Two-year follow-up after catheter-based radiotherapy to inhibit coronary restenosis.

BACKGROUND: Although early trials indicate the treatment of restenosis with radiation therapy is safe and effective, the long-term impact of this new technology has been questioned. The possibility of late untoward consequences, such as aneurysm formation, perforation, and accelerated vascular disease, is of significant concern. Furthermore, it is not known whether the beneficial effects of radiation therapy will be durable or whether radiation will only delay restenosis. METHODS AND RESULTS: A double-blind, randomized trial was undertaken to compare 192Ir with placebo sources in patients with previous restenosis after coronary angioplasty. Patients were randomly assigned to receive a 0.76-mm (0. 03-in) ribbon containing sealed sources of either 192Ir or placebo. All patients underwent repeat coronary angiography at 6 months. All living patients were contacted 24 months after their index study procedure. Patients were assessed with respect to the need for target-lesion revascularization or nontarget-lesion revascularization, occurrence of myocardial infarction, or death. Over a 9-month period, 55 patients were enrolled; 26 were randomized to 192Ir and 29 to placebo. Follow-up was obtained in 100% of living patients at a minimum of 24 months. Target-lesion revascularization was significantly lower in the 192Ir group (15.4% versus 44.8%; P<0. 01). Nontarget-lesion revascularization was similar in 192Ir and placebo patients (19.2% versus 20.7%; P=NS). There were 2 deaths in each group. The composite end point of death, myocardial infarction, or target-lesion revascularization was significantly lower in 192Ir-treated versus placebo-treated patients (23.1% versus 51.7%; P=0.03). No patient in the 192Ir group sustained a target-lesion revascularization later than 10 months. CONCLUSIONS: At 2-year clinical follow-up, treatment with 192Ir demonstrates significant clinical benefit. Although further follow-up (including late angiography) will be necessary, no clinical events have occurred to date in the 192Ir group to suggest major untoward effects of vascular radiotherapy. At the intermediate follow-up time point, vascular radiotherapy continues to be a promising new treatment for restenosis.

Three-year clinical and angiographic follow-up after intracoronary radiation : results of a randomized clinical trial.

BACKGROUND: Although several early trials indicate treatment of restenosis with radiation therapy is safe and effective, the long-term impact of this new technology has been questioned. The objective of this report is to document angiographic and clinical outcome 3 years after treatment of restenotic stented coronary arteries with catheter-based (192)Ir. METHODS AND RESULTS: A double-blind, randomized trial compared (192)Ir with placebo sources in patients with previous restenosis after coronary angioplasty. Over a 9-month period, 55 patients were enrolled; 26 were randomized to (192)Ir and 29 to placebo. At 3-year follow-up, target-lesion revascularization was significantly lower in the (192)Ir group (15. 4% versus 48.3%; P<0.01). The dichotomous restenosis rate at 3-year follow-up was also significantly lower in (192)Ir patients (33% versus 64%; P<0.05). In a subgroup of patients with 3-year angiographic follow-up not subjected to target-lesion revascularization by the 6-month angiogram, the mean minimal luminal diameter between 6 months and 3 years decreased from 2.49+/-0.81 to 2.12+/-0.73 mm in (192)Ir patients but was unchanged in placebo patients. CONCLUSIONS: The early clinical benefits observed after treatment of coronary restenosis with (192)Ir appear durable at late follow-up. Angiographic restenosis continues to be significantly reduced in (192)Ir-treated patients, but a small amount of late loss was observed between the 6-month and 3-year follow-up time points. No events occurred in the (192)Ir group to suggest major untoward effects of vascular radiotherapy. At 3-year follow-up, vascular radiotherapy continues to be a promising new treatment for restenosis.

Effect of intracoronary gamma-radiation therapy on in-stent restenosis: An intravascular ultrasound analysis from the gamma-1 study.

BACKGROUND: The aim of this study was to use serial volumetric intravascular ultrasound to evaluate the effect of gamma-radiation on recurrent in-stent restenosis. METHODS AND RESULTS: After successful reintervention, patients were randomized to receive either (192)Ir or placebo. Intravascular ultrasound studies with motorized pullback (0.5 mm/s) were performed immediately after irradiation and at 8-month follow-up in 70 patients. Paired volumetric analysis of the stented segment and of 5-mm proximal and distal reference segments was performed; this included measurements of the external elastic membrane, lumen, plaque and media (external elastic membrane minus lumen), stent, and intimal hyperplasia (stent minus lumen). Baseline proximal reference, stent, and distal reference measurements were similar in both groups. The changes in proximal and distal reference measurements of the external elastic membrane, plaque and media, and lumen areas were similar in both groups. However, the decrease in stented segment lumen volume was less in the (192)Ir patients than the placebo patients (-25+/-34 mm(3) versus -48+/-42 mm(3); P:=0.0225), and the increase in the volume of intimal hyperplasia in the stented segment was less in the (192)Ir patients than in the placebo patients (28+/-37 mm(3) versus 50+/-40 mm(3); P:=0.0352). When averaged over the length of the stented segment (32+/-13 mm versus 33+/-14 mm; P:=0.9), the increase in mean area of intimal hyperplasia was 0.8+/-1.0 mm(2) in the (192)Ir group and 1.6+/-1.2 mm(2) in the control group (P:=0.0065). Late stent-vessel wall malapposition was noted in one placebo patient and no (192)Ir patients. CONCLUSIONS: gamma-Radiation therapy can effectively prevent recurrent in-stent restenosis by inhibiting neointimal formation within the stent. At the stent edge, there were no significant differences between (192)Ir and placebo patients.

Endovascular brachytherapy for peripheral vascular disease.

The most common cause of morbidity and mortality in the United States is vascular disease, which afflicts a wide spectrum of organs such as the heart (cardiovascular system), brain (cerebrovascular system), kidney (renal system), liver (hepatic system), and extremities (peripheral vascular system). The most common pathology of vascular diseases is occlusion. Percutaneous Transluminal Angioplasty (PTA) is currently the most common nonsurgical treatment for obstructive arteries. Unfortunately, the long-term effectiveness of PTA is limited by a high restenosis rate. Efforts to reduce post-PTA restenosis, including laser, mechanical atherectomy, intravascular stenting, and pharmacologic agents, have not been successful. With recent advances in the pathogenesis of restenosis, we have learned that the major problem is the intimal hyperplastic reaction in response to vessel injury. Encouraging animal data in the use of various radiotherapeutic approaches to prevent restenosis has led to a large number of multi-national, multicenter, randomized trials on coronary vascular systems. Because early results have been in favor of radiation therapy, and because the basic process of restenosis is similar for coronary and noncoronary vascular systems, many investigators extend the application of radiotherapy to the prevention of restenosis in peripheral vascular systems. However, the clinical scenarios are much different for peripheral vascular systems than for the coronary vascular system. This article discusses the current views of the pathophysiology of restenosis, major clinical trials, and perspectives on future studies. Experimental studies on animal models have documented the profound effects of endovascular brachytherapy in reducing restenosis caused by angioplasty and stenting. Early results of clinical trials are encouraging and confirm these positive results. Long-term follow-up data are needed to show that radiation does prevent, not merely delay, restenosis; Several areas of opportunity exist for both basic science research and clinical studies to enhance our knowledge of the pathophysiology. This would optimize the treatment strategy, maximizing the benefits and minimizing late complications.

Barotrauma due to stent deployment in endovascular brachytherapy for restenosis prevention.

PURPOSE: In this study, the effect of barotrauma due to stent deployment is investigated for several commonly used commercial stents used in endovascular brachytherapy for restenosis prevention. METHODS AND MATERIALS: Restenosis due to intimal hyperplasia can occur anywhere along the clinical target volume, which is defined as the length of vessel receiving intervention or injury. The injury may be due to angioplasty, atherectomy (tissue removing), stenting, and stent deployment. Manufacturer specifications for several commonly used stents were reviewed and the results were tabulated. RESULTS: The barotrauma length of stents reviewed in this study ranges from 0.5 to 2.5 mm; the average was 1.7 mm. CONCLUSIONS: By considering specific barotrauma into the treatment length, one can provide adequate treatment margins to minimize edge failure or to avoid "geographic miss," which may improve the efficacy of endovascular brachytherapy.

Source displacement during the cardiac cycle in coronary endovascular brachytherapy.

PURPOSE: Preliminary clinical trials employing catheter-based endovascular brachytherapy show promising results in reducing restenosis after coronary intervention. Failure analysis of these studies showed a significant number of failures at the treatment margin. It is hypothesized that one of the possible causes for marginal failure is the longitudinal seed movement during the brachytherapy procedure. In this study a quantitative analysis was performed to determine the magnitude of the source displacement during the cardiac cycle. METHODS AND MATERIALS: Cine-angiograms of the Iridium-192 (Ir-192) active source seeds or dummy source seeds in place were reviewed frame by frame for 30 patients enrolled from various clinical trials using the Cordis catheter delivery system with a Ir-192 seed ribbon. The proximal and distal source points were measured in reference to branching vessels closest to the respective seed during the contrast phase of the cine-angiogram. The two frames showing the maximum source displacement were captured. After appropriate demagnification, longitudinal source displacement was measured. The data were tabulated for proximal vs. distal ends and for different coronary vessels. RESULTS: The longitudinal source displacement is significant with overall mean and standard deviation of 1.1 and 0.8 mm, respectively. The range is from 0.0 to 5.4 mm. CONCLUSION: The contribution of source movement should be included into the treatment length to avoid "geographic miss" and the subsequent marginal failure.

A subgroup analysis of the Scripps Coronary Radiation to Inhibit Proliferation Poststenting Trial.

INTRODUCTION: In the Scripps Coronary Radiation to Inhibit Proliferation Poststenting (SCRIPPS) Trial, 192Ir significantly reduced angiographic, ultrasonographic, and clinical endpoints of restenosis. The objective of this analysis was to quantitate the impact of patient, lesion and technical characteristics on late angiographic outcome. METHODS: Patients with restenotic, stented coronary lesions were randomized to receive either 192Ir or placebo sources. Late luminal loss and loss index were calculated for several patient subgroups, including patients with diabetes, in-stent restenosis, multiple previous percutaneous transluminal coronary angioplasty (PTCA) procedures, longer lesion lengths, saphenous vein grafts, small vessel diameters, and minimum dose exposures < 8.00 Gy. Two-factor analysis of variance was used to test for an interaction between patient characteristics and treatment effect. RESULTS: In the treated group, late loss was particularly low in patients with diabetes (0.19 mm), in-stent restenosis (0.17 mm), reference vessel diameters < 3.0 mm (0.07 mm), and patients who received a minimum radiation dose to the entire adventitial border of at least 8.00 Gy. The loss index in each of these subgroups was similarly low at -0.02, 0.03, -0.02, and 0.03, respectively. By 2-factor analysis of variance, a significant interaction between subgroup characteristic and treatment effect (late loss) was found in patients with in-stent restenosis (p = 0.035), and patients receiving a minimum dose of 8.00 Gy to the adventitial border (p = 0.009). CONCLUSION: In this pilot study, patient characteristics associated with a more aggressive proliferative response to injury appeared to confer an enhanced response to radiotherapy. Furthermore, a dose threshold response to 192Ir was found with an enhanced response occurring when the entire circumference of the adventitial border was exposed to at least 8.00 Gy.

Radiation therapy to inhibit restenosis: early clinical results.

BACKGROUND: Although several early trials indicate that treatment of restenosis with radiation therapy is safe and effective, the long-term impact of this new technology has been questioned. The objective of this report is to document angiographic and clinical outcome 3 years after treatment of restenosis of stented coronary arteries with catheter-based iridium-192 (192Ir). METHODS: A double-blind, randomized trial compared 192Ir with placebo sources in patients with previous restenosis after coronary angioplasty. Over a 9-month period, 55 patients were enrolled; 26 were randomized to 192Ir and 29 to placebo. RESULTS: At 3-year follow-up, target-lesion revascularization was significantly lower in the 192Ir group (15.4% vs. 48.3%; p < 0.01). The dichotomous restenosis rate at 3-year follow-up was also significantly lower in 192Ir patients (33% vs. 64%; p < 0.05). In a subgroup of patients with 3-year angiographic follow-up not subjected to target-lesion revascularization by the 6-month angiogram, the mean minimal luminal diameter between 6 months and 3 years decreased from 2.49 +/- 0.81 mm to 2.12 +/- 0.73 mm in 192Ir patients, but was unchanged in placebo patients. CONCLUSIONS: The early clinical benefits observed after treatment of coronary restenosis with 192Ir appear durable at late follow-up. Angiographic restenosis continues to be significantly reduced in 192Ir-treated patients, but a small amount of late loss was observed between the 6-month and 3-year follow-up time points. No events occurred in the 192Ir group to suggest major untoward effects of vascular radiotherapy. At 3-year follow-up, vascular radiotherapy continues to be a promising new treatment for restenosis.

Indomethacin versus radiation therapy for heterotopic ossification after hip arthroplasty.

This study compared the efficacy and cost of radiation therapy with indomethacin in the prophylaxis of heterotopic ossification following total hip replacement. Twenty-two patients received a radiation dose of 10 Gy in five fractions, 28 patients 8 Gy in one fraction, and 27 patients 25 mg oral indomethacin three times a day for either 7 or 21 days. Patients at higher risk for heterotopic ossification were more likely to receive radiation therapy than indomethacin. At a mean follow-up of 2 years, there were no differences in failure rates between the high-risk patients treated with radiation and the low-risk patients treated with indomethacin. Currently, the patient-billed cost of radiation is $1400 whereas the cost for indomethacin is approximately $100. Indomethacin appears to be as effective as radiation therapy in patients at low to moderate risk for heterotopic ossification and offers significant cost savings.

Practical considerations in setting up an intracoronary brachytherapy program: results of a multicenter survey.

PURPOSE: To identify logistic issues faced by radiation oncologists in initiating intracoronary radiation therapy (RT) and to delineate their role in these procedures. MATERIALS AND METHODS: Radiation oncologists from 12 sites (with combined experience of >500 cases) that participated in a randomized, double-blinded study of intracoronary RT completed a questionnaire that included demographics and experience, regulatory issues, scheduling and interaction with patients, time commitment, involvement of the radiation oncologist, and ideas for overcoming hurdles. RESULTS: Licensing was perceived as a substantial hurdle; Nuclear Regulatory Commission approval took more than 5 months at five of 12 sites. At two higher-volume sites, 10-20 procedures were performed per week; 75% of these radiation oncologists did not see the patient prior to the procedure and were not involved in obtaining informed consent. The mean time spent per case was 30-90 minutes; however, there were major concerns about case scheduling (<50% had any input in case scheduling) and after-hours coverage. Radiation oncologists performed fluoroscopy and cineangiography at most centers (92% and 83%); they also performed intracoronary contrast material injections (67%), interpreted intravascular ultrasonographic images (42%), and repositioned the intracoronary RT catheter (33%). CONCLUSION: The authors identify several issues that need to be addressed before intracoronary RT becomes a part of widespread clinical practice. Close collaboration between cardiologists and radiation oncologists at various levels is required to ensure that patients derive maximal benefit from this new technology.

Initial studies with gamma radiotherpay to inhibit coronary restenosis.

BACKGROUND: Early studies indicate brachytherapy is a potential clinical treamtent for restenosis after coronary angioplasty procedures. The objective of this study was to evaluate the safety and efficacy of gamma radiation plus stenting in patients' previous restenosis. METHODS: In patients with previous coronary restenosis, balloon dilatation and/or coronary stenting was undertaken and then patients were randomly assigned to receive either Iridium-192 or placebo. Quantitative coronary angiographic, intravascular ultrasonographic, and clinical follow-up was obtained. RESULTS: Of the 55 patients enrolled, 26 were treated with Iridium-192 and 29 were in the placebo group. Late luminal loss was significantly lower in the treated group compared to the placebo group (0.38 +/- 1.06 mm vs. 1.03 +/- 0.97 mm, p = 0.03). Restenosis (stenosis of > or = 50% at follow-up) was found in 17% of treated patients compared to 54% of placebo patients (p = 0.01). The need for target lesion revascularization was observed in 12% of patients in the treated group compared to 45% in the placebo group (p = 0.01). CONCLUSIONS: In this initial trial, at 12 months follow-up, patients with previous restenosis were benefited by catheter-based gamma radiation therapy.

Theoretical assessment of dose-rate effect in endovascular brachytherapy.

PURPOSE: Several prospective randomized clinical trials utilizing endovascular brachytherapy after coronary angioplasty have shown promising preliminary results. Numerous clinical trials have been initiated to evaluate different delivery systems and source types. In this study, the dose-rate effect is investigated using a biophysical model derived from linear-quadratic formalism. MATERIALS AND METHODS: The dose-rate effect is quantified using the Dale's formulation, which is based on a linear-quadratic model. This model converts the total absorbed dose into the biological equivalent dose (BED) based on the dose rate, total dose, treatment duration, biological endpoint (alpha/beta ratio), and sublethal damage repair constant. The calculations are performed for two common source configurations used in current clinical trials (192Ir and 90Sr/Y). RESULTS: At smaller radial distance, the dose rate is higher, hence BED increases due to the increase in the relative effectiveness per unit dose (RE) and absorbed dose for a given treatment duration. For 90Sr/Y source, a similar trend is observed; however, it is at a much greater magnitude. The RE for 192Ir is close to unity, which is equivalent to that of external beam irradiation. CONCLUSION: Although current clinical trials in endovascular brachytherapy report similar absorbed dose, the biological effects may be different due to the extremely high gradient of dose rate near the sources, a variety of isotopes and delivery systems, and different dose prescriptions. If the theoretical predictions in this study are validated in clinical trials, the proposed model can be useful to compare different protocols, design new delivery systems and isotopes, and optimize how radiation is delivered.

Theoretical assessment of late cardiac complication from endovascular brachytherapy for restenosis prevention.

PURPOSE: In this study, a theoretical assessment of late cardiac complication from endovascular brachytherapy is performed using the integrated logistic model. MATERIALS AND METHODS: Calculation were performed for various lengths of Ir-192 sources using alpha/beta = 3.2 for the endpoint of chronic ischemia, TD50/5 = 7,000 cGy, and TD5/5 = 5,000 cGy. The dose distribution over a standard heart was divided into volume elements with uniform dose (dose-volume histogram). Using linear-quadratic equation, the dose in each of the volume elements was converted into dose equivalent to standard fractionation external beam irradiation. The normal tissue complication probability (NTCP) for each volume element was calculated and combined together to arrive at the cumulative risk of late cardiac complication. The NTCP was plotted against the dose prescribed at 2-mm radial distance for four treatment lengths. RESULTS: (1) The overall risk of late cardiac toxicity (chronic ischemia within 5 years) was estimated to be less than 1% for current clinical trials using Ir-192. (2) There is a volume effect with higher risk for larger irradiated volume, which can come from longer treatment time, the same dose prescribed at a greater radial distance, and a longer source train. (3) The NTCP vs. dose demonstrates a sigmoidal relationship. There is a threshold dose (about 500 cGy), below which the risk is minimal; the gradient of the curve is greater for longer treatment length. CONCLUSION: If the prediction from this model is validated with clinical data, it will contribute to guidelines for dose prescription, dose escalation, evaluation of new source design, and multivessel treatment.

Normal transcutaneous oxygen pressure in skin after radiation therapy for cancer.

BACKGROUND: Chronic deleterious changes in human skin after radiation therapy often have been ascribed to progressive ischemia (decreased blood supply and oxygenation). Recent studies suggest, however, that damaged irradiated skin is not ischemic. Transcutaneous oxygen pressure (TCPO2), that accurately reflects skin oxygenation, was studied in 100 patients who had undergone prior extensive radiation therapy for cancer. METHODS: In the 100 patients, the mean time since radiation was 7.86 +/- 10.56 years (mean, +/- SD) (range, 1-58 years). Radiation skin effects were graded (0-4+), and TCPO2 was measured in irradiated and control nonirradiated sites, with patients first breathing room air, then 100% O2 6 l/min for 10 minutes. Data were stratified according to skin grades, sex, time since irradiation, site, type, and dose of radiation. RESULTS: The mean TCPO2 in patients breathing room air was 52.0 17.8 mm Hg (mean +/- SD) for all irradiated skin, compared with 131.8 +/- 51.1 at the same irradiated sites in response to oxygen breathing (P < 0.0001); the mean TCPO2 for normal, nonirradiated skin was 56.5 +/- 12.6 when patients were breathing room air, compared with 151.5 +/- 48.1 when breathing 100% oxygen (P < 0.0001). Higher skin damage grades correlated with increasing time after radiation therapy. However, neither increasing time after irradiation nor grade of skin damage correlated with TCPO2, which was normal in 88% of the patients. CONCLUSIONS: Human skin, even many decades after radiation therapy, retains normal tissue oxygenation and TCPO2 response to inspired oxygen. Postradiation scarring, poor healing, and rare ulceration are not solely due to ischemia and may be caused by other radiation effects, such as permanent changes in fibroblasts.

Physics and safety aspects of a coronary irradiation pilot study to inhibit restenosis using manually loaded 192Ir ribbons.

Radiation therapy has been successfully used in controlling some forms of benign tissue growth. A pilot study has been launched to evaluate the usefulness of localized radiation therapy in reducing restenosis after coronary angioplasty. In this randomized, double-blind study, patients with known restenosis received balloon angioplasty or additional stent implantation and were then randomized to receive either radiation or placebo treatment. Active sources consisted of 192Ir in the form of cylindrical seeds (0.3 x 0.05 cm). The seeds are embedded in a nylon ribbon. The nylon ribbon is passed through an indwelling coronary catheter. For this pilot trial, radioactive sources were exposed to blood elements and, therefore, required sterilization. A method of sterilization is described. A working team was developed to perform coronary radiation procedures at our institution. A description of the procedure is provided.

How long is enough? Defining the treatment length in endovascular brachytherapy.

The International Commission on Radiation Units and Measurement (IRCU) 50 has clearly defined treatment volumes in radiation therapy in the management of neoplasms. These concepts are applied to the field of endovascular brachytherapy (EVBT) for the prevention of postangioplasty restenosis. The following definitions are proposed: gross target length (GTL) is defined as the narrowed segment of the artery that requires intervention. Clinical target length (CTL) is defined as the intervened or injured length, which could be due to angioplasty, stent strut injury, stent deployment, or debulking procedures. Planning target length (PTL) is the CTL plus a margin to account for heart/catheter movement and uncertainty in target localization. The final treatment length (TL) is the PTL plus the effect of penumbra. The accurate specification of treatment length serves several important purposes. Based on an understanding of the different factors constituting the treatment length, adequate margins can be provided beyond the GTL; this will avoid geographic misses and minimize edge failures. These definitions of target length ensure treatment consistency and provide a standard terminology for communication among practitioners of EVBT, something of critical importance in the conduct of multi-institutional trials in this new and multidisciplinary therapy. Finally, since the efficacy of EVBT is critically dependent on the precision of radiation delivery, these guidelines ensure that the benefits of EVBT seen in prospective randomized trials can be translated into daily clinical practice at the community level.