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Vascular and Interventional Radiology |
1 From the Departments of Angiology (R.M.W., A.C.B., E.M.) and Radiation Therapy (B.P., R.P.), Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Received May 26, 2005; revision requested July 25; revision received July 29; accepted September 1; final version accepted November 2. Address correspondence to R.W. (e-mail: rmwolfram{at}hotmail.com).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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Materials and Methods: Each patient gave written informed consent to participate in the study, which was approved by the hospital's ethics committee. One hundred two patients (men, 53.9%; mean age, 72.1 years ± 8.7 [standard deviation]; lesion length, 8.1 cm ± 4.9) underwent percutaneous transluminal angioplasty (PTA) without further stent implantation. Patients were then assigned to either receive EBT (n = 51) by using an iridium 192 source, with a prescribed dose of 12 Gy at 3 mm from the source axis, or no further treatment (n = 51). Radiation was delivered without a centering catheter. Data were analyzed by using a Student t test for continuous values and a 
2 test to compare categorical values. A Cox proportional hazards regression analysis was performed to evaluate predictors of recurrence at follow-up.
Results: After 6 months, the restenosis rate for the 102 patients with completed 5-year follow-up was significantly reduced for the PTA plus EBT group versus the PTA alone group (29.4% vs 56.9%, P < .05). During follow-up we observed a late catch-up phenomenon, and after 5 years the recurrence rate was comparable in both groups (72.5% vs 72.5%, P > .99). Time to recurrence, however, was significantly delayed in the PTA plus EBT group (17.5 months ± 14.7 vs 7.4 months ± 6.8 for the PTA alone group, P < .05).
Conclusion: At 5-year follow-up, PTA followed by gamma radiation EBT with a dose of 12 Gy resulted in a delay but not an inhibition of restenosis when compared with that of PTA alone.
© RSNA, 2006
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INTRODUCTION |
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The purpose of our study was to report the 5-year results from the prospective randomized Vienna-2 trial, which was designed to evaluate the safety and effectiveness of adjunctive EBT compared with no further treatment after successful revascularization in patients with long-segment femoropopliteal lesions.
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MATERIALS AND METHODS |
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Entry criteria included the following: (a) minimum age of 40 years or older, (b) history of claudication (according to Rutherford stage 2 or 3) (13) for more than 3 months or critical limb ischemia with pain at rest with or without tissue damage, (c) de novo lesion with a minimal length of 5 cm or a recurrent lesion (after previous PTA) of any length, (d) technically successful PTA, defined as less than 30% residual stenosis, and (e) no further stent implantation.
According to these criteria, 113 patients were enrolled in the trial. After undergoing a successful recanalization procedure, patients were then randomly assigned to receive either EBT (n = 57; mean age, 71 years; age range, 43–87 years) with an iridium 192 (192Ir) source or no further treatment (n = 56; mean age, 73 years; age range, 51–89 years). Six-month follow-up was available in 107 patients, five patients were lost to follow-up after hospital discharge, and one patient died without information on recurrence. Five-year clinical follow-up information could be obtained in 102 patients (mean age, 72.1 years; age range, 53–89 years; PTA plus EBT: n = 51; men, 58.8%; PTA: n = 51; men, 49%; P values not significant).
PTA and EBT Procedures
Procedures were performed by one interventionist (E.M.) with approximately 15 years of experience in endovascular treatment as of 1996. All procedures were performed by using an ipsilateral anterograde puncture and a 6-F introducer sheath (Cordis Europe, Roden, the Netherlands), and angioplasty was performed with 5- or 6-mm balloon catheters (Smash; Schneider Europe, Bulach, Switzerland). Residual stenosis immediately after PTA (or recurrent stenosis in case of follow-up angiography) was determined by comparing the contrast medium (Ultravist 370; Schering, Berlin, Germany) column width (measurement obtained with a ruler) within the dilated segment at the point of maximal diameter reduction with that of an unaffected arterial segment immediately proximal to the dilated segment (8). The exact location of angioplasty was marked with a radiopaque ruler, and movement of the table and the angiographic unit was avoided to prevent parallax error.
In patients randomized to receive EBT, the standard 6-F sheath was then exchanged for a 55-cm 6-F sheath (Brite Tip; Cordis Europe), and its tip was positioned 15 mm distal to the dilated segment. After sheath placement, a 5-F, closed-tip, noncentered applicator (microSelection; Nucletron, Veenendaal, the Netherlands) (to accommodate the radiation source inserted during the afterloading procedure) was inserted and also placed 15 mm distal to the dilated segment. This radiation delivery catheter was equipped with a wire with markers at 1.0-cm intervals for exact measurement. During transportation of the patient to the brachytherapy unit, the sheath and applicator were fixed to the patient to prevent movement relative to the lesion. Exact positioning was radiographically verified before starting the afterloading procedure, and EBT was performed utilizing a remote high-dose rate afterloading device (microSelectron; Nucletron). Treatment was planned with a computer-assisted standard dose-calculation planning system (PLATO-BPS, version 13.2; Nucletron).
A reference dose of 12 Gy was prescribed at 3 mm from the source axis in the midplane of the applicator. In cases of ideal centering of the source in a vessel with a diameter of 5 mm, a dose of 15 Gy was calculated for the luminal surface, and a dose of 8 Gy was calculated for the adventitia. In case of decentering, a minimum dose of 9 Gy and a maximum dose of 44 Gy were calculated to the luminal surface; the corresponding doses to the adventitia were 6 and 12 Gy, respectively.
Radiation length included the total PTA length with an additional 1-cm safety margin proximal and distal to the dilated segment. After treatment planning, the applicator's proximal end was connected with a special 5-F adapter to the afterloader. To ensure optimal active source placement, an inactive test wire (dummy wire) was first placed in the dilated artery. After that, an 192Ir source (diameter, 1.1 mm; mean activity, 200 GBq; range, 150–366 GBq) was delivered. Mean irradiation time was 263 seconds (range, 154–656 seconds). The PTA procedure was prolonged to a total of approximately 30 minutes, because of patients' transportation to the brachytherapy unit and the irradiation procedure itself. Planning and application of the irradiation or the placebo therapy was performed by a radiation oncolgist (B.P.) with 1 year of experience in endovascular EBT as of 1996 and who was involved in the planning and application of the radiation or placebo therapy. The EBT procedure was technically feasible in all patients without complications. No patient experienced any therapy-related adverse events.
Pharmacotherapy
All patients received administration of aspirin (Lannacher, Lannach, Austria) (100 mg/d), which was initiated at least 2 weeks prior to intervention and prescribed indefinitely afterward. Peri-interventionally 5000 IU of standard heparin (Liquemin; Hoffmann-LaRoche, Basel, Swizerland) was administered, with an additional 1000 IU/h started before transportation to the brachytherapy unit, which was then continued until the following morning.
End Points and Follow-up
The primary end point of the Vienna-2 trial was angiographic patency at 6 months, which was defined as less than 50% restenosis of the target lesion, or patency verified with duplex sonography. A focal increase in peak systolic velocity of at least 140% (corresponding to a peak velocity ratio of 
2.4) was considered equivalent of a stenosis greater than 50% (14).
All patients underwent a clinical follow-up examination the day after PTA and after 1, 3, 6, 12, 24, 36, 48, and 60 months by a trained vascular specialist (R.M.W., with 2 years of experience as of 1996, and E.M., with 15 years of experience as of 1996). The examination consisted of symptom assessment, clinical examination, and noninvasive laboratory testing, including ankle-brachial arterial pressure measurement with Doppler ultrasonography (US) to calculate the ankle-brachial pressure index and color duplex US (5-MHz linear-array color probe, Model XP10; Acuson, Mountain View, Calif) of the femoropopliteal segment during each follow-up visit except for the visit at 1 month. During color duplex US, the maximum peak systolic velocity in the dilated region was determined and compared with the peak systolic velocity in the preceding unaffected arterial segment. A stenosis of 50% at the examined site (8,14) was determined with a focal increase in the peak systolic velocity of at least 140% (corresponding to a peak velocity ratio of 2.4).
In case of suspected recurrent stenosis, according to clinical or laboratory findings, intraarterial angiography was performed with eventual further PTA. Owing to the high sensitivity of color duplex US for detection of stenosis greater than 50%, follow-up angiography was not mandatory in cases of normal hemodynamic results; with patient consent, however, follow-up angiography was performed after 6 months or longer in patients without evidence of recurrence. All follow-up investigations were performed and analyzed by investigators (E.M., R.M.W.) blinded to group randomization. Treadmill testing was performed with a constant-workload protocol by using a constant speed (3.2 km/hr) and grade (12° inclination angle). In patients without clinical symptoms, treadmill testing was limited to 700 m. All data were independently evaluated by authors (R.M.W.; A.C.B., with 4 years of experience as of 1996; E.M.), and a consensus was reached in all cases.
Six-month Follow-up
Six-month follow-up data for the 102 patients who had completed 5 years of follow-up were extracted from our previously published study (8).
Definitions
Restenosis was defined as an angiographically verified stenosis of more than 50% narrowing of the luminal diameter within the recanalized segment compared with the diameter of normal segments of the vessel on the follow-up angiogram. In patients who underwent only duplex US, a peak velocity ratio 2.4 was used to indicate restenosis.
Target lesion revascularization was defined as clinically driven further PTA or surgical bypass of the treated lesion that was required because of the presence of at least 50% diameter stenosis of the target lesion.
Target vessel revascularization was defined as clinically driven further PTA or surgical bypass of the target vessel because of the presence of at least 50% diameter stenosis of the target lesion or any other lesions within the target vessel.
Statistical Analysis
The study was performed with a statistical power of 85% with a one-sided 
= .05 to enable detection of an absolute reduction of recurrence of 30% between the two treatment arms. Clinical and angiographic variables were compared between the groups. Variables were reported as mean ± standard deviation or median and range for continuous variables and as percentages for dichotomous variables. To assess the influence of the respective treatment, a Student t test or one-way analysis of variance was used to compare continuous variables and a 2 test or a Fisher exact test was used to assess dichotomous variables. A value of P of less than .05 was considered to indicate a significant difference. Freedom from recurrence in the two treatment arms was evaluated by using a Kaplan-Meier curve, and the log-rank test was used to determine a significant difference (P < .05) between the two groups during the 5-year follow-up.
Time of recurrence was judged according to recurrence of symptoms. For clinically asymptomatic patients, the date of the scheduled follow-up visit was taken as the failure date. Patients who died without information on recurrence were censored with the date of their last follow-up. Recurrence rates at 6 months and 5 years were compared between groups by using a 2 test; Cox proportional hazards regression multivariate analysis was performed with PTA plus EBT as a time-dependant covariate to identify variables associated with freedom from recurrence at 5 years; other covariates included into the final model were hypertension, diabetes mellitus, hyperlipidemia, prior cardiac event, smoking status, clinical stage, and arterial vessel runoff. All calculations were performed with statistical software (SPSS for Windows, version 12.0; SPSS, Chicago, Ill).
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RESULTS |
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2 test, P value not significant). Data are depicted in Table 3.
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The overall recurrence rate at 5 years was 37 of 51 (72.5%) patients in the PTA alone group versus 37 of 51 (72.5%) in the PTA plus EBT group (2 test, P > .99). Time to recurrence in the PTA group was 7.4 months ± 6.8 (range, 1–38 months) versus 17.5 months ± 14.7 (range, 3–49 months) in the PTA plus EBT group (P < .001) (Figure). Twenty-five (67.6%) patients in the PTA group had recurrence of clinical symptoms compared with 21 (56.6%) patients in the PTA plus EBT group, whereas 12 (32.4%) patients in the PTA group had only angiographic restenosis compared with that of 16 (43.4%) patients in the PTA plus EBT group (P = .43). When using a Cox regression model with time-dependent covariates, PTA plus EBT was confirmed to be related to patency at 5-year follow-up (hazard ratio, 0.68; 95% confidence interval: 0.014, 0.330; P = .01), whereas hypertension, diabetes mellitus, hyperlipidemia, prior cardiac event, smoking status, clinical stage, and arterial vessel runoff showed no significant influence.
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Peak velocity ratio.—The mean peak velocity ratio decreased from 7.1 (range, 2.7–18.0) in the PTA group and 6.3 (range, 2.9–12.2) in the PTA plus EBT group prior to intervention to 1.9 (range, 1.3–2.5) and 1.7 (range, 1.1–1.9), respectively, the day after intervention. The mean follow-up values were 3.3 (range, 1.3–9.4) at 6 months and 1.7 (range, 1.3–2.1) at 5 years in the PTA group versus 2.6 (range, 1.0–9.5) at 6 months and 1.7 (range, 1.3–2.7) at 5 years in the PTA plus EBT group. In patients with total occlusion, the peak velocity ratio cannot be calculated. Values of patients who underwent reintervention because of recurrent disease are not included.
Reinterventions
Target lesion revascularization was performed during a mean follow-up period of 5 years in 33 of 51 (64.7%) patients in the PTA group and in 32 of 51 (62.7%) patients in the PTA plus EBT group (P = .84). Target vessel revascularization was performed during a mean follow-up period of 5 years in 37 of 51 (72.5%) patients in the PTA group and in 36 of 51 (70.6%) patients in the PTA plus EBT group (P = .83).
Survival
During a mean follow-up of 5 years, 17 of 102 (16.7%) patients with follow-up information concerning survival died, 10 (three without information on recurrence) in the PTA group and seven (five without information on recurrence) in the PTA plus EBT group. Patients who died without information on recurrence were censored with the date of their last follow-up.
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DISCUSSION |
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The stepwise increase of recurrence in the irradiated group suggests that radiation may delay the biologic process of restenosis attributed to neointimal hyperplasia, but that a late catch-up phenomenon minimizes its long-term clinical benefit, which has already been reported previously for the coronary arteries (15). Furthermore, secondary effects of radiation therapy itself, as suggested by findings of clinical oncological studies (16,17), may contribute to the generation of late restenosis.
In previous trials investigating the effects of EBT after stent implantation in the coronary and peripheral arteries, late thrombosis appeared to be a major limiting problem (10,18,19). In our study, however, we did not observe any late thrombosis in the irradiated group, which is thought to be triggered primarily by delayed and impaired stent reendotheliazation. In the Vienna-2 trial, no stents were applied and balloon dilation alone apparently did not result in increased thrombogenicity of the vessel wall injury; thus, the current antiplatelet therapy recommendations of aspirin in combination with clopidogrel for 12 months and longer, after EBT and stent implantation, do not apply for EBT and balloon dilation alone, as aspirin alone was sufficiently able to prevent thrombosis, at least in the peripheral arteries.
In our investigation, efficacy of PTA plus EBT remained significant during the first 36 months of follow-up, as compared with that of PTA alone. Results of recently published trials in the peripheral arteries have described similar outcomes after 12 and 24 months (20,21). The setting in these two trials, however, prescribed doses of 18 and 14 Gy respectively, and the use of a centering device. No other data regarding long-term results of peripheral PTA and EBT are currently available, to our knowledge, except for a study from the mid-1990s which described consistent benefits of gamma radiation after 7 years in a small nonrandomized cohort of patients treated with PTA and stent implantation (12).
In a recently published trial, Waksman et al (11) presented the 5-year results from the Washington Radiation for In-stent Restenosis (WRIST) trial, where a dose of 15 Gy was prescribed at 2 mm from the source center to the target coronary in-stent restenosis. Waksman et al observed a similar decline in EBT efficacy over the observed time period. In the WRIST trial, however, even at 5-year follow-up, EBT appeared to be considerably more potent at preventing restenosis than did the placebo.
There are obvious differences between the settings in the Vienna-2 and the WRIST trials. The Vienna-2 trial compared PTA in the peripheral arteries with or without adjunct brachytherapy, and the WRIST trial investigated the effects of EBT for in-stent restenosis in the coronary arteries compared with placebo. Both trials, however, underlined the positive effects of gamma radiation to inhibit restenosis.
Our study had limitations. Angiographic follow-up was not available for all investigated patients. Furthermore, the study was limited to a single center, and EBT procedures could not be performed in the catheterization laboratory because of special shielding requirements for such high-activity gamma sources. Yet the patient transportation to the brachytherapy unit after peripheral revascularization was not associated with any problems.
In conclusion, to our knowledge the Vienna-2 trial is the first randomized trial to present 5-year outcomes of adjunct EBT after PTA in the femoropopliteal arteries. We were able to demonstrate that with the applied dose of 12 Gy, gamma irradiation appears to be a valuable tool to inhibit recurrence of disease at 6-month follow-up when compared with PTA alone (27.5%). Between 36 and 60 months, we observed a late catch-up phenomenon, and after 5 years, the recurrence rate (72.5% vs 72.5%, P > .99) was comparable in both groups. Time to recurrence, however, was significantly delayed in the PTA plus EBT arm (17.5 months ± 14.7 vs 7.4 months ± 6.8, P < .05).
The above-mentioned results together with findings from other investigations (11,15,22) suggest that the late catch-up phenomenon observed in the Vienna-2 trial may be directly related to the comparably low radiation dose of 12 Gy, aggravated by the lack of a centering device, which caused further substantial dose inhomogeneities.
The exact dose needed to successfully inhibit and not only delay the biologic process of restenosis in the peripheral arteries needs to be established, and we await the long-term outcomes of the Vienna-3 trial in which we applied a dose of 18 Gy with a centering device.
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ADVANCES IN KNOWLEDGE |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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FOOTNOTES |
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Abbreviations: EBT = endovascular brachytherapy • PTA = percutaneous transluminal angioplasty
Authors stated no financial relationship to disclose.
Author contributions: Guarantors of integrity of entire study, R.M.W., E.M.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, R.M.W., A.C.B.; clinical studies, R.M.W., B.P., E.M.; statistical analysis, R.M.W., A.C.B.; and manuscript editing, all authors
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References |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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This article has been cited by other articles:
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  C. J. White and W. A. Gray Endovascular Therapies for Peripheral Arterial Disease: An Evidence-Based Review Circulation, November 6, 2007; 116(19): 2203 - 2215. [Abstract] [Full Text] [PDF]
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 C. Klonaris, A. Katsargyris, A. Giannopoulos, and E. Bastounis Advances in Endovascular Treatment of Femoropopliteal Arterial Occlusive Disease Perspectives in Vascular Surgery and Endovascular Therapy, December 1, 2006; 18(4): 329 - 341. [Abstract] [PDF]
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