- Email: [email protected]
A Phase II study of external-beam radiotherapy and endovascular brachytherapy with PTA and stenting for femoropopliteal artery restenosis
Int. J. Radiation Oncology Biol. Phys., Vol. 66, No. 1, pp. 238 –243, 2006 Copyright © 2006 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/06/$–see front matter
doi:10.1016/j.ijrobp.2006.04.024
CLINICAL INVESTIGATION
Benign Disease
A PHASE II STUDY OF EXTERNAL-BEAM RADIOTHERAPY AND ENDOVASCULAR 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) and endovascular brachytherapy in the treatment of stenotic vascular lesions. Methods and Materials: Seventeen patients with high risk for restenosis of femoropopliteal arteries were enrolled in this study from February 2000 to August 2002. The external beam radiotherapy regimen consisted of 10 Gy in 5 fractions of 2 Gy, starting on Day 0. This was followed on Day 6 by angiography, stent placement, and intraluminal brachytherapy to a dose of 10 Gy at 1.2 mm from stent surface. The EBRT was continued from the same 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 alive with 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 distribution without any geographical miss or “candy wrapper” restenosis. No incidence of aneurysmal dilation of radiated vascular segment was observed. The treatment was feasible, well tolerated, and achieved 88% stenosis free survival. © 2006 Elsevier Inc. Endovascular brachytherapy, Vascular stents, Restenosis, Paris® catheter.
cytokines and other growth factors, which are activated by exposure of the media to various blood constituents, e.g., platelets (10, 11, 12). Migration of proliferating cells into subintima then occurs between days 4 and 7 (13). Thus irradiation of the entire vessel wall and its surroundings is the most important consideration in reducing the proliferative stimulus. Irradiation delivered immediately following injury will be highly effective due to the exquisite radiosensitivity of dividing cells (12). The delivery of a homogeneous dose of radiation to the target region (adventitia and vessel wall) is paramount but is technically difficult if only IVBT is used. Also, effective external beam radiotherapy (EBRT) would necessitate irradiation of a large volume of normal tissue to high doses with attendant late radiation toxicity. We therefore decided to reduce the inhomogeniety of dose distribution by a combination of both EBRT and high dose rate (HDR) brachy-
INTRODUCTION Neointimal hyperplasia (NIH) is the major component of restenosis following percutaneous transluminal angioplasty (PTA) of femoropopliteal blood vessels. Intravascular stenting in humans (without intraluminal radiotherapy) has reduced restenosis in coronary (1) and iliac arteries (2) but has been far less successful in femoropopliteal vessels. Addition of intravascular brachytherapy (IVBT) to PTA has reduced the incidence of restenosis (3), but owing to inhomogeneous dose distribution across the target lesion, both restenosis (or less than satisfactory patency rates) (4) and aneurysmal dilation of radiated segment (5) have occurred. The neointimal response originates from the adventitia (that is from the periphery of the blood vessel) and not from the intima (adjacent to the endothelial cell lining) (6, 7, 8). The proliferation of modified smooth muscle cells, myofibroblasts, (9) occurs 1 to 2 days post-angioplasty due to the release of
erdown, NSW, Australia) for their support in providing the Paris® catheters and Boston Scientific (Natick, MA) for providing stents. We are also thankful to Dr. Prabhakar Tripuraneni and Richard Fisher for helpful suggestions. Received Aug 31, 2005, and in revised form March 31, 2006. Accepted for publication April 1, 2006.
Reprint requests to: Kailash Narayan, M.D., F.R.A.N.Z.C.R., Ph.D., Division of Radiation Oncology, Peter MacCallum Cancer Centre, St. Andrew’s Place, Melbourne 3002, Australia. Tel: (⫹61) 3-9656 1057; Fax: (⫹61) 3-9656 1424; E-mail:
[email protected] Acknowledgments—The authors wish to thank Nucleotron (Camp238
RT for prevention of vascular re-stenosis
therapy. EBRT was used to irradiate the blood vessels and surrounding tissues to a modest cytostatic dose of 20 Gy and IVBT to treat the vascular lumen and subintima to a cytocidal dose. Objective To assess the safety of combined EBRT and IVBT in the treatment of stenotic vascular lesions, and to assess the incidence of restenosis and rate of target lesion revascularization post-treatment. MATERIALS AND METHODS The trial was conducted under a protocol approved by the Hospital Ethics Committee and the State Radiation Safety Committee. The choice of treatment modalities and the consequences were explained to all patients by a vascular surgeon and a radiation oncologist. All patients signed written informed consent.
Eligibility The inclusion criteria were (1) superficial femoral or popliteal artery restenosis within 18 months of a prior PTA or high risk for restenosis; (2) disease at an accessible site; (3) life expectancy of more than 6 months post-treatment; (4) patient fitness to tolerate surgical intervention; (5) accessibility for follow-up; (6) a patent tibial artery in the affected limb; and (7) WHO performance status 0 –2. Exclusion criteria were (a) a prior surgical bypass procedure at the site of the lesion; (b) radiotherapy to the diseased limb; (c) local or systemic contraindications (burns etc.); (d) prior anti-neoplastic chemotherapy; (e) a history of thrombotic tendencies; and (f) current smoker.
Treatment regimen Treatment was delivered over an 11-day period. Two courses each of 10 Gy in 5 fractions were given by EBRT (6MV x-rays) on Day 1 to 5 (Tuesday to Saturday) and 7 to 11 (Monday to Friday). On Day 7 (Monday am), PTA, stenting, and HDR-IVBT with a PARIS® catheter were carried out. The target lesion for EBRT was localized using duplex ultrasound before commencement of treatment, with the aid of a radio-opaque marker. The prescription dose for IVBT was 10 Gy at 1.2 mm from the surface of the stent.
Duplex ultrasound Duplex ultrasound was performed before commencement of EBRT to determine the location and extent of the target lesion. Radio-opaque markers were taped to the affected length at 4 points. These corresponded to the proximal (B) and distal (C) limits of the lesion (Fig 1). Points A and D were chosen close to the stenosis where blood flow was normal. Patients were then transferred to the simulator where X-ray films were taken and treatment fields marked on the skin, where lead shots were replaced by tattoo marks. These markings were used for daily treatment setup.
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prescription was to half the AP distance. Appropriate thicknesses of bolus were used. A dose of 10 Gy in 5 daily fractions of 2 Gy was given in the next 5 days, namely Tuesday to Saturday. On Monday the PTA and stenting were done, followed by HDR-IVBT. Immediately following brachytherapy the second installment of EBRT was started to give a further 10 Gy in 5 daily fractions.
Angiography, stenting, and insertion of PARIS® catheter Before angioplasty, the patient was admitted and administered a single dose of aspirin, 150 mg orally. At the time of percutaneous puncture a loading dose of heparin (100 units per kg) was given. During the procedure 500 mL Dextran 40 was given IV over a 4 h period. Under local anesthetic a percutaneous antegrade puncture was made in the common femoral artery and, under fluoroscopic control, a guide wire was passed through the superficial femoral artery and a 7 Fr sheath inserted. An angiogram was performed and the target lesion was identified and cannulated with a 0.035 inch guide wire. If an occlusion was present then a 5 Fr Van Andel catheter was introduced to traverse the lesion with Trumo® 035 guide wire. Once the lesion traversed was confirmed by angiogram, the guide wire was left in place. A 5 Fr Schindler Smash balloon catheter was introduced and dilated to an appropriate diameter. Following this, angiography was done and a stent (Boston Scientific Symphony) of appropriate diameter and length was introduced and deployed. At the completion of the deployment, further balloon dilatation was performed.
Brachytherapy Following the above intervention, a 7 Fr Paris® low pressure balloon catheter was inserted under fluoroscopic control and localized to the target. The Paris® catheter is a double lumen catheter system. The central lumen can be connected to the Nucletron HDR unit to drive in the check source or the active source. The outer lumen is used to inflate the balloon in segments to keep the inner source lumen centered along the length of the catheter. The catheter was 150 cm long. The inflatable balloon segment was 10 cm. A gold marker at the distal end helps to radiographically position the catheter 1 cm beyond the intervened segment of the artery (Fig. 2). The target length was the length of the stent plus a 1 cm margin proximal and distal to the stent. The catheter was deflated and secured on the skin before the patient was moved to the HDR suite. Before connecting the catheter to the HDR unit, the position was re-checked and the balloon inflated. A line source plan was used for the treatment as per prescription. No correction was applied for any small curvature of the catheter. Upon completion of treatment, the unit was disconnected from the catheter and Heparin was reversed with protamine sulfate. The catheter and guide wires were removed and pressure was applied to establish hemostasis at the puncture site. The patient remained in the hospital overnight for observation. All patients were put on 100 mg aspirin daily, indefinitely. The next installment of external beam radiotherapy was commenced the same day. Patients were examined before RT, the day after the intervention, and at 3, 6, 9, and 12 months following the procedure (Table 1). All patients were followed up to March 2005.
External-beam radiotherapy External-beam radiotherapy was started on the second day after intervention using 6 MV x-rays and using a pair of anterior-posterior– posterior-anterior (AP-PA) fields. A wider margin field was used with an upper border 3–5 cm superior to proximal target lesion, inferior border 3–5 cm inferior to the distal target lesion, and lateral borders 3 cm on either side of the lateral margins of the lesion. The radioopaque markers were helpful in identifying the lesion size. Dose
RESULTS From February 2000 to August 2002, 17 patients were enrolled in the study (Table 2). The patient demographic details are given in Table 3. The average age of the patients was 73 years (range, 62–91 years), The average length of the lesion was 5.4 cm (range, 1.1– 8.0 cm). Of the 17 patients, 15 were
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● Biology ● Physics
Volume 66, Number 1, 2006
Fig. 1. Simulation and localization. (A) Positioning of affected limb during Doppler study. (B) Corresponding data points on simulation film. A and D—Points beyond which blood flow is normal. B and C—Proximal and distal limits of the lesion.
alive at the time of last follow-up (range of follow-up, 33– 60 months). One patient died of stomach cancer and another died of renal failure secondary to complications of diabetes. Of the 15 surviving patients, 10 were asymptomatic and were active
normally (Table 4). Of the 5 symptomatic patients, 1 patient (No. 1) had PTA performed in the (untreated) right lower limb 36 months after the irradiation on the left leg. The PTA was unsuccessful, and a by-pass was done 3 months later. In another patient (No. 12), the right limb became progressively symptomatic and at 32 months from the original procedure in the left leg, a stent was placed in the right lower limb. In two patients (Nos. 13 and 15) the irradiated stent became occluded ⬎50%, requiring a by-pass procedure, at 18 and 25 months, respectively. Thus 2 of 17 patients failed in the treated segment. Target lesion revascularization in these patients was not attempted. None developed candy wrapper stenosis. DISCUSSION
Fig. 2. Inflated segmented Paris catheter with gold marker 1 cm distal to the lesion.
Clinical investigations have indicated that irradiation by both beta and gamma radiation done immediately after PTA
RT for prevention of vascular re-stenosis
● K. NARAYAN et al. Table 3. Patient data
Table 1. Study parameters prior RT and post RT Test
Pre RT
History Examination Blood tests* WHO performance status† Duplex U/S CXR Angiography Toxicity index‡
x x x x x x x x
241
1 month post RT
3 months post RT
6 months post RT
x x
x x
x x
x
x x
x
x
x x x x x
Abbreviations: EORTC ⫽ European Organization for Research and Treatment of Cancer; CXR ⫽ Chest X-ray; RTOG ⫽ Radiation Therapy Oncology Group; WHO ⫽ World Health Organization; RT ⫽ radiotherapy. * Blood tests to include: Full blood examination, Urea and electrolytes, Clotting profile, Liver function tests, Fasting serum cholesterol/triglycerides. † Performance status will be assessed using WHO criteria. ‡ Acute radiation morbidity–assessed according to EORTC/ RTOG acute score. Late morbidity–assessed according to EORTC/ RTOG late score.
in femoropopliteal arteries results in significant reduction in restenosis (14, 15, 16). Recently, Pokrajac (17), on a randomized study with 134 patients (Vienna-3 trial), obtained 70 – 80% patency in focal lesions. For lesions longer than 5 cm the patency was less than 30%. Since our study population is small, we could not arrive at any conclusions in regard to risk of restenosis and length of lesion. A patency rate of 88% (15 out of 17) at 24 months achieved with the combination of EBRT and brachytherapy in our study is superior to the 77.3% at 12 months reported in the Vienna-3 trial. One of the side effects of brachytherapy alone is the ‘edge
No. of patients in study Average age Site of lesion Left superior femoral artery Left popliteal artery Right superior femoral artery Median length of lesion ⬍2 cm 2.1–4 cm 4.1–6 cm ⬎6.1 cm Type of lesion Very high risk High risk
17 73 yrs (Range, 62–91 yrs) 8 4 5 5.42 cm (Range, 1.1–8 cm) 2 4 6 5 3 14
effect’ or the ‘candy wrapper effect,’ which is the occurrence of a new stenosis outside the edges of the irradiated segment or stent (18). It is characterized by negative remodelling and extensive intimal hyperplasia. This is due to either geographical miss or inadequate dose due to axial dose fall-off (17, 19). This effect is observed after radioactive stent implantation (20) and for catheter-based brachytherapy (21) in coronary artery stenosis patients. Serruys (19) attributes 75% edge failures or 40% of restenoses in the irradiated segment to geographical miss and underdosing. Similar data in peripheral vascular disease are not available although, by analogy, similar effects would be expected. The combination of EBRT and IVBT has a better chance to avoid such geographical misses and inadequate dose delivery. We did not observe any “candy wrapper” edge effect in this study. The irradiated target length in all our patients was 1 cm beyond the length of the lesion on either side. Use of external beam alone for irradiation of femoropopliteal artery, to prevent restenosis, has been reported by Fritz
Table 2. Patient details Patient no.
Sex
Age (y)
Target lesion
Type of lesion
Status at last FU
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
M F F M F M F F M F F F M F F M M
74 82 75 68 70 59 73 88 71 66 68 70 75 66 68 60 75
L.Sup.Fem. L.Sup.Fem. L.Popliteal L.Popliteal L.Popliteal L.Popliteal L.Sup.Fem. L.Sup.Fem. L.Sup.Fem. L.Sup.Fem. R.Sup.Fem L.Sup.Fem. R.Sup.Fem L.Sup.Fem. R.Sup.Fem R.Sup.Fem R.Sup.Fem
H.R.RS H.R.RS H.R.RS H.R.RS H.R.RS H.R.RS H.R.RS H.R.RS RS ⬍18 mo PTA RS ⬍18 mo PTA H.R.RS RS ⬍18 mo PTA H.R.RS H.R.RS H.R.RS H.R.RS H.R.RS
Patent Patent Patent Patent Patent, died Patent Patent Patent Patent Patent Patent Partial occlusion Claudification Partial occlusion Patent Patent Patent, died
Abbreviations: F ⫽ female; FU ⫽ follow up; H.R.R.S. ⫽ High Risk of Restenosis; RS ⫽ Restenosis; M ⫽ male; L.Popliteal ⫽ left popliteal; L.Sup.Fem. ⫽ left superficial femoral; PTA ⫽ percutaneous transluminal angioplasty; R.Sup Fem. ⫽ right superficial femoral.
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Table 4. Follow-up data No. of patients Patients available for FU Period of FU Living asymptomatically Living with symptoms but stent still patent Diseased
17 15 33–60 mo 10 5 2
Abbreviation: FU ⫽ follow up.
(22). In this study, 47 patients were treated to a dose of 21 Gy at 3 Gy per fraction with 6 MV x-rays and 48 had sham treatment. The radiation field had a lateral margin of 3 cm and a craniocaudal margin of 2 cm from the dilated segment. At 12 months there was a 33.3% failure rate in the sham group versus 45.7% in the EBRT group (p ⫽ 0.292). The authors concluded that the dose was insufficient and that IVBT was better. We did not observe any aneurysmal dilation of the irradiated vascular segment. Aneurysmal dilatation of vessels is usually seen following degeneration of the smooth muscle of the vascular wall. Degenerating muscle is replaced by fibrosis and collagen deposition which lack elastic recoil. Under the effect of persistent blood pressure the affected regions dilate, causing aneurysm (23). Radiation dose heterogeneity can easily occur from the linear brachytherapy source placed in the lumen of an irregularly thickened vessel wall. This can cause excessive radiation dose in thinned-out regions of affected vessel. Such excessive radi-
Volume 66, Number 1, 2006
ation dose can also destroy surface endothelium, exposing the denuded basement membrane and leading to thrombosis. In our study the combination of 20 Gy with EBRT and 10 Gy at 1.2 mm from the stent achieved 88% stenosis-free survival at 24 months post-angioplasty (15 out of 17 patients). Due to the combination of external beam and brachytherapy, a more homogeneous dose could be delivered across the vascular cross section. In keeping with the pathogenesis of arterosclerosis, where cell division and migration of neo-intimal cells occur from adventitia into subintima, the so-called shrinking field technique, as used in this study, may have led to the favorable result. Currently there are on-going clinical trials with the use of radioactive or drug-eluting stents. The latter seems to be more favored by interventional physicians. Favorable results are reported using polymer-sirolimus-eluting stents (24), 7-hexanoyltaxol-eluting stents (25), and actinomycin D-coated Multilink-Tetra stents (26). Radiation therapy in any form may lose its utility if the drug-eluting technology were found to be suitable and have long-term efficacy. In summary, arteriosclerotic stenosis can be effectively treated by a combination of EBRT and brachytherapy. Our results suggest that in patients with de novo, high risk, femoro-popliteal artery stenosis, the addition of external beam irradiation before and after intravascular brachytherapy, in addition to PTA and stenting, may significantly reduce the rate of restenosis.
REFERENCES 1. Serruys PW, de Jaegere P, Kiemeneji F, et al. A comparison of balloon-expandable stent implantation with balloon angioplasty in patients with coronary artery disease. N Eng J Med 1994;331:489 – 495. 2. Richter GM, Roeren TK, et al. Balloon expandable stent placement vs. PTA in iliac artery restenoses and occlusions: long term results of a randomised trial. J Vasc Interv Radiol 1992;3:9 –12. 3. Waksman R. Intracoronary radiation therapy for restenosis prevention: Status of clinical trials. Cardiovascular Rad Med 1999;1:20 –29. 4. Kruegar K, Zaehringer M, Bendel M, et al. De novo femoropopliteal stenoses: Endovascular gamma irradiation following angioplasty- angiographic and clinical follow-up in a prospective randomised controlled trial. Radiology 2004;231:546 – 554. 5. Condado JA, Waksman R, Gurdiel O, et al. Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty (PTCA) and intracoronary radiation therapy (ICRT) in humans. Circulation 1997;96:727–732. 6. Scott NA, Ross CE, Subramanian R, et al. Characterisation of the cellular response to coronary injury [Abstract]. Circulation 1994;90:1392. 7. Scott NA, Martin F, Simonet L, et al. Contribution of adventitial fibroblasts to vascular remodelling and lesion formation after experimental angioplasty in pig coronary arteries [Abstract]. FASEB J 1995;9:A845. 8. Scott NA, Cipolla GD, Ross CE, et al. Identification of a potential role for the adventitia in vascular lesion formation after balloon injury of porcine coronary arteries. Circulation 1996;93:2178 –2187.
9. Willems IE, Havenith MG, de May JG, et al. The alpha smooth muscle actin-positive cells in healing human myocardial scars. Am J Path 1994;145:868 – 875. 10. Associan RK, Grotendorst GR, Miller DM, et al. Cellular transformation by coordinate action of three peptide growth factors from human platelets. Nature 1984;309:804 – 806. 11. Baamgartner HR, Muggli R. Adhesion and aggression: Morphological demonstration and qualification in vivo and in vitr. In: Gorden JL, editor. Platelets and biology and pathology. Amsterdam: Elsevier: 1976. p. 23– 60. 12. Ip JH, Fuster V, Israel D, et al. The role of platelets, thrombin and hyperplasia in restenosis after coronary angioplasty. Am J Coll Cardiol 1991;17:77B– 88B. 13. Rubin P, Williams JP, Riggs PN, et al. Cellular and molecular mechanisms of radaiation inhibition of restenosis. Part 1: Role of macrophage and platelet-derived growth factor. Int J Radiat Onc Biol Phys 1998;40:929 –941. 14. Bottcher HD, Schopohl B, Liermann D, et al. Endovascular irradiation—a new method to avoid recurrent stenosis after stent implantation in peripheral arteries: Technique and preliminary results. Int J Radiat Oncol Biol Phys 1994;29:183–186. 15. Minar E, Pokrajac B, Maca T, et al. Endovascular brachytherapy for prophylaxis of restenosis after femoropopliteal angioplasty: Results of a prospective randomised study. Am Heart Assoc 2000;102:2694 –2699. 16. Waksman R, Laird JR, Jurkovitz CT, et al. Intravascular radiation therapy after balloon angioplasty of narrowed femoropopliteal arteries to prevent restenosis: Results of the Paris feasibility clinical trial. JVIR 2001;12:915–921. 17. Porajac B, Potter R, Wolfram RM, et al. Endovascular brachytherapy prevents restenosis after femoropopliteal angioplasty:
RT for prevention of vascular re-stenosis
18. 19.
20. 21.
Results of the Vienna-3 randomised multicenter study. Radiother Oncol 2005;74:3–9. Schiele TM, Staber L, Kantleehener R, et al. Edge effect and late thrombosis—inevitable complications of vascular brachytherapy? Z Kardiol 2002;91:869 – 878. Serruys PW, Sianos G, van der Giessen W, et al. Intracoronary b-radiation to reduce restenosis after balloon amgioplasty and stenting. The Beta Radiation in Europe (BRIE) Study. Eur Heart J 2002;23:1351–1359. Albiero R, Takahiro N, Adamian M, et al. Edge restenosis after implantation of high activity 32P radioactive beta-emitting stents. Circulation 2000;101:2454 –2457. Sabate M, Costa MA, Kozuma K, et al. Geographic miss: A cause of treatment failure in radio-oncology applied to intracoronary radiation therapy. Circulation 2000;101:2467– 2471.
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22. Fritz P, Stein U, Hasslacher C, et al. External beam radiotherapy fails to prevent restenosis after iliac or femoropopliteal percutaneous transluminal angioplasty: Results of a prospective randomised double-blind study. Int J Radiat Oncol Biol Phys 2004;59:815– 821. 23. Narayan K, Cliff WJ. Morphology of irradiated microvasculature: A combined invivo and electronmicroscopic study. Am J Pathology 1982;106:47– 62. 24. Schuler G. Polymer-sirolimus-eluting stents in de novo lesions. Herz 2004;29:152–161. 25. Eberhard G, Lansky A, Hauptmann KU, et al. J Am Coll Cardiol 2004;44:1368 –1372. 26. Serruys PW, Ormiston JA, Sianos G, et al. Zctinomycineluting stent for coronary revascularization: A randomised feasibility and safety study: the ACTION trial. J Am Coll Cardiol 2004;44:1363–1367.
doi:10.1016/j.ijrobp.2006.04.024
CLINICAL INVESTIGATION
Benign Disease
A PHASE II STUDY OF EXTERNAL-BEAM RADIOTHERAPY AND ENDOVASCULAR 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) and endovascular brachytherapy in the treatment of stenotic vascular lesions. Methods and Materials: Seventeen patients with high risk for restenosis of femoropopliteal arteries were enrolled in this study from February 2000 to August 2002. The external beam radiotherapy regimen consisted of 10 Gy in 5 fractions of 2 Gy, starting on Day 0. This was followed on Day 6 by angiography, stent placement, and intraluminal brachytherapy to a dose of 10 Gy at 1.2 mm from stent surface. The EBRT was continued from the same 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 alive with 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 distribution without any geographical miss or “candy wrapper” restenosis. No incidence of aneurysmal dilation of radiated vascular segment was observed. The treatment was feasible, well tolerated, and achieved 88% stenosis free survival. © 2006 Elsevier Inc. Endovascular brachytherapy, Vascular stents, Restenosis, Paris® catheter.
cytokines and other growth factors, which are activated by exposure of the media to various blood constituents, e.g., platelets (10, 11, 12). Migration of proliferating cells into subintima then occurs between days 4 and 7 (13). Thus irradiation of the entire vessel wall and its surroundings is the most important consideration in reducing the proliferative stimulus. Irradiation delivered immediately following injury will be highly effective due to the exquisite radiosensitivity of dividing cells (12). The delivery of a homogeneous dose of radiation to the target region (adventitia and vessel wall) is paramount but is technically difficult if only IVBT is used. Also, effective external beam radiotherapy (EBRT) would necessitate irradiation of a large volume of normal tissue to high doses with attendant late radiation toxicity. We therefore decided to reduce the inhomogeniety of dose distribution by a combination of both EBRT and high dose rate (HDR) brachy-
INTRODUCTION Neointimal hyperplasia (NIH) is the major component of restenosis following percutaneous transluminal angioplasty (PTA) of femoropopliteal blood vessels. Intravascular stenting in humans (without intraluminal radiotherapy) has reduced restenosis in coronary (1) and iliac arteries (2) but has been far less successful in femoropopliteal vessels. Addition of intravascular brachytherapy (IVBT) to PTA has reduced the incidence of restenosis (3), but owing to inhomogeneous dose distribution across the target lesion, both restenosis (or less than satisfactory patency rates) (4) and aneurysmal dilation of radiated segment (5) have occurred. The neointimal response originates from the adventitia (that is from the periphery of the blood vessel) and not from the intima (adjacent to the endothelial cell lining) (6, 7, 8). The proliferation of modified smooth muscle cells, myofibroblasts, (9) occurs 1 to 2 days post-angioplasty due to the release of
erdown, NSW, Australia) for their support in providing the Paris® catheters and Boston Scientific (Natick, MA) for providing stents. We are also thankful to Dr. Prabhakar Tripuraneni and Richard Fisher for helpful suggestions. Received Aug 31, 2005, and in revised form March 31, 2006. Accepted for publication April 1, 2006.
Reprint requests to: Kailash Narayan, M.D., F.R.A.N.Z.C.R., Ph.D., Division of Radiation Oncology, Peter MacCallum Cancer Centre, St. Andrew’s Place, Melbourne 3002, Australia. Tel: (⫹61) 3-9656 1057; Fax: (⫹61) 3-9656 1424; E-mail:
[email protected] Acknowledgments—The authors wish to thank Nucleotron (Camp238
RT for prevention of vascular re-stenosis
therapy. EBRT was used to irradiate the blood vessels and surrounding tissues to a modest cytostatic dose of 20 Gy and IVBT to treat the vascular lumen and subintima to a cytocidal dose. Objective To assess the safety of combined EBRT and IVBT in the treatment of stenotic vascular lesions, and to assess the incidence of restenosis and rate of target lesion revascularization post-treatment. MATERIALS AND METHODS The trial was conducted under a protocol approved by the Hospital Ethics Committee and the State Radiation Safety Committee. The choice of treatment modalities and the consequences were explained to all patients by a vascular surgeon and a radiation oncologist. All patients signed written informed consent.
Eligibility The inclusion criteria were (1) superficial femoral or popliteal artery restenosis within 18 months of a prior PTA or high risk for restenosis; (2) disease at an accessible site; (3) life expectancy of more than 6 months post-treatment; (4) patient fitness to tolerate surgical intervention; (5) accessibility for follow-up; (6) a patent tibial artery in the affected limb; and (7) WHO performance status 0 –2. Exclusion criteria were (a) a prior surgical bypass procedure at the site of the lesion; (b) radiotherapy to the diseased limb; (c) local or systemic contraindications (burns etc.); (d) prior anti-neoplastic chemotherapy; (e) a history of thrombotic tendencies; and (f) current smoker.
Treatment regimen Treatment was delivered over an 11-day period. Two courses each of 10 Gy in 5 fractions were given by EBRT (6MV x-rays) on Day 1 to 5 (Tuesday to Saturday) and 7 to 11 (Monday to Friday). On Day 7 (Monday am), PTA, stenting, and HDR-IVBT with a PARIS® catheter were carried out. The target lesion for EBRT was localized using duplex ultrasound before commencement of treatment, with the aid of a radio-opaque marker. The prescription dose for IVBT was 10 Gy at 1.2 mm from the surface of the stent.
Duplex ultrasound Duplex ultrasound was performed before commencement of EBRT to determine the location and extent of the target lesion. Radio-opaque markers were taped to the affected length at 4 points. These corresponded to the proximal (B) and distal (C) limits of the lesion (Fig 1). Points A and D were chosen close to the stenosis where blood flow was normal. Patients were then transferred to the simulator where X-ray films were taken and treatment fields marked on the skin, where lead shots were replaced by tattoo marks. These markings were used for daily treatment setup.
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prescription was to half the AP distance. Appropriate thicknesses of bolus were used. A dose of 10 Gy in 5 daily fractions of 2 Gy was given in the next 5 days, namely Tuesday to Saturday. On Monday the PTA and stenting were done, followed by HDR-IVBT. Immediately following brachytherapy the second installment of EBRT was started to give a further 10 Gy in 5 daily fractions.
Angiography, stenting, and insertion of PARIS® catheter Before angioplasty, the patient was admitted and administered a single dose of aspirin, 150 mg orally. At the time of percutaneous puncture a loading dose of heparin (100 units per kg) was given. During the procedure 500 mL Dextran 40 was given IV over a 4 h period. Under local anesthetic a percutaneous antegrade puncture was made in the common femoral artery and, under fluoroscopic control, a guide wire was passed through the superficial femoral artery and a 7 Fr sheath inserted. An angiogram was performed and the target lesion was identified and cannulated with a 0.035 inch guide wire. If an occlusion was present then a 5 Fr Van Andel catheter was introduced to traverse the lesion with Trumo® 035 guide wire. Once the lesion traversed was confirmed by angiogram, the guide wire was left in place. A 5 Fr Schindler Smash balloon catheter was introduced and dilated to an appropriate diameter. Following this, angiography was done and a stent (Boston Scientific Symphony) of appropriate diameter and length was introduced and deployed. At the completion of the deployment, further balloon dilatation was performed.
Brachytherapy Following the above intervention, a 7 Fr Paris® low pressure balloon catheter was inserted under fluoroscopic control and localized to the target. The Paris® catheter is a double lumen catheter system. The central lumen can be connected to the Nucletron HDR unit to drive in the check source or the active source. The outer lumen is used to inflate the balloon in segments to keep the inner source lumen centered along the length of the catheter. The catheter was 150 cm long. The inflatable balloon segment was 10 cm. A gold marker at the distal end helps to radiographically position the catheter 1 cm beyond the intervened segment of the artery (Fig. 2). The target length was the length of the stent plus a 1 cm margin proximal and distal to the stent. The catheter was deflated and secured on the skin before the patient was moved to the HDR suite. Before connecting the catheter to the HDR unit, the position was re-checked and the balloon inflated. A line source plan was used for the treatment as per prescription. No correction was applied for any small curvature of the catheter. Upon completion of treatment, the unit was disconnected from the catheter and Heparin was reversed with protamine sulfate. The catheter and guide wires were removed and pressure was applied to establish hemostasis at the puncture site. The patient remained in the hospital overnight for observation. All patients were put on 100 mg aspirin daily, indefinitely. The next installment of external beam radiotherapy was commenced the same day. Patients were examined before RT, the day after the intervention, and at 3, 6, 9, and 12 months following the procedure (Table 1). All patients were followed up to March 2005.
External-beam radiotherapy External-beam radiotherapy was started on the second day after intervention using 6 MV x-rays and using a pair of anterior-posterior– posterior-anterior (AP-PA) fields. A wider margin field was used with an upper border 3–5 cm superior to proximal target lesion, inferior border 3–5 cm inferior to the distal target lesion, and lateral borders 3 cm on either side of the lateral margins of the lesion. The radioopaque markers were helpful in identifying the lesion size. Dose
RESULTS From February 2000 to August 2002, 17 patients were enrolled in the study (Table 2). The patient demographic details are given in Table 3. The average age of the patients was 73 years (range, 62–91 years), The average length of the lesion was 5.4 cm (range, 1.1– 8.0 cm). Of the 17 patients, 15 were
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Fig. 1. Simulation and localization. (A) Positioning of affected limb during Doppler study. (B) Corresponding data points on simulation film. A and D—Points beyond which blood flow is normal. B and C—Proximal and distal limits of the lesion.
alive at the time of last follow-up (range of follow-up, 33– 60 months). One patient died of stomach cancer and another died of renal failure secondary to complications of diabetes. Of the 15 surviving patients, 10 were asymptomatic and were active
normally (Table 4). Of the 5 symptomatic patients, 1 patient (No. 1) had PTA performed in the (untreated) right lower limb 36 months after the irradiation on the left leg. The PTA was unsuccessful, and a by-pass was done 3 months later. In another patient (No. 12), the right limb became progressively symptomatic and at 32 months from the original procedure in the left leg, a stent was placed in the right lower limb. In two patients (Nos. 13 and 15) the irradiated stent became occluded ⬎50%, requiring a by-pass procedure, at 18 and 25 months, respectively. Thus 2 of 17 patients failed in the treated segment. Target lesion revascularization in these patients was not attempted. None developed candy wrapper stenosis. DISCUSSION
Fig. 2. Inflated segmented Paris catheter with gold marker 1 cm distal to the lesion.
Clinical investigations have indicated that irradiation by both beta and gamma radiation done immediately after PTA
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Table 1. Study parameters prior RT and post RT Test
Pre RT
History Examination Blood tests* WHO performance status† Duplex U/S CXR Angiography Toxicity index‡
x x x x x x x x
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1 month post RT
3 months post RT
6 months post RT
x x
x x
x x
x
x x
x
x
x x x x x
Abbreviations: EORTC ⫽ European Organization for Research and Treatment of Cancer; CXR ⫽ Chest X-ray; RTOG ⫽ Radiation Therapy Oncology Group; WHO ⫽ World Health Organization; RT ⫽ radiotherapy. * Blood tests to include: Full blood examination, Urea and electrolytes, Clotting profile, Liver function tests, Fasting serum cholesterol/triglycerides. † Performance status will be assessed using WHO criteria. ‡ Acute radiation morbidity–assessed according to EORTC/ RTOG acute score. Late morbidity–assessed according to EORTC/ RTOG late score.
in femoropopliteal arteries results in significant reduction in restenosis (14, 15, 16). Recently, Pokrajac (17), on a randomized study with 134 patients (Vienna-3 trial), obtained 70 – 80% patency in focal lesions. For lesions longer than 5 cm the patency was less than 30%. Since our study population is small, we could not arrive at any conclusions in regard to risk of restenosis and length of lesion. A patency rate of 88% (15 out of 17) at 24 months achieved with the combination of EBRT and brachytherapy in our study is superior to the 77.3% at 12 months reported in the Vienna-3 trial. One of the side effects of brachytherapy alone is the ‘edge
No. of patients in study Average age Site of lesion Left superior femoral artery Left popliteal artery Right superior femoral artery Median length of lesion ⬍2 cm 2.1–4 cm 4.1–6 cm ⬎6.1 cm Type of lesion Very high risk High risk
17 73 yrs (Range, 62–91 yrs) 8 4 5 5.42 cm (Range, 1.1–8 cm) 2 4 6 5 3 14
effect’ or the ‘candy wrapper effect,’ which is the occurrence of a new stenosis outside the edges of the irradiated segment or stent (18). It is characterized by negative remodelling and extensive intimal hyperplasia. This is due to either geographical miss or inadequate dose due to axial dose fall-off (17, 19). This effect is observed after radioactive stent implantation (20) and for catheter-based brachytherapy (21) in coronary artery stenosis patients. Serruys (19) attributes 75% edge failures or 40% of restenoses in the irradiated segment to geographical miss and underdosing. Similar data in peripheral vascular disease are not available although, by analogy, similar effects would be expected. The combination of EBRT and IVBT has a better chance to avoid such geographical misses and inadequate dose delivery. We did not observe any “candy wrapper” edge effect in this study. The irradiated target length in all our patients was 1 cm beyond the length of the lesion on either side. Use of external beam alone for irradiation of femoropopliteal artery, to prevent restenosis, has been reported by Fritz
Table 2. Patient details Patient no.
Sex
Age (y)
Target lesion
Type of lesion
Status at last FU
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
M F F M F M F F M F F F M F F M M
74 82 75 68 70 59 73 88 71 66 68 70 75 66 68 60 75
L.Sup.Fem. L.Sup.Fem. L.Popliteal L.Popliteal L.Popliteal L.Popliteal L.Sup.Fem. L.Sup.Fem. L.Sup.Fem. L.Sup.Fem. R.Sup.Fem L.Sup.Fem. R.Sup.Fem L.Sup.Fem. R.Sup.Fem R.Sup.Fem R.Sup.Fem
H.R.RS H.R.RS H.R.RS H.R.RS H.R.RS H.R.RS H.R.RS H.R.RS RS ⬍18 mo PTA RS ⬍18 mo PTA H.R.RS RS ⬍18 mo PTA H.R.RS H.R.RS H.R.RS H.R.RS H.R.RS
Patent Patent Patent Patent Patent, died Patent Patent Patent Patent Patent Patent Partial occlusion Claudification Partial occlusion Patent Patent Patent, died
Abbreviations: F ⫽ female; FU ⫽ follow up; H.R.R.S. ⫽ High Risk of Restenosis; RS ⫽ Restenosis; M ⫽ male; L.Popliteal ⫽ left popliteal; L.Sup.Fem. ⫽ left superficial femoral; PTA ⫽ percutaneous transluminal angioplasty; R.Sup Fem. ⫽ right superficial femoral.
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Table 4. Follow-up data No. of patients Patients available for FU Period of FU Living asymptomatically Living with symptoms but stent still patent Diseased
17 15 33–60 mo 10 5 2
Abbreviation: FU ⫽ follow up.
(22). In this study, 47 patients were treated to a dose of 21 Gy at 3 Gy per fraction with 6 MV x-rays and 48 had sham treatment. The radiation field had a lateral margin of 3 cm and a craniocaudal margin of 2 cm from the dilated segment. At 12 months there was a 33.3% failure rate in the sham group versus 45.7% in the EBRT group (p ⫽ 0.292). The authors concluded that the dose was insufficient and that IVBT was better. We did not observe any aneurysmal dilation of the irradiated vascular segment. Aneurysmal dilatation of vessels is usually seen following degeneration of the smooth muscle of the vascular wall. Degenerating muscle is replaced by fibrosis and collagen deposition which lack elastic recoil. Under the effect of persistent blood pressure the affected regions dilate, causing aneurysm (23). Radiation dose heterogeneity can easily occur from the linear brachytherapy source placed in the lumen of an irregularly thickened vessel wall. This can cause excessive radiation dose in thinned-out regions of affected vessel. Such excessive radi-
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ation dose can also destroy surface endothelium, exposing the denuded basement membrane and leading to thrombosis. In our study the combination of 20 Gy with EBRT and 10 Gy at 1.2 mm from the stent achieved 88% stenosis-free survival at 24 months post-angioplasty (15 out of 17 patients). Due to the combination of external beam and brachytherapy, a more homogeneous dose could be delivered across the vascular cross section. In keeping with the pathogenesis of arterosclerosis, where cell division and migration of neo-intimal cells occur from adventitia into subintima, the so-called shrinking field technique, as used in this study, may have led to the favorable result. Currently there are on-going clinical trials with the use of radioactive or drug-eluting stents. The latter seems to be more favored by interventional physicians. Favorable results are reported using polymer-sirolimus-eluting stents (24), 7-hexanoyltaxol-eluting stents (25), and actinomycin D-coated Multilink-Tetra stents (26). Radiation therapy in any form may lose its utility if the drug-eluting technology were found to be suitable and have long-term efficacy. In summary, arteriosclerotic stenosis can be effectively treated by a combination of EBRT and brachytherapy. Our results suggest that in patients with de novo, high risk, femoro-popliteal artery stenosis, the addition of external beam irradiation before and after intravascular brachytherapy, in addition to PTA and stenting, may significantly reduce the rate of restenosis.
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