Intravascular Brachytherapy in Lower-Extremity PAD
Is therapeutic radiotherapy a viable treatment option for PAD?
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It has been nearly 40 years since Dotter introduced percutaneous transluminal angioplasty (PTA) in 1964.1 Despite significant advances in technique and equipment, the major limitation to the endovascular treatment of peripheral arterial disease (PAD) is restenosis. This is particularly true for femoropopliteal interventions because of the extensive atherosclerotic burden in this vascular bed. The superficial femoral artery (SFA) is one of the most heavily diseased vessels in the body: occlusion is common, and there is often poor distal run-off, which creates a high-resistance, low-flow state. The reported 3- to 5-year patency rates for the endovascular treatment of femoropopliteal disease are as low as 38% to 58%.2,3
Based on the success of intracoronary brachytherapy to mitigate arterial restenosis, intravascular brachytherapy to both prevent and treat peripheral artery restenosis has been investigated.4 The first report of intravascular brachytherapy for the treatment of PAD was by Bottcher in 1994.5 Since then, several trials have demonstrated the angiographic and clinical efficacy of intravascular brachytherapy for the prevention and treatment of peripheral arterial restenosis.
TYPES OF BRACHYTHERAPY AND
MECHANISMS OF ACTION
Therapeutic radiotherapy for restenosis can be broadly classified as gamma emitters and beta emitters. Beta emitters are a result of the release of an unstable electron from the outer elemental shell.6 Both copper (Cu) 62 and strontium (Sr)/yttrium (Y) 90 are beta emitters with significantly different half-lives (Cu 62 = approx. 10 minutes, Sr/Y 90 = 28 years).6 Use of beta rays results in relatively less tissue penetration, but there is a higher dose per emission resulting in shorter dwell times.
Gamma rays are photons emitted from the nucleus. They are considered to have higher penetrating energies than beta rays, usually requiring greater shielding. Examples of gamma emitters are iridium (Ir) 192, iodine (I) 125, and palladium (Pd) 103. I 125 and Pd 103 are not pure gamma emitters; they also release x-rays. Furthermore, I 125 and Pd 103 have relatively low energy levels, which necessitate longer intra-arterial dwell times.6 Gamma radiation may be better suited for peripheral brachytherapy because it has less dose falloff than beta radiation; for smaller peripheral arteries, either gamma or beta irradiation is likely suitable.7
Absorption of radiation has several consequences at the cellular level. Radiation results in damage by directly ionizing essential components of cellular regulation or free radical production with subsequent molecular damage.7 Rapidly dividing cells are at the greatest risk of suffering from the effects of brachytherapy, particularly during the G2 and mitosis phases of the cell cycle.7 The targets of radiotherapy include vascular-associated monocytes and macrophages, and indeed some evidence suggests that adventitial cells are also targeted.6,7 The dosage range for vascular brachytherapy is 12 to 21 Gy.7
Treated lesions can be irradiated using multiple methods. External beam radiation has not been found to be particularly useful for deeper vessels, but it may have a limited role in the anastomosis site of arteriovenous fistulas for dialysis access.3,6,7 Typically, brachytherapy is delivered intravascularly through specially designed catheters. Catheters that allow for centering within the vessel lumen provide more uniform and predictable irradiation of the angioplastied vessel. Efforts have been made to design radioactive balloons and stents. The trials with radioactive stents have largely failed because of problems with dosimetry and frequent recurrences at the edges of the stent, creating the commonly referred to “candy-wrapper” effect.3,6,7
CLINICAL TRIALS OF PERIPHERAL BRACHYTHERAPY
Since Bottcher reported the use of intravascular brachytherapy for peripheral arterial disease in 1994, there have been several trials examining the utility of brachytherapy for the treatment of lower extremity PAD.2,5,8-11 Some of these were early pilot studies; however, several randomized clinical trials have been completed (Vienna-2, PARIS).12 Furthermore, there are several ongoing trials examining the utility of peripheral brachytherapy. Each of these trials has differed somewhat with regard to the inclusion criteria, radiation dosimetry, and use of centering devices (Table 1). The majority of trials excluded lesions that required stenting at the time of brachytherapy, but some evaluated the role of brachytherapy in stenting, as well as for in-stent restenosis.8,11
BRACHYTHERAPY FOR DE NOVO LESIONS AND RESTENOTIC LESIONS AFTER PTA
Based on the promising results of the pilot Vienna-1 study, the role of femoropopliteal brachytherapy for the treatment of de novo lesions and recurrent lesions after PTA was established with the Vienna-2 trial.5,12 The Vienna-2 study recruited 117 patients and randomized 113 patients (one refused brachytherapy, and three had early recurrence within 24 hours). Inclusion criteria for the study were claudication or critical limb ischemia, de novo stenosis or occlusion of > 5 cm in length, restenosis after previous PTA (regardless of length), and absence of stent implantation. Ir 192 was delivered to the lesion through a noncentered, closed-end catheter using a remote high dose rate afterloading system at a dose of 12 Gy to a depth of 3 mm from the source.12 Safety margins of 10 mm were added to the clinical target length to ensure adequate lesion irradiation.
One hundred seven patients were available for 6-month follow-up. Restenosis was observed in 54% of the PTA-alone group and 28% of the PTA and brachytherapy group. At 1 year, the restenosis rate in the PTA-alone group was 61% and 36% in the PTA and brachytherapy group. Subgroup analysis confirmed the beneficial effects of brachytherapy. In restenotic lesions after previous PTA, brachytherapy reduced the restenosis rate from 61% to 33%. The restenosis rate for occluded lesions was 76% after PTA and 37% after PTA with brachytherapy. Similarly, lesions greater than 10 cm had a reduction in restenosis from 72% (PTA alone) to 38% (PTA with brachytherapy). Although lesions in diabetics showed benefit with brachytherapy, the results were not as significant (57% vs 46%, respectively).
Similar to the Vienna-2 study, PARIS (Peripheral Arterial Radiation Investigational Study) evaluated the efficacy of Ir 192 for the prevention of restenosis after PTA. Lesion selection included SFA stenosis length between 5 cm and 15 cm, occlusion length up to 5 cm, and vessel diameter between 4 mm and 8 mm. Using an afterloader system, 14 Gy was delivered into the vessel wall using a target depth of half the reference diameter plus 2 mm. As in the Vienna-2 trial, 10-mm safety margins were employed. Unlike the Vienna-2 trial, however, the PARIS trial employed a centering catheter for more uniform and predictable irradiation (Figure 1). Rest and exercise ankle-brachial index (ABI) and Rutherford class were measured at 1, 6, and 12 months; angiographic follow-up was done at 6 months.10 Results of the preliminary study demonstrated an increase in rest and exercise ABI at 1 year (0.67 and 0.51 to 0.89 and 0.72, respectively). Maximum treadmill-walking time increased from 3.4 minutes to 4.4 minutes at 30 days, and 4 minutes at 1 year. Follow-up angiography on 30 patients revealed a lesion restenosis rate of 10% (segment, 11.5%). Adverse outcomes were rare, with no dissections and one aneurysm formation.
Based on the favorable results of the PARIS feasibility study, a randomized, double-blind, placebo-controlled trial of brachytherapy in the treatment of femoropopliteal occlusive disease was undertaken. The randomized portion of this trial was terminated early because of slow enrollment (only 200 patients were randomized). A preliminary analysis of the data from the randomized trial was recently presented at the 2003 American College of Cardiology annual scientific sessions in Chicago. The clinical results and restenosis rates were essentially equivalent between the radiation and control groups in this study (oral communication, Waksman R, ACC 2003). Interpretation of the study results was hampered by incomplete follow-up, with availability of follow-up angiograms in less than half of the patients in each group. Of note, the restenosis rate in the control group was lower than expected (28%), likely obscuring any potential benefit of the radiation.
BRACHYTHERAPY FOR IN-STENT RESTENOSIS
In recent years, infrainguinal stenting has been reserved for inadequate PTA results because of the high rate of in-stent restenosis. Restenosis rates are particularly high when stents are employed for the treatment of long segment disease (Figure 2). Subsequent reintervention on these restenosed stents is problematic, with high recurrence rates. In a landmark study by Liermann et al,8 patients with recurrent restenosis or reocclusion within femoral stents were treated with brachytherapy after successful repeat PTA. Forty patients underwent brachytherapy with an Ir 192 afterloading source at a surface dose of 12 Gy. The follow-up ranged from 4 months to 7.5 years. There was no clinical deterioration or restenosis in 82.5% of the patients. The brachytherapy was found to be safe with no late complications attributable to the radiation. The brachytherapy procedure added approximately 45 minutes to the procedure (primarily accounted for by transport time to the afterloading room).8 The encouraging results from this trial were a harbinger of future successes with brachytherapy for the treatment of coronary in-stent restenosis.
NEW STENT IMPLANTATION AT TIME OF BRACHYTHERAPY
Brachytherapy delays and limits the endothelialization process when applied to the coronary circulation and has been associated with an increased risk of late stent thrombosis. This has been ameliorated by the prolonged use of potent antiplatelet therapy after the brachytherapy procedure. The safety and efficacy of peripheral arterial stenting at the time of brachytherapy has been evaluated in the Vienna-4 study.11 Thirty-three patients with symptomatic femoropopliteal occlusive arterial disease underwent stenting with self-expanding stents (Easy Wallstent, Boston Scientific Corporation, Natick, MA) after inadequate PTA (residual stenosis > 30% or severe dissection). The stent, plus 1-cm safety margins, were irradiated with a centered Ir 192 afterloading source at 14 Gy.11 Restenosis or reocclusion was observed in 10 (30%) of treated arteries. Seven of these recurrences were late thrombotic occlusions presenting at 3.5 to 6 months (six of these were successfully thrombolysed) and three patients had restenosis (one at the proximal stent margin, one in the proximal stent, and one 2 cm from the proximal stent edge).11 Patients were treated with acetylsalicylic acid 100 mg for 2 weeks prior to the procedure and long-term thereafter; furthermore, clopidogrel 75 mg was used for 1 month after a loading dose of 300 mg immediately prior to the implantation of the stent. Similar results were found in the study by Bonvini: late acute thrombotic occlusion occurred exclusively in stented femoropopliteal segments receiving brachytherapy, concomitant with the discontinuation of clopidogrel.13 The results of these two studies mirror the coronary experience and highlight the need for more prolonged postprocedure treatment with clopidogrel. The thrombotic risk may be heightened in patients with poor distal runoff, and in these patients in whom a stent is implanted at the time of brachytherapy, long-term dual antiplatelet therapy (eg, aspirin and clopidogrel for at least 12 months) is mandatory.
OTHER PERIPHERAL ARTERIAL APPLICATIONS OF BRACHYTHERAPY
The use of brachytherapy for other peripheral arterial locations has been examined. Experimental reports of brachytherapy for the treatment of carotid artery disease have been evaluated, although there must be judicious restraint and case selection to avoid nerve injury and late thrombosis. Both external beam radiation and brachytherapy have been used for hemodialysis shunts with encouraging results. Also, the high restenosis rate associated with transjugular intrahepatic portosystemic shunts makes brachytherapy an appealing treatment or preventive strategy. Other areas of investigation include renal artery in-stent restenosis and venous disease.6
Although effective for the prevention of restenosis after PTA and for the treatment of in-stent restenosis, gamma radiation is logistically difficult to perform. The high-activity, Ir 192 source (usually in the 10-Ci range) that is required to treat long lesions in larger peripheral arteries cannot be safely used in the catheterization lab or endovascular suite. It is a requirement that patients be transported to the radiation oncology suite for this treatment where adequate shielding is available. In many hospitals, this is not practical or feasible. For this reason, beta radiation would be a more desirable alternative if it were shown to be effective. Although several trials have demonstrated efficacy for beta radiation in the coronary arteries, there is limited experience with beta radiation in the peripheral arteries. Novoste Corporation (Atlanta, GA) has initiated the MOBILE trial to test the efficacy of beta radiation for the treatment of SFA in-stent restenosis. This trial will randomize patients with SFA in-stent restenosis to PTA versus PTA followed by brachytherapy using the Corona system (Novoste Corporation) (Figure 3). The study design will allow treatment of lesions up to 30 cm using multiple steps with the 6-cm-long source.
Intravascular brachytherapy for the prevention or treatment of restenosis has demonstrated encouraging results, especially for femoropopliteal arterial disease. The restenosis rate after PTA is approximately halved with the use of brachytherapy, providing durable long-term results. Furthermore, brachytherapy is effective for in-stent restenosis. At the appropriate dose, the complication rate of intravascular radiation (such as aneurysm formation or damage to surrounding neurovascular tissue) is low. The presence of “edge-effect” or “candy-wrapper” effect suggests that adequate safety margins are necessary to prevent stimulation of neointimal formation in balloon-injured, but not adequately irradiated, segments. If new stents are implanted at the time of brachytherapy, long-term dual antiplatelet therapy is recommended to prevent late stent thrombosis. Ongoing clinical trials such as MOBILE and BRAVO will provide additional evidence of the safety and efficacy of intravascular brachytherapy, as will the final publication of the PARIS trial.
Robert S. Dieter, MD, is a cardiovascular medicine interventional fellow at the University of Wisconsin, in Madison, Wisconsin. He holds no financial interest in any product or manufacturer mentioned herein. Dr. Dieter may be reached at (608) 262-2122; email@example.com.
John R. Laird, Jr, MD, is the Director of Peripheral Vascular Interventions at the Cardiovascular Research Institute, Washington Hospital Center, Washington, DC. He holds no financial interest in any product or manufacturer mentioned herein. Dr. Laird may be reached at (202) 877-5975; John.R.Laird@Medstar.net.
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