Feasibility of Intracoronary β-Irradiation to Reduce Restenosis After Balloon Angioplasty

It is well established that the long-term benefit of percutaneous transluminal coronary angioplasty (PTCA) is compromised by the occurrence of restenosis in 30% to 50% of patients.¹² This contributes to limitation of application of the procedure to relatively simple clinical cases (usually one or two stenotic sites) and leads to significant additional morbidity and costs related to relapses. Pharmacological approaches to restenosis prevention have been disappointing,³⁴⁵ and only stents have been conclusively shown to have a limited but favorable impact.⁶⁷ Several recent studies have shown the efficacy of intra-arterial γ-irradiation in animal models of postangioplasty restenosis⁸⁹¹⁰ and its applicability in human femoral arteries.¹¹¹² We developed a novel technique of endovascular β-irradiation using an endoluminally centered pure metallic ⁹⁰Y source¹³¹⁴¹⁵ that can be used in an ordinary catheterization laboratory environment. Experimental evaluation of this approach in the hypercholesterolemic rabbit model demonstrated marked efficacy of an 18-Gy radiation dose for neointimal hyperplasia inhibition.¹⁵ The purpose of this pilot study was to evaluate in a clinical setting (1) the feasibility of intra-arterial β-radiation delivery and (2) the safety of an 18-Gy β-radiation dose delivered to the inner arterial surface during a 6-month follow-up period.

Methods

Radiation Delivery System

The intra-arterial β-radiation delivery system that we described previously¹⁴¹⁵ consists of two principal working elements: a ⁹⁰Y β-emitting source (half-life, 64.1 hours; maximal energy, 2.284 Mev) and a centering balloon that allows homogeneous radiation dose distribution to the vessel wall (Schneider-Europe AG).

The radioactive source consists of a 29-mm-long flexible coil with an outer diameter of 0.34 mm (0.014 in) manufactured from titanium-coated pure yttrium wire of 0.1-mm diameter (Fig 1A). It is secured at the end of a 0.014-in thrust wire between two (distal and proximal) radiopaque tungsten markers, which allows excellent flexibility of the entire system and permits precise localization of the source under fluoroscopy.

The centering device is designed to obtain a central position of the flexible ⁹⁰Y source inside the arterial lumen (Fig 1B). It consists of a 30-mm-long segmented balloon with four interconnected compartments mounted on a double-lumen plastic shaft with an internal (source) blind lumen diameter of 0.40 mm (0.016 in). The 20-mm-long distal tip of this device enables its introduction in a monorail fashion over a conventional 0.014-in angioplasty guide wire. Three radiopaque tungsten markers are located at the balloon waists and allow positioning of the device at the site of the previous angioplasty using fluoroscopy. A flexible stainless steel stylet is placed inside the source lumen of the centering device to optimize tracking of the system through the guiding catheter and the target coronary artery. It is withdrawn before source insertion.

The activity of ⁹⁰Y sources used varied between 6 and 30 mCi. During the time intervals between procedures, the sources were stored inside a shielding container. A Luer connector established continuity between the centering device source lumen and the inner lumen of the shielding container, allowing easy manual advancement of the source.

Because the half-life of ⁹⁰Y is 64 hours, the useful clinical life of a source after activation is ≈1 week.

Procedure

All interventions were done with the use of local 1% lidocaine anesthesia, anticoagulation with heparin, aspirin, and sedation with benzodiazepines and morphine as needed, according to current practice. After an ordinary successful PTCA procedure was performed through a 7F or an 8F guiding catheter, a centering device with the same diameter as the balloon that was used for angioplasty was inserted in the lumen of the artery and positioned to fully cover the PTCA segment length. After withdrawal of the stylet from the centering device source lumen, the centering balloon was then inflated (Fig 2) with contrast medium (iohexol 518 mg/mL, Schering AG) at a pressure of 5 bar. If a dummy ⁸⁹Y wire could be advanced into and retrieved without difficulty from the inflated centering balloon, the ⁹⁰Y source was then advanced into the centering device up to the stress point and left in this position for the time necessary to apply the 18-Gy inner arterial surface dose. Fluoroscopy was used to confirm the correct position of the source inside the centering balloon (Fig 2). After irradiation, stents were used as needed to improve unsatisfactory results.

Two cardiologists, one radiation oncologist, and one technician remained in the catheterization laboratory during the entire procedure. Only routine radioprotection measures were used. During intracoronary irradiation, the radiation dose in contact with the patient's right chest side was 24±7 μSv/h (range, 15 to 30), and no radiation was detectable at the level of the operator's head. In comparison, during fluoroscopy in the same positions, the radiation doses were 45±25 μSv/h (range, 30 to 100) and 20±3 μSv/h (range, 15 to 25), respectively (Monitor 4, S.E. International).

Selection of Patients

Patients >64 years old who were scheduled to undergo angioplasty of one of the native coronary arteries because of angina were eligible for the study. The target lesion was required to have a ≥50% diameter stenosis as determined with quantitative coronary angiography (QCA), to be <20 mm long, and to be located in a vessel with a >2.5 mm reference diameter.

Patients were excluded from the study enrollment for (1) contraindication to bypass surgery if needed, (2) anticipated difficulties with long-term follow-up, or (3) extreme tortuosity of the coronary artery proximal to the target lesion. Additional periprocedural exclusion criteria were (4) failed PTCA, (5) failed intra-arterial centering balloon positioning, and (6) failed dummy wire insertion or retrieval. Patient baseline clinical characteristics are presented in Table 1. Indications for stent placement were those currently used in our institution and included (1) “bail-out” situations (major dissection and/or reduced flow after PTCA and intracoronary irradiation) and (2) insufficient angiographic result with a significant residual stenosis. After the procedure, long-term aspirin (100 mg daily) was administered to all patients. In case of stent implantation, ticlopidine (500 mg daily) was also administered for 1 month. The study was carried out according to the principles of the Declaration of Helsinki and with the approval of the Ethical Review Board of the University Hospital of Geneva. Written informed consent was obtained from each patient.

Clinical and Angiographic Follow-up

Patients and/or their physicians were contacted by telephone at 1, 3, and 6 months after the procedure. Clinical examination and exercise testing were performed before the second coronary angiography at 6 months. When prompted by recurrent symptoms or signs of ischemia, the follow-up angiography was done before the 6-month time point. All of the angiograms were analyzed with the help of a QCA analysis system (AWOS, Siemens). Restenosis was considered to have occurred if the percent diameter stenosis was >50%. The following were scored as clinical events if they occurred between the time of the initial procedure and the 6-month follow-up: death, cerebrovascular accident, myocardial infarction, or revascularization of the previously treated lesion.

Statistical Analysis

Values are given as mean±SD.

Results

Between June 21 and November 15, 1995, fifteen patients (6 women and 9 men; mean age, 71±5 years) underwent intracoronary β-irradiation with an intra-arterially centered ⁹⁰Y source immediately after a conventional PTCA procedure (Table 1).

Procedural and Early Clinical Outcome

None of the selected patients were excluded from the study on the basis of periprocedural exclusion criteria. In all, the PTCA/irradiation procedure was technically feasible, and the delivery of the 18-Gy dose to the inner arterial surface was accomplished without complications.

In 2 patients, the irradiated lesions were situated in relatively distant arterial segments (right posterolateral artery in patient 14 and right coronary bifurcation distal to venous bypass graft anastomosis in patient 12). Centering balloon positioning followed by dose delivery was uneventful in both.

In 11 patients (Table 1), the dose was delivered during a single centering balloon inflation. In 4 of the patients, because of poor tolerance to prolonged inflation, the delivery to the 18-Gy dose was achieved by a sequence of two or three balloon inflations with source withdrawal and repositioning as needed. The total exposure time per patient was 391±206 seconds (range, 153 to 768 seconds), and the entire intracoronary irradiation procedure prolonged the ordinary PTCA procedure by an additional 10 to 30 minutes. In 4 patients, the intervention was completed by intracoronary stent implantation (Johnson and Johnson Interventional Systems Co) because of major dissection induced by the initial balloon angioplasty in two patients (bail-out) and because of a suboptimal angiographic result with a significant residual stenosis in the other two patients.

No immediate or in-hospital complications were observed in the patients, and all were discharged at 1 to 7 days after the intervention. Serial creatine kinase and ECG monitoring revealed no significant changes after the procedure compared with baseline.

Clinical and Angiographic Outcome at Follow-up

During the follow-up period of 178±17 days (range, 150 to 225 days), at least one clinical event occurred in 5 of the 15 patients (Table 2). Angiographic restenosis (Table 2 and Fig 3) occurred in 6 patients (40%; 95% confidence interval, 16% to 68%). The minimal luminal diameter, reference vessel diameter, and percent diameter stenosis were 0.9±0.4 mm, 2.8±0.5 mm, and 68±12% at baseline; 2.5±0.6 mm, 2.7±0.5 mm, and 11±8% just after the procedure; and 1.7±0.9 mm, 2.7±0.7 mm, and 39±25% at 6-month follow-up, respectively. In 4 patients with restenosis, repeat PTCA of the lesion treated with β-irradiation was performed. All PTCA procedures for restenosis performed in the irradiated arterial segments were uncomplicated and lead to good angiographic results. Further stenting was necessary in one patient (patient 3) for marked elastic recoil. This patient developed recurrent symptoms 2 months after the second procedure, with evidence of myocardial ischemia in the territory of the culprit left anterior descending coronary artery, and underwent elective bypass surgery. Two other patients with angiographic restenosis were not further revascularized: patient 14 because he remained asymptomatic with a negative stress test despite a 55% restenosis, and patient 10 because control angiography showed total occlusion at the previously treated site with well developed collaterals to the distal vessel. In the latter patient, radiotherapy had been combined with angioplasty for recurrent within-stent restenosis, and recurrent angina was treated by increasing medical treatment.

In patients 13 and 15, disease progression was noted in another artery and was treated by further angioplasty. In patient 15, in whom the PTCA/irradiation procedure had been performed in the right coronary artery (Fig 3) and showed no restenosis at 5 months, PTCA of a new tight lesion of the proximal LAD was complicated by transmural anterior myocardial infarction 5 days after hospital discharge. Thrombolytic therapy was used but lead to fatal intracerebral hemorrhage.

In no case was the development of an aneurysm or angiographically detectable thrombus in the irradiated arterial segment observed at follow-up.

It is noteworthy that among 5 patients with stents (patients 2, 3, 4, and 13, stents were implanted during PTCA/irradiation procedure; patient 10, within-stent restenosis), three angiographic restenoses (in patients 3, 10, and 13) were observed. The three remaining restenoses (in patients 9, 12, and 14) occurred in 10 patients without stent implantation.

Discussion

With the aim of reducing the development of atherosclerosis, the first in vivo use of intravascular radiotherapy was reported 32 years ago by Friedman et al.¹⁶ The concept was more recently revived by Liermann et al¹¹ to modulate the postangioplasty restenotic process, and a number of studies have documented the favorable impact of intraluminal γ-irradiation on the occurrence of neointimal hyperplasia in several animal models.⁸⁹¹⁷¹⁸ Liermann et al¹¹¹² used a ¹⁹²Ir source for irradiation of femoropopliteal arterial segments after stent implantation. The use of a γ source made it necessary to transport patients from the catheterization laboratory to a shielded afterloading room before radiation treatment. A dose of 12 Gy was prescribed at a distance of 3 mm from the source, but no centering was used. Follow-up periods of ≤69 months in 29 patients suggest a favorable impact on restenosis and show excellent clinical tolerance, with no vascular or perivascular side effects.¹⁹ Condado et al²⁰ were the first to report the use of intracoronary γ-irradiation; they also used a ¹⁹²Ir source. A dose of either 20 or 25 Gy was prescribed, and no acute complications were noted. Teirstein et al²¹ are also evaluating in a clinical setting the use of ¹⁹²Ir after stenting in coronary arteries. The source is noncentered, and its relatively low activity makes it possible to administer radiotherapy in the catheterization laboratory.

Intravascular β-Irradiation

To the best of our knowledge, the present series represents the first report on the clinical use of endovascular β-irradiation. In a similar manner to γ sources, endovascular β-irradiation is also remarkably effective in different animal models to prevent fibrointimal proliferation in response to vessel injury.¹⁵¹⁷ The use of β sources has several advantages over γ-irradiation: (1) lower undue irradiation of surrounding periarterial structures, due to a steeper depth-dose fall-off curve; (2) less radioprotection problems, making it compatible with a conventional catheterization laboratory; and (3) ability to deliver a high focal dose over a short period of time.

The present series demonstrates feasibility and lack of medium-term toxicity of an 18-Gy dose of β-irradiation delivered to the balloon/artery interface. Our technical success was 100%, and we encountered no particular difficulty in reaching the lesion or delivering the planned radiation treatment. Because our centering balloon is occlusive in the coronary lumen once inflated and because the activity of the ⁹⁰Y sources that were used was fairly low in this initial series, it was necessary for 4 of the 15 patients to be treated with two or three fractionated doses, with intermittent balloon deflations and source retrieval, while ischemia was allowed to subside temporarily. When sources with higher activity are available, this should no longer present any difficulty. Because of the steep depth-dose fall-off curve, the time necessary to administer the planned 18-Gy dose was greatly influenced by the diameter of the centering balloon (mean exposure time, 281±50 seconds for 2.5-mm, 322±209 seconds for 3-mm, and 561±191 seconds for 3.5-mm-diameter centering balloons). The dose fall-off also makes it important to center the source within the vascular lumen, and such centering is a distinguishing feature of our approach compared with other systems.^11172021 Centering of the source is intended to homogenize the radiation dose delivered to different points of the arterial wall within the treated segment. In the case of atherosclerotic human coronary arteries, the target smooth muscle cells are situated within a thin-walled (0.3 to 2 mm thick) tubular structure.²²²³ Endoluminal inflation of the centering balloon forces the target tissues to occupy a position as equidistant as possible in respect to the radiation source, thereby allowing good circumferential and axial dose distribution. The increased distance between source and arterial wall induced by balloon inflation can be compensated for by an appropriately calculated exposure time. It is obvious that an eccentric intraluminal position of the source would result in areas of both relative underdosage and overdosage with respect to the prescribed dose level.¹⁰¹² This could be clinically relevant because it has been suggested that low radiation doses (4 to 8 Gy) may stimulate rather than inhibit neointimal proliferation,²⁴ whereas higher doses (≥30 Gy) could lead to late vascular complications.²⁵²⁶ Obviously, our centering balloon cannot take into account any degree of eccentricity of the lumen itself within the atherosclerotic vessel; it will ensure, however, that no section of the arterial wall is exposed to toxic doses of radiation because the minimal distance between source and inner arterial surface is determined by the radius of the inflated balloon. The prescribed dose to the vessel wall is a maximal dose that cannot be exceeded.

Safety

In keeping with our data from experiments with animals¹⁵ and those of others,⁹ this early clinical experience suggests no evidence of clinical or angiographically detectable toxicity of β-brachytherapy after a follow-up period of 6 months. We specifically noted no angiographic appearance suggestive of aneurysm formation and no intraluminal filling defect suggesting thrombus deposition. One patient (patient 10) did develop late target segment occlusion without myocardial infarction or resting ECG changes, but this occurrence was fairly nonspecific because at the time of the radiotherapeutic procedure, the patient was being treated for the third time at the same site after within-stent restenosis. One patient died (patient 15), but this occurred after treatment for a new unstable coronary lesion in another vessel and was clearly unrelated to the radiation treatment. Condado et al²⁷ reported the occurrence of a single coronary aneurysm at follow-up after intracoronary γ-irradiation. It should be noted, however, that the prescribed dose was 20 to 25 Gy and that no centering device was used. Liermann et al¹¹¹⁹ observed no vascular or perivascular lesions that could be attributed to intravascular radiotherapy during follow-up periods of ≤69 months. However, radiation-induced arteriopathy is a well recognized complication of external radiation therapy. It is usually a late complication, occurring after a mean of 16 years (range, 3 to 29 years) after treatment of a large field.²⁸ It is generally accepted that after mediastinal irradiation in cancer patients, the risk of the development of significant epicardial coronary artery disease is increased in comparison with the normal population.²⁹ In addition, the experimental data of Gillette et al²⁶ show that intraoperative radiation therapy with single doses of >30 Gy to a large field are capable of inducing late vascular lesions. Although it remains uncertain whether any parallel should be made between large-field radiotherapy to healthy arteries and the very local irradiation of a barotraumatized atheromatous vessel segment, it will be necessary to carefully evaluate the late impact of intravascular radiotherapy with the use of prolonged follow-up periods before definitive conclusions can be made regarding the safety of intraluminal β-irradiation. Radiation treatment delivered to non-oncological patients also raises the concern of radiation-induced carcinogenesis, but because β-irradiation delivers an extremely low dose beyond the immediate target lesion and because the exposed tissues (eg, arteries, veins, cardiac muscle, pericardium) have a low spontaneous carcinogenicity rate, this risk appears to be extremely low.

Study Limitations

The present study demonstrates excellent technical feasibility but was not designed to evaluate the efficacy of intracoronary β-brachytherapy. Six of the 15 patients developed angiographic restenosis, using the predefined criterion of a 50% diameter stenosis by quantitative coronary angiography. Although the confidence interval is wide due to the small number of patients studied, the observed restenosis rate does not suggest a major impact of an 18-Gy dose on the restenotic process. Despite limitations inherent to a pilot study involving a heterogeneous group of only 15 patients, it may be important to note that 5 of the 6 patients with restenosis at 6 months had only a moderate degree of narrowing: ≈50% to 60% range (Fig 3). This could be interpreted as suggesting a favorable but insufficient impact of the chosen dose.

Not only is the optimal dose still undefined, but so is the target. Recent work by several groups³⁰³¹ suggests that the adventitia may play an important role in the genesis of vascular remodeling after angioplasty. It is also possible that the adventitia may serve as a source of myofibroblasts that subsequently migrate within the media before replication.³⁰

The dose of 18 Gy was chosen on the basis of our work with animals¹⁵ and is broadly comparable to that prescribed by other groups, both clinically and in animal models. The irradiation delivery system we used in this study provides a good reproducible circumferential and axial dose distribution at the surface of the centering balloon inflated to a standard pressure of 5 bar,¹⁴ However, the dose fall-off as a function of arterial wall thickness remains important. For ⁹⁰Y, the intramural dose gradient consists of a >50% decrease for each millimeter of arterial tissue depth. Thus, the delivery of an 18-Gy radiation dose at the centering balloon/arterial surface interface results in a dose of ≈8 Gy at 1 mm and <4 Gy at 2 mm of arterial wall depth. This dose gradient may not be relevant in rabbit arteries that do not exceed 0.4 mm in thickness (V. Verin, MD, unpublished observations) but could be critical for clinical use. Taking into account that coronary arterial wall thickness in patients varies between 0.3 and 2 mm,²²²³ our chosen dose of 18 Gy could have lead to insufficient inhibition and even to stimulation of smooth muscle cells situated in the external wall layers of atherosclerotic coronary arteries. This could be corrected for by increasing the centering balloon/arterial surface interface dose. Clearly, a clinical dose-finding evaluation is necessary before a controlled randomized efficacy trial can be appropriately designed.

We know from our data¹⁵ and those of others⁸⁹¹⁰¹⁷ that intraluminal radiotherapy is a powerful inhibitor of fibrointimal proliferation. It is, however, also plausible that it would be capable of favorably influencing constrictive arterial remodeling after PTCA by diminishing the contraction force of the healing arterial wall. The evaluation of radiation effect on surgical wound contraction³²³³ demonstrates a significant reduction in wound strength after irradiation. A single dose of 18 Gy before wound infliction reduces wound strength by 50% to 65% compared with control within 3 months of follow-up.³²

Conclusions

The present data demonstrate the clinical feasibility of intracoronary β-brachytherapy and fail to reveal any complications that could be attributed to its use. Definitive conclusions regarding safety will have to await longer-term evaluation. Proof of efficacy will require strict dose-finding evaluation of higher doses than those used in the present pilot study followed by a controlled, randomized trial using both clinical and angiographic end points.

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Footnotes