Radiation inhibition of arterial restenosis - A new frontier

The effectiveness of many different radiation modalities under a variety of circumstances supports the existence of a therapeutic window. The catheter-based systems consist of radioactive wires, seeds or solutions delivering radiation within minutes of angioplasty at varying dose rates. These catheters can be either centered or non-centered, and using the American Association of Physicists in Medicine (AAPM) definitions, prescribe the dose at 2 mm from the source center (Nath et al. (143) under review). A dose of 15-30 Gy is given over a 5-30 min period, depending on the source strength. In contrast, radioactive stents are believed to give similar cumulative doses of 15-30 Gy, but over a period of days to month(s) and the dose is targeted more superficially at 0.1 to 0.5 mm depth. There is a dose response effect with sources in the range of 1 to 12 μCi, with increasing effectiveness at the higher dose rates. External irradiation has proved effective, but not in all circumstances. Often the applied doses have been too low or too high, and the added factor of stent use may have contributed to the negative results in some studies because of an increase in dose scatter. In addition, the volumes irradiated have been much larger than those with brachytherapy. It should be noted that a number of authors have demonstrated the advantages of 3-D conformal therapy in more uniformly irradiating small volumes such as coronary artery segments (5, 144, 145). Dose fractionation that can only be applied using external irradiation, using well-established radiation regimens corresponding to those used for palliative treatments, may also prove to be effective (146). The most consistent finding in all of these studies is the lack of acute and late toxicities, at 3 to 6 months in animals studies, but, more importantly, there has been excellent arterial tolerance in clinical trials of both coronaries (at 2-3 years follow-up) and peripheral vessels (6-7 years follow-up). However, longer follow-up studies are needed in both the laboratory and the clinic. Our conclusion, therefore, is that there is clear evidence of a therapeutic window confirming the effectiveness of irradiation. Using endovascular brachytherapy, the therapeutic window is narrow because large single doses are used, but they are well tolerated because of the small volumes and the rapid decrease in dose with tissue depth. Using external irradiation, fractionation should widen the therapeutic window over single doses, but if conformal therapy is not available, then larger volumes could compromise the results. With radioactive stents, extremely low dose rates lead to protracted irradiation, but with only very small volumes of vessel being exposed. However, there are the additional factors of varying dose rates and the peaks and troughs in spatial dose distribution to be considered. In summary, therefore, we believe that there is a therapeutic window for the use of irradiation in the prevention of restenosis since the dose required to injure arteries is much greater than the doses being used therapeutically. Therefore, on the basis of both experimental and clinical findings of radiation inhibition of arterial restenosis, we predict that this endeavor will prove to be a new frontier.