Improved survival of patients with cervical cancer treated with image-guided brachytherapy compared with conventional brachytherapy.

OBJECTIVE: Since the Group Européen de Curiethérapie and the European Society for Radiotherapy and Oncology (GEC-ESTRO) published recommendations for 3D MRI-based image-guided adaptive brachytherapy (IGBT) in the treatment of cervical cancer, many institutions have implemented this technique and favourable results were documented. We investigated if introduction of IGBT in our centre indeed improved treatment outcomes and reduced toxicity compared to conventional brachytherapy (CBT). METHODS: A retrospective analysis was done of outcomes of patients with stage IB-IVA cervical cancer treated with primary radiation therapy with curative intent between 2000 and 2012. Outcome measures were overall and disease-free survival, pelvic control, distant metastasis and treatment related adverse events (AE). RESULTS: 126 patients were analysed; 43 had been treated with CBT between 2000-2007, and 83 with IGBT between 2007-2012. External beam radiation (mean; 46.6Gy) was combined with concurrent weekly cisplatin (51.6%), or hyperthermia (24.6%); radiation alone was used in 23.8%. Median follow-up was 121.8months for CBT patients, vs. 42.3months for IGBT. Complete remission was achieved in 83.7% of patients in the CBT group and in 98.8% of IGBT patients (p<0.01). Overall survival at 3years was 51% and 86%, respectively (p=0.001). Pelvic recurrence was found in 32% vs. 7% (p<0.001). Most patients had low grade adverse events. High grade (3-4) AE occurred in 15.4% vs. 8.4% at 3years (p=0.06). CONCLUSION: Introduction of IGBT for cervical cancer has led to significantly increased 3-year locoregional control and survival rates, whilst reducing late morbidity.

Endovascular brachytherapy for the prevention of restenosis after femoropopliteal angioplasty. Results of the VARA Trial.

AIM: Endovascular brachytherapy (EBT) has been proposed as a method to prevent restenosis. We performed a prospective randomised multicenter study to determine its efficacy for prophylaxis of restenosis after femoropopliteal percutaneous transluminal angioplasty (PTA). METHODS: Patients with symptomatic stenotic or totally occluding lesions in the femoropopliteal artery were randomised to be treated with PTA plus EBT or PTA alone. In case of EBT, 14 Gy was applied by an 192Ir source to the vessel wall. Clinical examination, ankle-brachial pressure index (ABPI) and duplex ultrasound were planned after 6 and 12 months. The primary endpoint was significant restenosis of the treated segment at duplex ultrasound after 12 months. RESULTS: Fifty-three of the 60 patients who eventually met the inclusion criteria could be studied. After 12 months, restenosis rates were 44% (12/27) in the PTA group versus 35% (8/23) in the PTA + EBT group (c2 test, P=0.51). There was no difference in mandatory reintervention between the 2 groups. Overall, EBT resulted in an absolute risk reduction of significant restenosis of 9%, yet in patients with totally occlusive disease this reduction was 32%. CONCLUSIONS: This study suggests an effect of EBT on the occurrence of restenosis only after PTA of occluded femoropopliteal lesions. Due to a too small number of patients analysed this difference is not statistically significant.

Gamma radiation induces positive vascular remodeling after balloon angioplasty: a prospective, randomized intravascular ultrasound scan study.

BACKGROUND: Endovascular brachytherapy (EBT) has been shown to prevent restenosis after percutaneous transluminal coronary angioplasty (PTA) in both animal and clinical studies. However, as yet, the effect of EBT on peripheral arteries is unknown. OBJECTIVE: This intravascular ultrasound scan (IVUS) study evaluates the effect of EBT on the extent of plaque growth and vascular remodeling after PTA of the femoropopliteal artery. METHODS: Twenty-four patients with obstructive disease of the femoropopliteal artery underwent standard PTA. Patients were randomized to receive no additional therapy or additional EBT (192-Iridium) after PTA. IVUS investigation was performed after PTA and at 6-month follow-up. A comparison was made between patients without EBT (n = 16) and with EBT (n = 8) in the change in lumen, vessel, and plaque area and plaque dissections seen with IVUS at 6-month follow-up. RESULTS: At follow-up, IVUS revealed a significant difference in lumen area change between patients without and with EBT (-9% and +23%, respectively; P =.03). This difference was the result of a significant difference in vessel area change (+2% and +19%, respectively; P =.05). In both groups of patients, a similar increase in plaque area (+12% and +16%, respectively; P =.80) was encountered. Plaque dissections encountered immediately after PTA were absent at follow-up in patients without EBT, whereas in four of the eight patients with EBT, a persistent dissection was encountered. CONCLUSION: This randomized IVUS study showed that gamma-radiation after PTA has a positive effect on lumen dimensions at 6-month follow-up by inducing positive vascular remodeling (ie, vascular dilatation); gamma-radiation seemed not to affect plaque growth. In addition, gamma-radiation has an effect on the healing process of dissections after PTA.

Routine intracoronary beta-irradiation. Acute and one year outcome in patients at high risk for recurrence of stenosis.

AIMS: Intracoronary radiation is a promising therapy potentially reducing restenosis following catheter-based interventions. Currently, only limited data on this treatment are available. The feasibility and outcome in daily routine practice, however, is unknown. METHODS AND RESULTS: In 100 consecutive patients, intracoronary beta-radiation was performed with a (90)Strontium system (Novoste Beta-Cathtrade mark) following angioplasty. Predominantly complex (73% type B2 and C) and long lesions (length 24.3+/-15.3 mm) were included (37% de novo, 19% restenotic and 44% in-stent restenotic lesions). Radiation success was 100%. Mean prescribed dose was 19.8+/-2.5 Gy. A pullback procedure was performed in 19% lesions. Geographic miss occurred in 8% lesions. Periprocedural thrombus formation occurred in four lesions, dissection in nine lesions. During hospital stay, no death, acute myocardial infarction, or repeat revascularization was observed. Major adverse cardiac events occurred predominantly between 6 and 12 months after the index procedure with major adverse cardiac event-free survival of 66% at 12 months (one death, 10 Q-wave myocardial infarctions, 23 target vessel revascularizations; ranked for worst event). CONCLUSION: Routine catheter-based intracoronary beta-radiation therapy after angioplasty is safe and feasible with a high acute procedural success. The clinical 1-year follow-up showed delayed occurrence of major adverse cardiac events between 6 and 12 months after the index procedure.

Initial observation regarding changes in vessel dimensions after balloon angioplasty and stenting followed by catheter-based beta-radiation. Is stenting necessary in the setting of catheter-based radiotherapy?

AIMS: We sought to compare the effect of intracoronary beta-radiation on the vessel dimensions in de novo lesions using three-dimensional intravascular ultrasound quantification after balloon angioplasty and stenting. METHODS AND RESULTS: Forty patients (44 vessels; 28 balloon angioplasty and 16 stenting) treated with catheter-based beta-radiation and 18 non-irradiated control patients (18 vessels; 10 balloon angioplasty and 8 stenting) were investigated by means of three-dimensional volumetric intravascular ultrasound analysis post-procedure and at 6-8 months follow-up. Total vessel (EEM) volume enlarged after both balloon angioplasty and stenting (+37 mm(3) vs +42 mm(3), P=ns), but vessel wall volume (plaque plus media) also increased similarly (+33 mm(3) vs +49 mm(3), P=ns) in the irradiated patients. Lumen volume remained unchanged in both groups (+3 mm(3) vs -7 mm(3), P=ns). In the stent-covered segments, neointima at follow-up was significantly smaller in the irradiated group than the control group (8 mm(3) vs 27 mm(3), P=0.001, respectively), but the total amount of tissue growth was similar in both groups (33 mm(3) vs 29 mm(3), P=ns). CONCLUSIONS: Intracoronary beta-radiation induces vessel enlargement after balloon angioplasty and/or stenting, accommodating tissue growth. Additional stenting may not play an important role in the prevention of constrictive remodelling in the setting of catheter-based intracoronary beta-radiotherapy.

"Edge Effect" of (32)p radioactive stents is caused by the combination of chronic stent injury and radioactive dose falloff.

BACKGROUND: Radioactive stents have been reported to reduce in-stent neointimal thickening. An unexpected increase in neointimal response was observed, however, at the stent-to-artery transitions, the so-called "edge effect." To investigate the factors involved in this edge effect, we studied stents with 1 radioactive half and 1 regular nonradioactive half, thereby creating a midstent radioactive dose-falloff zone next to a nonradioactive stent-artery transition at one side and a radioactive stent-artery transition at the other side. METHODS AND RESULTS: Half-radioactive stents (n=20) and nonradioactive control stents (n=10) were implanted in the coronary arteries of Yucatan micropigs. Animals received aspirin and clopidogrel as antithrombotics. After 4 weeks, a significant midstent stenosis was observed by angiography in the half-radioactive stents. Two animals died suddenly because of coronary occlusion at this mid zone at 8 and 10 weeks. At 12-week follow-up angiography, intravascular ultrasound and histomorphometry showed a significant neointimal thickening at the midstent dose-falloff zone of the half-radioactive stents, but not at the stent-to-artery transitions at both extremities. Such a midstent response (mean angiographic late loss 1.0 mm) was not observed in the nonradioactive stents (mean loss 0.4 to 0.6 mm; P< 0.01). CONCLUSIONS: The edge effect of high-dose radioactive stents in porcine coronary arteries is associated with the combination of stent injury and radioactive dose falloff.

Clinical and angiographical follow-up after implantation of a 6--12 microCi radioactive stent in patients with coronary artery disease.

AIMS: This study is the contribution by the Thoraxcenter, Rotterdam, to the European(32)P Dose Response Trial, a non-randomized multicentre trial to evaluate the safety and efficacy of the radioactive Isostent in patients with single coronary artery disease. METHODS AND RESULTS: The radioactivity of the stent at implantation was 6--12 microCi. All patients received aspirin indefinitely and either ticlopidine or clopidogrel for 3 months. Quantitative coronary angiography measurements of both the stent area and the target lesion (stent area and up to 5 mm proximal and distal to the stent edges) were performed pre- and post-procedure and at the 5-month follow-up. Forty-two radioactive stents were implanted in 40 patients. Treated vessels were the left anterior descending coronary artery (n=20), right coronary artery (n=10) or left circumflex artery (n=10). Eight patients received additional non-radioactive stents. Lesion length measured 10+/-3 mm with a reference diameter of 3.07+/-0.69 mm. Minimal lumen diameter increased from 0.98+/-0.53 mm pre-procedure to 2.29+/-0.52 mm (target lesion) and 2.57+/-0.44 mm (stent area) post-procedure. There was one procedural non-Q wave myocardial infarction, due to transient thrombotic closure. Thirty-six patients returned for angiographical follow-up. Two patients had a total occlusion proximal to the radioactive stent. Of the patent vessels, none had in-stent restenosis. Edge restenosis was observed in 44%, occurring predominantly at the proximal edge. Target lesion revascularization was performed in 10 patients and target vessel revascularization in one patient. No additional clinical end-points occurred during follow-up. The minimal lumen diameter at follow-up averaged 1.66+/-0.71 mm (target lesion) and 2.12+/-0.72 (stent area); therefore late loss was 0.63+/-0.69 (target lesion) and 0.46+/-0.76 (stent area), resulting in a late loss index of 0.65+/-1.15 (target lesion) and 0.30+/-0.53 (stent area). CONCLUSION: These results indicate that the use of radioactive stents is safe and feasible, however, the high incidence of edge restenosis makes this technique currently clinically non-applicable.

Relationship between tensile stress and plaque growth after balloon angioplasty treated with and without intracoronary beta-brachytherapy.

AIMS: We investigated the influence of tensile stress on plaque growth after balloon angioplasty with and without beta-radiation therapy. METHODS AND RESULTS: Thirty-one consecutive patients successfully treated with balloon angioplasty were analysed qualitatively and quantitatively by means of an ECG-gated three-dimensional intravascular ultrasound post-procedure and at follow-up. Eighteen patients were irradiated with catheter-based beta-radiation ((90)Sr/(90)Y source) and 13 were not (control). Studied segments were divided into 2 mm subsegments. Thus 184 irradiated and 111 non-irradiated subsegments were included. Tensile stress was calculated according to Laplace's law. The radiation dose was calculated by means of dose-volume histograms. Plaque growth was positively correlated to tensile stress in both the radiation and control groups (r=0.374, P=0.0001 and r=0.305, P=0.001). Low-dose subsegments (<6 Gy) had a significant correlation (r=0.410, P=0.0001) whereas no correlation was observed in the effective-dose subsegments (> or = 6 Gy). Multivariate analysis identified tensile stress as the only independent predictor of plaque increase in non-irradiated subsegments, whereas actual dose and plaque morphology were stronger predictors in irradiated subsegments. CONCLUSION: The results of this study suggest that plaque growth is related to tensile stress after balloon angioplasty. Intracoronary brachytherapy may alter the biophysical process on plaque growth when the prescribed dose is effectively delivered.

Three-dimensional intravascular ultrasound assessment of noninjured edges of beta-irradiated coronary segments.

BACKGROUND: The "edge effect," late lumen loss at the margins of the treated segment, has become an important issue in the field of coronary brachytherapy. The aim of the present study was to assess the edge effect in noninjured margins adjacent to the irradiated segments after catheter-based intracoronary beta-irradiation. METHODS AND RESULTS: Fifty-three vessels were assessed by means of 3-dimensional intravascular ultrasound after the procedure and at 6- to 8-month follow-up. Fourteen vessels (placebo group) did not receive radiation (sham source), whereas 39 vessels were irradiated. In the irradiated group, 48 edges (5 mm in length) were identified as noninjured, whereas 18 noninjured edges were selected in the placebo group. We compared the volumetric intravascular ultrasound measurements of the noninjured edges of the irradiated vessels with the fully irradiated nonstented segments (IRS, n=27) (26-mm segments received the prescribed 100% isodose) and the noninjured edges of the vessels of the placebo patients. The lumen decreased (6 mm(3)) in the noninjured edges of the irradiated vessels at follow-up (P:=0. 001). We observed a similar increase in plaque volume in all segments: noninjured edges of the irradiated group (19.6%), noninjured edges of the placebo group (21.5%), and IRS (21.0%). The total vessel volume increased in the IRS in the 3 groups. No edge segment was subject to repeat revascularization. CONCLUSIONS: The edge effect occurs in the noninjured margins of radiation source train in both irradiated and placebo patients. Thus, low-dose radiation may not play an important role in this phenomenon, whereas nonmeasurable device injury may be considered a plausible alternative explanation.

Geographic miss: a cause of treatment failure in radio-oncology applied to intracoronary radiation therapy.

BACKGROUND: A recognized limitation of endovascular beta-radiation therapy is the development of new stenosis at the edges of the irradiated area. The combination of injury and low-dose radiation may be the precursor of this phenomenon. We translated the radio-oncological concept of "geographic miss" to define cases in which the radiation source did not fully cover the injured area. The aims of the study were to determine the incidence and causes of geographic miss and evaluate the impact of this inadequate treatment on the outcome of patients treated with intracoronary beta-radiation. METHODS AND RESULTS: We analyzed 50 consecutive patients treated with beta-radiation after percutaneous coronary intervention. The prescribed dose ranged between 12 and 20 Gy at 2 mm from the source axis. By means of quantitative coronary angiography, the irradiated segment (IRS) and both edges were studied before and after intervention and at 6-month follow-up. Edges that were injured during the procedure constituted the geographic miss edges. Twenty-two edges were injured during the intervention, mainly because of procedural complications that extended the treatment beyond the margins of the IRS. Late loss was significantly higher in geographic miss edges than in IRSs and uninjured edges (0.84+/-0.6 versus 0.15+/-0.4 and 0.09+/-0.4 mm, respectively; P<0.0001). Similarly, restenosis rate was significantly higher in the injured edges (10% within IRS, 40.9% in geographic miss edges, and 1.9% in uninjured edges; P<0.001). CONCLUSIONS: These data support the hypothesis that the combination of injury and low-dose beta-radiation induces deleterious outcome.

Residual plaque burden, delivered dose, and tissue composition predict 6-month outcome after balloon angioplasty and beta-radiation therapy.

BACKGROUND: Inhomogeneity of dose distribution and anatomic aspects of the atherosclerotic plaque may influence the outcome of irradiated lesions after balloon angioplasty (BA). We evaluated the influence of delivered dose and morphological characteristics of coronary stenoses treated with beta-radiation after BA. METHODS AND RESULTS: Eighteen consecutive patients treated according to the Beta Energy Restenosis Trial 1.5 were included in the study. The site of angioplasty was irradiated with the use of a beta-emitting (90)Sr/(90)Y source. With the side branches used as anatomic landmarks, the irradiated area was identified and volumetric assessment was performed by 3D intracoronary ultrasound imaging after treatment and at 6 months. The type of tissue, the presence of dissection, and the vessel volumes were assessed every 2 mm within the irradiated area. The minimal dose absorbed by 90% of the adventitial volume (D(v90)Adv) was calculated in each 2-mm segment. Diffuse calcified subsegments and those containing side branches were excluded. Two hundred six coronary subsegments were studied. Of those, 55 were defined as soft, 129 as hard, and 22 as normal/intimal thickening. Plaque volume showed less increase in hard segments as compared with soft and normal/intimal thickening segments (P<0.0001). D(v90)Adv was associated with plaque volume at follow-up after a polynomial equation with linear and nonlinear components (r = 0.71; P = 0.0001). The multivariate regression analysis identified the independent predictors of the plaque volume at follow-up: plaque volume after treatment, D(v90)Adv, and type of plaque. CONCLUSIONS: Residual plaque burden, delivered dose, and tiss composition play a fundamental role in the volumetric outcome at 6-month follow-up after beta-radiation therapy and BA.

Outcome from balloon induced coronary artery dissection after intracoronary beta radiation.

OBJECTIVE: To evaluate the healing of balloon induced coronary artery dissection in individuals who have received beta radiation treatment and to propose a new intravascular ultrasound (IVUS) dissection score to facilitate the comparison of dissection through time. DESIGN: Retrospective study. SETTING: Tertiary referral centre. PATIENTS: 31 patients with stable angina pectoris, enrolled in the beta energy restenosis trial (BERT-1.5), were included. After excluding those who underwent stent implantation, the evaluable population was 22 patients. INTERVENTIONS: Balloon angioplasty and intracoronary radiation followed by quantitative coronary angiography (QCA) and IVUS. Repeat QCA and IVUS were performed at six month follow up. MAIN OUTCOME MEASURES: QCA and IVUS evidence of healing of dissection. Dissection classification for angiography was by the National Heart Lung Blood Institute scale. IVUS proven dissection was defined as partial or complete. The following IVUS defined characteristics of dissection were described in the affected coronary segments: length, depth, arc circumference, presence of flap, and dissection score. Dissection was defined as healed when all features of dissection had resolved. The calculated dose of radiation received by the dissected area in those with healed versus non-healed dissection was also compared. RESULTS: Angiography (type A = 5, B = 7, C = 4) and IVUS proven (partial = 12, complete = 4) dissections were seen in 16 patients following intervention. At six month follow up, six and eight unhealed dissections were seen by angiography (A = 2, B = 4) and IVUS (partial = 7, complete = 1), respectively. The mean IVUS dissection score was 5.2 (range 3-8) following the procedure, and 4.6 (range 3-7) at follow up. No correlation was found between the dose prescribed in the treated area and the presence of unhealed dissection. No change in anginal status was seen despite the presence of unhealed dissection. CONCLUSION: beta radiation appears to alter the normal healing process, resulting in unhealed dissection in certain individuals. In view of the delayed and abnormal healing observed, long term follow up is indicated given the possible late adverse effects of radiation. Although in this cohort no increase in cardiac events following coronary dissections was seen, larger populations are needed to confirm this phenomenon. Stenting of all coronary dissections may be warranted in patients scheduled for brachytherapy after balloon angioplasty.

The effect of 32P beta-radiotherapy on both vessel remodeling and neointimal hyperplasia after coronary balloon angioplasty and stenting: a three-dimensional intravascular ultrasound investigation.

Intracoronary radiation is a promising therapy to decrease restenosis after percutaneous intervention. The aim of this pilot study was to determine the mechanism of intracoronary beta-radiation after balloon angioplasty and stenting in a double-blind placebo-controlled randomized fashion. Twenty-six patients were randomized to either placebo (n = 6) or 3 doses (28, 35 and 42 Gy) of beta-radiation (n = 20) using the Guidant brachytherapy system (27 mm long 32P source wire). Of these, 21 patients underwent post-procedure and 6-month follow-up three-dimensional intravascular ultrasound (IVUS) assessment. Volumetric quantification was performed by means of a semi-automated contour detection system after an ECG-gated motorized pullback IVUS imaging and three-dimensional reconstruction. We compared the volumetric changes (Delta) of total vessel volume (TVV), plaque volume (PV) and lumen volume (LV) after 6 months between placebo (dummy wire) and irradiated patients. In addition, the volume of neointimal hyperplasia was quantified within the stented segments. There was an opposite behavior of TVV and LV change between placebo (DeltaTVV = -24 mm3 and DeltaLV = -42 mm3) and irradiated (DeltaTVV = +18 mm3 and (DeltaLV = +5 mm3) patients. The mean neointimal formation within the stented segment in the irradiated patients (n = 7) was 1.9 mm3 (1.5%). Our results suggest that beta-radiation affects vessel remodeling after percutaneous intervention and inhibit neointimal formation in stented patients.

Peripheral vascular brachytherapy: an introduction.

The response of cells to ionising radiation has been extensively studied for the past 30 years. When radiation is absorbed in biological material, it can directly ionise a critical site (direct effect) or interact with other molecules to produce reactive free radicals, which can subsequently damage critical biological molecules (indirect effect). DNA is considered the critical target damaged by ionising radiation by both direct and indirect processes. Since radiotherapy had proven to be effective in the treatment of non-malignant proliferative processes, it was assumed that this adjunctive treatment would also inhibit vascular restenosis. The major difference between external and intravascular radiation is dose distribution. Intravascular delivery results in extremely high doses to the lumen with a fall-off in dose as a function of distance from the source; whereas, external beam would deliver a uniform dose over the entire volume of tissue treated. Unlike in the coronary circulation most of the peripheral vessels treated are greater than 3 mm in diameter; in fact many are 7 to 10 mm in diameter. Since beta radiation is related to lower penetration properties and more heterogeneous distribution of radiation in comparison to gamma radiation, it is therefore necessary to use a gamma radiation source because it would be difficult to irradiate the sub-intimal tissue with a beta source centred in a large vessel. Radiation can and does have the potential to destroy blood vessels. The challenge in vascular brachytherapy is to treat blood vessels to a point where restenosis is inhibited; yet the vessel is not irreparably damaged.

Endovascular brachytherapy in coronary arteries: the Rotterdam experience.

PURPOSE: The use of endovascular coronary brachytherapy to prevent restenosis following percutaneous transluminal coronary angioplasty (PTCA) began in April 1997 at the Department of Interventional Cardiology of the Thoraxcenter at the University Hospital of Rotterdam. This article reviews the more than 250 patients that have been treated so far. METHODS AND MATERIALS: The Beta-Cath System (Novoste), a manual, hydraulic afterloader with 12 90Sr seeds, was used in the Beta Energy Restenosis Trial (BERT-1.5, n = 31), for compassionate use (n = 25), in the Beta-Cath System trial (n = 27) and in the Beta Radiation in Europe (BRIE, n = 14). Since the Beta-Cath System has been commercialized in Europe, 57 patients have been treated and registered in RENO (Registry Novoste). In the Proliferation Reduction with Vascular Energy Trial (PREVENT), 37 patients were randomized using the Guidant-Nucletron remote control afterloader with a 32P source wire and a centering catheter. Radioactive 32P coated stents have been implanted in 102 patients. In the Isostent Restenosis Intervention Study 1 (IRIS 1), 26 patients received a stent with an activity of 0.75-1.5 microCi, and in the IRIS 2 (European 32P dose response trial), 40 patients were treated with an activity of 6-12 microCi. In two consecutive pilot trials, radioactive stents with non-radioactive ends (cold-end stents) and with ends containing higher levels of activity (hot-end stents) were implanted in 21 and 17 patients, respectively. RESULTS: In the BERT-1.5 trial, the radiation dose, prescribed at 2 mm from the source train (non-centered), was 12 Gy (10 patients), 14 Gy (10 patients) and 16 Gy (11 patients). At 6-month follow-up, 8 out of 28 (29%) patients developed restenosis. The target lesion revascularization rate (TLR) was 7 out of 30 (23%) at 6 months and 8 out of 30 (27%) at 1 year. Two patients presented with late thrombosis in the first year. For compassionate use patients, a restenosis rate (RR) of 53% was observed. In the PREVENT trial, 34 of 37 patients underwent an angiographic 6-month follow-up. The doses prescribed at 0.5 mm depth into the vessel wall were 0 Gy (8), 28 Gy (9), 35 Gy (11) and 42 Gy (8). TLR was 14% in the irradiated patients and 25% in the placebo group. One patient developed late thrombosis. In the IRIS 1 trial, 23 patients showed an RR of 17% (in-stent). In the IRIS 2 trial, in-stent restenosis was not seen in 36 patients at 6-month follow-up. However, a high RR (44%) was observed at the stent edges. CONCLUSIONS: The integration of vascular brachytherapy in the catheterization laboratory is feasible and the different treatment techniques that are used are safe. Problems, such as edge restenosis and late thrombotic occlusion, have been identified as limiting factors of this technique. Solutions have been suggested and will be tested in future trials.

Preserved endothelium-dependent vasodilation in coronary segments previously treated with balloon angioplasty and intracoronary irradiation.

BACKGROUND: Abnormal endothelium-dependent coronary vasomotion has been reported after balloon angioplasty (BA), as well as after intracoronary radiation. However, the long-term effect on coronary vasomotion is not known. The aim of this study was to evaluate the long-term vasomotion of coronary segments treated with BA and brachytherapy. METHODS AND RESULTS: Patients with single de novo lesions treated either with BA followed by intracoronary beta-irradiation (according to the Beta Energy Restenosis Trial-1.5) or with BA alone were eligible. Of these groups, those patients in stable condition who returned for 6-month angiographic follow-up formed the study population (n=19, irradiated group and n=11, control group). Endothelium-dependent coronary vasomotion was assessed by selective infusion of serial doses of acetylcholine (ACh) proximally to the treated area. Mean luminal diameter was calculated by quantitative coronary angiography both in the treated area and in distal segments. Endothelial dysfunction was defined as a vasoconstriction after the maximal dose of ACh (10(-6) mol/L). Seventeen irradiated segments (89.5%) demonstrated normal endothelial function. In contrast, 10 distal nonirradiated segments (53%) and 5 control segments (45%) demonstrated endothelium-dependent vasoconstriction (-19+/-17% and -9.0+/-5%, respectively). Mean percentage of change in mean luminal diameter after ACh was significantly higher in irradiated segments (P=0.01). CONCLUSIONS: Endothelium-dependent vasomotion of coronary segments treated with BA followed by beta-radiation is restored in the majority of stable patients at 6-month follow-up. This functional response appeared to be better than those documented both in the distal segments and in segments treated with BA alone.

beta-Particle-emitting radioactive stent implantation. A safety and feasibility study.

BACKGROUND: This study represents the Heart Center Rotterdam's contribution to the Isostents for Restenosis Intervention Study, a nonrandomized multicenter trial evaluating the safety and feasibility of the radioactive Isostent in patients with single coronary artery disease. Restenosis after stent implantation is primarily caused by neointimal hyperplasia. In animal studies, beta-particle-emitting radioactive stents decrease neointimal hyperplasia by inhibiting smooth muscle cell proliferation. METHODS AND RESULTS: The radioisotope (32)P, a beta-particle emitter with a half-life of 14.3 days, was directly embedded into the Isostent. The calculated range of radioactivity was 0.75 to 1.5 microCi. Quantitative coronary angiography measurements were performed before and after the procedure and at 6-month follow-up. A total of 31 radioactive stents were used in 26 patients; 30 (97%) were successfully implanted, and 1 was embolized. Treated lesions were in the left anterior descending coronary artery (n=12), the right coronary artery (n=8), or the left circumflex coronary artery (n=6). Five patients received additional, nonradioactive stents. Treated lesion lengths were 13+/-4 mm, with a reference diameter of 2.93+/-0. 47 mm. Minimum lumen diameter increased from 0.87+/-0.28 mm preprocedure to 2.84+/-0.35 mm postprocedure. No in-hospital adverse cardiac events occurred. All patients received aspirin indefinitely and ticlopidine for 4 weeks. Twenty-three patients (88%) returned for 6-month angiographic follow-up; 17% of them had in-stent restenosis, and 13% had repeat revascularization. No restenosis was observed at the stent edges. Minimum lumen diameter at follow-up averaged 1.85+/-0.69 mm, which resulted in a late loss of 0.99+/-0. 59 mm and a late loss index of 0.53+/-0.35. No other major cardiac events occurred during the 6-month follow-up. CONCLUSIONS: The use of radioactive stents with an activity of 0.75 to 1.5 microCi is safe and feasible.

Geometric vascular remodeling after balloon angioplasty and beta-radiation therapy: A three-dimensional intravascular ultrasound study.

BACKGROUND: Endovascular radiation appears to inhibit intimal thickening after overstretching balloon injury in animal models. The effect of brachytherapy on vascular remodeling is unknown. The aim of the study was to determine the evolution of coronary vessel dimensions after intracoronary irradiation after successful balloon angioplasty in humans. METHODS AND RESULTS: Twenty-one consecutive patients treated with balloon angioplasty and beta-radiation according to the Beta Energy Restenosis Trial-1.5 were included in the study. Volumetric assessment of the irradiated segment and both edges was performed after brachytherapy and at 6-month follow-up. Intravascular ultrasound images were acquired by means of ECG-triggered pullback, and 3-D reconstruction was performed by automated edge detection, allowing the calculation of lumen, plaque, and external elastic membrane (EEM) volumes. In the irradiated segments, mean EEM and plaque volumes increased significantly (451+/-128 to 490.9+/-159 mm(3) and 201.2+/-59 to 241.7+/-74 mm(3); P=0.01 and P=0.001, respectively), whereas luminal volume remained unchanged (250.8+/-91 to 249.2+/-102 mm(3); P=NS). The edges demonstrated an increase in mean plaque volume (26.8+/-12 to 32. 6+/-10 mm(3), P=0.0001) and no net change in mean EEM volume (71. 4+/-24 to 70.9+/-24 mm(3), P=NS), resulting in a decrease in mean luminal volume (44.6+/-16 to 38.3+/-16 mm(3), P=0.01). CONCLUSIONS: A different pattern of remodeling is observed in coronary segments treated with beta-radiation after successful balloon angioplasty. In the irradiated segments, the adaptive increase of EEM volume appears to be the major contributor to the luminal volume at follow-up. Conversely, both edges showed an increase in plaque volume without a net change in EEM volume.

Late coronary occlusion after intracoronary brachytherapy.

BACKGROUND: Intracoronary brachytherapy appears to be a promising technology to prevent restenosis. Presently, limited data are available regarding the late safety of this therapeutic modality. The aim of the study was to determine the incidence of late (>1 month) thrombosis after PTCA and radiotherapy. METHODS AND RESULTS: From April 1997 to March 1999, we successfully treated 108 patients with PTCA followed by intracoronary beta-radiation. Ninety-one patients have completed at least 2 months of clinical follow-up. Of these patients, 6.6% (6 patients) presented with sudden thrombotic events confirmed by angiography 2 to 15 months after intervention (2 balloon angioplasty and 4 stent). Some factors (overlapping stents, unhealed dissection) may have triggered the thrombosis process, but the timing of the event is extremely unusual. Therefore, the effect of radiation on delaying the healing process and maintaining a thrombogenic coronary surface is proposed as the most plausible mechanism to explain such late events. CONCLUSIONS: Late and sudden thrombosis after PTCA followed by intracoronary radiotherapy is a new phenomenon in interventional cardiology.

Compassionate use of intracoronary beta-irradiation for treatment of recurrent in-stent restenosis.

Recurrent in-stent restenosis after balloon angioplasty poses a serious management problem. Previously g-radiation has been shown to be effective in patients with in-stent restenosis. The aim of the study was to determine the feasibility and safety of b-radiation in patients with recurrent in-stent restenosis. From May 1997 to December 1998, 18 patients were treated with balloon angioplasty (n = 8) or laser (n = 10), followed by intracoronary b-radiation at a prescribed dose of 16 Gray at 2 mm from the source, for reference diameters by quantitative coronary angiography < 3.25 mm or 20 Gray for reference diameters > or =3.25 mm. Vessels treated were as follows: left anterior descending: (n = 5); circumflex: (n = 4); right coronary artery: (n = 6); saphenous vein graft: (n = 3). Average recurrence rate was 2.4 +/- 0.7 and the restenotic length was 16 +/- 7 mm. b-radiation was successfully delivered in all patients. Two patients presented complications related to laser debulking: a non-Q wave myocardial infarction in one and a re-angioplasty due to uncovered distal dissection in another. Geographical miss, defined as an area which has been injured but not covered by the radiation source, was demonstrated in 8 patients. Seventeen patients (94%) completed the 6-month angiographic follow-up. Restenosis (> 50% Diameter Stenosis) was observed in 9 patients (53%), leading to target lesion revascularization in 8 patients (47%). Six of the 9 restenoses were located in areas with geographical miss. Intracoronary b-radiation for recurrent in-stent restenosis appears to be a safe and feasible management strategy. However, the mismatch between injured and irradiated area may lead to failure of this therapy.