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VASCULAR BRACHYTHERAPY - HYPE OR HOPE

Thomas Alexander
Senior Consultant Cardiologist, Kovai Heart Center, Coimbatore.

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Percutaneous transluminal balloon angioplasty has gained wide acceptance in the treatment of coronary artery disease. However the major drawback of this procedure is the problem of restenosis which varies between 13 and 57%. [1] With the exception of intracoronary stents, which has been shown to reduce restenosis rates, all other attempts to reduce restenosis by pharmacological or mechanical means have been unsuccessful. Intracoronary radiation therapy is a new and exciting approach to the prevention and treatment of restenosis.

Radiation has been shown to be highly effective and safe in treating benign vascular malformations and also in preventing keloid formation. Radiation delays normal wound healing by impairing smooth muscle function. In animal models of coronary restenosis, radiation reduced the intimal hyperplasia associated with restenosis following balloon injury. Radiation exerts many biological effects. It inhibits smooth muscle proliferation, reduces macrophage infiltration, exerts a beneficial effect on apoptosis, inhibits expression of prostaglandin growth factors alpha and beta, and may lead to a reduction in thrombosis.

The rationale for its use is based on the enhanced sensitivity of actively proliferating cells to the lethal effects of ionising radiation. This reduces neointimal proliferation, prevents vessel contraction, the efficacy of catheter based endovascular gamma or beta irradiation in rabbit and porcine iliac vessels. [2] Regardless of the type of radioactive source, at doses of 10 to 18 Gy, these studies showed a marked reduction in the number of intimal smooth muscle cells and the thickness of the neointimal tissue layer. Hehrlein and his colleagues were the first to describe the use of radioactive stents, which they implanted in non-diseased rabbit iliac arteries. [3] These emitted both beta and gamma radiation and were able to demonstrate reduced neointimal formation at 4 weeks.

A variety of isotopes, beta or gamma, and platforms to deliver the radiation for use in brachytherapy are currently under trials. Two basic platforms are available, the catheter based systems and radioactive stents.

GAMMA VERSUS BETA EMITTERS

Isotopes considered for vascular therapy include gamma emitters and beta emitters. Radiation energy from beta emitters diminishes rapidly with distance from the emission source, with minimal energy at more than 2 mm. While the therapeutic use of beta emitters is practical in the catheterization lab and minimizes exposure to staff and remote tissues, it also presents challenges for effective delivery to the vascular wall Radiation source must be centered within the artery to provide uniform circumferential energy. Cellular proliferation following percutaneous transluminal coronary angioplasty (PTCA) begins in the media and extends to the adventitia and therefore, may be beyond the range of beta emitters in large peripheral vessels.

Alternatively, gamma emitters easily penetrate targeted tissues with greater homogeneity. However, treatment duration required to deliver the prescribed energy with gamma emitters is long, and extensive precautions to shield cath personnel are required.

Radioactive beta-emitting stents have the advantage of uniform dosimetry, safely for the laboratory personnel and easy storage. However the early trial results are not as encouraging and the problem of edge restenosis is yet to be sorted out,

An important part of the procedure is to ensure adequate and uniform dosimetry to the target tissue. Eccentric lesions make this more difficult especially if beta radiation is used. Various centering devices are currently being tried so as to ensure adequate doses to the intima, media and the adventitia.

A brief review of the presently available systems and trial results are summarised below.

CLINICAL STUDIES IN NATIVE CORONARY LESIONS

Three clinical trials (Condado, [4] BERT, [5] and PREVENT) have shown that radiation reduced restenosis following angioplasty in native coronary vessels. PREVENT was a randomized trial which showed that patients treated with P-32 radiation had a 26% restenosis rate compared to 44% for control patients (60% of the study patients received stents). On the other hand, neither the Verin [6] nor ARREST trials showed decreased restenosis. These trials used lower doses of radiation than PREVENT, which may explain the difference in outcomes.

CLINICAL STUDIES IN CORONARY IN-STENT RESTENOSIS

Radiation therapy for the treatment of in-stent restenosis has generated a great deal of interest. Three randomized trials (Scripps, [7] WRIST, [8] and ARTISTIC) have shown that patients assigned to the radiation group had restenosis rates of 17% to 20%, while control patients had restenosis rates over 50%.

CLINICAL STUDIES OF RADIOACTIVE STENT

The investigational use of radioactive stents has generated more disappointing results. The IRIS 1A [9], IRIS 1B, [10] and Milan trials have had restenosis rates in the 30% to 50% range. These trials have identified the so-called edge (or "candy wrapper") effect with an increased incidence of focal restenosis at the stent edges. It is hypothesized that the decreased radiation dosage at the edges of the stents may in fact stimulate restenosis, while the higher doses emitted in the middle of the stents may inhibit restenosis.

ONGOING TRIALS

Over a dozen ongoing trials are currently using both gamma and beta emitters in the management of native coronary lesions, vein graft disease, small vessel disease, and in-stent restenosis. These trials may help clarify whether radiation is effective at reducing restenosis. These studies will also provide valuable information regarding the optimal dose of radiation, which emitter is superior, and whether this strategy is safe.

Current gamma coronary trials
Study	Isotope	Design
ARREST	Ir192	native/provisional stent
ARTISTIC	Ir192	instent
GAMMA-I	Ir192	restenosis
GRANITE	Ir192	native/instent
SMARTS	Ir192	small vessel
SVG-WRIST	Ir192	SVG
Long WRIST	Ir192	long lesions

CONCLUSIONS

Vascular brachytherapy appears to be a breakthrough in the prevention and management of restenosis. The early trials definitely prove the feasibility of this technology. However these results are only preliminary and a lot of work needs to be done before its use in clinical practice. The issues that need to be addressed include:

1. Ideal type, dose and method of radiation delivery.
2. Safety guidelines for the cath lab personnel.
3. Role and need for a radiation oncologist.
4. Need for and type of centering devices.
5. Late effects of radiation on the vessel wall including aneurysm formation
   and stent edge restenosis.

REFERENCES

1. Hirsh Feld JW Jr, Schwartz JS, Jugo R, et al. Restenosis after coronary angioplasty: A multivariate statistical model to relate lesion and procedure variables to restenosis. J Am Coll Cardiol 1991; 18 : 647-56.
2. Waksman R, Robinson KA, Crocker IR, et al. Intracoronary radiation before stent implantation inhibits neointima formation in stented porcine coronary arteries. Circulation 1995; 92 : 1383-6.
3. Hehrlein C, Zimmerman M, Melz J, et al. Radioactive coronary stent implantation inhibits neointimal proliferation in non atherosclerotic rabbits. (abstract) Circulation 1993; 88 suppl : I-651.
4. Condado JA, Waksman R, Gurdiel O, Espinosa R, Gonzalez J, et al. Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation 1997; 96 : 727-32.
5. King SB, Williams DO, Chougule P, Klein JL, Waksman R, Hilstead R, MacDonald J, Anderberg K, Crocker IR. Endovascular beta-radiation to reduce restenosis after coronary balloon angioplasty: Results of the beta energy restenosis trial (BERT). Circulation 1998; 97 : 2025-30.
6. Verin V, Urban P, Popowski Y, Schwager M, Nouet P, Dorsaz PA, Chatelain P, Kurtz JM, Rutishauser W. Feasibility of intracoronary beta-radiation to reduce restenosis after balloon angioplasty: A clinical pilot study. Circulation 1997; 95 : 1138-44.
7. Terstein PS, Massullo V, Jani S, Popma JJ, Russo RJ, Steuterman S, Morris NB, Leon MB, Tripuraneni P. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997; 336 : 1697-1703.
8. Waksman R, White RL, Chan RC, et al. Localised intracoronary radiation therapy for patients with resrenosis: Preliminary results from a randomised clinical study. Circulation 1997; 96 : I-219.
9. Fischell TA, Carter AJ, Laird JR. The beta-particle-emitting radioisotope stent (isostent): Animal studies and planned clinical trials. Am J Cardiol 1996; 78 : 45-50.
10. Baim DS, Fischell T, Weissman NJ, Laird JR, Marble SJ, Ho KK. Short term (1 month) results of the IRIS feasibility study of a beta-particle emitting radioisotope stent. Circulation 1997; 96 : I-218.

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