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DOI: 10.1148/radiol.2302021690
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(Radiology 2004;230:556-560.)
© RSNA, 2004

Radiation Oncology

Endovascular Brachytherapy: Effect on Acute Inflammatory Response after Percutaneous Femoropopliteal Arterial Interventions1

Martin Schillinger, MD, Wolfgang Mlekusch, MD, Roswitha M. Wolfram, MD, Alexandra C. Budinsky, MD, Markus Exner, MD, Helmut Rumpold, MD, Oswald Wagner, MD, Boris Pokrajac, MD, Richard Pötter, MD and Erich Minar, MD

1 From the Departments of Angiology (M.S., W.M., R.M.W., A.C.B., H.R., O.W., E.M.), Medical and Chemical Laboratory Diagnostics (M.E.), and Radiotherapy and Radiobiology (B.P., R.P.), University of Vienna, Medical School, Waehringer Guertel 18–20, A-1090 Vienna, Austria. Received December 13, 2002; revision requested February 27, 2003; final revision received May 8; accepted July 2. Address correspondence to M.S. (e-mail: martin.schillinger@akh-wien.ac.at).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To investigate whether endovascular brachytherapy diminishes vascular inflammation in response to femoropopliteal percutaneous transluminal angioplasty (PTA) or stent implantation in two double-blind randomized-controlled trials.

MATERIALS AND METHODS: Forty-seven consecutive patients from two double-blind randomized-controlled trials were studied. Patients either underwent femoropopliteal PTA with endovascular gamma irradiation (n = 8) or placebo irradiation (n = 7) or underwent PTA and stent implantation with brachytherapy (n = 15) or placebo irradiation (n = 17). High-sensitivity C-reactive protein (CRP), serum amyloid A (SAA), and fibrinogen levels were measured at baseline and 8, 24, and 48 hours after the intervention. The change of acute phase parameters from baseline to 48 hours after intervention indicated the extent of the inflammatory response and was compared between patients undergoing brachytherapy and those undergoing placebo irradiation. Fisher exact test was used for comparison of categorical data, and nonparametric statistical methods were applied for analysis of continuous data (Mann-Whitney U tests for unpaired data and Friedman analysis for repetitive measurements).

RESULTS: Median patient age was 70 years (interquartile range, 56–74 years); 33 (70%) patients were men and 14 (30%) were women. Clinical characteristics and baseline values of acute phase parameters were similar between groups. A statistically significant increase in CRP, SAA, and fibrinogen values was observed after PTA and stent implantation, both in the patients who underwent brachytherapy and in those who underwent placebo irradiation. Compared with placebo irradiation, however, brachytherapy did not significantly reduce any acute phase parameter from baseline to 8, 24, or 48 hours after the intervention (P > .05 for all comparisons).

CONCLUSION: Endovascular brachytherapy did not diminish early vascular inflammation in response to PTA or stent implantation and even induced a trend toward an increased inflammatory response.

© RSNA, 2004

Index terms: Arteries, extremities • Arteries, femoral, 922.1267, 922.1282, 922.454 • Arteries, grafts and prostheses, 922.1267, 924.1267 • Arteries, popliteal, 924.1267, 924.1282, 924.454 • Arteries, transluminal angioplasty, 922.1282, 922.454, 924.1282, 924.454 • Therapeutic radiology, experimental studies, 92.47, 92.1269


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Endovascular brachytherapy yields improved patency rates after femoropopliteal percutaneous transluminal angioplasty (PTA) and stent implantation (1–5). The development of recurrent lumen narrowing, however, is not completely inhibited by application of irradiation therapy (3,5). Occurrence of restenosis involves constrictive vascular remodeling and neointimal or in-stent neointimal hyperplasia (6–10). It could be demonstrated that PTA and stent implantation induce a vascular inflammatory response (9–12), which is an essential trigger for the underlying proliferation of myofibroblasts and accumulation of extracellular matrix proteins, both of which lead to late lumen loss (11,13–17). Several studies elucidated a close correlation between restenosis and the acute phase parameters C-reactive protein (CRP), serum amyloid A (SAA), and fibrinogen (8,11,13–15,18–20).Consistently, suppression of the inflammatory response—as demonstrated with the sirolimus-eluting stents (21)—seems to be crucial to effectively prevent restenosis. Thus, the purpose of our study was to investigate whether endovascular brachytherapy diminishes vascular inflammation in response to femoropopliteal PTA or stent implantation in two double-blind randomized controlled trials.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design
We studied 47 consecutive patients from two randomized controlled double-blind trials (subsets from the Vienna-3 and Vienna-5 studies) who either underwent femoropopliteal PTA with endovascular gamma irradiation (n = 8) or with placebo irradiation (n = 7) or underwent PTA and stent implantation with brachytherapy (n = 15) or with placebo irradiation (n = 17) from March 1, 2000 to March 1, 2001. The studies complied with the Declaration of Helsinki and were approved by the local ethics committee. All patients gave their written informed consent.

Inclusion and Exclusion Criteria
Part of the study protocols was previously published (3). Briefly, patients older than 40 years who had a history of claudication lasting more than 3 months, or with critical limb ischemia and a de novo lesion in the femoropopliteal region with a length of at least 5 cm, or with a recurrent lesion (after previous PTA) of any length were eligible for inclusion in this study, dependent on initial technical success based on a residual stenosis of less than 30% on the final angiogram. Patients who underwent only PTA were included in the Vienna-3 study, whereas patients who required additional stent implantation were included in the Vienna-5 study.

After successful primary interventions, patients were randomly assigned to undergo further brachytherapy or placebo irradiation with adaptive randomization according to the following stratification criteria: de novo lesion versus recurrent lesion, stenosis versus occlusion, and claudication versus critical limb ischemia.

Interventions
Procedures were performed by one interventionist with more than 15 years experience in endovascular treatment (E.M.) by using an ipsilateral antegrade puncture with 8-F sheaths. After angiographic documentation of lesion morphology (length of the lesion, degree of stenosis, or presence of occlusion) and runoff vessels, PTA was performed with 5- or 6-mm balloon catheters (Smash; Boston Scientific, Natick, Mass) corresponding to the proximal nondisease vessel area. The criterion for stent implantation was suboptimal primary technical success defined as either (a) a remaining stenosis of more than 30% after PTA, (b) an elastic recoil at the dilated segment after repeated PTA with a remaining stenosis greater than 30% at the dilated segment, or (c) an arterial dissection leading to greater than 30% reduction in lumen diameter. Easy Wallstents (Boston Scientific) were used in case of stent implantation. The amount of contrast agent, dose of heparin, and duration of fluoroscopy were routinely recorded.

After successful procedures with a residual stenosis of less than 30%, a centering catheter for application of brachytherapy or placebo irradiation was deployed across the site where PTA or stent placement was performed, and the patient was transferred to a brachytherapy unit. Details of the brachytherapy protocol are described elsewhere (3). In brief, an iridium 192 source was used with a remote high-dose-rate afterloading device (microSelectron; Nucletron, Veenendaal, the Netherlands) to apply a reference dose of 18 Gy at a depth of "radius plus 2 mm" after PTA and a reference dose of 14 Gy within a distance of "postintervention radius plus 2 mm" after stent implantation, respectively. Planning and application of the irradiation or placebo therapy were performed by one of the authors (B.P.).

Patient Data
Two independent observers (M.S. and W.M.) recorded patient demographic data, medical history, risk factors, data from physical examination, and routine laboratory findings with a standard questionnaire at admission. Data were checked for interobserver agreement at the time the patient was discharged from the hospital. In case of discrepancies, the patient was reevaluated by both investigators in consensus.

Laboratory Assessments
Antecubital venous blood samples for determination of CRP, SAA, and fibrinogen levels were obtained at baseline before the intervention and 8, 24, and 48 hours after the intervention. We used high-sensitivity assays (N Latex CRP Mono and N Latex SAA, Dade Behring, Vienna, Austria; Fibrinogen Clauss, Stago/ Roche, Basel, Switzerland) with a sensitivity of 0.03 mg/dL, 3.8 mg/L, and 20 mg/dL and coefficients of variation of 4.6%, 6.4%, and 5.2%, respectively, for measurement of CRP, SAA, and fibrinogen levels. All laboratory investigations were performed with supervision of two authors in consensus (M.E. and H.R.).

Statistical Analysis
Continuous data are presented as the median and interquartile range (IQR) (range, from the 25th to the 75th percentile). Discrete data are given as counts and percentages. Fisher exact test was used to compare groups of categorical data. The Mann-Whitney U test was used to compare unpaired groups of continuous data. Friedman tests were applied to analyze repetitive measurements. A two-sided P value of less than .05 was considered to indicate a significant difference. Calculations were performed with statistical software (SPSS for Microsoft Windows, version 10.0; SPSS, Chicago, Ill).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
The records of all 47 patients enrolled in the two brachytherapy trials had complete data, and these cases were included in the final analysis. Median patient age was 70 years (IQR, 56–74 years); 33 patients (70%) were men and 14 (30%) were women. Median age was 61 years (IQR, 54–72 years) in men and 73 years (IQR, 71–76 years) in women. Forty-one (87%) of 47 patients had severe claudication that limited their lifestyle with a median maximum walking distance of 80 m (IQR, 40–120 m). The remaining six (13%) patients were treated for critical limb ischemia. Demographic data, clinical characteristics, and procedure-related variables of patients who underwent PTA or stent implantation are given in the Table. Variables were equally balanced between patients who underwent brachytherapy and those who underwent placebo irradiation in both intervention groups. There was no significant difference between all variables listed.


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  		Demographic Data, Clinical Characteristics, and Procedure-related Variables of 47 Patients Undergoing Femoropopliteal PTA or Stent Implantation

 
Levels of acute phase parameters immediately before the intervention were comparable between the groups (Table). During the first 48 hours after PTA and stent implantation, we observed a significant increase in CRP, SAA, and fibrinogen levels in the patients who underwent brachytherapy and in the patients who underwent placebo irradiation (Friedman test, P < .05). We found no significant reduction in the extent of postintervention acute phase response, however, as indicated by the change of CRP, SAA, and fibrinogen levels from baseline to 8, 24, and 48 hours after brachytherapy compared with placebo irradiation (Figure). On the contrary, it seemed that brachytherapy was associated with a rather enhanced acute phase response, as CRP and SAA levels were significantly more elevated after stent implantation and brachytherapy than after plain stent implantation, particularly within the first 24 hours after the procedure (Figure).



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  		Inflammatory response after PTA or stent implantation, as measured with the change of CRP, SAA, and fibrinogen levels from baseline to 8, 24, and 48 hours after the intervention. Box plots indicate median, IQR (from the 25th to the 75th percentile), and total range.

 
After PTA, a trend toward a higher increase of acute phase parameters at 24 hours was seen in the patients who underwent brachytherapy compared with those who underwent placebo irradiation. For example, the median increase in CRP levels from baseline to 48 hours after PTA was 2.69 mg/dL (26.9 mg/L) (IQR, 0.26–5.49 mg/dL [2.6–54.9 mg/L]) for brachytherapy and 0.39 mg/dL (3.9 mg/L) (IQR, 0.16–2.35 mg/dL [1.6–23.5 mg/L]) for placebo irradiation (P = .37). The median increase in CRP levels from baseline to 48 hours after stent implantation was 1.20 mg/dL (12.0 mg/L) (IQR, 0.69–3.96 mg/dL [6.9–39.6 mg/L]) versus 1.80 mg/dL (18.0 mg/L) (IQR, 0.8–2.48 mg/dL [8.0–24.8 mg/L]) (P = .79).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
We found that endovascular brachytherapy did not diminish the acute phase response after femoropopliteal endovascular treatment. Thus, the improvement in patency rates after brachytherapy (1–5) cannot be explained by suppression of vascular inflammation but is most probably caused by the antimitogenic effects of radiation therapy (22).

The beneficial effects of endovascular brachytherapy for prophylaxis of restenosis after femoropopliteal PTA or stent implantation, particularly in patients with long and complex lesions, are well described (1,3,5); to our knowledge, however, the effect of radiation on the target tissue is not known entirely. Although the classic concept of radiation therapy suggests that migration and proliferation of smooth muscle cells from the media and myofibroblasts from the adventitia are inhibited, it may also be speculated that the activity of inflammatory cells in the vessel wall is influenced by application of irradiation therapy. It is generally agreed that this vascular inflammatory process at the treated segment plays a key role in driving the pathomechanisms that lead to restenosis (7–20). Inhibition of inflammation, as has been shown to occur after sirolimus-eluting stent implantation (21), seems crucial to effectively suppress neointimal hyperplasia and constrictive vascular remodeling. Putting these findings together with our findings, we conclude that a lack of antiinflammatory capacity of endovascular brachytherapy may be one of the reasons for the incomplete long-term success of this technique. Certainly, other factors such as dose-finding problems, inadequate centering of the radiation catheter, and late thrombotic in-stent reocclusions also contribute to the technical failures of brachytherapy reported in the literature (1–5).

Clinical side effects reflecting a systemic inflammatory reaction, as has been reported with covered stent-grafts in the femoropopliteal area (23), were not observed with brachytherapy. It remains unclear why brachytherapy caused a slightly increased inflammatory response in the perivascular tissue, although this response was insignificant. Nevertheless, it is well known that repetitive high doses of gamma irradiation are capable of inducing considerable inflammation (referring to the side effect of irradiation dermatitis after transcutaneous tumor irradiation therapy). Thus, a combination of brachytherapy with anti-inflammatory treatment (eg, administration of high-dose statins) may be worth further examination. Another side effect of enhanced vascular inflammation after brachytherapy may be the activation of the coagulation cascade. In this context, higher early thrombosis rates have been reported, particularly after stent implantation and brachytherapy (5); however, this may also be a consequence of the antimitogenic effects of brachytherapy and a delayed reendothelialization at the segment where a stent was placed.

The time interval of 48 hours for determination of acute phase reactants in the present study was used on the basis of former observations, which ascertained a significant increase of CRP, SAA, and fibrinogen levels within this time period and a considerable prognostic impact of 0–48-hour values with respect to restenosis after femoropopliteal interventions (11,13–15,18–20). Nevertheless, our current conclusions are limited to an early vascular inflammatory response, as we did not measure late vascular inflammation in these studies.

We are aware that the number of patients enrolled in the present study was rather small, particularly in the subgroup of patients who underwent PTA. Nevertheless, those patients who underwent brachytherapy after PTA and after stent implantation showed a trend toward an enhanced inflammatory response rather than a diminished response. It seems unlikely that if patient numbers were increased this effect would be reversed; therefore, our conclusions seem adequate.

Furthermore, it has to be acknowledged that we included data from two different studies comparing brachytherapy versus placebo irradiation after PTA (Vienna-3) and after stent implantation (Vienna-5), and that different brachytherapy doses were used in these studies. A higher dose was used after PTA than after stent implantation, which makes a direct comparison difficult; however, patients who received the higher dose (18 Gy) after PTA tended to exhibit a more extensive inflammatory response than did patients who received a lower dose (14 Gy) after stent implantation. Patients who underwent placebo irradiation after PTA and stent implantation compared well with respect to postintervention inflammation. This supports the view that increasing doses of brachytherapy induce vascular inflammation at the treated segment.

Endovascular brachytherapy does not diminish early vascular inflammation in response to PTA or stent implantation, and it even induced a trend toward an increased inflammatory response that reached limited significance only at 24 hours after stent implantation. Thus, the reduced rates of restenosis after brachytherapy cannot be explained by an antiinflammatory radiation effect.


   FOOTNOTES
 
Abbreviations: CRP = C-reactive protein, IQR = interquartile range, PTA = percutaneous transluminal angioplasty, SAA = serum amyloid A

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


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 

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