With the growing popularity of peripheral vascular medicine, identifying a reliable treatment to the plaguing recurrence of restenosis will increase and augment the benefits of vascular intervention. Investigators have shown that the endovascular delivery of radiation therapy is one such treatment. Combating restenosis in the peripheral vascular system is contingent upon understanding the processes, mechanisms, and potential targets affected by using brachytherapy. The successful outcome of clinical trials in the coronary arteries facilitated recognition of vascular brachytherapy (VBT) to become standard of care for the treatment of in-stent restenosis (ISR). Expansion of the indications to de novo lesions identified the potential but also limitations of the technology (late thrombosis and edge effect). Simultaneously, investigators embarked on a series of studies utilizing VBT as adjunct therapy for intervention in peripheral arteries.
As patients in the baby boomer generation near their 60s, the full impact of peripheral and coronary atherosclerosis in the United States is apparent. Whereas coronary vascular procedures increase at a rate of 8% per year, there is greater growth in the frequency of peripheral procedures, estimated at 19% per year. Despite new advances such as drug-eluting stents, atherectomy devices, thrombectomy, and endoluminal grafts, the restenosis rate after peripheral artery intervention continues to compromise the overall success of these procedures.
Restenosis is still considered the “Achilles heel” of percutaneous endovascular intervention.1,2,3,4,5,6,7,8 Among the approaches for restenosis prevention and treatment in the peripheral arterial system (PAS), only VBT is reported to be safe and effective in this select group of patients. This article reviews the status of VBT, the available systems and dosimetry for use, and provides a summary of the latest reports from the clinical trials utilizing VBT to prevent or treat restenosis in the PAS.
The vessel size of the PAS favored the use of gamma radiation because of the penetration characteristics of the emitter. The majority of investigational work performed in the PAS used Ir-192 in doses of 14 to 18 Gy prescribed at 2 mm from the source center.
Gamma rays are photons that originate from the center of the nucleus, as opposed to X-rays, which originate from the orbital outside of the nucleus. Gamma rays have deeply penetrating energies between 20 keV and 20 MeV, which require an excess of shielding, as compared to beta and X-ray emitters. The only gamma-ray isotope currently in use is Ir-192. Other isotopes which emit both gamma- and X-rays are Iodine-125 (I-125) and Palladium-103 (Pd-103), which have lower energies and require higher activities to deliver the prescribed dose in an acceptable dwell time (<20 min). The latter isotopes are either not available in such activities or too expensive for this application. The dosimetry of Ir-192 is well understood and as a result of the lesser fall-off in dose compared with beta emitters, the dose gradient at the area of interest is acceptable. Ir-192 is available in activities of up to 10 Ci, but because of the high penetration, the average shielding of a catheterization laboratory will not be able to handle more than 500-mCi source in activity. This limitation is associated with dwell times >12 minutes for doses >15 Gy when prescribed at 2-mm radial distance from the source.
Beta rays are high-energy electrons emitted by nuclei and contain too many or too few neutrons. These negatively charged particles have a wide variety of energies including transition energy, particularly between parent-daughter cells, and have a wide variety of half-lives, from several minutes (Cu-62) to 30 years (Sr/Y-90). Beta emitters rapidly lose their energy to the surrounding tissue and their range is within 1 cm of tissue. Therefore, they are associated with a higher gradient to the near wall. The use of beta sources for vascular application is attractive from both the radiation exposure and safety points of view.
External beam radiation is a viable option for the treatment of peripheral vessels because it allows a homogenous dose distribution with the possibility of fractionation.
External radiation is currently used in a few centers for the treatment of ISR of the superficial femoral artery (SFA). Preliminary reports are encouraging, although caution should be applied to this strategy because of the potential for radiation injury to the nerve, vein, and the skin. Preliminary attempts with external radiation for the treatment of arteriovenous dialysis grafts failed to reduce the restenosis rate. This unsuccessful attempt was attributed to the conservative use of low doses and thrombosis of these grafts. Using sterotactic techniques to localize the radiation to the target area may improve the results of this approach.
In their study, Therasse et al.9 tested the theory that external beam radiation would be more practical to administer than VBT after percutaneous transluminal angioplasty (PTA) in reducing restenosis. After femoropopliteal PTA without stent placement, 99 patients were randomly assigned to 0 Gy (placebo; n = 24), 7 Gy (n = 24), 10.5 Gy (n = 26), or 14 Gy (n = 25) of external beam radiation of the PTA site (with a 3-cm margin at both extremities) in 1 session 24 hours after PTA. Restenosis >50% was present in 50%, 65%, 48%, and 25% of patients, for the 0-, 7-, 10.5-, and 14-Gy groups, respectively (p = 0.072). At 18 months, repeated revascularizations were required in 25% of patients in the 0-Gy group versus 12% of patients in the 14-Gy group (p = 0.24). It was found that a single session of external beam radiation of 14 Gy of the femoropopliteal angioplasty site significantly reduced restenosis at 1 year.9
The most common catheter-based system used for SFA application is the MicroSelectron HDR system (Nucletron-Odelft, Delft, Netherlands), which uses a computerized, high-dose rate afterloader system that delivers a 3-mm stepping, 10 Ci activity of Ir-192 into a closed-lumen radiation catheter (Figure 41-1). The Peripheral Brachytherapy Centering Catheter (Paris; Guidant Corporation, Indianapolis, IN) is a 7-F, double-lumen catheter with multiple centering balloons near its distal tip that enable the catheter to be in the center of the lumen of large peripheral vessels during inflation. The Paris catheter is no longer available. The only closed-end lumen catheter available is that used for oncology applications.
The only catheter-based beta system available is the BetaCath system, with a source train of up to 60 mm, which can be pulled back to allow coverage of long lesions (Figure 41-2). The main limitation of the system is the penetration of the beta emitter, which is weakened significantly beyond 5 mm. This system can be used for below-the-knee applications or for other small vessels, including in-stent renal stenosis. It is recommended to perform the radiation prior to the intervention to ensure better centering and a higher dose to the treated proliferating tissue.
Other innovative catheter-based radiation system developments have been halted because of the declining interest in the VBT field or slow recruitment into clinical trials. Included among these halted developments was the Radiance balloon system (Radiance Medical Systems; Irvine, CA), which was particularly attractive for peripheral applications because it is associated with apposition of a solid beta P-32 source attached to the inner balloon surface into the surface of the vessel wall. Another approach was the use of low X-ray energy delivered intraluminally via a catheter. The emitter was 5 mm in length and 1.25 to 2.0 mm in diameter and could be administered distally to the lesion and pulled back to cover the entire lesion length.
The Corona system, a modification of the BetaCath system, was used to accommodate beta systems with the Sr/Y-90 emitter in the peripheral system. In this system, the balloon was filled with CO2, allowing centering and preventing dose attenuation. A clinical study in SFA for ISR lesions entitled MOBILE was terminated because of poor enrollment. The Corona system was also used in the BRAVO study for patients with AV dialysis grafts.
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