Vascular Radiation Therapy to Reduce Coronary Artery Restenosis

PRACTICAL RADIATION ONCOLOGY FOR THE SURGICAL ONCOLOGIST

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VASCULAR RADIATION THERAPY TO REDUCE CORONARY ARTERY RESTENOSIS Prakash B. Chougule, MD

The evolving role of vascular radiation therapy in patients with coronary artery disease is evident by the number of in vitro studies performed in the late 1980s and early 1990s and the subsequent clinical trials that followed. The interest in this field stemmed from failure of several other treatment modalities in the management of restenosis after percutaneous transluminal angioplasty (PCTA). This article outlines the scope of the problem (restenosis),the pathophysiology of restenosis after PCTA, attempted and available treatment modalities for restenosis, and the promise of vascular radiation therapy. BACKGROUND

Since its introduction in 1977 by Gruntzig et al,'2,13the technique of PCTA has become a serious rival of coronary bypass surgery as a therapeutic modality for coronary artery disease. Approximately 1 million angioplasties are performed each year worldwide, 50% (425,000) of them in the United States. Unfortunately, restenosis of the dilated segment after This translates into apPCTA occurs in 30% to 50% of proximately 150,000 patients with restenosis at an annual cost of $850 million. Although the exact pathophysiology of restenosis is still not well understood, elastic recoil, neointimal hyperplasia, and chronic vessel constriction (negative remodeling) are believed to be the most important preFrom the Department of Radiation Oncology, Brown University School of Medicine, Rhode Island Hospital, Providence, Rhode Island SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 9 NUMBER 3 . JULY 2000

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disposing factors in the formation of the restenotic In several clinical trials, pharmacologic agents have not shown any reduction in reThis led to introduction of interventional techniques such as directional atherectomy and endovascular These techniques did show promising results with restenosis in the 20%to 30%range in select patient groups such as discrete single lesion, proximal location of the lesion, and the left anterior descending coronary but the restenosis rate has increased again due to broadened indications for stenting5 These failed therapeutic approaches led to the increasing interest in intravascular brachytherapy. Low-dose ionizing radiation has been shown to be effective in suppressing excessive scar formation in conditions such as heterotopic bone formation,25 p t e r y g i ~ m , 3and ~ , ~Graves' ~ exophthalmos4and has become the basis for several preclinical and clinical trials. PRECLlNlCAL STUDIES

Several animal studies, including laboratory experiences with both external beam radiation and brachytherapy, have been reported. Schwartz et a130 at the Mayo Clinic tested doses of 4 Gy and 8 Gy using an orthovoltage unit to treat stented pig coronary arteries. Their analysis performed 4 weeks later revealed poorer results in irradiated animals compared with the controls, with the higher dose animals faring poorly. Use of orthovoltage x-rays may have been a negative factor, with orthovoltage x-rays being more likely to cause local areas of high dose because of electronic disequilibrium. Styles et a132and Marijianowski et alZ6used a 14-Gy dose with megavoltage x-rays delivered immediately before, after, and 2 days after balloon injury in pig coronary arteries and observed reduced neointimal formation compared with controls. At the 14-Gy dose, the lumens were smaller because of negative remodeling (contracture of the vessel). At higher doses of 21 Gy with external irradiation after angioplasty or stenting, profound and consistent suppression of neointimal formation and maintenance of the lumen area were noticed. Catheter-based irradiation studies in animals, on the other hand, appear to be consistent in the benefit of reduction in neointimal formation. Wiedermann et a14z,43 reported persistent suppression of neointimal formation in arteries treated 4 weeks after angioplasty in a porcine model that was treated with 20 Gy prescribed to 1.5 mm depth and harvested at 6 months. Waksman et alS7 also demonstrated profound suppression of neointimal formation using an 1921rsource using a 3.5-, 7-and 14-Gy dose prescribed to a depth of 2 mm. The benefits persisted at 6 months in arteries treated with 7 and 14 Gy. Mazur et alz7reported similar findings of suppression of intimal thickening after 10 to 25 Gy at 1.5 mm depth from a high-dose rate afterloading the iridium source 4 weeks after injury. The benefit was seen in the left circumflex and left anterior descending coronary arteries but not in the right coronary artery. Waksman et a139reported similar findings after stenting. The Emory group further studied the use of beta emitting sources

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[radioactive ytrrium (90Y), strontium (90Sr),and rhenium (186Re)]and showed a similar effect on the neointima. The beta sources were encapsulated in a stainless-steel seed, and doses of 7 Gy and 14 Gy were prescribed to 2 mm depth.38The beta sources had an advantage of a significant reduction in radiation exposure compared with prolonged treatment times and radiation safety issues with 1921r.Doses of up to 56 Gy were tested due to the rapid dose rate fall-off with the beta source. Robinson et alz9reported results from a beta emitting Is6Reliquid-filled balloon catheter to deliver doses of 15,20, and 30 Gy at 0.5 mm depth from the balloon-lumen interface. This system had the advantage of allowing a homogeneous dose delivery to the luminal surface. Neointimal suppression was seen at doses of 20 and 30 Gy. Intravascular brachytherapy also was tested in the setting of a radioactive stent and was reported by Hehrlein et al14,15and Fischell et a1.8Stents were made radioactive with radioactive phosphorous (32P)and tested in rabbit coronary arteries. The radioactive stent technically was promising in that it would address the mechanical problem of constriction of the artery and inhibit neointimal formation and smooth muscle cell proliferation. CLINICAL TRIALS IN HUMANS

The first human experience with intracoronary radiation was reported by Condado et a13in Venezuela, where 21 patients were treated to prevent restenosis. Iridium wire was inserted to deliver a dose of 20 to 25 Gy at 1.5 mm from the center. A 6-month angiographic follow-up revealed a restenosis rate of 28% and a late loss index (lumen diameter loss of the initial gain) of 19%.Although two patients developed subacute occlusion and an additional patient developed a pseudoaneurysm at the treatment site, the feasibility of intracoronary radiation therapy with no significant late effects of radiotherapy was established. The Scripps Coronary Radiation Trial to Inhibit Proliferation Post Stenting (SCRIPPS) was the first randomized trial to compare intracoronary iridium-based brachytherapy treatment to placebo. Patients with restenosis were randomized after either PCTA or stenting. A minimum dose of 8 Gy was delivered to the adventitia, with a maximum dose of 30 Gy to the closest point near the source. With 55 patients randomized, 29 patients received radiation, which showed an angiographic restenosis rate of 53.6% in the control group and 16.7%in the irradiated The late loss index was 12%in the treated vessels versus 60%in the control group (Table 1).The treatment effect was statistically better in patients with in-stent restenosis, lesions within vessels less than 3 mm in diameter, and for lesions that received 8 Gy or more minimum dose.33 The first beta radiation clinical trial was reported by Verin et a136in Switzerland. A 90Ycoil was inserted into a closed-end balloon catheter after PCTA to deliver a dose of 18 Gy to the luminal surface. A 6-month follow-up revealed a restenosis rate of 40% and a late loss index of 50%. Because of unfavorable results, the Swiss group initiated a dose finding

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Table 1. RESULTS FROM THE SCRIPPS TRIAL

restenosis rate late loss index

Placebo

Treatment Group*

1%)

1%)

P Value

54 12

*Iridium 192 (Gamma) Source: Data from Teirstein PS, Massullo V, Jani S, et al: Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 336:1697-1703, 1997.

study. The first Food and Drug Administration approved clinical trial of intracoronary brachytherapy in the United States was conducted at Emory University and Rhode Island Hospital (Brown University).lsIn this phase 1-11 study, called the Beta Energy Restenosis Trial (BERT 1 trial), 23 patients were enrolled to test the feasibility and safety of 9OSr, a beta-emitting radiation source, within the coronary artery. Doses of 12, 14, and 16 Gy were delivered through a source train contained in a transfer device and transferred hydraulically within an over-the-wire delivery catheter system (Novoste Corporation, Norcross, GA). A late loss index of 4% was noted in BERT 1 trial compared with 43% in the historic lovastatin41trial. After the successful feasibility study at Emory and Brown University, the BERT 1 trial was extended for additional patients treated at the Montreal Heart Institute and the Thorax Center in Rotterdam. The results of the first 64 patients continued to show a lower restenosis rate and late loss index of 14% and 3%, respectively, compared with 42% and 43%, respectively, in the lovastatin restenosis trial (Table 2). A dose-response relationship also was noted with reduced late loss index seen in smaller vessels. The first trial using a radioactive stent was reported by Baim et a12in which a 32P-impregnated radioactive (mean activity 6.9 pCi) PalmazSchatz stent was used in 30 patients with de novo or restenotic lesions of native coronary vessels. A restenosis rate of 31% at 6 months was reported in this clinically feasible trial. FUTURE CLINICAL TRIALS

The SCRIPPS group has expanded their study as a multicenter, double-blind, randomized trial (Gamma I) with the intent of accruing 250 patients with in-stent restenosis and comparing a placebo group with a treatment group. The Washington Heart Center also has initiated an inTable 2. RESULTS FROM THE BERT TRIAL Lovastatin Trial

BERT Trial

(""4

("/.I

restenosis rate late loss index 90Sr(Beta) Source (Novoste Corporation, Norcross, GA): Data from Croker I: Radiation therapy to prevent coronary artery restenosis. Semin Radiat Oncol9:134-143,1999.

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stent restenosis trial called WRIST (Washington Radiation for Instant Restenosis Trial) in which 130 patients will be randomized to receive radiation or placebo. Both the Gamma I and the WRIST trials will use an 1921r gamma source. A large multicenter trial (Beta Cath Trial using the Novoste Beta Cath system) was opened to enroll 1100 patients with restenosis in a triple masked randomized trial for patients with restenosis or stenosis in native coronary arteries. Patients who have successful angioplasty with less than 30% residual stenosis and no major dissection will be randomized to receive radiation or placebo. Patients with suboptimal angioplasty results will receive brachytherapy before stent implantation. Two dose schedules are being used based on vessel size. For smaller vessels with diameters of 2.5 to 3.3 mm, 14 Gy will be prescribed at 2 mm; for larger vessels with 3.3 to 4 mm diameter, 18 Gy will be prescribed at 2 mm. This dose schedule was developed based on the findings from the BERT 1 trial. A parallel-randomized trial called the Stents and Radiation Therapy Trial (START) (Novoste Corp) also was started to test the efficacy of beta radiation for patients with in-stent restenosis. Clinical trials are also underway using a 32Pwire source that delivers radiation within a helical centering balloon (Guidant Corporation, Houston, TX). After the initial feasibility trial called PREVENT (Proliferation Reduction with Vascular Energy Trial), which randomized patients at radiation doses of 16,20, and 24 Gy at 1 mm from the balloon-lumen interface, a phase I11 randomized study called Internal Hyperplasia Inhibition with Beta In-stent (INHIBIT) trial (Guidant Corp) was initiated. Another beta source trial using la6Re (Navius and Endosonics Corporation, Rancho Cordova, CA), which potentially would allow a more homogeneous dose to the vessel wall, is underway. The Columbia University Restenosis Elimination (CURE)trial by Columbia University and the RADIANT trial (vascular therapies) showed a better dose homogeneity to the vessel wall through a liquid source preparation, using ls8Resource. SUMMARY

Restenosis has indeed become an Achilles' heel in patients treated with angioplasty and coronary artery stents. Animal studies as well as clinical trials that use vascular brachytherapy have been promising and have a great potential to reduce restenosis after angioplasty and coronary artery stents. With the addition of brachytherapy to PCTA or stent therapy, the restenosis rate could drop enough to reduce significantly the need for coronary bypass surgery. A 30% reduction in restenosis could mean a savings of approximately $300 million. Several different systems are being tested in clinical trials and are likely to evolve into highly technical and user friendly devices that would allow for better planning and delivery of radiation treatments. Attempts at reducing the radiation dose to the user, the patient, and the personnel also will become a factor in the development of future devices. Simultaneously, the concerns from the delivery of a high dose of radiation to the coronary vessels and the surrounding

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heart still remain. Coronary thrombosis, infarction, and fibrosis of the myocardium are possible long-term complications that many clinicians, radiobiologists, and physicists have raised concerns about. The results of large clinical trials and long-term follow-up hopefully will help establish the role of vascular brachytherapy in clinical practice. ACKNOWLEDGMENT The author acknowledges Mary L. DerManouelian for her assistance in preparation of the manuscript.

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Address reprint requests to Prakash B. Chougule, MD Department of Radiation Oncology Rhode Island Hospital 593 Eddy Street Providence, RI 02903