Intravascular brachytherapy to prevent restenosis: dosimetric considerations.

Acute myocardial infarction is often the result of occlusion of one or more coronary arteries. Occlusion and restenosis (re-closing of the vessel) are principal reasons that percutaneous transluminal coronary angioplasty (PTCA) may fail to provide long-term benefit. PTCA has been a popular treatment, which is less invasive than surgeries involving revascularization of the myocardium, promising a better quality of life for patients. Unfortunately, the rate of restenosis after balloon angioplasty is high (approximately 30-50% in the first year after treatment). Recent data suggest that intraluminal irradiation of coronary arteries in conjunction with balloon angioplasty and/or stent implantation reduces the proliferation of smooth muscle cells and neointima formation, thereby inhibiting restenosis. In order to study radiation dosimetry in the patient and for this therapy, dose distributions for electrons and photons, with discrete energies, were simulated for blood vessels of diameter 1.5, 3 and 4.5 mm irradiated with balloon and wire sources. Electron and photon transport was performed in a simple model representing the system used for irradiation using the MCNP 4B code (Monte Carlo N-Particles). Specific calculations for balloon and wire sources were also carried out for a few radionuclides. In this work, strengths and drawbacks conceming the use of each radionuclide simulated, as well as source geometries are discussed. The dosimetry performed in this study will improve understanding of the benefit-to-risk ratio in intracoronary brachytherapy.     

Why and how to avoid stenting during brachytherapy

Intracoronary radiation is a promising therapy to reduce restenosis after percutaneous coronary intervention. It may be anticipated that radiation and intracoronary stents - the current standard coronary revascularization procedure - have a synergic antirestenosis effect. However, this potential benefit has not been proven in the clinical scenario. Indeed, this combined approach (stenting plus brachytherapy) may even be harmful. Delayed endothelialization and late stent malapposition are important drawbacks of implanting a metallic prosthesis in the setting of radiation therapy. Owing to the relatively high frequency of late thrombosis after stenting irradiated coronary arteries, the Food and Drug Administration required that the labeling of both gamma- and beta-radiation devices recently approved for clinical use explicitly advise avoidance of the placement of new stents. The pathophysiologic aspects as well as the clinical implications of the implantation of a new stent in association with radiation delivered by radioactive stents or catheter-based systems are discussed in this paper.     

Methods to improve dose uniformity for radioactive stents in endovascular brachytherapy

Intravascular brachytherapy (IVBT) has rapidly gained acceptance as a new treatment modality for reducing restenosis and improving the success rate of percutaneous transluminal coronary angioplasty (PTCA). Recent clinical results on patients treated with beta-emitting 32P stents suggest that radiation reduces in-stent restenosis but may exacerbate neointimal growth at the edges of the stents. This has been referred to as the "candy wrapper effect." It is well known that radioactive stents yield extremely inhomogeneous dose distributions, with low doses delivered to tissues in between stent struts, at the ends of the stent, and also at depth. Some animal model studies suggest that low doses of radiation may stimulate rather than inhibit neointimal growth in an injured vessel, and it is hypothesized that dose inhomogeneity at the ends of a stent may contribute to the candy wrapper effect. We present here a theoretical study comparing dose distributions for beta stents vs. gamma stents; "dumbbell" radioactive loaded stents vs. uniformly loaded stents; and stents with alternate strut design. Calculations demonstrate that dose inhomogenieties between stent struts, at the ends of stents, and at depth can be reduced by better stent design and isotope selection. Prior to the introduction of radioactive stents, criteria for stent design included factors such as trackability, flexibility, strength, etc. We show here that if stent design also includes criteria for strut shape and spacing that improved dose distributions are possible, which in turn could reduce the candy wrapper effect.     

New methods of making blocked coronary arteries patent again.

The use of percutaneous transluminal coronary angioplasty is limited by procedural complications and the serious drawback of restenosis, but some new techniques have been developed in an attempt to lower the complication rate for difficult lesions and reduce the rate of restenosis. These include devices to physically remove atheromatous plaque, such as the Simpson Coronary AtheroCath and the transluminal extraction catheter, as well as devices to ablate the plaque in situ, including the Rotablator and the excimer laser catheter. Although each device may have advantages in certain types of lesion, few data on their use have been reported in properly controlled randomised trials. The data available so far do not suggest that these devices will be safer than balloon angioplasty or that they will reduce restenosis. However, using metallic stents to support coronary arteries after balloon angioplasty seems to reduce acute complications and to lower the rate of restenosis, and the use of stents is likely to increase.     

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

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

Brachytherapy with gamma radiation of a coronary artery for in-stent restenosis may induce the regression of in-stent restenosis of an adjacent coronary artery without angioplasty. First case report and review of the literature

Here, we present a case of a 63-year-old male who presented with in-stent restenosis of two coronary arteries simultaneously (mid circumflex and proximal ramus). After the brachytherapy of the circumflex artery for in-stent restenosis, the patient refused the staged procedure for the ramus in-stent restenosis. After approximately 2 years, the patient underwent coronary angiography for recurrent chest pain. Surprisingly, the proximal ramus stent showed marked regression of in-stent restenosis. We hypothesized that the gamma brachytherapy of the circumflex artery could have induced the regression of in-stent restenosis of the adjacent ramus artery due to the deep tissue penetration of gamma radiation. Based on our observation, we believe that in the treatment of in-stent restenosis of a coronary artery, the initial balloon angioplasty may not be as important as the radiation itself. This observation warrants further study to evaluate the effect of external or internal radiation on in-stent restenosis without balloon angioplasty. If our hypothesis is confirmed, the treatment of in-stent restenosis with external radiation could substantially simplify the treatment of this disease. This case report follows a brief review of the literature.     

Efficiency of endovascular re-interventions for evolving restenosis of different types of stents

The paper compares the results of different treatment options (balloon angioplasty and restenting) for in-stent restenosis in case of evolving restenosis of drug- and nondrug eluting stents. The investigation enrolled 496 coronary heart disease patients with clinical presentation of angina pectoris and/or signs of myocardial ischemia, as well as hemodynamic restenosis of a previously implanted stent. Of them, 216 and 280 patients had restenosis of previously implanted drug- and nondrug-eluting stents, respectively. In the patients with non-drug-eluting stent restenosis, recurrent angina pectoris and the frequency of repeated restenosis were significantly more frequently observed after balloon dilatation than after drug-eluting stent implantation (28.4 and 10.2%; p < 0.05; 19.9 and 8.7%; p < 0.05). In those with drug-eluting stent restenosis, recurrent angina pectoris and the frequency of repeated restenosis did not differ significantly between balloon dilatation of restenosis and implantation of a second drug-eluting stent.     

Oxidative stress in myocardial ischaemia reperfusion injury: a renewed focus on a long-standing area of heart research

Advances in the treatment of coronary artery disease have seen a significant drop in mortality and morbidity particularly amongst patients with acute myocardial infarction (MI). In particular, percutaneous trans-luminal balloon angioplasty (PTCA) with stenting to re-open atherosclerotic coronary arteries has yielded marked improvement in clinical outcome for patients with acute MI. Furthermore, with the advent of drug-eluting stents occurrence rates for coronary artery restenosis, one common clinical problem associated with angioplasty and stent deployment, have declined markedly. However, coronary restenosis in diabetic patients remains an on-going problem. The success of drug-eluting stents has seen a renewed focus on myocardial ischaemia reperfusion (IR) injury as this represents one area of research where many questions remain unanswered. In particular, the relationship between myocardial IR injury and decreased myocardial micro-vasculature re-flow post PTCA (that ultimately leads to poor clinical outcome and myocardial damage/dysfunction) is one area of research with the potential to decrease current complication rates further in patients suffering myocardial IR injury sustained during MI. This review discusses the role for oxidative stress, oxidant source(s) and both gene regulation and stem-cell therapy as potential strategic targets in the ischaemic myocardium, with the ultimate aim of providing significant cardioprotection in the setting of acute MI.     

Long period of balloon inflation and the implantation of stents potentiate smooth muscle cell death. Possible role of chronic vascular injury in restenosis

BACKGROUND: It has been suggested that the severity of acute vascular injury immediately after percutaneous transluminal coronary angioplasty (PTCA) or stent implantation correlates with the extent of neointimal hyperplasia and restenosis. However, the influence of prolonged or chronic vessel injury on the pathogenesis of restenosis is unclear. METHODS: Rabbit iliac arteries were balloon dilated for a short (1 min) or prolonged (10 min) period of time, or were chronically dilated and received a Palmaz-Schatz stent (balloon inflation for 1 min). All arteries were overexpanded to a balloon:artery ratio of 1.2:1 as determined by angiography. The arteries were removed 30 min and 4 weeks after the angioplasty procedures. The sites of injury were evaluated by gross histology and transmission electron microscopy (TEM). Cell death of medial smooth muscle cells (SMCs) was specified by TEM images 30 min after the procedures. Computer-assisted quantification of the neointimal cross-sectional areas was performed after 4 weeks using a light microscope connected to a digital image analyser. RESULTS: The results show that prolonged balloon dilatation and stent implantation increased necrotic SMC death compared with balloon dilatation for 1 min. After 30 min, increased staining of SMC nuclei, enlarged intercellular spaces and changes in SMC shape in the media indicated cell death induced by prolonged balloon dilatation or chronic stent injury. Stent implantation markedly augmented vessel damage by persistent compression of the media, compared with a balloon dilatation for 1 or 10 min. Both prolonged balloon dilatation and stent implantation increased neointimal hyperplasia at 4 weeks compared with balloon dilatation for 1 min (0.6 3 0.2 and 1.0 3 0.2 mm(2) versus 0.2 3 0.1 mm(2), P < 0.001 versus dilatation for 1 min). CONCLUSION: Prolonged or chronic vascular expansion due to long balloon-inflation periods or the implantation of stents increases medial SMC death, which subsequently stimulates neointimal growth in this restenosis model. Chronic vascular injury may be an important stimulus for restenosis after angioplasty procedures.     

Endovascular brachytherapy in coronary arteries: the Rotterdam experience

Purpose: The use of endovascular coronary brachytherapy to prevent restenosis following percutaneous transluminal coronary angioplasty (PTCA) began in April 1997 at the Department of Interventional Cardiology of the Thoraxcenter at the University Hospital of Rotterdam. This article reviews the more than 250 patients that have been treated so far.Methods and Materials: The Beta-Cath System (Novoste), a manual, hydraulic afterloader with 12 90Sr seeds, was used in the Beta Energy Restenosis Trial (BERT-1.5, n=31), for compassionate use (n=25), in the Beta-Cath System trial (n=27) and in the Beta Radiation in Europe (BRIE, n=14). Since the Beta-Cath System has been commercialized in Europe, 57 patients have been treated and registered in RENO (Registry Novoste). In the Proliferation Reduction with Vascular Energy Trial (PREVENT), 37 patients were randomized using the Guidant-Nucletron remote control afterloader with a 32P source wire and a centering catheter. Radioactive 32P coated stents have been implanted in 102 patients. In the Isostent Restenosis Intervention Study 1 (IRIS 1), 26 patients received a stent with an activity of 0.75-1.5 μCi, and in the IRIS 2 (European 32P dose response trial), 40 patients were treated with an activity of 6-12 μCi. In two consecutive pilot trials, radioactive stents with non-radioactive ends (cold-end stents) and with ends containing higher levels of activity (hot-end stents) were implanted in 21 and 17 patients, respectively.Results: In the BERT-1.5 trial, the radiation dose, prescribed at 2 mm from the source train (non-centered), was 12 Gy (10 patients), 14 Gy (10 patients) and 16 Gy (11 patients). At 6-month follow-up, 8 out of 28 (29%) patients developed restenosis. The target lesion revascularization rate (TLR) was 7 out of 30 (23%) at 6 months and 8 out of 30 (27%) at 1 year. Two patients presented with late thrombosis in the first year. For compassionate use patients, a restenosis rate (RR) of 53% was observed. In the PREVENT trial, 34 of 37 patients underwent an angiographic 6-month follow-up. The doses prescribed at 0.5 mm depth into the vessel wall were 0 Gy (8), 28 Gy (9), 35 Gy (11) and 42 Gy (8). TLR was 14% in the irradiated patients and 25% in the placebo group. One patient developed late thrombosis. In the IRIS 1 trial, 23 patients showed an RR of 17% (in-stent). In the IRIS 2 trial, in-stent restenosis was not seen in 36 patients at 6-month follow-up. However, a high RR (44%) was observed at the stent edges.Conclusions: The integration of vascular brachytherapy in the catheterization laboratory is feasible and the different treatment techniques that are used are safe. Problems, such as edge restenosis and late thrombotic occlusion, have been identified as limiting factors of this technique. Solutions have been suggested and will be tested in future trials.     

Release of TNF-alpha during stent implantation into saphenous vein aortocoronary bypass grafts and its relation to plaque extrusion and restenosis

The reduction in plaque volume during stent implantation is associated with the release of particulate debris and plaque-derived soluble substances. We studied the potential release of the proinflammatory cytokine TNF-alpha into the coronary circulation and whether such release is related to the reduction in plaque volume and, possibly, a predictor for restenosis. In 18 male patients (n = 24 stents) with severe stenosis in a saphenous vein aortocoronary bypass graft (SVG), we used a distal balloon occlusion-aspiration device during stent implantation. The aspirate TNF-alpha levels were determined before and after stent implantation and related to the angiographic and intravascular ultrasound-assessed severity of stenosis and restenosis. We found that TNF-alpha is, indeed, released into the aspirate of stented SVG (9 +/- 1 and 28 +/- 3 pg/ml before and after stent implantation, respectively, P < 0.0001) and that such release is related to the reduction in plaque volume (r = 0.88, P < 0.0001) and associated with restenosis after 5 mo (r = 0.71, P = 0.001). The periprocedural release of plaque-derived TNF-alpha possibly represents the amount and activity of the atherosclerotic process and might be a predictor for restenosis.     

On the need for massive additional shielding of a catheterization laboratory for the implementation of high dose rate 192Ir intravascular brachytherapy

Purpose: There is a widespread belief in the cardiology and radiation oncology community that high dose rate 192Ir intravascular brachytherapy cannot be implemented without massive additional shielding of the conventional catheterization labs. The purpose of this work is to show that this is a myth, which is not based on sound radiation protection principles.Methods: Exposure rates in air were calculated for a variety of point and line sources of 192Ir. Exposures per treatment at different distances from the source were calculated for a typical intravascular brachytherapy treatment of a 15-Gy dose at a radial distance of 2 mm from the source and for source lengths in the range of 0 to 10 cm. Additionally, exposure rates outside the catheterization lab were calculated for various lead shielding thicknesses typical of conventional X-ray facilities. These rates were used along with the NCRP recommendations on radiation facility design to assess shielding requirements.Results: For a treatment dose of 15 Gy at 2 mm, the occupational exposure per treatment at 2 m in air without any tissue attenuation or shielding was 7.8 mR for a lesion length of 3.0 cm. This exposure/treatment is independent of the dose rate or the activity of the source. However, it increases as lesion length is increased, increasing from 5.4 to 24.9 mR as lesion length increased from 2 to 10 cm. Exposures in unrestricted areas outside the catheterization lab using the NCRP shielding rationale can be kept below 2 mR per treatment and using appropriate workload, use, and occupancy factors below 2 mR per week.Conclusions: The feasibility of implementing a high dose rate 192Ir intravascular brachytherapy program in a catheterization laboratory is totally independent of the dose rate or the activity of the source. If it is feasible to implement 192Ir brachytherapy in a conventional catheterization lab using low activity 192Ir seeds, then it is also feasible to do so with a high activity 192Ir afterloader.     

Calculation of dose distribution near an innovative concentric balloon catheter for endovascular brachytherapy

Purpose: Using a radioactive solution-filled catheter for intravascular irradiation has the potential problem of chemical and radiological toxicity in the case of a balloon rupture. In order to reduce this risk, an innovative concentric balloon catheter was developed.Methods and Materials: The concentric balloon was made by inner and outer balloons filled with saline and radioactive solution, respectively. The optimal inner radius was determined by comparing the dose rate reduction vs. the volume reduction for various inner and outer radii for 188Re, 32P, and 90Y solutions.Results: For a balloon with an outer radius of 1.5 mm, there was no advantage of a concentric balloon. For balloons with outer radii of 3.0 and 5 mm, the optimal inner radius was 1.5 and 3 mm, respectively.Conclusions: With the newly designed concentric balloon, the risk of toxicity can be reduced while keeping the dose rate high enough so that the treatment times within tolerable limits are still maintained.     

Drug-eluting stents: from bench to bed

The introduction of stents to clinical practice in 1987 was the major breakthrough in the field of percutaneous coronary intervention (PCI). The use of stenting has drastically improved the outcomes of traditional PCI. First stents were approved for bailout and treatment of dissections, reducing dramatically the need for emergent coronary artery bypass grafting (CABG) as a result of vessel closure during PCI. Later stents were proven to reduce the restenosis rate of PCI from 30%-40% with balloon angioplasty to 15%-20% with stents, primarily by eliminating elastic recoil and vascular remodeling as shown by intravascular ultrasound (IVUS) studies. These outcomes have led to a wide acceptance of stenting as the strategy of choice for more than 80% of all PCI procedures performed. The current review focuses on the following topics: (1) strategies in drug selection to reduce neointimal proliferation, (2) stent designs and polymer selection as a platform for drug-eluting stents, (3) review of major preclinical and clinical experimental work performed in the field, and (4) a discussion of the potential and limitations of the technology.     

Coronary stent implantation without balloon predilatation: a single-center experience

OBJECTIVE: Assessment of safety and efficacy of coronary stent deployment, without balloon predilatation. BACKGROUND: With newer high-performance balloon-premounted stents it has become more common to attempt coronary stent deployment without balloon pre- or postdilatation. METHODS: During 1998 524 coronary angioplasties were performed in the authors' institute, of which 279 resulted in coronary stenting. Of these 101 (36.2%) were stents without balloon predilatation (SWBP). PTCA was performed according to standard technique using mostly 7 F. guiding catheters, and 'rapid exchange' balloons and pre-mounted stents. RESULTS: Seventy-two patients had acute coronary syndromes (41 acute MI or post-MI angina, 28 unstable angina, 10 rescue PTCA after failed thrombolysis). Mean age was 56.4 3 11.1 years, 84.5% were males. Sixty per cent of the lesions were ACC-AHA type B2 or C. Target arteries were LAD 57.6%, LCX 21.2%, RCA 14.1% and SVG 7.1%. Procedure time was 18.2 3 17.3 minutes. Mean heparin dose was 3850 3 1570 units. Twenty-two patients received abciximab prior to stent deployment. Seven stents were not deployed without previous balloon dilatation and were retrieved safely via the guiding catheters and deployed after balloon dilatation. There was no stent embolization, ectopic suboptimal or partial stent deployment. Immediate angiographic success was obtained in 95 patients (94.1%). Minimal lumin diameter (MLD) increased from 0.27 3 0.15 to 3.23 3 2.1 mm. There were two in-hospital deaths (1.9%) due to cardiogenic shock. An intra-aortic balloon pump was required in eight patients. Two patients (1.9%) experienced subacute stent thrombosis. CONCLUSION: SWBP in selective groups of patients and lesions is feasible and safe. Larger randomized comparative trials are needed to assess the benefits and cost saving of this approach.     

Endovascular brachytherapy in the prevention of vascular restenosis

Purpose: To evaluate the technical feasibility and efficacy of endovascular brachytherapy for prophylaxis of restenosis after femoropopliteal percutaneous transluminal angioplasty (PTA). Materials and methods: Ten patients with recurrence of stenosis in the femoropopliteal region underwent PTA followed by endovascular irradiation with Iridium-192 a high-dose rate after-loading technique. We used a single fraction of dose 12 Gy given in 3 mm from the source axis in the stenotic vessel segment. Results: During follow-up of 59–580 days restenosis occurred in four patients 111, 460, 472 and 580 days after irradiation. All other patients are without restenosis. No radiation-associated side effects were observed. Conclusions: Endovascular brachytherapy of restenosis in the femoropopliteal region is technically feasible, and may be done as a part of the PTA. These encouraging results open the possibility of reduction of restenosis by the present method.     

Local methylprednisolone delivery using a BiodivYsio phosphorylcholine-coated drug-delivery stent reduces inflammation and neointimal hyperplasia in a porcine coronary stent model

Phosphorylcholine (PC)-coated stents have shown excellent blood and tissue biocompatibility in porcine coronary arteries. The purpose of this study was to determine the efficacy of local methylprednisolone (MP) delivery using PC-coated stents to inhibit inflammatory response and in-stent neointimal hyperplasia in an overstretched porcine coronary model. BiodivYsio (Biocompatibles, Farnham, Surrey, UK) PC-coated drug delivery (DD) stents and DD stents loaded with a high dose of MP (269 microg) were implanted in the coronary arteries of 20 pigs with a balloon/artery ratio of 1.2 : 1. At five days the peri-strut inflammatory response score and thrombus score of the MP-loaded DD stents were lower than in the control stents. The neointimal hyperplasia of MP-loaded DD stents was significantly reduced (0.80 +/- 0.10 versus 0.48 +/- 0.10 mm(2), p < 0.01). At four-week follow-up, the inflammatory response of MP-loaded stents was lower than the control stents, but without significant difference. The MP-loaded stents showed decreased peri-strut arterial injury and in-stent neointimal hyperplasia (2.42 +/- 0.87 versus 1.62 +/- 0.71 mm(2), p < 0.05). It is concluded that local vascular delivery of a high dose of MP from PC-coated DD stents could effectively decrease inflammatory response and thrombus formation after oversized stent deployment and result in a significant reduction of neointimal hyperplasia.     

Nanoparticulate carriers for the treatment of coronary restenosis

The current treatment for coronary restenosis following balloon angioplasty involves the use of a mechanical or a drug-eluting stent. Despite the high usage of commercially-available drug-eluting stents in the cardiac field, there are a number of limitations. This review will present the background ofrestenosis, go briefly into the molecular and cellular mechanisms of restenosis, the use of mechanical stents in coronary restenosis, and will provide an overview of the drugs and genes tested to treat restenosis. The primary focus of this article is to present a comprehensive overview on the use of nanoparticulate delivery systems in the treatment of restenosis both in-vitro and in-vivo. Nanocarriers have been tested in a variety of animal models and in human clinical trials with favorable results. Polymer-based nanoparticles, liposomes, and micelles will be discussed, in addition to the findings presented in the field of cardiovascular drug targeting. Nanocarrier-based delivery presents a viable alternative to the current stent based therapies.     

Partial breast irradiation techniques in early breast cancer

Whole breast irradiation represents an integral part of combined breast-conserving treatment of early breast cancer. A new concept includes replacing traditionally fractionated whole breast postoperative radiotherapy by accelerated partial breast irradiation. The latter involves a variety of techniques and may be applied intraoperatively or shortly after the surgery. The intraoperative techniques include photon or electron external beam irradiation and interstitial high dose rate (HDR) brachytherapy, whereas the postoperative techniques comprise interstitial brachytherapy, be it HDR, pulse dose rate (PDR) or low dose rate (LDR), intracavitary brachytherapy and external beam radiotherapy using electrons, photons or protons. This article presents accelerated partial breast irradiation techniques, ongoing phase III trials evaluating their value and recommendations for clinical practice.