Santosh Yajnik, MD

Coronary artery disease is the major cause of morbidity and mortality in the United States. More than 1 million angioplasty procedures are performed annually and 80% to 90% of patients undergoing angioplasty also undergo stent placement. It is estimated that approximately 15% of these patients subsequently develop in-stent restenosis and these patients have historically proven to be very difficult to manage.

Ionizing radiation therapy is used to limit hyperplasia and cellular proliferation in many oncologic and nononcologic conditions. Some nonmalignant applications of ionizing radiation therapy include the treatment of keloid formation, pterygia, and heterotopic bone formation.

In balloon injury models done in animals, intravascular radiation therapy was shown to reduce neointimal proliferation and restenosis in coronary arteries after balloon injury.1,2 These results led to the first study done in humans with coronary artery de novo stenosis. In 1994, Condado et al performed a single-arm prospective trial using iridium 192 vascular brachytherapy (VBT) in 21 patients. This study demonstrated that gamma-emitting radiation therapy was safe and effective in decreasing the incidence of late restenosis following coronary angioplasty in humans.3,4

Elizabeth Brunton, RN

Several prospective randomized clinical trials from 1995 to 2002, which all demonstrated the efficacy of radiation therapy in reducing in-stent restenosis, have led to the Food and Drug Administration (FDA) approval of three delivery systems for coronary artery in-stent restenosis. It is estimated that about 100,000 patients were treated with VBT in 2002 at 500 clinical centers across the United States. VBT after repeat angioplasty is the standard of care for the treatment of an estimated 150,000 patients annually who suffer in-stent restenosis following coronary angioplasty.

Important Clinical Trials

A comprehensive review of VBT, encompassing more than 6,000 patients enrolled in numerous phase II and III trials, is beyond the scope of this article. However, three pivotal trials that have played a significant role in the FDA approval of the three primary delivery systems in use will be discussed. The lessons learned from each trial were incorporated into subsequent trials with continued improvement of the results and decreasing complications. Likewise, the systems of VBT, including the delivery catheters, radiation sources, and storage devices, were continually improved. The current crop of VBT systems are vastly superior, easier to use, and safer to deliver, and have wider applications.

The GAMMA I trial used intravascular ultrasound-based dosimetry to deliver 8 Gy of ionizing radiation to the farthest media-adventitia junction while limiting the dose at the closest media-adventitia junction to <30 Gy.5 This was the first multi-institutional double-blind randomized trial done in patients with in-stent restenosis, and it led to the approval of the first system for use by the FDA. GAMMA I enrolled 252 patients at 12 centers and randomized them to VBT with an 192Ir source or placebo. There was a significant reduction in the target lesion revascularization (TLR) rate from 45% to 24% at 9 months and a significant reduction in angiographic restenosis rate from 50.5% to 21.6% at 6 months in favor of the VBT arm over placebo. The major complication of VBT was late thrombosis, and this occurred in 5.3% of patients. In subsequent trials, two measures were instituted that reduced the incidence of late thrombosis to the baseline levels: patients were placed on antiplatelet agents for 612 months and concurrent deployment of stents at the time of radiation therapy was avoided.

The START trial led to the approval of the second system by the FDA.6 This trial was a 50 institution-wide prospective, double-blind, randomized clinical trial that evaluated the effectiveness of 90Sr/Y-based VBT. The dose prescribed ranged from 18.4 Gy to 23 Gy at 2-mm radius and depended on the diameter of the vessel. The TLR and angiographic restenosis rates were both significantly decreased in favor of VBT over placebo. In this study, the catheter could not be delivered to the target site in 1.3% of cases and the radiation sources could not be delivered in 0.6% of cases.

Figure 1. Isotopes utilized in the three primary systems for delivery of vascular brachytherapy.

The INHIBIT trial led to FDA approval of the third system for in-stent restenosis. This multi-institutional double-blind trial enrolled 332 patients and was carried out at 27 institutions. For lesions with a maximum injury length of <47 mm, 20 Gy was prescribed at 1 mm from the balloon surface using fixed dosimetry.7,8 Manual repositioning of the catheter was allowed to treat lesions longer than the source length of 27 mm. The TLR and angiographic in-stent restenosis rates were decreased at 9 months follow-up from 29% to 11% and 49% to 16%, respectively.

These three prospective randomized trials clearly demonstrated improvement in both TLR and angiographic restenosis rates in favor of VBT over placebo for patients with in-stent restenosis and led to FDA approval of three systems for delivery of VBT for in-stent restenosis of coronary arteries. These trials also helped establish VBT as the standard of care for cardiac patients with in-stent restenosis.

Subsequent trials helped to confirm the efficacy of VBT in longer lesions up to 80 mm, in saphenous vein graft in-stent restenosis, with a lack of any acute or subacute complications with tandem positioning of radiation sources.

FDA-Approved Delivery Systems

The first system approved currently contains a nylon ribbon containing 10-14 192Ir seeds. Treatment lengths using this system range from 39 to 55 mm in fixed intervals. It entails manual advancement of the 192Ir ribbon, which is housed when not in use in a lead storage container. The ribbon is advanced into a noncentered closed-end delivery catheter that is 3.7 Fr in diameter. The treatment time per lesion is 15-20 minutes and sources are normally replaced on a monthly basis in order to limit treatment times.

Prabhakar Tripuraneni, MD

The advantages of using 192Ir include lack of attenuation of the ionizing radiation by the metallic stent or from calcifications that may be present in the luminal wall and a superior depth-dose gradient compared to beta-emitting sources. The disadvantages of 192Ir include potential increased ionizing radiation exposure of the staff in the catheterization laboratory, the need for lead shielding, the requirement of all the staff leaving the catheterization laboratory suite during the delivery, and increased treatment times compared with beta-emitting sources.

The second system approved contains 30, 40, and 60 mm 90Sr/Y seed trains that can be hydraulically delivered via a noncentered 3.5 and 5 Fr catheter. The seeds are stored in a handheld device. The hydraulic delivery system uses sterile water to advance and retract the sources. Fixed dosimetry is used at 2-mm radius.

The advantages of this system include the lack of radiation exposure to staff in the catheterization laboratory and short treatments that range from 3 to 5 minutes. The long half-life of 90Sr means that the sources can be used almost indefinitely. However, every 6 months, the system will need to be tested and delivery times are adjusted to account for the decay of the source. The disadvantages include a poor depth-dose gradient compared with 192Ir and more attenuation of radiation by metallic stents and calcifications resulting in possible underdosing of the target. Beta-emitting sources are not ideal for treating large vessels because of their poor depth-dose delivery.

The third system approved by the FDA for in-stent restenosis uses a 32 phosphorus wire to deliver radiation to lesions <52 mm, in vessels with diameters ranging from 2.4 to 3.7 mm. It contains a 20-mm 32P source wire with a computerized stepping delivery system from a computerized remote afterloader. To compensate for the poor depth-dose characteristics, centering balloons of 2.5, 3.0, and 3.5 mm diameter are used. Fixed dosimetry of 20 Gy at 1 mm from the balloon surface into the vessel wall is utilized. The centering balloon utilizes a trichannel design, which allows distal and side branch perfusion during treatment. The FDA has approved manual tandem stepping to treat longer lesions with this system. Treatment times range from 2 to 4 minutes.

Like the second system, advantages of this system include lack of radiation exposure to the catheterization laboratory staff and short treatment time. The disadvantages of this system, like other beta-emitting systems, include attenuation by the metallic stent and calcium, and inability to treat large-diameter vessels due to lack of approved larger-diameter balloons. The poor depth delivery was compensated by the use of centering balloons.

While three systems for in-stent restenosis have been approved by the FDA, most clinical centers utilize only one system. There are some research centers, such as Scripps Clinic in La Jolla, Calif, where we have all three systems for use in VBT. This gives us a unique perspective on the use and efficacy of these systems. All three systems have their distinct advantages and disadvantages. The additional time for the VBT part of the procedure is in the range of 15-25 minutes. The direct and indirect costs of VBT for any of these systems are about the same. Direct comparison of efficacy is not known at this time and generally assumed to be about equivalent.

Interdisciplinary Aspects of VBT

VBT involves a close collaboration between the interventional cardiologist (IC), radiation oncologist (RO), and medical physicist (MP). The patient is assessed by both the cardiologist and radiation oncologist prior to any intervention and informed consent is obtained. The overall care is provided by the IC and the radiation part is delivered by the RO in collaboration with the IC.

The FDA has mandated that VBT be carried out by a team containing each of the aforementioned specialists. The responsibilities of each practitioner have been summarized previously by Tripuraneni and colleagues9,10 and will be briefly described. The IC performs the angioplasty and is responsible for determining the site and size of the lesion and diameter of the lumen. The IC consults with the RO and they jointly determine the appropriateness of the lesion for VBT, the choice of isotope and delivery system, and the delineation of target length. The RO is the authorized user of the VBT delivery system. The RO evaluates the patient prior to the procedure and obtains informed consent for VBT. The RO, along with the MP, is responsible for radiation safety. During the procedure, the RO reviews the relevant clinical findings and anatomy with the cardiologist and jointly determines the appropriateness of VBT. The RO determines the target length, prescription point, and safe delivery of radiation. Along with the MP, the RO should oversee quality assurance of the delivery system. Both the IC and RO should remain available at the catheterization laboratory during the VBT procedure.

The MP, in conjunction with the RO, is responsible for the safety of the delivery system and radiation source, source calibration, radiation protection preparedness, radiation safety, treatment plan formulation, quality assurance of the delivery system, and surveying the patient and room after treatment delivery.

Thus, the delivery of VBT is a multidisciplinary process involving the cooperation of the IC, RO, and MP. This is a unique situation for both the cardiologist and the oncologist. VBT has brought in these two dissimilar specialties with no experience of working together in the past. This has caused some tension, unique challenges, and opportunities to provide the optimal care.

At Scripps Clinic, we have become accustomed to working closely with our interventional cardiologists in doing VBT for the past 8 years. Most VBT procedures are scheduled on Tuesdays and Thursdays whereby the RO and MP are available throughout the whole day. All practitioners are provided with a copy of the schedule well in advance of the intended procedure. This allows the appropriate preparation of the RO and MP to deliver VBT. All patients are seen by the RO in advance to obtain the informed consent for the VBT part of the procedure in addition to the IC’s informed consent. On an individual basis, VBT is delivered at other times of the week with prior discussion and agreement of the IC and RO. This usually happens no more than once or twice a month. These “emergency” add-on cases are usually to provide the optimal care for a patient with unstable angina from in-stent restenosis, or to avoid keeping the patient in the hospital for 3 days for “VBT day.” Each group needs to work out the practical details of VBT delivery based on the availability of the IC, RO, and MP; patient population; characteristics; and other factors. It is a significant resource allocation from radiation oncology departments and an additional time commitment from catheterization laboratories.

Peripheral VBT

There are currently no FDA-approved devices for use in peripheral VBT. About 400,000 peripheral interventional procedures are performed annually in the United States. The pathophysiology, lumen diameter, and incidence of restenosis are diverse and dependent upon location within the peripheral vascular system. Initial feasibility studies have shown a response to VBT in the periphery that is similar to that in the coronary circulation. The Peripheral Artery Radiation Investigational Study (PARIS) is a multi-institutional randomized trial evaluating VBT using the high dose rate afterloading system in superficial femoral-popliteal arteries.11 The initial feasibility phase of this study is completed and the results of the second phase are eagerly anticipated. If peripheral VBT becomes the standard of care, then, depending on the local practices, interventional radiologists may join the interdisciplinary team of providers who help deliver VBT.

The BETACATH trial was a multi-institutional randomized trial in 1,456 patients with coronary de novo stenosis that failed to show a benefit to VBT based on either clinical or objective parameters.12

Drug-Eluting Stents

Drug-eluting stents (DES) using antiproliferative agents such as sirolimus/rapamycin or paclitaxel have shown significant success in the reduction of restenosis in de novo lesions over placebo in randomized clinical trials.13,14 The current enthusiasm for drug-eluting stents, however, may possibly make vascular brachytherapy obsolete. Drug-coated stents may abolish, or nearly abolish, in-stent restenosis. Since coronary brachytherapy has been proven effective only as a treatment for in-stent restenosis, its fate in the DES world seems to be uncertain. We have data from numerous trials including SCORES, FIM, RAVEL, SIRIUS, TAXUS I, and TAXUS II. The largest of these, SIRIUS, was a 1,058-patient, multicenter, randomized trial comparing sirolimus-eluting stents to placebo in patients with intermediate length (15-30 mm) de novo, native coronary artery disease. Restenosis of the target lesion was present in only 8.9% of treated patients, a 75% reduction compared to the placebo arm. Similarly, in the 536-patient TAXUS II trial (which treated patients with somewhat shorter de novo lesions), the slow-release paclitaxel stent demonstrated a target lesion restenosis rate of only 5.5%. In all these trials, DES have been used for smaller and simpler lesions. The risk of restenosis is much higher in longer and complex lesions, and the initial data on DES is not very encouraging with higher rates of restenosis in this group of patients. Some believe DES will more than double the current number of patients undergoing stent implantation to approximately 2 million a year by 2005. If so, even a very smallsuch as 5%rate of failure will translate into a substantial absolute number of candidates for VBT, such as 100,000 per year, even in a DES era.


VBT is the standard of care for in-stent restenosis of coronary arteries. About 100,000 patients at 500 clinical centers were treated with VBT in 2002. The data for the efficacy of VBT in the peripheral arteries is pending at this time. VBT in peripheral arteries is expected to be efficacious, with anticipated FDA approval in the third quarter of 2003. Drug-eluting stents, once they are approved for use in the United States, as early as the second quarter of 2003, will probably impact the number of patients that receive VBT. However, in the next several years, the number of patients receiving VBT will increase due to the use of DES in longer and complex lesions with increased risk of failure, an estimated doubling of coronary vascular interventions over the next 3 years, and the expected approval of VBT for peripheral vessels. VBT involves a multidisciplinary approach of the interventional cardiologist/interventional radiologist, radiation oncologist, and medical physicist working closely together. The introduction and continued provision of VBT involve resource allocation and commitment from the hospital administration, interventional cardiology, interventional radiology, and radiation oncology groups. With the current reimbursement schedules, the VBT programs are viable and offer a valuable service to patients with coronary artery disease in decreasing in-stent restenosis.

Santosh Yajnik, MD, is a resident, radiation oncology, Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York.

Elizabeth Brunton, RN, is radiation oncology nurse

Prabhakar Tripuraneni, MD, is head, Division of Radiation Oncology, Scripps Clinic, La Jolla, Calif


  1. Weiderman JG, Marboe C, Schwartz A, et al. Intracoronary irradiation reduces restenosis after balloon angioplasty in a porcine model. J Am Coll Cardiol. 1994:23;1491-8
  2. Waksman R, Robinson KA, Crocker IR, et al. Endovascular low dose irradiation inhibits neointima proliferation after coronary artery balloon injury in a swine: a possible role for radiation therapy in restenosis prevention. Circulation. 1995;91:1533-9.
  3. Condado J, Gurdiel O, Espinosa R, et al. Long-term angiographic and clinical outcome following balloon angioplasty and intracoronary radiation therapy in humans [abstract]. Circulation. 1996;94(suppl I):I-209.
  4. Condado J. Basis of endovascular radiation therapy in human coronary arteries. Semin Intervent Cardiol. 1997;2:115-8.
  5. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med. 2001;344:250-6.
  6. Popma J, Heuser R, Suntharalingam M, et al for the START Investigators. Late clinical and angiographic outcomes after use of 90Sr/Y beta radiation for the treatment of in-stent restenosis. J Am Coll Cardiol. 2000;36:311-12.
  7. Waksman R, Raizner A, Chiu K, et al. Beta radiation to inhibit recurrence of in-stent restenosis: clinical and angiographic results of the multicenter, randomized double blind study. Circulation Online. 2000;102:e9046
  8. Waksman R, Bhargava B, White LR, et al. Intracoronary beta radiation therapy inhibits recurrence of in-stent restenosis. Circulation. 2000;101:1895-98.
  9. Tripuraneni P, Berger B. Summary and future of vascular brachytherapy in 2000. In: Meyer JL, ed. The Radiation Therapy of Benign Diseases: Current Indications and Techniques. Farmington, Conn: Karger; 2001;35:211-215.
  10. Task Force on CART, American Society for Therapeutic Radiology and Oncology. Role and responsibilities for radiation oncologists and various specialists involved in the delivery of coronary artery radiation therapy (CART)/coronary vascular brachytherapy (CVBT). Int J Radiat Oncol Biol Phys. In press.
  11. Waksman R, Laird JR, Jurkovitz CT, et al. Peripheral Artery Radiation Investigational Study (PARIS) Investigators. Intravascular radiation therapy after balloon angioplasty of narrowed femoropopliteal arteries to prevent restenosis: results of the PARIS feasibility clinical trial. J Vasc Interv Radiol. 2000;12:915-21.
  12. Kuntz RE, Speiser B, Joyal M, et al. Acute and midterm clinical outcomes after use of 90Sr/90Y beta radiation for the treatment of native coronary artery obstructions: acute results from the Novoste Beta-Cath System Trial. Presented at: American College of Cardiology, 49th Annual Scientific Session; March 12-16, 2000; Anaheim, Calif.
  13. Morice MC, Serruys PW, Sousa JE, et al for the RAVEL study group. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346:1773-80.
  14. Fattori R, Piva T. Drug-eluting stents in vascular intervention. Lancet. 2003;361:247-249.