Mechanisms and Methods to Resolve Edge Effect

Vascular brachytherapy (VBT) has evolved as a viable method to treat in-stent restenosis (ISR), which is due to neointimal hyperplasia distributed either focally or diffusely over the entire length of the stent.1 Radiation acts by inhibiting all phases of the cell division cycle.2 192Iridium is the only g isotope that has been tested clinically in VBT, while 32P, 90Sr/90Y and 188Rh are the b sources tested. Iridium is an energetic gamma emitter, which is not attenuated by calcifications in the vessel wall or the presence of a metallic stent. The disadvantage, however, is that it requires long dwell time and requires the operator and other personnel to be away from the patient during radiation therapy. 90Sr is the most commonly used b emitter with the longest half life of 28.5 years.3 The parent-daughter isotopes 90Sr/90Y have the advantage, since dwell times are short, radiation protection concerns for personnel are not required and luminal surface dose is less, since it is one of the most energetic b emitters. The disadvantage here is the potential for attenuation by calcification in the vessel wall and stents. 32P is a relatively poor b emitter and requires a high dose to the luminal surface in order to deliver an adequate dose to adventitia. In order to treat longer lesions, one has to use step the source, which may increase treatment times. The problems associated with VBT have been surmounted by understanding the mechanisms and pathogenesis. For example, the problem of late thrombosis has been overcome by prolonging antiplatelet therapy. It is recommended to continue clopidogrel at least up to 12 months after VBT.4 Occurrence of restenosis at the edges of irradiated segments on angiographic follow-up was identified as a limitation to VBT, since it is associated with the need for repeat revascularizations. This phenomenon was initially noted with radioactive stents5 but is also seen with catheter-based radiation therapy.6 By definition, edge effect means stenosis on angiographic follow-up occurring after VBT less than 5 mm proximal or distal to the tip of the radiation source.7 Intravascular and pathologic studies showed that aberrant neointimal proliferation outside the stent margins predominantly contributed to the edge effect phenomenon.8 The increased tissue at the edge consists of smooth muscle cells in disarray and abundant extracellular matrix. Observational studies showed that the edge effect occurred more likely when the full radiation dose was not delivered all along the injured segment and missed its edge. Failure to deliver full radiation dose to the injured segment due to fall-off of the radiation from the source is termed geographical miss.9 As a result, a lower radiation dose interacts with injured segments of the vessel and may promote proliferative response. The edge effect after VBT was first described in clinical practice with 32P stents. The observation of tissue growth in the first 1 to 3 mm proximal and distal to the stent edges suggested that low-dose radiation at the stent boundaries did not inhibit the intimal proliferation triggered by the stent injury. However, increasing the activity of b-emitting stents was not sufficient to prevent the edge effect.10 A clinical attempt to reduce the edge effect was to extend the radioactive stents with nonradioactive edges (“cold ends”) in order to control the remodeling component of edge stenosis.11 It was then observed that the stenosis migrated from the stent edges to the cold ends segments.12 The START 40 trial showed that the restenosis rate in radiated, nonstented segments was higher with 30 mm 90Sr source (10.2%, 16.3 mm long lesions) than with 40 mm source (5.8%, 17.4 mm long lesions).13 This clearly demonstrated that extending the radiation margins reduced the edge effect. Theoretically, optimal radiation margin is defined as the minimal margin required to eliminate gradient of neointimal proliferation within the stent without adverse effect to the vessel. However, data are limited to determine this length. Retrospectively, the incidence of edge effect was 9% in the BRIE trial14 and 9.4% in the WRIST study.15 The Vienna experience showed that margins of 5 mm are required to prevent 95% of the edge effects.16 The European RENO registry was initiated after the edge effect was well identified and consequently tried to avoid geographical miss.17 Their data showed that the restenosis rate within the injured segment was 16.7%, 24.1% and 27.7% for 60 mm source (30.9 mm long lesions), 40 mm source (19 mm long lesions) and 30 mm source (15.5 mm long lesions), respectively. This suggests that radiation margins of 15 mm (30 mm lesions covered with 60 mm sources) prevent the edge effect more likely than 7.5 mm margins (15 mm lesions covered with 30 mm sources). In an experimental model of stent injury in swine, it was shown that extending the radiation margin from 10 mm to 14.5 mm improves the coverage of the stent edge and that higher dose with 22Gy and 10 mm margins were sufficient to prevent the edge effect, suggesting that shorter margins might be adequate when a higher radiation dose was delivered.18 In this study, as well as in the WRIST trials, there was no evidence of deleterious effect of g-radiation on normal noninjured vessel.19 In summary, the following points will highlight the measures to reduce edge effect. 1. The initial objective of the treatment before radiation should be to minimize the vessel injury and to enlarge the lumen at the lesion segment only. 2. Radiation coverage should be extended by 10–15 mm with gamma sources and 5–10 mm with beta sources from the injured segment. 3. Additional stenting should be minimized inside and outside the reference stent at the time of the radiation procedure. 4. When additional stenting is unavoidable, the best strategy is to increase the radiation dose. Animal studies have demonstrated that an increase of the dose from 15 to 22 Gy is sufficient to prevent edge effect. The following case study illustrates important aspects of VBT to produce an optimal result. This relates to the injured segment of the artery, additional stenting, use of other PCI devices and coverage of the injured segment/stent with a radiation source. Case Report. A 65-year-old male presented with a past history of coronary artery bypass graft (1999) and hypercholesterolemia and is an ex-smoker. He had exertional angina and a positive thallium scan for ischemia. Percutaneous coronary intervention (PCI) with stenting of the left main (LM) and circumflex (LCx) was performed in December 2000. He had recurrence of angina in February 2001. Cardiac catheterization at that time revealed LAD and RCA totally occluded, LIMA to LAD patent, free RIMA to diagonal patent and SVG to OM occluded. Subtotal occlusion of LM/LCX with diffuse in-stent restenosis was evident. He underwent PCI of the LM/LCx in February 2001. The total occlusion was recanalized with excimer laser and balloon angioplasty (3.0 x 30 mm balloon). Additional stents were deployed to cover a distal dissection (3.0 x 15 mm) and recoil of tissue in the LM (3.0 x 9 mm). The segment was then treated with gamma brachytherapy according to the Integrillin WRIST protocol. Nineteen seeds (57 mm) of 192-Iridium at a prescribed dose of 15 Gy at 2 mm were delivered via an intravascular brachytherapy system (Checkmate™ System, Cordis Corporation, Miami Lakes, Florida). The patient was prescribed clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals, New York, New York) for at least 12 months. He recently (April 2003) represented with a NQWMI, and the cardiac catheterization revealed edge stenosis of LM/LCx at both margins of the previously treated in-stent restenosis segment as noted angiographically (Figure 1). Discussion. In this case, the source was placed at the guiding catheter; nevertheless, the patient presented with ostial LM stenosis. The LM restenosis can be attributed to either inadequate margins of the source or this edge effect could be explained by insufficient dose to this segment. The distal edge in the LCX effect can be attributed to lack of source coverage. Finally, this case demonstrates the importance of adequate radiation margins but suggests that there may be other confounders to the edge effect phenomenon.

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