- Email: [email protected]
Peripheral vascular brachytherapy
INVITED CLINICAL REVIEW
Peripheral vascular brachytherapy Anton N. Sidawy, MD, MPH,a Jonathan M. Weiswasser, MD,a and Ron Waksman, MD,b Washington, DC Ongoing advances in peripheral endovascular technology have been met with disappointing results because of restenosis within the treated vessel. In particular, stent balloon angioplasty of peripheral vessels has yet to achieve patency rates that approximate conventional treatment in the long term. Recent advances in stent, balloon, and wire construction include the incorporation of radioactive substances in an attempt to ameliorate the inflammatory response provoked by typical endovascular manipulation, a technique termed vascular brachytherapy. ␥- and -isotopes and external beam radiation target the very cell population whose activity results in the development of neointimal hyperplasia. Although most clinical research examining the efficacy of vascular brachytherapy has emerged from the coronary artery literature, the use of vascular brachytherapy also has been examined in the peripheral arterial tree and has shown promising results. Current data indicate that vascular brachytherapy is a safe and accessible adjunctive endovascular maneuver that may improve the short-term patency rate of peripheral endovascular applications. The effects on long-term patency rates remain indeterminate compared to conventional therapy. (J Vasc Surg 2002;35:1041-7.)
As technology advances the treatment of vascular disease, it is clear that the limits of many endovascular interventions are defined by the development of restenosis in treated vessels. Although most data on this subject have been gleaned from work performed on coronary vessels, recent data on peripheral arteries have illustrated the predictable similarity between the two arterial beds, most notably the mechanisms for disease formation and restenosis after manipulation. Currently, endovascular treatment of infrainguinal disease, for example, consists mainly of percutaneous transluminal angioplasty (PTA) and stent balloon angioplasty (SBA). Although these methods have yielded encouraging results, with 5-year clinical success rates ranging from 42% to 58%,1,2 they have yet to match or supercede surgical methods in most cases. SBA has the added promise of a mechanical scaffold to encourage patency; however, it has produced 5-year patency rates in the 20% to 50% range,3,4 which are encouraging results but not comparable with those of surgical bypass procedures in the infrainguinal position. These results lay truth to the claim that SBA does not provide any additional benefit to PTA in infrainguinal disease and that PTA itself should be reserved for specific short segment stenoses in patients unable to tolerate an open procedure for limb salvage. From the Veterans Affairs Medical Centera and the Washington Hospital Center.b Competition of interest: Dr Waksman has received research support from Nucletron. Reprint requests: Anton N. Sidawy, MD, MPH, 50 Irving St, NW (112), Washington, DC 20422 (e-mail: [email protected]). Copyright © 2002 by The Society for Vascular Surgery and The American Association for Vascular Surgery. 0741-5214/2002/$35.00 ⫹ 0 24/9/123751 doi:10.1067/mva.2002.123751
These results, especially with progression distally into the arterial tree, are attributable to the development of restenosis and reocclusion of the vessel, mostly through the development of neointimal hyperplasia. It is this process that arterial brachytherapy attempts to address. MECHANISMS OF RESTENOSIS Three mechanisms are responsible for the development of restenosis: elastic recoil, intimal hyperplasia, and late vascular constriction, all grouped under the catch phrase “negative remodeling.”5-7 In the peripheral system, restenosis is seen mainly in small-sized and medium-sized arteries. Whereas manipulations in larger arteries, such as the iliac system, yield patency rates that are much more promising, manipulations in smaller vessels are plagued by lesion length, degree of stenosis, plaque burden, vessel size, and proximal and distal flow, all factors that seem to contribute to restenosis. The development of elastic recoil is contingent on the elastin fibers prevalent in the substance of the arterial wall and the ability of these fibers to morphologically alter the caliber of the artery. This effect is observed shortly after injury (manipulation) of the vessel and may be theoretically ameliorated with placement of an intraluminal scaffolding (stent). Neointimal hyperplasia and vascular constriction are prominent remodeling mechanisms that affect longterm outcome and parallel mechanisms observed in wound healing elsewhere in the body. Negative remodeling results if this hyperplasia leads to significant luminal stenosis. Many have investigated the cellular and inflammatory mechanisms that lead to the development of late phase stenosis. As it relates to vascular brachytherapy, this is the phenomenon and target cell population that arterial irradiation attempts to modulate. Strong support exists for 1041
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1042 Sidawy, Weiswasser, and Waksman
Table I. Major ␥ isotopes and physical properties  energy (MeV) Radionuclide 192 125 103
Ir I Pd
Half-life 73.8 days 60.1 days 17.0 days
Emission Photon Photon Photon
Method of production Neutron activation Neutron activation Neutron activation
Photon energy (MeV)
Average
Maximum
Average
Maximum
0.18 – –
0.67 – –
0.37 0.028 0.020
1.06 0.035 0.021
Ir, Iridium; I, iodine; Pd, palladium.
monocyte-derived macrophages as pivotal in the development of restenosis. The endothelial injury sustained in the deployment of a stent or remodeling from angioplasty elicits the expression of chemokines (interleukin-6, platelet-derived growth factor [PDGF], tumor necrosing factor). These chemokines attract macrophages and T cells in a manner similar to the sequestration after the development of an atherosclerotic plaque and typical of the response of the surrounding adventitia to endothelial injury. Sequestration of inflammatory cells begins in either the endothelium of the vasa vasorum or the luminal lining of endothelial cells and is observed over a longer time course with the implantation of a stent, which provides continuous stimulation of the inflammatory cascade. The ultimate development of neointimal hyperplasia is thought to be the result of the direct effects of the monocyte/macrophage system or surrounding endothelium through stimulatory mechanisms or of the development and differentiation of myofibroblasts with the inflammatory process, primarily through stimulation of macrophages with PDGF and interleukin-6 and the stimulation of smooth muscle cells with PDGF and transforming growth factor.8-11 Although these mechanisms contribute to the failure of PTA or SBA, the development of elastic recoil affects short-term patency and technical success, whereas neointimal hyperplasia and contracture alter longer term outcome. BASIC RADIOTHERAPY Radiation physics and the effect of ionizing radiation on biologic tissues has been a subject of study since its discovery in the early 20th century. For therapeutic purposes, radiation can be divided into two classes: ␥-emitters and -emitters. ␥-Emitters emit energy in the form of photons, high-energy electromagnetic particles, which are generated by and originate in the nucleus, whereas -emitters generate electrons from the outer orbit of unstable elements. The energy from these emissions is absorbed by the tissues where it has an ionizing effect, setting into motion chemical cascades that result in terminal cellular damage. This energy, as quantified per unit of tissue, defines the dose of radiation and can be labeled as gray or rad, where 1 Gy ⫽ 100 cGy and 1 rad ⫽ 1 cGy. The activity of an isotope, the unit of which is the curie, describes a quantity of radioactive material (1 gm of radium ⫽ 1 Ci), and the half life is the amount of time that must elapse before only half of the original nuclei remain. ␥-Rays interact with tissue by imparting energy to the tissue and setting electrons from the tissue into motion.
With ␥-rays, a rapid decay or gradient in dose is seen as the target acquires distance from the source, yet ␥-rays have high penetrating energies (20 keV to 20 MeV) so that work with these isotopes necessitates excessive shielding. Table I lists three major ␥-isotopes and their physical properties.6 The only pure ␥-emitter in clinical use is iridium-192. Its dosimetry has been well studied, and it has a dose gradient that makes it particularly suited to brachytherapy. Compared with -emitters, the ␥-gradient of radioactivity is attenuated to a much lesser degree with increasing distance from the source. With activities as high as 10 Ci, most manipulations with typical iridium must be performed in a radiation oncology suite because most interventional suites have the capacity to shield only against 500 mCi. Certain ␥-isotopes emit both ␥-ray and x-ray radiation, such as iodine-125 and palladium-103. These isotopes have lower energies and must be prescribed in much higher activities to achieve a desired dose in an acceptable dwell time (15 minutes). As a result, these isotopes are not commonly encountered in vascular brachytherapy because they are not available in activity levels that would provide the desired dose or because they are too expensive. -Emitters, alternatively, emit energy with release of an unstable electron. Unlike ␥-rays and x-rays, -rays have a finite range in tissue that is proportional to their energy, yet they emit higher doses per emission. Hence, the activity necessitated to create a prescribed dose is less. This property translates into easier shielding and handling properties. Compared with ␥-emitters, -emitters have a steeper energy gradient as they lose their activity more rapidly to surrounding tissues. -Emitters have great potential for vascular brachytherapy, especially in situations where they can be applied in close proximity to the vessel wall. The choice of substrate is largely determined by its half-life; certain elements, such as copper-62, can have half-life periods measured in minutes, whereas elements such as strontium/yttrium 90 reach their half-life in 30 years. VASCULAR BRACHYTHERAPY Extensive research conducted during the last 40 years has shown the effect that ionizing radiation has on living tissues, most notably the direct ionization of critical structures (ie, DNA) or the indirect destruction of critical molecules subsequent to the formation of free radicals. The use of radiation to counteract the development of abnormal hyperplasia is well documented, as is the attenuating effect of radiation on collagen synthesis.7 Vascular brachytherapy is the delivery of small to moderate doses of local radiation
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to a segment of the arterial tree in an attempt to disrupt the development of neointimal hyperplasia or the process of atherosclerosis. In particular, intraluminal delivery of radiation after endovascular manipulation has been shown to reduce restenosis in manipulated arteries.12-15 The paradox that a method that is implicated in the development of vascular stenosis could be used to prophylax against that very phenomenon necessitates special consideration of dose and mechanism of delivery.13 Radiation has long been known to cause vascular injury by causing both intimal injury and stimulation and slow activation of cells of the monocyte/macrophage lineage. Neointimal hyperplasia shares this cell line as a precursor, which seems to suggest that vascular brachytherapy relies on the destruction of macrophages to diminish the development of restenosis. Strong laboratory evidence exists for the T cellderived monocyte/macrophage as the “target cell” in the delivery of vascular radiation as a means to prevent restenosis.14,15 Hence, the target cell in vascular brachytherapy seems to be the local monocyte/macrophage system (for the elaboration of chemokines and local growth mediators) or the myofibroblast (the end result of the inflammatory stimulation). Delivery of ␥-irradiation or -irradiation can be accomplished through several platforms, most of which are catheter or stent based. Catheters used for delivery include line source wires, radioactive seeds or balloons, and inflatable systems with radioactive gas or liquid. The choice of isotope depends on the anatomy of the vessel, the properties of the treated lesion, and the proper identification of target tissue that necessitates treatment. Anatomically, important parameters that also need consideration include the diameter and the curvature of the vessel, the eccentricity of the plaque, the lesion length, the composition of the plaque, the amount of calcium, and the presence or absence of a stent in the treated segment.16 Ideally, the source should distribute radiation to only a few millimeters distance and have a minimal dose gradient and low dose exposure to surrounding tissues with dwell times of 15 minutes or less. Variables such as half-life (as it pertains to multiple applications), radiation exposure to patient and operator, shielding equipment, and cost are all secondary considerations. At present, evidence supports targeting the adventitia and the vessel wall and plaque.17,18 Currently, the American Brachytherapy Society recommends that for peripheral applications the average luminal radius of the isotope exceed 2 mm with a dose in the range of 12 to 18 Gy.19 Ir-192, as described previously, is a pure ␥-emitter and is commonly used in clinical medicine. Typical Ir-192 has activities that necessitate that it be used in heavily shielded environments. However, Ir-192 can be generated with lesser activities, enabling its use in the typical interventional suite. For example, Ir-192 can be used to treat a focal stenosis in a smaller artery with an average dwell time of 20 minutes (for a dose of more than 15 Gy) when administered at a 2-mm radial distance from the source. -Rays have a gradient that exposes the near wall to a higher dose of ionizing radiation yet have a lower penetra-
Sidawy, Weiswasser, and Waksman 1043
tion compared with ␥-emitters because they lose energy rapidly and have a range of total exposure of approximately 1 cm. As described previously, -emitters appear to be a promising source of radiation in vascular brachytherapy because of the relatively lower exposure to nonaffected tissue and operator and less collateral radiation within the prescribed dwell time. Typical -emitters used in vascular brachytherapy include rhenium-188 and rhenium-186, which are in liquid form, and xenon-133, which is gaseous. Phosphorus-32 is a solid -emitter used frequently. DELIVERY SYSTEMS Great attention has focused on delivery systems for vascular brachytherapy. Primarily these include administration of external radiation, radioactive stents, and catheterbased systems. External beam radiation has the advantage of being noninvasive and the disadvantage of collateral exposure. The most significant literature on this method is in the treatment of arteriovenous access for dialysis, where external beam radiation has little systemic side effects with administration to the limb yet may have potential for reducing stenoses in these grafts.20 Radioactive stents provide continuous exposure of radiation through an established method of therapy. Histomorphologic studies in rabbit iliac arteries have confirmed the diminutive effect on neointimal hyperplasia that stent delivered radiation imparts.21 The primary disadvantage of radioactive stent placement relates to the lack of homogeneity of delivered radiation across the stent. The geometry of current stent design allows for certain areas to exude a greater dose of radiation, whereas other areas may be underserving. This phenomenon, particularly evident at the borders of the stent, is termed “edge effect” and can result in intimal hyperplasia in areas where dosages are minor compared with other areas that may overdose the artery, resulting in thrombosis or tissue necrosis. In particular, the struts of the stent have been implicated in dose reductions of as much as 86%,22 and further work is now focusing on altering stent geometry to adjust the activity at the edges and center of the stent. Attempts have recently included construction of stents with “cold ends” but have not been met with acceptable restenosis rates in coronary vessels.23 Catheter-based delivery systems are varied and are the most commonly used method in clinical trials examining the efficacy of peripheral brachytherapy. The MicroSelectron-HDR (Nucletron-Odelft, The Netherlands) uses a computerized, high dose rate afterloader, which delivers a 3-mm stepping 10 Ci in activity of Ir-192 into a centered, closed end, segmented balloon radiation catheter (Fig). Remote afterloading allows rapid deployment of radiation (avoiding exposure to unaffected tissue), decreased exposure to personnel, and the ability to accurately shape the radiation dose by adjusting the source position, treatment time, and radiation dose. The Peripheral Brachytherapy Centering Catheter (PARIS catheter; Guidant, Santa Clara, Calif) is a double lumen catheter with multiple centering balloons near its tip. The design of the catheter allows for
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Arteriogram of SFA lesion (A) before angioplasty, (B) with PARIS catheter in place, and (C) after treatment at 6-month follow-up visit.
guidewire passage, catheter centering, and administration of radiation. The use of a guidewire constructed of Ir-192 introduced through manual manipulation allows treatment of short lesions in small vessels and necessitates a longer dwell time, imparting a dose of around 500 mCi. Some have investigated the use of an angioplasty balloon to administer liquid (Re-188) or gas (Xe-133) phase radioactive components to the arterial tree or even angioplasty balloons with radioactive components.24 These -emitters allow for uniform dosimetry given an even proximity to the vessel wall but carry the additional risk of possible spillage through balloon rupture. A novel technique was recently reported in which polypropylene mesh was labeled with 50 mCi of tritium and 50 mCi of calcium-45 (both -emitters) and wrapped around denuded rabbit carotid arteries. Although no appreciable difference was seen in the denuded surfaces of the experimental group compared with the control group, a reduction was found in neointimal area, maximal intimal thickness, and ultimate luminal stenosis. This technique may provide an effective surgical adjunct that uses the biology of endovascular vascular brachytherapy.25 LIMITATIONS OF BRACHYTHERAPY Two major complications specific to vascular brachytherapy have emerged from the clinical trials examining this technique: edge stenosis (or recently, radiation edge) and late thrombosis. Late thrombosis is thought to be a delay in intimal healing after radiation therapy and may be ameliorated by aspirin and or clopidogrel bisulfate therapy.26 The edge effect, described in association with stentbased delivery systems, also has been noted to occur with catheter-based systems and different isotopes. The uneven distribution of radiation with edges receiving a smaller dose compared with the therapeutic (and perhaps overtherapeutic) center of delivery results in the edges expressing the results of subtherapeutic radiation damage (proliferation)
and the core conferring overtherapy (thrombosis, tissue damage). To date, no study has shown that the administration of vascular brachytherapy poses any undue risk to patient or operator, yet broader based studies and longer follow-up periods are necessary. CLINICAL RESULTS Peripheral vascular. The most common application for the use of vascular brachytherapy in peripheral arteries is the treatment of superficial femoral artery (SFA) lesions. A list of the trials conducted for this application is displayed in Table II. The initial studies examining the feasibility of peripheral vascular brachytherapy were performed in Frankfurt by Liermann et al27 and were conducted in 30 patients with in-stent restenosis of SFA. With the MicroSelectron-HDR system in a noncentered catheter, 30 patients first underwent atherectomy and PTA followed by irradiation with Ir-192 for a total dose of 12 Gy, 3 mm into the vessel wall. After a 7-year follow-up period, no adverse effects were reported, and the 5-year patency rate was 82%, with an 11% restenosis rate. Late occlusion occurred in two of 28 patients (7%) after 16 months. The effectiveness of the MicroSelectron system was further investigated in a randomized, placebo-controlled trial in Vienna with Ir-192 in a noncentering, close-end lumen catheter delivering 12 Gy in 113 patients after femoropopliteal PTA. Patients were followed at 6 and 12 months and showed a 54% restenosis rate in the PTA group, whereas the group with PTA followed by irradiation had a 6-month restenosis rate of 28% (P ⬍ .013). A similar 50% difference in restenosis rate was observed at 12 months (63% versus 35%).28 Moreover, the same group reported on the effects of brachytherapy as prophylaxis against restenosis in long segment femoropopliteal arteries undergoing PTA and stent placement. In this study, 33 patients with femoropopliteal lesions with a mean length of 17 cm underwent PTA and stent implantation followed by Ir-192 delivered through a centered catheter to a total dose of 14
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Table II. Trials conducted Study Frankfurt Vienna 1 Vienna 2 Vienna 3 Vienna 4 Swiss PARIS I PARIS II
Enrolled
Randomized
Centering catheter
Dose (Gy)
Distance (mm)
Patency rate
30 10 113 200 100 120 40 300
– – Yes Yes Yes Yes No Yes
– – Yes Yes Yes – Yes Yes
12 12 12 18 14 12 14 14
3 3 r⫹2 r⫹2 r⫹2 r⫹2 r⫹2 r⫹2
82% 60% 72% – – 72% 87% –
r, Radius.
Gy. They report a 6-month recurrence rate of 30% (10/33) and a secondary (ie, after thrombolysis) patency rate of 88% (29/33) at 6 months.29 In the United States, the first large-scale trial to examine the effect of ␥-therapy on vascular stenosis was the Peripheral Arterial Radiation Investigational Study (PARIS), a Food and Drug Administration-approved, multicenter, randomized, double-blind study. With a centered segmental end lumen balloon catheter and the MicroSelectron-HDR afterloader, the primary endpoints of the study were 6-month patency and restenosis rates and reduction of more than 30% of the treated lesions after delivery of 14 Gy in conjunction with PTA of the SFA. In addition, funtional patency was determined with treadmill exercise testing and an ankle brachial index (ABI) improvement of 0.1 compared with pre-PTA values. In the feasibility phase of PARIS, 40 patients with claudication were enrolled. The mean lesion length was 9.9 ⫾ 3.0 cm, with a mean reference vessel diameter of 5.4 ⫾ 0.5 mm. After successful PTA, a segmented balloon-centering catheter was positioned to cover the PTA site. The patients were transported to the radiation oncology suite and treated with radiation with a high dose rate MicroSelectron afterloader. The isotope used for this study was Ir-192 (maximum of 10 Ci in activity), and the prescribed dose was 14 Gy to 2 mm into the vessel wall. ABI and maximum walking time were evaluated with a repeat angiogram at 6 months. Radiation was delivered successfully in all but two patients because of technical difficulties. No procedural, in-hospital, or 30-day complications occurred in any of the treated patients. At 3 months, maximum walking time on treadmill was increased from 3.56 ⫾ 2.7 minutes at baseline to 4.53 ⫾ 2.7 minutes (P ⫽ .01) and ABI was also improved from 0.7 ⫾ 0.2 to 1.0 ⫾ 0.2. Among the first 20 patients who returned for 5-month angiographic follow-up, only one patient needed revascularization of the treated site. No evidence has been found of arterial aneurysms or perforations. The 6-month angiographic follow-up was completed on 30 patients; 13.3% of them had evidence of clinical restenosis. The feasibility study of PARIS showed that the delivery of a high dose rate ␥-radiation via a centering catheter is feasible and safe after PTA to SFA lesions.30 The randomization phase for this study is scheduled to be completed by early 2002.
Carotid brachytherapy. Just as the horizon of endovascular treatment of carotid lesions is undergoing serious consideration and attention, the use of brachytherapy in the carotid position is largely experimental and in animal models. Wohlfrom and colleagues26 report on the diminutive effects of Re-188 on postinjury neointimal hyperplasia in the carotid arteries of hypercholesterolemic rabbits. A dose of 15 Gy began to show reduction of the proliferative response, whereas 45 Gy completely abolished the proliferative response.31 A similar result was obtained by Sarac et al,32 who showed a reduction in neointimal hyperplasia in injured rat common carotid arteries with increasing doses of ␥-radiation. Compared with controls in animals at 3 weeks, a significant reduction was seen in neointimal hyperplasia in Ir-192 irradiated rats.32 Rubin et al33 showed an attenuation of the proliferative response with radiation by examining rat carotid artery subjected to balloon catheter manipulation followed by increasing doses of radiation in the form of externally placed Ir-192 to a maximum dose of 15 Gy. They showed a reduction in the amount of the hyperplastic lesion up to 6 months after injury that was concurrent with a demonstrated reduction in activated macrophages/monocytes, further showing this cell population to be the primary target of vascular brachytherapy.33 Dialysis access. The use of brachytherapy, both endovascular and external beam, has been studied extensively as a means to prolong/preserve patency of dialysis access. Trerotola et al34 showed the effects of endoluminally delivered Ir-192 in five dogs with bilateral polytetrafluoroethylene dialysis access grafts. Each animal served as its own control, outflow injury was obtained with placement of a wall stent, and animals were followed for 10 months. They showed a reduction in neointimal hyperplasia in irradiated accesses.34 A pilot study was conducted at Emory University in 1994 to examine the effect of low dose radiation on neointimal hyperplasia in patients with failed PTA of the venous outflow of dialysis access grafts. Patients were enrolled if, after PTA, they had a ⬎50% luminal stenosis. They first underwent repeat PTA, followed by placement of a 5F sheath across the lesion. Patients then were transported to the radiation oncology suite where, with the MicroSelectron HDR afterloader, 14 Gy was delivered with high activity Ir-192 source 2 mm into the arterial wall. Patients
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were sent home after withdrawal of the catheter and were followed with color flow Doppler scan bimonthly and angiogram at 6 months. Eleven patients with 18 lesions underwent treatment, and a 40% patency rate at 44 weeks was reported.35 This study had many limitations, including a limited patient population with already failed endovascular manipulation and some variability in the type of graft treated and the actual dose of radiation delivered (7 to 90 Gy), and ultimately the results suggest that radiation therapy did not alter outcome compared with PTA alone. More recently, external beam therapy was examined as a method of reducing restenosis in arteriovenous dialysis grafts after angioplasty with or without stent placement. The results, again on the basis of a small patient population, showed no adverse effects of radiation exposure. However, three of 10 patients had restenosis develop at the original site, and one patient had a stenosis develop at the edge of a stent. Five patients had de novo stenoses develop in proximal veins necessitating intervention,36 which concurred with previous results obtained in the Emory pilot study. Endovascular brachytherapy has been used successfully in the treatment of failing Brescia-Cimino hemodialysis fistulas,37 and external beam therapy continues to be intensively investigated as a method for preventing postangioplasty restenosis of dialysis access. Although clearly feasible with little adversity, the effect of radiation in significantly preventing restenosis in dialysis access heretofore remains inconclusive.20 Other peripheral vascular locations. Another peripheral application of vascular brachytherapy includes prevention of restenosis of transjugular intrahepatic portosystemic shunts for patients with portal hypertension. These shunts, which have a reported stenosis rate of as high as 70% at 6 months and thrombosis as early as 2 weeks, may significantly benefit from radiation therapy as a means of supporting patency in this high risk group of patients.38 Anecdotal reports of endovascular brachytherapy of renal artery stenosis39 and of treatment of central venous strictures first treated with PTA can be found.40
4.
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6. 7. 8. 9.
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12.
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18.
CONCLUSION Despite new technologies and devices, restenosis remains the major limitation of intervention in the peripheral vascular system. The results from preliminary studies show that radiation in the form of vascular brachytherapy has the potential to alter the rate of restenosis after intervention. With the further progression of these studies and their promising results, the use of vascular brachytherapy might change the practice of peripheral intervention, resulting in an improved long-term patency rate for our patients.
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25. Waksman R, Ajani A, White R, et al. Prolonged antiplatelet therapy to prevent lat thrombosis after intracoronary ␥-radiation in patients with in-stent restenosis. Circulation 2001;103:2332. 26. Wohlfrom M, Kotzerke J, Kamenz J, et al. Endovascular irradiation with the liquid beta emitter Rhenium-188 to reduce restenosis after experimental wall injury. Cardiovasc Res 2001;49:169-76. 27. Liermann DD, Bottcher HD, Kollath J, et al. Prophylactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoropopliteal arteries. Cardiovasc Intervent Radiol 1994;17:12-6. 28. Minar E, Pokrajac B, Maca T, et al. Endovascular brachytherapy for prophylaxis of restenosis after femoropopliteal angioplasty: results of a prospective randomized study. Circulation 2000;102:2674-6. 29. Wolfram RM, Pokrajac B, Ahmadi R, et al. Endovascular brachytherapy for prophylaxis against restenosis after long-segment femoropopliteal placement of stents: initial results. Radiology 2001;220:724-9. 30. Waksman R, Laird J, Jurkovitz C, et al. Intravascular radiation therapy after balloon angioplasty of narrowed femoropopliteal arteries to prevent restenosis: results of the PARIS feasibility clinical trial. J Vasc Intervent Radiol 2001;12:915-21. 31. Rosenthal D. Low dose beta irradiation for the prevention of intimal hyperplasia after vascular surgical procedures. 28th Global: Vascular and Endovascular Issues, Techniques, and Horizons 2001;XI:5.1. 32. Sarac T, Riggs P, Williams J, et al. The effects of low-dose irradiation on neointimal hyperplasia. J Vasc Surg 1995;22;17-24. 33. Rubin P, Williams J, Riggs P, et al. Cellular and molecular mechanisms of radiation inhibition of restenosis. Part I: role of macrophage and
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38.
39.
40.
platelet-derived growth factor. Int J Radiat Oncol Biol Phys 1998;40: 929-41. Trerotola S, Carmody T, Timmerman R, et al. Brachytherapy for the prevention of stenosis in a canine hemodialysis graft model: preliminary observations. Radiology 1999;212:748-54. Waksman R, Crocker I, Kikeri D, et al. Long term results of endovascular radiation therapy for prevention of restenosis in the peripheral vascular system. Circulation 1996;94:I-300:1745. Parikh S, Nori D, Rogers D, et al. External beam radiation therapy to prevent post angioplasty dialysis access restenosis: a feasibility study. Cardiovasc Radiat Med 1999;1:36-41. Manninen H, Kaukanen E, Ikaheimo R, et al. Brachial arterial access: endovascular treatment of failing Brescia-Cimino hemodialysis fistulas—initial success and long-term results. Radiology 2001;218:711-8. Raat H, Stockx L, Ranschaert E, et al. Percutaneous hydrodynamic thrombectomy of acute thrombosis in transjugular intrahepatic portosystemic shunt (TIPS): a feasibility study in five patients. Cardiovasc Intervent Radiol 1997;20:180-3. Stuckle C, Laufer U, Kirchner J, et al. Successful treatment of intimal hyperplasia in renal arteries by endovascular brachytherapy. Cardiovasc Radiat Med 2001;2:114-8. Wong F, Kwok P, Ngan R, et al. Prevention of restenosis of central venous stricture after percutaneous transluminal angioplasty and endovascular stenting by brachytherapy. Kidney Int 1999;55:742-3.
Submitted Feb 4, 2002; accepted Feb 5, 2002.
IMAGES AND REFLECTIONS A new section in the Journal of Vascular Surgery, Images and Reflections, gives authors the opportunity for reflection by submitting creative writing (prose or poetry), photographs, artwork, and unique aspects of medical history. Submissions must be limited to one journal page. Please contact the Editor before submission.
Peripheral vascular brachytherapy Anton N. Sidawy, MD, MPH,a Jonathan M. Weiswasser, MD,a and Ron Waksman, MD,b Washington, DC Ongoing advances in peripheral endovascular technology have been met with disappointing results because of restenosis within the treated vessel. In particular, stent balloon angioplasty of peripheral vessels has yet to achieve patency rates that approximate conventional treatment in the long term. Recent advances in stent, balloon, and wire construction include the incorporation of radioactive substances in an attempt to ameliorate the inflammatory response provoked by typical endovascular manipulation, a technique termed vascular brachytherapy. ␥- and -isotopes and external beam radiation target the very cell population whose activity results in the development of neointimal hyperplasia. Although most clinical research examining the efficacy of vascular brachytherapy has emerged from the coronary artery literature, the use of vascular brachytherapy also has been examined in the peripheral arterial tree and has shown promising results. Current data indicate that vascular brachytherapy is a safe and accessible adjunctive endovascular maneuver that may improve the short-term patency rate of peripheral endovascular applications. The effects on long-term patency rates remain indeterminate compared to conventional therapy. (J Vasc Surg 2002;35:1041-7.)
As technology advances the treatment of vascular disease, it is clear that the limits of many endovascular interventions are defined by the development of restenosis in treated vessels. Although most data on this subject have been gleaned from work performed on coronary vessels, recent data on peripheral arteries have illustrated the predictable similarity between the two arterial beds, most notably the mechanisms for disease formation and restenosis after manipulation. Currently, endovascular treatment of infrainguinal disease, for example, consists mainly of percutaneous transluminal angioplasty (PTA) and stent balloon angioplasty (SBA). Although these methods have yielded encouraging results, with 5-year clinical success rates ranging from 42% to 58%,1,2 they have yet to match or supercede surgical methods in most cases. SBA has the added promise of a mechanical scaffold to encourage patency; however, it has produced 5-year patency rates in the 20% to 50% range,3,4 which are encouraging results but not comparable with those of surgical bypass procedures in the infrainguinal position. These results lay truth to the claim that SBA does not provide any additional benefit to PTA in infrainguinal disease and that PTA itself should be reserved for specific short segment stenoses in patients unable to tolerate an open procedure for limb salvage. From the Veterans Affairs Medical Centera and the Washington Hospital Center.b Competition of interest: Dr Waksman has received research support from Nucletron. Reprint requests: Anton N. Sidawy, MD, MPH, 50 Irving St, NW (112), Washington, DC 20422 (e-mail: [email protected]). Copyright © 2002 by The Society for Vascular Surgery and The American Association for Vascular Surgery. 0741-5214/2002/$35.00 ⫹ 0 24/9/123751 doi:10.1067/mva.2002.123751
These results, especially with progression distally into the arterial tree, are attributable to the development of restenosis and reocclusion of the vessel, mostly through the development of neointimal hyperplasia. It is this process that arterial brachytherapy attempts to address. MECHANISMS OF RESTENOSIS Three mechanisms are responsible for the development of restenosis: elastic recoil, intimal hyperplasia, and late vascular constriction, all grouped under the catch phrase “negative remodeling.”5-7 In the peripheral system, restenosis is seen mainly in small-sized and medium-sized arteries. Whereas manipulations in larger arteries, such as the iliac system, yield patency rates that are much more promising, manipulations in smaller vessels are plagued by lesion length, degree of stenosis, plaque burden, vessel size, and proximal and distal flow, all factors that seem to contribute to restenosis. The development of elastic recoil is contingent on the elastin fibers prevalent in the substance of the arterial wall and the ability of these fibers to morphologically alter the caliber of the artery. This effect is observed shortly after injury (manipulation) of the vessel and may be theoretically ameliorated with placement of an intraluminal scaffolding (stent). Neointimal hyperplasia and vascular constriction are prominent remodeling mechanisms that affect longterm outcome and parallel mechanisms observed in wound healing elsewhere in the body. Negative remodeling results if this hyperplasia leads to significant luminal stenosis. Many have investigated the cellular and inflammatory mechanisms that lead to the development of late phase stenosis. As it relates to vascular brachytherapy, this is the phenomenon and target cell population that arterial irradiation attempts to modulate. Strong support exists for 1041
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1042 Sidawy, Weiswasser, and Waksman
Table I. Major ␥ isotopes and physical properties  energy (MeV) Radionuclide 192 125 103
Ir I Pd
Half-life 73.8 days 60.1 days 17.0 days
Emission Photon Photon Photon
Method of production Neutron activation Neutron activation Neutron activation
Photon energy (MeV)
Average
Maximum
Average
Maximum
0.18 – –
0.67 – –
0.37 0.028 0.020
1.06 0.035 0.021
Ir, Iridium; I, iodine; Pd, palladium.
monocyte-derived macrophages as pivotal in the development of restenosis. The endothelial injury sustained in the deployment of a stent or remodeling from angioplasty elicits the expression of chemokines (interleukin-6, platelet-derived growth factor [PDGF], tumor necrosing factor). These chemokines attract macrophages and T cells in a manner similar to the sequestration after the development of an atherosclerotic plaque and typical of the response of the surrounding adventitia to endothelial injury. Sequestration of inflammatory cells begins in either the endothelium of the vasa vasorum or the luminal lining of endothelial cells and is observed over a longer time course with the implantation of a stent, which provides continuous stimulation of the inflammatory cascade. The ultimate development of neointimal hyperplasia is thought to be the result of the direct effects of the monocyte/macrophage system or surrounding endothelium through stimulatory mechanisms or of the development and differentiation of myofibroblasts with the inflammatory process, primarily through stimulation of macrophages with PDGF and interleukin-6 and the stimulation of smooth muscle cells with PDGF and transforming growth factor.8-11 Although these mechanisms contribute to the failure of PTA or SBA, the development of elastic recoil affects short-term patency and technical success, whereas neointimal hyperplasia and contracture alter longer term outcome. BASIC RADIOTHERAPY Radiation physics and the effect of ionizing radiation on biologic tissues has been a subject of study since its discovery in the early 20th century. For therapeutic purposes, radiation can be divided into two classes: ␥-emitters and -emitters. ␥-Emitters emit energy in the form of photons, high-energy electromagnetic particles, which are generated by and originate in the nucleus, whereas -emitters generate electrons from the outer orbit of unstable elements. The energy from these emissions is absorbed by the tissues where it has an ionizing effect, setting into motion chemical cascades that result in terminal cellular damage. This energy, as quantified per unit of tissue, defines the dose of radiation and can be labeled as gray or rad, where 1 Gy ⫽ 100 cGy and 1 rad ⫽ 1 cGy. The activity of an isotope, the unit of which is the curie, describes a quantity of radioactive material (1 gm of radium ⫽ 1 Ci), and the half life is the amount of time that must elapse before only half of the original nuclei remain. ␥-Rays interact with tissue by imparting energy to the tissue and setting electrons from the tissue into motion.
With ␥-rays, a rapid decay or gradient in dose is seen as the target acquires distance from the source, yet ␥-rays have high penetrating energies (20 keV to 20 MeV) so that work with these isotopes necessitates excessive shielding. Table I lists three major ␥-isotopes and their physical properties.6 The only pure ␥-emitter in clinical use is iridium-192. Its dosimetry has been well studied, and it has a dose gradient that makes it particularly suited to brachytherapy. Compared with -emitters, the ␥-gradient of radioactivity is attenuated to a much lesser degree with increasing distance from the source. With activities as high as 10 Ci, most manipulations with typical iridium must be performed in a radiation oncology suite because most interventional suites have the capacity to shield only against 500 mCi. Certain ␥-isotopes emit both ␥-ray and x-ray radiation, such as iodine-125 and palladium-103. These isotopes have lower energies and must be prescribed in much higher activities to achieve a desired dose in an acceptable dwell time (15 minutes). As a result, these isotopes are not commonly encountered in vascular brachytherapy because they are not available in activity levels that would provide the desired dose or because they are too expensive. -Emitters, alternatively, emit energy with release of an unstable electron. Unlike ␥-rays and x-rays, -rays have a finite range in tissue that is proportional to their energy, yet they emit higher doses per emission. Hence, the activity necessitated to create a prescribed dose is less. This property translates into easier shielding and handling properties. Compared with ␥-emitters, -emitters have a steeper energy gradient as they lose their activity more rapidly to surrounding tissues. -Emitters have great potential for vascular brachytherapy, especially in situations where they can be applied in close proximity to the vessel wall. The choice of substrate is largely determined by its half-life; certain elements, such as copper-62, can have half-life periods measured in minutes, whereas elements such as strontium/yttrium 90 reach their half-life in 30 years. VASCULAR BRACHYTHERAPY Extensive research conducted during the last 40 years has shown the effect that ionizing radiation has on living tissues, most notably the direct ionization of critical structures (ie, DNA) or the indirect destruction of critical molecules subsequent to the formation of free radicals. The use of radiation to counteract the development of abnormal hyperplasia is well documented, as is the attenuating effect of radiation on collagen synthesis.7 Vascular brachytherapy is the delivery of small to moderate doses of local radiation
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to a segment of the arterial tree in an attempt to disrupt the development of neointimal hyperplasia or the process of atherosclerosis. In particular, intraluminal delivery of radiation after endovascular manipulation has been shown to reduce restenosis in manipulated arteries.12-15 The paradox that a method that is implicated in the development of vascular stenosis could be used to prophylax against that very phenomenon necessitates special consideration of dose and mechanism of delivery.13 Radiation has long been known to cause vascular injury by causing both intimal injury and stimulation and slow activation of cells of the monocyte/macrophage lineage. Neointimal hyperplasia shares this cell line as a precursor, which seems to suggest that vascular brachytherapy relies on the destruction of macrophages to diminish the development of restenosis. Strong laboratory evidence exists for the T cellderived monocyte/macrophage as the “target cell” in the delivery of vascular radiation as a means to prevent restenosis.14,15 Hence, the target cell in vascular brachytherapy seems to be the local monocyte/macrophage system (for the elaboration of chemokines and local growth mediators) or the myofibroblast (the end result of the inflammatory stimulation). Delivery of ␥-irradiation or -irradiation can be accomplished through several platforms, most of which are catheter or stent based. Catheters used for delivery include line source wires, radioactive seeds or balloons, and inflatable systems with radioactive gas or liquid. The choice of isotope depends on the anatomy of the vessel, the properties of the treated lesion, and the proper identification of target tissue that necessitates treatment. Anatomically, important parameters that also need consideration include the diameter and the curvature of the vessel, the eccentricity of the plaque, the lesion length, the composition of the plaque, the amount of calcium, and the presence or absence of a stent in the treated segment.16 Ideally, the source should distribute radiation to only a few millimeters distance and have a minimal dose gradient and low dose exposure to surrounding tissues with dwell times of 15 minutes or less. Variables such as half-life (as it pertains to multiple applications), radiation exposure to patient and operator, shielding equipment, and cost are all secondary considerations. At present, evidence supports targeting the adventitia and the vessel wall and plaque.17,18 Currently, the American Brachytherapy Society recommends that for peripheral applications the average luminal radius of the isotope exceed 2 mm with a dose in the range of 12 to 18 Gy.19 Ir-192, as described previously, is a pure ␥-emitter and is commonly used in clinical medicine. Typical Ir-192 has activities that necessitate that it be used in heavily shielded environments. However, Ir-192 can be generated with lesser activities, enabling its use in the typical interventional suite. For example, Ir-192 can be used to treat a focal stenosis in a smaller artery with an average dwell time of 20 minutes (for a dose of more than 15 Gy) when administered at a 2-mm radial distance from the source. -Rays have a gradient that exposes the near wall to a higher dose of ionizing radiation yet have a lower penetra-
Sidawy, Weiswasser, and Waksman 1043
tion compared with ␥-emitters because they lose energy rapidly and have a range of total exposure of approximately 1 cm. As described previously, -emitters appear to be a promising source of radiation in vascular brachytherapy because of the relatively lower exposure to nonaffected tissue and operator and less collateral radiation within the prescribed dwell time. Typical -emitters used in vascular brachytherapy include rhenium-188 and rhenium-186, which are in liquid form, and xenon-133, which is gaseous. Phosphorus-32 is a solid -emitter used frequently. DELIVERY SYSTEMS Great attention has focused on delivery systems for vascular brachytherapy. Primarily these include administration of external radiation, radioactive stents, and catheterbased systems. External beam radiation has the advantage of being noninvasive and the disadvantage of collateral exposure. The most significant literature on this method is in the treatment of arteriovenous access for dialysis, where external beam radiation has little systemic side effects with administration to the limb yet may have potential for reducing stenoses in these grafts.20 Radioactive stents provide continuous exposure of radiation through an established method of therapy. Histomorphologic studies in rabbit iliac arteries have confirmed the diminutive effect on neointimal hyperplasia that stent delivered radiation imparts.21 The primary disadvantage of radioactive stent placement relates to the lack of homogeneity of delivered radiation across the stent. The geometry of current stent design allows for certain areas to exude a greater dose of radiation, whereas other areas may be underserving. This phenomenon, particularly evident at the borders of the stent, is termed “edge effect” and can result in intimal hyperplasia in areas where dosages are minor compared with other areas that may overdose the artery, resulting in thrombosis or tissue necrosis. In particular, the struts of the stent have been implicated in dose reductions of as much as 86%,22 and further work is now focusing on altering stent geometry to adjust the activity at the edges and center of the stent. Attempts have recently included construction of stents with “cold ends” but have not been met with acceptable restenosis rates in coronary vessels.23 Catheter-based delivery systems are varied and are the most commonly used method in clinical trials examining the efficacy of peripheral brachytherapy. The MicroSelectron-HDR (Nucletron-Odelft, The Netherlands) uses a computerized, high dose rate afterloader, which delivers a 3-mm stepping 10 Ci in activity of Ir-192 into a centered, closed end, segmented balloon radiation catheter (Fig). Remote afterloading allows rapid deployment of radiation (avoiding exposure to unaffected tissue), decreased exposure to personnel, and the ability to accurately shape the radiation dose by adjusting the source position, treatment time, and radiation dose. The Peripheral Brachytherapy Centering Catheter (PARIS catheter; Guidant, Santa Clara, Calif) is a double lumen catheter with multiple centering balloons near its tip. The design of the catheter allows for
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1044 Sidawy, Weiswasser, and Waksman
Arteriogram of SFA lesion (A) before angioplasty, (B) with PARIS catheter in place, and (C) after treatment at 6-month follow-up visit.
guidewire passage, catheter centering, and administration of radiation. The use of a guidewire constructed of Ir-192 introduced through manual manipulation allows treatment of short lesions in small vessels and necessitates a longer dwell time, imparting a dose of around 500 mCi. Some have investigated the use of an angioplasty balloon to administer liquid (Re-188) or gas (Xe-133) phase radioactive components to the arterial tree or even angioplasty balloons with radioactive components.24 These -emitters allow for uniform dosimetry given an even proximity to the vessel wall but carry the additional risk of possible spillage through balloon rupture. A novel technique was recently reported in which polypropylene mesh was labeled with 50 mCi of tritium and 50 mCi of calcium-45 (both -emitters) and wrapped around denuded rabbit carotid arteries. Although no appreciable difference was seen in the denuded surfaces of the experimental group compared with the control group, a reduction was found in neointimal area, maximal intimal thickness, and ultimate luminal stenosis. This technique may provide an effective surgical adjunct that uses the biology of endovascular vascular brachytherapy.25 LIMITATIONS OF BRACHYTHERAPY Two major complications specific to vascular brachytherapy have emerged from the clinical trials examining this technique: edge stenosis (or recently, radiation edge) and late thrombosis. Late thrombosis is thought to be a delay in intimal healing after radiation therapy and may be ameliorated by aspirin and or clopidogrel bisulfate therapy.26 The edge effect, described in association with stentbased delivery systems, also has been noted to occur with catheter-based systems and different isotopes. The uneven distribution of radiation with edges receiving a smaller dose compared with the therapeutic (and perhaps overtherapeutic) center of delivery results in the edges expressing the results of subtherapeutic radiation damage (proliferation)
and the core conferring overtherapy (thrombosis, tissue damage). To date, no study has shown that the administration of vascular brachytherapy poses any undue risk to patient or operator, yet broader based studies and longer follow-up periods are necessary. CLINICAL RESULTS Peripheral vascular. The most common application for the use of vascular brachytherapy in peripheral arteries is the treatment of superficial femoral artery (SFA) lesions. A list of the trials conducted for this application is displayed in Table II. The initial studies examining the feasibility of peripheral vascular brachytherapy were performed in Frankfurt by Liermann et al27 and were conducted in 30 patients with in-stent restenosis of SFA. With the MicroSelectron-HDR system in a noncentered catheter, 30 patients first underwent atherectomy and PTA followed by irradiation with Ir-192 for a total dose of 12 Gy, 3 mm into the vessel wall. After a 7-year follow-up period, no adverse effects were reported, and the 5-year patency rate was 82%, with an 11% restenosis rate. Late occlusion occurred in two of 28 patients (7%) after 16 months. The effectiveness of the MicroSelectron system was further investigated in a randomized, placebo-controlled trial in Vienna with Ir-192 in a noncentering, close-end lumen catheter delivering 12 Gy in 113 patients after femoropopliteal PTA. Patients were followed at 6 and 12 months and showed a 54% restenosis rate in the PTA group, whereas the group with PTA followed by irradiation had a 6-month restenosis rate of 28% (P ⬍ .013). A similar 50% difference in restenosis rate was observed at 12 months (63% versus 35%).28 Moreover, the same group reported on the effects of brachytherapy as prophylaxis against restenosis in long segment femoropopliteal arteries undergoing PTA and stent placement. In this study, 33 patients with femoropopliteal lesions with a mean length of 17 cm underwent PTA and stent implantation followed by Ir-192 delivered through a centered catheter to a total dose of 14
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Sidawy, Weiswasser, and Waksman 1045
Table II. Trials conducted Study Frankfurt Vienna 1 Vienna 2 Vienna 3 Vienna 4 Swiss PARIS I PARIS II
Enrolled
Randomized
Centering catheter
Dose (Gy)
Distance (mm)
Patency rate
30 10 113 200 100 120 40 300
– – Yes Yes Yes Yes No Yes
– – Yes Yes Yes – Yes Yes
12 12 12 18 14 12 14 14
3 3 r⫹2 r⫹2 r⫹2 r⫹2 r⫹2 r⫹2
82% 60% 72% – – 72% 87% –
r, Radius.
Gy. They report a 6-month recurrence rate of 30% (10/33) and a secondary (ie, after thrombolysis) patency rate of 88% (29/33) at 6 months.29 In the United States, the first large-scale trial to examine the effect of ␥-therapy on vascular stenosis was the Peripheral Arterial Radiation Investigational Study (PARIS), a Food and Drug Administration-approved, multicenter, randomized, double-blind study. With a centered segmental end lumen balloon catheter and the MicroSelectron-HDR afterloader, the primary endpoints of the study were 6-month patency and restenosis rates and reduction of more than 30% of the treated lesions after delivery of 14 Gy in conjunction with PTA of the SFA. In addition, funtional patency was determined with treadmill exercise testing and an ankle brachial index (ABI) improvement of 0.1 compared with pre-PTA values. In the feasibility phase of PARIS, 40 patients with claudication were enrolled. The mean lesion length was 9.9 ⫾ 3.0 cm, with a mean reference vessel diameter of 5.4 ⫾ 0.5 mm. After successful PTA, a segmented balloon-centering catheter was positioned to cover the PTA site. The patients were transported to the radiation oncology suite and treated with radiation with a high dose rate MicroSelectron afterloader. The isotope used for this study was Ir-192 (maximum of 10 Ci in activity), and the prescribed dose was 14 Gy to 2 mm into the vessel wall. ABI and maximum walking time were evaluated with a repeat angiogram at 6 months. Radiation was delivered successfully in all but two patients because of technical difficulties. No procedural, in-hospital, or 30-day complications occurred in any of the treated patients. At 3 months, maximum walking time on treadmill was increased from 3.56 ⫾ 2.7 minutes at baseline to 4.53 ⫾ 2.7 minutes (P ⫽ .01) and ABI was also improved from 0.7 ⫾ 0.2 to 1.0 ⫾ 0.2. Among the first 20 patients who returned for 5-month angiographic follow-up, only one patient needed revascularization of the treated site. No evidence has been found of arterial aneurysms or perforations. The 6-month angiographic follow-up was completed on 30 patients; 13.3% of them had evidence of clinical restenosis. The feasibility study of PARIS showed that the delivery of a high dose rate ␥-radiation via a centering catheter is feasible and safe after PTA to SFA lesions.30 The randomization phase for this study is scheduled to be completed by early 2002.
Carotid brachytherapy. Just as the horizon of endovascular treatment of carotid lesions is undergoing serious consideration and attention, the use of brachytherapy in the carotid position is largely experimental and in animal models. Wohlfrom and colleagues26 report on the diminutive effects of Re-188 on postinjury neointimal hyperplasia in the carotid arteries of hypercholesterolemic rabbits. A dose of 15 Gy began to show reduction of the proliferative response, whereas 45 Gy completely abolished the proliferative response.31 A similar result was obtained by Sarac et al,32 who showed a reduction in neointimal hyperplasia in injured rat common carotid arteries with increasing doses of ␥-radiation. Compared with controls in animals at 3 weeks, a significant reduction was seen in neointimal hyperplasia in Ir-192 irradiated rats.32 Rubin et al33 showed an attenuation of the proliferative response with radiation by examining rat carotid artery subjected to balloon catheter manipulation followed by increasing doses of radiation in the form of externally placed Ir-192 to a maximum dose of 15 Gy. They showed a reduction in the amount of the hyperplastic lesion up to 6 months after injury that was concurrent with a demonstrated reduction in activated macrophages/monocytes, further showing this cell population to be the primary target of vascular brachytherapy.33 Dialysis access. The use of brachytherapy, both endovascular and external beam, has been studied extensively as a means to prolong/preserve patency of dialysis access. Trerotola et al34 showed the effects of endoluminally delivered Ir-192 in five dogs with bilateral polytetrafluoroethylene dialysis access grafts. Each animal served as its own control, outflow injury was obtained with placement of a wall stent, and animals were followed for 10 months. They showed a reduction in neointimal hyperplasia in irradiated accesses.34 A pilot study was conducted at Emory University in 1994 to examine the effect of low dose radiation on neointimal hyperplasia in patients with failed PTA of the venous outflow of dialysis access grafts. Patients were enrolled if, after PTA, they had a ⬎50% luminal stenosis. They first underwent repeat PTA, followed by placement of a 5F sheath across the lesion. Patients then were transported to the radiation oncology suite where, with the MicroSelectron HDR afterloader, 14 Gy was delivered with high activity Ir-192 source 2 mm into the arterial wall. Patients
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were sent home after withdrawal of the catheter and were followed with color flow Doppler scan bimonthly and angiogram at 6 months. Eleven patients with 18 lesions underwent treatment, and a 40% patency rate at 44 weeks was reported.35 This study had many limitations, including a limited patient population with already failed endovascular manipulation and some variability in the type of graft treated and the actual dose of radiation delivered (7 to 90 Gy), and ultimately the results suggest that radiation therapy did not alter outcome compared with PTA alone. More recently, external beam therapy was examined as a method of reducing restenosis in arteriovenous dialysis grafts after angioplasty with or without stent placement. The results, again on the basis of a small patient population, showed no adverse effects of radiation exposure. However, three of 10 patients had restenosis develop at the original site, and one patient had a stenosis develop at the edge of a stent. Five patients had de novo stenoses develop in proximal veins necessitating intervention,36 which concurred with previous results obtained in the Emory pilot study. Endovascular brachytherapy has been used successfully in the treatment of failing Brescia-Cimino hemodialysis fistulas,37 and external beam therapy continues to be intensively investigated as a method for preventing postangioplasty restenosis of dialysis access. Although clearly feasible with little adversity, the effect of radiation in significantly preventing restenosis in dialysis access heretofore remains inconclusive.20 Other peripheral vascular locations. Another peripheral application of vascular brachytherapy includes prevention of restenosis of transjugular intrahepatic portosystemic shunts for patients with portal hypertension. These shunts, which have a reported stenosis rate of as high as 70% at 6 months and thrombosis as early as 2 weeks, may significantly benefit from radiation therapy as a means of supporting patency in this high risk group of patients.38 Anecdotal reports of endovascular brachytherapy of renal artery stenosis39 and of treatment of central venous strictures first treated with PTA can be found.40
4.
5.
6. 7. 8. 9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
CONCLUSION Despite new technologies and devices, restenosis remains the major limitation of intervention in the peripheral vascular system. The results from preliminary studies show that radiation in the form of vascular brachytherapy has the potential to alter the rate of restenosis after intervention. With the further progression of these studies and their promising results, the use of vascular brachytherapy might change the practice of peripheral intervention, resulting in an improved long-term patency rate for our patients.
19.
20.
21.
22.
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Submitted Feb 4, 2002; accepted Feb 5, 2002.
IMAGES AND REFLECTIONS A new section in the Journal of Vascular Surgery, Images and Reflections, gives authors the opportunity for reflection by submitting creative writing (prose or poetry), photographs, artwork, and unique aspects of medical history. Submissions must be limited to one journal page. Please contact the Editor before submission.