Ian R. Crocker

RADIATION FOR PREVENTION OF RESTENOSIS : WHERE ARE WE ?

Restenosis, which is the Achilles’ heel of vascular interventions, has energized many investigators to find a new solution for this process. Despite the development of new devices and treatments such as laser, directional atherectomy, rotablator, stents, and gene therapy, none of these solutions has proved optimal, and restenosis remains unacceptably high. Recently, the novelty of using radiotherapy for prevention of restenosis has brought multiple specialties to the field of vascular brachytherapy. Currently, cardiologists, interventional radiologists, radiation oncologists, physicists, and radiobiologists are collaborating in developing this new technology. This special issue of the Journal, as well as the recent meetings dedicated to vascular radiotherapy, reflect the interest and the speed of the development of this new technology (3, 4). This novelty is of profound interest on two fronts: (a) Endovascular brachytherapy may improve the immediate and long-term success of interventional techniques, and (b) This treatment. by potentially reducing the number of repeat interventional procedures, presents the opportunity for true savings to the health care system with restenosis currently costing the US health care system close to 1 billion dollars annum (20). Considerable progress has been made in the recent past in understanding restenosis. Sophisticated analysis of tissue specimens retrieved from animal models and atherectomy specimens involving the use of in situ hybridization and cell culture techniques have revealed important markers and mechanisms of proliferation. The use of intravascular ultrasound has, in addition, enabled us to better define and optimize the angioplasty and stent procedure and as a result reduce the risk of restenosis (8, 15). Intravascular ultrasound (IVUS) has also been of singular benefit in elucidating the importance of vessel contracture (negative remodeling) to the restenotic process (5). Acute vascular recoil leading to an unsatisfactory angioplasty result occurs in 34% of patients and is successfully managed by intracoronary stenting. There is no reason to believe that endovascular brachytherapy will effectively treat this process. Neointimal hyperplasia and vascular remodeling, which are the main contributing factors in the majority of patients, both appear to be proliferative processes and may be effectively treated with radiation ( IO). Although the main contributors for restenosis have been identified, we still do not have the ability to predict on the basis of clinical, angiographic, or ultrasound parameters which patients will develop restenosis and which patients’ vessels will remain. Therefore, if this new therapy proves to be the Holy Grail in preventing restenosis. we would have to treat a large patient population raising the question, *‘Are we ready yet?” Several articles in this issue and preclinical work that has been completed support the contention that radiation may effectively reduce the problem of restenosis. There are numerous studies in a variety of animal models of restenosis which demonstrate that radiation can inhibit restenosis when the benefit is assessed acutely (2-4 weeks) and chronically (6 months) ( 1,6,7. I I, 12, 16-19,22). In these studies, radiation has been delivered externally. by radioactive stent or by a catheter-based device. The number of clinical studies is fewer but has permitted longer follow-up to assess the durability of this benefit. Of foul reported studies of intracoronary radiation therapy only two allow us any potential assessment of the benefit of ICRT: the study of Condado et al. (2) from Caracas, and the SCRIPPS study from LaJolla [Tierstein et crl. (2 1) 1. The study of Condado et (11. was a small (21 patients) single-arm study of ICRT following a coronary interventional procedure which now has (i-month follow-up data. Although the restenosis rate in this study falls within the range seen following coronary angioplasty, one provocative finding is that the overall mean luminal diameter (assessed by QCA) increased with time, suggesting that not only inhibition of neointimal hyperplasia but also positive remodeling had occurred. The failure to reduce the overall restenosis rate in this study may relate to small patient numbers and suboptimal angioplasty. The SCRIPPS study