Treatment of Bifurcation In-Stent Restenotic Lesions with Beta Radiation Using Strontium 90 and Sequential Positioning “Pullback

Treatment of bifurcation lesions has been associated with lower success and higher complications rates. They represent a major interventional challenge. Redistribution of plaque (snowplow effect) often leads to occlusion of the side branch. To lower the risk of plaque shift, the kissing balloon technique was developed. Stenting of both vessels provided no advantage in terms of procedural success and late outcome versus a simpler strategy of stenting only the parent vessel. Various others techniques, such as rotational or excimer laser atherectomy, have been proposed, but the incidence of side branch compromise is still high. The incidence of restenosis in such lesions remains high (40–60%) independent of the technique used.1 This prospective study was carried to investigate the immediate and long-term outcome of kissing balloon angioplasty with beta radiation therapy for the treatment of in-stent restenosis in bifurcation lesions. Five randomized, placebo-controlled trials have established that beta- and gamma-based intravascular brachytherapy reduces the incidence of restenosis and clinical event rates following percutaneous coronary intervention (PCI) for the treatment of in-stent restenosis. In these randomized studies, the treatment effect of any kind of radiation was over 30% for any analyzed parameter with a similar benefit for both beta emitters (Sr-90, P-32) and gamma emitters (Ir-192).2–8 Until now, no reports of using this technique in bifurcation lesions have been published. Treatment device. The intraluminal beta radiation catheter delivery system (Novoste™ Beta-Cath™ System, Novoste Corporation, Norcross, Georgia), approved for use in the United States on November 3, 2000, by the US Food and Drug Administration, consists of two components.9 The first component is the transfer device that hydraulically transports a 30 mm, 40 mm or 60 mm Sr-90/Y-90 beta radiation source train (RST) to and from the treatment zone. The second component is a 5 French, triple lumen coronary delivery catheter designed to contain the RST during the intracoronary treatment. The RST is comprised of 12, 16 or 24 individual sources measuring 2.5 mm in length and 0.64 mm in diameter. At each end of the RST is a radiopaque non-radioactive source to identify the position of the source train under fluoroscopy. Each source has an average individual activity of 3.5 mCi and typical dose rate of 8.5cGy/s at 2 mm from its centerline axis in water. The delivery catheter is inserted over a standard 0.014´´ guidewire and is positioned in the designated treatment area by the interventional cardiologist. The radiation oncologist injects sterile water through the transfer device to send the radioactive sources to the end of the catheter and to return the radioactive sources after the appropriate dwell time. Treatment prescription. The recommended dose prescription for a single application of radiation following PCI for the Beta-Cath™ catheter system is 18.4 Gy at 2 mm for vessels whose reference vessel diameter (RVD) is Pullback technique. The extension of radiation treatment length beyond the length of the Beta-Cath™ catheter system RST requires sequential positioning or “pullback” of the catheter. In an ideal situation, the proximal seed of the distal RST would be exactly juxtaposed to the distal seed of the proximal source train. Because precise positioning of a source train is impractical in a moving target, the recommended technique is to attempt to achieve a “one active source to one active source” overlap to ensure that an adequate dose of radiation is delivered to the entire treated segment, as previously described.10 The same methodology may extend to bifurcation lesions treating sequentially the two vessels, where the overlap stands in the largest vessel area at the level of the carena, reputed to be thicker and more resistant to treatment (Figure 1). Methods Dosimetry methods. iPlan™ is a PC-based vascular treatment planning system that has been previously validated.11 The calculation of dose surrounding the source train is based upon the recommendations of the AAPM TG-60. This software allows quantitative and qualitative evaluation of the dose distribution with a variety of radiation source trains (32P, 192Ir and 90Sr/Y). All dosimetric analyses were carried out with this software. The dosimetry of the pullback technique has been previously reported.10 Two separate studies were undertaken to evaluate the dose at bifurcation with currently commercially available source preparations 192Ir, 32P and 90Sr/Y. With the use of intravascular ultrasound imaging, dosing was normalized for each system to 18.4 Gy at 2 mm: 1. Evaluation of minimum and maximum dose to the branch vessel lumen from irradiation of the main vessel using 90Sr/Y, 192Ir and 32P with variable hinge angles (Figure 2 and 3). 2. Evaluation of dose surface histograms (DSH; lumen and external elastic lamina [EEL]) with 2 seed overlap using 90Sr/Y and 192Ir source preparations and a hinge angle of 45 degrees (Figures 4–6). The other beta system for which pullback has been described is the Galileo™ System (Guidant Corporation, Temecula, California). The recommended dose prescription for this system is 20 Gy at 1 mm from the luminal surface. The dose at 2 mm in a small (3.0 mm RVD) and large (3.5 mm RVD) vessel is compared for these two prescription methods and then the effect of an overlap for a vessel of 3 mm is presented. Longitudinal movement of a vascular brachytherapy delivery catheter has been reported during the treatment time likely as a result of the systolic and diastolic phase of the cardiac cycle.12 In this paper, the longitudinal source displacement within the target segment was significant with a mean and standard deviation 1.1 and 0.8 mm, respectively. The observed range of catheter movement varied from 0.4 mm to 5.4 mm. The movement occurs on both the distal and proximal ends of the source train. This longitudinal source displacement may lead to a reduction in the peak overlap dose during a pullback treatment. Clinical materials. From August 1999 through April 2002, 5 patients were treated for in-stent restenosis in bifurcation lesions using pullback technique at the Institut de Cardiologie de Montréal in the Novoste Beta Radiation Compassionate Use Registry. Specific institutional informed consent was obtained from all patients. Results Bifurcation dosimetry (Figure 3) illustrates the result of the dosimetry with the 30 and 45 degree hinge angle. Figures 5 and 6 illustrate the dose surface histograms. Both beta emitters contributed higher doses to the branch vessel at short distances from the bifurcation than did the gamma emitter with P32 contributing the highest dose. At further distances down the branch vessel, the gamma emitters but none of the beta emitters contributed significant vessel dose. With smaller hinge angles, the increased doses are more significant. EEL and lumen DSH were significantly higher for both beta and gamma emitters with seed overlap; maximum (D10) doses of 39 to 46 Gy were calculated for the luminal surface for Iridium and Strontium, respectively. With smaller hinge angles, the increased doses are more significant. Longitudinal catheter movement. Longitudinal movement of the catheter tends to blur out the effect of hot spots at the junction.12 Source movement of 1 and 2 mm will result in 5% and 18% reduction of the dose enhancement factor (DEF) for a 1 source overlap. Source movement of 3 mm reduces the DEF by 24%. Thus, longitudinal source movement will reduce the peak dose. Clinical and angiographic outcomes. The mean age of the patients was 63 years old. Two patients were female, and 2 were diabetic. The mean lesion length was 49.4 mm ± 19.8 mm with a mean reference vessel diameter of 3.0 mm ± 0.5 mm. Of the lesions treated, one involved the left main (LM) with the left anterior descending (LAD) and circumflex (Cx) (Figure 7), three were Cx and a marginal branch (Figure 8) and the last one was a saphenous vein graft (SVG) and its branching on the right coronary artery (RCA) (Table 1). Cutting balloons were used routinely, and kissing balloon with plain old balloon angioplasty (POBA) concluded the angioplastic intervention preceding the beta radiation. Long-term antiplatelet therapy with clopidogrel was prescribed for at least a year. Clinical follow-up information is available on all 5 patients at a mean follow-up of 25.4 months (15 to 44 months). One patient (SVG) had peri-procedural non-Q wave myocardial infarction. Another patient required re-PTCA of the target vessel after 8 months for an edge lesion of 60% (Figure 9). This was treated by simple balloon angioplasty (TVR no TLR). Angiographic follow-up was obtained in 4 out of the 5 patients at 6 to 8 months. A single patient had an edge new lesion; a 73-year-old woman who had radiation on the SVG refused the angiographic follow-up claiming no symptoms (Table 2). There were no aneurysms or zones of ectasia in the treated arterial segments. None of the follow-up angiograms exhibited any thrombus, aneurysm formation or unhealed dissections at the site of overlap. All patients stayed asymptomatic at the last clinical follow-up, including the only TVR who now carries a follow-up of 44 months post-radiation. Discussion This report is about the use of Sr-90/Y-90 beta radiation to treat in-stent restenosis of bifurcation lesions. The technique appears to be feasible, is similar to the pullback technique, is safe, is secure and is clinically useful. Treatment with this beta radiation catheter system entails a dose prescription, which is about half of what is currently recommended with the 32P system with equivalent or possibly better result, with absence of potential injury by the centering balloon (Galileo INHIBIT 24% of restenosis13 versus 14% in START5,14). If with P32, in the INHIBIT trial, treated coronary segments can receive twice as much dose as with the Beta-Cath™ catheter and show no evidence of negative clinical or angiographic outcomes, then it is axiomatic that exposing short coronary segments to overlapped radioactive sources delivering 1.8 times the prescription dose should also be well tolerated.15 In addition, in the INHIBIT trial, approximately 40% of the patients were treated with pullback without apparent deleterious effects.6 This study is limited by virtue of the fact that there was no randomization, the sample size was small, not all patients had angiographic follow-up and the length of follow-up is limited. At this point in time, it would be difficult to propose a randomized study given the profound effect of radiation on both angiographic and clinical outcomes as observed in the Long WRIST trial,7 in RENO16,17 and in this single-center experience.10 It is possible that further follow-up of these patients might reveal late effects not evident at the 24-month mean clinical follow-up, but the 24-month clinical follow-up of the START patients18 (> 200 patients) has not shown any “catch up phenomenon.” Given the degree of benefit already observed and the lack of early adverse events, it is unlikely that late effects will negate the benefit of treatment of bifurcation lesions with radiation therapy.

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