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Int. J. Radiation Oncology Biol. Phys., Vol. 66, No. 1, pp. 238–243, 2006Copyright © 2006 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/06/$–see front matter

doi:10.1016/j.ijrobp.2006.04.024

LINICAL INVESTIGATION Benign Disease

A PHASE II STUDY OF EXTERNAL-BEAM RADIOTHERAPY ANDENDOVASCULAR BRACHYTHERAPY WITH PTA AND STENTING FOR

FEMOROPOPLITEAL ARTERY RESTENOSIS

KAILASH NARAYAN, M.D., F.R.A.N.Z.C.R., PH.D.,* MICHAEL DENTON, F.R.A.C.S.,†

RAM DAS, PH.D.,* DAVID BERNSHAW, M.R.A.C.P., F.R.A.N.Z.C.R.,*ALDO ROLFO, DIP.APPL.SCI. M.B.A.,* SYLVIA VAN DYK, DIP.APPL.SCI.,* AND

ALEX MIRAKIAN, F.R.A.N.Z.C.R.*

*Division of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; †Department of Vascular Surgery,Epworth Hospital, Melbourne, Australia

Purpose: To assess the safety and seek evidence of efficacy of combined external-beam radiotherapy (EBRT) andendovascular brachytherapy in the treatment of stenotic vascular lesions.Methods and Materials: Seventeen patients with high risk for restenosis of femoropopliteal arteries were enrolledin this study from February 2000 to August 2002. The external beam radiotherapy regimen consisted of 10 Gyin 5 fractions of 2 Gy, starting on Day 0. This was followed on Day 6 by angiography, stent placement, andintraluminal brachytherapy to a dose of 10 Gy at 1.2 mm from stent surface. The EBRT was continued from thesame day to another 10 Gy in 2 Gy daily fractions for 5 days.Results: The follow up ranged from 33 months to 60 months. At the time of analysis 15 of 17 patients were alivewith patent stents. Of these, 10 were symptom-free. Two patients died of unrelated causes.Conclusions: The combination of EBRT and endovascular brachytherapy provided adequate dose distributionwithout any geographical miss or “candy wrapper” restenosis. No incidence of aneurysmal dilation of radiatedvascular segment was observed. The treatment was feasible, well tolerated, and achieved 88% stenosis freesurvival. © 2006 Elsevier Inc.

Endovascular brachytherapy, Vascular stents, Restenosis, Paris® catheter.

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INTRODUCTION

eointimal hyperplasia (NIH) is the major component ofestenosis following percutaneous transluminal angioplastyPTA) of femoropopliteal blood vessels. Intravascular stent-ng in humans (without intraluminal radiotherapy) has re-uced restenosis in coronary (1) and iliac arteries (2) but haseen far less successful in femoropopliteal vessels. Additionf intravascular brachytherapy (IVBT) to PTA has reducedhe incidence of restenosis (3), but owing to inhomogeneousose distribution across the target lesion, both restenosis (oress than satisfactory patency rates) (4) and aneurysmalilation of radiated segment (5) have occurred. The neoin-imal response originates from the adventitia (that is fromhe periphery of the blood vessel) and not from the intimaadjacent to the endothelial cell lining) (6, 7, 8). The pro-iferation of modified smooth muscle cells, myofibroblasts,9) occurs 1 to 2 days post-angioplasty due to the release of

Reprint requests to: Kailash Narayan, M.D., F.R.A.N.Z.C.R.,h.D., Division of Radiation Oncology, Peter MacCallum Can-er Centre, St. Andrew’s Place, Melbourne 3002, Australia.el: (�61) 3-9656 1057; Fax: (�61) 3-9656 1424; E-mail:ailash.narayan@petermac.org

cknowledgments—The authors wish to thank Nucleotron (Camp- A

238

ytokines and other growth factors, which are activated byxposure of the media to various blood constituents, e.g.,latelets (10, 11, 12). Migration of proliferating cells intoubintima then occurs between days 4 and 7 (13). Thusrradiation of the entire vessel wall and its surroundings ishe most important consideration in reducing the prolifera-ive stimulus. Irradiation delivered immediately follow-ng injury will be highly effective due to the exquisiteadiosensitivity of dividing cells (12). The delivery of aomogeneous dose of radiation to the target region (ad-entitia and vessel wall) is paramount but is technicallyifficult if only IVBT is used. Also, effective externaleam radiotherapy (EBRT) would necessitate irradiationf a large volume of normal tissue to high doses withttendant late radiation toxicity. We therefore decided toeduce the inhomogeniety of dose distribution by a com-ination of both EBRT and high dose rate (HDR) brachy-

rdown, NSW, Australia) for their support in providing the Paris®

atheters and Boston Scientific (Natick, MA) for providing stents.e are also thankful to Dr. Prabhakar Tripuraneni and Richard

isher for helpful suggestions.Received Aug 31, 2005, and in revised form March 31, 2006.

ccepted for publication April 1, 2006.

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herapy. EBRT was used to irradiate the blood vesselsnd surrounding tissues to a modest cytostatic dose of 20y and IVBT to treat the vascular lumen and subintima

o a cytocidal dose.

bjectiveTo assess the safety of combined EBRT and IVBT in the

reatment of stenotic vascular lesions, and to assess thencidence of restenosis and rate of target lesion revascular-zation post-treatment.

MATERIALS AND METHODS

The trial was conducted under a protocol approved by theospital Ethics Committee and the State Radiation Safety Com-ittee. The choice of treatment modalities and the consequencesere explained to all patients by a vascular surgeon and a radiationncologist. All patients signed written informed consent.

ligibilityThe inclusion criteria were (1) superficial femoral or popliteal

rtery restenosis within 18 months of a prior PTA or high risk forestenosis; (2) disease at an accessible site; (3) life expectancy of morehan 6 months post-treatment; (4) patient fitness to tolerate surgicalntervention; (5) accessibility for follow-up; (6) a patent tibial artery inhe affected limb; and (7) WHO performance status 0–2. Exclusionriteria were (a) a prior surgical bypass procedure at the site of theesion; (b) radiotherapy to the diseased limb; (c) local or systemicontraindications (burns etc.); (d) prior anti-neoplastic chemotherapy;e) a history of thrombotic tendencies; and (f) current smoker.

reatment regimenTreatment was delivered over an 11-day period. Two courses

ach of 10 Gy in 5 fractions were given by EBRT (6MV x-rays) onay 1 to 5 (Tuesday to Saturday) and 7 to 11 (Monday to Friday).n Day 7 (Monday am), PTA, stenting, and HDR-IVBT with aARIS® catheter were carried out. The target lesion for EBRT was

ocalized using duplex ultrasound before commencement of treat-ent, with the aid of a radio-opaque marker. The prescription dose

or IVBT was 10 Gy at 1.2 mm from the surface of the stent.

uplex ultrasoundDuplex ultrasound was performed before commencement of

BRT to determine the location and extent of the target lesion.adio-opaque markers were taped to the affected length at 4 points.hese corresponded to the proximal (B) and distal (C) limits of the

esion (Fig 1). Points A and D were chosen close to the stenosis wherelood flow was normal. Patients were then transferred to the simulatorhere X-ray films were taken and treatment fields marked on the skin,here lead shots were replaced by tattoo marks. These markings weresed for daily treatment setup.

xternal-beam radiotherapyExternal-beam radiotherapy was started on the second day after

ntervention using 6 MV x-rays and using a pair of anterior-posterior–osterior-anterior (AP-PA) fields. A wider margin field was used withn upper border 3–5 cm superior to proximal target lesion, inferiororder 3–5 cm inferior to the distal target lesion, and lateral borders 3m on either side of the lateral margins of the lesion. The radio-

paque markers were helpful in identifying the lesion size. Dose w

rescription was to half the AP distance. Appropriate thicknesses ofolus were used. A dose of 10 Gy in 5 daily fractions of 2 Gy wasiven in the next 5 days, namely Tuesday to Saturday. On Monday theTA and stenting were done, followed by HDR-IVBT. Immediatelyollowing brachytherapy the second installment of EBRT was startedo give a further 10 Gy in 5 daily fractions.

ngiography, stenting, and insertion of PARIS® catheterBefore angioplasty, the patient was admitted and administered a

ingle dose of aspirin, 150 mg orally. At the time of percutaneousuncture a loading dose of heparin (100 units per kg) was given.uring the procedure 500 mL Dextran 40 was given IV over a 4 heriod. Under local anesthetic a percutaneous antegrade puncture wasade in the common femoral artery and, under fluoroscopic control,guide wire was passed through the superficial femoral artery and aFr sheath inserted. An angiogram was performed and the target

esion was identified and cannulated with a 0.035 inch guide wire. Ifn occlusion was present then a 5 Fr Van Andel catheter was intro-uced to traverse the lesion with Trumo® 035 guide wire. Once theesion traversed was confirmed by angiogram, the guide wire was leftn place. A 5 Fr Schindler Smash balloon catheter was introduced andilated to an appropriate diameter. Following this, angiography wasone and a stent (Boston Scientific Symphony) of appropriate diam-ter and length was introduced and deployed. At the completion of theeployment, further balloon dilatation was performed.

rachytherapyFollowing the above intervention, a 7 Fr Paris® low pressure

alloon catheter was inserted under fluoroscopic control and localizedo the target. The Paris® catheter is a double lumen catheter system.he central lumen can be connected to the Nucletron HDR unit torive in the check source or the active source. The outer lumen is usedo inflate the balloon in segments to keep the inner source lumenentered along the length of the catheter. The catheter was 150 cmong. The inflatable balloon segment was 10 cm. A gold marker at theistal end helps to radiographically position the catheter 1 cm beyondhe intervened segment of the artery (Fig. 2). The target length was theength of the stent plus a 1 cm margin proximal and distal to the stent.he catheter was deflated and secured on the skin before the patientas moved to the HDR suite. Before connecting the catheter to theDR unit, the position was re-checked and the balloon inflated. A line

ource plan was used for the treatment as per prescription. No cor-ection was applied for any small curvature of the catheter.

Upon completion of treatment, the unit was disconnected from theatheter and Heparin was reversed with protamine sulfate. The cath-ter and guide wires were removed and pressure was applied tostablish hemostasis at the puncture site. The patient remained in theospital overnight for observation. All patients were put on 100 mgspirin daily, indefinitely. The next installment of external beamadiotherapy was commenced the same day. Patients were examinedefore RT, the day after the intervention, and at 3, 6, 9, and 12 monthsollowing the procedure (Table 1). All patients were followed up to

arch 2005.

RESULTS

From February 2000 to August 2002, 17 patients werenrolled in the study (Table 2). The patient demographic de-ails are given in Table 3. The average age of the patients was3 years (range, 62–91 years), The average length of the lesion

as 5.4 cm (range, 1.1–8.0 cm). Of the 17 patients, 15 were

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240 I. J. Radiation Oncology ● Biology ● Physics Volume 66, Number 1, 2006

live at the time of last follow-up (range of follow-up, 33–60onths). One patient died of stomach cancer and another died

f renal failure secondary to complications of diabetes. Of the5 surviving patients, 10 were asymptomatic and were active

Fig. 1. Simulation and localization. (A) Positioning of affecsimulation film. A and D—Points beyond which blood flo

ig. 2. Inflated segmented Paris catheter with gold marker 1 cm

bistal to the lesion.

ormally (Table 4). Of the 5 symptomatic patients, 1 patientNo. 1) had PTA performed in the (untreated) right lower limb6 months after the irradiation on the left leg. The PTA wasnsuccessful, and a by-pass was done 3 months later.

In another patient (No. 12), the right limb became progres-ively symptomatic and at 32 months from the original proce-ure in the left leg, a stent was placed in the right lower limb.n two patients (Nos. 13 and 15) the irradiated stent becameccluded �50%, requiring a by-pass procedure, at 18 and 25onths, respectively. Thus 2 of 17 patients failed in the treated

egment. Target lesion revascularization in these patients wasot attempted. None developed candy wrapper stenosis.

DISCUSSION

Clinical investigations have indicated that irradiation by

b during Doppler study. (B) Corresponding data points onrmal. B and C—Proximal and distal limits of the lesion.

ted lim

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n femoropopliteal arteries results in significant reduction inestenosis (14, 15, 16). Recently, Pokrajac (17), on a random-zed study with 134 patients (Vienna-3 trial), obtained 70–0% patency in focal lesions. For lesions longer than 5 cm theatency was less than 30%. Since our study population ismall, we could not arrive at any conclusions in regard to riskf restenosis and length of lesion. A patency rate of 88% (15ut of 17) at 24 months achieved with the combination ofBRT and brachytherapy in our study is superior to the 77.3%t 12 months reported in the Vienna-3 trial.

One of the side effects of brachytherapy alone is the ‘edge

Table 1. Study parameters prior RT and post RT

Test Pre RT1 monthpost RT

3 monthspost RT

6 monthspost RT

istory x x x xxamination x x x xlood tests* xHO performancestatus† x x xuplex U/S x x x xXR x xngiography x xoxicity index‡ x x x x

Abbreviations: EORTC � European Organization for Researchnd Treatment of Cancer; CXR � Chest X-ray; RTOG � Radia-ion Therapy Oncology Group; WHO � World Health Organiza-ion; RT � radiotherapy.

* Blood tests to include: Full blood examination, Urea andlectrolytes, Clotting profile, Liver function tests, Fasting serumholesterol/triglycerides.

† Performance status will be assessed using WHO criteria.‡ Acute radiation morbidity–assessed according to EORTC/

TOG acute score. Late morbidity–assessed according to EORTC/TOG late score.

Table 2.

Patient no. Sex Age (y) Target

1 M 74 L.Sup2 F 82 L.Sup3 F 75 L.Pop4 M 68 L.Pop5 F 70 L.Pop6 M 59 L.Pop7 F 73 L.Sup8 F 88 L.Sup9 M 71 L.Sup

10 F 66 L.Sup11 F 68 R.Sup12 F 70 L.Sup13 M 75 R.Sup14 F 66 L.Sup15 F 68 R.Sup16 M 60 R.Sup17 M 75 R.Sup

Abbreviations: F � female; FU � followRestenosis; M � male; L.Popliteal � left popl

percutaneous transluminal angioplasty; R.Sup Fem. �

ffect’ or the ‘candy wrapper effect,’ which is the occurrencef a new stenosis outside the edges of the irradiated segmentr stent (18). It is characterized by negative remodelling andxtensive intimal hyperplasia. This is due to either geo-raphical miss or inadequate dose due to axial dose fall-off17, 19). This effect is observed after radioactive stentmplantation (20) and for catheter-based brachytherapy (21)n coronary artery stenosis patients. Serruys (19) attributes5% edge failures or 40% of restenoses in the irradiatedegment to geographical miss and underdosing. Similar datan peripheral vascular disease are not available although, bynalogy, similar effects would be expected. The combina-ion of EBRT and IVBT has a better chance to avoid sucheographical misses and inadequate dose delivery. We didot observe any “candy wrapper” edge effect in this study.he irradiated target length in all our patients was 1 cmeyond the length of the lesion on either side.Use of external beam alone for irradiation of femoropopli-

eal artery, to prevent restenosis, has been reported by Fritz

t details

Type of lesion Status at last FU

H.R.RS PatentH.R.RS PatentH.R.RS PatentH.R.RS PatentH.R.RS Patent, diedH.R.RS PatentH.R.RS PatentH.R.RS PatentRS �18 mo PTA PatentRS �18 mo PTA PatentH.R.RS PatentRS �18 mo PTA Partial occlusionH.R.RS ClaudificationH.R.RS Partial occlusionH.R.RS PatentH.R.RS PatentH.R.RS Patent, died

.R.R.S. � High Risk of Restenosis; RS �

.Sup.Fem. � left superficial femoral; PTA �

Table 3. Patient data

o. of patients in study 17verage age 73 yrs (Range, 62–91 yrs)ite of lesionLeft superior femoral artery 8Left popliteal artery 4Right superior femoral artery 5edian length of lesion 5.42 cm (Range, 1.1–8 cm)�2 cm 22.1–4 cm 44.1–6 cm 6�6.1 cm 5

ype of lesionVery high risk 3High risk 14

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242 I. J. Radiation Oncology ● Biology ● Physics Volume 66, Number 1, 2006

22). In this study, 47 patients were treated to a dose of 21 Gyt 3 Gy per fraction with 6 MV x-rays and 48 had shamreatment. The radiation field had a lateral margin of 3 cm andcraniocaudal margin of 2 cm from the dilated segment. At 12onths there was a 33.3% failure rate in the sham group versus

5.7% in the EBRT group (p � 0.292). The authors concludedhat the dose was insufficient and that IVBT was better.

We did not observe any aneurysmal dilation of the irra-iated vascular segment. Aneurysmal dilatation of vessels issually seen following degeneration of the smooth musclef the vascular wall. Degenerating muscle is replaced bybrosis and collagen deposition which lack elastic recoil.nder the effect of persistent blood pressure the affected

egions dilate, causing aneurysm (23). Radiation dose het-rogeneity can easily occur from the linear brachytherapyource placed in the lumen of an irregularly thickenedessel wall. This can cause excessive radiation dose in

Table 4. Follow-up data

o. of patients 17atients available for FU 15eriod of FU 33–60 moiving asymptomatically 10iving with symptoms but stent still patent 5iseased 2

Abbreviation: FU � follow up.

hinned-out regions of affected vessel. Such excessive radi- r

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