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Published online before print June 21, 2002, 10.1148/radiol.2242010882
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(Radiology 2002;224:519-528.)
© RSNA, 2002

Vascular and Interventional Radiology

Endovascular Gamma Irradiation of Femoropopliteal de Novo Stenoses Immediately after PTA: Interim Results of Prospective Randomized Controlled Trial1

Karsten Krueger, MD, Peter Landwehr, MD, Mark Bendel, MD, Monika Nolte, PhD, Hartmut Stuetzer, MD, Rudolf Bongartz, MD, Markus Zaehringer, MD, Guido Winnekendonk, MD, Axel Gossmann, MD, Rolf-Peter Mueller, MD and Klaus Lackner, MD

1 From the Departments of Radiology (K.K., P.L., M.Z., G.W., A.G., K.L.), Radiooncology (M.B., M.N., R.B., R.P.M.), and the Institute for Medical Statistics, Informatics and Epidemiology (H.S.), University of Cologne, Joseph-Stelzmann-Strasse, D-50924 Cologne, Germany. From the 2001 RSNA scientific assembly. Received May 4, 2001; revision requested June 28; revision received October 9; accepted December 10. Supported by grant 1/98 from Cologne Fortune, a research program of the University of Cologne. Address correspondence to K.K. (e-mail: karsten.krueger@uni-koeln.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To report an interim analysis of whether centered endovascular irradiation with the iridium 192 (192Ir) source immediately after percutaneous transluminal angioplasty (PTA) of de novo femoropopliteal stenoses lowers the restenosis rate.

MATERIALS AND METHODS: Thirty patients undergoing PTA to treat femoropopliteal stenoses were randomized for prophylaxis against restenosis with centered endovascular irradiation with a 192Ir source (a dose of 14 Gy 2 mm deep to the vessel wall, irradiation group) or no irradiation (control group). Angiographic follow-up was available for 22 patients at 6 months (irradiation group, n = 10) and 12 patients at 12 months (irradiation group, n = 6). Duplex sonography, treadmill testing, and interviews were performed the day before and the day after PTA and after 1, 3, 6, 9, and 12 months. Results of angiography, duplex sonography, treadmill testing, and interviews were evaluated with a t test and multivariate analysis of variance (clinical characteristics, {chi}2 test).

RESULTS: Baseline characteristics were comparable in the two groups. Interim analysis of the 6-month follow-up data revealed a trend toward a significantly lower restenosis rate in the irradiation group. The change in the degree of stenosis compared with that after PTA was -14.7% ± 20.8 (mean ± SD) in the irradiation group versus 37.7% ± 27.3 in the control group (P = .001) and became even more marked at 12 months (-9.5% ± 34.5 vs 45.5% ± 40.7 [P = .03], respectively). The follow-up results of treadmill testing and interviews showed a nonsignificant benefit for the irradiation group. One thromboembolic complication occurred during irradiation. No side effects were observed during follow-up.

CONCLUSION: Endovascular irradiation with a centered 192Ir source immediately after PTA of de novo femoropopliteal stenoses reduces the restenosis rate.

© RSNA, 2002

Index terms: Arteries, radiation • Arteries, restenosis, 92.44 • Arteries, stenosis or obstruction, 92.72, 92.721 • Arteries, transluminal angioplasty, 92.1281, 92.1286, 92.454 • Iridium, radioactive


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Percutaneous transluminal angioplasty (PTA) is one of the standard treatments for femoropopliteal stenoses (1). However, this treatment is limited because of poor long-term outcome attributable to the known high rate of restenosis (2,3). The incidence of restenosis varies between 20% and 70% (4–7), depending on the length, degree, and morphology of the stenotic lesions and the patency of runoff vessels (2). The clinical and economic effect of restenosis is great, because many patients require an invasive reintervention.

Today, it is believed that two main components contribute to the development of restenosis. First, intimal hyperplasia is caused by proliferation of smooth muscle cells and matrix formation (8–11). Second, negative remodeling leads to constriction of the entire vessel (12).

In recent years, a variety of medical therapies have been implemented in an attempt to lower the restenosis rate, all with only limited success (3,13–21). Catheter-based endovascular irradiation (brachytherapy) has shown promising results in animal experiments and clinical studies by reducing restenosis in coronary arteries after stent application or PTA (22–29). The use of endoluminal irradiation for femoropopliteal arteries is currently under investigation. Initial data from clinical studies (30–32) have demonstrated that irradiation therapy can help prevent restenosis.

However, limited data are available thus far on the effectiveness of brachytherapy in preventing restenosis after the treatment of de novo stenoses. The majority of clinical studies were performed with recurrent in-stent stenoses in coronary arteries. We designed a prospective randomized controlled trial to determine whether centered endovascular irradiation with the iridium 192 (192Ir) source given immediately after PTA of de novo femoropopliteal stenoses can reduce the rate of restenosis. We report the results of an interim analysis.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The trial was approved by the institutional review board. Informed consent was obtained from each patient before enrollment in the study.

Patients
According to the study protocol, 40 patients aged 50 years or older with arterial occlusive disease stage 2a–3, on the basis of Fontaine classification, and de novo femoropopliteal stenosis were to be enrolled in the study. The maximum length of the stenosis was 8 cm (occlusion maximum, 5 cm). Patients with untreated stenoses proximal to the region of PTA or with less than one runoff vessel were excluded. PTA was the only endovascular treatment allowed. Patients with malignant diseases were excluded.

Randomization
A program (Ranlist, Macintosh version 1.0; Department of Biomathematics, M. D. Anderson Cancer Center, University of Texas, Houston) was used to generate a restricted randomization schedule with fixed block length between balance points. Sealed envelopes were used. Patients were blinded to randomization. Randomization of patients to the group with centered endovascular irradiation (irradiation group) or that without endovascular irradiation (control group) was performed after successful PTA and placement of the centering catheter.

Primary and Secondary Outcome Measures
According to protocol, the specified primary outcome measure was the individual change in the angiographically defined degree of stenosis, that is, intraindividual differences between 6- and 12-month follow-up and immediately following PTA.

Secondary outcome measures included absolute degree of stenosis; contrast material opacity in the stenosis at 6- and 12-month angiographic follow-up; and results of structured interviews, color duplex sonography, and treadmill testing.

Periinterventional Pharmacotherapy
All patients were given aspirin (100 mg) and low-dose heparin (Hoffmann-La Roche, Grenzbach-Wyhlen, Germany; 7,500 IU) administered subcutaneously 1 day before PTA. During intervention, an intravenous bolus of 5,000–7,500 IU of heparin was administered. Partial thrombin time was measured with a bedside test (CoaguChek Plus coagulation monitor; Boehringer Mannheim, Mannheim, Germany) before the patients were transported to and after returning from the department of radiooncology. Subcutaneous administration of heparin (7,500 IU twice a day) was continued for 24 hours after intervention. Aspirin (100 mg daily) was continued indefinitely. One patient in the irradiation group with aspirin intolerance received clopidogrel (Plavix; Sanofi-Synthelabo, Berlin, Germany) instead.

Intervention
After digital subtraction angiography (Multistar Top; Siemens Medical Systems, Erlangen, Germany) of the lower extremity, balloon dilation was performed (P.L., K.K., K.L.) according to conventional practice. The approach—ipsilateral or crossover femoral—was dictated by the vascular anatomy of the aortic bifurcation and the tortuosity of the iliac vessels. The crossover approach was performed with a flexible 8-F crossover sheath (Arrow International, Reading, Pa). A short 8-F sheath (Angiomed; Medizintechnik, Karlsruhe, Germany) was used for the antegrade ipsilateral technique. The balloon diameter (Sailor PTA catheter; Invatec, Concesio Brescia, Italy) was between 5 and 6 mm, depending on the vessel diameter proximal to the stenosis. The length of the balloon (1.5–8.0 cm) overlapped the length of stenosis as little as possible. The location of the balloon during PTA and the balloon inflation pressure were documented. Dilation lasted exactly 1 minute. Overdilation was avoided. If the result of the first dilation was not satisfactory, 1-minute dilations were repeated until less than 30% diameter reduction was successful. Morphology of the stenosis was registered. Optimal spatial resolution was verified with a 20-cm image intensifier. After successful dilation, angiography of the treated leg was performed to exclude thromboembolic complications. The length of the stenosis was measured with a ruler that was fixed on the skin of the treated leg during the whole procedure.

After successful PTA, a centering catheter with a 10-cm-long segmented balloon (Paris; Guidant, Tememla, Calif) for centering the radioactive source was carefully inserted (K.K., P.L.) into the artery. The centering catheter was placed so that its segmented balloon overlapped the stenosis by at least 1 cm at each end. The diameter of the centering catheter was 1 mm smaller than that of the balloon catheter to ensure residual blood flow during irradiation and to prevent additional damage to the vessel wall. Before the patient was transported to the brachytherapy unit, the exact position of the centering device was verified and documented with radiography, and the sheath with the centering catheter was taped to the skin. The transport of patients to the radiooncology department took 5–10 minutes.

Endovascular Gamma Irradiation
Endovascular irradiation was performed (M.B., M.N., R.B.) by using a 0.9-mm-diameter wire and an afterloading device (microSelectron; Nucletron, Veenendaal, the Netherlands) with a high-dose-rate 192Ir source, after the correct position of the centering catheter was once more verified and documented. The balloon of the centering catheter was inflated to a pressure of 4 atm. The irradiation dose was 14 Gy calculated at 2 mm deep to the vessel wall. The whole length of the centering catheter was exposed to irradiation. The duration of irradiation was calculated with a computerized system (Plato-BPSV 13.1; Nucletron, Veenendaal, the Netherlands) on the basis of the diameter and length of the centering catheter and the actual activity of the source. The irradiation time varied (range, 207.2–453.7 seconds; mean, 318.43 seconds ± 93.53). The current source strength minimum was 4.174 Ci (15.44 x 1010 Bq); maximum, 9.101 Ci (33.67 x 1010 Bq); and mean, 6.58 Ci (24.35 x 1010 Bq ± 1.99).

To reduce the risk of thromboembolic complications while the centering balloons were being inflated, irradiation was interrupted after 3 minutes for 120 seconds, and the centering balloons were deflated. The control patients underwent the same procedure as the irradiated patients, except that an inactive dummy probe was inserted instead of a gamma source. After the procedure in the brachytherapy unit, the centering catheter was removed immediately. The patients were transported back to the catheter unit, where angiography was performed to exclude thromboembolic or other complications.

All angiograms were scored according to a system proposed by the Society for Vascular Surgery and modified by Williams et al (33). The outflow was divided into four segments: abdominal, pelvic, thigh, and calf. Each vessel was assigned importance. The degree of vascular disease was classified as 0, normal or minimal stenosis (0%–19% diameter stenosis); 1, 20%–49% diameter stenosis; 2, 50%–99% diameter stenosis; 2.5, occlusion of less than half the length of the vessel; and 3, occlusion of more than half the length of the vessel. The resistance of each segment was calculated by multiplying the vessel importance by the score of vascular disease. In normal or minimally diseased vessels, a factor of 1 was added. Total resistance was calculated by adding the resistance of the four segments. For example, the resistance index of a patient with normal findings at angiography would equal 4.

Scoring of the angiograms was performed (K.K., P.L.) and determined with consensus, without discrepancy in any case. The measurements with a vessel edge-detection software (Siemens Medical Systems) integrated in the angiographic device were used to determine the degree of stenosis before and after PTA. We believe this, together with the clearly defined criteria of the scoring system, was the reason for the high degree of agreement.

The maximum degree of stenosis (diameter reduction) before and after PTA and at follow-up was quantified with the vessel edge-detection software. First, a vessel segment proximal to the dilated region was defined as normal. The degree of stenosis was calculated from the ratio of the normal diameter to the minimal vessel diameter within the stenosis. Additionally, the opacity in the stenotic region during the passage of the contrast medium before and after PTA was determined and related to the opacity in the normal defined vessel segment proximal to the stenosis. The measurement of the degree of stenosis and reduction in opacity was performed by one investigator (M.Z.) without knowledge of group randomization.

Follow-up
Patients were examined 1 day before and 1 day after randomization and after 1, 3, 6, 9, and 12 months with a structured interview (M.Z., G.W.) and color-coded duplex sonography (M.Z., A.G.). Treadmill testing was performed (G.W., A.G.) the day before and at 1, 3, 6, 9, and 12 months after PTA. Follow-up angiography was performed (M.Z., A.G.) 6 and 12 months after PTA. Each investigation was performed by one investigator.

The structured interview was performed face-to-face and consisted of the maximum walking distance and degree of pain (none, 4 points; slight, 3 points; intermediate, 2 points; strong, 1 point; or not possible, 0 points) during low-, normal-, and high-velocity walking distance of 100 m and when climbing one, two, or three stairs. The answers were scored, and a maximum of 35 points was possible.

Treadmill testing was performed at 3 km/h and a slope of 12° for a maximum of 10 minutes, according to recommendations by Rutherford et al (34). For patients with known heart disease, the slope was reduced to 6° or 0°. The walking distance to first symptoms and that at the termination of the test was documented.

The ankle-brachial index of the proximal and distal thigh and the distal calf of both legs was measured with color duplex sonography. The peak velocity ratio of the stenosis was also determined (ratio of maximum blood velocity just before and within the stenosis).

Follow-up angiography was performed on an outpatient basis. The treated leg was investigated with fine-needle (Vygon, Ecouen, France) intraarterial digital subtraction angiography. Efforts were made to image the region of former balloon dilation in the same projection as that at PTA. The vessel diameter and the contrast material opacity in the former stenotic region were measured (M.Z.) as described earlier. Vessel diameter was measured at the upper and lower edges of the irradiation field, defined as the location of upper and lower edges of the centering catheter at the time of irradiation (±5 mm) and scored as follows: 0, 0%–19% diameter stenosis; 1, 20%–49% diameter stenosis; and 2, 50%–99% diameter stenosis. New stenoses inside (not including the former stenotic region) and outside the irradiated part of the vessel were evaluated in the same manner.

Investigators (M.Z., G.W., A.G.) involved in the follow-up were without knowledge of group randomization. Group randomization was known only to investigators (K.K., P.L., M.B., M.N., R.B.) who performed the PTA or the endovascular irradiation.

Rationale and Methods for Statistical Analysis
As the clinical data became available during the scheduled angiographic follow-up, a strong trend became apparent: The irradiated patients had no restenoses compared with the control patients. This behooved the study board to perform an interim analysis for ethical reasons. This time, 30 patients (23 men, seven women; age range, 51–73 years; mean age, 60.8 years ± 5.4), 15 patients in each group, were randomized and included in the study.

A t test was used to evaluate the hypothesis of equal means of the primary target variable in both arms after 6 months. An analogous analysis was performed with the 12-month follow-up data. Additionally, observed clinical parameters, usually used to describe the outcome (absolute degree of stenosis, opacification of stenosis, structured interview, color-coded duplex sonography, treadmill testing), were exploratively analyzed alone to draft a hypothesis for a rationale for further studies. Explorative comparisons of these clinical parameters were done with parametric tests (t test) and {chi}2 statistics (baseline clinical characteristics), depending on scale quality and distribution properties. Additionally, results of treadmill testing, color-coded duplex sonography, and interview were assessed with an explorative repeated measurement analysis by using an appropriate general linear model (multivariate analysis of variance). P values were reported without adjustment for multiplicity or interim monitoring. Computations for test statistics were performed (SPSS 10 for Macintosh; SPSS, Chicago, Ill). Summary statistics cited in the text are usually given as means ± SD.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The baseline characteristics of the 22 patients (10 patients in the irradiation group and 12 patients in the control group) at 6-month angiographic follow-up after randomization at the time of interim analysis, which included risk factors for vascular occlusive disease, were compared (Table 1).


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  		TABLE 1. Baseline Clinical Characteristics of Patients at 6-month Angiographic Follow-Up

 
Interventions
PTA and irradiation.—Table 2 lists PTA and endovascular irradiation data and characteristics of stenoses before and after PTA. The centering catheter was placed in all patients without problems (Fig 1). Endovascular irradiation or placement of the dummy wire was performed successfully. It was not possible to place the catheter with the 192Ir source in one patient with antegrade puncture of the femoral artery because of the sharp angle of the sheath at the side of puncture. Taping the sheath closer to the skin, which reduced the sheath angle, solved the problem. One patient had a thromboembolic occlusion of a lower limb vessel during PTA and brachytherapy and required local thrombolysis (Medac, Hamburg, Germany; urokinase at 100,000 IU/h), which was successful. The patient is part of this study.


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  		TABLE 2. Angiographic and Procedural Characteristics

 


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  		Figure 1. Posteroanterior angiograms. Left: Digital subtraction angiogram in a patient with a short high-grade de novo stenosis (arrow) of the superficial femoral artery. Middle: Unsubtracted angiogram shows a catheter with a 10-cm-long segmented balloon used to center the 192Ir source in the artery. The centering catheter overlapped the length of stenosis by at least 1 cm at both sides. Patients received anticoagulant therapy during inflation of the balloon of the centering catheter to avoid blood clotting. Right: Digital subtraction angiogram shows the result of PTA performed in the same patient.

 
Periinterventional color duplex sonography.—The peak velocity ratio improved significantly (P < .001) from 5.0 ± 2.3 to 1.5 ± 0.5 in the irradiation group and from 8.9 ± 5.1 to 1.3 ± 0.4 in the control group. The control group showed higher values at baseline (P = .04). The ankle-brachial index increased significantly (P < .001) from 0.72 ± 0.11 to 0.98 ± 0.15 in the irradiation group and from 0.70 ± 0.13 to 0.93 ± 0.11 in the control group. The proximal and distal thigh-brachial index was only slightly different before and after PTA between the two groups: proximal thigh, 1.15 ± 0.15 versus 1.04 ± 0.19 before PTA and 1.14 ± 0.19 versus 1.05 ± 0.14 after PTA; distal thigh, 0.89 ± 0.19 versus 0.80 ± 0.23 before PTA and 1.09 ± 0.14 versus 1.06 ± 0.12 after PTA for the irradiation versus control group, respectively).

Periinterventional treadmill test.—The pain-free walking distance before and at 1 month after PTA improved significantly (P < .001) from 80.1 m ± 49.1 to 325.7 m ± 189.5 in the irradiation group and from 97.7 m ± 132.4 to 287.3 m ± 191.5 in the control group, with no significant difference between the two groups (P = .85).

The total walking distance before and 1 month after PTA improved significantly (P < .001) from 226.8 m ± 133.1 to 376.4 m ± 169.6 in the irradiation group and from 200.9 m ± 183.5 to 325.8 m ± 169.2 in the control group, with no significant difference between the two groups (P = .68).

Periinterventional interview.—The average score on the interview before and 1 month after PTA improved significantly (P < .001) from 17.2 points ± 5.43 to 28.7 points ± 5.1 in the irradiation group and from 14.0 points ± 8.6 to 26.4 points ± 5.8 in the control group. There was no significant difference between the two groups (P = .26).

Follow-up
Angiographic follow-up was available for 22 patients after 6 months (10 patients in the irradiation group and 12 patients in the control group) and 12 patients after 12 months (six patients in both groups). The results of angiographic examination at 6 and 12 months after PTA are summarized in Table 3. After 6 months, a restenosis of greater than 50% was observed in none of patients in the irradiation group (Fig 2) but in five of 12 patients in the control group (Fig 3). Compared with the means after PTA, the means of the individual differences in the degree of stenosis after 6 months were significantly different between the irradiation and the control groups (P = .001). At 6-month follow-up, the vessel diameter of the dilated region increased by a mean of 14.7% ± 20.8 in the irradiation group compared with a decrease of 37.7% ± 27.3 in the control group (P = .001).


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  		TABLE 3. Angiographic Results

 


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  		Figure 2. Posteroanterior digital subtraction angiograms in a patient with peripheral occlusive disease stage 2b, according to Fontaine classification. Left: Intraarterial angiogram obtained before PTA shows a circumscribed high-grade de novo stenosis of the superficial femoral artery (arrow). Middle: Angiogram obtained after successful PTA, shows slight vessel-wall irregularities. The proximal and distal edges (arrows) of endovascular radiation are marked. Right: Angiogram obtained after 6 months demonstrates a normal vessel within the region of PTA and at the edges of the irradiated segment.

 


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  		Figure 3. Posteroanterior intraarterial digital subtraction angiograms in a patient with peripheral occlusive disease stage 2b, according to the Fontaine classification. Left: Angiogram obtained before PTA shows a short high-grade stenosis of the popliteal artery (arrow). Middle: Image shows the result of a successful PTA without endovascular irradiation. Right: Angiogram obtained after 6 months shows more than 50% restenosis (arrow).

 
Two patients in the irradiation and one patient in the control group developed new asymptomatic stenoses of 20%–49% at the proximal edge of the former centering catheter position, which were detected at 6-month follow-up angiography.

Two days after hospital discharge, one patient who underwent brachytherapy had an occlusion of the femoral artery 10 cm proximal to the dilated region on the side of the puncture, which was probably due to vessel dissection. The occlusion was not resolvable with thrombolysis. The dilated and irradiated part of the artery was patent at angiographic intervention 1 month after randomization. The patient was not included in the presented interim results because 6-month follow-up was not available.

The peak velocity ratio of the stenotic region was at 1 month 1.2 ± 0.3 versus 1.4 ± 0.5; at 3 months, 1.2 ± 0.3 versus 1.7 ± 0.6; at 6 months, 1.2 ± 0.3 versus 2.0 ± 1.4; at 9 months, 1.3 ± 0.3 versus 2.0 ± 1.2; and at 12 months, 1.1 ± 0.3 versus 3.0 ± 3.7 for the irradiation and the control group, respectively. The two groups were significantly different according to the general linear model (P = .014).

The mean value of the ankle-brachial index of the distal calf was at 1 month 1.00 ± 0.18 versus 0.92 ± 0.11; at 3 months, 1.00 ± 0.19 versus 0.91 ± 0.18; at 6 months, 0.87 ± 0.13 versus 0.85 ± 0.25; at 9 months, 0.93 ± 0.14 versus 0.84 ± 0.16; and at 12 months, 0.93 ± 0.14 versus 0.83 ± 0.2 for the irradiation and the control group, respectively. Differences between the groups were not significantly different according to the general linear model (P = .22).

The pain-free walking distance and the maximum walking distance with treadmill testing was slightly better in the irradiation than in the control group. For the irradiation versus the control group, the respective pain-free walking distance at 3 months was 335.6 m ± 187.6 versus 349.0 m ± 166.3; at 6 months, 339.4 m ± 185.3 versus 307.0 m ± 170.2; at 9 months, 347.6 m ± 179.4 versus 275.2 m ± 191.2; and at 12 months, 329.2 m ± 185.5 versus 297.9 m ± 205.8, respectively. For the irradiation versus the control group, the total walking distance at 3 months was 386.4 m ± 157.6 versus 366.5 m ± 159.9; at 6 months, 395.9 m ± 140.1 versus 345.4 m ± 174.8; at 9 months, 397.7 m ± 135.6 versus 369.9 m ± 178.1; and at 12 months, 393.0 m ± 143.0 versus 357.8 m ± 170.4, respectively. The differences between the two groups were not significant (P = .72 and 0.59 for the pain-free walking distance and total walking distance, respectively).

At 3–12 months, there was a slight nonsignificant (P = .28) benefit in the interview score for the irradiation versus the control group: at 3 months, 28.2 ± 4.9 versus 28.2 ± 4.1; at 6 months, 27.3 ± 5.3 versus 25.7 ± 6.2; at 9 months, 26.1 ± 4.7 versus 22.7 ± 8.3; at 12 months, 26.1 ± 3.7 versus 22.2 ± 8.1, respectively.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of an interim analysis indicate that endovascular irradiation immediately after PTA of de novo femoropopliteal stenoses reduces the restenosis rate. On the basis of the follow-up results in 22 patients at 6 months and 12 patients at 12 months, the study board decided to terminate randomized enrollment in the study. All 30 patients already randomized will undergo follow-up according to the study protocol. Furthermore, the follow-up will be continued for both groups to identify any late sequelae of endovascular irradiation. So far, no complications of endovascular irradiation such as edge effects, late thrombosis, or development of aneurysms have been observed during follow-up.

The effectiveness of beta and gamma emitters to reduce the restenosis rate has been investigated in clinical trials with coronary arteries. The randomized Scripps Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS) trial (23,35,36) and the Washington Radiation for In-Stent Restenosis Trial (25) assigned patients who underwent percutaneous revascularization of coronary arteries to receive a placebo or irradiation with the 192Ir source. Irradiation with the beta emitter phosphorus 32 was performed in the Proliferation Reduction with Vascular Energy Trial (27).

Recently, findings from published randomized trials confirmed the reduction in recurrent in-stent restenosis (37) and in untreated coronary stenoses (38) with intracoronary gamma irradiation. Further studies on coronary arteries are under way (22).

A limited number of trials investigated the effectiveness of endoluminal irradiation in femoropopliteal arteries. In a nonrandomized study on recurrent stenoses of femoropopliteal arteries initiated in 1990 (32), endovascular gamma irradiation administered at a dose of 12 Gy calculated 3 mm from the source center was delivered into a noncentered catheter following interventional procedures (PTA, directional atherectomy, or stent placement). Long-term results as many as 7.5 years after treatment demonstrated a patency rate of 84%. The same irradiation protocol was used in a nonrandomized trial (31) on long-distance restenoses of femoropopliteal arteries. But, four of 10 enrolled patients developed restenoses. In a recently published study, the same group (30) used the same dose and delivery system for endovascular irradiation, which lowered the restenosis rate of long-distance femoropopliteal lesions from 53.7% to 28.3% at 6 months after PTA. Limitations of the study were the mixture of de novo and restenotic lesions and an angiographic follow-up of only 64% of the enrolled patients. Follow-up with color-coded duplex sonography to detect restenoses can be difficult in the distal part of the femoral artery, in calcified arteries, or in obese patients.

Recently, the results of the nonrandomized feasibility part of the Peripheral Arteries Radiation Investigational Study (PARIS trial) were reported (39). The angiographic restenosis rate 6 months after PTA of de novo femoropopliteal stenoses was 17.2% in 35 patients. A centering catheter was used to deliver a dose of 14 Gy 2 mm deep to the vessel wall.

Despite the fact that endovascular brachytherapy used to prevent restenosis has attracted a lot of interest in recent years (eg, the U.S. Food and Drug Administration granted approval for intracoronary in-stent restenosis on November 3, 2000 [40]), there are several methodologic aspects that should be discussed.

The literature contains limited data on endoluminal irradiation of de novo lesions in coronary and peripheral arteries. The recent approval of irradiation of in-stent restenoses by the Food and Drug Administration did not include indication for de novo coronary stenoses. Authors of studies (27,41,42) on coronary and peripheral arteries often reported data on a mixture of restenotic and de novo lesions. The dose-finding study by Verin et al (37) was one of the first, to our knowledge, to use brachytherapy in patients with previously untreated coronary stenoses only. De novo stenoses of femoropopliteal arteries were treated in the feasibility part of the PARIS trial (39). The results of the PARIS trial and of our study support the hypothesis that endovascular irradiation of de novo lesions of femoral or popliteal arteries may be effective in reducing the restenosis rate.

The inclusion criteria of our study differ slightly from those of other trials on peripheral arteries. The first difference is stenosis length. We treated short stenoses (10–80 mm). The length of stenoses was longer in the Frankfurt Trial (43) (range, 40–160 mm), the Pilot Vienna Study (31) (range, 90–220 mm), the Vienna Study (30) (mean length, 16.7 cm), and the PARIS study (range, 50–150 mm) (44).

The fact that stenosis length can influence the rate of restenosis after gamma irradiation was demonstrated in a subanalysis of the GAMMA-I trial (26) of coronary arteries. The reduction in restenosis rate was 70% in lesions less than 30 mm long compared with 48% in 30–45-mm long lesions. So far, we have not observed any differences in the diameters of vessels with irradiated lesions equal to or less than 2 cm or greater than 5 cm at 6 months (-14.8% ± 16.8 vs -11.8% ± 47.8). However, the enrollment of patients with short stenoses in our trial may be one explanation for the more favorable outcome after irradiation compared that of other trials (30,44).

The optimal irradiation dose and the optimal target volume are currently the subject of investigation. Findings from experimental studies indicate that the adventitia is involved in the pathophysiology of restenosis (45). For this reason, we focused the calculated dose of irradiation at the adventitia of the vessel wall. Although the inhibitory effect of irradiation has proved to be dose dependent in both animal experiments (46–48) and clinical studies of coronary arteries (37), no dose-finding studies have been conducted thus far for femoropopliteal arteries. Perhaps, the higher dose is another reason that our study findings showed a lower restenosis rate than those in the Minar et al study (30). In their study, a dose of 8 Gy was delivered to the adventitia in the case of source centering compared with the higher dose of 14 Gy in our trial.

The centering of the irradiation source is another subject of discussion (49). In the case of decentering, a dose between 9 and 44 Gy (calculated dose, 15 Gy) to the luminal surface was reported in the Vienna Study (30). Therefore, poor centering of the radioactive source within the arterial lumen areas, with under- or overdosage with respect to the prescribed dose, will result, which may unpredictably influence the effectiveness of irradiation. However, there is an added risk involved with centering catheters. An 8-F sheath is necessary to insert the centering catheter, instead of a 6-F sheath if endovascular irradiation is performed without centering or a 5-F sheath if endovascular irradiation is not performed at all. The 8-F sheath increases the risk for complications of the procedure.

The complication in one of our patients, who developed an occlusion of the proximal superficial femoral artery following an antegrade punction, might be attributed to the large (8-F) sheath. The balloon of the centering catheter has to be inflated during irradiation to keep the source in the middle of the artery. The inflation time depends mainly on the activity of the source, the vessel diameter, and the irradiated distance. In our study, the maximum time of irradiation was approximately 7 minutes. Therefore, patients received anticoagulant therapy, and partial thrombin time was documented before and after irradiation. Irradiation was interrupted after 3 minutes for at least 2 minutes, and the centering balloon was deflated to allow blood flow. Under these conditions, we encountered only one thromboembolic occlusion of a runoff vessel. However, the frequency of this complication was the same as that with balloon dilation alone (one of 22 patients). To date, there have been no reports in the literature about centering device-related complications in peripheral arteries. In coronary arteries, a spiral balloon catheter for source centering was evaluated with good results (50).

The length of irradiation is another point of discussion. In our study, the whole length of the centering balloon (10 cm) was irradiated, that is, the length of the irradiated segment was at least 1 cm longer than the length of stenosis on both sides, in most cases, even more than 1 cm. We intentionally irradiated a distance that was much longer than the dilated region to avoid the "edge" or "candy wrapper" effects, which are well known from coronary studies (25,42,51–53). The inhibition of restenosis in coronary arteries after gamma irradiation of in-stent restenosis was found to be stronger at the center of the lesion than at the edges (25,54).

In a study (42) in which balloons with rhenium 188 were used after balloon dilation or stent placement in coronary arteries, the target lesion restenosis rate was only 12%, whereas new stenoses occurred at the proximal or distal end of the irradiation zone. The total restenosis rate was markedly lower when the length of the irradiated segment was more than twice the lesion length. The same phenomenon was observed in the GAMMA-I trial. An edge effect was noted in patients in whom the area of lesion covered with radioactive seeds was too small (26). Geographic mismatch is another possible reason for the edge effect (51).

In our study, no differences between the two groups were observed at the edges of the centering catheter. After 6 months, two new 20%–49% proximal-edge stenoses were found in the irradiation group compared with one new 50%–99% stenosis at the proximal edge of the centering catheter in the control group. No new stenosis developed at the distal edge of the irradiated vessel segment. The optimal length of irradiation after PTA or stent placement must still be elucidated with long-term follow-up results from clinical studies (55).

Late thrombosis proves a major complication in coronary arteries (56–59) and may be responsible for the increased incidence of myocardial infarction in patients receiving intracoronary irradiation (38). Review of findings from both randomized and nonrandomized studies found that 9% of patients who received irradiation had late thrombosis compared with less than 2% of patients in the control group (58). Late thrombosis was not a problem in our study and the Vienna study (30), probably because only PTA was performed. In coronary arteries, late thrombosis occurred after stent placement and has been attributed to a pronounced delay in endothelialization. Our preliminary data indicate that no anticoagulant besides aspirin (in one patient, clopidogrel) is necessary after endovascular irradiation of dilated femoropopliteal arteries.

So far, we observed a tendency toward a modest dilation of the irradiated vessel segment within 6 months after PTA. The same was observed in single cases in the Vienna Study (30). Vascular remodeling might contribute to this phenomenon (60). However, close long-term follow-up will determine whether, as our interim results 12 months after PTA suggest, the vessel diameter will remain stable or whether aneurysmatic dilation will develop.

There are some limitations of our study. Despite significant differences in angiographic follow-up results between irradiated and control patients, the results of treadmill testing, structured interviews, and, in part, color-coded duplex sonography showed only nonsignificant advantages for the irradiation group. Possible reasons are the relatively low number of patients and the degree of stenosis which is probably still below the threshold for symptoms in most of the patients in the control group. A longer follow-up will show whether future significant differences will develop between the two groups. We did not perform intravascular sonography, which may be helpful for dose calculations.

In eccentric lesions after PTA, inhomogeneous dose distribution can occur despite the use of a centering catheter. Furthermore, intravascular sonography has advantages over angiography for measuring the lumen diameter and determining the structure of intimal hyperplasia and plaque material (11,23,53,61,62). Another limitation is the unknown long-term effect of gamma irradiation after PTA of de novo of femoropopliteal stenoses. Results of the SCRIPPS trial (35,36) indicate that the benefit of irradiation to prevent restenosis may last for at least 2–3 years. A long-term benefit of more than 7.5 years was reported after irradiation of restenotic and femoral arteries with stents (63). However, major differences in the design of our study, such as dose and length of irradiation or source centering, do not allow conclusions to be drawn about the long-term outcome in the patients in our study.

In conclusion, the results of our interim analysis suggest that endovascular irradiation with a centered 192Ir gamma source immediately following PTA of de novo femoropopliteal stenoses reduces the restenosis rate.


   FOOTNOTES
 
See also the editorial by McCowan and Baker in this issue.

Abbreviation: PTA = percutaneous transluminal angioplasty

Author contributions: Guarantors of integrity of entire study, K.K., P.L., K.L.; study concepts, K.K., P.L., K.L., M.B.; study design, R.B., M.B., K.K., P.L.; literature research, K.K., P.L., G.W., A.G.; clinical studies, R.P.M., M.N., K.K., P.L., M.Z.; data acquisition, K.K., P.L., M.Z., G.W., A.G.; data analysis/interpretation, K.K., P.L., K.L.; statistical analysis, H.S.; manuscript preparation and editing, K.K.; manuscript definition of intellectual content, K.K., P.L., K.L., M.B., M.Z.; manuscript revision/review, K.K., H.S.; manuscript final version approval, K.K., K.L.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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