When approximations aren’t enough – Limitations with intravascular brachytherapy

Not only has the time for personalized treatment of cardiovascular disease arrived but patient outcomes have been put in jeopardy when patient specific anatomy is not considered.

The future of medicine is in screening, prediction, early diagnosis and individually tailored treatments including post-treatment follow-up, i.e. in personalised medicine. A recent editorial in Nature Medicine discusses the scarcity of personalized medicine for treatment of cardiovascular disease while it has revolutionized cancer therapy [1]. In radiation therapy specifically, clinical research and technological advances in imaging and radiation delivery systems have enabled the capability to personalize treatments for accurate delivery of radiation dose to the tumours and limiting dose to nearby radiation sensitive healthy tissues based on clinical parameters and patient-specific anatomical information.

Due to recent insights in disease mechanisms and emerging treatment strategies, the time is opportune to develop personalized treatments for cardiovascular disease. Introducing personalized medicine for cardiovascular disease should not only be pursued as a means of improving outcomes and identifying novel treatment strategies, it must be pursued to ensure that existing treatments are appropriate and will be effective. There exists a modality of treatment for cardiovascular disease for which the absence of patient specific information is not only a disadvantage but may actually hinder successful treatment. Intravascular Brachytherapy (IVBT) is a form of radiation therapy used to treat in-stent restenosis (ISR). After the advent of the bare-metal stents in the 1990s, a new difficulty arose when sites initially treated with a stent became re-stenoted in the months following initial treatment. IVBT involves applying a dose of ionizing radiation to the arterial walls immediately after stent implantation to destroy neointimal tissue which may proliferate and lead to ISR.

It is well known that if an inadequate dose of radiation is delivered to the target area, or if the size of the target area is underestimated, the treatments may fail, and patient outcomes will be jeopardized [2]. Early attempts to implement IVBT involved coating stents with beta emitting radioactive isotopes. Treated arteries became re-stenoted on each side of the radioactive stent where the radiation dose fell off due to insufficient coverage of the radioactive isotope at the stent ends. This side effect lead to the development of catheter-based devices, where beta emitting radioactive sources (radioactive seeds) are guided temporarily to the stented site (dwell position) immediately after stent implantation and kept at the site for a certain amount of time (dwell time) until an adequate dose is delivered.

Compared to other forms of radiation therapy, treatment planning in IVBT is archaic. It consists of an estimation of the patient’s artery diameter by visual inspection under fluoroscopy and then referring to a reference sheet which lists the dwell times for different vessel diameters. This method of treatment planning assumes that the patient’s artery is a perfect cylinder, that the radioactive seeds are centered in the cylinder, and that all tissue and materials surrounding the treatment site are water equivalent.

With the advantage of modern software and computing capabilities, we have been able to revisit the underlying assumptions of IVBT. In a tank of water (which serves as a crude approximation for patient tissue), the range of beta particles from the isotopes used in IVBT is about 2 mm, which corresponds to the distance from the surface of the radioactive seed to the target region. In the water-equivalent approximation, the target region receives the prescribed dose of radiation. In a real-world delivery, the beta particles interact and are absorbed by non-water equivalent materials such as the metallic cardiac guide wire, the stent and calcifications as well as patient tissue. Recent work indicates that the cardiac guidewire used to guide the radioactive seeds to the treatment site blocks the ionizing radiation and can cause dose reductions as high as 48% in regions behind the guidewire alone [3] [4]. When the presence of arterial stent struts and calcified plaques are considered, the dose of radiation can be reduced by more than 60% in localized regions. The target volume is behind these heavily attenuating media and will not receive the prescribed dose, i.e. the delivered dose will be much less than the prescribed dose.

This all might seem inconsequential if IVBT weren’t undergoing a small revival. The use of IVBT was reduced due to the advent and adoption of drug-eluting stents (DES) in the early 2000s. However, a need for IVBT still exists. Patients treated with DES require coronary reintervention [5]. The typical modality of treatment for patients whose DES failed is to insert another DES at the initial site of stent failure. For a group of patients with multiple DES implemented at the same site IVBT has been shown to be a safe and effective treatment [6]. A need for IVBT is still being communicated by cardiologists; a 2016 editorial in the Journal of the American College of Cardiology calls for IVBT to be considered for patients with DES failure [7].

The world of medical physics can at times be separated from the world of physicians. There isn’t always adequate knowledge exchange between medical physicists and their colleagues; the concerns of physicists can seem technical and out of touch with the concerns of practitioners. This is one instance where it is important physicians have at least a rudimentary understanding of the physics underlying a treatment modality so that it can inform their practice. Cardiologists should be wary of applying current IVBT technology when they have reason to believe that large calcified plaques exist at the treatment site or multiple stents have been previously implanted, as the dense bulk material serves to block ionizing radiation from reaching the target neointimal tissue; both of these factors may be contraindications for IVBT.

If IVBT is going to see continued use, the medical community owes it to patients to ensure that device manufacturers modernize their devices and seek out solutions to the real and significant problems that have been identified with IVBT products, otherwise manufacturers will continue to produce the same IVBT devices which have been on the market for more than 15 years now. We have suggested solutions to improve current IVBT delivery systems and dosimetry [3] [4] but only if the cardiology community is informed and insists that devices allow for patient specific treatment planning, will manufacturers make meaningful changes to their products. The reluctance and concerns of a small group of informed medical physicists is not enough to prompt any change in the current practice of IVBT.

Written by Joseph DeCunha and Shirin A. Enger

[1] Nature Medicine Editorial Board. Taking personalized medicine to heart. Nature Medicine 2018; 24:113.

[2] van der Giessen WJ, Regar E, Harteveld MS, et al. “Edge Effect” of 32-P Radioactive Stents is Caused by the Combination of Chronic Stent Injury and Radioactive Dose Falloff. Circulation 2001; 104:2236-2214.

[3] DeCunha J, Janicki C, Enger S.A. A retrospective analysis of catheter-based sources in intravascular brachytherapy. Brachytherapy 2017; 16:586-596.

[4] DeCunha J, Enger S.A. A new delivery system to resolve dosimetric issues in intravascular brachytherapy. Brachyherapy 2018; article in press.

[5] Ohri N, Sharma S, Kini A, et al. Intracoronary brachytherapy for in-stent restenosis of drug-eluting stents. Adv