33 Techniques of Intravascular Brachytherapy
Sri Gorty and Prabhakar Tripuraneni
S. Gorty, MD
Radiation Oncologist, Robert and Beverly Lewis Cancer Care Center, Pomona Valley Hospital Medical Center, 1910 Royalty Drive, Pomona, California, USA
P. Tripuraneni, MD, FACR
Scripps Clinic/Scripps Green Hospital, 10666 N. Torrey Pines Rd., MSB-1, La Jolla, CA 92037-1092, USA
clear that, regardless of the intervention, restenosis remains a major problem. There are several reasons restenosis may occur: immediate recoil of the artery after PTCA, remodeling of the artery over time caus- ing recoil of the artery, and scar formation in the PTCA area.
Radiotherapy has long been successfully used in treating benign conditions such as keloids, hetero- topic bone formation, pterygia, and more recently macular degeneration. As radiation delays the heal- ing process, it has been postulated that radiotherapy could be used to delay the scar formation within a coronary artery and therefore decrease the risk of restenosis.
In the late 1990s, brachytherapy proved to be effec- tive in decreasing neointimal hyperplasia and subse- quent restenosis after stenting in animal models. In 1995, the first human randomized trial was carried out at the Scripps Clinic in La Jolla, CA, confirming the efficacy of gamma irradiation in using iridium- 192 seeds in decreasing in-stent restenosis after repeat angioplasty (Teirstein et al. 1997). Over the next 5 years, three major systems were developed:
the Checkmate system using iridium-192 seeds, the Galileo system using phosphorus-32 wire, and the Beta-Cath system using strontium-90 (Sr-90) seeds (Fig. 33.1; Leon et al. 2001; Popma et al. 2002; Sieber et al. 2005; Urban et al. 2003). These three systems were approved by the Food and Drug Administra- tion (FDA) for use in humans for coronary in-stent restenosis after repeat angioplasty (Bhargava et al 2004). A slight increase in sub-acute thrombosis was noted and was effectively treated with anti-plate- let agents with no other significant complications (Giap et al.1999a,b).
Radioisotope-coated stents were studied in clini- cal trials and were found to be ineffective due to candy wrapper failure at the edges of the stents.
A large trial was carried out for de novo stenosis randomizing between PTCA with or without stent- ing versus the same with IVB using the Beta-Cath system. This trial demonstrated no added benefit from IVB. There were many trials for peripheral ves- 33.1
Introduction
Coronary artery disease (CAD) is an important factor in the morbidity and mortality of Ameri- cans. There are many ways to treat CAD, including medications, percutaneous transluminal coronary angioplasty (PTCA), stent placement, and coronary artery bypass surgery. Recent advances include intravascular brachytherapy (IVB) and drug-elut- ing stents (DESs).
The advent of PTCA has created the subspecialty of interventional cardiology. The deployment of stents has significantly decreased the acute compli- cation of acute closure and dissection, resulting in the wider use of PTCA. However, stent placement has increased the risk of neointimal hyperplasia.
Restenosis of the coronary artery is a significant problem in the United States. In 2000, there were an estimated 882,000 coronary artery procedures in the United States. Of these, 6% involved a PTCA alone, 30–50% of which were at risk of restenosis. Of the procedures, 76% involved the use of a stent. The risk of restenosis in these individuals was 20–30%.
Finally, 18% of the procedures were carried out on patients with an in-stent restenosis. In this subset, the risk of restenosis was very high at 40–80%. It is
CONTENTS
33.1 Introduction 837 33.2 Beta-Cath System for
Coronary In-Stent Restenosis 838 References 841
sels, mainly for femoral popliteal arteries, mostly in Vienna, Austria, other parts of Europe, and in the United States. The pivotal trial for the femoral pop- liteal artery, testing the efficacy of brachytherapy using a centering balloon “Paris” catheter with a high dose rate remote afterloader, did not show any superior efficacy with radiation over angioplasty.
However, the single institution and multi-institution trials in Europe have shown the efficacy of the same technique in both de novo and in-stent restenosis of femoral popliteal arteries both with and without centering catheters. IVB has not been approved for use in peripheral vessels in the United States. A few prospective trials were done using external beam radiation both for coronary in-stent restenosis and femoral popliteal stenosis with mixed results. The prevailing opinion is that external beam is not the way to go (Tripuraneni et al. 2001)!
It is estimated that, in 2002, there were approxi- mately 50,000–80,000 cases of IVB done in the US alone and more around the world. At about that time, DESs using rapamycin and later taxol were coming into clinical trials. The early clinical trials and the subsequent randomized trials for coronary de novo stenosis confirmed the benefit of DESs in significantly reducing in-stent restenosis from about 15–18% to less than 2–4%. This is a good example of a new “destructive technology” that evolved into clinical use, obviating the need for an older technol- ogy that is quite useful. The newer DES technology significantly decreased the need for IVB by dramati- cally decreasing the in-stent restenosis occurrence.
Since DESs have significantly decreased or elimi- nated the need for IVB for coronary in-stent reste-
nosis, the major manufacturers, Johnson & Johnson and Guidant, have discontinued the manufacturing and support of their respective systems, Checkmate and Galileo. Therefore, with the lack of availability of delivery catheters and radioisotopes for the two discontinued systems in 2005, the only system that is currently available for IVB is the Beta-Cath system and it will be reviewed in this chapter.
IVB is a truly multi-disciplinary procedure involv- ing an interventional cardiologist, a radiation oncol- ogist, and a medical physicist. The cardiologist is responsible for obtaining vascular access, determin- ing the location and the extent of the in-stent reste- notic lesion, performing the PTCA (preferably with- out further stent placement), and finally positioning the brachytherapy delivery catheter in the appropri- ate position. The radiation oncologist is responsible for obtaining informed consent for the radiation por- tion of the procedure, determining the details of the IVB delivery, and prescribing and delivering IVB.
The medical physicist is responsible for the initiation of the Cath Lab Radiation Safety Quality Assurance Program, radiation delivery time calculations, and assistance with the delivery of IVB and safekeeping of the equipment (Tripuraneni et al. 2001).
33.2
Beta-Cath System for Coronary In-Stent Restenosis
The Novoste Beta-Cath system uses Sr-90 as its radioactive source. The Sr-90 has a half-life of 28 years. It decays into yttrium-90(Y90) and a 0.54- MeV beta particle. The Y90 has a half-life of 64 h and decays into zirconium-90 and a 2.27-MeV beta particle. The zirconium-90 is a stable isotope and does not undergo any further decay.
The Sr-90 of the Beta-Cath system has several advantages. It has a long half-life, so the source does not have to be replaced frequently (Azeem et al. 2005). The dose rate is high enough that the dose is delivered in less than 5 min. As the penetration of beta particles is small, the physicians and cath- eter lab staff can stay with the patient during the procedure with manageable radiation protection precautions. The dose to the surrounding organs is minimal.
The Beta-Cath system consists of four main components: the source train, the transfer device, the Beta-Cath delivery catheter, and accessories (Fig. 33.2). It is a hydraulic delivery system. It comes
Fig. 33.1. Beta-Cath system
in two diameters, with an outer diameter of 5 French (slightly less than 2 mm in diameter) and 3.5 French (a bit more than 1 mm in diameter). The larger diameter of the 5-F system comes in three lengths of 30, 40, and 60-mm source trains. The smaller diam- eter of the 3.5-F system comes in only two lengths of 30 mm and 40 mm. The source train consists of Sr-90 seeds, each 2.5 mm in length. There are non- radioactive marker seeds at both the proximal and distal ends of the radioactive sources and are useful in fluoroscopic verification of the appropriate place- ment of the radioactive seeds and also the visual verification of the return of the all sources into the delivery device (Fig. 33.3). For practical purposes, we use a 40-mm long 3.5-F system and a 40-mm and 60-mm-long 5-F system. The smaller diameter cath- eter is used for smaller and tortuous vessels. This should cover the majority of the instances of IVB for both native coronary and saphenous vein graft in- stent restenosis.
The Beta-Cath delivery catheter is a triple lumen catheter that allows the use of a guidewire to place it into the coronary artery. The transfer device houses the radiation sources with the hydraulic delivery system. Once the Beta-Cath delivery cath- eter is placed into the coronary artery to be irradi-
ated, the transfer device is connected to the cath- eter making it a closed loop system. With the help of hydraulic pressure, the sources are sent into the delivery catheter end and radiographically verified.
They are kept in place for the designated length of time to deliver the desired dose. At the end of the procedure, the switch is reversed and the seeds are brought back into the transfer device with hydraulic pressure. After visual verification of source return, the transfer device is disconnected from the delivery catheter. The delivery catheter is then removed from the coronary artery.
The first step involves placing the Beta-Cath system into a sterile bag. The bag is then closed. In the next step, we attach a syringe filled with saline through the opening in the bag and into the Beta- Cath system. We have found that attaching two syringes using a three-way stopcock seems to assure that we have enough saline for the procedure, but this makes the unit slightly harder to handle. The catheter is then attached to the system and the system is primed. Once the system is primed, the unit is ready.
During the angioplasty, the reference vessel diam- eter (RVD) is estimated to determine the dose to be delivered. After the angioplasty has been accom- plished, the brachytherapy catheter is placed in the appropriate position. This catheter is placed over the existing guidewire and through the guide catheter.
There are radio opaque markers on the brachyther- apy catheter which can be seen on fluoroscopy and help with positioning of the catheter. The treatment portion of the catheter should be placed across the entire area of injury caused by the angioplasty, not just the area of restenosis. In addition, it is impor- tant to add margins at both the proximal and distal ends of at least 5 mm and more to minimize edge restenosis.
Once the catheter is in the appropriate position, the saline-filled syringe is used to deliver hydraulic pressure to move the source train into the appropri- ate position. Once the source positioning in the target is fluoroscopically confirmed, constant pressure on the syringe will keep the sources in the appropriate position. This can be verified by periodic fluoros- copy and by watching the pressure monitor on the
Fig. 33.2. Close up view of the transfer device and the delivery catheter
Fig. 33.3. Strontium-90 seeds of 2.5 mm length (60-mm long source train) and radio opaque markers at both ends for radio- graphic visualization
Beta-Cath system. After the prescribed dose is deliv- ered (usually in less than 5 min), the syringe is used to apply hydraulic pressure to return the source to the unit. The return of the sources needs to be veri- fied visually before disconnecting the delivery cath- eter from the transfer device.
The IVB team must be ready to handle both cardiac and radiation emergencies in the catheter lab and be able to quickly remove the radioactive sources. A quality management program, with appropriate training, needs to be in place.
• Dose: 18.4 Gy is prescribed at a 2-mm radius from the center of the source axis for vessels with a refer- ence vessel diameter between 2.7 mm and 3.3 mm.
If the RVD is greater than 3.3 mm and less than or equal to 4 mm, then 23 Gy is delivered. With the source activity, the typical delivery times are in the range of 2–5 min. With the long half-life of strontium, the delivery times are adjusted once in 6 months (Tripuraneni et al. 2001).
• Volume to be irradiated: The gross target volume is the in-stent restenotic length of the vessel. The clinical target volume is the dilated portion of the vessel. The planning target volume includes margins of at least 5 mm, if not more, at both the proximal and distal ends of the dilated portion of the vessel (Fig. 33.4; Giap et al. 2001a; Giap et al.
2001b, Tripuraneni et al. 2002).
• Longer lesions: For lesions longer than 40 mm in the injured length of the vessel, the sequential positioning and pullback technique has been suc- cessfully used. Care should be taken to avoid any significant overlap or gap in order to minimize hot or cold spots. The branch vessels are useful in the positioning; so also is careful review of the cine angiograms in the same position of the table and the gantry (Crocker et al. 2001).
• Saphenous vein graft in-stent restenosis: The Beta- Cath system has been successfully used in the treatment of saphenous vein graft in-stent reste- nosis. Typically, these vessels have larger diame- ters in the range of 3–5 mm, so the dose may need to be adjusted (Schiele et al. 2003).
• Bifurcations: The sequential positioning and pullback technique may be used in the treatment of bifurcation in-stent restenosis (Costa et al.
2003).
• Repeat irradiation: The success rate of repeat irradiation of the same segment of the restenotic vessel after first IVB is lower. There appears to be no additional significant complications from repeat irradiation (Bae et al. 2004).
Enrollment is complete in two major ongoing trials that randomize patients having in-stent reste- nosis and will compare the use of drug-coated stents with the standard arm of IVB. The results are eagerly awaited and will determine the fate of any further continued use of IVB in the US (Tripuraneni 2003).
There are several small studies reviewing the effi- cacy of IVB in the management of instances of in- stent restenosis after the use of DESs. It appears that the efficacy of IVB is somewhat lower in this group of drug resistant in-stent restenosis. The results of studies with a larger number of patients and longer follow-up are awaited.
In summary, IVB has revolutionized the entry of brachytherapy in the management of cardiac disease and was briefly the most common brachy- therapy technique used. For a year or two, IVB was also the most common radiotherapy technique used for non-malignant conditions. However, with the advent of DESs, the incidence of in-stent restenosis
Fig. 33.4. Adequate margins at both ends of dilated segment of in-stent restenosis are included for irradiation
of coronary arteries has dramatically decreased, thereby obviating the need for IVB. The results of the randomized trials comparing the efficacy of IVB with drug-coated stents and the long-term results of a large group of patients with drug-resistant in-stent restenosis will determine the future of IVB, if any!
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