(Circulation. 1997;95:1095-1097.)
© 1997 American Heart Association, Inc.
Articles |
ß-Radiation to Reduce Restenosis
Too Little, Too Soon?
the Scripps Clinic and Research Foundation, 10666 North Torrey Pines Rd, La Jolla, Calif 92037.
Correspondence to Paul Teirstein, MD, Scripps Clinic and Research Foundation, 10666 North Torrey Pines Rd, La Jolla, CA 92037.
Key Words: Editorials • radioisotopes • restenosis • angioplasty
 |
Introduction |
|---|
 Top Introduction References |
|---|
With almost 1 million procedures undertaken worldwide each year, coronary angioplasty is flourishing. This elegant technique, however, continues to be plagued by a restenosis rate of 30% to 60%.1 Efforts to reduce restenosis have been herculean. Literally, scores of pharmaceutical agents have been tested in clinical trials.2 3 4 Despite initial promising results in experiments with animals, each clinical trial has been a disappointment. Coronary stents stand alone as the only intervention that has been proved to decrease restenosis. In the STRESS and BENESTENT trials, the implantation of a single Palmaz-Schatz coronary stent was associated with a 30% reduction in restenosis rates.5 6 The impact of stents on restenosis, however, is purely mechanical.7 8 Stent implantation expands the vessel lumen further than the use of balloon angioplasty alone. This larger lumen creates more space for the still ubiquitous intimal proliferation. Stents do not diminish the cellular response to injury. In fact, the proliferative response, as measured on the basis of late loss after the procedure, is actually increased by the use of stents. Stents decrease restenosis by simply increasing the capacity of the artery to tolerate intimal proliferation. Despite extensive clinical testing, no agent has been shown to inhibit the proliferative component of restenosis.
Radiotherapy is the latest in a long line of potential antiproliferative agents to be enthusiastically tested as an adjunct to angioplasty. There is much to recommend the use of radiotherapy in the fight against restenosis. In more than 100 years of clinical experience, radiotherapy has proved to be highly effective in inhibiting cellular proliferation, in both malignant and benign disease. Examples of benign hyperplastic entities that have been effectively treated with radiotherapy include the exuberant fibroblastic activity of keloid scar formation, heterotopic ossification, desmoid/aggressive fibromatosis, Peyronie's disease, and pterygium.9 10 11 12 13 In these benign proliferative disorders, doses of 700 to 1000 cGy in one treatment <72 hours after the stimulus have proved to be effective in inhibiting fibroblastic activity without significantly interfering with the normal healing process. Wiedermann et al14 and Waksman et al15 were the first to demonstrate significant reduction in intimal proliferation using radiotherapy in the swine model of restenosis. Subsequently, numerous groups demonstrated the efficacy of both 
- and ß-radiation in various animal models of restenosis. Others have successfully inhibited neointimal proliferation with the use of ß-emitting radioactive stents. Importantly, these animal models demonstrated efficacy without evidence of necrosis, significant fibrosis, or aneurysm formation. Inspired by these early preclinical trials and the encouraging clinical work of Bottcher et al,16 who applied radiotherapy to peripheral vessels, several clinical trials have been initiated to test this new treatment in the coronary circulation.
In this issue of Circulation, Verin and colleagues17 describe the first human coronary application of ß-radiation to reduce restenosis. The trial is a small feasibility study and lacks a control group. The findings are disappointing. With the use of a standard definition of 
50% diameter stenosis at 6-month follow-up, 6 of the 15 patients treated sustained restenosis. This 40% restenosis rate is very similar to historical restenosis rates without the use of radiotherapy. A more sensitive measurement of the impact of radiotherapy on preservation of the postprocedural luminal diameter is the "late loss index," which is defined as late loss (in mm) divided by the acute gain (in mm). The late loss index is the "tax rate" associated with coronary intervention and refers to the percentage of increase in luminal diameter achieved at the initial procedure that is given up at follow-up. Historically, the late loss index usually ranges from 0.40 to 0.50.8 With the data presented in this trial (acute gain of 1.6 mm and late loss of 0.8 mm), we can estimate an unimpressive late loss index of 0.50; this is not very encouraging.
The radioactive source used in this trial was 90Y, a ß-emitter. The benefits of the use of a ß-emitter include its ease of use and practical integration into current catheterization laboratory policies and procedures. Radiation energy from 90Y, like other ß sources, diminishes rapidly with distance. This isotope penetrates poorly and therefore does not require any special radiation shielding in the catheterization laboratory. The virtues of ß-emitters that make them practical for use in the catheterization laboratory, however, also create challenges to the delivery of an effective dose to the coronary wall. Investigators have localized the cellular proliferation that follows balloon angioplasty to the media and even adventitia of the artery.18 The arterial wall of a diseased human coronary artery can easily be 2 mm thick in an artery containing eccentric plaque. The Figure
illustrates an estimate of the dose-depth relation of a 90Y linear source, with the assumption that the desired target dose is 18 Gy (the dose that was used in the present study and has been proven to be effective in numerous animal models of restenosis). Dosimetric evaluation very close to radioactive sources is difficult to perform. This figure is adapted from the preclinical work of Popowski et al,19 who are coauthors of the present study. When 18 Gy is prescribed to be administered to the luminal surface of the vessel wall, the dose delivered at a depth of 1 mm is only 
5.4 Gy. At a depth of 2 mm, the dose is only 2.7 Gy. This represents only 15% of the prescribed dose. Therefore, despite the authors' use of a centering device, it is very difficult to determine the actual dose of radiation delivered to the region of the arterial wall containing actively proliferating cells. The authors' negative findings must therefore be viewed in light of the strong possibility that they administered a lower-than-intended radiation dose to the actively proliferating tissue elements. Furthermore, Waksman et al demonstrated potentiation of the effects of radiotherapy if treatment is given 48 hours after balloon injury. Another possible explanation for the authors' negative results is that the radiotherapy was given too soon after balloon angioplasty. Of course, any requirement for a repeat invasive procedure would severely limit the practical application of this technique.
|
Although the authors found no discernible impact on restenosis, they are to be commended for developing an elegant delivery system that effectively centers the radioactive source within the lumen. The study procedures were executed successfully and without complications. The authors' use of a segmented balloon-centering device raises numerous questions regarding the design of centering devices. One problem with centering is knowing where the center is. In a diseased coronary artery, plaque formation is usually eccentric. On the basis of histologic and intravascular ultrasound examination, the media and adventitia are usually disrupted and replaced by a heterogeneous collection of cholesterol, calcium, and fibrous tissue elements. The arterial wall is not round but instead contains numerous lumps, bumps, and bulges. This is quite different from the uniform, circular lumen found in animal models of restenosis. A catheter centered in the lumen, therefore, is not necessarily centered with respect to the arterial wall.
Another critical design question concerns the need for coronary perfusion during radiation delivery. The device used in this study does not provide perfusion. Given the high specific activity of the 90Y emitter that was used, the prescribed dose was delivered in just 391±206 seconds. Despite this very short dwell time, the radioactive source had to be transiently withdrawn and the centering balloon deflated in 27% of patients due to the presence of intolerable ischemia. A centering device that allows perfusion would solve this problem and allow even longer dwell times. A second theoretical concern is the potential reduction in efficacy when radiotherapy is used in an ischemic environment. Tissue ischemia is associated with diminished radiotherapy kill rates when applied to other disease entities. In theory, radiotherapy is most effective when treating well-oxygenated, actively dividing cells.
Clearly, a dose-finding study with ß-radiotherapy is required, as well as continued studies using other emitters. One potentially effective ß-emitter is a radioactive, ß-emitting coronary stent. Metal stents have been made radioactive by ion implantation of 31P beneath the metal surface followed by exposure of them to neutron irradiation to convert 31P into 32P20 or by activation of stainless steel stents in a cyclotron.21 The ß-emitting radioactive stent is applied directly to the vessel wall, which may provide more favorable dosimetry. Other radiotherapy sources such as 192Ir, a -emitter that provides more homogeneous dosimetry but is more complicated to use in the catheterization laboratory, are also under active investigation. The results of a double-blind, randomized clinical trial of the use of 192Ir plus coronary stents for restenotic lesions (the SCRIPPS trial) have been reported.22
Although the results of the present study raise questions about the effectiveness of the use of radiotherapy to reduce restenosis, we should not be pessimistic. With 100 years of clinical experience to draw on, we know that in radiotherapy, dose and timing are critical to success. The negative results of this trial are quite possibly the result of improper dosimetry and/or timing. In our quest for a vascular antiproliferative agent, radiotherapy remains high on the list of potentially efficacious treatments.
|
Acknowledgments |
|---|
We thank Shirish Jani, PhD, for his expert consultation and assistance in preparing the manuscript.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
|
TopIntroductionReferences |
|---|
1. Holmes DR Jr, Vliestra RE, Smith HC, Vetrovec GW, Cowley MJ, Faxon DP, Gruentzig AR, Kelsey SF, Detre KM, Van Raden MJ, Mock MB. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): a report from the PTCA Registry of the National Heart, Lung and Blood Institute. Am J Cardiol. 1984;53(suppl):77C-81C.
2.
Popma JJ, Califf RM, Topol EJ. Clinical trials of restenosis after coronary angioplasty. Circulation. 1991;84:1426-1436.
3. Serruys PW, Klein W, Rutsch W, Heyndrickx G, Emanuelsson H, Ball SG, Wijns W, Schroeder E, Liebermann H, Eichorn E, Willerson JT, Khaja F, Alexander RW, Baim D, van Gool R, Meikert R. PARK: the Post Angioplasty Restenosis Ketanserin Trial. J Am Coll Cardiol. 1993;21:322A. Abstract.
4. Faxon D, Sprio T, Minor S, Douglas J, Cote G, Dorosti K, Gottlieb R, Califf R, Topol E, Gordon J. Enoxaparin, a low molecular weight heparin, in the prevention of restenosis after angioplasty: results of a double-blind randomized trial. J Am Coll Cardiol. 1992;19:258A. Abstract.
5.
Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, Belardi J, Sigwart U, Colombo A, Goy JJ, van den Heuvel P, Delcan J, Morel M-A, for the BENESTENT Study Group. A comparison of balloon-expandable stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med. 1994;331:489-495.
6.
Fischman DL, Leon MB, Baim D, Schatz RA, Penn I, Detre K, Savage MP, Veltri L, Ricci D, Nobuyoshi M, Cleman M, Heuser R, Almond D, Teirstein P, Fish D, Colombo A, Brinker J, Moses J, Hirshfeld J, Bailey S, Ellis S, Rake R, Goldberg S, for the STRESS Trial Investigators. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med. 3314;496:501.
7. Kuntz RE, Safian RD, Levin MJ, Reis GJ, Diver DJ, Baim DS. Novel approach to the analysis of restenosis after the use of three new coronary devices. J Am Coll Cardiol. 1992;19:1493-1499.[Abstract]
8. Kuntz RE, Gibson CM, Nobuyoshi M, Baim DS. Generalized model of restenosis after conventional balloon angioplasty, stenting and directional atherectomy. J Am Coll Cardiol. 1993;21:15-25.[Abstract]
9.
Reitamo JJ. The desmoid tumor, IV: choice of treatment results and complications. Arch Surg. 1983;118:1318-1322.
10. MacLennan I, Keys HM, Evarts CM, Rubin P. Usefulness of post-operative hip irradiation in the prevention of heterotopic bone formation in a high risk group of patients. Int J Radiat Oncol Biol Phys. 1984;10:49-53.
11. Enhamre A, Hammar H. Treatment of keloids with excision and post-operative x-ray irradiation. Dermatologica. 1983;167:90-93.[Medline] [Order article via Infotrieve]
12. Alth G, Koren H, Gasser G, Edler R. On the therapy of indurated penis plastica by means of radium moulages. Strahlentherapie. 1985;161:30-34.[Medline] [Order article via Infotrieve]
13. Bahrassa F, Datta R. Postoperative beta radiation treatment of pterygium. Int J Radiat Oncol Biol Phys. 1983;9:679-684.[Medline] [Order article via Infotrieve]
14. Wiedermann JG, Marboe C, Amols H, Schartz A, Weinberger J. Intracoronary irradiation markedly reduces restenosis after balloon angioplasty in a porcine model. J Am Coll Cardiol. 1994;23:1491-1498.[Abstract]
15.
Waksman R, Robinson KA, Crocker IR, Gravanis MB, Cipolla GD, King SB III. Endovascular low-dose irradiation inhibits neointima formation after coronary artery balloon injury in swine: a possible role for radiation therapy in restenosis prevention. Circulation. 1995;91:1533-1539.
16. Bottcher HD, Schopohl B, Liermann D, Kollath J, Adamietz IA. 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.[Medline] [Order article via Infotrieve]
17.
Verin V, Urban P, Popowski Y, Schwager M, Nouet P, Dorsaz PA, Chatelain P, Kurtz JM, Rutishauser W. Feasibility of intracoronary ß-irradiation to reduce restenosis after balloon angioplasty. Circulation. 1997;95:1138-1144.
18.
Scott NA, Cipolla GD, Ross CE, Dunn B, Martin FH, Simonet L, Wilcox JN. Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation. 1996;93:2178-2187.
19. Popowski Y, Verin V, Papirov I, Nouet P, Rouzaud M, Schwager M, Urban P, Rutishauser W, Kurtz JM. Intra-arterial 90Y brachytherapy: preliminary dosimetric study using a specially modified angioplasty balloon. Int J Radiat Oncol Biol Phys. 1995;33:713-717.[Medline] [Order article via Infotrieve]
20.
Laird JR, Carter AJ, Kufs WM, Hoopes TG, Farb A, Nott SH, Fischell RE, Fischell DR, Virmani R, Fischell TA. Inhibition of neointimal proliferation with low-dose irradiation from a ß-particle–emitting stent. Circulation. 1996;93:529-536.
21.
Hehrlein C, Gollan C, Donges K, Metz J, Riessen R, Fehsenfeld P, von Hodenberg E, Kubler W. Low-dose radioactive endovascular stents prevent smooth muscle cell proliferation and neointimal hyperplasia in rabbits. Circulation. 1995;92:1570-1575.
22. Teirstein PS, Massullo V, Jani S, Popma JJ, Mintz GS, Russo RJ, Schatz RA, Steuterman S, Morris NB, Guarneri EM. Radiation therapy following coronary stenting: 6-month follow-up of a randomized cllinical trial. Circulation. 1996;94(suppl I): I-210. Abstract.
This article has been cited by other articles:
 |
|
 |
|
  H. C. Lowe, S. N. Oesterle, and L. M. Khachigian Coronary in-stent restenosis: Current status and future strategies J. Am. Coll. Cardiol., January 16, 2002; 39(2): 183 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Kuntz and D. S. Baim Prevention of Coronary Restenosis : The Evolving Evidence Base for Radiation Therapy Circulation, May 9, 2000; 101(18): 2130 - 2133. [Full Text] [PDF]
|
|
|
|
|
|
J. Fareh, R. Martel, P. Kermani, and G. Leclerc Cellular Effects of ß-Particle Delivery on Vascular Smooth Muscle Cells and Endothelial Cells : A Dose-Response Study Circulation, March 23, 1999; 99(11): 1477 - 1484. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||