Vascular Brachytherapy Beyond Coronary Disease

Stephen Ramee: Thank you very much for inviting me, Bill. It is important to think of the opportunities for vascular brachytherapy beyond the heart because although the heart is clearly where we all train, cardiology programs in general have had tunnel vision and have focused on the heart to the exclusion of the rest of the vascular tree. Imagine if you had to pay for drug-eluting stents by the inch; how much the cost of a similar stent, such as 20 centimeters or 30 centimeters long — rather than millimeters long. I think this is another application not just for drug-eluting stents but potentially for vascular brachytherapy as well. Just keep in mind that atherosclerosis is a systemic disease. In our practice, roughly one-third of the interventional cases performed are non-cardiac interventions such as stroke interventions, renal artery stenting, treatment for impotence, and claudication. With better diagnostic imaging, including MRA and ultrafast CT scanning, we will be able to identify larger numbers of patients needing intervention. Therefore, screenings will be better and less invasive, and more patients will be treated preventatively. In summary, the improvement of diagnosis means increased treatment opportunities. The potential vascular brachytherapy market for stent disease alone in the absence of a way to recanalize an occluded femoral artery is substantial. There is currently about a 2:1 ratio of interventions to surgeries, with 70,000 interventions and 45,000 surgeries performed. However, there are about 250,000 patients managed medically for either claudication or critical ischemia and about 210,000 who are undiagnosed but symptomatic. These people are all potential candidates for angioplasty, stenting, and vascular brachytherapy if they develop restenosis. If we develop a technique for crossing total occlusions in the femoral artery, that market will double and will approach the numbers of the coronary market. The problem with femoral artery stenting is that restenosis has been the legacy of failure. The long-term patency rate of femoral artery stents is in the 50% range in most series. This brings up the need for vascular brachytherapy. We completed one trial called the Nucleaton Paris trial, headed by Ron Waksman. The Paris feasibility trial included angiographic follow-up in 20 patients and showed a remarkably low restenosis rate of only 10% in lesions up to 20 cm in length. This is in the absence of stenting, which is really quite dramatic. We have completed enrollment in the Paris double-blind, randomized clinical trial involving over 230 patients at 12 centers. The follow-up is in progress. I think it will actually be quite interesting to compare the randomized patients because we don’t know which patients received which treatment. We do have results from the randomized Vienna trial showing a 30–40% reduction in restenosis in the radium-treated patients versus placebo at 6 and 12 months. However, the use of gamma radiation for this application does pose some significant logistical problems such as shielding, procedure length of time, and the need to move the patient from one floor to the other for radiation treatment. I think the radiation field offers some promising opportunities. This is the new Corona™ Transfer device, which uses a 60 mm source train. The balloon is different because it uses a CO2 inflation that does not attenuate the radiation so you can treat vessels up to 8 mm in diameter and 60 mm in length (6 cm). Thus, you can treat vessels from 5–8 mm in diameter using different sized balloons. The MOBILE trial, headed by Gary Ansel, is a randomized prospective study involving superficial femoral and popliteal arteries with lesion lengths between 4–30 cm. The patients will be randomized; the efficacy and safety endpoints are shown. Most of the patients will be randomized to balloon angioplasty for restenotic lesions and may or may not receive a stent. They will then be treated with vascular brachytherapy or no adjunctive treatment, then followed up at 9 months. Since the vessel is very vulnerable to Doppler evaluation, they will receive a Doppler ultrasound to determine whether restenosis has occurred. MOBILE will be a fairly simple trial to conduct and will look at in-stent restenosis or restenosis without a stent. There is also an unmet clinical need for the treatment of the hemodialysis arterial-venous graft which will be addressed by the BRAVO trial. BRAVO will look at vascular brachytherapy versus placebo for restenosis lesions in the dialysis access site — another potentially huge market for coated stents and especially for vascular brachytherapy. In conclusion, although drug-eluting stents are the proposed silver bullet aimed at preventing restenosis, they are not a treatment for restenosis. In fact, I don’t think it makes sense to place drug-eluting stents in a restenotic vessel because when the drug-eluting stent works and the restenotic scar tissue falls away, a stent may end up in the lumen. The preliminary results for the treatment of in-stent restenosis, at least in one yet unpublished Italian trial, showed a restenosis rate of 61.5% for in-stent restenosis which is cause for concern over drug-eluting stents in the restenotic lesion. The late effect of the drug-eluting stent — and I’m talking about over a year — even in simple lesions, is still unknown and is cause for further study. William O’Neill: Thank you very much, Stephen and everyone. This has been a terrific meeting so far.