Brachytherapy: Applications and Technique, 1st Edition

11. Vascular Brachytherapy


Huan Giap

Prabhakar Tripuraneni

Vascular disease is the number one cause of mortality and morbidity in the United States. It accounts for over 1.4 million deaths annually. The most common pathology of vascular disease is an occlusive or stenotic process due to atherosclerotic plaque. Approximately 1 million coronary angioplasty procedures are performed annually in the United States at an estimated cost of 5 billion dollars, and this number continues to rise. The magnitude of the impact to society due to peripheral vascular disease (PVD) is also significant compared with that of heart disease. Currently, more than 400,000 vascular interventions are performed in the United States annually for PVD (including atrioventricular [AV] graft for dialysis). The placement of coronary stents has significantly decreased the incidence of restenosis, but there remains a population of 150,000 patients each year who present with in-stent restenosis of coronary arteries. These patients have proven to be a therapeutic challenge for the medical community.

Over the past few decades, major improvement in the management of vascular disease has been made, with one of the most significant contributions being the development of percutaneous vascular recanalization and balloon angioplasty. The main concept behind the percutaneous transluminal angioplasty (PTA) procedure is that the atherosclerotic plaque can be physically removed by a specially designed catheter. Within the a few years of its introduction, the minimally invasive PTA became the well-established standard for many vascular disorders previously treated with invasive surgery. Unfortunately, long-term efficacy of PTA is limited by the high rate of excessive wound healing causing restenosis. Restenosis is common, morbid, and expensive. It also limits the number of vascular interventions to be performed. Initial therapeutic approaches focused on pharmaceutical agents, mechanical devices (atherectomy or tissue removing), physical devices (stenting), and more recently, gene therapy. None of these have been successful. Therefore, restenosis remains the “Achilles heel” of PTA. Over the last 10 years, multiple prospective randomized trials have been performed to show that risk of restenosis is reduced by radiation therapy. The U.S. Food and Drug Administration (FDA) approved three delivery systems for endovascular brachytherapy for use in patients with in-stent restenosis in native coronary arteries in 2002. These trials led to FDA approval of the Checkmate device using Iridium 192 (192Ir) by Cordis Corporation, the BetaCath device using Strontium 90 (90Sr) by Novoste Corporation, and the Galileo device using Phosphorus 32 (32P) by Guidant Corporation for use in patients with in-stent restenosis in native coronary arteries. The use of vascular brachytherapy (VBT) exploded onto the scene of interventional cardiology and was quickly incorporated into the mainstream of interventional cardiology clinical practice. VBT was performed in approximately 100,000 patients at 300 centers across the United States in 2002. VBT was the most common application of brachytherapy in the United States for a few years. However, in the last few years, VBT has been replaced by drug-eluting stents not necessarily due to better efficacy, but due to convenience. The radiation oncology community was significantly stressed to suddenly provide this extra level of service. That it was in an operative/interventional clinical setting was additionally difficult. Although enthusiasm for VBT has decreased with the advent of drug-eluted stent therapy, the evolution of vascular brachytherapy into the practice of interventional cardiology carries significant historic value. It helped redefine the role of radiation oncology as a leading modality in the development of new technology in the field of nonmalignant diseases from its basic science beginnings into mature clinical practice. This chapter describes the basic pathophysiology, major clinical trials, treatment planning approaches, and future perspectives for VBT.

Normal Artery Anatomy

The arteries are not just a collection of uniform tubes or ducts. They are a sophisticated system of complex dynamic biomechanical structures that carry out multiple metabolic and mechanical functions under a wide range of conditions. A typical artery consists of three concentric zones or layers, which are intima, media, and adventitia (see Fig. 11.1)

The intima extends from the endothelial lining to the internal elastic lamina (IEL). The intima consists of the endothelium, subendothelial connective tissue, basal lamina, and IEL. The endothelial cells regulate several important processes such as coagulation, platelet aggregation, fibrinolysis, leukocyte adhesion, and cell migration. These cells serve as a selective interface for diffusion, convection, and active transport of circulating substances. These very delicate endothelial cells provide a system of checks and balances that control the final thrombotic-fibrinolytic state. Subacute and late thrombosis after VBT may be a consequence of crush injury and radiation-induced injury to the endothelial cells secondary to the disruption of this delicate system, leading to abnormal thrombotic-fibrinolytic events.

The media layer extends from the IEL to the external elastic lamina (EEL). In some vessels, the EEL is not indistinct from the adventitia. The media consists mostly of smooth muscle cells (SSMC). The main function of the SMC is to maintain vascular tone. When the vessel wall is injured by angioplasty, the macrophages and other cells can “turn on” the SMC from a quiescent state into synthetic, migratory, and proliferative states. This chain reaction can lead to neointimal hyperplasia. Because the macrophages are sensitive to radiation, they can be inactivated by low dose radiation. This simplified explanation is the basis for the use of radiation in preventing restenosis.

Figure 11.1 Cross section of the layers of the coronary artery.


Ionizing radiation has been used to inhibit growth for years. Low dose of radiation therapy has been utilized for decades to treat nononcologic hyperproliferative disorders that include arteriovascular malformation (AVM), heterotropic ossification (HO), gynecomastia, keloids, and pterygium.1 The molecular and cellular basis of the antiproliferative action of radiation therapy in these benign conditions has been extensively investigated both in animal studies and clinical trials. Postangioplasty restenosis is a hyperproliferative response to tissue injury. A cascade of events due to altered local hemodynamics and endothelial injury leads to this hyperproliferative, excessive, and uncontrolled growth.

The pathophysiology of restenosis after coronary artery intervention is a multifactorial process that consists of vascular injury secondary to intervention followed by the physiologic response to the injury.2 It is believed that the injury occurs in the intimal and medial layers but the response to this injury occurs in the medial and adventitial layers. The vascular restenosis process can be divided into early and late phases. The early phase of restenosis involves vessel recoil that can result in an acute decrease in lumen diameter. The cause is physical stretching and contraction of injured or torn segments in the treated segment. The late phase of restenosis involves late vessel remodeling which results in contracture of the EEL. This leads to neointimal hyperplasia, the growth of myofibroblasts and extracellular matrix that narrows the vessel lumen.3

Stenting during the angioplasty procedure has led to a significant decrease in restenosis rates following angioplasty. However, in-stent restenosis persists as a significant and difficult clinical problem. It is believed that stenting at the time of angioplasty prevents vascular recoil and contracture of the vessel lumen but does not prevent neointimal proliferation. VBT targets this aspect of the restenosis process not prevented by stenting. It is believed that the adventitial layer is the main source of cells that produce neointimal proliferation. Adventitial myofibroblasts are the main target of ionizing radiation.4

The cellular and molecular targets of ionizing radiation in reducing vascular restenosis have been extensively studied. Although the injury from angioplasty and stenting occurs in the intimal and medial layers, it is the proliferative response in the medial and adventitial layers of the vessel lumen that leads to restenosis. It is believed that this overly exuberant response to arterial wall injury after angioplasty results in approximately 40% of patients exhibiting excessive healing and restenosis after angioplasty. Prosthetic stent implantation has significantly reduced the incidence of restenosis.5 However, a restenosis rate of 20% to 25% persists.6 Even modest doses of ionizing radiation therapy reduce in-stent restenosis rates by targeting the reproductive ability of the myofibroblast precursor cell and disrupting a complex anti-inflammatory and wound-healing response.

Coronary Anatomy, Normal Artery Anatomy, and Interventional Cardiology Terminology Coronary Anatomy

The left and right coronary arteries, which arise from the left and right aortic sinuses, provide the major blood supply to the heart. They course in an epicardial manner and then terminate in a capillary network, forming a ring-loop system in two orthogonal planes. The right coronary artery and the left circumflex artery course along the AV groove and form a circle between the atria and ventricles, whereas the left anterior descending (LAD) and the posterior descending right coronary artery form a half-circle along the interventricular groove and encircle the left ventricular apex (see Fig. 11.2).7

The left main coronary artery (yellow) originates from the left sinus of Valsalva and quickly branches to give rise to the LAD (orange) and left circumflex (LCx) (green) arteries. The LAD wraps around the apex of the left ventricle in most patients and gives rise to septal, diagonal, and other branches that extend to the right ventricular wall. The LCx (green) circumflex artery follows the same direction as the left main to enter the left atrioventricular (AV) grove, and then it moves away from the LAD. The LCx gives off the obtuse marginal branches proximally, then it wraps around the posterior of the heart and gives off the posterolateral (PL) branches (purple). The right coronary artery arises from the right sinus of Valsalva and can be divided into the proximal, mid, and distal segments. It gives rise to the infundibular artery, which provides blood to the right ventricular outflow tract, the sinus node artery, and the atrioventricular nodal artery. The right coronary artery also gives rise to acute marginal branches, which supply the right ventricular wall, the posterior descending artery, and several posterolateral branches (purple).

Figure 11.2 Anatomic layout of coronary arteries.

Interventional Cardiology and Restenosis Terminology

See Figure 11.3 for interventional cardiology and restenosis terminology.

The world of interventional cardiology is one of acronyms and this section is included to assist in understanding the literature.8 (TLA, is a three letter abbreviation!)

·     Angioplasty: A nonsurgical treatment for obstructive coronary artery disease (CAD) using a miniaturized balloon catheter to dilate obstructive lesions in coronary vessels.

·     Coronary artery bypass grafting (CABG): A surgical technique to improve myocardial blood flow. Arterial or venous conduits are used to bypass obstructive coronary lesions and reroute blood flow to the left ventricular myocardium.

·     Diameter stenosis: This term refers to the percentage of obstruction of a coronary vessel as determined by quantitative coronary angiographic analysis. The percent diameter stenosis is calculated by measuring the vessel diameter at the level of highest degree of obstruction and comparing it to the normal reference vessel diameter. The following equation illustrates the determination of percent diameter stenosis:

where MLD = minimal lumen diameter.

·     Acute gain: A term used to characterize the acute results of percutaneous coronary revascularization (PCR) procedures. The initial or acute gain represents the change in luminal diameter at the location of the target lesion undergoing revascularization. The equation used to calculate initial or acute gain follows:

MLDpostprocedure - MLDpreprocedure

Figure 11.3 Schematic representation of the most common interventional cardiology conditions and terminology.

·     Late loss: A term used to describe the change over time in the vessel lumen diameter of a lesion treated with percutaneous coronary interventional (PCI) procedures. This term characterizes the tendency toward a loss of some of the initial gain achieved during PCI procedures. The following equation illustrates the method used to calculate late loss:

Late loss (mm) = MLDpostprocedure - MLDfollow-up

·     Late loss index: A term that reflects the loss over time of the initial gain achieved with PCI procedures. The loss index is calculated as follows:

·     Edge effect (candy wrapper effect): Restenosis of a previously irradiated lumen at the edges of the target volume (TV). This effect is felt to be secondary to hyperplastic changes and negative remodeling at the edges of the irradiated segment.

·     Major adverse cardiac events (MACE): This term is used to describe a composite of various endpoints used in interventional cardiology trials to describe outcomes. MACE varies among different trials and common components of the endpoint include death, myocardial infarction, repeat revascularization, and repeat hospitalization.

·     Minimum lumen diameter (MLD): This is a quantitative coronary angiography (QCA) term used to describe the diameter in millimeters of a target vessel undergoing PCI. The MLD is the smallest measurement of lumen diameter at the site of intervention in the target vessel. The MLD before and after PCI procedures is used to assess the acute and long-term success rates of percutaneous revascularization procedures.

·     Percutaneous coronary intervention (PCI): This term is used to describe in detail all percutaneous revascularization procedures including angioplasty, atherectomy, and other techniques used to accomplish catheter-based revascularization therapy.

·     Percutaneous coronary revascularization (PCR): This term is essentially identical to PCI and reflects a composite term used to describe all catheter-based PCR techniques and procedures.

·     Percutaneous transluminal coronary angioplasty (PTCA): This term is synonymous with balloon angioplasty and is used interchangeably as an acronym.

·     Quantitative coronary angiography (QCA): This is a technique used to analyze the acute and long-term results of PCR procedures. Computer-based techniques using automated edge detection systems are used to measure coronary vessel diameters and calculate percentage obstruction of atherosclerotic lesions. QCA techniques are used in interventional cardiology trials to assist in determining the incidence of restenosis following PCI procedures.

·     Reference vessel diameter (RVD): This measurement assists in characterizing the severity of obstruction in a coronary vessel containing an atherosclerotic lesion. The reference vessel diameter (mm) is the maximum dimension of the vessel in a normal-appearing segment adjacent to a significantly obstructive lesion. The reference vessel diameter allows calculation of the percent diameter stenosis.

·     Target lesion revascularization (TLR): A term used in the clinical definition of coronary restenosis. TLR is repeat revascularization of a lesion due to recurrent obstruction at the site of prior revascularization.

·     Target vessel revascularization (TVR): This refers to revascularization of a vessel that previously underwent PCI. This term is inclusive of TLR and occurrence of obstructive lesions requiring revascularization at other sites within the target vessel.

Coronary Brachytherapy Major Trials

γ–Emitting Sources

The first study using intracoronary brachytherapy in humans was done in Venezuela by Condado et al.9,10,11 This feasibility study in 21 patients with 22 coronary lesions utilized a 192Ir source inserted by monorail into a closed-end lumen catheter after balloon angioplasty. The prescribed dose was 20 to 25 Gy but actual dose ranged from 19 to 92 Gy. The TLR rate was 18% at 2-year follow-up. The 5-year follow-up results confirmed the feasibility and durability of brachytherapy in reducing restenosis.

The Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting-1 (SCRIPPS-1)1 (SCRIPPS-1) trial was the first double-blind, randomized, placebo-controlled study done in humans using VBT.12,13,14,15,16,17 This single institution study was initiated in 1995 in patients with native coronary artery and vein-graft restenosis. Fifty-five patients were randomized to 192Ir or placebo after angioplasty. The prescribed dose using intravascular ultrasound (IVUS) measurements dosimetry was <8 Gy to the furthest external elastic lumina while holding dose at the closest external elastic lumina to <30 Gy. SCRIPPS-1 found a TLR rate of 23% versus 48% in favor of radiation treatment at 5 years. The event-free survival rate was improved in the radiation arm over placebo. The 3-year angiographic rate of stenosis was significantly higher in the placebo arm compared with radiation therapy (64% vs. 33%).

The Washington Radiation for In-Stent Restenosis Trial (WRIST) was initiated in 1997 and randomized 130 patients with in-stent restenosis of native coronary arteries or saphenous vein grafts to 192Ir brachytherapy or placebo.18,19 Fixed dosimetry was used to prescribe 15 Gy to 2.0 mm radius for lumen diameter <4 mm and 2.4 mm radius for lumen diameter >4 mm. At 6 months' follow-up, TLR was significantly improved by radiation therapy from 63% to 14% and angiographic restenosis rate from 58% to 19%.

The GAMMA I trial was the first industry-sponsored multi-institutional trial to determine the effectiveness of VBT for in-stent restenosis in native coronary arteries.20 The GAMMA I trial led to FDA approval of the Checkmate System by Cordis Corporation for in-stent restenosis of native coronary arteries. This study was a placebo-controlled, double-blind, randomized trial conducted at 12 institutions. The study randomized 252 patients to receive VBT or placebo. Dosimetry similar to the SCRIPPS-1 trial was utilized. The TLR rate was improved from 45% to 24% at 9 months and angiographic restenosis rate, from 50.5% to 21.6% at 6 months in favor of VBT over placebo. The late thrombosis rate in this study was 5.3%. Late thrombosis occurred most often in patients who had stents placed at the time of radiation therapy delivery. Although the results of this trial were not as robustly in favor of VBT as the SCRIPPS-1 trial, it was felt that this was associated with a learning curve for IVUS dosimetry in this multi-institutional trial.

The WRIST PLUS trial maintained 120 patients on clopidogrel therapy for 6 months' after VBT. At 6 months' follow-up, this study showed that extended antiplatelet therapy prevented the complication of late thrombosis that was seen in the GAMMA I study.21

Patients who undergo coronary artery bypass graft surgery with saphenous vein grafts have approximately a 40% rate of graft failure at 10 years. These patients often undergo stent procedures that also have a high rate of failure. Waksman et al. reported the results of a multicenter, placebo-controlled, prospective study done in patients with evidence of in-stent restenosis of saphenous vein grafts. They enrolled 120 patients after successful revascularization to either treatment with manually loaded 192Ir or placebo. A closed-end noncentered delivery catheter was utilized and 5 mm of overlap with normal segment of vessel was employed at both ends of the lesion to ensure adequate margin. The dose ranged from 14 to 15 Gy for vessel diameters of 2.5 to 4.0 mm and 18 Gy for vessel diameter >4.0 mm. There was a significant difference in the TLR rate in favor of the 192Ir arm versus placebo (17% vs. 37%) at 12 months' follow-up. Radiation therapy was the only significant predictor of freedom from a major cardiac event (MACE) at 12 months' follow-up. The authors concluded that these data supported the use of γ-emitting radiation therapy for in-stent restenosis of saphenous vein grafts.

β-emitting Sources

The START trial led to the FDA approval of the BetaCath system by Novoste Corporation for in-stent restenosis of native coronary arteries.22,23 This double-blind trial at over 55 centers in the United States and Europe randomized 476 patients with in-stent restenosis to VBT or placebo. The prescribed dose at a reference distance of 2 mm from the source center was 18.4 Gy if the vessel diameter was between 2.70 and 3.35 mm and 23.0 Gy if the vessel diameter was between 3.36 and 4.0 mm. TLR rates were 26.8% versus 17% at 8 months' follow-up in favor of the VBT arm over placebo. The 8-month angiographic restenosis rate (>50% lumen diameter stenosis) within the area treated with radiation therapy was 45.2% versus 28.8% in favor of the VBT arm. In this study, the radiation sources were not successfully delivered in 0.6% of cases and the delivery catheter was not delivered in 1.3% of cases. The authors concluded that β-emitting VBT was both safe and effective in treating patients with in-stent restenosis.

The START 40/20 trial had the same enrollment criteria as the START trial but the source train was 40 mm instead of 30 mm. This study found a lower geographic miss rate with the longer source train compared with the 30-mm source train used in the START trial.24

The INHIBIT trial led to FDA approval of the Galileo system by Guidant Corporation for in-stent restenosis of native coronary arteries.25,26 This trial was carried out at 27 institutions and enrolled 332 patients. Three hundred and fourteen of these patients successfully received the intended treatment. Lesions <47 mm were treated. This study used an automated delivery and retrieval system and a 32P β-emitting source. The catheter was centered and 20 Gy was prescribed at 1 mm from the catheter surface. Both the TLR and angiographic in-stent restenosis rates were significantly improved in the radiation therapy arm when compared with the placebo arm. The TLR rate was improved from 26% to 8% in favor of the VBT. The source was 27 mm in length and manual repositioning of the source was permitted for lesions that exceeded the source length. When repositioning manually, no overlap >2 mm was permitted and no gap >1 mm was permitted. No significant problems with the manual repositioning technique were identified in this trial.

In summary, for in-stent restenosis of native coronary arteries, the GAMMA I, START, and INHIBIT trials led to FDA approval of the Checkmate, BetaCath, and Galileo systems, respectively. The Checkmate system was approved for 45 mm long injured length using IVUS-based dosimetry, the BetaCath system was approved for 20 mm long injured length with 2 mm radial dosimetry (modified on the basis of the vessel diameter), and the Guidant system was approved for 47 mm long injured length with prescription 1 mm from the balloon surface with manual tandem stepping permitted if treating a target length longer than the source length.

De Novo Stenosis

VBT was not FDA approved for de novo coronary artery stenosis. The largest ever multi-institutional, double-blind randomized trial carried out for VBT was the BETACATH trial for coronary de novo stenosis.27 In this trial, 1456 patients were randomized after balloon angioplasty to receive VBT or no treatment. If the angioplasty was not felt to be adequate, patients received stenting after VBT or placebo. There was no statistically significant difference in TLR between VBT and placebo. At 8 months' follow-up, the angiographic in-lesion restenosis rate was improved by VBT versus placebo in patients who had angioplasty without stenting (34% vs. 21%) but patients underwent edge failures that negated this benefit. Moreover, in the stented group, there was an increase in restenosis in the VBT arm versus placebo (35% vs. 45%). There appeared to be hyperproliferation at the edges of the treated volume in the VBT group in patients that were stented. This study identified late thrombosis as the significant complication of VBT in stented patients. This has led to the use of long-term antiplatelet therapy to prevent late thrombosis in patients receiving VBT. Therefore, VBT has not been proved to be of benefit in patients with CAD who present with de novo stenosis. The geographic miss inherent in performing brachytherapy before the final injury length had been determined was the most likely cause for failure in this trial.

Treatment Planning

Patient Selection

The following patients are potential candidates for coronary brachytherapy:

·     Patients with in-stent restenosis of native coronary arteries

·     Patients with in-stent restenosis of saphenous vein graft

The following patients are not potential candidates for coronary brachytherapy:

·     De novo stenosis

·     Patients who received previous radiation therapy for the vessel

·     Patients who received previous vascular brachytherapy to the same area

·     Patients who receive external beam radiation for malignancy such as lymphoma and lung carcinoma

·     Patients with history of left breast cancer who received previous radiation therapy with external beam should be reviewed carefully to assure the vessel was not in the previous treatment field

·     Patients aged <18 years of age

·     Pregnant patients

Coronary Brachytherapy: Delivery System and Treatment Planning

Delivery Systems for Coronary Vascular Brachytherapy Trial

The delivery of brachytherapy for coronary vessels requires coordination of the interventional cardiologists (ICs), radiation oncologists, and physicists to assure safe and proper treatment delivery with efficient utilization of time. This is also a requirement from the FDA. The roles and responsibilities of these specialists are defined.

Vascular access for coronary intervention is gained by the IC. The right femoral artery is the most common site for vascular access, and other sites include the left femoral artery bilateral radial, brachial, and axillary arteries. A guidewire is inserted at the access site over which a dilator is placed. An intravascular Teflon sheath is inserted over the dilator to secure the vascular access site. This sheath allows for rapid exchange of catheters, limits blood loss, and can be used to monitor the vascular pressures of the patient.

The common terminology for the diameter of a guiding catheter is French (F), and 1 F equals 0.33 mm. The size of interventional catheters has been rapidly decreasing and most interventional procedures can now be performed with 5 to 6 F catheters. Coronary guidewires are steerable and can be advanced through the guiding catheter into the coronary artery. The guidewire is used to advance the balloon catheter. The balloon catheter is made up of a support shaft to allow for advancement through the arterial lumen, a central lumen for the guidewire, and an inflation channel. During the angioplasty procedure, the IC advances the balloon catheter into the area of stenosis and expands the balloon, with the intention of opening the stenosis. Stenting the previously narrowed region became an extremely popular and effective means to prevent restenosis after angioplasty.

If the patient presents with in-stent restenosis, VBT can be applied to reduce restenosis rates. The patient should be evaluated by the radiation oncologist before coronary intervention. A history of prior stenting and any prior radiation therapy should be obtained. Informed consent for coronary intervention is obtained by the cardiologist and that for VBT is obtained by the radiation oncologist.

The radiation oncologist is typically called to the cardiac catheterization lab after the coronary intervention has been initiated by the IC. The applicator and source insertion for VBT is described in detail by the American College of Radiology (ACR) policy statement on the performance of coronary vascular brachytherapy.28 The procedure requires the presence of an IC, radiation oncologist (who is the authorized user of the delivery system), and medical physicist. The TV is determined jointly on the basis of the lesion size, injured length of vessel, and vessel diameter. The delivered dose is determined on the basis of the diameter of the vessel, the current activity of the radioactive source, and is recorded in the prescription/written directive.

Because each of the three FDA-approved delivery systems has unique characteristics, it is important for the entire team to be familiar with each system and its capabilities. Moreover, the ACR recommends that preestablished procedure guidelines for brachytherapy developed by the team of radiation oncologist, medical physicist, and IC be in place before performing VBT.

The IC is responsible for the general medical care of the patient while the patient is in the catheter lab. The IC performs the angioplasty and all physical manipulation of catheters within the coronary arteries. The radiation oncologist positions the source within the treatment catheter after consultation with the cardiologist regarding the location of the lesion and geometry of the vascular anatomy. The IC then checks the positioning of the source to confirm proper positioning. Documentation of position is usually by cineangiography which is stored electronically. Both the IC and radiation oncologist monitor the entire delivery of radiation therapy. The radiation oncologist removes the source from the patient and oversees the surveying of the patient and room by the medical physicist at the close of radiation delivery. The IC then performs final imaging and recovers the patient.

The three delivery systems that have been approved by the FDA for coronary brachytherapy application include the Checkmate system by Cordis Corporation, the BetaCath system by Novoste Corporation, and the Galileo system by Guidant Corporation.

The Checkmate system by Cordis Corporation is the only FDA-approved system that uses a γ-emitting source. The system uses 192Ir seeds manufactured by Best Industries. The Checkmate system contains a lead “pig” for storage of the source. The source is manually advanced by the radiation oncologist through a specialized, noncentered monorail closed-end 3.7 French delivery catheter. The Checkmate system (see Fig. 11.4) is approved for use with the 10- and 14-seed ribbon with treatment lengths of 39 and 55 mm. Each seed measures 3 mm and there is a gap of 1 mm between seeds. There are metallic dummy seeds at both ends of the catheter because 192Ir is not very radio-opaque. Both IVUS-based and fixed dosimetry may be used and typical dwell times range from 15 to 25 minutes. The source is changed on a monthly basis to keep treatment times reasonable.

Figure 11.4 The Checkmate Coronary Brachytherapy System (J&J Corp). The isotope remained within the shielded container and was manually pushed out with hard wire connections into the treatment area. Significant shielding issues made this quite cumbersome for most interventional cardiology laboratories.

The BetaCath System by Novoste Corporation was the most commonly used β-emitting delivery system. It contained a handheld manual device that used a closed-loop hydraulic system with sterile water to deliver and retract a 30 and 40 mm Strontium 90/Yttrium 90 (90Sr/90Y) seed train to the target. The device used a 3.5 or 5 F catheter, fixed dosimetry at 2 mm with differential dosing depending on vessel diameter, and dwell times ranging from 3 to 4 minutes. The catheter is noncentering. This remains the only commercial coronary vascular device in the market in 2006 (see Figure 11.5 and 11.6).

Figure 11.5 Novoste BetaCath system was a handheld device with 90Sr seeds within Lucite shielding. The seeds were propelled with a closed hydrolic system by the radiation oncologist. The β sources posed less shielding issues.

Figure 11.6 Novoste BetaCath Catheter.

The dose prescription depended on the reference diameter, which was determined angiographically by the cardiologist. The dose was prescribed to a fixed radial distance of 2 mm from the center (see Table 11.1). Figure 11.7 is an example of a right coronary artery with diffuse in-stent restenosis. Figure 11.8 shows the brachytherapy with the Novoste BetaCath System in place with margins around the disease and intervention. Figure 11.9 shows the 12-month follow-up angiogram with a successful outcome.

The Galileo system by Guidant Corporation was the second β-emitting delivery system approved by the FDA for in-stent restenosis of native coronary arteries. The delivery system had the ability to deliver the source electronically through a computerized stepping delivery afterloader. The system had a 20-mm 32P source wire with a centering balloon catheter that was 2.5, 3.0, or 3.5 mm. The centering catheter spiral balloon allowed for side and distal blood flow and perfusion and treatment lengths of 27 or 54 mm. Treatment times ranged from 2 to 5 minutes (see Figure 11.10). Table 11.2 compares some physical properties of the three coronary treatment devices.

Table 11.1 Dose Prescription Based on Reference Diameter for Betacath

Reference Diameter

Dose to 2 mm Radius


18.4 Gy


23.0 Gy



Figure 11.7 Preinterventional angiography demonstrating diffuse in-stent restenosis (ISR).

Figure 11.8 BetaCath brachytherapy—treated area after angioplasty performed with 5 mm margins proximally and distally prevent a geographic miss at either end of the target area.



Figure 11.9 A 12-month follow-up angiography demonstrates no recurrence of in-stent restenosis (ISR) within the treated segment.

Imaging Modalities

Two imaging modalities are used in vascular brachytherapy: Angiography and IVUS. Images from angiography are obtained from fluoroscopy while contrast is given. The images are actually the shadow of the lumen of vessel, visualized by the contrast material. The images do not give any information about the wall of the vessels. These images are two dimensional or planar. The plane of the view is chosen by the cardiologist to best view the vessel of interest. Owing to the nature of the fluoroscopic imaging, the magnification factor is not the same at different parts of the image. The images can be static or in dynamic mode (cine). The images are stored for review. Despite all these downsides, this is the main modality used by the cardiologist during the intervention process. It allows the visualization of the metallic stent, guidewire, and other markers (see Figure 11.11).

Figure 11.10 Three frames showing the Galileo System and catheter.

Table 11.2 Comparison of the Physical Properties of the Three Coronary Treatment Devices





Maximum Energy

Average Energy

Cordis Checkmate



74 day

612 keV

370 keV

Novoste BetaCath



28 year

2270 keV

970 keV

Guidant Galelio



14 day

1710 keV

690 keV

Intravascular Ultrasound Measurements

IVUS is a three-dimensional imaging modality. A high-frequency sound wave is sent radially to the vessel wall and its echo is received and processed electronically. Each axial IVUS image shows details of the lumen and the vessel wall. IVUS images are acquired like computed tomography (CT) scan images; there is an automatic acquisition of images as the device is withdrawn along the vessel. These axial images can be combined and reconstructed to show the sagittal and coronal images. The measurement from these images is subject less to distortion so it is more accurate than angiography. There is a reference millimeter marker on the vertical and horizontal axes of the IVUS images. Most IVUS software allow some quantification on the image, such as distance, area, and volume measurement. Figure 11.12 shows a schematic of the orientation of the US waves. Figure 11.13 demonstrates clinical utility in coronary interventions.

Figure 11.11 This is the most typical image used in interventional cardiology—two-dimensional representation of three-dimensional reality. Considerable skill and experience help the cardiologist choose the best plane of image to guide diagnosis and intervention.


Figure 11.12 A schematic of the orientation of the intravascular ultrasound (IVUS) fan of sound that generates the image. The images are real time, and still photos are selected to demonstrate structures and to take highly accurate measurements with the software.

Treatment Planning

It is essential to treat the stenotic lesion with adequate margins to prevent edge restenosis. Edge restenosis is the term for higher-than-expected restenosis rates at the edges of the treated volume. Possible etiologies for the edge effect include geographic miss of the lesion, barotrauma secondary to balloon inflation distal to the treated volume, source movement during the treatment, and dose falloff and penumbra at the edge of the treated volume.

Source Movement Effect

Giap et al. retrospectively reviewed source displacement during the cardiac cycle in 30 patients who underwent VBT at Scripps Clinic.29 They found a mean longitudinal source displacement of 1.1 mm (range 0.0 to 5.4 mm). The authors recommend adding the contribution from source movement to the TV to ensure adequate coverage and avoidance of a geographic miss.

Figure 11.14 shows an example of longitudinal seed displacement during cardiac cycle. The two frames (A and B) were captured during the cineangiogram and they represent the maximal distal source displacement. If the vessel branch is used as the reference point, A shows only one seed distal to this reference point. B, which was captured <1 second later, shows two seeds distal to the reference point. After performing precise measurement and de-magnification, the magnitude of the seed movement for the distal end is 3.3 mm. Similar calculation was done for the proximal end, and the value is 1.5 mm.

Barotrauma Effect

After angioplasty, a metallic stent is usually placed into the vessel by balloon expansion. Barotrauma refers to the injury to the vessel wall due to the balloon inflation or from the stent deployment balloon. The length of the balloon used for stent deployment is typically longer than the stent itself. Figure 11.15 shows a bare-metal stent on its deployment balloon.

Distal and proximal regions of dilatation and barotrauma without stenting to protect from recoil are at risk for restenosis.

Figure 11.13 Three frames demonstrating intravascular ultrasound (IVUS) imaging. A: Shows the stent as a white dotted line most clearly seen superiorly. B: Shows the IVUS catheter and the guidewire. C: Demonstrates the lumen, the stent, and the external elastic lamina (EEL).

Figure 11.14 A and B: Frame capture pictures from a cineangiograph demonstrating significant beat-to-beat movement of the treatment catheter during therapy.

In a study from Scripps Clinic, current stent designs were reviewed; providing an assessment of barotrauma due to stent deployment in vascular brachytherapy, the barotrauma length averaged 1.7 mm (range 0.5 to 2.5 mm).30 Table 11.3 reviews nine commonly used stents and their corresponding barotrauma lengths. To minimize a marginal failure at the edges of the treatment volume, it is important to include the entire region of barotrauma in the treated length.

To Center or Not Center

The following images show the cross-sectional view of the three catheters in the treated lumen for the Cordis Checkmate, Novoste BetaCath, and Guidant Galelio systems, respectively. The Checkmate catheter is a noncentering single lumen; the BetaCath catheter is also noncentering but has a triple lumen hydraulic system; and the Galileo catheter is a centering and single lumen (see Figure 11.16).

There was significant debate regarding whether centering the radiation source within the delivery catheter system would improve the safety and efficacy of VBT. Proponents of centering argued that regardless of the isotope used, centering the radiation source improves precision and reproducibility over noncentered sources. These proponents of centering argued that using a noncentered source can introduce significant variability in the dose received by the circumferential target.31 Others believed that centering is not important for coronary VBT.32 They argued that positive results in both animal and human trials had been observed without the use of centered delivery catheters and no study had shown a benefit to centering against noncentering. They also stated that variability of the lumen diameter and movement of the delivery catheter within the lumen leaves little capacity for reproducible centering within the coronary vasculature. It is important to note that it is logical to see the benefit of centering of the source within the treated vessel wall so that the radiation is distributed uniformly to the vessel wall. By using the centering catheter within a diseased lumen, which is often noncentric due to plaque, the source could be noncentered with respect to the vessel wall. Because the range of γ source is longer, the effect of noncentering was less significant for γ sources compared with β sources.

Figure 11.15 A typical stent deployed on its balloon. Note the tapering proximal and distal ends, contributing to barotrauma injury outside the stented region.

Table 11.3 Review of Nine Commonly Used Stents and Their Corresponding Unprotected Barotrauma Lengths

Stent (Manufacturer)

Stent Diameter (mm)

Stent Length (mm)

Balloon Length (mm)

Unprotected Barotrauma Length (mm)

Stent Deployment Pressure (atm)

Crown (J&J, Cordis)

3.0, 3.5, 4.0

15, 22, 30

17, 24, 32



Mini-Crown (J&J, Cordis)

2.25, 2.5, 2.75, 3.0, 3.25

11, 15

13, 17




3.0, 3.5, 4.0

8, 12, 18, 24, 30

12, 16, 22, 28, 34



Multi-Link (ACS)

3.0, 3.5

15, 25

20, 30



Multi-Link OTW Duet (ACS)

3.0, 3.5, 3.75

8, 13, 18, 23, 28, 38

11.5, 17.2, 21.9, 26.8, 30.5, 41.2

1.75, 2.1, 1.95, 1.9, 1.25, 1.6


Multi-Link Rx Duet (ACS)

3.0, 3.5, 3.75

8, 13, 18, 23, 28, 38

11.5, 17.2, 21.9, 27.3, 30.5, 41.2

1.75, 2.10, 1.95, 2.15, 1.25, 1.60


NIR Primo (BSC/SciMed)

2.5, 3,0, 3.5, 4.0

9, 16, 25, 32

13, 20, 29, 36



NIR on Ranger (BSC/SciMed)

2.5, 3,0, 3.5, 4.0

9, 16, 25, 32

13, 20, 29, 36



NIR on Ranger with SOX (BSC/SciMed)

2.5, 3,0, 3.5, 4.0

16, 25, 32

17, 26, 33



γ versus β Sources

There exists a debate on whether γ- or β-emitting sources are better for VBT. A study comparing the dosimetry of β versus γ radiation sources for catheter-based VBT found that the dose reduction beyond a calcified plaque or a metallic stent could be >20% for the β-emitting 90Sr but was negligible for the γ-emitting 192Ir.33

Figure 11.16 Three schematic cross sections of the three Coronary Artery Radiation Therapy (CART) systems. A: The Checkmate System (J&J, Corp), B: The BetaCath System (Novoste Corp), and C: The Galileo System (Guidant Corp)


The advantages of γ-emitting sources include the fact that they have an improved depth-dose gradient compared with β-emitting sources and are not attenuated by calcium inside vessel lumens or by metallic stents. However, γ-emitting sources expose the catheter lab staff to increased ionizing radiation and require lead shielding to be placed in the catheter lab. The treatment times are longer with γ-emitting sources. On the other hand, β-emitting sources have shorter penetration than γ sources and can be attenuated by calcium or stents, leading to potential underdosing of the target. β-emitting sources may have longer half-lives, higher specific activity, and higher dose rate, and treatment times are shorter than with γ-emitting sources.34 The Beta versus Gamma Utrecht Trial (BEGUT) compared β- versus γ-emitting sources for use in VBT in a single-institution randomized, prospective study.35 The BEGUT was designed to compare safety and feasibility. The initial results of the study were negative.

It is debatable whether a γ or a β isotope is superior for VBT. It is not possible to answer the question with existing clinical data. The ideal isotope is that which is safest for the patient, operator, and public, and most efficacious. It is not possible to interchange isotopes between different systems, and so it is more appropriate to compare the results of systems rather than isotopes.

Dose Rate Effects

The biologic consequences of radiation depend not only on the total dose but also on the dose rate at which the radiation is delivered. The absorbed dose measures only the quantity of energy absorbed per unit mass of tissue (Joules per kilogram). The rate at which this dose is delivered has been shown to correlate with the biologic sequelae of the radiation. The dose rate effect in endovascular brachytherapy was investigated using a biophysical model derived from linear-quadratic formalism.36 The goal was to compare the biologic equivalent doses (BED) for different delivery systems. In CART, the dose rate effect is important for three reasons. First, the radiation is applied close to the source, where the dose rate gradient (falloff) is extremely high, hence the biologic effectiveness varies. Second, different clinical trials utilized different source types, strengths, and designs. In these trials, the same total dose prescription to same radial distance was delivered at different dose rates. The typical dose rate for the WRIST trial (192Ir source) is approximately 50 cGy per minute at 2 mm radial distance versus 500 cGy per minute for the START trial (90Sr/90Y source). Furthermore, different trials prescribe different doses at different radial distances. Thirdly, different source types and designs have different dose gradient profiles; therefore, different dose rates may be delivered.

There are several clinical implications of dose rate effects in CART. First, the concept of BED should be considered when different clinical studies are compared, especially if these employ different source types/designs and dose prescriptions. One should remember that the unit of absorbed dose (centigray or rad) is only a measure of amount of energy deposit per unit mass. Theoretically, whether higher BED means greater benefit or greater risk depends on several factors such as the following:

1. Spatial relation of target cells and limiting structures. Higher BED in CART is advantageous if the target tissue is closer to the source than the critical tissues. An ideal situation is demonstrated in the following example in which the target tissue is at 2 mm and the limiting tissue is at 4 mm from the 90Sr/90Y source. The difference in physical dose distribution due to the sharp dose gradient of brachytherapy yields a 4.8 times higher dose to the target (spatial advantage). If the dose rate effect is taken into account, the BED at target tissue is 13.9 times higher (spatial and biologic advantage). This assumption may be substantiated by the preliminary finding that the target cells for restenosis are the endothelial and vessel SMCs located in the coronary vessel, which is ranged from 2 to 5 mm in diameter. If this assumption of the relative spatial relation of target and critical structure is correct, the biologic therapeutic window is much greater for CART than for external beam data, and this may explain the fact that the animal data for CART is much more consistent than that of external beam.37

2. Dose threshold to cause a late cardiac complication or to inhibit restenosis. The therapeutic window is greater if the dose response curve for restenosis inhibition lies to the left of the dose complication curve. For example, if a BED of 5,000 is required to cause a complication, and a BED of 1,000 is required to inhibit restenosis, then the therapeutic window is great. In contrary, if it takes a BED of 500 to cause a complication and a BED of 10,000 to inhibit restenosis, then there is no therapeutic window.

Edge Failure (“Geographic Miss”)

When restenosis occurs after CART, the renarrowing is found at the treatment edges in one third to one half of patients. The etiology of edge failure is likely to be multifactorial but most likely results from inadequate radiation dose delivered to injured lesion margins. Many factors can lead to higher-than-expected edge failure. These include geographic miss, which arises from misalignment of the radioactive source within the injured segment of the vessel. In several studies using catheter-based radiation, careful, quantitative coronary angiographic measurements have documented a surprisingly high incidence of inadequate coverage of the injured region by the radioactive source. The balloon catheters used to initially open the stenotic segment can slip forward or backward (“watermelon seeding”), causing unintended injury to the lesion margins. Also, barotrauma from both angioplasty and stent deployment contribute to arterial wall injury beyond the nominal lengths of the balloons or stents.38 Longitudinal seed displacement may also contribute to higher-than-expected restenotic rates at lesion margins owing to the movement of the radioactive seeds relative to the coronary vessel during the cardiac cycle.39 Figure 11.17 is a schematic depiction of the stent and the clinical target in vascular brachytherapy. In addition to more movement in the distal portion of arteries, the movement also varies with the particular artery (possibly more in the circumflex, for example). Uncertainty in target localization can occur because of the difficulty in visual estimation of proximal and distal lesion ends. This uncertainty is compounded by different magnification and obliquity of various projections during fluoroscopy and cine and the relative lack of reference points available (branch vessels are commonly used as reference points for targeting). Lastly, the dose falloff and penumbra effect of the particular isotope used can contribute to marginal failure.

CART cannot be effective in regions injured by angioplasty or atherectomy where radiation is not delivered. Although the causes of edge failure are still unclear and most likely multifactorial, several strategies have been used to decrease edge failures. First, careful cine documentation of injury to the vessel at each and every balloon angioplasty or stent placement (discouraged to minimize late thrombosis); second, careful determination of the proximal and distal extent of the injury to the vessel, ideally with a side branch reference point; and, lastly, providing a very wide margin (i.e., 4 to 10 mm) of radiation coverage on either side of the injured vessel region. These measures will not eliminate edge failure, but will probably considerably reduce its occurrence.

Figure 11.17 Barotrauma schematic.

Vascular Brachytherapy Terminology

On the basis of ICRU 62, terminology for CART volumes was proposed taking into consideration both radial and longitudinal dimensions.40 This terminology will help define the TV with the attention to appropriate margins to decrease edge failures. The gross target volume (GTV) is the length of stenotic segment with appropriate radius which may vary during the length. The clinical target volume (CTV) is the interventional length which is delineated by the most proximal and most distal extents of injury and is always larger than GTV. CTV is often asymmetric from GTV or may be more on one end than the other. The planning target volume (PTV) is the CTV plus a margin to account for both the heart and catheter movements and inaccuracies in the visual delineation of the ends of CTV. The uncertainty or magnitude of the margin depends upon the location of the target within the vessel, the delivery system (centered or noncentered), and the cardiac cycle. The TV is the volume irradiated on the basis of the PTV and the penumbra of effect of the isotope which depends upon the isotope, source design, and the prescription distance (see Table 11.4).

Complications of Vascular Brachytherapy: Subacute Thrombosis

Similar to the first attempts at stent implantation, initial enthusiasm for CART was dampened by reports of target thrombosis, particularly thrombosis occurring late (>30 days) after treatment. In early trials, late thrombosis following VBT was observed to occur in 3% to 10% of patients and independent of the isotope and delivery system tested. The thrombotic episode usually manifested itself as a sudden target vessel occlusion, resulting in a heart attack 1 to 9 months after radiation treatment.

There is no uniform definition or criteria for subacute thrombosis. Total occlusions can be subdivided into two groups: (i) symptomatic late thrombosis, occurring more than 30 days after the index procedure, resulting in myocardial infarction and confirmed by angiogram, and (ii) silent late occlusions, occurring more than 30 days after the index procedure. These total occlusions that are seen on the protocol required follow-up angiogram without clinical symptoms of myocardial infarction.

The emergence of this complication seriously jeopardized radiation as a viable treatment modality for coronary disease. Careful study, however, yielded two helpful clues that led to a dramatic reduction in radiation-associated late thrombosis:

1. The overwhelming majority of patients sustaining a late thrombosis had a new stent implanted at the time of the radiation procedure.

2. Almost all patients sustaining late thrombosis had discontinued antiplatelet therapy. Two strategies to prevent late thrombosis were initiated. First, the implantation of new stents during or immediately after treatment with brachytherapy was strongly discouraged. Second, antiplatelet therapy was extended for 6 to 12 months following the radiation therapy procedure. This strategy has now been tested with apparent success in several large series. In more recent trials with the above strategies, the incidence of late thrombosis was similar to placebo levels in the range 1% to 3%. In the SCRIPPS III trial, the late thrombosis rate was zero. Stent placement at the time of radiation delivery can cause both increased late thrombosis and, possibly, decreased efficacy of the brachytherapy itself. Pooled retrospective data from the SCRIPPS 1, WRIST, and GAMMA I trials for patients with in-stent restenosis show an even more pronounced effect of brachytherapy in patients without new stent placement than patients with stent placement.

Table 11.4 Target volumes Definitions for CART


Stenotic or restenotic lesion


Intervened or injured (angioplasty, stent, stent deployment, atherectomy) length


CTV + uncertainty for heart/catheter movement + uncertainty in target localization


PTV + penumbra effect

GTV, gross target volume; CTV, clinical target volume; PTV, planning target volume; TV, target volume.

Theoretical Assessment of Late Complications from Vascular Brachytherapy

The theoretical risk of late cardiac complication from endovascular brachytherapy was quantified using an integrated logistic model from a study by Giap et al. The calculation was performed for various lengths of 192Ir sources using α/β = 3.2 for the endpoint of chronic ischemia, TD 50/5 = 7,000 cGy, TD5/5 = 5,000 cGy. The dose distribution over a standard heart is divided into volume elements with uniform dose (dose-volume histogram). Using the linear-quadratic equation, the dose in each of the volume elements is converted into a dose equivalent to standard fractionation external beam irradiation (EBI). The normal tissue complication probability (NTCP) for each volume element is calculated and combined together to arrive at the cumulative risk of late cardiac complication. The NTCP is plotted against dose prescribed at 2 mm radial distance for four treatment lengths as shown in Figure 11.18.

There are several conclusions from this study. (i) The overall risk of late cardiac toxicity (chronic ischemia within 5 years) is estimated to be <1% for clinical trials utilizing 192Ir; (ii) there is a volume effect with higher risk for larger irradiated volume, which can come from longer treatment time, same dose prescribed at greater distance, and a longer source train; and (iii) the NTCP versus dose demonstrates a sigmoidal relationship. There is a threshold dose (approximately 500 cGy), below which the risk is minimal; the gradient of the curve is greater for longer treatment lengths. If this model is validated with clinical data, it would play an important role in serving as a guideline for dose prescription, dose escalation, evaluation of new source design, and multivessel treatment.

Figure 11.18 Graph showing normal tissue complication probability (NTCP) percent as a function of prescribed doses at 2 mm reference radius for different seed train lengths.


Drug-Eluting Stents

The competing technologies currently undergoing initial studies include drug-coated stents, photodynamic therapy, sonotherapy, and gene therapies. Of these, drug-eluting stents (DESs) were the most promising and have, in 2006, largely transformed clinical care in interventional cardiology. The DES consists of three components: Stent, drug, and a releasing mechanism. The drugs are antiproliferative agents. There are two FDA-approved DESs in the market: Cypher and Taxus. The Cypher stent utilizes the drug sirolimus, which is a weak antibiotic, but a powerful immunosuppressant. Sirolimus blocks cell cycles from progressing from G1 to S phase, preventing proliferation and migration of SMCs. The new sirolimus derivatives are Everolimus, ABT-578, and biolimus. The Taxus stent utilizes paclitaxel, which is an antineoplastic agent. Paclitaxel binds to tubulin, blocking microtubule disassembly, preventing the cell from moving from G2 to M phase. It interferes with the mitotic spindle apparatus, and hence blocks smooth muscle cell migration. It interferes with microtubule functions, affecting mitosis and extracellular secretion.41

The first DES was approved by the FDA in April 2003. Several large, prospective, randomized trials have confirmed the efficacy of drug-eluted stents as an antiproliferative treatment following revascularization with angioplasty.

In the SIRIUS trial, 1058 patients with de novo coronary stenosis undergoing percutaneous coronary intervention were randomized to sirolimus-eluting stent or bare stent. The sirolimus-eluting stent resulted in significant reduction in clinical restenosis compared with control, with only 8.9% of treated patients experiencing restenosis.42 In the Taxus-IV study, the polymer-based, paclitaxel-eluting TAXUS stent had a 1-year rate of TLR of 4.4% compared with 15.1% for the identical-appearing bare-metal EXPRESS stent.43

The question is, which is the better stent. There is a European multicenter randomized, controlled single-blind study with 1012 patients, which compares Sirolimus against Taxol stents for coronary de novo lesions. Results at 9 months are shown in the Table 11.5.44

The advent of drug-eluted stent therapy and its success in preventing restenosis of de novo stenosis has mitigated the enthusiasm for vascular brachytherapy. Because vascular brachytherapy had been the only proven therapy to prevent in-stent restenosis, it is logical to compare DES with brachytherapy in this category. There are two recently published prospective randomized trials that compare drug-coated stents with brachytherapy for in-stent restenotic lesions: The SISR and TAXUS V trials. Both studies show superiority of DES over brachytherapy for in-stent restenosis within bare-metal stents. SISR is a prospective, multicenter, randomized trial of 384 patients with in-stent restenosis who were enrolled between February 2003 and July 2004 at 26 academic and community medical centers to receive either vascular brachytherapy (n = 125) or the sirolimus-eluting stent (n = 259).45 The main endpoints measure target vessel failure (cardiac death, myocardial infarction, or target vessel revascularization) at 9 months' postprocedure. The rate of target vessel failure was 21.6% (27/125) with vascular brachytherapy and 12.4% (32/259) with the sirolimus-eluting stent (relative risk [RR], 1.7; 95% confidence interval [CI], 1.1 to 2.8; p = 0.02). TLR was required in 19.2% (24/125) of the vascular brachytherapy group and 8.5% (22/259) of the sirolimus-eluting stent group (RR, 2.3 [95% CI, 1.3 to 3.9]; p = 0.004). At follow-up angiography, the rate of binary angiographic restenosis for the analysis segment was 29.5% (31/105) for the vascular brachytherapy group and 19.8% (45/227) for the sirolimus-eluting stent group (RR, 1.5 [95% CI, 1.0 to 2.2]; p = 0.07). Compared with the vascular brachytherapy group, MLD was larger in the sirolimus-eluting stent group at 6-month follow-up (mean [SD], 1.52 [0.63] mm vs. 1.80 [0.63] mm; p <0.001), reflecting greater net lumen gain in the analysis segment (0.68 [0.60] vs. 1.0 [0.61] mm; p <0.001) due to stenting and no edge restenosis. This study shows that Sirolimus-eluting stents result in superior clinical and angiographic outcomes compared with vascular brachytherapy for the treatment of restenosis within a bare-metal stent.

Table 11.5 Sirolimus versus Taxol Stents—Results at Nine Months44




Major adverse cardiac events


10.8% (p = 0.009)

Target lesion revascularization


8.3% (p = 0.03)



11.7% (p = 0.02)

Myocardial infarction


3.5% (p = 0.50)

The TAXUS V ISR trial is also a prospective, multicenter, randomized trial conducted between June 6, 2003, and July 16, 2004, at 37 North American academic and community-based institutions in 396 patients with in-stent restenosis of a previously implanted bare-metal coronary stent (vessel diameter, 2.5 to 3.75 mm; lesion length, <46 mm).46 Patients were randomly assigned to undergo angioplasty followed by VBT with a β source (n = 201) or paclitaxel-eluting stent implantation (n = 195). Clinical and angiographic follow-up at 9 months were performed to assess endpoints. Diabetes mellitus was present in 139 patients (35.1%). Median reference vessel diameter was 2.65 mm and median lesion length was 15.3 mm. In the VBT group, new stents were implanted in 22 patients (10.9%) and in the paclitaxel-eluting stent group, multiple stents were required in 57 patients (29.2%), with median stent length of 24 mm. Follow-up at 9 months was complete in 194 patients in the VBT group and 191 patients in the paclitaxel-eluting stent group (96.5% and 97.9%, respectively). For VBT and paclitaxel-eluting stents, respectively, the number of events and 9-month rates for ischemic TLR were 27 (13.9%) versus 12 (6.3%) (RR, 0.45; 95% CI, 0.24 to 0.86; p = 0.01); for ischemic target vessel revascularization, 34 (17.5%) versus 20 (10.5%) (RR, 0.60; 95% CI, 0.36 to 1.00; p = 0.046); and for overall MACE, 39 (20.1%) versus 22 (11.5%) (RR, 0.57; 95% CI, 0.35 to 0.93; p = 0.02), with similar rates of cardiac death or myocardial infarction (10 [5.2%] vs. 7 [3.7%]; RR, 0.71; 95% CI, 0.28 to 1.83; p = 0.48) and target vessel thrombosis (5 [2.6%] vs. 3 [1.6%]; RR, 0.61; 95% CI, 0.15 to 2.50; p = 0.72). Angiographic restenosis at 9 months was 31.2% (53 of 170 patients) with VBT and 14.5% (25 of 172 patients) with paclitaxel-eluting stents (RR, 0.47; 95% CI, 0.30 to 0.71; p <0.001). This study concluded that the treatment of bare-metal in-stent restenotic lesions with paclitaxel-eluting stents rather than angioplasty followed by VBT reduces clinical and angiographic restenosis at 9 months and improves event-free survival.

There are several criticisms of these studies. First, the analysis zone for VBT is longer than DES, hence biasing the angiographic analysis in favor of the DES group. Second, the follow-up in these studies is only at 9 months, longer follow-up is necessary to adequately assess the relative safety issues and late efficacy. Given the marked differences in delivering DES and the VBT, the blinding of the investigators was not possible. The angiographic restenosis rates at 9 months for both studies are approximately 30% for VBT this group of patients with small lesions, which is somewhat inferior compared with previous randomized data on VBT. The studies used a β source, which is the BetaCath system, which has somewhat subjective dose prescription of either 18.4 or 23 Gy depending on the reference vessel diameter. Judging the vessel size in these studies, most patients received the lower dose of 18.4 Gy at 2 mm radius, which is considered to be low by most radiation oncologists. These two studies address a small group of ISR patients with short lesions, 15 mm length, in native vessels. The results cannot be extrapolated to treat longer lesions or non-native vessels. VBT has been used in much longer lesions, up to 40 to 50 mm length, in both native and vein-graft lesions.


Coronary Artery Vascular Brachytherapy in the ERA of a Drug-Eluting Stents World

The success of drug-eluted stent therapy in reducing rates of restenosis is a significant advance in the care of patients and should be welcomed by all physicians. Although the enthusiasm for vascular brachytherapy has been diminished by the success of drug-eluted stent therapy, there does remain a future for vascular brachytherapy in the care of patients. At first glance, it does appear that the results from these SISR and TAXUS V trials would lead to the demise of VBT. Perhaps, this conclusion may be too premature. Will all patients and lesion subtypes be equally susceptible to drug-coated stents? In the SIRIUS study, most diabetic patients treated with sirolimus stents had profound reductions in restenosis, but those with vessels smaller than 2.5 mm still had restenosis rates of almost 20% (although improved compared with placebo). Furthermore, absolutely no data exists regarding the effectiveness of drug-coated stents for saphenous vein-graft stenoses. Likewise, long, diffuse disease has not been studied. Also, there appears to be a lack of drug effect where drug is lacking, particularly at the stent margins. Most current drug coatings are hydrophobic, resulting in little or no diffusion beyond the stent margin. This probably explains why restenosis, when observed in a drug-coated stent patient, usually occurs at the stent margins. Can devices be designed to extend drug effect laterally into areas of balloon injury at stent margins?

The results of the SISR and TAXUS V studies do not address groups of patients with ISR after DES placement. The 9-month failure rate after DES for ISR is 15% to 20% from these two randomized studies. There are emerging retrospective data supporting the use of VBT for DES failure. It is anticipated that the success of drug-eluted stent therapy may eventually double the number of patients undergoing stent implantation. If approximately 2 million patients were to undergo drug-eluted stent therapy annually, even a small percentage of patients who fail to be successfully managed with the therapy could result in thousands of patients requiring vascular brachytherapy. Moreover, subsets of patients such as patients with diabetes and those with longer, more complex lesions are less successfully managed with drug-eluted stent therapy. These patients may be candidates for vascular brachytherapy. Moreover, drug-eluted stents remain expensive, especially when multiple stents must be used for a single patient. If reimbursement is not proportional to the increased costs of using multiple stents within a single patient, adoption of drug-eluted stent therapy across the world may be slowed.47

It is likely that vascular brachytherapy shall continue to play a role in the management of patients. More importantly, the randomized trials conducted in thousands of patients using vascular brachytherapy confirmed its efficacy as the first successful antiproliferative treatment for in-stent restenosis of coronary arteries. Moreover, the success of vascular brachytherapy led to the innovation of drug-eluted stent therapy. Several lessons learned while conducting randomized trials with vascular brachytherapy promise to improve the efficacy of drug-eluted stent therapy. Adequate dosimetric margins are needed at the sites of balloon-mediated injury to prevent the candy-wrapper or margin effect of restenosis at the edges of the treated volume. Late thrombosis, an adverse effect of vascular brachytherapy, could be prevented with the prolonged use of antiplatelet therapy. The lessons learned from VBT are presently incorporated into drug-coated stent trials. Regardless of how often VBT is used in the future, it leaves behind a legacy of success and innovation that continues to inform trials in this area.

Peripheral Vascular Brachytherapy

Noncoronary peripheral atherosclerotic vascular disease (PVD) affects more than 10 million people in the United States and 20% of people over 70 years of age. Up to half of these patients have symptomatic lower-extremity PVD. Risk factors for PVD include the following: more than 50 years old, history of smoking, history of diabetes, obesity, lack of exercise, history of high blood pressure, history of high cholesterol, history of hyperlipidemia, and genetic factors. The most common symptom of PVD is intermittent claudication, defined as pain on walking that is relieved by rest. Intermittent claudication accounts for 90% of all symptomatic cases of PVD and 75% of all diagnosed cases of PVD. In PVD, the femoral and/or popliteal arteries tend to be highly diffuse, long chronic total occlusions or long segments with multiple narrowed areas. Treatment options for PVD include conservative medical management and more aggressive invasive therapies including PTA, surgical bypass, and amputation. An estimated 600,000 interventional procedures are performed for the treatment of lower limb arterial disease each year, including PTA, bypass surgery, and amputation. Procedural estimates for the year 2006 identify PVD treatments as follows: 70,000 angioplasties with or without stent placement, 150,000 bypass surgeries, and 30,000 limb amputations.

Table 11.6 Cost of Peripheral Restenosis Interventions


Bypass Surgery (Gold Standard)




$2,300 angioplasty



$3,000 atherectomy



$3,100 stenting



$8,300—1 d

Cost of restenosis


$11,000 each time

Patients with carotid artery disease have significant morbidity and mortality rates. Approximately 5% of the hypertensive patients have renal artery stenosis. Approximately 400,000 peripheral angioplasties are performed in the United States annually. Unfortunately, just like the case of coronary arteries, restenosis is a significant problem in PVD. Beside causing symptoms and adding procedures to patients, restenosis is costly as shown in Table 11.6.48

Compared with open bypass surgery, nonsurgical interventions offer the potential for decreased operative mortality, shorter hospital stays, and fewer wound complications. These advantages can translate into increased cost-effectiveness if patency rates equal those of a vein bypass. However, the need for repeat procedures can be the “Achilles heel” of these nonsurgical interventions. The initial benefits of lower cost of nonsurgical interventions as compared with open bypass can be offset by repeat procedures needed to maintain patency. Therefore, the indication for nonsurgical intervention as opposed to surgery or conservative medical management still remains the matter of debate if one considers the cost factor. One study estimates an open bypass to be twice as expensive as an endovascular repair, but at 15-month follow-up, the cost per patient or cost per patent vessel is five times higher for an endovascular approach.49

Risk Factors for Restenosis

Risk factors for the development of restenosis in PVD have been identified. One can classify the risk factors as patient specific and lesion specific. Diabetic patients are at particularly high risk for restenosis in CAD and PVD. These patients have characteristically increased endothelial dysfunction associated with increased platelet activity and a more aggressive cellular response to injury. Most studies have shown female gender to be associated with a higher risk of restenosis. Furthermore, patients with known systemic inflammatory condition (as measured with C-reactive protein, lipoprotein (a), postprocedural von Willebrand factor, and plasminogen activator inhibitor-1 antigen) are also at higher risk of restenosis.50

There are several lesion-specific risk factors associated with restenosis. Muscular arteries (distributing), which have a high vascular smooth muscle content in their media in general, have a higher restenosis rate than elastic (conductance) arteries. Other lesion-specific factors are vessel diameter, lesion length, plaque burden, and the status of the distal (runoff) vessels. One of the most powerful predictors of restenosis is the vessel diameter—smaller vessels (and those with a smaller lumen diameter after PTA/stenting) are at greater risk of restenosis. Furthermore, lesions with a greater plaque burden and those with a poor distal runoff are more susceptible to developing significant restenosis. Table 11.7 lists the restenotic risk for various peripheral vessels.

Table 11.7 Average Restenosis Rate at 1 year After Percutaneous Transluminal Angioplasty


Average Restenotic Rate at 1 Year





Iliac after percutaneous transluminal angioplasty


Iliac after stent


Superficial Femoral Artery (SFA), popliteal, and tibioperoneal


From Dieter RS, Laird Jr. Overview of restenosis in peripheral arterial interventions. Endovasc Today. May 2005, Vol. 3, No. 3, Pages 413–422

Similar to coronary artery, the biology of restenosis in PVD can be divided into three phases. Immediately after angioplasty, the vessel can undergo acute vessel recoil, which can be treated effectively with stenting. The second phase of restenosis involves the late negative remodeling of the vessel. After injury, the myofibroblasts in the adventitia may be stimulated to produce a collagen-rich, extracellular matrix. Furthermore, endothelial injury induced by angioplasty and stenting results in the exposure of collagen in the subintimal space, von Willebrand factor, and the lipid core. This injury results in the activation of platelets with subsequent release of growth factors and other mediators of inflammation. This inflammation stimulates the third phase of restenosis—the activation and migration of vascular SMCs and fibroblasts into the area of injury. The histology of late vessel restenosis is of limited cellularity. Restenotic lesions are composed primarily of SMCs, proteoglycans, collagen, and extracellular material.51

Parallel to the effort in coronary artery, investigators have attempted to expand the idea to utilize radiation to reduce the risk of restenosis in PVD because the basic biology of restenosis is found to be similar. However, there are some major differences in clinical, anatomic, and technical aspects of the two areas52:

1. PVD involves more organs than CAD. Therefore, there are more diverse clinical situations, manifestations, and endpoints. In addition to the typical vessel parameters such as late loss or late loss index, it is challenging to define measurable clinical endpoints for a diverse group of “host” organs (extremities, kidney, liver, etc.), which are different not only in anatomy but also in complex functions.

2. Anatomy. There are differences in vessel dimensions such as length, diameter, thickness, curvature, and orientation. Unlike coronary vessels, most peripheral vessels have a diameter >3 mm and, in fact, are typically approximately 7 to 10 mm; some may be as large as 20 mm (e.g., the aorta). The peripheral arterial tree, because it is larger and more diverse than the coronary circulation, poses very different clinical scenarios and endpoints.

3. Pathology. PVD tends to have much larger/longer restenosis lesions and are more likely to be multifocal.

4. Technical Aspects. Owing to a larger vessel diameter, endovascular brachytherapy using seed- or wire-based catheter system requires high-energy γ source (192Ir) because β or low-energy γ sources would underdose the subintimal walls. Most trials in peripheral vascular systems currently utilize a high dose rate (HDR)192Ir source, because the manual loading technique with low dose rate seeds typically used in coronary system requires higher activity (more exposure to personnel) and longer treatment time; these pitfalls are rectified by the HDR remote afterloader system. However, the manual afterloader system has two advantages over the HDR remote afterloader system: (i) Source positioning can be adjusted in vivo; (ii) angulation of the delivery catheter can be recognized by the operator of the manual afterloader and can then be corrected by a more forceful push on the source wire and change in the torque as need be. In contrast, the HDR remote afterloader may abort the treatment. Although it is possible to deliver HDR treatment with sources other than high-energy γ emitters in the vascular lab with modification of room to meet shielding requirements, almost all treatments with high-energy γ sources such as 192 Ir are delivered in the department of radiation oncology. Therefore, the logistics of patient transportation must be considered in protocol design: Increase in overall catheterization time, minimal movement of catheter systems, anticoagulation, and personnel are some mitigating factors. Furthermore, the use of a centering device may be more critical for peripheral vascular system than for coronary vessels to assure dose uniformity.

5. The impact of the drug-eluting stent is not as much in PVD as in coronary system. The SIROCCO study, which used sirolimus-eluting nitinol stent, did not find the impact of DES over uncoated stent. The in-stent mean percent diameter stenosis was 22.6% in the DES group versus 30.0% in the uncoated stent group (p = 0.294) at 6 months. DES had late recurrence and mechanical problems.53

Superficial Femoral and Popliteal Arteries

These vessels are the most affected vessels in the body. Their occlusion is common. There are more than 100,000 interventions per year for these vessels. There is often poor distal runoff, which creates a high resistance and low flow state. Because they are muscular (distributing) arteries, the superficial femoral, popliteal, and tibial vessels have high rates of restenosis after percutaneous interventions. The primary patency rates for PTA of femoropopliteal lesions averages 61% at 1 year (47% to 86%). At 3 to 5 years, the patency rate after endovascular treatment ranges 38% to 58%.54 The patency rate depends on the type of lesion (stenosis vs. occlusion) and the indication (claudication vs. critical limb ischemia). Three-year patency rates range from 61% for claudicants with stenoses to 30% in patients with critical limb ischemia and occlusions.55 Femoropopliteal lesions that have been stented have 3-year patency rates of 58% to 66%.56 Beside the coronary vessels, these vessels accumulated the most clinical studies in evaluating the role of vascular brachytherapy in reducing restenosis. Tables 11.8 and 11.9 list the important studies, of which an excellent review was done by Schillinger and Minar.57

Several observations may be derived from this table. Almost all studies were performed in Europe except for the Peripheral Artery Radiation Investigational Study (PARIS) that was done in the United States and Europe. All studies utilized remote afterloading HDR 192Ir sources. Unlike the studies in coronary vessels, these studies examined the use of VBT for prophylaxis of restenosis after PTA of de novo lesions, prophylaxis of restenosis after PTA of recurrent lesions, and prophylaxis of in-stent restenosis. Studies were done with and without additional bare metallic stent after VBT.

The Frankfurt trial reported by Bottcher et al. was the first to present the safety and feasibility of VBT in PVD.58 Twenty-eight patients with post-PTA recurrent lesions (mean length = 6.7 cm) in SFA were treated with repeated PTA plus stent implantation and VBT. A dose of 12 Gy was given at a fixed radius of 3 mm using HDR 192Ir and a noncentering 5 F catheter. The patency rate at 5 years is 82%. Three patients developed restenosis and two presented with thrombotic occlusion at 16 and 37 months.

The Switzerland Trial reported by Zehnder et al.59 on 100 patients with recurrent SFA lesions after PTA were randomized to repeated PTA alone versus PTA plus VBT (12 Gy at 3 mm radius using a noncentering 5 F catheter and HDR 192Ir). At 1 year, the rate of restenosis was lower in the VBT group at 23% versus 42% for the control group (p = 0.028). Gallino et al.60 reported another Switzerland multicenter trial with 335 patients who were prospectively randomized to a 2 by 2 factorial design with PTA alone, PTA plus VBT, PTA plus probucol, and PTA plus VBT and probucol. Stenting was allowed as a bailout procedure for failed PTA. Probucol, which is an antioxidant and has been used as medication to lower cholesterol, has been found effective in reducing the rate of restenosis after balloon coronary angioplasty. For the VBT, a dose of 14 Gy was prescribed to the reference radius plus 2 mm without centering catheter. There was an alarmingly high rate of late thrombotic reocclusion (27%) in patients receiving stenting and VBT, which almost always happens at the withdrawal of antithrombotic drug. No late thrombotic reocclusion was seen in patients receiving PTA and VBT. Despite this, the 6-month restenosis rate is still lower in patients receiving VBT (17% vs. 35%, p <0.01), and probucol made no difference.

Table 11.8 Peripheral Artery Radiation Therapy (part) Trials


Study Design

Number of Patients

Stent Use

Delivery System

Dose (Gy)

Late Thrombosis

Restenosis Rate (VBT vs. Control)

Frankfurt trial Bottcher et al. (1990–1997)

Single center phase II. In-stent restenosis. SFA, 4.5–14 cm (6.7 cm)



HDR 192Ir noncentering

12 Gy at 3 mm



Switzerland trial Zehnder et al. (1997)

Phase III randomized study of VBT vs. PTA



HDR 192Ir noncentering

12 Gy at 3 mm

Not reported

23% vs. 42% (p = 0.028)

Vienna 2 Pokrajac et al. (1996–1998)

Single center, phase III. Both de novo and restenotic lesions 113 pt. First randomized study



HDR 192Ir, noncenter

12 Gy at 2.5 or 3.0 mm (low dose)


36% vs. 65% (p <0.05)

Vienna 3 1998–2002

Multicenter randomized double-blind



HDR 192Ir centering

18 Gy to adventitia


10% vs. 35% (p <0.05)

Switzerland Greiner, et al. (1997)

Phase II, then 4-arm phase III. (PTA, VBT, Aspirin (ASA), probucol)



HDR 192Ir, noncentering

14 Gy to reference radius + 2 mm


17% vs. 35% (p <0.01)

PARIS 1998 United States

Multicenter Phase II, then phase III at 12 centers



HDR 192Ir centering

14 Gy to catheter balloon radius + 2 mm


13%9% vs. 28% (p =0.92)

VBT, vascular brachytherapy; HDR, high dose rate; PTA, percutaneous transluminal angioplasty; PARIS, Peripheral Artery Radiation Investigational Study.

Table 11.9 Peripheral Artery Radiation Therapy (part) Trials de Novo Lesions



Number of Patients

Stent Used

Delivery System

Dose (Gy)

Late Thrombosis

Restenosis Rate (VBT vs. Control)

Swiss (Gallino et al.)

Phase III 2 × 2 (probucol)


Bailout for failed PTA

HDR 192Ir noncentering

14 at R + 2 mm

5% (27% in VBT + stent)

17% vs. 35% at 6 mo (no benefit from probucol)

German (Krueger et al.)

Phase III



HDR 192Ir centering



7% vs. 38% at 2 y

PARIS feasibility

Phase II



HDR 192Ir centering

14 at R + 2 mm


13% at 12 mo

PARIS (12 centers in the United States and Europe)

Phase III



HDR 192Ir centering

14 at R + 2 mm


75 patients: 28% vs. 28% at 6 mo

PTA, percutaneous transluminal angioplasty; VBT, vascular brachytherapy; PARIS, Peripheral Artery Radiation Investigational Study; HDR, high dose rate.

The PARIS study is the only FDA-approved study at 12 centers in the United States and Europe. In the initial phase II, VBT was delivered successfully to 35 of 40 patients at 4 centers using a specially designed double lumen—centering catheter. The angiographic restenosis at 6 months was 17% and the clinical restenosis at 12 months was 13%. The second phase of this study is a prospective randomized, double-blind control study with 300 patients at 12 centers in the United States and Europe. Only 203 patients (of the 300 intended) were enrolled. A dose of 14 Gy was prescribed to the adventitia, which was defined at 2 mm depth from the surface of the balloon. The preliminary data was presented by Waksman.61 Unfortunately, angiographic follow-up data were available only in 75 of the 203 patients (37%). Binary restenosis rates were 28.6% in the VBT compared with 27.5% for the control group (p = 0.92). There were no differences in percent stenosis, target vessel revascularization, late loss, ankle-brachial index (ABI), or maximum walking distance. There is no further follow-up publication of this study. For patients over 65, maximum walking times at 6 and 12 months were better in the VBT group. There are several criticisms of the results. First, the enrollment was poor: Only 203 patients of the intended 300 enrolled. Second, the follow-up angiography was available only for 75 patients. Third, the restenosis in the control arm was lower than expected rates of 40% to 60%. This study should be considered incomplete rather than negative.

For the SFA, the investigators at Vienna had done the most extensive series of clinical studies. All their studies were done with HDR 192Ir. The Vienna-01 Trial was a successful pilot phase I study on 10 patients.62 The Vienna-02 Trial was the prospective randomized trial from November 1996 to August 1999 on 113 patients with de novo (>5 cm) or recurrent (any length) femoropopliteal lesions. Patients were randomized to treatment with PTA alone or PTA plus VBT, where a dose of 12 Gy given at 3 mm radius with noncentering catheter. The median lesion length was 15 cm. Stenting was not allowed in the study. At 12 months, the restenosis rate was 36% in the PTA + VBT group versus 65% in the PTA group (p <0.05). The improvement in the patency was maintained after 3 years of follow-up. There was no late thrombotic occlusion (LTO) in this study.63 The authors believed that they could improve the outcome by increasing the prescribed dose and achieve better dose distribution using the centering catheter. This led them to the Vienna-03 Trial in 1998. In this Austrian multicenter randomized double-blind study, comparisons were made between PTA + VBT versus PTA alone. The dose in this study was 18 Gy at adventitia using the balloon-centering catheter. This dosing was comparable to that of PARIS. Unlike PARIS, patients with longer lesions were eligible (mean lesion length = 10 cm). The primary endpoint is angiographic restenosis at 12 months. The restenosis rate at 6 months was 10% for the VBT versus 35% for the placebo, and at 12 months, the restenosis rate was 23% for the VBT versus 53% for the placebo. This significant result confirmed the benefit of VBT. There was no LTO observed in this study.64 The Vienna-04 study was a pilot phase I–II study to evaluate the interaction of VBT and stenting. Thirty-three patients received VBT with the dose and delivery system similar to PARIS (14 Gy at 2 mm beyond the average lumen radius and PARIS balloon-centering catheter). All patients received 1 month of clopidogrel and indefinite aspirin. The restenosis rate was 30% at 6 months, and seven patients developed sudden LTO between 3.5 and 7 months.65 The Vienna-05 Trial extended from the Vienna-04 into a prospective, double-blind study comparing PTA + stenting versus PTA + stenting + VBT.66 The dose prescription and delivery system are similar to the Vienna-04 study except that all patients were put on clopidogrel for 1 year. A total of 88 patients with mean treatment length of 16.8 cm were enrolled. The primary endpoint of the study was angiographic binary restenosis of more than 50% at 6-month follow-up. The secondary endpoint was either percutaneous or surgical TLR after 6 months. The overall 6-month recurrence rate was 35% in patients who underwent only stent implantation and 33% in patients who underwent both stent implantation and VBT (p = 0.89). Nine (10%) patients developed early reocclusion in the segment treated with a stent (two patients [4%] in the stent group and seven [17%] in the stent and brachytherapy group); of these patients, three in the stent and brachytherapy group experienced reocclusion within 24 hours of the intervention. Late (>30 days after intervention) thrombotic occlusion was observed in three patients (7%) in the stent and brachytherapy group. All of the LTO occurred after the discontinuation of clopidogrel. The authors concluded that VBT does not improve 6-month patency after femoropopliteal stent implantation in high-risk patients because of a high incidence of early and late thrombotic occlusion.

Infrapopliteal (Tibial-Peroneal) Vascular System

These vessels are smaller than the femoral–popliteal system. They are more difficult to manage and respond less to conventional treatment. Early results of percutaneous revascularization for occlusive disease below the knee were disappointing. The risk of complications and restenosis remains increased in the smaller and often more diffusely diseased and calcified vessels. Brown et al. from St Luke's/Roosevelt Hospital Center performed PTA in 11 patients facing reconstructive surgery for limb salvage. Of 16 diseased tibial runoff vessels, 15 were successfully dilated. They reported restenosis rate at 44% at 2 years after PTA.67 Jahnke et al. from Germany reported their experiences during an 18-month period, when a total of 19 infrapopliteal lesions in 15 consecutive patients were treated primarily by high-speed rotational atherectomy (HSRA) by using the Rotablator device. Control angiography was carried out at 6 months in 9 of 15 patients, allowing direct assessment of 12 of 19 treated lesions. Among six high-grade restenoses and five total occlusions in the treated vascular segments, only one arterial lumen (of 12) remained patent without presenting a hemodynamically relevant restenosis.68

Renal Vascular System

Renal occlusive disease is the major cause of hypertension and renal failure. Estimates of the prevalence of renovascular hypertension vary from <1% in the general population to 30% to 40% at some referral centers. The definitive diagnosis of renovascular hypertension requires correction of the stenosis and subsequent cure of the hypertension. However, among patients with significant renal artery stenosis, only approximately 50% have hypertension. Atherosclerotic renovascular disease is the cause of nearly 75% of renal stenoses.69 Olin et al. reported the prevalence of >50% renal artery stenosis in patients with atherosclerosis of other peripheral arteries. Approximately one third of patients with abdominal aortic aneurysm, aortoiliac occlusive disease, or lower extremity occlusive disease had renal artery stenosis and 13% had high-grade bilateral disease.70

Natural history studies have shown that renal artery stenosis progresses in roughly 20% of patients yearly and that progression to total occlusion (and loss of renal function) occurs in approximately 5% of patients a year. In two such studies,71 39% of lesions of >75% stenosis on initial evaluation were totally occluded at 4-year angiographic follow-up. In patients in whom progression to occlusion occurs, hypertension does not become significantly worse, and the occlusion is usually clinically silent. In light of these facts and the improvements in antihypertensive medications, renal artery revascularization is more often performed to preserve renal function than to treat renovascular hypertension.

Fibrous dysplasia (a group of congenital dysplasias of various layers of the arterial wall) accounts for most of the remaining cases of renovascular disease. Medial fibroplasia is the most common type. This disorder is more common in women than men and tends to occur in persons 25 to 50 years of age. In 1978, Grüntzig et al. reported the first successful treatment of renal artery stenosis with a balloon catheter.72 PTA has been shown to be very effective for renal artery stenosis due to medial fibroplasia. Most series have shown rates of 90% or higher for technical success and clinical benefit. Long-term patency, including secondary patency after redilatation, reportedly exceeds 95%. However, results of balloon angioplasty for treatment of atherosclerotic renal artery stenoses have been disappointing, especially in the ostial location. The alternative to balloon angioplasty for percutaneous revascularization is stent placement in the renal artery. Reports of several studies involving metallic stents to treat renal artery stenosis have been published, including one study that focused specifically on ostial lesions resistant to balloon dilatation.73 The results are encouraging. Technical success rates of almost 100% and long-term secondary patency rates of higher than 90% after repeated intervention have been reported. Rates of restenosis after initial intervention have ranged from 10% to 20%. Clinical cure occurs in approximately 20% of cases of stenosis of atherosclerotic origin and approximately 60% of lesions resulting from medial fibroplasia. In addition, clinical success (defined as cure of or improvement in hypertension) in lesions of either origin ranges from 80% to 90%. Percutaneous revascularization is also performed to preserve renal function in patients with >75% stenosis either bilaterally or unilaterally when only one kidney is present. The success of the intervention depends on the preexisting level of renal function. In general, patients who have a serum creatinine level of 4 mg/dL or higher are unlikely to benefit from revascularization. In appropriately selected patients, improvement in or stabilization of renal function can be expected in 80% to 90% of cases.

The treatment of choice for renal artery stenosis is generally percutaneous angioplasty. Most lesions require stenting because of the aorto-ostial location of atherosclerotic renal artery stenosis. Many studies have shown that the rate of restenosis after PTA ranges from 45% to 65% and that after PTA and stenting of renal arteries is between 15% and 25%. In the GREAT trial, the restenosis rate in the bare-metal stent arm was 14.3%.74 The risk factors for higher restenosis rate are smokers, vessels <4 mm in diameter, and longer follow-up duration. Unlike coronary arteries in which most restenosis occurs in the first 6 months after intervention, there is a late recurrence rate with renal system.51 Review of published literature on MEDLINE shows a total of eight publications on 31 patients. The Washington hospital center used HDR 192Ir to treat 10 patients before PTA, and they reported a patency rate of 90% at 1 year.75 In another publication from Switzerland, Stoeteknuel-Friedli et al. reported treating 11 patients with ISR with HDR 192Ir. They used the dose of 14 Gy at 5 mm radius, and reported the patency in 8 of 11 patients at 18 months.76 Another report from the University of Kentucky by Jahraus et al. is on five patients with ISR treated with 90Y/90Sr source. They reported the patency in four out of five patients at 7 months.77

Atrioventricular Graft Vascular System

In the United States, approximately 300,000 patients suffer from end-stage renal disease (ESRD); 85% of these patients will be treated by hemodialysis. In the absence of a kidney transplant, these patients will require artificial hemodialysis for their lifetime. Patients undergoing hemodialysis require a direct artery–vein access that is easy to locate and which will provide optimal blood flow during treatment. Unfortunately, a number of hemodialysis patients do no have adequate vessels to form a fistula (a connection) between a vein and an artery; therefore, a synthetic graft must be inserted. Synthetic grafts are the most widely used type of vascular access in the United States, the most common being the polytetrafluoroethylene (PTFE) graft. PTFE grafts are easily inserted, easily maintained, and have moderate resistance to infection and a low incidence of aneurysm formation. Typically, these grafts are placed as a straight connection or as a loop in either the forearm or the arm; this loop connects an artery to a vein and allows for easy access during hemodialysis treatment. As reported by the United States Renal Data System (USRDS), hemodialysis access failure is the most frequent cause of hospitalization among ESRD patients and costs the US health care system approximately 1 billion dollars per year. Preservation of access sites is of paramount importance as patients are being treated with hemodialysis for longer periods (almost 50% are treated for 5 years). Balloon angioplasty has been used for maintaining, rather than restoring, the graft when tissue growth narrows the passageway. Although surgery is reasonably effective, there are associated problems. Balloon angioplasty is usually required over a long term, because uncontrolled tissue growth within the graft is very common. The long-term follow-up information on PTFE grafts show that 60% have narrowed within the first year and 40% have narrowed by 2 years. Venous stenosis and thrombosis (due to venous neointimal hyperplasia) is the most common cause of hemodialysis vascular access dysfunction. At the clinical level, this manifests in the form of a 50%, 1-year primary patency for new grafts and a dismal 40% 3-month survival for thrombosed grafts.78 However, despite the magnitude of the clinical problem, there are currently no effective therapies for this condition. We as well as others have previously demonstrated that venous neointimal hyperplasia in PTFE dialysis grafts is composed of SMCs/myofibroblasts, a perigraft macrophage layer, and microvessels within the venous neointima. Interestingly, there is strong experimental evidence that demonstrates that radiation therapy blocks the proliferation and activation of these cell types. In addition, endovascular radiation therapy has already been successfully used to prevent restenosis following coronary angioplasty. Two modalities of radiation have been used to treat the AV graft: External beam from linear accelerator and brachytherapy. Table 11.10 compares the two modalities.

Table 11.10 Radiation Modalities: External Beam Versus Brachytherapy


Vascular Brachytherapy

External Beam Radiation


Better target localization

Allows fractionation


Less volume of normal tissue

Allows postangioplasty timing


Higher dose possible

May be better for superficial vessels


Better for deep vessels

More dose uniformity


Less dependent on organ motion

Less problem with radiation protection



Less problem with sterility


Less dose uniformity
Source change
Radiation protection required (more for γ)
Long treatment time
No fractionation

Has to be done in Rad Onc (transport)
Large treatment volume (8 × 8 cms)
Limited dose (8 Gy)
Organ motion

In 1994, a phase I–II study at Emory University was done to treat patients who had failed PTA of arteriovenous dialysis grafts using the HDR 192Ir. Waksman et al. reported a 40% patency rate at 44 weeks; however, the long-term results of this study were similar to PTA without radiation.79 Parikh and Nori et al. reported a phase I–II study utilizing external radiation doses of 12 and 18 Gy for AV dialysis shunts in 10 patients. The result is similar to the Waksman's study. At 6 months, TLR was 40%, but at 18 months, all grafts failed and required intervention.80 Cohen et al. randomized 31 patients to PTA or stent placement alone, followed by external beam radiation of 14 Gy in 2 fractions, and they reported restenosis rates of 45% versus 67% in the irradiated and control groups, respectively, at 6 months.81

New studies are currently underway using low-dose external radiation to reduce restenosis of vascular access for AV grafts in hemodialysis patients, as are other studies using a centering device to deliver an accurate homogenous dose of radiation after PTA. BRAVO (Beta Radiation for Treatment of Arterial–Venous Graft Outflow) was a pilot study utilizing the Corona system with a 90Sr/90Y β emitter. In a study of 10 patients with an average of 3.9 previous angioplasties to their AV graft, there was 60% primary patency and 80% cumulative patency at 12-month mean follow-up.

Iliac Vascular System

The restenosis rate after percutaneous treatment of iliac artery stenosis has been extensively studied. The iliac arteries are conductance vessels (elastic) with a high elastin content in their media. Consequently, the rate of restenosis is expected to be relatively low. The 1-year patency rate after PTA of iliac stenoses averages 78% (67% to 92%), whereas for iliac occlusions, it averages 68% (59% to 94%). The 1-year patency rate for stenting of iliac stenoses averages 90% (78% to 97%), and for iliac occlusions it averages 72% (68% to 94%).82 In the Dutch Iliac Stent Trial, clinical success was similar at 2 years for claudicants who underwent PTA or stenting of iliac disease.83 The angiographic restenosis rate after stenting in the Palmaz multicenter Registry was 8% at 9 months, and in the Wallstent Registry, it was 12% at 6 months. In the more recent CRISP trial, the 12-month primary patency rate for the SMART stent was 94.7% (as determined by duplex and ABI). Although there remains some controversy regarding whether stenting is superior to PTA for iliac stenoses, most operators favor a low threshold for provisional stenting.51

Figure 11.19 demonstrates synchronous bilateral HDR noncentered catheter placement to enable a single conjoint isodose plan (see Figure 11.20).

Aortic Vascular System

Claudication due to stenosis of the aorta alone is relatively unusual. Nevertheless, angioplasty of discrete aortic stenoses has been technically successful in more than 90% of cases and has produced good long-term patency in the small groups of patients who have been included in follow-up studies. Acute and chronic total occlusions of the aorta can also be treated successfully with combinations of thrombolytic therapy, angioplasty, and intravascular stenting. Occlusive disease of the aortoiliac bifurcation and the iliac arteries is the most common cause of claudication in patients under the age of 50. Currently, most such cases are treated with balloon angioplasty followed by placement of intraluminal stents. Stents are metallic devices that are either balloon expandable or self-expanding. They provide a scaffold for the arterial lumen to prevent vessel recoil and to seal and prevent propagation of dissections produced by angioplasty. Aortoiliac stenting generally produces results similar to those of aortofemoral bypass, and its long-term patency rates are reported to be as high as 90%. Restenosis rate after PTA or stenting is approximately 10% to 35%. The etiology of restenosis in aorta has been postulated to be due to either intimal hyperplasia or heterotropic formation. There are few case reports of brachytherapy in the treatment of restenosis in aorta.

Figure 11.19 Anteroposterior localization and treatment planning radiograph for a bilateral iliac in-stent restenosis case. 1,500 mm, 6 F blind-ended catheters were introduced bilaterally with radio-opaque marker strands. The left strand extends up into the aorta and the right strand almost abuts the left. Computer-based optimization for HDR will even out any risk of hot or cold spot, even for a slightly inaccurate placement.

Figure 11.20 Computer-generated representation (Plato TPS, Nucletron Corp) of a composite plan using two noncentering catheters synchronously placed in the iliac arteries. The single plan allows minimization of hot and cold spots, especially around the bifurcation region.

Hepatic Vascular System

Patients in their final stage of liver disease are affected by several major complications: variceal hemorrhage, ascites, hepatorenal syndrome, spontaneous bacterial peritonitis, and hepatic encephalopathy. Portal hypertension is the leading cause of varices and ascites.

Transjugular intrahepatic portosystemic shunt (TIPS) is created by making an intrahepatic tract between the hepatic and portal veins using an angiographic technique through a transjugular approach. This tract is then dilated and kept patent by placement of a metallic, self-expanding, compliant stent. TIPS have long been used to lower portal pressures in the setting of variceal hemorrhage and refractory ascites, their major associated complications being the development of hepatic encephalopathy and shunt stenosis, which are seen in up to 50% of patients within 6 months.

Several thousand TIPS procedures are performed annually in the United States. Since its introduction by Rosch, Hanafee, and Snow in 1969, TIPS has been used in various clinical situations.84 Its primary function in patients with cirrhosis is to decrease portal hypertension by decompression of both the hypertensive hepatic sinusoids and the portal vein. Therefore, the clinical goals for the TIPS procedure are management of acute variceal bleeds,85 decrease in recurrent variceal bleeds,86 and management of refractory ascites.87 Although liver transplantation is indicated whenever these complications are present, there are still many patients who have to be managed through them, either while waiting for a liver or because they have contraindications to liver transplantation. The appropriate management of these patients is crucial, not only because these complications can be life threatening but also because it is now clear that influencing the pretransplant status of patients results in better transplant outcomes.

There has, however, been a high incidence of post-TIPS failure, leading to recurrence of varices and ascites. The development of TIPS malfunction is multifactorial. Three causes are (i) acute thrombosis (<5% incidence); (ii) stent retraction (2% incidence); and (iii) most commonly, shunt stenosis. In Sanyal's review88 of the natural history of TIPS, 51 of 70 patients (73%) developed shunt stenosis within 6 months of TIPS placement. Three patterns of stent stenosis are observed: (i) hepatic vein stenosis, (ii) diffuse neointimal hyperplasia, and (iii) both factors combined.

The three patterns of stent stenosis have been amenable to balloon dilatation and placement of another stent within the original stent. However, the repeated interventions required to correct failure of the initial shunt add significant risk to the patient, as well as increase health care cost. It was hypothesized that minimizing the process of neointimal hyperplasia at the time of initial TIPS placement would reduce the risk of restenosis, and therefore the probability of TIPS failure. This would translate into improved chances to receive a new liver, as well as improve patient survival and quality of life.

Pokrajac et al.89 reported a study from the University of Vienna with five patients with in-stent restenosis of TIPS. The indications for initial TIPS were a Budd-Chiari syndrome in two female patients and recurrent variceal bleeding by alcoholic liver cirrhosis in three male patients. TIPS were created with Wallstents (10 mm diameter in four patients) and Palmaz stent (10 mm diameter in one patient). The redilatation was done in all five patients 6 months after first stenting because of restenosis (>50% stent lumen reduction) or occlusion of the stent. A 5 F closed-end, noncentered catheter was used for delivery of remote afterloading HDR 192Ir. A dose of 12 Gy was prescribed at 3 mm distance from the source axis in the mid-plane of the applicator for three patients and in 5 mm distance for two patients. The authors reported that normal patency (<50% lumen reduction) of the stent was achieved at 44 months' follow-up (based on duplex ultrasound and portography) in all three patients with liver cirrhosis, whereas further revisions were necessary in the two patients with Budd-Chiari syndrome (after 5.5 and 18 months). No acute, subacute, or late side effects of radiation were seen. A phase I–II study was initiated at Scripps Clinic using a centering catheter (PARIS catheter) and IVUS-guided dose prescription. The distance from the center of the catheter to the transhepatic tract (the “source-to-target distance”) was measured by IVUS. A dose of 10 Gy was prescribed to a radial distance equal to the farthest source-to-target distance plus an additional 2 mm. The dose to the shortest source-to-target distance was limited to 30 Gy. Because the centering balloon had a minimum radius of 4 mm, it was expected that the maximum dose to the closest tract wall would be <30 Gy. The minimum dose delivered to the target region will determine the control rates; the maximum dose delivered to the sensitive tissue will determine the complication rate. Treatment length was equal to the stent length plus 1.5 cm proximally and 1.5 cm distally. Figure 11.21 shows the localization and treatment planning radiograph of one of the few TIPS brachytherapy cases performed with the PARIS catheter in the United States.

Carotid Vascular System

Approximately 500,000 new cases of stroke occur annually in the United States. Stroke is a leading cause of death and severe disability. Carotid artery disease accounts for approximately one third of strokes. Symptoms of carotid artery stenosis include carotid transient ischemic attack (defined as distinct focal neurologic dysfunction persisting for <24 hours), focal cerebral ischemia producing a nondisabling stroke, transient monocular blindness (amaurosis fugax), and disabling stroke. Carotid endarterectomy, the accepted conventional therapy for obstructive carotid disease, has been shown to be superior to medical therapy for both symptomatic and asymptomatic obstructions.90 There has been a resurgence of interest recently in percutaneous treatment as an alternative to surgical endarterectomy. Carotid artery PTA and stenting are rapidly emerging as an efficacious modality for treating symptomatic and asymptomatic carotid artery occlusive disease. A recent review by Wholey et al.91 summarized the worldwide experience of carotid artery stent placement from nonrandomized, observational studies. The reported rates of major and minor strokes and death appear to be similar to those for endarterectomy involving high-risk patients. As an elastic (conductance) artery, the restenosis rate is expected to be low. Indeed, the restenosis rate has ranged from 5% to 8% after carotid PTA and/or stenting.92 Risk factors identified for restenosis after carotid artery stenting include female gender, advancing age (in contrast to carotid endarterectomy, in which younger age predicts restenosis), and, variably, the number of stents implanted. Restenosis lesions after carotid endarterectomy are at higher risk of in-stent restenosis. Interestingly, residual stenosis after the carotid artery stenting procedure, but not vessel size after the procedure per se, has been found by some to be a predictor of restenosis.93 The other risk factor is irradiation from previous head and neck malignancy. There are animal data supporting the use of radiation in reducing restenosis in rabbits and rats. Investigators from Germany94 reported the use VBT 68 male New Zealand White rabbits after endothelial denudation of the right common carotid artery with a Fogarty catheter. Endovascular irradiation was performed with a Rhenium 188 (188Re)-filled 3.0-mm balloon catheter using different dosages (0, 7.5, 15, 30, 45, and 60 Gy at the surface of the vessel). Then 4 weeks after the intervention, the vessels were excised and histologically analyzed. They found that at 7.5 Gy, the intimal area did not differ significantly from the control, and neointimal hyperplasia was decreased significantly at 15 and 30 Gy and completely inhibited at the highest dosages of 45 and 60 Gy. There are several case reports of success of VBT in this setting in human data.95,96,97 There is some consideration in the use of VBT in reducing risk of restenosis after carotid stenting.98

Figure 11.21 Anterioposterior localization and treatment planning radiograph of one of the few transjugular intrahepatic portosystemic shunt (TIPS) brachytherapy cases treated on compassionate use exemption in the United States. Note that a previous nonfunctioning TIPS stent is to the side of the target stent. Weak contrast is used to show the balloon without undue attenuation of therapeutic dose. The treatment plan is a straight-line optimization to a given radius and length prescribed by the treating physician.


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