**7. Discussion and recommendations**

The ARUBA trial, published in 2014, compared interventional therapy with medical management of unruptured brain AVMs. It was a broad trial involving 39 active clinical sites in nine countries. The study recruited 223 patients during the period from April 2007 to April 2013. About 114 of the patients were assigned to interventional therapy and 109 to medical management. The conclusions were that the risk of death or stroke is significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0.27). Naturally, the study elicited a plethora of reactions that we will not fully cover since they are outside the scope of this review. Some, that were relatively more supportive, identified ARUBA as the only randomized trial at that time (2010) with clear clinical outcomes comparing different interventional treatments for brain AVMs with conservative medical therapy [100]. More reactions were less supportive, criticizing the pragmatic design, the patients' heterogeneity, the lack of standardization of the treatment arm, the choice of outcome measures, the short follow-up period, the small population, and so forth [87, 101, 102]. The controversy also led the European societies dealing with the treatment of AVMs to conduct a consensus conference at the European level [104]. Among the statements made were two key points which we quote: "There are sufficient indications to treat unruptured AVMs Grade 1–2 SM" and "There **may** be indications for treating patients with higher SM grades, based on a case-to-case consensus decision of the experienced team." One clear consensus emerges—further research is advocated to delineate the optimal management of unruptured AVMs, particularly those with SM grade≥3 [103]. Furthermore, judicious observation of the literature since ARUBA indicates that there may be a lacuna or at least weakness in interventional modalities when addressing high SM grade AVMs. This fact has not traversed the community unnoticed. All three main interventional modalities present a similar line—advancement in existing treatment paradigms, treatment planning, and intra-operative measures. However, to date, the core challenge persists. We feel that one possible cause is the limitations inherent in present approaches that lead to diminishing returns with every new improvement (necessitating ever-increasing technological and financial investments). The two leading avenues of interventional choice for medium-to-large lesions are currently multi-modal and staged treatment. When considering multi-modal treatment, we must take into account other factors besides medical outcomes. Multi-disciplinary AVM treatment suffers from a fundamental market/commercial flaw. Every manufacturer focuses on its core technologies (whether they are embolic agents, radiation therapy equipment, etc.), and these typically do not complement one another. This considerably impedes R&D of novel multi-modal techniques and protocols by leaving them in the hands of mostly research endeavors that lack the financial resources of commercial companies. Interestingly, this fact is clearly reflected in the literature. The number of papers we reviewed dealing with single modality treatment is an order of magnitude larger (speaking cautiously…) than those adopting a multi-modal approach. This trend continues for the number of patients treated. To conclude, we fear that multi-modal treatment faces inherent financial and technical limitations that strongly impede its chances of reaching full potential and will continue to do so in the near future. Fractionated radiation and multi-session (staged) embolization also suffer similar logistic and economic flaws. It is very challenging to repeatedly admit patients to very complex and expensive procedures also requiring highly experienced medical experts who are typically in "short supply," and advanced facilities, particularly in radiation treatment. Considering this state of affairs, we conclude that it could be advantageous to consider a treatment approach that has not been used to address AVM in the past—continuous mild

irradiation provided via an implantable active source. The use of such implants in Brachytherapy is very well established and dates back decades (if not a century). Much knowledge has been accumulated in the field (we will not review the subject due to lack of space). Such an implant has the potential to elicit a hyperproliferative effect facilitating lumen closure by thickening of the vascular wall by exploiting the "candy wrapper" or edge effect (see further data below).

First, let us attempt to convince the readers that this approach merits medical investigation. In Section 6.1, we explained that there are two major changes in tissue when exposed to radiation—degeneration and proliferation. Both changes are dose- and time-dependent. Therefore, there is room for adjusting and augmenting each by controlling radiation kinetics and spatial distribution patterns. Active stent studies show proliferation and restenosis reduction (typically in-stent) but also induction (typically at the stent edges). Albiero et al. implanted 122 32P radioactive β-emitting stents (activity levels of 0.75–12.0 μCi) in 91 lesions in 82 patients [105]. After 6-month follow-up, they found that intrastent restenosis was 0–16% (depending on implant activity; high activity stents showed no restenosis). However, they also found that restenosis at stent edges was 41–52% (maximal for the lowest activity stents!). They concluded that the use of active stents in patients with coronary artery disease is feasible and named this edge effect as the "candy wrapper." They speculated that the effect was a result of low radiation at the stent edges combined with an aggressive approach to stenting (pre-dilatation with an oversized balloon). Shortly after, they also demonstrated that stents with higher initial activity levels of 12–21 μCi (54 lesions) reduced intrastent neointimal hyperplasia compared with stents of 3–12 μCi (42 lesions) [106]. However, they did not eliminate edge restenosis (38% for the lower activity stents were reduced just to 30% for the higher activity stents). Since they used a non-aggressive stent implantation strategy (pre-dilatation with a non-oversized balloon) in the second study, they also ruled out that the edge effect is attributable to the implantation procedure. Wardeh et al. implanted 31 stents in 26 patients [107]. They corroborated this deduction (also attributing the edge effect to low radiation levels) and concluded that the use of low activity radioactive stents is safe and feasible. Sianos et al. analyzed 175 human vessels (131 were eventually eligible) treated according to the beta-radiation in Europe (BRIE) study protocol [108]. They wanted to evaluate the impact of Geographical Miss (GM—a situation in which the radiation source does not fully cover the injured vessel segment) on edge restenosis after intracoronary beta-radiation therapy. The injured edges of the effective irradiated segment (EIRS) constituted the GM edges. Restenosis was defined as diameter stenosis >50% at follow-up (6 months). They found GM affected 41.2% of the edges and significantly increased edge restenosis to 16.3% compared with 4.3% in non-GM edges (for both proximal and distal edges). GM associated with stent injury increased edge restenosis more than that associated with balloon injury (from 3.6% with no GM to 18.75% compared with from 5.36 to 10.71%, respectively). However, EIRS restenosis was similar between vessels with and without GM (24.3 and 21.6%, respectively), thus indicating a dominant effect for radiation fall origins. Van der Giessen et al. investigated the edge effect in the coronary arteries of Yucatan micropigs [109]. They fabricated half radioactive and half non-radioactive stents (*n* = 20, with 10 regular stent controls). Their design introduced a mid-stent radioactive dose falloff zone next to a non-radioactive stent-artery transition at one side and a radioactive stent-artery transition at the other side. They demonstrated a significant mid-stent stenosis at 4 weeks followup. Two animals died suddenly because of coronary occlusion at this mid-zone at 8 and 10 weeks. At 12 weeks, there was a significant neointimal thickening at the mid-stent dose-falloff zone of the half-radioactive stents but not at the stent-toartery transitions at both extremities. No mid-stent response was observed in the

## *Advocating Intraluminal Radiation Therapy in Cerebral Arteriovenous Malformation Treatment DOI: http://dx.doi.org/10.5772/intechopen.89662*

non-radioactive stents. They concluded that the edge effect is associated with the combination of stent injury and radioactive dose falloff. Studies performed on both human subjects and animal models found a significant neointimal increase at low activity stents edges [110]. These findings seem clinically significant since low-dose-related neointimal hyperproliferation, when compared with conventional radiosurgery, does not appear to be associated with damage to the Tunica Adventitia or Vasa Vasorum, hyaline phenotypes, or any endothelial disfunction (degeneration traits). Desouky et al. recently reviewed the targeted and non-targeted effects of ionizing radiation [111]. They describe cell and tissue response to low-dose/dose rate ionizing radiation. Cells exposed to such radiation exhibit increased cellular communication and resistance to future irradiation. They conclude that exposure of human cells to low radiation induces molecular processes that are different from those induced by high dose radiation. Furthermore, the effects of ionizing radiation are not restricted to irradiated cells but also affect non-irradiated cells via mechanisms termed "Radiation Bystander Effects" and "Radioadaptive Response" [111]. This suggests that a low-dose/dose rate source can potentially affect a larger volume than that anticipated from direct energy absorbance evaluations based on our experience with high-energy treatments.

The edge effect has always been treated as an adverse phenomenon. However, in AVM treatment, the objective is precisely the opposite of most traditional vascular procedures—obliteration rather than revascularization. Here, we suggest that if exploited properly, this effect may prove highly beneficial. Let us explain its potential advantages:


#### **Figure 8.**

*Illustration of the conceptual differences between the presumed radiation traits required from a continuous source and those required from the current two predominant treatment modalities—radiosurgery and FT. Left: radiation dose/rate kinetics. Right: isodose map (the same dashing indicates equal radiation levels). The continuous source is constantly effective, thus necessitating significantly reduced doses/rates and facilitating a much better contained radiation distribution field, reduced affected brain volume, and potentially reduced AREs.*

high-intensity energy doses/rates. Mild radiation also ensures a much better contained isodose distribution compared with the target volume and thus affected brain volume (**Figure 8**).


To conclude, if proven feasible, low-radiation implants could add several unique benefits to AVM treatment and we advocate studying their use.

*Advocating Intraluminal Radiation Therapy in Cerebral Arteriovenous Malformation Treatment DOI: http://dx.doi.org/10.5772/intechopen.89662*
