Clinical Trials of Intracoronary Gamma Radiation Therapy for In-Stent Restenosis

In-stent restenosis (ISR) has become a major clinical problem. The rate of ISR is 7–37% of patients who undergo stent implantation and is dependent on patient characteristics, lesion morphology, and procedural technique.1 The recurrence rate after treatment for ISR varies among reported series but remains high, ranging from 50–85%, regardless of treatment modalities, including balloon angioplasty, rotational atherectomy, excimer laser ablation, and re-stenting. The diffuse pattern of ISR (> 10 mm) is associated with even higher rates of recurrence and presents a therapeutic challenge.2–4 Serial intravascular ultrasound (IVUS) studies have demonstrated that ISR results primarily from neointimal tissue hyperplasia distributed either focally or diffusely over the entire length of the stent.5,6 Recently, drug-coated stents (especially sirolimus) have shown extraordinary promise with excellent immediate angiographic and intravascular ultrasound results including the one-year follow-up data; however, their utility for ISR is unknown.7,8 Clinical feasibility studies in patients with ISR have suggested reduced post-angioplasty restenosis after gamma and beta radiation therapy.9,10 The only gamma emitter used in clinical trials for ISR is 192Iridium (192Ir). The efficacy of intracoronary gamma radiation therapy in reducing clinical and angiographic restenosis in patients with ISR has been confirmed by a number of clinical trials (Table 1). This review is intended to update and summarize the current status of clinical trials utilizing gamma vascular brachytherapy to prevent the recurrence of ISR. SCRIPPS (Scripps Coronary Radiation to Inhibit Proliferation Post Stenting). SCRIPPS was the first randomized trial to determine the safety and efficacy of intracoronary gamma radiation given as adjunctive therapy to stents. In this study, there were 26 of 54 patients who were randomized to receive 192Ir (8–30 Gy, dosimetry guided by IVUS) utilizing a ribbon (19–35 mm) delivered in a non-centered, closed-end lumen catheter at the treatment site (dwell time: 20–45 minutes). Only 35 patients in this cohort were patients with ISR. This study demonstrated that at 6 months, the angiographic restenosis rate was reduced with radiation (17% vs. 54%; p 4 mm in diameter. The patients with restenosis at follow-up were eligible to receive radiation if initially randomized to placebo. The closed-end lumen catheter with either the active or the placebo seeds was delivered successfully to all patients. A mean dwell time of 21.1 ± 4.8 minutes was well tolerated in irradiated patients. At 30 days, there were no adverse events related to the radiation therapy. At 6 months, the restenosis rate was significantly lower in the irradiated group compared to control (15% vs. 43%; p = 0.004). The need for repeat intervention at the treatment site was significantly reduced by 79% in the irradiated group compared to control (10% vs. 48%; p = 1 vessel (native coronary artery or saphenous vein graft) followed by IRT with 192Iridium (14 or 15 Gy to 2 mm). At this time, a total of 173 patients have been enrolled. The mean age of the cohort is 63 ± 16 years (A total of 70% males and 45% diabetics, also 87% had previous cardiac bypass grafting). The target lesion involved a saphenous vein graft in 40% of cases; in addition, a total of 40% of patients received re-stenting. The IRT was delivered successfully in all cases with a mean source train length of 61 ± 19 mm. Six-month, one- and two-year events confirm sustainable outcomes in this refractory patient cohort who did not respond to conventional standard of care. GAMMA-1. GAMMA-1 was a multicenter, randomized, double-blind trial studying the effects of hand-delivered 192Ir ribbon using intravascular ultrasound to guide dosimetry (dose range 8–30 Gy) in 252 patients with ISR. Six-month angiographic results revealed significant reductions in the in-stent (22% vs. 52%) and in-lesion (33% vs. 56%; p = 0.006) angiographic restenosis rates of the radiation arm versus control. Subanalysis for lesion length demonstrated a 70% reduction in the angiographic restenosis rate for lesions = 50% occurring £ 5 mm proximally and distally to the last seed of the radiation source) and geographic miss (injured segments not covered by the radiation source).18 Edge restenosis occurred in 10% of IRT patients and 4.7% of controls (p = NS). In patients with geographic miss, edge restenosis occurred in 21% of IRT patients and 7% of controls. In both groups (IRT and controls), late edge lumen loss was greater in IRT patients than controls (p

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