European High-Activity 32P Radioactive Stent Experience
Brachytherapy by implantation of a radioactive stent is an alternative approach to catheter-based systems to reduce restenosis. The pilot clinical trials using P radioactive beta-emitting stents at low-to-intermediate activity (0.5-3.0 µCi) showed that restenosis at 6 months was not different from that of currently available non-radioactive stents. The evaluation of the efficacy in reducing restenosis of radioactive stents with higher activities (3-24 µCi) started in Europe (Milan, Rotterdam and Vienna) between 1998 and 1999. In the Milan and Rotterdam experience, P radioactive stents with an activity of 3-12 µCi demonstrated a reduction of intra-stent restenosis to < 4%. However, a high-edge restenosis > 30% was observed in the first 1-3 mm outside the stent margins. This edge effect might be due to a low dose of radiation at the stent margins combined with systematic balloon injury in the reference segments. The hypothesis that a further increase in stent activity (12-21 µCi) associated with a reduced balloon injury outside the stent could solve the problem of edge restenosis was not confirmed by the Milan experience; edge restenosis still occurred in 26% of the lesions treated by a single P radioactive stent, even if a nonaggressive stent implantation strategy was used. Two approaches under investigation to solve the problem of edge restenosis are: 1) lengthening the stent with a non-radioactive stent (cold-ends stent) to prevent negative remodeling; and 2) extending the area of irradiation beyond the balloon-injured area by an increased activity at the stent ends (hot-ends stent).

Intracoronary radiation therapy (brachytherapy) is one of the most promising strategies to prevent restenosis after percutaneous coronary interventions. Brachytherapy can be delivered by either catheter-based systems or radioactive stents.

Catheter-based systems deliver the radiation dose to the vessel wall soon after coronary intervention at a high dose rate in a relatively short period of time ranging from 2-5 minutes (beta-emitters) to 15-25 minutes (gamma-emitters), with the goal to sterilize most of the target cells located in the media and adventitia. Positive results using catheter-based systems in the reduction of restenosis have been obtained using both gamma- and beta-radiation in the animal model, and in humans.

Implantation of a radioactive stent is an alternative approach to reduce restenosis, mainly because it is simple to use (the technique used to implant a radioactive stent is nearly identical to that required to implant a non-radioactive stent) and it does not require the presence of a radiation oncologist and a radiation safety officer. Stents deliver radiation at a very low dose rate in a relatively long period of time (several weeks). The radioisotope P, a pure beta-particle emitter, has been employed the most because of its short half-life (14.3 days), limited range of tissue penetration (95% of the dose is delivered within 4 mm of the stent edge), minimum exposure to the catheterization staff, and rapid drop-off to < 1/1,000 of the original dose at 5 months post-implantation. Radioactive P stents at low activity of 0.75 µCi and at high activity of 12 µCi deliver a total dose of approximately 8 Gy and 140 Gy, respectively, to the tissue at 0.5 mm from the stent surface over a 28-day period. The total dose of high-activity radioactive P stents, although delivered over a longer period of time, is higher than that delivered by catheter-based systems, which range from 8-50 Gy at 1 mm into the vessel wall.

Animal studies in pig iliac arteries, rabbit iliac arteries, and pig coronary arteries have shown the efficacy of radioactive beta-particle emitting stents at low (< 1 µCi) to high activity (>= 3 µCi) in the inhibition of subsequent neointimal growth.