Chapter 17 Intracoronary brachytherapy
INTRODUCTION TO RADIATION BIOLOGY AND SYSTEMS
Radiation inhibits smooth muscle cell (SMC) proliferation and intimal hyperplasia by intervening in the cell cycle to cause cell death to radiosensitive cells, especially those undergoing mitosis following vascular injury. Radiation acts by absorbing into the target molecules such as DNA, RNA, or enzymes, by interacting with these molecules via formation of highly reactive free radicals, or by inducing programmed cell death, called apoptosis. Radiation may reduce restenosis by inhibiting the first wave of cell proliferation in the adventitia and the media, by inducing favorable remodeling,1 and by suppression of macrophages and adventitial myofibroblasts.2,3
EXPERIMENTAL FOUNDATION OF BRACHYTHERAPY
Brachytherapy evolved into clinical practice based on firm and elaborate experimental animal data. These involved external beam radiation by Schwartz et al.,4 catheter based systems by several investigators utilizing gamma radiation with 192Ir (Waksman et al. at Emory University,5,6 Wiedermann et al. at Columbia University,7,8 and Raizner et al. at Baylor University9), using beta radiation with 90Sr/Y (Verin et al.11, Waksman12), and beta radiation with 32P by Raizner et al. All these investigators have shown reduction in neointimal hyperplasia in the irradiated arteries utilizing doses ranging from 6-56 Gy.
Further experiments have been conducted using radioactive stents by Fischell et al.13 Hehrlein et al.,14,15 Laird et al.16,17 Radioactive stents, which were implanted in an atherosclerotic pig model, failed to show superiority over control non-radioactive stents with any of the treated doses at six months.17
Waksman et al.,18 Weinberger et al.,19 Robinson et al.,20 Makkar et al.,21 and Kim et al.22 used liquid isotope-filled balloons to irradiate porcine coronaries. The emitters used for this technology were 133Xenon, 188Re (14 Gy), and 166Ho (9, 18 Gy). These pre-clinical studies showed reduction in neointimal tissue as assessed by IVUS and histomorphometry. The concept of the radioisotope filled balloons is attractive because it has the advantages of centering and ease of use; however, a potential leakage hazard is of great concern.
CLINICAL TRIALS
Several series of clinical trials were conducted to understand the safety, efficacy, and durability of VBT mainly in the US and Europe. While both gamma and beta radiations were studied for the treatment of ISR, only beta sources were studied for de novo lesions. Detailed discussion of the clinical trials is out of scope for this chapter, but a brief summary of the landmark clinical trials conducted thus far with gamma and beta emitters is presented. Salient features of the studies published in major journals are shown in Table 17.1.
TABLE 17.1 RESULTS OF MAJOR CLINICAL TRIALS WITH GAMMA AND BETA RADIATION PUBLISHED IN PEER REVIEWED JOURNALS, ARRANGED IN CHRONOLOGICAL ORDER
Clinical trials of gamma radiation
The first study of intracoronary radiation in human coronary arteries was conducted in 1994 by Condado et al. in which 21 patients (22 lesions – two-thirds being de novo lesions) were treated with 192Ir after routine balloon angioplasty. On angiographic follow up at six months, a binary restenosis rate of 28.6% was reported,23 which remained the same at five years. Angiographic complications included four aneurysms (two procedure related and two occurring within three months). At three and five years, all aneurysms except one remained unchanged and no other angiographic complications were observed.24
Gamma radiation for in-stent restenosis
SCRIPPS trials
Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting (SCRIPPS) was the first randomized trial to evaluate the safety and efficacy of intracoronary γ radiation as adjunctive therapy to stents. Follow up at six months and three years showed significantly lower restenosis rates in the 192Ir group − 17% and 33%, respectively, compared to placebo (54% and 63%). A subgroup analysis of the 35 patients enrolled due to ISR showed a 70% reduction in the recurrence rate in the irradiated group compared to placebo.25,26 There were no evident clinical complications resulting from the radiation treatment, and clinical benefits were maintained at five years, with a significant reduction in the need for target lesion revascularization (TLR).27
Washington Radiation for In-Stent restenosis Trial (WRIST) series
Original WRIST was the first study to evaluate the effectiveness of radiation therapy in patients with ISR. In this study, 130 patients (100 with native coronaries and 30 with saphenous vein grafts) with ISR lesions (up to 47 mm in length) were randomized to receive either 192Ir or placebo. At six months, the radiation group showed a reduction in restenosis (19% vs. 58% in placebo) and 79% and 63% reduction in the need for revascularization and MACE, respectively, compared to placebo.28 Extended follow up of these patients showed durable beneficial effect of radiation at one year, three years29 and five years30 in MACE rates compared to placebo. MACE rates were significantly lower at five years follow up, albeit at the expense of repeat revascularization procedures suggesting that radiation may delay, in part, the biological processes and that a late catch-up phenomena or late thrombosis will reduce the long-term benefit of radiation.
Other landmark trials in this series were SVG-WRIST which evaluated the effect of radiation therapy in patients with diffuse ISR lesions in saphenous vein grafts,31 Long WRIST in patients with diffuse ISR in native coronary arteries (lesion length 36 to 80 mm),32 Long WRIST High Dose which tested the efficacy of an 18 Gy dose of radiation, WRIST Plus and WRIST 12 which tested the efficacy of prolonged Clopidogrel therapy (up to 6 months and 12 months, respectively) to reduce the incidence of late thrombosis, and WRIST 21 which tested whether escalation of radiation dose to 21 Gy would improve the clinical outcomes beyond Long WRIST High Dose. These studies have demonstrated superiority of radiation therapy in the treatment of ISR in vein graft disease (SVG-WRIST) and diffuse lesions (Long WRIST). The Long WRIST High Dose registry showed that a 3 Gy increase in the dose, from 15 to 18 Gy, provided additional reduction in MACE rates.33 The strategy of prolonged antiplatelet therapy for six months in WRIST Plus reduced thrombosis rates from 9.6% to 2.5% – levels comparable to non-irradiated controls.34 WRIST 12 has demonstrated further reduction in MACE and TLR with 12 months of Clopidogrel therapy.35 Based on these observations, it has become standard practice to provide at least 12 months of Clopidogrel therapy for patients undergoing radiation therapy for ISR. Further escalation of dose from 18 Gy to 21 Gy was studied in WRIST 21 but has not been shown to improve the results. Hence, a dose of 18 Gy may be sufficient to treat ISR with γ radiation.
GAMMA trials
GAMMA-1, a multicenter, randomized trial conducted with IVUS-guided dosimetry, showed significant reductions in the in-stent and in-lesion restenosis rates compared to 50.5% and 55.3% in the control group. The greatest benefit was obtained in patients with long lesions and/or diabetes. In this study, it was observed that the late thrombosis phenomenon was more frequent in patients treated with radiation therapy than with placebo (5.3% vs. 0.8%). All patients in the 192Ir group who presented with late thrombosis had new stents placed within the in-stent target lesion at the time of the procedure.36 This trial demonstrated the efficacy of intracoronary gamma radiation for the prevention of ISR recurrence, and increased awareness regarding the correlation between late thrombosis and an increased risk of myocardial infarction (MI).
Gamma-2, a registry of 125 patients including complex lesions such as calcific lesions requiring rotablation, used a fixed dose of 14 Gy at 2 mm from the center of the source and showed a reduction of 52% and 40% in in-stent and in-lesion restenosis, respectively, and a reduction of 48% and 36% in TLR rates and MACE rates, respectively.37
ARTISTIC I and II
Angiorad Radiation Technology for In-Stent restenosis Trial In native Coronaries (ARTISTIC) examined the usage of the AngioRad system in patients with ISR in native coronary arteries. At three years, the cumulative MACE rate was 24.1% in placebo patients and 22.8% in the AngioRad group.38 ARTISTIC II used the same system in 236 patients and tested the efficacy as measured by a composite clinical end-point at nine months after radiation. These results were compared to the historical control group of 104 patients from the ARTISTIC I and WRIST studies. The Kaplan-Meier estimate of freedom from target vessel failure (TVF) for the placebo group was 52% while in the irradiated group it was 85.5%.39
Beta Radiation for ISR
BETA WRIST
In this study, beta radiation was shown to be effective in the treatment of ISR in 50 patients. These patients demonstrated a 58% reduction in the rate of TLR and a 53% reduction in TVR at six months compared to the historical control group of WRIST.40 The clinical benefit was maintained at two-year follow up with a reduction in TLR (42 % vs. 66%), TVR (46% vs.72%), and MACE (46 % vs. 72%) compared to placebo. This study showed that the efficacy of beta and gamma emitters for the treatment of ISR appeared similar at longer-term follow up.
START and START 40/20
In the START (Stents And Radiation Therapy) Trial, 476 patients were randomized to either placebo or an active radiation train 30 mm in length using the BetaCath system.41 Late thrombosis as a complication of brachytherapy was first recognized during this trial and antiplatelet therapy was prolonged to at least 90 days.
During multiple studies of radiation, including START, the medical community became aware of the mismatch between the interventional injury length and radiation length – the so-called ‘geographic miss’ phenomenon – with the potential to compromise clinical outcome.42
INHIBIT and GALILEO INHIBIT
INHIBIT (Intimal Hyperplasia Inhibition with Beta In-stent Trial) examined the efficacy of the Galileo system for the treatment of ISR in 332 patients.43
At nine months, 32P significantly reduced rates of TLR and MACE. Tandem positioning to cover diffuse lesions >22 mm with 32P was safe and effective. Galileo INHIBIT was an international, multicentered registry of 120 patients with ISR in which 32P was delivered at 20 Gy at 1 mm into the vessel wall. There was a reduction in the primary clinical end point defined as MACE-TLR by 49% and reduction in angiographic endpoint of binary restenosis by 74% in the stented segment and by 27% in the analysis segment.44 The thrombosis rate was low, 1.5%, and similar to the control group, 1.2%.
Balloon catheter-based beta radiation Trials for ISR
BRITE, BRITE-II, 4R, and CURE
Beta radiation using the Radiance system was administered in 32 patients in the feasibility study called BRITE (Beta Radiation to prevent In-sTent rEstenosis). Seventy percent of the dose was administered when the balloon was inflated. At six months, TVR (3%), MACE (3%), and in-stent binary restenosis rates (0%) were the lowest reported to-date in any vascular brachytherapy series.45 The BRITE II study evaluated the efficacy of beta radiation using the RDX system in 429 patients randomized to either radiation (n=321) or placebo (n=108). The RDX system demonstrated safety characterized by high technical success rates (>95%), low periprocedural complications (<1%), and low 30-day MACE (<1%). The most prevalent location of restenosis was within the radiated vessel outside the injured zone despite lower rates of geographic miss (8.5%).46 The RDX system demonstrated a very low ISR rate (10. 9% vs. 46.1%) and proved to optimize the results when compared to historical studies.
4R, a South Korean registry evaluated β-radiation therapy with 188Re-MAG3-filled balloon following rotational atherectomy for diffuse ISR in 50 patients. The mean dose was 15 Gy and the mean irradiation time was 201.8 ± 61.7 seconds. No adverse events occurred during the follow up period. The six-month binary angiographic restenosis rate was 10.4%. Two potential limitations of this technology included reduced dosing at the balloon margins (edge effect) and the risks of balloon rupture with radiation spill. In the event of balloon rupture using 188Re, concomitant administration of potassium perchlorate may mitigate thyroid uptake.47
The Columbia University Restenosis Elimination (CURE) study evaluated liquid 188Re injected into a perfusion balloon. Thirty patients were treated with balloon alone and 30 patients were stented (with subsequent 188Re therapy). The delivered dose was 20 Gy to the balloon surface with a dwell time of 6.9 ± 2.2 minutes. At 12 months follow up in the first 37 patients, the rate of TLR-free survival was 75%.48
RENO and BRIE
Registry Novoste (RENO) is a registry of 1098 consecutive patients using the Novoste BetaCath system. Six-month follow up data showed non-occlusive restenosis in 18.8% of patients, total occlusion in 5.7%, and a MACE rate of 18.7% (1.9% deaths from any cause, 2.6% from acute MI, 13.3% from TVR by PCI and 3.3% from TVR by CABG).49 The Beta Radiation in Europe (BRIE) study evaluated the safety and efficacy of the BetaCath system in patients with up to two discrete lesions, de novo and restenotic, in different vessels. The binary in-stent restenosis was 9.9%, excluding total occlusions, was 4.9%.50 This study highlights the full potential of brachytherapy, provided late total occlusions are minimized by prolonged antiplatelet therapy.
