Editorial comment on "Long-term adverse effects of radiation inhibition of restenosis".

Appearing in this issue is an article entitled “Long-term adverse effects of radiation inhibition of restenosis: radiation injury to the aorta and branch arteries in a canine model,” by B. E. Powers, H. D. Thames, and E. L. Gillette. This is an interesting article, both for its intrinsic merit, and for its history. From the historical perspective, the authors present data from an experiment which began nearly 15 years ago, for purposes far removed from restenosis. Their original investigations (1, 2) were focused on the nature of long-term injury to the aorta following intraoperative radiation therapy (IORT). In those original articles, they reported an ED50 for severe aortic thrombi and aneurysm of 35 Gy IORT at 5-year follow-up (i.e., necropsy). Also of note was the fact that far fewer such injuries were observed at 2-year follow-up. In the new paper, the authors have reanalyzed their 15-year old data with special emphasis on questions of particular interest vis a vis restenosis. They now report on findings such as radiation-induced intimal proliferation, adventitial fibrosis, media thickening, and radiation effects on smaller diameter arteries of 1–3-mm diameter. In light of the recent explosion of interest in endovascular brachytherapy, this reanalysis, with special attention to histomorphic factors of particular relevance to restenosis, is of special interest. Their data at 5-year follow-up is, to my knowledge, unique. Many of the results presented, both here and in the original papers, may be rather sobering, particularly for people who believe that 6-month, or even 2-year follow-up data tell the whole story. Findings such as adventitial areas 6 times normal at 5 years postirradiation for 40-Gy single fraction dose, or intimal proliferation at doses , 15–20 Gy or . 50 Gy, or adventitial fibrosis, will hopefully whet the reader’s appetite for examining this paper in greater detail. Such findings, even if translatable to humans, may ultimately be considered a small price to pay in exchange for successful prevention of restenosis, but we would certainly be remiss to ignore such warnings. These warnings could not have come at a more appropriate time. Endovascular brachytherapy as a prophylactic treatment for prevention of restenosis in coronary arteries is arguably one of the more promising radiation bandwagons today. We have many reasons to be excited about the future of this relatively new therapy. Over 500,000 patients per year undergo coronary angioplasty in the United States, with a comparable number receiving such treatments internationally. Second only to bypass surgery, it is the most common and successful treatment modality for coronary artery disease. Yet, approximately 30–50% of patients fail treatment within 6 months. In the 25 years since Andreas Gruentzig introduced the coronary balloon catheter (3), cardiologists have searched (although unsuccessfully) for an adjuvant and/or concomitant therapy that could counteract the major negative side effect of angioplasty—namely restenosis. The increased use of permanently implanted stents over the past 5–10 years has reduced restenosis rates to approximately 20–40%; however, even with stents, the annual cost burden of coronary artery restenosis exceeds $1 billion annually in the United States alone. Thus, early animal studies (first reported in 1994) which showed a 70% reduction in restenosis rates with endovascular brachytherapy (4) were received with great interest, spawned many additional new studies, and culminated in the initiation of human clinical trials. The first doubleblinded, randomized human clinical trial was started in early 1995 at the Scripps Institute (5). This blinded, randomized trial of 55 patients confirmed, in humans, that endovascular radiation could indeed reduce the rate of restenosis by approximately 70%. Until very recently, all endovascular brachytherapy studies, both in humans and in animals, have had at least two significant characteristics in common: