Intracoronary brachytherapy

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Chapter 17 Intracoronary brachytherapy

PRAMOD. KUCHULAKANTI, MD, RON. WAKSMAN, MD

KEY POINTS

image Coronary vascular brachytherapy (VBT), using beta and gamma emitters, has revolutionized the treatment of in-stent restenosis (ISR).
image ISR continues to be a challenge to the interventional cardiology community, despite several advancements in stent technology, including DES.
image VBT is the only Food and Drug administration (FDA) approved technology to treat ISR thus far.

INTRODUCTION TO RADIATION BIOLOGY AND SYSTEMS

Radiation inhibits smooth muscle cell (SMC) proliferation and intimal hyperplasia by intervening in the cell cycle to cause cell death to radiosensitive cells, especially those undergoing mitosis following vascular injury. Radiation acts by absorbing into the target molecules such as DNA, RNA, or enzymes, by interacting with these molecules via formation of highly reactive free radicals, or by inducing programmed cell death, called apoptosis. Radiation may reduce restenosis by inhibiting the first wave of cell proliferation in the adventitia and the media, by inducing favorable remodeling,1 and by suppression of macrophages and adventitial myofibroblasts.2,3

Among several isotopes developed for the use in VBT, only the gamma emitter 192Ir, beta emitters 90Sr/90Y, 32P, 188Rh, and 99W found clinical application. The main platforms that deliver radiation are catheter-based systems such as line source wires, radioactive seeds, radioactive gas and liquid filled balloons, or stents. The latter are no longer used because they created the problem of narrowing at the ends of the stent – the ‘candy-wrapper effect’.

192Ir is administered by the CheckMate system (Cordis Corporation, Miami, FL), which requires manual loading of the radioactive seeds. The AngioRad system (Vascular Therapies, Norwalk, CT) uses a flexible, 30 mm 192Ir wire source. The Galileo system (Guidant Corporation, Irvine, CA) administers 32P with automated stepping technology and a centering balloon. The RDX system (Radiance Medical, San Diego, CA) also administers 32P, however, the isotope is incorporated directly into the balloon material of the PTCA-type catheter. 90Sr/Y is administered by BetaCath system (Novoste Corporation, Norcross, GA), which employs a hydraulic technique to deliver the radioactive seeds. 188Re is obtained from the 188W/188Re radionuclide generator as a solution which is injected into the coronary dilatation balloon and can be applied at the target by inflating the balloon.

EXPERIMENTAL FOUNDATION OF BRACHYTHERAPY

Brachytherapy evolved into clinical practice based on firm and elaborate experimental animal data. These involved external beam radiation by Schwartz et al.,4 catheter based systems by several investigators utilizing gamma radiation with 192Ir (Waksman et al. at Emory University,5,6 Wiedermann et al. at Columbia University,7,8 and Raizner et al. at Baylor University9), using beta radiation with 90Sr/Y (Verin et al.11, Waksman12), and beta radiation with 32P by Raizner et al. All these investigators have shown reduction in neointimal hyperplasia in the irradiated arteries utilizing doses ranging from 6-56 Gy.

Further experiments have been conducted using radioactive stents by Fischell et al.13 Hehrlein et al.,14,15 Laird et al.16,17 Radioactive stents, which were implanted in an atherosclerotic pig model, failed to show superiority over control non-radioactive stents with any of the treated doses at six months.17

Waksman et al.,18 Weinberger et al.,19 Robinson et al.,20 Makkar et al.,21 and Kim et al.22 used liquid isotope-filled balloons to irradiate porcine coronaries. The emitters used for this technology were 133Xenon, 188Re (14 Gy), and 166Ho (9, 18 Gy). These pre-clinical studies showed reduction in neointimal tissue as assessed by IVUS and histomorphometry. The concept of the radioisotope filled balloons is attractive because it has the advantages of centering and ease of use; however, a potential leakage hazard is of great concern.

Long-term animal studies utilizing beta and gamma emitter sources were disappointing

Although salutary effects were reported by Wiedermann and Waksman in six-month studies utilizing gamma and beta radiation, data with beta emitters (32P and 90Sr/Y) were associated with increased mortality, thrombosis, and neointima formation compared to control. Few of the observations in long-term animal studies are reproduced in humans such as late thrombosis, delayed restenosis, and inferior results with additional stenting. The discrepancy between the long-term animal results and the human results at 3–5 years follow up can be explained by the differences in the species, normal porcine coronary artery versus atherosclerotic human coronary artery, and the age of the animals.

CLINICAL TRIALS

Several series of clinical trials were conducted to understand the safety, efficacy, and durability of VBT mainly in the US and Europe. While both gamma and beta radiations were studied for the treatment of ISR, only beta sources were studied for de novo lesions. Detailed discussion of the clinical trials is out of scope for this chapter, but a brief summary of the landmark clinical trials conducted thus far with gamma and beta emitters is presented. Salient features of the studies published in major journals are shown in Table 17.1.

TABLE 17.1 RESULTS OF MAJOR CLINICAL TRIALS WITH GAMMA AND BETA RADIATION PUBLISHED IN PEER REVIEWED JOURNALS, ARRANGED IN CHRONOLOGICAL ORDER

image

Clinical trials of gamma radiation

The first study of intracoronary radiation in human coronary arteries was conducted in 1994 by Condado et al. in which 21 patients (22 lesions – two-thirds being de novo lesions) were treated with 192Ir after routine balloon angioplasty. On angiographic follow up at six months, a binary restenosis rate of 28.6% was reported,23 which remained the same at five years. Angiographic complications included four aneurysms (two procedure related and two occurring within three months). At three and five years, all aneurysms except one remained unchanged and no other angiographic complications were observed.24

Gamma radiation for in-stent restenosis

The efficacy of 192Ir in reducing clinical and angiographic restenosis in patients with in-stent restenosis was confirmed by a number of studies, including two single-center trials, SCRIPPS and WRIST; and multicenter trials, GAMMA-1 and −2; and ARTISTIC.

SCRIPPS trials

Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting (SCRIPPS) was the first randomized trial to evaluate the safety and efficacy of intracoronary γ radiation as adjunctive therapy to stents. Follow up at six months and three years showed significantly lower restenosis rates in the 192Ir group − 17% and 33%, respectively, compared to placebo (54% and 63%). A subgroup analysis of the 35 patients enrolled due to ISR showed a 70% reduction in the recurrence rate in the irradiated group compared to placebo.25,26 There were no evident clinical complications resulting from the radiation treatment, and clinical benefits were maintained at five years, with a significant reduction in the need for target lesion revascularization (TLR).27

SCRIPPS II for ISR in diffuse lesions (30–80 mm), SCRIPPS III with prolonged antiplatelet therapy (6–12 months of Plavix®), and SCRIPPS IV to evaluate higher doses (17 Gy versus 14 Gy) followed the original SCRIPPS study and have shown, respectively, that radiation is effective for diffuse lesions, that prolonged platelet therapy reduces late thrombosis and additional stenting is to be avoided, and that optimization of radiation dose improves the outcomes further in diffuse lesions.

Washington Radiation for In-Stent restenosis Trial (WRIST) series

Original WRIST was the first study to evaluate the effectiveness of radiation therapy in patients with ISR. In this study, 130 patients (100 with native coronaries and 30 with saphenous vein grafts) with ISR lesions (up to 47 mm in length) were randomized to receive either 192Ir or placebo. At six months, the radiation group showed a reduction in restenosis (19% vs. 58% in placebo) and 79% and 63% reduction in the need for revascularization and MACE, respectively, compared to placebo.28 Extended follow up of these patients showed durable beneficial effect of radiation at one year, three years29 and five years30 in MACE rates compared to placebo. MACE rates were significantly lower at five years follow up, albeit at the expense of repeat revascularization procedures suggesting that radiation may delay, in part, the biological processes and that a late catch-up phenomena or late thrombosis will reduce the long-term benefit of radiation.

Other landmark trials in this series were SVG-WRIST which evaluated the effect of radiation therapy in patients with diffuse ISR lesions in saphenous vein grafts,31 Long WRIST in patients with diffuse ISR in native coronary arteries (lesion length 36 to 80 mm),32 Long WRIST High Dose which tested the efficacy of an 18 Gy dose of radiation, WRIST Plus and WRIST 12 which tested the efficacy of prolonged Clopidogrel therapy (up to 6 months and 12 months, respectively) to reduce the incidence of late thrombosis, and WRIST 21 which tested whether escalation of radiation dose to 21 Gy would improve the clinical outcomes beyond Long WRIST High Dose. These studies have demonstrated superiority of radiation therapy in the treatment of ISR in vein graft disease (SVG-WRIST) and diffuse lesions (Long WRIST). The Long WRIST High Dose registry showed that a 3 Gy increase in the dose, from 15 to 18 Gy, provided additional reduction in MACE rates.33 The strategy of prolonged antiplatelet therapy for six months in WRIST Plus reduced thrombosis rates from 9.6% to 2.5% – levels comparable to non-irradiated controls.34 WRIST 12 has demonstrated further reduction in MACE and TLR with 12 months of Clopidogrel therapy.35 Based on these observations, it has become standard practice to provide at least 12 months of Clopidogrel therapy for patients undergoing radiation therapy for ISR. Further escalation of dose from 18 Gy to 21 Gy was studied in WRIST 21 but has not been shown to improve the results. Hence, a dose of 18 Gy may be sufficient to treat ISR with γ radiation.

GAMMA trials

GAMMA-1, a multicenter, randomized trial conducted with IVUS-guided dosimetry, showed significant reductions in the in-stent and in-lesion restenosis rates compared to 50.5% and 55.3% in the control group. The greatest benefit was obtained in patients with long lesions and/or diabetes. In this study, it was observed that the late thrombosis phenomenon was more frequent in patients treated with radiation therapy than with placebo (5.3% vs. 0.8%). All patients in the 192Ir group who presented with late thrombosis had new stents placed within the in-stent target lesion at the time of the procedure.36 This trial demonstrated the efficacy of intracoronary gamma radiation for the prevention of ISR recurrence, and increased awareness regarding the correlation between late thrombosis and an increased risk of myocardial infarction (MI).

Gamma-2, a registry of 125 patients including complex lesions such as calcific lesions requiring rotablation, used a fixed dose of 14 Gy at 2 mm from the center of the source and showed a reduction of 52% and 40% in in-stent and in-lesion restenosis, respectively, and a reduction of 48% and 36% in TLR rates and MACE rates, respectively.37

ARTISTIC I and II

Angiorad Radiation Technology for In-Stent restenosis Trial In native Coronaries (ARTISTIC) examined the usage of the AngioRad system in patients with ISR in native coronary arteries. At three years, the cumulative MACE rate was 24.1% in placebo patients and 22.8% in the AngioRad group.38 ARTISTIC II used the same system in 236 patients and tested the efficacy as measured by a composite clinical end-point at nine months after radiation. These results were compared to the historical control group of 104 patients from the ARTISTIC I and WRIST studies. The Kaplan-Meier estimate of freedom from target vessel failure (TVF) for the placebo group was 52% while in the irradiated group it was 85.5%.39

Clinical trials of beta radiation

Large-scale clinical studies testing the effectiveness of beta radiation for de novo, restenotic and ISR lesions, and vein grafts have paralleled the encouraging results of gamma radiation.

Beta Radiation for ISR

BETA WRIST

In this study, beta radiation was shown to be effective in the treatment of ISR in 50 patients. These patients demonstrated a 58% reduction in the rate of TLR and a 53% reduction in TVR at six months compared to the historical control group of WRIST.40 The clinical benefit was maintained at two-year follow up with a reduction in TLR (42 % vs. 66%), TVR (46% vs.72%), and MACE (46 % vs. 72%) compared to placebo. This study showed that the efficacy of beta and gamma emitters for the treatment of ISR appeared similar at longer-term follow up.

START and START 40/20

In the START (Stents And Radiation Therapy) Trial, 476 patients were randomized to either placebo or an active radiation train 30 mm in length using the BetaCath system.41 Late thrombosis as a complication of brachytherapy was first recognized during this trial and antiplatelet therapy was prolonged to at least 90 days.

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 the potential to compromise clinical outcome.42

To verify the benefits of extending the radiation margins by 10 mm (5 mm at each end) to ensure coverage of injured segment, START 40/20, a 207-patient registry that mirrored START was conducted. Compared to the control arm of START, patients in START 40/20 had a reduction of 44% in restenosis in the analysis segment, 50% reduction in TLR, 34% reduction in TVR, and 26% reduction in MACE. This registry demonstrated no deleterious effects of adding 10 mm of length to the source train, but there was a lack of a relationship between ‘geographic miss’ and clinical or angiographic outcomes for ISR.

INHIBIT and GALILEO INHIBIT

INHIBIT (Intimal Hyperplasia Inhibition with Beta In-stent Trial) examined the efficacy of the Galileo system for the treatment of ISR in 332 patients.43

At nine months, treatment with 32P reduced binary restenosis by 67% and 50% in the stented and analysis segments, respectively. There were no differences in the edge effect rates between the active and control-treated groups.

At nine months, 32P significantly reduced rates of TLR and MACE. Tandem positioning to cover diffuse lesions >22 mm with 32P was safe and effective. Galileo INHIBIT was an international, multicentered registry of 120 patients with ISR in which 32P was delivered at 20 Gy at 1 mm into the vessel wall. There was a reduction in the primary clinical end point defined as MACE-TLR by 49% and reduction in angiographic endpoint of binary restenosis by 74% in the stented segment and by 27% in the analysis segment.44 The thrombosis rate was low, 1.5%, and similar to the control group, 1.2%.

Balloon catheter-based beta radiation Trials for ISR

BRITE, BRITE-II, 4R, and CURE

Beta radiation using the Radiance system was administered in 32 patients in the feasibility study called BRITE (Beta Radiation to prevent In-sTent rEstenosis). Seventy percent of the dose was administered when the balloon was inflated. At six months, TVR (3%), MACE (3%), and in-stent binary restenosis rates (0%) were the lowest reported to-date in any vascular brachytherapy series.45 The BRITE II study evaluated the efficacy of beta radiation using the RDX system in 429 patients 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 the injured zone despite lower rates of geographic miss (8.5%).46 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.

4R, a South Korean registry evaluated β-radiation therapy with 188Re-MAG3-filled balloon following rotational atherectomy for diffuse ISR in 50 patients. The mean dose was 15 Gy and the mean irradiation time was 201.8 ± 61.7 seconds. No adverse events occurred during the follow up period. The six-month binary angiographic restenosis rate was 10.4%. Two potential limitations of this technology included reduced dosing at the balloon margins (edge effect) and the risks of balloon rupture with radiation spill. In the event of balloon rupture using 188Re, concomitant administration of potassium perchlorate may mitigate thyroid uptake.47

The Columbia University Restenosis Elimination (CURE) study evaluated liquid 188Re injected into a perfusion balloon. Thirty 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 ± 2.2 minutes. At 12 months follow up in the first 37 patients, the rate of TLR-free survival was 75%.48

RENO and BRIE

Registry Novoste (RENO) is a registry of 1098 consecutive patients using the Novoste BetaCath system. Six-month follow up data showed non-occlusive restenosis in 18.8% of patients, total occlusion in 5.7%, and a MACE rate of 18.7% (1.9% deaths from any cause, 2.6% from acute MI, 13.3% from TVR by PCI and 3.3% from TVR by CABG).49 The Beta Radiation in Europe (BRIE) study evaluated the safety and efficacy of the BetaCath system in patients with up to two discrete lesions, de novo and restenotic, in different vessels. The binary in-stent restenosis was 9.9%, excluding total occlusions, was 4.9%.50 This study highlights the full potential of brachytherapy, provided late total occlusions are minimized by prolonged antiplatelet therapy.

Tungsten WRIST

In a feasibility study using Tungsten (199W) wire dose range (18–25 Gy), in 30 patients with ISR in native coronaries, Waksman et al. have shown the safety and comparable results to other beta and gamma sources.51

Beta radiation for de novo lesions

Several clinical studies were undertaken to test the effectiveness of beta radiation for de novo lesions concurrent to the trials of ISR. Important early studies included the Geneva trial,52 the dose-finding study BERT (Beta Energy Restenosis Trial) which used 90Y,53 and the Proliferation REeduction with Vascular ENergy Trial (PREVENT)54 that utilized 32P.

BERT

BERT was a feasibility study of 23 patients with de novo lesions using the Novoste system.53 No complications or adverse events were noticed at 30 days and at nine months follow up. Three patients underwent repeat revascularization to the target lesion. The Canadian arm of this study included 30 patients, and at six months follow up, the angiographic restenosis rate was 10% with negative late loss and late loss index.55 The European arm of 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 US and Canadian trials. Overall, the restenosis rate based on 64 of the 80 patients in the BERT series is 17%, and the late loss and late loss indexes were below 5%. Over 50% of the patients had larger minimal lumen diameter (MLD) at follow up compared to control, and a sub study of IVUS demonstrated vessel remodeling at the irradiated site.56

PREVENT

PREVENT was a randomized study of 105 patients with de novo (70%) or restenotic (30%) lesions. Angiographic restenosis at six months was 8.2% (target site) and 22.4% (target site plus adjacent segments) compared to 39.1% and 50.0% in the control group, respectively.54 The one-year MACE (death, MI, and TLR) was less in radiation group though not statistically significant. The occurrence of MI due to thrombotic events after discharge occurred in seven patients who received radiation therapy and in none in the control group.

DOSE-FINDING STUDY GROUP

This was the only study which tested optimization of dose in a randomized fashion to 9, 12, 15, and 18 Gy using Yttrium-90 in 183 patients. Stenting after radiation was required in 47% of patients because of residual stenosis or major dissection. At six-month angiographic follow up, a significant dose-dependent benefit was evident. Thrombosis or late occlusion of the target vessel occurred in 3.3% of patients who were treated with only balloon angioplasty and in 14.3% patients who received new stents. This study demonstrated a marked reduction in restenosis in non-stented 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 adjunctive to PTCA.57

BETA-CATH

In this large randomized study, 1455 patients with sub optimal results after balloon angioplasty were treated with a stent and then assigned to 90Sr/Y or placebo treatment.58 In patients treated with balloon angioplasty alone, radiated patients (n=264) tended to have lower TVF (14.2%) compared to placebo patients (20.4%, n=240). In the 452 patients treated with extended antiplatelet therapy who received a new stent, there were no differences in the 240-day TVF rate. Comparison of placebo and radiation treatment from pooled PTCA and stent groups (antiplatelet therapy ≥60 days) showed similar eight-month TLR and TVF-MACE.

An interesting point in this study was the low TVF in the irradiated balloon-only group. This was attributed to a reduction in angiographic restenosis within the initial lesion site in these patients (21.4% vs. 34.3% in placebo group), although the restenosis rates were similar in the analysis segment (treated segment + the radiation margins). The loss of benefit at the treatment margins is attributable to ‘geographic miss’ due to the relatively short treatment length in the study. This was the first to identify the higher-than-expected rate of late stent thrombosis when radiation was used with new stent implantation.

SVG BRITE

This study examined the RDX system using a 32P emitter at a dose of 20 Gy at 1 mm from the balloon surface in saphenous vein grafts of 49 patients; 24 of whom were treated for de novo lesions. New stents were implanted in most patients with de novo lesions. The outcome of the patients with de novo lesions was encouraging with only 8% TVR and 12% angiographic restenosis rate.59

ECRIS

EndoCoronary-Rhenium-Irradiation-Study (ECRIS) was a randomized trial in which 225 patients (71% de novo lesions) were randomly assigned to receive β-irradiation using 188Re-filled balloon catheter or no additional intervention. Clinical and procedural data did not differ between the groups except that there was a higher rate of stenting in the control group (63%) compared with the rhenium-188 group (45%). After six months of follow up, late loss was significantly lower in the irradiated group compared with the control group, both of the target lesion (0.11±0.54 versus 0.69±0.81 mm) and of the total segment (0.22±0.67 versus 0.70±0.82 mm). This was also evident in the subgroup of patients with de novo lesions and independent from stenting. Binary restenosis rates and TVR were significantly lower after rhenium-188 brachytherapy compared with the control group.60

BRIDGE

The BRIDGE study is a multicenter, randomized, controlled trial of 112 patients which evaluated the acute and long-term efficacy of intravascular brachytherapy with 32P (20 Gy at 1 mm in the coronary wall) immediately following direct stenting in de novo lesions. TVR and MACE rates at one year in the irradiated group (20.4% and 25.9%, respectively) were higher than in the control group (12.1% and 17.2%, respectively).61

Clinical trials with radioactive emitting 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. The first clinical trials included IRIS, the Milan dose-finding study, and the Vienna experience. In IRIS (Isostent for Restenosis Intervention Study) pilot trials, 32P radioactive Palmaz-Schatz stents were developed with varying radioactivities and were implanted with a high rate of technical success but limited by an angiographic restenosis rate (stent and edges) of 40% at six months follow up.62 The Milan dose-finding study showed that activities >3 μCi (32P stents 0.75–12 μCi) profoundly inhibited intimal hyperplasia, however restenosis still occurred in >40% of lesions at the stent edges, that is, the ‘candy wrapper’ effect.63,64 These findings were replicated in the Vienna study using high activity (6–21 μCi) stents.65 An effort to circumvent edge restenosis by ‘hot’ and ‘cold’ end stents failed to prevent edge effect with an angiographic restenosis rate of 33% in 56 implanted stents.66 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.

Beta versus gamma brachytherapy

While contemporaneous clinical trials to-date have demonstrated comparability of clinical efficacy of beta and gamma brachytherapy,67 beta systems have several inherent advantages, such as reduced radiation exposure to operators and catheterization laboratory personnel, less shielding requirements, and easier handling of sources that have lead to more widespread acceptance of this technology. Potential limitations of beta sources in larger vessels (for example, 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.

Limitations to brachytherapy

Although clinical trials using vascular brachytherapy for both coronary and peripheral applications have demonstrated positive results in reducing restenosis rates, these trials have also identified two major complications related to the technology – late thrombosis and edge stenosis. Late thrombosis is probably due to the delay in healing associated with radiation. It has been estimated that late thrombosis can be remedied through prolonged administration of antiplatelet therapy following intervention. The main explanation for the occurrence of edge effect is a combination of low dose at the edges of the radiation source and an injury created by the device for intervention, which is not covered by the radiation source. It is shown that wider margins of radiation treatment to the intervening segment significantly reduce the edge effect.

Peripheral brachytherapy

Since the manifestation of coronary atherosclerosis and peripheral artery disease is primarily evident in older patient populations, and because patients in the baby boomer generation are nearing their 60s, the full impact of peripheral and coronary atherosclerosis in the US is upon us. Whereas coronary vascular procedures increase at a rate of 8% per year, there is greater growth in the frequency of peripheral procedures, estimated at 19% per year.

Restenosis in the peripheral arterial system

Restenosis following PTA is mainly seen in small and medium peripheral arteries, such as the saphenous femoral-popliteal arteries (SFA) and renal arteries, with diffuse atherosclerotic disease. The mechanisms for a high rate of recurrence after intervention in the peripheral arterial system (PAS) are mainly attributed to exuberant healing response with smooth muscle proliferation,68,69 early and late recoil after balloon angioplasty,70,71 mechanical problems with stents, such as stent fractures and crushing, in-stent restenosis, and aggressive progression of the atherosclerotic disease.

Radiation systems for the peripheral vascular system

The vessel size of the PAS favored the use of gamma radiation due to the penetration characteristics of the emitter. The majority of investigational work performed in the PAS used Ir-192 in doses of 14–18 Gy prescribed at 2 mm from the source center. Several radiation systems for peripheral endovascular brachytherapy have been suggested and are under development and testing.

External radiation

External beam radiation is a viable option for the treatment of peripheral vessels. It allows a homogenous dose distribution with the possibility of fractionation.

External radiation is currently used in a few centers for the treatment of in-stent restenosis of the SFA. Preliminary reports are encouraging, although caution should be applied to this strategy because of the potential for radiation injury to the nerve, vein, and the skin. Preliminary attempts with external radiation for the treatment of AV dialysis grafts failed to reduce the restenosis rate. This unsuccessful attempt was attributed to the conservative use of low doses and thrombosis of these grafts. Using sterotactic techniques to localize the radiation to the target area may improve the results of this approach.

Catheter-based gamma systems

The most common catheter-based system used for SFA application is the MicroSelectron HDR system (Nucletron-Odelft, Delft, The Netherlands), which uses a computerized, high-dose rate afterloader system that delivers a 3 mm stepping, 10 Ci activity of Ir-192 into a closed-lumen radiation catheter. The Peripheral Brachytherapy Centering Catheter (Paris, Guidant Corporation, Indianapolis, IN) is a 7 F, double-lumen catheter with multiple centering balloons near its distal tip that enable the catheter to be in the center of the lumen of large peripheral vessels during inflation. The Paris catheter is no longer available. The only closed-end lumen catheter available is the one used for oncology applications.

Catheter-based beta systems

The only catheter-based beta system available is the BetaCath system, with a source train of up to 60 mm, which can be pulled back to allow coverage of long lesions. The main limitation of the system is the penetration of the beta emitter, which is weakened significantly beyond 5 mm. This system can be used for below-the-knee applications or for other small vessels, including in-stent renal stenosis. It is recommended to perform the radiation prior to the intervention to ensure better centering and a higher dose to the treated proliferating tissue.

Clinical trials

Superficial femoral artery

Liermann and Schopohl were the first to perform VBT for the treatment of in-stent restenosis in the peripheral arteries. Known as the Frankfurt Experience, this pilot study was conducted in 30 patients with ISR in their SFAs.72–75 Patients underwent atherectomy and PTA followed by endovascular radiation using the MicroSelectron HDR afterloader and a noncentering catheter with Ir-192. No adverse effects from the radiation treatment were reported at up to seven-year follow up. The five-year patency rate of the target vessel was 82%, with only 11% stenosis within the treated segment reported. Late total occlusion developed in 7% of the treated vessels after 37 months.

The Vienna experience

A series of studies was conducted at the University of Vienna. The majority were randomized studies targeting the SFA with or without stents using the MicroSelectron HDR afterloader with or without a centering catheter utilizing different doses.

Vienna I was a pilot study with an indication of radiation safety after PTA that showed only 60% patency at one year.76 The Vienna II trial had 113 patients with de novo or recurrent femoropopliteal lesions who were randomized to PTA + brachytherapy (n=57) or PTA alone (n=56). The primary end point of cumulative patency rates at 12-month follow up was higher in the PTA + brachytherapy group (63.6%) compared to the PTA group (35.3%). The patients from this study were followed-up to 36 months and demonstrated durability of the results.77 In Vienna III, a centering catheter that was used for the same patient population with a dose of 18 Gy showed a restenosis rate of 23.4% in the irradiated group compared to 53.3% in the placebo arm.78 Vienna IV was a pilot study examining radiation with stenting of the SFA; and Vienna V was a randomized study for similar indications. Both Vienna IV and V demonstrated an increase rate of subacute and late thrombosis when stents were combined with radiation, with up to 16.7% in the radiation group versus 4.3% in the control stenting without radiation. Once thrombosis was controlled, the radiation group had less restenosis.79

The PARIS trials

The Paris Radiation Investigational Study (PARIS) is the first FDA-approved, multicenter, randomized, double-blind, control study involving 300 patients following PTA to SFA stenosis using a gamma radiation 192-Ir source. Utilizing the MicroSelectron HDR afterloader, a treatment dose of 14 Gy is delivered via a centered segmented end-lumen balloon catheter. The primary objectives of this study are to determine angiographic evidence of patency and a reduction of >30% of the restenosis rate of the treated lesion at six months. A secondary endpoint is to determine the clinical patency at 6 and 12 months by treadmill exercise and by the ankle-brachial index (ABI). In the feasibility phase of PARIS, 40 patients with claudication were enrolled. The mean lesion length was 9.9±3.0 cm with a mean reference vessel diameter of 5.4±0.5 mm. The six-month angiographic follow up was completed on 30 patients; 13.3% of them had evidence of clinical restenosis.80

Due to poor enrolment, only 203 patients with claudication and femoropopliteal disease were enrolled in the study. After successful PTA, a segmented centering balloon catheter was positioned to cover the PTA site. The patients were transported to the radiation oncology suite and randomized to receive either radiation therapy using the MicroSelectron HDR afterloader with Ir-192 at a dose of 14 Gy at 2 mm into the vessel wall (105 patients), or treatment with a sham control in 98 patients. Patients were followed for 12 months, with clinic visits at 1, 6, and 12 months and follow up angiography at 12 months. The restenosis rate at follow up was similar in both groups (28.6% brachytherapy vs. 27.5% placebo). There was no significant difference in MLD, late loss, or the number of total occlusions. Exercise ABI, resting ABI, and maximum walking time were not different between treatment groups. For patients older than 65 years, maximum walking times at 6 and 12 months were better in the brachytherapy group. In the subgroups of patients with diabetes, male patients, or patients receiving Clopidogrel or who have a proximal/medial lesion, maximum walking time in the brachytherapy group was better than in the placebo at 6 months but not different at 12 months.

More studies to support the effectiveness of gamma radiation for in-stent restenosis were recently published by Krueger et al.81 In this study, 30 patients who underwent PTA for de novo femoropopliteal stenoses were randomly assigned to undergo 14 Gy centered endovascular irradiation (irradiation group, n=15) or no irradiation (control group, n=15). Intra-arterial angiography was performed 6, 12, and 24 months after treatment; and duplex ultrasonography was performed the day before and after PTA and at 1, 3, 6, 9, 12, 18, and 24 months later. Baseline characteristics did not differ significantly between the two groups. Mean absolute individual changes in degree of stenosis, compared with the degrees of stenosis shortly after PTA in the irradiation group versus in the control group were 10.6% ± 22.3 versus 39.6% ± 24.6 (P < .001) at 6 months, 2.0% ± 34.2 versus 40.6% ± 32.6 (P =.002) at 12 months, and 7.4% ± 43.2 versus 37.7% ± 34.5 (p= .043) at 24 months. The rates of target lesion restenosis at six months (p=.006) and 12 months (p=.042) were significantly lower in the irradiation group. The authors concluded that endovascular radiation was effective for patients who were treated with angioplasty for de novo femoropopliteal lesions.

Restenostic lesions and VBT

The effectiveness of VBT for restenotic SFA lesions was examined in another randomized study reported by Zehnder et al. In this study, gamma radiation was used at a dose of 12 Gy. The primary endpoint was >50% restenosis at 12 months assessed by duplex Doppler. The recurrence rate in the radiation arm was 23% versus 42% in the PTA alone group.82 This study demonstrated that VBT can be effective in restenotic lesions.

Brachytherapy and Probucol

In another randomized four-arm study for patients with PTA lesions, patients were randomized to VBT, VBT and probucol, probucol alone, or placebo. The recurrence rate in the radiation arm alone was 17%, VBT and probucol was 20%, probucol alone was 27%, and the placebo group was 42%. This study confirms prior observations regarding the effectiveness of VBT for the treatment of SFA lesions without additional benefit of probucol when compared to PTA alone.83

Studies with Beta Radiation for SFA stenosis

Two studies that utilized the Corona system were the MOBILE study that targeted in-stent restenosis lesions and the LIMBER (Limb Ischemia Treatment and Monitoring post Vascular Brachytherapy to prevent Restenosis) study.

Drug-eluting stents and brachytherapy

Evidence is favorable for the efficacy of DES to reduce restenosis in de novo lesions and experience is growing with other lesions including in-stent restenosis of BMS. In the randomized ISAR-DESIRE study, Kastrati et al. reported restenosis rates of 14.3% with sirolimus-eluting stents and 21.7% with paclitaxel-eluting stents.84 Recent randomized and non randomized studies comparing vascular brachytherapy and DES confer that DES are showing similar safety and efficacy profile when compared to vascular brachytherapy. In the SISR trial there was reduction in target lesion revascularization in the DES group compared with VBT although this study borrowed patients from the historical Gamma 1 and Gamma 2 it appears that DES are effective as vascular brachytherapy even for diffuse ISR lesions.85,86 Thus the role of vascular brachytherapy in the coronary arteries remained for the treatment of DES restenosis. The RESCUE (Radiation for drug Eluting Stent in Coronary FailUrE) study was an international registry of patients who present with ISR of a previously placed coronary DES and assigned to treatment with either beta or gamma radiation following PCI. Eight months follow up data in 61 patients showed 6 (10%) MACE and similar TLR and TVR.87

Although DES reduced significantly the rate of TLR in coronary arteries, recent series of more complex lesions and subset of patients reports restenosis rates of up to 10% with over 2 000 000 DES implanted annually. Thus we anticipate that nearly 100 000 patients will present with DES restenosis. The encouraging results from the RESCUE trial combined with evidence-based historical data from previous brachytherapy trials will keep this technology in vogue.

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