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Radiation Oncology |
1 From the Departments of Angiology (R.M.W., R.A., M.H., R.B., E.M.), Radiotherapy and Radiobiology (B.P., C.F., R.P.), and Cardiology (M.G.), University of Vienna General Hospital, Währinger Gürtel 18-20, A-1097 Vienna, Austria. Received November 28, 2000; revision requested January 11, 2001; revision received March 19; accepted April 9. Address correspondence to E.M. (e-mail: erich.minar@akh-wien.ac.at).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Thirty-three patients (23 men, 10 women; mean age, 66 years) with femoropopliteal lesions (mean treated length, 17 cm; range, 4–30 cm) underwent PTA and stent implantation followed by brachytherapy with a centering catheter. A dose of 14 Gy was delivered to the adventitia by using an iridium 192 source. Long-term pharmacotherapy with acetylsalicylic acid was combined with clopidogrel for 1 month. Follow-up examinations included measurement of the ankle-brachial index, color-coded duplex ultrasonography, and angiography.
RESULTS: The overall 6-month recurrence rate was 30% (10 of 33 arteries). Seven patients developed sudden late thrombotic occlusion of the segment with the stent 3.5–6 months after stent implantation. Considering the overall results after successful local thrombolysis in six of these seven patients, only four (12%) of 33 arteries with a stent had in-stent restenosis caused by neointimal hyperplasia.
CONCLUSION: The study results are promising concerning the possibility of reducing in-stent restenosis by means of brachytherapy after long-segment femoropopliteal placement of stents. The high incidence of late thrombotic occlusion requires optimization of the antithrombotic regimen.
Index terms: Arteries, stenosis or obstruction, 92.72 • Arteries, transluminal angioplasty, 92.1286 • Iridium, radioactive • Stents and prostheses, 92.1286 • Stents and prostheses, radiation, 92.1286
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Authors of recent studies have focused on intravascular radiation as a new treatment option for restenosis. Ionizing radiation has been shown to decrease neointimal formation within stents in animal models (7) and in initial clinical trials within the coronary circulation (8). Furthermore, intracoronary gamma radiation used as adjunct therapy for patients with in-stent restenosis substantially reduced both angiographic and clinical restenosis (9). Recently, we (10) demonstrated the effectiveness of endovascular brachytherapy for prophylaxis against restenosis after femoropopliteal PTA without stents. The 1-year patency rate was 63% in the brachytherapy group versus 35% in the control group (10).
We performed this study because, to our knowledge, there are currently no clinical data concerning the feasibility, safety, and possible effectiveness of endovascular brachytherapy for the prevention of restenosis after femoropopliteal placement of stents.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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According to these criteria, 33 patients (in one patient both extremities were treated) were included in this prospective pilot study. The baseline characteristics of the 33 patients (23 men, 10 women; mean age, 66 years; age range, 48–91 years) with presenting symptoms, associated diseases and risk factors, and lesion characteristics are listed in Table 1. The mean length of the arterial segment treated with angioplasty and stents was longer than the mean lesion length that was used to determine indication for PTA (Table 1), since angioplasty and placement of stents also included segments with moderate stenoses in the adjacent proximal and distal region.
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Angioplasty and Brachytherapy Procedures
An ipsilateral anterograde puncture and a 6-F introducer sheath (Cordis Europe, Roden, the Netherlands) were used in all procedures. Angioplasty was performed with 5- or 6-mm balloon catheters (Smash; Schneider Europe, Bülach, Switzerland). The degree of residual stenosis immediately after PTA or the degree of recurrent stenosis in cases of follow-up arteriography was determined by comparing the width of the vessel filled with contrast medium (the measurements were made with a ruler) at the point of maximal diameter reduction within the treated segment to that of an unaffected arterial segment immediately proximal to the dilated segment.
The region in which angioplasty was performed was marked with a radiopaque ruler, and movement of the table and angiographic unit was avoided to prevent parallax error. Because of angiographically insufficient results, angioplasty was then followed by the implantation of self-expanding stents (Easy Wallstent; Boston Scientific, Natick, Mass). The number of implanted stents (diameter range, 5–7 mm; length range, 3–10 cm) is given in Table 1. After further dilation with the balloon diameter corresponding to the diameter of the artery, the 6-F sheath was replaced by an 8-F sheath (Super Arrow Flex; Arrow International, Reading, Pa) to allow introduction of the 7-F centering catheter (Paris; Nucletron, Veenendaal, the Netherlands). This catheter was advanced until its tip was 15 mm distal to the segment with the stent. Then the sheath and the catheter were fixed to the patient to prevent movement relative to the lesion during the transportation to the brachytherapy unit. The actual position of the centering catheter in relation to the distal end of the stent was verified by means of radiography before starting brachytherapy.
Brachytherapy was performed by using a remote afterloading device with a high dose rate, as it is used in brachytherapy in general (microSelectron; Nucletron). Treatment was planned with a computer-assisted standard dose calculation planning system (PLATO-BPS, version 13.2; Nucletron). A dose of 14 Gy was prescribed at 2 mm beyond the average luminal radius (ie, vessel radius + 2 mm) according to the recent recommendations of the American Association of Physicists in Medicine Task Group 60 (11).
The target for radiation was the total length of the artery with stents, measured with the radiopaque ruler fixed to the leg of the patient over the segment with the stent, with the addition of 10 mm on each end to prevent possible underdosing at the stent edge. Before starting endovascular irradiation with the iridium 192 (192Ir) source, the balloons of the centering catheter were inflated to a pressure of 4 atm to allow centering of the source. Then the closed lumen catheter was connected to the afterloader. An 192Ir source with a diameter of 1.1 mm and a mean activity of 200 GBq (range, 150–366 GBq) was delivered. The mean overall treatment time was 412 seconds (range, 253–604 seconds). After irradiation, the centering catheter and sheath were removed immediately, and the puncture site was manually compressed for about 20 minutes. The patients were asked to report any complaints during the entire brachytherapy procedure. Furthermore, any problems with source application were recorded. In all patients, the puncture site was evaluated with duplex US the day after the procedure.
Peri- and Postinterventional Pharmacotherapy
After successful passage of the guide wire through the lesion, 5,000 IU of standard heparin (Liquemin; Hoffmann-La Roche, Basel, Switzerland) was administered through the sheath. Further continuous administration of heparin at a dose of 1,000 IU/h was started before the patients were transferred to the brachytherapy unit and was continued until the next morning. Long-term pharmacotherapy with acetylsalicylic acid (100 mg/day initiated at least 2 weeks prior to the intervention) was combined with 75 mg of clopidogrel (Plavix; Sanofi, Paris, France) per day for 1 month—a dose of 300 mg was started in the catheter laboratory immediately before stent implantation.
Follow-up
Follow-up examinations included clinical follow-up at 1, 3, and 6 months by a trained vascular specialist and noninvasive laboratory testing after 3 and 6 months performed by trained technicians, including ankle-brachial arterial pressure measurement with Doppler US to calculate the ankle-brachial pressure index and treadmill testing when possible. Treadmill testing was performed with a constant-workload protocol by using a constant speed (3.2 km/h) and grade (12° inclination angle). In patients without clinical symptoms, treadmill testing was ended after 700 m. Color duplex US with a 5-MHz linear-array color probe (XP10; Acuson, Mountain View, Calif) of the femoropopliteal segment was also performed.
The peak velocity ratio was calculated as the ratio of the maximum peak systolic velocity in the dilated region compared with the peak systolic velocity in the preceding normal arterial segment. A focal increase in the peak systolic velocity of at least 140% (corresponding to a peak velocity ratio of 
2.4) was considered indicative of a stenosis greater than 50% at that site (12). If recurrent stenosis was suspected on the basis of clinical or laboratory findings (deterioration of the ankle-brachial pressure index by at least 0.15 from the maximum postprocedural level, a peak velocity ratio in the treated segment of at least 2.4, or both), intraarterial angiography was performed with eventual further PTA.
Because of the high sensitivity of color duplex US for the detection of a stenosis greater than 50%, angiographic evaluation was not mandatory in cases of normal hemodynamic results, but, with patient consent, angiography was performed after 6 months in patients not suspected of having restenosis. In selected cases, angiography was combined with intravascular US. The intravascular US studies were analyzed by considering the maximal thickness of the neointimal layer within the stent and the stent edges and the corresponding maximal percentage of area stenosis caused by neointimal hyperplasia tissue. Formation of neointimal hyperplasia was also evaluated on the angiograms.
Primary Patency
The primary end point of this pilot study was the anatomic patency of the treated vessel after 6 months. Restenosis was defined as an angiographically verified stenosis of greater than 50% narrowing of the lumen diameter, as compared with the diameter of normal segments of the vessel on the follow-up angiogram.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Follow-up information obtained after 6 months by means of clinical examination and noninvasive laboratory testing (measurement of ankle-brachial pressure index and duplex US) was obtained in 32 patients (33 extremities). No patient was lost to follow-up; one patient died of acute myocardial infarction after 2 months. At 6 months, angiography was performed in 24 patients (75%).
Patency at 6 Months
The overall recurrence rate was 30% (10 of 33 arteries). Seven patients presented with sudden thrombotic occlusion of the segment with the stent 3.5–6 months after intervention, and another three patients had restenosis: one at the proximal stent edge (Fig 1), one within the proximal part of the stent (Fig 2), and one about 2 cm from the proximal stent edge.
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Six of 10 patients with recurrence had a poor runoff (one or no patent lower leg artery) during primary intervention. All three patients with no patent lower leg artery developed sudden thrombotic occlusion.
Hemodynamic Results
The ankle-brachial pressure index, peak velocity ratio, and treadmill test results are given in Table 2. With treadmill testing, the maximum walking distance was evaluated. A limited walking distance was caused by claudication in only three patients. In our setting, treadmill testing was ended after 700 m in patients without clinical symptoms.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Recent study findings (8,9,14,15) provide strong evidence supporting the use of gamma and beta radiation in the treatment of coronary in-stent restenosis. Compared with the number of coronary circulation studies, there is a limited number of studies (10,16,17) with clinical data concerning the use of brachytherapy in the peripheral circulation. Recently, we demonstrated in a randomized study (10) the effectiveness of endovascular brachytherapy for prophylaxis against restenosis after femoropopliteal PTA without stents. Boettcher et al (16) have presented data that showed that endovascular irradiation is both feasible and safe in humans. This group, using the same high-dose-rate afterloading technique with an 192Ir source as we did, used endovascular brachytherapy to prevent intimal hyperplasia in the femoropopliteal segment. Unlike in our study, they used postangioplasty irradiation without a centering device only in segments with in-stent restenosis and shorter lesion lengths of 4.5–14 cm (mean, 6.7 cm).
Our study group consisted of patients with a particular risk of restenosis especially due to the mean treated lesion length of 17 cm. Gray et al (18), studying a comparable patient group with femoropopliteal stents and a mean treated lesion length of 16 cm, reported a high incidence of recurrence, with a 6-month patency rate of 47% and a 12-month patency rate of only 22%. The 6-month patency rate in our study was 70% (23 of 33 arteries). However, considering the overall results after successful local thrombolysis in six of seven patients with sudden late thrombotic occlusion, only four (12%) of 33 of the arteries with stents had in-stent restenosis due to neointimal hyperplasia. Our results support the effectiveness of irradiation for the prevention of in-stent restenosis after long-segment femoropopliteal placement of stents. Figure 2 demonstrates an impressive example for the effectiveness of irradiation in suppressing formation of neointimal hyperplasia.
Sudden late thrombotic occlusion of the segment with the stent was observed in seven (21%) of 33 arteries at 3.5–6 months after intervention. In a recent article, Costa et al (19) reported a relatively high incidence (6.6%) of sudden thrombotic events 2–15 months after percutaneous transluminal coronary angioplasty followed by intracoronary beta radiation. These late thrombosis rates appeared to be higher in patients treated with stents and irradiation (8.8%) than in patients treated with balloons and irradiation (3.2%). The Washington Radiation for In-Stent Restenosis Trial (9) reported a 7% late thrombosis rate. Further analyses suggested that patients treated with gamma irradiation for in-stent restenosis have an increased risk of late thrombosis when a new stent is deployed, as compared with those who undergo treatment without stents (20).
Waksman (21) discussed in an editorial some evidence that thrombosis and not neointimal hyperplasia is probably the major cause of these late stent occlusions. Our data provide further evidence for this mechanism, since the angiograms obtained after successful thrombolysis in six patients demonstrated moderate formation of neointima within the stent in only one patient, and two patients had substantial stenosis at the proximal stent edge.
The increased rate of late thrombotic occlusions seems to be due to delayed re-endothelialization in balloon-injured irradiated vessels with stents. The antithrombotic regimen used in our study, clopidogrel (75 mg/day) in combination with acetylsalicylic acid (100 mg/day) for 1 month, followed by long-term treatment with acetylsalicylic acid alone, was not sufficient to prevent late thrombotic occlusions; therefore, optimization of the antithrombotic regimen was indicated. This is also stressed by the recently published results (14) of a large multicenter trial that used brachytherapy for the treatment of coronary in-stent restenosis. In that trial, late thrombosis was observed only after discontinuation of antiplatelet therapy with ticlopidine or clopidogrel. We have since modified our regimen by prolonging pharmacotherapy with clopidogrel instead of acetylsalicylic acid for at least 12 months. However, it is not yet currently known if this extended therapy will mitigate or solve the problem of late stent thrombosis after irradiation.
Three of six patients with thrombotic stent occlusion had substantial stenosis in the arterial segment proximal to the stent, as demonstrated after successful thrombolysis, and all three patients with no patent lower leg artery during the primary intervention developed sudden stent occlusion. Therefore, optimization of the arterial inflow and runoff also seems necessary to prevent thrombotic stent occlusion. We recommend early reintervention in cases of recently developed stenosis proximal and/or distal to the stent, and we now avoid femoropopliteal placement of stents and irradiation in patients with poor runoff.
The brachytherapy protocol used in this study—a dose of 14 Gy prescribed at 2 mm beyond the average luminal radius with the intention to be delivered to the adventitia—is in accordance with the recommendations of a task group of the American Association of Physicists in Medicine (11) for peripheral brachytherapy. The problem of dose inhomogeneity due to an eccentric catheter position within the lumen—one of the main problems in many former brachytherapy trials—was prevented in our study by the use of a centering catheter. Although source centering for gamma emitters such as 192Ir is not as critical as it is for beta emitters (22), the use of a source centering system may further improve the overall therapeutic ratio by reducing restenosis rates without a corresponding increase in toxicity. However, even if the source is perfectly centered, dose asymmetries will continue to result from eccentrically located plaques or where the target length incorporates a substantial angulation or curvature.
The length of the artery to be irradiated in our study corresponded to the total length of the segment with the stent, with an additional 1 cm at each end, which was chosen as a safety margin to prevent an edge effect. Despite this safety margin, we observed stenosis at the proximal stent edge in three patients. Otherwise, there were no problems at the distal stent edge. This may be explained by some geographic miss in radiation delivery within the proximal segment with the stent. Because of the length (mean, 17 cm) of the segment with the stent, the exact measurement of this length—which was performed with a radiopaque ruler fixed to the skin over the segment with the stent—may be difficult, and eventual inaccuracies could lead to the underestimation of the calculated target length for irradiation in the proximal segment. Otherwise, exact placement of the centering catheter distal to the segment with the stent allows accurate dosimetry within this segment. In ongoing studies, we are avoiding this problem by exactly measuring the length of the segment with the stent by using a guide wire with markers at 1.0-cm intervals.
In the 6-month follow-up, four patients developed new lesions in the target vessel about 1–2 cm proximal to the segment that contained the stent and that was formerly dilated. However, we cannot definitely exclude mechanical trauma such as balloon injury to these areas during the intervention.
A limitation of the brachytherapy approach used in our study is that it cannot be performed in the normal interventional radiology suite owing to the special shielding requirements for such high-activity sources. However, transportation of patients to the brachytherapy unit can be performed without problems after peripheral interventions.
In summary, our data from endovascular brachytherapy, in which a centering device was used after long-segment femoropopliteal placement of stents, are promising concerning the prevention of in-stent restenosis by suppressing formation of neointimal hyperplasia. Subsequently, we have started a randomized trial to further determine the value of this approach.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, R.M.W., R.P., E.M.; study concepts, R.P., E.M.; study design, R.M.W., B.P., R.P., E.M.; literature research, R.M.W.; clinical studies, R.M.W., B.P., R.A., M.H., E.M.; data acquisition, R.M.W., R.A., M.H.; data analysis/interpretation, R.M.W., R.A., C.F., M.G., M.H., R.B.; statistical analysis, R.M.W.; manuscript preparation, R.M.W., B.P., E.M.; manuscript definition of intellectual content, all authors; manuscript editing, R.M.W.; manuscript revision/review, B.P., R.P., E.M.; and final version approval, all authors.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  T. Zeller Current state of endovascular treatment of femoro-popliteal artery disease Vascular Medicine, August 1, 2007; 12(3): 223 - 234. [Abstract] [PDF]
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 R. M. Wolfram, A. C. Budinsky, B. Pokrajac, R. Potter, and E. Minar Endovascular Brachytherapy for Prophylaxis of Restenosis after Femoropopliteal Angioplasty: Five-year Follow-up--Prospective Randomized Study Radiology, September 1, 2006; 240(3): 878 - 884. [Abstract] [Full Text] [PDF]
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R. M. Wolfram, A. C. Budinsky, B. Pokrajac, R. Potter, and E. Minar Vascular Brachytherapy with 192Ir after Femoropopliteal Stent Implantation in High-Risk Patients: Twelve-month Follow-up Results from the Vienna-5 Trial Radiology, July 1, 2005; 236(1): 343 - 351. [Abstract] [Full Text] [PDF]
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M. Schillinger, W. Mlekusch, R. M. Wolfram, A. C. Budinsky, M. Exner, H. Rumpold, O. Wagner, B. Pokrajac, R. Potter, and E. Minar Endovascular Brachytherapy: Effect on Acute Inflammatory Response after Percutaneous Femoropopliteal Arterial Interventions Radiology, February 1, 2004; 230(2): 556 - 560. [Abstract] [Full Text] [PDF]
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