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Examination of the barriers standing between MBRS and the clinic.
Problems discussed include use case, photon energy, targeting method, radiation source, and biology.
Potential solutions are presented.
In spite of its long demonstrated potential, microbeam radiosurgery (MBRS) has yet to be developed into a clinical tool. This article examines the problems associated with MBRS, and potential solutions. It is shown that a path to a clinically useful device is emerging.
In conventional radiotherapy, the ability to destroy a cancerous tumor is limited by normal tissue toxicity. Typically, a total dose between 50 and 100 Gy is delivered to malignant tissue. While higher doses would certainly lead to greater tumor control, such higher doses are not possible because of damage to surrounding healthy tissue.
A number of scientific studies on small animals over the past two decades have demonstrated the astonishing fact that healthy tissue can tolerate an enormous amount of dose (>300 Gy) when delivered in small diameter beams or thin planes of radiation (<700 μm), termed microbeam radiation [
]. Although cells in the direct paths of the microbeams are killed, the adjacent non-irradiated tissues mount a healing response. Studies have also demonstrated that malignant tissue can be destroyed by microbeam radiation via cross-firing from several directions [
]. Thus, MBRS appears to have tremendous potential to control internal disease with little or no toxicity to surrounding healthy tissue.
In spite of its extraordinary potential, MBRS has yet to become available to the clinic. The problems which have kept MBRS from the clinic, along with potential solutions, are examined herein.
From an industrial perspective, there are five major problems associated with the current state-of-the-art of MBRS. These are use case, photon energy, targeting method, radiation source, and biology. Each of these problems is discussed below.
Although several small animal models have been used (mice, rats, rabbits, and piglets), nearly all pre-clinical MBRS studies to date have focused on brain tissue. While a device that would cure brain cancer is greatly desired, such a device would command a small market from the perspective of an industrial manufacturer of radiotherapy equipment. Cancer statistics for the USA in the year 2013 show that brain cancers accounted for 1.4% of all cancers [
]. See Fig. 1. To warrant the long and expensive route of product development, it is necessary to show that MBRS is effective in destroying many more types of malignant tissue while still sparing the corresponding many more types of healthy tissue.
For conventional radiotherapy, lung cancer is a large (14% of all cancers) but woefully underserved market because radiation often induces pulmonary fibrosis. Pulmonary fibrosis alone can lead to death. Recently, Varian Medical Systems, Inc. (USA), in collaboration with the European Synchrotron Radiation Facility (France), launched a study to determine whether or not microbeam radiation induces fibrosis in the lungs of rats. The results of this study are pending, and will be reported at a later date.
By way of this article, the MBRS research community is respectfully called upon to explore the effects of microbeam radiation on yet more types of tissue and cancers; e.g., liver, pancreas, kidney, bladder, etc.
All MBRS studies have employed spectra of low energy photons which peak between 50 and 150 keV. While such photon energies are sufficient for small animals, they are not sufficient to provide dose at depth in human patients. Figure 2 shows the percentage depth dose curves for 500 μm diameter pencil beams of monochromatic 200 keV and 2 MeV photons. At 20 cm depth, which is half-way into the wide portions of a human patient, 200 keV photons supply only 5% of incident dose. The lower energy photons used in MBRS provide even less. 2 MeV photons, such as used in conventional radiotherapy, provide 35% of incident dose at 20 cm depth.
Figure 2 also shows that peak dose deposition for low energy photons occurs at the surface of the patient; i.e., at the skin. This is important because there are many nerve endings in skin, and damage to the skin is very painful. Even though damage created by microbeams at the skin may be expected to heal nicely, such damage will likely be painful during the healing process. Peak dose deposition for high energy photons, however, occurs below the skin, allowing for pain-free experience.
The primary reason low energy photons have been used in MBRS studies up to now is that it has been the thinking of researchers in the field that the lateral dose deposition profile (i.e., in the direction orthogonal to the direction of beam propagation) must have a square wave shape [
]. That is, the dose in the valley regions of the microbeam array must be low and flat, the dose in the peak regions must be high and flat, and the transition between the two regions must be sharp. This dose profile assures that there is no damage to healthy tissue in the valley regions, thereby allowing such undamaged tissue to provide a healing response to the destruction generated in the peak regions. Because of the phenomenon of Compton scattering, high energy photons yield a rounded lateral dose deposition profile. Figure 3 shows the lateral dose deposition profiles for 500 μm diameter pencil beams of 200 keV and 2 MeV photons. The 2 MeV photon case clearly does not meet the square wave profile requirement. Because of dose tails extending into the valley regions, microbeams with photon energies above 200 keV have been considered unacceptable.
With this article, a shift in thinking is proposed. It is herein argued that the shape of the lateral dose deposition profile is immaterial. Rather, what is important is that the biological damage zone created by a microbeam be sufficiently narrow that the undamaged regions on either side are able to induce healing. It is proposed that the Compton scattering of high energy photons be taken into account in choosing the width of the incident microbeam. The incident width must be chosen such that the peak and tail regions of the dose deposition profile create a biological damage zone which can be healed. Figure 4 graphically portrays this new approach. If the biological damage zone created by the square wave dose deposition profile is capable of being healed, then clearly so is the biological damage zone created by the rounded dose deposition profile.
It must be noted at this juncture that the peak plus tail regions for microbeam photons in the MeV energy range are quite large. Monte Carlo calculations show that for a 100 μm diameter incident microbeam of 2 MeV photons, the tail falls below 10% of the peak at a diameter of 400 μm. This implies relatively large biological damage zones. Studies have shown, however, that microbeam widths as large as 700 μm perform satisfactorily [
The utility of microbeams at higher energies than currently used must be explored experimentally. If it cannot be shown that significant dose can be deposited at depth while also avoiding painful skin damage, it is unlikely that microbeam radiosurgery will be clinically useful.
The most successful microbeam targeting technique employed to date for the destruction of diseased tissue involves the interlacing of microbeam arrays fired from several ports [
]. See Fig. 5. This technique creates a broad beam dose profile at the target, as does conventional radiotherapy. It is reasonable to presume that with this targeting technique, a malignant tumor may be controlled as well as, and in accordance with, conventional radiotherapy dosing protocols.
Patient motion, however, presents a serious problem for the interlacing technique. It is anticipated that a clinical device will deliver the microbeam arrays associated with each port sequentially in time. (A device that would have several radiation sources, allowing for simultaneous delivery of microbeam arrays from all ports, would be cost prohibitive.) In transitioning from one port to the next, either the microbeam radiation source (preferred) or the patient will be repositioned. If patient registration relative to the microbeam tracks from any port is lost during the repositioning procedure, the interlacing of damaged regions at the target will not occur properly, and a broad beam damage pattern will not be achieved. Patient motion on the order of a single microbeam width will compromise the effectiveness of the interlacing technique. Patient motion larger than this is guaranteed in practice.
It is helpful now to recall what studies have revealed regarding the biology associated with microbeams. With regard to the preferential tumoricidal effect of microbeams, the evidence gathered so far indicates that differences in the microvasculature of tumors and normal tissue are responsible. The blood vessels of tumors are faster growing and immature, larger in diameter, fewer in density, and more tortuous in shape than the blood vessels of normal tissue. The tumor blood vessels damaged by microbeams are unable to repair, whereas the normal tissue blood vessels heal [
Given the knowledge of the effect of microbeams on microvasculature, it is herein proposed that a dicing technique rather than an interlacing technique be used to destroy malignant tissue. See Fig. 6. Each plane of microbeam radiation will destroy the tumor blood vessels in its path. By arranging the planes of microbeam radiation to dice the target tissue into small volumes, the blood supply to these small volumes of tissue will be cut off. The tumor will die by way of ischemia.
One study employed the dicing geometry on brain tumor bearing rats [
]. However, radiation from each of the three ports was not delivered in the same treatment session. Radiation deliveries from the second and third ports were 24 and 48 h after the first, respectively. Although survival times increased significantly for the irradiated animals, histological investigation showed that the tumors were not ablated. For the proposed dicing technique to work, radiation from all ports must be delivered in the same treatment session.
Note that the dicing targeting method is insensitive to patient motion during the repositioning procedure between ports.
Further studies on the dicing targeting technique are warranted.
The most daunting obstacle standing between MBRS and the clinic is the radiation source. Presently, effective microbeam arrays can be generated only by synchrotron sources. A synchrotron is required for low beam divergence and high dose rate. The low beam divergence is necessary to keep the microbeams from spreading to larger widths as they pass through a patient. The high dose rate is required so that patient motion during microbeam delivery does not broaden the damage region. Unfortunately, synchrotrons are very large devices with construction and operation costs at levels that only nation states can provide.
Several groups around the world are working to develop a new type of radiation source that employs inverse Compton scattering (ICS) [
]. Figure 7 displays the ICS process in which a high energy electron collides with a low energy photon to yield a high energy photon and a reduced energy electron. First generation ICS sources are expected to produce radiation very similar to that of synchrotron radiation, with the exception of dose rate. Later generations of ICS sources are expected to match the dose rate of synchrotrons. ICS sources are expected to be a few meters in diameter, rather than the kilometer diameter typical of synchrotrons. Also, ICS sources are expected to cost about as much as today's linear accelerators used in conventional radiotherapy. Figure 8 shows a first generation ICS source developed at Lyncean Technologies located in Palo Alto, California, USA.
A small footprint, low cost alternative to the synchrotron, such as an ICS source, must be developed if MBRS is to become a clinical tool.
Further elucidation of the biological underpinnings of MBRS is needed. Two fundamental biology questions should be answered.
First, how is a cell killed by the extremely high doses delivered by MBRS? In conventional fractionated radiotherapy, a dose of 2 Gy is delivered per fraction. It is understood that cell death occurs by reason of radiation induced DNA damage and subsequent mitotic catastrophe [
]. The dose regime of MBRS so far exceeds current practice that the kill mechanism comes into question. Do cells die by mitotic catastrophe, intrinsic apoptosis, regulated necrosis, autophagy, or a combination of these known death subroutines [
]? Could there be a more physical mechanism? Could purely physical damage to the stroma of the cells be the cause of death?
The second fundamental biology question which must be answered is the more important. How is normal tissue destroyed by microbeams “healed” by adjacent non-irradiated tissue? This is the most surprising feature of MBRS. In conventional broad beam radiotherapy, healing of normal tissue irradiated with doses above 2 Gy does not occur. The response of normal tissue to microbeams is the breath-taking feature which motivates industrial interest. Yet, this feature is not at all understood. The subject of macroscopic wound healing has been studied extensively over many years [
]. The processes involved are complicated, with events happening on molecular, cellular, and tissular levels, over time frames of minutes, hours, days, weeks, and months. Are the same processes involved for microscopic radiation-induced wounds?
Although it is not necessary to answer these fundamental biology questions completely before making use of MBRS in the clinic, further understanding of the biological processes involved will most certainly lead to better treatments.
Although significant obstacles must be overcome, it appears possible to bring MBRS into the clinic. It is hoped that this article will spur scientific researchers and product developers alike to address the issues raised. It is hoped that the extraordinary potential of MBRS to fight the insidious disease of cancer may be realized.
The COST Action TD1205 (SYRA3) is kindly acknowledged for financial support associated with publication costs.
The use of a deuteron microbeam for simulating the biological effects of heavy cosmic-ray particles.
Bilogical mechanisms underlying the preferential destruction of gliomas by x-ray microbeam radiation.
in: Miller L.M. Pages P. National synchrotron light source activity report. National Technical Information Service,
Springfield, VirginiaNovember 2014 (U.S. Department of Commerce; 2002, Abstract No. Dilm0599)