Endovascular Brachytherapy for Prophylaxis against Restenosis after ...

Radiation Oncology Roswitha M. Wolfram, MD Boris Pokrajac, MD Ramazanali Ahmadi, MD Claudia Fellner, PhD Mariann Gyo ¨ ngyo ¨ si, PhD Markus Haumer, MD Robert Bucek, MD Richard Po ¨ tter, MD Erich Minar, MD

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 Published online: August 21, 2001 10.1148/radiol.2203010038 Radiology 2001; 220:724 –729 Abbreviation: PTA ⫽ percutaneous transluminal angioplasty 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, Wa¨hringer Gu¨rtel 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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RSNA, 2001

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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Endovascular Brachytherapy for Prophylaxis against Restenosis after Long-Segment Femoropopliteal Placement of Stents: Initial Results1 PURPOSE: To evaluate the feasibility, safety, and effectiveness of endovascular brachytherapy for the prevention of restenosis after long-segment femoropopliteal percutaneous transluminal angioplasty (PTA) and stent implantation. 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.

Restenosis has remained until now a major limitation to the clinical usefulness of percutaneous transluminal angioplasty (PTA), and poor long-term results, especially after the treatment of longer lesions in the femoropopliteal region, have been reported (1–3). The two primary phenomena that contribute to restenosis after successful angioplasty are chronic vessel constriction (remodeling) and neointimal hyperplasia by means of cell proliferation (4). Stents can reduce the constricting effect of vascular remodeling. However, the major drawback of stent implantation is the enhanced occurrence of neointimal proliferation within the stent, and currently available metallic stents do not substantially improve the outcome of femoropopliteal PTA (5,6). Therefore, antiproliferative strategies may be an important adjunct to the placement of stents. 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

TABLE 1 Baseline Characteristics of Patient Charts Characteristic

Findings

Diabetes Current cigarette smoker Arterial hypertension Cholesterol (mg/dL)† Low-density lipoprotein cholesterol (mg/dL)† Triglycerides (mg/dL)‡ Angina pectoris and/or prior myocardial infarction Duration of symptoms (mo) Clinical stage Claudication Pain at rest Tissue damage Lesion De novo Recurrent Stenosis Occlusion Lesion length (cm) Segment with the stent length (cm) Runoff vessels 0 or 1 patent artery 2 or 3 patent arteries Number of stents per patient 1 2 3

12* 14* 23* 224 ⫾ 54 132 ⫾ 39 223 ⫾ 232 12* 8 ⫾ 10 28* 1* 5* 25 9 23 11 12 (1–25) 17 (4–30) 17 17 20* 7* 7*

Note.—Continuous data from 34 extremities in 33 patients are presented as mean plus or minus SD. * Data are the number of patients. † To convert to millimoles per liter multiply by 0.02586. ‡ To convert to millimoles per liter multiply by 0.01129.

concerning the feasibility, safety, and possible effectiveness of endovascular brachytherapy for the prevention of restenosis after femoropopliteal placement of stents.

MATERIALS AND METHODS Patients Between October 1998 and May 1999, 161 consecutive patients who were treated in our department with PTA for femoropopliteal lesions were screened for entry into this study. To be eligible, the patients had to fulfill the following criteria: (a) minimum age of 50 years; (b) history of claudication (Rutherford stage 2 or 3) for more than 3 months (median, 8 months; range, 3– 48 months) or critical limb ischemia with pain at rest with or without tissue damage; (c) adequate inflow in the aortoiliac vessels documented at color duplex ultrasonography (US) as the primary screening examination—furthermore, the Volume 220

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lesions had to be at least 10 cm distant to the femoral bifurcation to prevent problems with anterograde recanalization; and (d) angiographically insufficient result after PTA (residual stenosis of at least 30% diameter reduction and/or severe dissection). 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. Each patient gave his or her written informed consent to participate in the study, which was approved by the ethics committee of our hospital.

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, Bu ¨ lach, 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 pharmacother-

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apy 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 ⱖ2.4) 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. 726

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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.

RESULTS The irradiation procedure was technically feasible without complications in all patients. The patients experienced no adverse events. There were no problems with sheath removal. The inflation of the centering balloons, as much as 10 minutes, during irradiation was well tolerated by all patients. The examination of the puncture site with duplex US the day after the intervention demonstrated no complications. 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. In six of seven patients with late thrombotic occlusion, intraarterial thrombolysis with urokinase in combination with abciximab was initiated successfully. The angiograms obtained after successful thrombolysis demonstrated formation of moderate neointimal hyperplasia within the stent in only one patient. Two patients had substantial stenosis at the proximal stent edge, and three patients had stenosis in the segment proximal (as much as 2 cm) to the stent. In one patient, no stenosis could be demonstrated after successful thrombolysis (Fig 3). If we consider the results obtained after local thrombolysis, only four (12%) of 33 arteries with stents (in two patients in the restenosis group and in two patients in the group with late thrombotic occlusion) had in-stent restenosis within the

Figure 1. Anteroposterior angiogram obtained in a 73-year-old man 6 months after stent implantation and endovascular brachytherapy demonstrates severe restenosis (upper arrow) at the proximal stent edge (upper arrow). The segment with the stent is between the arrows. The lower arrow points to the distal stent edge.

stent or at the proximal stent edge. In one of these four patients, the neointimal hyperplasia causing restenosis developed in a segment of the stent that had not been irradiated. For technical reasons, it was possible in this patient to irradiate only the distal 20 cm of the segment with the stent (covering a length of 27 cm). Angiography and intravascular US (Fig 2) demonstrated an excellent 6-month result, with complete lack of neointimal hyperplasia in this irradiated segment, while the proximal (nonirradiated) stent area showed severe restenosis with substantial neointimal hyperplasia. Four (19%) of 21 arteries with originally stenotic leWolfram et al

sions and six (50%) of 12 with primary occlusions developed recurrence. 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.

Intravascular US Results Intravascular US was performed in seven patients after 6 months. Intravascular US results in a patient with severe neointimal hyperplasia within the stent is demonstrated in Figure 2. In the other six patients, intravascular US demonstrated only circumscript, mostly eccentric, neointimal hyperplasia. The mean maximal thickness of the neointimal layer was 0.8 mm (range, 0.4 –1.5), and the corresponding mean percentage of stenosis within this area was 24% (range, 11%– 47%).

DISCUSSION

Figure 2. Images obtained in a 61-year-old woman 6 months after treatment of a 27-cm longdistance femoropopliteal lesion with stent implantation and endovascular brachytherapy. (a) Anteroposterior angiogram shows the segment with the stent between the solid arrows and the border (open arrow) between the distal irradiated segment, with excellent angiographic result, and the proximal nonirradiated segment with neointimal hyperplasia. (b) Anteroposterior angiogram shows the segment with the stent corresponding to the proximal part of a, a region (thin solid arrow) of severe stenosis (75%) caused by neointimal hyperplasia (see c), and a segment (double solid arrow) without neointimal hyperplasia (see d). The thick solid arrow points to the proximal stent edge and the open arrow points to the border between irradiated and nonirradiated segment. (c) Transverse intravascular US image demonstrates severe concentric neointimal hyperplasia, with a thickness of 2 mm within the stent struts (arrows; see b). (d) Transverse intravascular US image demonstrates excellent 6-month results within the irradiated segment. Stent struts are marked by arrows. Volume 220

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Results of two randomized trials (5,6) in patients with femoropopliteal lesions revealed no improvement of long-term success rate after primary stent placement, as compared with PTA alone. Vroegindeweij et al (5) reported a 12month patency rate of 62% in the group with stents versus 85% in the PTA group, and Cejna et al (6) reported a cumulative 1-year angiographic primary patency rate of 63% in both groups. Therefore, the recent recommendations by the TransAtlantic InterSociety Consensus Working Group (13) stated that femoropopliteal placement of stents as a primary approach is not indicated. The disappointing results of stent implantation are mainly due to increased neointimal cell proliferation within the stent. Since ionizing radiation has the potential to decrease formation of neointimal hyperplasia (7), this treatment has generated much recent interest for the prevention of restenosis after angioplasty and stent placement. Recent study findings (8,9,14,15) provide strong evidence supporting the use of


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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-doserate 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 longsegment 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 728

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Figure 3. Anteroposterior angiograms obtained in a 60-year-old man with sudden thrombotic occlusion (left panel) 3.5 months after stent implantation and endovascular brachytherapy (middle panel) during local thrombolysis, and (right panel) after successful local thrombolysis without residual stenosis. The segment with the stent is between the arrows.

TABLE 2 Hemodynamic Results Measurement Mean ankle-brachial-index Range Number of extremities Mean peak velocity ratio Range Number of extremities Treadmill test results† (m) Range Number of patients

Before Intervention

After 1 Day

0.61 (0.32–0.88) 34 4.49 (2.8–9.2) 23† 71 (10–234) 22‡

0.88 (0.35–1.10) 34 1.31 (1.0–1.8) 34 193 (50–700) 23‡

After 3 Months

After 6 Months

0.87 (0.25–1.29) 33* 1.43 (1.0–2.4) 33* No data No data No data

0.87 (0.23–1.10) 24* 1.64 (1.0–4.5) 24* 360 (50–700) 21‡

* Values for patients with reintervention because of recurrence are not included. † Eleven patients presented with an occlusion; therefore, the PVR could not be evaluated prior to intervention. ‡ Treadmill testing was not possible in all patients because of critical limb ischemia or orthopedic problems.

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 forma-

tion 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 occluWolfram et al

sions; 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 Volume 220

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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 highactivity 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. References 1.

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