘‘geographic miss’’) and with the unbridled use of new stents, which increase that late subacute thrombosis rate [20]. 4.3. Dose-Finding Study Group The Dose-Finding Study Group was a prospective, randomized, multicenter, dose-finding trial. The primary objective was to determine the effect of 9, 12, 15, and 18 Gy of beta radiation (90Yttrium) at a tissue depth of 1 mm on restenosis rates after PTCA in de novo lesions. Of the 183 patients randomized, 181 received the prescribed doses of beta radiation: 45 received 9 Gy, 45 received 12 Gy, 46 received 15 Gy, and 45 received 18 Gy. Stenting after radiation was required in 47% of the patients because of residual stenosis or major dissection. At 6 months angiographic follow-up, a significant dose-dependent benefit was evident. There was abrupt thrombosis or late occlusion of the target vessel in 4 out of 120 (3.3%) patients who were treated with only balloon angioplasty and in 7 of the 49 (14.3%) patients who received new stents. This study demonstrated a marked dose –response reduction in restenosis in nonstented arteries after administration of 18 Gy of beta radiation, especially in patients who underwent plain balloon angioplasty, suggesting that beta radiation therapy should be evaluated as an adjunct to PTCA [23].
4.2. Proliferation Reduction with Vascular Energy Trial 4.4. Beta-Cath PREVENT was a prospective, randomized, sham-controlled, multicenter study of 105 patients with de novo (70%) or restenotic (30%) lesions who were randomized to either placebo or three different doses of 32P beta radiation (16, 20, and 24 Gy to a depth of 1 mm into the artery wall) to prevent restenosis after PTCA or stenting. The binary restenosis rate at 6 months angiographic follow-up was 8.2% at the target site for the radiation-treated group versus 39.1% for the control group ( P = .001). Restenosis at the target site, including its 5 mm proximal and distal margins, was 22.4% for patients who received treatment versus 50.0% for the control group ( P = .02) [3]. Late (12 months) MACE [death, myocardial infarction (MI), and TLR] occurred in 13 (16%) patients in the brachytherapy group and in 6 (24%) control patients ( P = NS). If TVR is included, MACE occurred in 26% versus 32% ( P = NS), respectively. The occurrence of MI due to thrombotic events after discharge happened in seven patients who received radiotherapy but in no patients from the control group. Lumen narrowing adjacent to the target site, the so-called ‘‘edge effect,’’ contributed significantly to the diminution of the clinical benefit. Prolonged antiplatelet therapy and a reduced use of new stents at the time of radiation were recommended to minimize these complications. PREVENT showed that beta radiation with a 32P source
The Beta-Cath System trial was the first prospective, randomized, multicenter trial in 1455 patients designed to assess the value of vascular brachytherapy for the prevention of restenosis in de novo lesions. Patients who had an acceptable ‘‘stand alone’’ balloon angioplasty results were assigned to treatment with a 30-mm 90Sr/ Y source train or sham. Patients with a suboptimal result after balloon angioplasty were treated with a stent and then assigned to 90Sr/ Y or placebo treatment [24]. The primary endpoint of the study was an 8-month target vessel failure (TVF) (death, MI, TVR). The inclusion criteria included a single lesion and single vessel intervention with a de novo or restenotic lesion >50% (by visual assessment) in vessels between 2.7 and 4.0 mm RVD. The radiation dose prescription point was calculated at 2 mm from center of source axis: 16.1 Gy in RVD z2.7 to V3.3 mm and 20.7 Gy in RVD >3.3 to V4.0 mm. Baseline demographic and angiographic characteristics were similar between groups. In patients treated with balloon angioplasty alone, 90Sr/ Y was administered in 264 patients and placebo was administered in 240 patients. The 240-day TVF rate tended ( P = .06) to be lower in patients treated with
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90
Sr/ Y (14.2%) than in patients treated with placebo (20.4%). This beneficial effect was attributable to a reduction in angiographic restenosis within the initial lesion site in patients treated with 90Sr/ Y (21.4% vs. 34.3% in placebo-treated patients; P = .003), although the restenosis rates were similar in the entire analysis segment, including the radiation margins (31.0% vs. 36.0%; P = .27). The loss of benefit at the treatment margins is attributable to ‘‘geographic miss’’ due to the relatively short treatment length in the study. In patients treated with the new stents and short-term antiplatelet therapy, late (>30 day) thrombotic stent occlusion was found and the antiplatelet therapy was extended to 6 months in patients with a new stent. In the 452 patients treated with extended antiplatelet therapy who received a new stent, there were no differences in the 240-day TVF rate (23.9% in 90Sr/ Y-treated patients vs. 20.8% in patients treated with placebo). These results were again attributable to short radiation lengths and ‘‘geographic miss.’’ This Beta-Cath study was the first to identify the higherthan-expected rate of late stent thrombosis when radiation was used with new stent implantation. The primary clinical endpoint, TVF, was not shown to be significantly lower in the combined radiation arms compared with combined placebo arms. The paradox of positive treatment effect for 90Sr/ Y seen in lesion segment analysis and the negative treatment effect of 90Sr/ Y seen in the analysis segment likely explains the negative treatment effect of 90Sr/ Y on clinical restenosis in stents and merits further investigation. ‘‘Geographic miss’’ may have contributed to the negative results of 90Sr/ Y. The overall positive results in the lesion segment analysis and the strong trends in the clinical outcomes in the PTCA branch suggest a potential role for 90Sr/ Y radiation in the treatment of de novo coronary lesions if the increase of restenosis in the ‘‘analysis segment’’ can be solved. 4.5. SVG BRITE This study was a feasibility study examining the RDX System using hot balloon with 32P emitter and a dose of 20 Gy at 1 mm from the balloon surface in saphenous vein grafts. In this study, 49 patients were enrolled; 24 of these were treated for de novo lesions. New stents were implanted in most patients with de novo lesions. The outcome of the patients with the de novo lesions was encouraging with only 8% 12-month TVR rate and 13% angiographic restenosis rate from the entire analysis segment (allowing for edge effects) after beta brachytherapy of de novo SVG lesions. While caution is in order given the small number of patients studied and the lack of a concurrent control population, these data warrant further investigation of this promising application, especially as the efficacy of potential alternatives, such as drug-eluting stents, has not yet been investigated in SVG lesions [25].
4.6. ECRIS ECRIS is a randomized trial in patients with de novo and restenotic lesions using a 188Re-filled balloon catheter reported by Martin Ho¨her from Ulm conducted in a single center. In the study, 225 patients (71% de novo lesions) were randomly assigned to receive 22.5 Gy intravascular h-irradiation in 0.5 mm tissue depth (n = 113) or to receive no further intervention (n = 112). Clinical and procedural data did not differ between the groups, except a higher rate of stenting in the control group (63%) compared with the 188Re group (45%; P < .02). After 6 months follow-up, late loss was significantly lower in the irradiated group compared to the control group, both of the target lesion (0.11 F 0.54 vs. 0.69 F 0.81 mm; P < .00000003) and of the total segment (0.22 F 0.67 vs. 0.70 F 0.82 mm; P < .00002). This was also evident in the subgroup of patients with de novo lesions and independent from stenting. Binary restenosis rates were significantly lower at the target lesion (6.3% vs. 27.5%; P < .00008) and of the total segment (12.6% vs. 28.6%; P < .007) after 188Re brachytherapy compared to the control group. TVR was significantly lower in the 188Re (6.3%) compared to the control group (19.8%; P =.006). The authors concluded that intracoronary h-brachytherapy with a 188Re liquid-filled balloon is safe and efficiently reduces restenosis and revascularization rates after coronary angioplasty [26] (for a summary of the studies performed, see Table 2).
5. Radioactive stents In contrast to brachytherapy using removable sources, radioactive stents (permanent implants) have beta-emitting atoms (32P) on the stent surface and emit beta particles that are absorbed by neointimal tissue to a depth of 1 –2 mm into the vessel wall over longer periods of time. This isotope was selected because of its short half-life, minimal tissue exposure, and relative safety. In radioactive stents with activity levels of 0.75 to 12 ACi, the total dose of 8 to 140 Gy is delivered to the tissue at 0.5 mm from the stent surface over a 28-day period [27]. The first clinical trials included the IRIS trials, the Milan dose-finding study, and the Vienna experience. In the IRIS pilot trials, 32P radioactive Palmaz– Schatz stents were developed with varying radioactivities: IRIS 1A 0.5– 1.0 ACi and IRIS 1B 0.75 –1.5 ACi. These stents were implanted with a high rate of technical success but were limited by an angiographic restenosis rate (stent and edges) of 40% at 6 months follow-up [28]. The Milan dose-finding study showed that activities >3 ACi (32P stents 0.75 –12 ACi) profoundly inhibited intimal hyperplasia; however, restenosis still occurred in >40% of lesions at the stent edges, i.e., the ‘‘candy wrapper’’ effect [29,30]. A strategy of less aggressive stent implantation
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Table 2 Clinical trials using catheter-based systems with beta emitters in coronaries for de novo lesions Study name
Design
Radiation system
Isotope and dose
Results and status
Geneva
Open-label registry of 15 patients post-PTCA.
90
Completed. Demonstrated feasibility, safety. Restenosis rate (40%).
BERT
Open-label registry of 23 patients post-PTCA.
BRIE
Registry of 149 patients.
Mechanical loading of fixed wire via a segmented centered balloon. Hydraulic hand delivery of seed train in a noncentered 5.0 F catheter. Beta-Cath System.
BETA-Cath
Multicenter, prospective, randomized, blinded study of 1455 patients post-PTCA and provisional stenting. Prospective, randomized, multicenter dose-finding trial in 183 patients post-PTCA. Multicenter, prospective, randomized, sham-controlled study of 105 patients post-PTCA or stenting. Open-label registry of 60 patients. Feasibility study of 24 patients. Single-center, randomized trial of 225 patients.
Dose-Finding Study Group PREVENT
CURE SVG BRITE ECRIS
Y, 18 Gy to the balloon surface.
90 Sr/ Y, 12, 14, or 16 Gy to 2 mm from source.
Beta-Cath System
90 Sr/ Y, 14 or 18 Gy 2 mm from source axis.
Completed. Restenosis rate of 15% with late loss of 10% and loss index of 5%. TVR rates with PTCA were 22% and 31% at 6 months and 1 year follow-up, respectively. 240-day TVF rate was 14.2% with 31% restenosis rate.
Automatic afterloader of fixed wire via a centered balloon. Automatic afterloader.
90 Y, 9 (n = 45), 12 (n = 45), 15 (n = 46), or 18 (n = 45) Gy at a tissue depth of 1 mm. 32 P, 16, 20, or 24 Gy to 1.0 mm into the artery wall.
Significant dose-dependent benefit was evident at 6 months follow-up. 22.4% restenosis at 6 months with MACE 16% at 1 year.
Liquid injected into perfusion balloon. RDX System using hot balloon. Liquid-filled balloon catheter.
188
TLR-free survival was 75% in first 37 patients at 12 months. 8% TVR and 13% restenosis rates at 1 year. TVR was 6.3% and late loss was significantly lower at 6 months follow-up.
failed to alleviate the edge restenosis problem. These findings were replicated in the Vienna study using high activity (6 –21 ACi) stents [31]. In an effort to circumvent edge restenosis, ‘‘hot-’’ and ‘‘cold-end’’ stents were developed. The theoretical advantage of ‘‘hot end’’ stents was to extend the area of irradiation beyond the balloon injured extremities; this technology failed to prevent edge effect with an angiographic restenosis rate of 33% in 56 implanted stents. ‘‘Cold end’’ stents were developed to prevent remodeling at the injured extremities. Restenosis rates of 22% were not different when compared to nonradioactive stents [32]. In summary, while radioactive stents effectively inhibit intrastent neointimal hyperplasia, the problem of edge restenosis has not been solved with either less aggressive stent implantation or modification of the stent ends. Currently, there is no indication for their clinical use, and the future application of this technology is questionable.
6. Beta versus gamma radiotherapy While contemporaneous clinical trials to date have demonstrated comparability of clinical efficacy of beta and gamma brachytherapy, beta systems have several inherent advantages. Reduced radiation exposure to operators and Cath lab personnel, less shielding requirements, and easier handling of sources have lead to more widespread acceptance of beta technology. Potential limitations of beta
90
Sr/ Y, 14 – 18 Gy at 2 mm from the centerline of the source axis.
Re, 20 Gy to balloon surface.
32 P, 20 Gy at 1 mm from balloon surface. 188 Re, 22.5 Gy at 0.5 mm.
sources in larger vessels (e.g., vein grafts, peripheral arteries, and renal access grafts) may be offset by the use of sources with higher activity, centering mechanisms, and appropriately longer dwell times.
7. Lessons from the clinical trials and optimization of the results The clinical trials have identified three major issues related to the technology, which resulted in complications. These are the late thrombosis, seen more in the gamma studies but also in the beta trials; the edge effect phenomenon, seen primarily with the radioactive stent but also with the use of catheterbased systems; and finally delayed restenosis probably related to initial lower doses. Over the last years, we have come up with solutions to these limitations. Late thrombosis has been nearly eliminated with a minimum of 6 months prolonged antiplatelet therapy (12 months preferred). The edge effect phenomenon has been minimized with the use of wider radiation margins at least 10 mm from the injured segment, and we anticipate that mild escalation in the radiation dose will attenuate the late recurrences rate. In a recent postmarketing surveillance study with the use of the Beta-Cath System, the TVR rate in commercial use of 3,695 patients treated for ISR was 3.8%, demonstrating that the implementation of the lessons learned from the clinical trials results in better outcomes in the real world of angioplasty.
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8. Future perspectives Coronary radiation therapy trials using the beta isotopes Sr/ Y, 90Y, and 32P have all initiated angiographic and clinical benefit in patients with ISR and, to a lesser extent, in those with de novo lesions. The degree of benefit is comparable to gamma radiation, and there may be practical advantages of beta radiation with respect to ease of use in the Cath lab. Vascular brachytherapy using beta radiation may be considered the standard of care in patients with ISR, although further refinements may be useful to define the optimal dose and treatment targets. With the availability of drug-eluting stents, the frequency of ISR may be reduced, but brachytherapy will remain useful in refractory cases of ISR and potentially as an alternative to drug-eluting stent use in patients unfavorable for stenting, such as those with small vessels and long lesions. Additional studies using longer source trains are warranted. Finally, advancements in brachytherapy technology, alternative isotopes with more favorable features, improved operator skills, and refined dosimetry are likely to further improve the short- and long-term outcomes of vascular brachytherapy and potentially expand its application to larger groups of patients.
90
[11]
[12]
[13]
[14]
[15]
[16]
[17]
References [1] Casterella PJ, Teirstein PS. Prevention of coronary restenosis. Cardiol Rev 1999;7:219 – 31. [2] Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, Belardi J, Sigwart U, Colombo A, Goy JJ, van den Heuvel P, Delcan J, Morel M, for the Benestent Study Group. A comparison of balloon-expandable stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994;331: 489 – 95. [3] Bonan R, diMonda R, Hillstead RA. The beta-cath system. In: Waksman R, Serruys PW, editors. Handbook of vascular brachytherapy. 2nd ed. London: Martin Dunitz, 2000. pp. 69 – 81. [4] Raizner AE, Eno RP, Calfee RV. The guidant GALILEO intravascular radiotherapy system. In: Waksman R, Serruys PW, editors. Handbook of vascular brachytherapy. 2nd ed. London: Martin Dunitz, 2000. pp. 83 – 93. [5] Buchbinder M, Strathearn G, Tam LA, Trauthen B. RDX radiation delivery system: balloon-based radiation therapy. In: Waksman R, Serruys PW, editors. Handbook of vascular brachytherapy. 2nd ed. London: Martin Dunitz, 2000. pp. 145 – 52. [6] Waksman R, White RL, Chan RC, Bass BG, Geirlach L, Mintz GS, Satler LF, Mehran R, Serruys PW, Lansky AJ, Fitzgerald P, Bhargava B, Kent KM, Pichard AD, Leon MB. Intracoronary gammaradiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165 – 71. [7] Popma J. Late clinical and angiographic outcomes after use of 90 Sr/90 Y beta radiation for the treatment of in-stent restenosis: results from the 90Sr Treatment of Angiographic Restenosis (START) Trial. J Am Coll Cardiol 2000;36:311 – 2. [8] Kim HS, Waksman R, Cottin Y, Kollum M, Bhargava B, Mehran R, Chan RC, Mintz GS. Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis. J Am Coll Cardiol 2001;37:1026 – 30. [9] Ajani AE, Waksman R. Intracoronary beta radiation: state of the art. J Interv Cardiol 2001;14(6):601 – 9. [10] Waksman R, Raizner AE, Yeung AC, Lansky AJ, Vandertie L.
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Use of localised intracoronary beta radiation in treatment of in-stent restenosis: the INHIBIT randomised controlled trial. Lancet 2003; 359(9306):551 – 7. Waksman R on behalf of the Galileo INHIBIT and INHIBIT investigators. Manual stepping of 32 P h-emitter for diffuse in-stent restenosis lesions, tandem versus single position. Clinical and Angiographic Outcome from a Multicenter Randomized Study. Presented at AHA 2001. Waksman R, Buchbinder M, Reisman M, Lansky AJ, Trauthen B, Whiting J, Li A. Balloon based radiation therapy for treatment of instent restenosis in human coronary arteries: results from the BRITE I study. Catheter Cardiovasc Interv 2002;57(3):286 – 94. Waksman R on behalf of the BRITE II Investigators. Balloon based radiation for coronary in-stent restenosis: 9 month results from the BRITE II study. Presented at ACC 2003. Park SW, Hong MK, Moon DH, Oh SJ, Lee CW, Kim JJ, Park SJ. Treatment of diffuse in-stent restenosis with rotational atherectomy followed by radiation therapy with a rhenium-188-mercaptoacetyltriglycine-filled balloon. J Am Coll Cardiol 2001;38(3): 631 – 7. Weinberger J, Giedd KN, Simon AD, Marboe C, Knapp FF, Trichter F, Amols H. Radioactive beta-emitting solution-filled balloon treatment prevents porcine coronary restenosis. Cardiovasc Radiat Med 1999;1(3):252 – 6. Coen V, Serruys P, Sauerwein W, Orecchia R, Von Rottkay P, Coucke P, Ehnert M, Urban P, Bonan R, Levendag P, RENO Investigators. RENO, a European postmarket surveillance registry, confirms effectiveness of coronary brachytherapy in routine clinical practice. Int J Radiat Oncol Biol Phys 2003;55(4):1019 – 26. Sianos G, Kay IP, Costa MA, Regar E, Kozuma K, de Feyter PJ, Boersma E, Disco C, Serruys PW. Geographical miss during catheterbased intracoronary beta-radiation: incidence and implications in the BRIE study. J Am Coll Cardiol 2000;38:415 – 20. Verin V, Urban P, Popowski Y, Schwager M, Nouet P, Dorsaz PA, Chatelain P, Kurtz JM, Rutishauser W. Feasibility of intracoronary beta-irradiation to reduce restenosis after balloon angioplasty. A clinical pilot study. Circulation 1997;95(5):1138 – 44. King SB, Williams DO, Chougule P, Klein JL, Waksman R, Hilstead R, Macdonald J, Anderberg K, Crocker IR. Endovascular betaradiation to reduce restenosis after coronary balloon angioplasty. Results of the Beta Energy Restenosis Trial (BERT). Circulation 1998;97:2025 – 30. Raizner AE, Oesterle SN, Waksman R, Serruys PW, Colombo A, Lim YL, Yeung AC, van der Giessen WJ, Vandertie L, Chiu JK, White LR, Fitzgerald PJ, Kaluza GL, Ali NM. Inhibition of restenosis with h-emitting radiotherapy report of the Proliferation Reduction with Vascular Energy Trial (PREVENT). Circulation 2000; 102:951 – 8. Bonan R, Arsenault A, Tardif JC, et al. Beta Energy Restenosis Trial, Canadian Arm. Circulation 1997;96:I-219. Gijzel AL, Wardeh AJ, van der Giessen WJ, et al. h-energy to prevent restenosis: the Rotterdam contribution to the BERT 1.5 trial-1 yr. follow-up. Eur Heart J 1999;370 (abstract 1945). Verin V, Popowski Y, de Bruyne B, Baumgart D, Sauerwein W, Lins M, Kovacs G, Thomas M, Calman F, Disco C, Serruys PW, Wijns W, Dose-Finding Study Group. Endoluminal beta-radiation therapy for the prevention of coronary restenosis after balloon angioplasty. N Engl J Med 2001;344:243 – 9. Results from late-breaking clinical trials sessions at ACC 2001. J Am Coll Cardiol 2001;38:595 – 612. Shirai K. The radiance P-32 Rdx balloon in saphenous vein grafts: a comparison of de-novo and in-stent restenotic lesions in the SVG Brite Trial. Presented at ACC 2003. Hoher M, Wohrle J, Wohlfrom M, Kamenz J, Nusser T, Grebe OC, Hanke H, Kochs M, Reske SN, Hombach V, Kotzerke J. Intracoronary beta-irradiation with a rhenium-188-filled balloon catheter: a randomized trial in patients with de novo and restenotic lesions. Circulation 2003;107(24):3022 – 7.
R. Waksman et al. / Cardiovascular Radiation Medicine 4 (2003) 54–63 [27] Albiero R, Adamian M, Kobayashi N, Amato A, Vaghetti M, Di Mario C, Colombo A. Short- and intermediate-term results of (32)P radioactive beta-emitting stent implantation in patients with coronary artery disease: The Milan Dose – Response Study. Circulation 2000; 101:18 – 26. [28] Moses J. IRIS trials low-activity 32P stent. Advances in cardiovascular radiation therapy III, Washington, DC 1999;387 – 8 (abstract). [29] Albiero R, Nishida T, Adamian M, Amato A, Vaghetti M, Corvaja N, Di Mario C, Colombo A. Edge restenosis after implantation of high activity (32)P radioactive beta-emitting stents. Circulation 2000; 101:2454 – 7.
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[30] Serruys PW, Kay IP. I like the candy, I hate the wrapper: the (32)P radioactive stent. Circulation 2000;101:3 – 7 (editorial). [31] Wexberg P, Siostrzonek P, Kirisits C, et al. High activity radioactive BX — stents for reduction of restenosis after coronary interventions: the Vienna P-32 dose response study. Circulation 1999; 100:I-156. [32] Wardeh A, Albiero R, Kay IP, Knook AH, Wijns W, Kozuma K, Nishida T, Ferrero V, Levendag PC, van der Giessen WJ, Colombo A, Serruys PW. Angiographic follow-up after radioactive ‘‘cold ends’’ stent implantation: a multicenter trial. Circulation 2002; 105(5):550 – 3.
Beta emitter systems and results from clinical trials State of the art Ron Waksman a,*, Albert Raizner b, Jeffrey J. Popma c a
Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010, USA b Methodist Hospital, Houston, TX 77030, USA c Brigham & Women’s Hospital, Boston, MA 02215, USA
Received 1 August 2003; received in revised form 12 August 2003; accepted 12 August 2003
Abstract
Vascular brachytherapy has been established as the standard of care for the treatment of in-stent restenosis (ISR). Both beta and gamma emitters are currently in use for the prevention of ISR recurrence. The use of beta sources for vascular application is attractive from both the radiation exposure and safety points of view, and a wide variety of beta sources are available for this application. This review is intended to summarize the clinical trials utilizing beta emitter systems for the treatment of ISR and de novo lesions and their subsequent results. D 2003 Elsevier Inc. All rights reserved.
Keywords:
Radiation; Restenosis; Vascular brachytherapy
1. Introduction Vascular brachytherapy using beta and gamma radiation has revolutionized the treatment of restenosis following coronary stent placement and may also be useful in preventing the initial restenotic event in patients undergoing balloon angioplasty and stent placement. Annually, there are 900,000 coronary angioplasties performed on de novo and restenotic lesions in the United States alone [1]. Despite the widespread application (70 – 80%) of stent implantation to reduce restenosis, 15 – 35% of these patients still develop restenosis, usually within 6 –9 months after the procedure [1,2]. Accordingly, nearly 200,000 patients develop in-stent restenosis (ISR) in this country each year. Attempts to expand vascular brachytherapy for use in de novo lesions were initially encouraging but its use in this setting has lost momentum with the encouraging results of the drug-eluting stent technology. The question of vascular brachytherapy utilization for de novo lesions remains viable but unanswered, especially with the mixed results reported with
* Corresponding author. Tel.: +1-202-877-8575; fax: +1-202-8772715. E-mail address: [email protected] (R. Waksman). 1522-1865/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1522-1865(03)00169-0
drug-eluting stents on difficult subsets of patients and its associated costs. The beta isotopes currently in preclinical or clinical use include 90-Yttrium (90Y), 90-Strontium (90Sr/ Y), 32Phosphorus (32P), 106-Ruthenium (106Ru), 133-Xenon (133Xe), 186-Rhenium (186Re), and 188-Rhenium (188Re). The clinical implication is that beta emitters are very effective in smaller vessels ( < 4 mm) but may lose their ability to deliver adequate amounts of radiation in larger vessels ( z 4 mm), such as saphenous vein grafts of peripheral vessels. This review is intended to give an overview of beta emitter systems and summarize the current status of clinical trials utilizing beta radiation therapy.
2. Beta emitter systems in vascular brachytherapy There are three systems of beta emitters currently in use: the Beta-Cath System (Novoste, Norcross, GA), the Guidant GALILEO Intravascular Radiotherapy System (Guidant, Houston, TX), and the RDX Radiation Delivery System (Radiance Medical, San Diego, CA). The Beta-Cath System (Fig. 1) is a proprietary catheterbased delivery system that delivers localized beta radiation to a coronary artery at the site of coronary intervention. Used immediately after percutaneous transluminal coronary
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The Guidant GALILEO System (Fig. 2) consists of three components: a source wire containing 32P, a source delivery unit or afterloader, and a centering catheter, which has a perfusion balloon that centers the source wire within the artery and allows for side branch and distal perfusion during the active radiation treatment. The system allows for a short dwell time, the centering of the radiation source allows for a more controlled delivery, and the afterloader provides an automatic ‘‘hands-off’’ application to deliver and retrieve the source [4]. The RDX System (Fig. 3) uses a 32P isotope incorporated directly into the balloon material of a PTCA-type catheter using a trilayer sealed source design. The expanded balloon provides centering but at the expense of obstructing flow during the dwell time, thus mandating a sequential inflation/ deflation program. Additionally, direct vessel apposition of the source reduces the required activity to deliver
Fig. 1. Beta-Cath System (Novoste, Norcross, GA).
angioplasty (PTCA), the system is composed of two separate components: the transfer device, which contains a radiation source train, and the delivery catheter, which is a single-use, self-centering, multilumen catheter that is positioned at the coronary artery treatment site. The radiation source train is delivered to the treatment site and returned to the transfer device using a saline-injected hydraulic system. The system functions as a closed loop system in which the radioactive source is never directly in contact with the patient’s blood or tissue [3].
Fig. 2. Guidant GALILEO III Intravascular Radiotherapy System (Guidant, Corporation, Houston, TX).
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Fig. 3. RDX Radiation Delivery System (Radiance Medical, San Diego, CA).
therapeutic doses to the target tissue, allowing simplistic shielding and a disposable device design [5].
3. Beta radiation clinical trials for ISR 3.1. Beta WRIST Beta Washington Radiation for In-Stent Restenosis Trial (WRIST) examined the efficacy of beta radiation for prevention of ISR using a design similar to original WRIST [6]. This registry included 50 patients who were treated for ISR in native coronaries, 2.5 –4.0 mm in diameter with lesions < 50 mm in length. Beta radiation using a 90Y source was administered using a centering catheter and an afterloader system. Clinical outcomes of these patients were compared to those of the original WRIST cohort (randomized to either placebo or 192Ir). Angiographic restenosis at 6 months in Beta WRIST was 22% with a late total occlusion rate of 12%. In comparison to the historical control group of WRIST, Beta WRIST patients demonstrated a 58% reduction in the rate of target lesion revascularization (TLR) and 53% reduction in target vessel revascularization (TVR) at 6 months ( P < .001). No differences were detected in comparison to the gamma-radiated patients of WRIST. The clinical benefit was maintained at a 2-year follow-up with the beta radiation reducing TLR (42% vs. 66%; P = .016), TVR (46% vs. 72%; P = .009), and major adverse cardiac events (MACE) (46% vs. 72%; P = .008) compared to placebo. The efficacy of beta and gamma emitters for the treatment of ISR appeared similar at longer term follow-up. 3.2. START and START 40/20 A pivotal multicenter randomized trial, stents and radiation therapy (START), involved 476 patients in over 55 centers throughout the United States and Europe and was designed to determine the efficacy and safety of the Beta-
Cath System for the treatment of ISR [7]. Patients were randomized to either placebo or an active radiation train 30 mm in length. The inclusion criteria were single ISR lesions >50% (by visual assessment) in native coronary target vessels between 2.7 and 4.0 mm in diameter. The target lesion (V20 mm) required treatment with a 20-mm balloon and a 30mm source train. In the radiated patients, the mean lesion length was 16.3 mm in arteries and 2.8 mm in diameter. After successful angioplasty, these patients were treated with the Beta-Cath System containing 90Sr/ Y seeds, delivering beta radiation through a closed-end lumen catheter. The dose prescribed at a point 2 mm from the center of source axis was based on visual assessment of reference vessel diameter (RVD); 18.4 Gy in RVD z2.7 to V3.3 mm and 23 Gy in RVD >3.3 to V4.0 mm. The duration of the antiplatelet therapy was initially based on operator preference and was modified in early 1999 to at least 90 days of clopidogrel 75 mg/qd following recommendations from the Beta-Cath Trial Data Safety Monitoring Board, where late thrombosis as a complication of brachytherapy was first recognized. At 8 months, the angiographic restenosis rate in the irradiated segments was 24% versus 46% in the placebo group ( P < .001). In the irradiated group, TLR was 13% as compared to 22% in control ( P =.008), with similar reductions of TVR (16% vs. 24%; P =.028) and MACE (18% vs. 26%; P =.026). There were late thrombotic events in radiated patients. During multiple studies of radiation, including START, the medical community became aware of the mismatch between the interventional injury length and radiation length, the so-called ‘‘geographic miss’’ phenomenon, with its potential to compromise clinical outcome [8]. The START 40/20 trial was a 207-patient registry that mirrored START and ensured an adequate irradiation margin with 10 mm of radiation therapy applied proximal and distal to the injury zone (additional 5 mm each end) [9]. In comparison to the START population, START 40/20 patients were older, had more unstable angina, and more prior treatments for ISR, with similar angiographic indices including RVD and lesion length. Compared to the control arm of START, patients in START 40/20 had a 44% reduction in restenosis in the analysis segment compared to 36% in radiated arm of START; a 50% reduction in TLR ( P =.002) compared to 42% in radiated arm of START; a 34% reduction in TVR ( P =.03) compared to 34% in START, and a 26% reduction in MACE ( P =.10) compared to 31% in the irradiated arm of START. While the START 40/20 registry showed no deleterious effects of adding 10 mm of length to the source train, there was a lack of a relationship between ‘‘geographic miss’’ and clinical or angiographic outcomes for ISR. 3.3. Intimal Hyperplasia Inhibition with Beta In-stent Trial The Intimal Hyperplasia Inhibition with Beta In-stent Trial (INHIBIT) was a multicenter randomized study
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involving 332 patients in 29 U.S. and international sites, which examined the efficacy of the GALILEO System for the treatment of ISR [10]. The GALILEO System uses a 32 P source delivered in a centered delivery catheter with a dose of 20 Gy to a depth of 1 mm into the vessel wall. This system provides the potential advantage of a more homogenous dose distribution, reduced radiation exposure, and a perfusion balloon to ensure distal vessel flow during treatment dwell time. The study mandated at least 3 months of antiplatelet therapy and 307 patients completed 9 months of clinical follow-up. Radiation was delivered successfully in 315 patients, was tolerated well in all but 2 patients, and there were no adverse effects related to the radiation procedure. At 9 months, treatment with 32P reduced the primary angiographic endpoint of binary restenosis by 67% ( P =.0001) in the stented segment and by 50% ( P =.0003) in the analysis segment. There were no differences in the edge effect rates between the active and the control-treated groups. The radiated patients had reduced late loss (0.4 vs. 0.6 mm; P < .001) and improved minimal lumen diameter (MLD) (1.52 vs. 1.38 mm; P =.01). At 9 months, 32P significantly reduced rates of TLR (11% vs. 29%; P < .001) and MACE (14% vs. 31%; P < .001). Tandem positioning to cover more diffuse longer lesions >22 mm with 32P was safe and equally effective. 3.4. GALILEO INHIBIT GALILEO INHIBIT is an international multicentered registry of 120 patients with ISR treated with an automatic afterloader (Guidant GALILEO Radiotherapy System) via a helical centering balloon. 32P delivered at 20 Gy at 1 mm into vessel wall reduced the primary clinical endpoint defined as MACE TLR at 9 months by 49% ( P = .003). The thrombosis rate was low, 1.5%, and similar to the control group, 1.2%. Treatment with 32P reduced the primary angiographic endpoint of binary restenosis by 74% ( P < .0001) in the stented segment and by 27% ( P =.036) in the analysis segment [11]. 3.5. Beta Radiation to Prevent In-stent Restenosis Beta Radiation to Prevent In-stent Restenosis (BRITE) is a U.S. feasibility study to test the RDX Radiation System, which uses a balloon catheter encapsulating a 32P radioactive sleeve for the treatment of ISR. In the BRITE trial, 27 patients were treated with PTCA (26 balloon, 1 rotoblator) for lesions < 25 mm in length. Following intervention, the catheter was successfully delivered in all but 1 patient. The prescribed dose mean was 19.8 F 0.4 Gy at 1 mm from the inflated source surface and delivered in an average dwell time of 482 F 39 s. Seventy percent of the dose was administered when the balloon was inflated. The transit time was 8.5 s and no cases were interrupted. All patients were treated with clopidogrel, 75 mg daily for 3 months. There were no procedural complications or MACE at a
57
30-day clinical follow-up. At 6 months, TVR (3.7%), MACE (3.7%), and angiographic binary restenosis rates (7.7%) were the lowest reported to date in any vascular brachytherapy series [12]. The specific dosimetry and source apposition characteristics of the RDX system may have contributed to these encouraging results. 3.6. BRITE II The objective of the BRITE II study was to evaluate the efficacy of beta radiation using the RDX System (‘‘hot balloon,’’ incorporating a solid 32P h-isotope into the balloon material using a tri-layer-sealed source design) versus placebo for the prevention of reintervention of instent restenotic lesions in native coronary arteries measured by clinically driven TVR at 9 months. Four hundred and twenty-nine patients were randomized to either radiation (n = 321) or placebo (n = 108). The RDX System demonstrated safety characterized by high technical success rates (>95%), low periprocedural complications ( < 1%), and low 30-day MACE ( < 1%). The most prevalent location of restenosis was within the radiated vessel outside of the injured zone despite lower rates of geographical miss (8.5%). Final analysis is not complete, but the RDX System met the study assumption of a 42% reduction in TVR with significant improvement over placebo. MACE in the irradiated group was lower compared to control 27% versus 45% ( P < .02). The RDX System demonstrated a very low ISR rate (10.9% vs. 46.1%) and proved to optimize the results when compared to historical studies. Although the system will probably not be released for marketing due to commercial considerations, the BRITE II study confirmed again in a randomized study the utility of vascular brachytherapy for the treatment of ISR [13]. 3.7. 4R 4R is a South Korean registry evaluating h-radiation therapy with a 188Re-MAG3-filled balloon following rotational atherectomy for diffuse ISR (length >10 mm). Radiation was delivered successfully to 50 patients with a dose of 15 Gy at 1.0 mm into the vessel wall. The mean irradiation time was 201.8 F 61.7 s. No adverse events occurred during the follow-up period (mean 10.3 F 3.7 months). Six-month binary angiographic restenosis rate was 10.4%. Two potential limitations of this technology include reduced dosing at the balloon margins (edge effect) and the risks of balloon rupture with radiation spill. In the event of balloon rupture using 188 Re, concomitant administration of potassium perchlorate may mitigate thyroid uptake [14]. 3.8. Columbia University Restenosis Elimination The Columbia University Restenosis Elimination (CURE) Study evaluated liquid 188Re injected into a perfusion
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with a 20-mm balloon) de novo or restenotic lesions in different vessels who have undergone stand-alone PTCA or who are candidates for provisional stent placement. In the initial 149 patients, 6-month and 1-year rates of TVR with PTCA were 22% and 31%, respectively [17] (for a summary of the studies performed, see Table 1).
balloon; 30 patients were treated with balloon alone and 30 patients were stented (with subsequent 188Re therapy). The delivered dose was 20 Gy to the balloon surface with a dwell time of 6.9 F 2.2 min. At 12 months follow-up in the first 37 patients, the rate of TLR-free survival was 75% [15]. 3.9. RENO AND BRIE Other studies assessing the efficacy of beta radiation are currently underway. Registry Novoste (RENO) is an active registry of 1098 consecutive patients treated in 46 centers in Europe and the Middle East with the Novoste Beta-Cath System. Six-month follow-up data were obtained for 1085 patients. Of 1174 target lesions, 94.1% were located in native vessels and 5.9% in a bypass graft; 17.7% were de novo lesions, 4.1% were restenotic, and 77.7% were in-stent restenotic lesions. Intravascular brachytherapy was technically successful in 95.9% of lesions. Angiographic followup was available for 70.4% of the patients. Nonocclusive restenosis was seen in 18.8% and total occlusion in 5.7% of patients [16]. The Beta Radiation in Europe (BRIE) Study was designed to evaluate the safety and efficacy of the BetaCath System in patients with up to two discrete (treatable
4. Beta radiation clinical trials for de novo lesions Large-scale clinical studies testing the effectiveness of beta radiation for de novo, restenotic, and in-stent restenotic lesions have paralleled the encouraging results of gamma radiation. Important early studies included the Geneva trial [18], which used 90Y, the dose-finding Beta Energy Restenosis Trial (BERT), which used 90Sr/ Y [19], and the Proliferation Reduction with Vascular Energy Trial (PREVENT) that utilized 32P emitter [20]. 4.1. Beta Energy Restenosis Trial BERT was a feasibility study limited to 23 patients enrolled at two centers (Emory and Brown Universities). The study was designed to test the 90Sr/ Y source delivered
Table 1 Clinical trials for ISR using catheter-based systems with beta radiation Study name
Design
Radiation system
Isotope and dose (Gy)
Results and status
90
Completed. Restenosis rate of 22% at 6 months. MACE 46% at two years. Similar results to the gamma wrist group. Completed. Demonstrated reduction of 50% in restenosis (analysis segment) and 55% in MACE. Completed. Showed reduction in TLR, TVR, and MACE (35%) in the irradiated group. No late thrombosis. Completed. 50%, 34%, and 26% reduction in TLR, TVR, and MACE, respectively. Completed. TVR, MACE, and restenosis rates were 3.7%, 3.7%, and 7.7%, respectively, at 6 months. ISR 10.9% and geographical miss 8.5% at 9 months. 10.4% restenosis rate at 6 months.
Beta WRIST
Registry for 50 patients with ISR in native coronaries.
A centering catheter and an afterloader system.
Y, 20.6 Gy at 1 mm from surface.
INHIBIT
Multicenter, double-blind, randomized trial involving 332 patients. Multicenter, randomized, double-blind design involving 476 patients. 207 patients with more prior treatments for ISR than in START. Feasibility study of 27 patients with ISR lesions <25 mm. Randomized study involving 429 patients. South Korean registry of 50 patients with ISR>10 mm.
GALILEO System using a centered delivery catheter.
32
P, 20 Gy at 1 mm into vessel wall.
Beta-Cath System — 30 mm source train.
90 Sr/ Y, 18 – 20 Gy at 2 mm from center of source axis.
Beta-Cath System — 40 mm source train.
90
RDX System with balloon catheter.
32 P, 20 Gy at 1.0 mm from the balloon surface.
RDX System.
32
Liquid-filled balloon following rotational atherectomy. Liquid injected into perfusion balloon. Guidant GALILEO System automatic afterloader via a helical centering balloon. Beta-Cath System.
188 Re-MAG3, 15 Gy at 1 mm into the vessel wall.
START
START 40/20 BRITE
BRITE II 4R
CURE GALILEO INHIBIT
Open-label registry of 60 patients. International multicenter registry of 120 patients.
BRIE
Registry of 149 patients.
SVG BRITE
Feasibility study. 49 patients enrolled; 25 with ISR.
RDX System using hot balloon.
Sr/ Y, 18 – 20 Gy at 2 mm.
P, 20 Gy at 1 mm.
188
Re, 20 Gy to balloon surface.
32
P, 20 Gy at 1 mm into vessel wall.
90
Sr/ Y, 14 – 18 Gy at 2 mm from the centerline of the source axis. 32 P, 20 Gy at 1 mm from balloon surface.
TLR-free survival was 75% in first 37 patients at 12 months. MACE TLR reduced by 49% with 1.5% thrombosis rate.
TVR rates with PTCA were 22% and 31% at 6 months and 1 year follow-up, respectively. 36% TVR and 26% restenosis rates at 1 year.
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by a prototype hydraulic delivery system (Novoste, Norcross, GA) [19]. The prescribed doses in this study were 12, 14, or 16 Gy and the treatment time did not exceed 3.5 min. The radiation was successfully delivered 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. One patient underwent stent implantation to a segment proximal to the irradiated site. Angiographic follow-up at 6 months assessed by QCA detected late loss of 10% with a late loss index of 5%. The Canadian arm of this study included 30 patients from the Montreal Heart Institute utilizing the same system under the same protocol [21]. At 6 months follow-up, the angiographic restenosis rate was 10% with negative late loss and late loss index. Intravascular ultrasound (IVUS) analysis of this cohort demonstrated larger lumen at 6 months follow-up with reduction of the wall area. The European arm of the BERT (BERT 1.5) was conducted at the Thoraxcenter in Rotterdam, The Netherlands, in an additional 30 patients who were treated successfully with balloon angioplasty. Angiographic restenosis in this cohort was higher than reported in the U.S. and Canadian trials. Overall, the restenosis rate based on 64 of the 80 patients in the BERT series was 17%, and the late loss and late loss index were below 5%. Over 50% of the patients had larger MLD at follow-up compared to control, and a substudy of IVUS demonstrated vessel remodeling at the irradiated site [22].
59
wire and a centering catheter was safe and effective in reducing neointimal formation within the target site in patients undergoing PTCA. However, caution should be exercised so as to not injure the vessels proximal and distal to the radiation source (‘‘geographic miss’’) and with the unbridled use of new stents, which increase that late subacute thrombosis rate [20]. 4.3. Dose-Finding Study Group The Dose-Finding Study Group was a prospective, randomized, multicenter, dose-finding trial. The primary objective was to determine the effect of 9, 12, 15, and 18 Gy of beta radiation (90Yttrium) at a tissue depth of 1 mm on restenosis rates after PTCA in de novo lesions. Of the 183 patients randomized, 181 received the prescribed doses of beta radiation: 45 received 9 Gy, 45 received 12 Gy, 46 received 15 Gy, and 45 received 18 Gy. Stenting after radiation was required in 47% of the patients because of residual stenosis or major dissection. At 6 months angiographic follow-up, a significant dose-dependent benefit was evident. There was abrupt thrombosis or late occlusion of the target vessel in 4 out of 120 (3.3%) patients who were treated with only balloon angioplasty and in 7 of the 49 (14.3%) patients who received new stents. This study demonstrated a marked dose –response reduction in restenosis in nonstented arteries after administration of 18 Gy of beta radiation, especially in patients who underwent plain balloon angioplasty, suggesting that beta radiation therapy should be evaluated as an adjunct to PTCA [23].
4.2. Proliferation Reduction with Vascular Energy Trial 4.4. Beta-Cath PREVENT was a prospective, randomized, sham-controlled, multicenter study of 105 patients with de novo (70%) or restenotic (30%) lesions who were randomized to either placebo or three different doses of 32P beta radiation (16, 20, and 24 Gy to a depth of 1 mm into the artery wall) to prevent restenosis after PTCA or stenting. The binary restenosis rate at 6 months angiographic follow-up was 8.2% at the target site for the radiation-treated group versus 39.1% for the control group ( P = .001). Restenosis at the target site, including its 5 mm proximal and distal margins, was 22.4% for patients who received treatment versus 50.0% for the control group ( P = .02) [3]. Late (12 months) MACE [death, myocardial infarction (MI), and TLR] occurred in 13 (16%) patients in the brachytherapy group and in 6 (24%) control patients ( P = NS). If TVR is included, MACE occurred in 26% versus 32% ( P = NS), respectively. The occurrence of MI due to thrombotic events after discharge happened in seven patients who received radiotherapy but in no patients from the control group. Lumen narrowing adjacent to the target site, the so-called ‘‘edge effect,’’ contributed significantly to the diminution of the clinical benefit. Prolonged antiplatelet therapy and a reduced use of new stents at the time of radiation were recommended to minimize these complications. PREVENT showed that beta radiation with a 32P source
The Beta-Cath System trial was the first prospective, randomized, multicenter trial in 1455 patients designed to assess the value of vascular brachytherapy for the prevention of restenosis in de novo lesions. Patients who had an acceptable ‘‘stand alone’’ balloon angioplasty results were assigned to treatment with a 30-mm 90Sr/ Y source train or sham. Patients with a suboptimal result after balloon angioplasty were treated with a stent and then assigned to 90Sr/ Y or placebo treatment [24]. The primary endpoint of the study was an 8-month target vessel failure (TVF) (death, MI, TVR). The inclusion criteria included a single lesion and single vessel intervention with a de novo or restenotic lesion >50% (by visual assessment) in vessels between 2.7 and 4.0 mm RVD. The radiation dose prescription point was calculated at 2 mm from center of source axis: 16.1 Gy in RVD z2.7 to V3.3 mm and 20.7 Gy in RVD >3.3 to V4.0 mm. Baseline demographic and angiographic characteristics were similar between groups. In patients treated with balloon angioplasty alone, 90Sr/ Y was administered in 264 patients and placebo was administered in 240 patients. The 240-day TVF rate tended ( P = .06) to be lower in patients treated with
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90
Sr/ Y (14.2%) than in patients treated with placebo (20.4%). This beneficial effect was attributable to a reduction in angiographic restenosis within the initial lesion site in patients treated with 90Sr/ Y (21.4% vs. 34.3% in placebo-treated patients; P = .003), although the restenosis rates were similar in the entire analysis segment, including the radiation margins (31.0% vs. 36.0%; P = .27). The loss of benefit at the treatment margins is attributable to ‘‘geographic miss’’ due to the relatively short treatment length in the study. In patients treated with the new stents and short-term antiplatelet therapy, late (>30 day) thrombotic stent occlusion was found and the antiplatelet therapy was extended to 6 months in patients with a new stent. In the 452 patients treated with extended antiplatelet therapy who received a new stent, there were no differences in the 240-day TVF rate (23.9% in 90Sr/ Y-treated patients vs. 20.8% in patients treated with placebo). These results were again attributable to short radiation lengths and ‘‘geographic miss.’’ This Beta-Cath study was the first to identify the higherthan-expected rate of late stent thrombosis when radiation was used with new stent implantation. The primary clinical endpoint, TVF, was not shown to be significantly lower in the combined radiation arms compared with combined placebo arms. The paradox of positive treatment effect for 90Sr/ Y seen in lesion segment analysis and the negative treatment effect of 90Sr/ Y seen in the analysis segment likely explains the negative treatment effect of 90Sr/ Y on clinical restenosis in stents and merits further investigation. ‘‘Geographic miss’’ may have contributed to the negative results of 90Sr/ Y. The overall positive results in the lesion segment analysis and the strong trends in the clinical outcomes in the PTCA branch suggest a potential role for 90Sr/ Y radiation in the treatment of de novo coronary lesions if the increase of restenosis in the ‘‘analysis segment’’ can be solved. 4.5. SVG BRITE This study was a feasibility study examining the RDX System using hot balloon with 32P emitter and a dose of 20 Gy at 1 mm from the balloon surface in saphenous vein grafts. In this study, 49 patients were enrolled; 24 of these were treated for de novo lesions. New stents were implanted in most patients with de novo lesions. The outcome of the patients with the de novo lesions was encouraging with only 8% 12-month TVR rate and 13% angiographic restenosis rate from the entire analysis segment (allowing for edge effects) after beta brachytherapy of de novo SVG lesions. While caution is in order given the small number of patients studied and the lack of a concurrent control population, these data warrant further investigation of this promising application, especially as the efficacy of potential alternatives, such as drug-eluting stents, has not yet been investigated in SVG lesions [25].
4.6. ECRIS ECRIS is a randomized trial in patients with de novo and restenotic lesions using a 188Re-filled balloon catheter reported by Martin Ho¨her from Ulm conducted in a single center. In the study, 225 patients (71% de novo lesions) were randomly assigned to receive 22.5 Gy intravascular h-irradiation in 0.5 mm tissue depth (n = 113) or to receive no further intervention (n = 112). Clinical and procedural data did not differ between the groups, except a higher rate of stenting in the control group (63%) compared with the 188Re group (45%; P < .02). After 6 months follow-up, late loss was significantly lower in the irradiated group compared to the control group, both of the target lesion (0.11 F 0.54 vs. 0.69 F 0.81 mm; P < .00000003) and of the total segment (0.22 F 0.67 vs. 0.70 F 0.82 mm; P < .00002). This was also evident in the subgroup of patients with de novo lesions and independent from stenting. Binary restenosis rates were significantly lower at the target lesion (6.3% vs. 27.5%; P < .00008) and of the total segment (12.6% vs. 28.6%; P < .007) after 188Re brachytherapy compared to the control group. TVR was significantly lower in the 188Re (6.3%) compared to the control group (19.8%; P =.006). The authors concluded that intracoronary h-brachytherapy with a 188Re liquid-filled balloon is safe and efficiently reduces restenosis and revascularization rates after coronary angioplasty [26] (for a summary of the studies performed, see Table 2).
5. Radioactive stents In contrast to brachytherapy using removable sources, radioactive stents (permanent implants) have beta-emitting atoms (32P) on the stent surface and emit beta particles that are absorbed by neointimal tissue to a depth of 1 –2 mm into the vessel wall over longer periods of time. This isotope was selected because of its short half-life, minimal tissue exposure, and relative safety. In radioactive stents with activity levels of 0.75 to 12 ACi, the total dose of 8 to 140 Gy is delivered to the tissue at 0.5 mm from the stent surface over a 28-day period [27]. The first clinical trials included the IRIS trials, the Milan dose-finding study, and the Vienna experience. In the IRIS pilot trials, 32P radioactive Palmaz– Schatz stents were developed with varying radioactivities: IRIS 1A 0.5– 1.0 ACi and IRIS 1B 0.75 –1.5 ACi. These stents were implanted with a high rate of technical success but were limited by an angiographic restenosis rate (stent and edges) of 40% at 6 months follow-up [28]. The Milan dose-finding study showed that activities >3 ACi (32P stents 0.75 –12 ACi) profoundly inhibited intimal hyperplasia; however, restenosis still occurred in >40% of lesions at the stent edges, i.e., the ‘‘candy wrapper’’ effect [29,30]. A strategy of less aggressive stent implantation
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Table 2 Clinical trials using catheter-based systems with beta emitters in coronaries for de novo lesions Study name
Design
Radiation system
Isotope and dose
Results and status
Geneva
Open-label registry of 15 patients post-PTCA.
90
Completed. Demonstrated feasibility, safety. Restenosis rate (40%).
BERT
Open-label registry of 23 patients post-PTCA.
BRIE
Registry of 149 patients.
Mechanical loading of fixed wire via a segmented centered balloon. Hydraulic hand delivery of seed train in a noncentered 5.0 F catheter. Beta-Cath System.
BETA-Cath
Multicenter, prospective, randomized, blinded study of 1455 patients post-PTCA and provisional stenting. Prospective, randomized, multicenter dose-finding trial in 183 patients post-PTCA. Multicenter, prospective, randomized, sham-controlled study of 105 patients post-PTCA or stenting. Open-label registry of 60 patients. Feasibility study of 24 patients. Single-center, randomized trial of 225 patients.
Dose-Finding Study Group PREVENT
CURE SVG BRITE ECRIS
Y, 18 Gy to the balloon surface.
90 Sr/ Y, 12, 14, or 16 Gy to 2 mm from source.
Beta-Cath System
90 Sr/ Y, 14 or 18 Gy 2 mm from source axis.
Completed. Restenosis rate of 15% with late loss of 10% and loss index of 5%. TVR rates with PTCA were 22% and 31% at 6 months and 1 year follow-up, respectively. 240-day TVF rate was 14.2% with 31% restenosis rate.
Automatic afterloader of fixed wire via a centered balloon. Automatic afterloader.
90 Y, 9 (n = 45), 12 (n = 45), 15 (n = 46), or 18 (n = 45) Gy at a tissue depth of 1 mm. 32 P, 16, 20, or 24 Gy to 1.0 mm into the artery wall.
Significant dose-dependent benefit was evident at 6 months follow-up. 22.4% restenosis at 6 months with MACE 16% at 1 year.
Liquid injected into perfusion balloon. RDX System using hot balloon. Liquid-filled balloon catheter.
188
TLR-free survival was 75% in first 37 patients at 12 months. 8% TVR and 13% restenosis rates at 1 year. TVR was 6.3% and late loss was significantly lower at 6 months follow-up.
failed to alleviate the edge restenosis problem. These findings were replicated in the Vienna study using high activity (6 –21 ACi) stents [31]. In an effort to circumvent edge restenosis, ‘‘hot-’’ and ‘‘cold-end’’ stents were developed. The theoretical advantage of ‘‘hot end’’ stents was to extend the area of irradiation beyond the balloon injured extremities; this technology failed to prevent edge effect with an angiographic restenosis rate of 33% in 56 implanted stents. ‘‘Cold end’’ stents were developed to prevent remodeling at the injured extremities. Restenosis rates of 22% were not different when compared to nonradioactive stents [32]. In summary, while radioactive stents effectively inhibit intrastent neointimal hyperplasia, the problem of edge restenosis has not been solved with either less aggressive stent implantation or modification of the stent ends. Currently, there is no indication for their clinical use, and the future application of this technology is questionable.
6. Beta versus gamma radiotherapy While contemporaneous clinical trials to date have demonstrated comparability of clinical efficacy of beta and gamma brachytherapy, beta systems have several inherent advantages. Reduced radiation exposure to operators and Cath lab personnel, less shielding requirements, and easier handling of sources have lead to more widespread acceptance of beta technology. Potential limitations of beta
90
Sr/ Y, 14 – 18 Gy at 2 mm from the centerline of the source axis.
Re, 20 Gy to balloon surface.
32 P, 20 Gy at 1 mm from balloon surface. 188 Re, 22.5 Gy at 0.5 mm.
sources in larger vessels (e.g., vein grafts, peripheral arteries, and renal access grafts) may be offset by the use of sources with higher activity, centering mechanisms, and appropriately longer dwell times.
7. Lessons from the clinical trials and optimization of the results The clinical trials have identified three major issues related to the technology, which resulted in complications. These are the late thrombosis, seen more in the gamma studies but also in the beta trials; the edge effect phenomenon, seen primarily with the radioactive stent but also with the use of catheterbased systems; and finally delayed restenosis probably related to initial lower doses. Over the last years, we have come up with solutions to these limitations. Late thrombosis has been nearly eliminated with a minimum of 6 months prolonged antiplatelet therapy (12 months preferred). The edge effect phenomenon has been minimized with the use of wider radiation margins at least 10 mm from the injured segment, and we anticipate that mild escalation in the radiation dose will attenuate the late recurrences rate. In a recent postmarketing surveillance study with the use of the Beta-Cath System, the TVR rate in commercial use of 3,695 patients treated for ISR was 3.8%, demonstrating that the implementation of the lessons learned from the clinical trials results in better outcomes in the real world of angioplasty.
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8. Future perspectives Coronary radiation therapy trials using the beta isotopes Sr/ Y, 90Y, and 32P have all initiated angiographic and clinical benefit in patients with ISR and, to a lesser extent, in those with de novo lesions. The degree of benefit is comparable to gamma radiation, and there may be practical advantages of beta radiation with respect to ease of use in the Cath lab. Vascular brachytherapy using beta radiation may be considered the standard of care in patients with ISR, although further refinements may be useful to define the optimal dose and treatment targets. With the availability of drug-eluting stents, the frequency of ISR may be reduced, but brachytherapy will remain useful in refractory cases of ISR and potentially as an alternative to drug-eluting stent use in patients unfavorable for stenting, such as those with small vessels and long lesions. Additional studies using longer source trains are warranted. Finally, advancements in brachytherapy technology, alternative isotopes with more favorable features, improved operator skills, and refined dosimetry are likely to further improve the short- and long-term outcomes of vascular brachytherapy and potentially expand its application to larger groups of patients.
90
[11]
[12]
[13]
[14]
[15]
[16]
[17]
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