Considerations on Radiation Source Selection and Utilization in Vascular Brachytherapy<br />

The initial evaluation of radiotherapy in animal models of restenosis focused on the used of 192Iridium ribbons, a commercially available source. After initial animal studies revealed that therapy with this isotope reliably inhibited vascular renarrowing following balloon angioplasty, investigation into alternative, more “user-friendly” radiation delivery sources and systems was undertaken. Permanently implanted radioactive stents were very successful in animal models and clinical trials at inhibiting neointimal proliferation within the stent but created problems of narrowing at the ends of the stent (candy-wrapper effect) and are no longer being used. Temporary application of radiation with wires or trains of radioactive seeds proved to be the most effective way of preventing restenosis, and these approaches are discussed here. Although many isotopes have been proposed for intravascular brachytherapy (Table 1), only 6 have seen use in human clinical trials, and of those, only 3 are approved for clinical use in the United States. The three approved isotopes are 192Iridium (Checkmate™ System, Cordis Corporation, Miami Lakes, Florida), 90Strontium/Yttrium (Beta-Cath™ System, Novoste Corporation, Norcross, Georgia) and 32Phosphorous (Galileo® III Intravascular Radiotherapy System, Guidant Corporation, Temecula, California). The following discussion will focus on the purported advantages and disadvantages of the different isotopes and discuss relevant issues to their use. 192Iridium 192Iridium (192Ir) is the only gamma emitter that has been used and clinically tested in vascular brachytherapy. It emits a variety of gamma energies ranging from 296 to 612 keV with an average energy of 370 keV. The half-life is 74 days. The commercially available system (Checkmate System) contains “standard” 192Ir seeds manufactured by Best Industries. The seeds are 0.5 mm in diameter and 3 mm in length with a 1 mm interseed spacing, and ribbons containing 6, 10 and 14 are commercially available. Treatment times for intravascular brachytherapy are typically 15–40 minutes. The 192Ir system consists of a cylindrical lead storage “pig” with manual advancement of the source into a specially designed treatment catheter. The advantage of this isotope is it is an energetic gamma emitter that is not attenuated by calcifications in the vessel wall or the presence of a metallic stent. The disadvantage of 192Ir for vascular brachytherapy is the longer duration of treatment than with the beta isotopes and the radiation protection concerns associated with its use. Because of the greater penetration of the source, higher doses are delivered to normal tissues outside the arterial wall making the radiation burden the patient receives significant. In general, exposure rates at the bedside when a patient is undergoing vascular brachytherapy with an Iridium source are around 15–20 mR/hr, which is similar to exposure rates with fluoroscopy. Treatment requires the placement of lead shields at the bedside to protect the staff. Even with the shields, most of the staff remain outside the catheterization laboratory for the majority of the treatment to minimize radiation exposure. Because of the need to maintain relatively short treatment times, sources are typically replaced on a monthly basis, creating additional exposure and workload for the physicist to receive, return and calibrate sources compared with longer half-life isotopes like 90Strontium. 32Phosphorous The original 32Phosphorous (32P) system (Galileo System) contained a 27 mm source wire of encapsulated 32P. The current delivery system contains a source measuring 20 mm in length, which is automatically stepped to create treatment lengths of 20, 40 or 60 mm. The delivery system consists of a sophisticated computer controlled stepping motor, similar to a conventional high-dose rate (HDR) unit, and a centering catheter, which generally allows downstream perfusion during treatment. 32P is a pure beta emitter with a 14-day half-life and 1.71 MeV maximum beta energy. When using a relatively poorly penetrating beta emitter like 32P, one has to deliver a very high dose to the luminal surface in order to deliver adequate dose to the adventitia (the presumed target of vascular brachytherapy). The problem of high maximum doses delivered to the luminal surface may be magnified by underinflation of the balloon, which may be required if the balloon cannot be inflated during the treatment due to ischemia. Given that complications are generally associated with the maximum dose delivered to a volume of tissue, the modest energy of the beta emissions of this source represent a significant disadvantage. The centering catheter of the 32P system helps ensure that excessive dose is not administered to the luminal surface. In order to treat longer lesions with this system, one has to step the source unlike the Strontium or Iridium seed trains, which are available in various lengths. Because of the 14-day half-life, this system requires source exchange at least monthly and daily correction of treatment time. 90Strontium/Yttrium The most commonly used beta source is the beta emitting parent/daughter pair of 90Strontium/Yttrium (90Sr/Y). 90Sr is a pure beta emitter with 28.5-year half-life and 546 keV maximum beta energy. The daughter isotope 90Y is also a pure beta emitter with 64-hour half-life and 2.27 MeV maximum beta energy. It is primarily the 90Y betas that are used for therapy, as the 90Sr betas are mostly absorbed by the stainless steel encapsulation and the surrounding catheter. The 90Sr system (Beta-Cath System) contains sources that are 2.5 mm in length. Source trains of 12 (30 mm), 16 (40 mm) and 24 seeds (60 mm) are commercially available. The sources are stored in a hand-held transfer device and are advanced by a closed loop hydraulic system, which uses sterile water to advance (and then retract) the sources. The advantage of the 90Sr system is the relatively short treatment times (3–5 minutes) and the absence of radiation protection concerns associated with the use of a beta emitter. 90Sr/Y is one of the most energetic beta emitters, which helps reduce the luminal surface dose. The long half-life of the isotope permits the sources to be exchanged on a 6-month basis with no need to change the treatment times during that 6-month period. The disadvantage of this isotope is the potential for attenuation of the betas by calcifications or stents. What Dose is Necessary to Suppress Neointima Formation? Retrospective dosimetric studies from a group of patients treated in the Beta Energy Restenosis Trial (BERT) revealed that the minimum dose delivered to the external elastic lamina (EEL) was associated with success or failure in suppressing neointima formation and restenosis (Figure 1). Given the differences in penetration of 90Sr and 32P, it would be anticipated that quantitative differences in the dose volume histograms with the use of Strontium and Phosphorous for equivalent suppression of neointima formation would be apparent. This is exactly what was observed in a retrospective review of patients treated in Rotterdam at the Thoraxcenter with the 90Sr and 32P systems (Figure 2). Does Vessel Tortuosity Matter? Most stenotic segments treated with vascular brachytherapy are relatively short, and the effect of curvature on the dose prescription and dosimetry has been generally discounted. Cases of marked curvature of the vessel (hinge angle of Do Radiation Source Trains Need a Centering Balloon? One thing that is clear from the preclinical studies of restenosis is that a broad range of doses seem to be effective in preventing restenosis. Work carried out by the Emory group with gamma and beta sources has shown that doses of 3.5 to 56 Gy were effective in reducing restenosis in comparison to controls. One may conclude from the above investigators’ work that 1) delivery of a homogeneous dose to the entire vessel wall is unnecessary, 2) the target cell lies deep to the luminal surface either in the media or the adventitia and 3) a broad range of doses are effective in preventing restenosis. We know that the most an active centering device can accomplish is to center the source in the lumen. From histologic sections and intravascular ultrasound studies, we know that the vessel wall is not of uniform thickness and that the lumen is not necessarily in the center of the vessel. The question then arises as to whether active lumen centering improves the homogeneity of dose to the vessel wall in average-sized coronary vessels throughout the treated segment. In order to look at that issue, we performed a dosimetric analysis of a group of patients who had undergone intravascular ultrasound at the time of intracoronary radiation therapy treated on the BERT trial in Montreal and compared the results associated with centered and noncentered source configurations. The BERT trial was the first FDA-approved trial of intracoronary radiation therapy. Eligibility criteria for this trial included a symptomatic stenosis (> 70%) in a native coronary vessel with a reference vessel diameter of 2.5 to 3.5 mm. Following successful percutaneous transluminal coronary angioplasty (residual stenosis

1. Laird J, Carter A, Kufs W, et al. Inhibition of neointimal proliferation with low-dose irradiation from a beta-particle-emitting stent. Circulation 1996;93(3):529–536. 2. Soares C. Radiation: The basics. Vascular Radiotherapy Monitor 1998;1(1). 3. Li A, Eigler N, Litvack F, Whiting J. Characterization of a positron emitting V48 nitinol stent for intracoronary brachytherapy. Medical Physics 1998;25(1):20–28. 4. Janicki C, Duggan D, Coffey C, Fischell D, Fischell T. Radiation dose from a Phosphorous-32 impregnated wire mesh vascular stent. Medical Physics 1997;24(3):437–445. 5. Xu Z, Reinstein L, Yang G, Pai S, Gluckman G, Almond P. The investigation of P-32 wire for catheter-based endovascular irradiation. Medical Physics 1997;24(11):1788–1792. 6. Soares C, Halpern D, Wang CK. Calibration and characterization of beta-particle sources for intravascular brachytherapy. Medical Physics 1998;25(3):339–346. 7. Fox T, Soares C, King SB III, et al. Effect of curvature on dosimetry from a beta-emitting source train. Presented at Advances in Cardiovascular Radiation Therapy II, March 8–10, 1998, in Washington, DC. 8. Fox T, Soares C, King SB III, et al. Co-linear alignment of a beta-emitting radiation source train: Dose effect of misalignment at the junction. Presented at Advances in Cardiovascular Radiation Therapy II, March 8–10, 1998, in Washington, DC. 9. Fox T, Lobdell J, Robinson K, et al. Attenuation of dose from a 90-Sr/Y line source by a stainless-steel stent. Presented at the Second Annual Symposium on Radiotherapy to Reduce Restenosis, January 16–17, 1998, in LaJolla, California. 10. Amols H. Dose distributions pre- and post-stenting for beta sources. Presented at Advances in Cardiovascular Radiation Therapy II, March 8–10, 1998, in Washington, DC. 11. Marijnissen J, Levendag P, Coen V, et al. Gamma and beta source dosimetry and dose volume histograms from intravascular ultrasound (IVUS). Presented at Advances in Cardiovascular Radiation Therapy II, March 8–10, 1998, in Washington, DC.