Serruys, Patrick W. MD, PhD; Levendag, Peter C. MD, PhD
Key Words: Editorials, radioisotopes, brachytherapy.
Writing an editorial on a newly emerged mode of therapy is a dilemma: either one emphasizes the promises of this new modality of treatment at the risk of being perceived as a noncritical and naive editorialist, or the potential hazards and the inherent limitations of the novel treatment are highlighted with the possibility of the editorialist being perceived as a nommaginative killjoy. 
Those in 1976 and 1977 who saluted the advent of percutaneous balloon coronary angioplasty as the future panacea for the treatment of CAD were obviously overly enthusiastic. Those who saw this technique as only a crude, blind, unrealistic, dangerous cracking procedure for enlarging stenotic lesions have been retrospectively ridiculed by its overwhelmingly worldwide application.
The advent of brachytherapy can be likened to the introduction of angioplasty. We may ask ourselves whether this new modality of treatment is going to turn the world of interventional cardiology upside down by eliminating the restenosis phenomenon. Indeed, this would finally give to angioplasty its "lettres de noblesses," probably rehabilitate the debulking techniques, give the ultimate boost to nonsurgical percutaneous and intracoronary revascularization strategies, and merge the world of the interventional cardiologist with that of the radiotherapist. What a revolution in perspective!
Before being carried away by the dream of the promised land, let us analyze the newly published clinical evidence on which we have to build our case. As a matter of fact, there are only two very small series of 15 and 22 patients treated by intracoronary brachytherapy. [2,3] We eagerly await the publication of the results of the Scripps series (n = 55 patients), which seem promising. Each publication on brachytherapy thus far is accompanied by an editorial with rather revealing titles. In March 1997, after the publication by Verin et al  of the first 15 patients treated by beta-brachytherapy, Teirstein  posed the question "beta-radiation to reduce restenosis: too little, too soon?" emphasizing our ignorance in terms of correct dosage and correct timing of application. Let us critically review the present study by Condado et al  before drawing any premature conclusions.
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Can We Judge the Results of Brachytherapy on a Luminogram?
In 1997, it might be arguable to still use the luminogram approach of the angiographer to assess the results of a brand-new pioneering modality of treatment. Because the authors have chosen the loss in MLD as their yardstick of assessment, let us judge their results according to the classic rules of the QCA game. The loss in MLD is classically determined between the measurement made at the end of the procedure and those made at follow-up, including the 0 mm and 100% diameter stenosis of any total obstruction or occlusion, subacute or chronic. Then the loss in MLD observed in the present study is 0.44 mm, a value very common and familiar to the trialists who have used QCA to detect a beneficial effect on restenosis of a drug or a device. The 0.45 mm measurement is not much at variance with the losses observed in the CARPORT (0.27 mm),  MERCATOR (0.26 mm),  MARCATOR (0.33 mm),  PARK (0.25 mm),  HELVETICA (0.28 mm),  BENESTENT (0.32 mm),  and REDUCE trials  and in the Lovastatin study (0.40 mm),  which was analyzed by the Emory University core laboratory with the same methodology as used in the present study. It might be retorted that the calculation of the loss should be done with respect to the value observed after recoil, 24 hours after the procedure. In that case, the loss is close to zero, and it might be claimed that the restenosis phenomenon has been "biologically" erased. Which is right and correct, the first or the second assessment?
On the one hand, the investigators have to be commended for their methodological approach of postponing their "angiographic baseline by 24 hours"; on the other hand, "the QCA experts in recoil" [13,14] will feel uneasy with variations in MLD such as reported in the present study over the first 24 hours. It is as if a floating baseline (made of spasm, recoil, and thrombus, etc) has been created because meticulous rules of assessment of recoil (eg, a careful watching delay of 15 minutes before measurement) have been overlooked. 
A large, multicenter, prospective study, analyzed by a central core laboratory, using edge detection and video densitometry in patients treated intravenously by anti-thrombin demonstrated that the average change in MLD 24 hours after PTCA was close to zero.  In other words, are we dealing with a poorly controlled early loss in the study by Condado et al  (-0.45 mm at 24 hours) or with a perfect absence of late loss (on average 4.7 micro meter between 24 hours and 6 to 14 months!)? When the individual changes in MLD between the 24-hour and the 6- to 14-month assessments are analyzed, it is apparent that eight lesions show a decrease in MLD (average loss of 0.62 mm, including two occlusions) whereas nine lesions show a late increase in MLD (average "negative" loss of +0.56 mm, ranging from 0.05 mm to 1.16 mm).
Similarly, 10 (45%) of the 22 treated lesions in the study by Condado et al  showed an increase in MLD from the postprocedural treatment to the 6- to 14-month follow-up; a rather puzzling observation at first sight, but less surprising when one considers that in general 28% of all balloon-dilated lesions show a negative loss on QCA. [15,16] However, the suspicion remains that brachytherapy may biologically dichotomize the well-known gaussian distribution of luminal loss, facilitating a favorable remodeling (enlargement) of certain lesions, while others with a less favorable anatomic substrate (calcified?) or a less appropriate radiation exposure do not respond.
The point we are trying to make is that fluoroscopy and angiography, even quantitative, is probably not the proper method of analysis of the "to be and has been" irradiated lesion. In this pioneering phase, it is probably essential to analyze in great detail the anatomic substrate and the complex three-dimensional morphology of the coronary vessel to be irradiated, as well as the geometric relationships of the radiating source with the vessel wall. A three-dimensional view and quantitative assessment of the entire vessel with its three tissular layers might become an essential prerequisite to calculate precisely and safely the doses of radiation needed. The interpretation of the medium and long-term results should be based on a detailed analysis of the effects of radiation on the subintima, media, and adventitia; the relative contribution of neointimal proliferation versus adventitial remodeling must be differentiated to understand the mechanism of action of this new modality of post-PTCA treatment. In other words, intravascular ultrasound may have found a privileged field of application. The much-awaited publication of 55 patients treated by Teirstein and coworkers will undoubtedly confirm this.
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The First Steps (or Missteps?) in a Search for a Therapeutic Window
A truly new interdisciplinary frontier in medicine has emerged: radiation therapy for the "not-so-benign" intracoronary restenotic lesion. It is an interesting dialectic between the "good" and the "evil" of ionizing radiation on diseased coronary arteries, a paradigm of potentially undue sequelae with longevity and a dose of radiation that can reduce the restenosis rate, reported to be as high as 30% to 50% after PTCA alone or 22% to 32% after stenting. [17,10] Yet, this seemingly paradoxical "friend or foe" perspective is analogous to using known carcinogens such as some chemotherapeutic agents and radiation when treating cancer. Endovascular brachytherapy, with its first application in rabbits being reported by Friedman et al in 1964,  is the latest of these and seems extremely promising. Condado et al  were the first to use192 Ir, a gamma-emitter, in a rather favorable (77% de novo lesions) subset of angioplasty patients; they must be applauded for reporting on the "long-term" (follow-up of 6 to 14 months) results. The fact that radiation per se affects blood vessels, however, was recognized as early as 1899, when Gassmann  published his findings on the histology of two cases of x-ray induced ulceration. Moreover, since the very first use of x-rays for either diagnostic or therapeutic purposes, the presence of blood vessel (heart) abnormalities in radiation-damaged tissues has always impressed pathologists. [20,21] It was not until the 1990s that numerous long-term follow-up reports (mean follow-up > 10 years) of large cohorts of patients treated for Hodgkin's disease and breast cancer became available and revealed an unexpectedly high incidence of pericardial and CAD in survivors, with relative risk ratios varying from 2.6 to 3.8. The increased risk of radiation-related CAD was to some extent found to be dose and volume dependent. [22,23] In the case of single-fraction endovascular brachytherapy, one is dealing with small volumes and tight dose distributions. However, radiobiology dictates that the acute effects of a single dose of, for example, 12 Gy (or 20 Gy), using the linear-quadratic model for a surviving fraction S, with S = e sup -aD-bD2, would be biologically equivalent to 36 Gy (or 92 Gy) in terms of late effects when given in a conventional fractionated schedule (2 Gy per daily fraction; alpha/beta = 3 Gy). [24-26] The disparity of dose-response between early and late effects is exemplified for a range of doses by Figure 1. The single doses prescribed by Condado et al  were 18 Gy (1 patient), 20 Gy (11 patients), and 25 Gy (9 patients); in fact, for the assumption that the catheter was in the center of the artery, the mean luminal surface dose was calculated to be 35.6 +/- 11.1 Gy and the peripheral dose 23.3 +/- 7.5 Gy. Obviously, with regard to the (yet-to-be-established) incidence of true late effects, these doses might be considered well over the vascular tolerance limits. Regarding the other side of the coin, ionizing radiation has proven to be a very potent antiproliferative agent. That is, even low doses (< 1 Gy) of radiation have shown to be very effective in various nonmalignant conditions such as eczema, psoriasis, periarthritis humeroscapularis, epicondylitis, knee arthrosis, hidradenitis, parotiditis, and panaritium. Moreover, in a review by Trott,  the risk-benefit ratio for radiotherapy using these very low doses was found to be more favorable than those of the best available alternative treatments, particularly for some of the dermatological conditions.  The pendulum of fairy tales produced by scientific committees such as the National Academy of Science calling radiation therapy for benign diseases "irresponsible" and "always cancer-inducing"  has now apparently swung back to the present day Cinderellas of radiation therapy using "intermediate" doses (eg, 6 to 20 Gy) for a variety of benign disorders.
Currently, radiation is frequently used for the prevention of keloid  and heterotopic bone formation,  for stabilizing or improving visual acuity in cases of macula degeneration,  for obliteration of arteriovenous malformations,  and for reducing the vascular restenosis rate after angioplasty. However, with respect to endovascular brachytherapy, a number of scientific questions and controversies still have to be resolved. Weinberger et al  caution against 10 Gy as being stimulatory after PTCA, ie, too low doses of radiation might have a stimulatory effect on the formation of neointimal hyperplasia. Several groups have shown that 14 to 20 Gy of local irradiation via the temporary insertion of gamma-emitters can inhibit restenosis in animal models. They also showed evidence for an increase in inhibitory effects at 48 hours after PTCA rather than concomitant with it. [34,35] This makes timing, although conceptually difficult to implement in current angioplasty procedures, an important subject for further study. Wiederman et al  reported, in contrast to Waksman et al,  that whereas intracoronary irradiation of 20 Gy markedly reduces neointimal hyperplasia after overstretch balloon angioplasty alone in a pig model, it is ineffective when intravascular stenting is added. There is also debate as to what the precise target (cell) is, ie, the key contributor to restenosis. Research interest has been focused on the interaction between cells and cytokines induced by injury. Rubin et al  recently proposed a unified theorem for arterial stenosis and restenosis: the dominant cell that initiates postangioplasty restenosis is the same as that which initiates the artherosclerotic plaque, ie, the monocyte-derived macrophage. They believe that the target cell for radiation is the endothelium of the fine microvasculature of the vasa vasorum and postulate that, macrophages being particularly radiosensitive, there might be a dose and temporal therapeutic window. Brenner et al  propose that doses of > 20 Gy, which would be required to completely eliminate the proliferating smooth muscle cell population, are too large because of the unacceptable risk of late complications. Doses of < 20 Gy will delay restenosis by 1 to 3 years. Whether such doses can avert restenosis permanently is unclear, because permanent prevention depends critically on the assumptions that those smooth muscle cells that survive irradiation have a significantly limited capacity for proliferation. However, given that the end result after angioplasty in most cases is an eccentric coronary artery lumen, most authors at this point in time favor doses of < 20 Gy, prescribed to a distance of [nearly =] 2 to 3 mm from the source. Catheter-based therapy in humans has been used with either192 Ir sources, which primarily emit photons, or90 Sr/sup 90 Y and sup 32 P sources, which emit beta-particles.  Although no available isotope is ideal,192 Ir certainly has a small advantage in terms of radial dose uniformity. [39,40] Because the required activity of192 Ir will be on the order of 1010 Bq, it is likely that safety considerations will mandate the use of specially designed HDR computerized afterloading units. The study by Condado et al  describes a manually afterloaded, noncentered,192 Ir source (activity of 529 to 982 mCi), with doses prescribed at 1.5 mm. With this technique, there are inherent radioprotection problems: eg, adequate shielding measures, to reduce the maximal dose the treating physicians receive annually to 2 mSv, would have required [nearly =] 28 mm of lead. Furthermore, due to the noncentered source, it is extremely worrisome that some of the vessels apparently were treated to a nominal dose of 25 Gy whereas actually, acute doses of up to 92.5 Gy could have been delivered to the lumen wall (cave; see also Figure 1). Two patients in fact experienced total occlusion at 30 and 38 days, and one developed a pseudoaneurysm; moreover, as discussed previously, it seems far too early to definitively comment on the total number of potential late side effects. Despite the uncertainties with dosimetry in small vessels such as coronary arteries, standardization of radiation dose prescription is absolutely essential. Fortunately, the American Association of Physicists Task Group 60, with the assistance of the National Institute of Standards, is currently addressing issues regarding the ideal isotopes to be used and prescription of the dose for endovascular brachytherapy.
Let us be frank and honest: we are not so much impressed but rather puzzled by the results of the present study. To the three basic questions raised in this paper (feasible? safe? efficacious?), our answers would be: feasible? yes, because it has been done; safe? we doubt it; and efficacious? we don't think so. After all, maybe the two authors of this editorial are just two killjoys.
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