Fast

Neutron Therapy
Sevil Rahnama UBC #53255097 Physics 404 December 2, 2011

Abstract

Fast Neutron Therapy, first introduced in 1938, has emerged as an advance radiation therapy that is capable of killing very large, and radio-resistant tumors. Using high-energy neutrons, the beam is capable of producing very large secondary charged particles (electrons) that are able to cause double-stranded DNA damage that can effectively destroy the cell. Other therapy methods only damage the DNA and the cell can repair itself. The therapy causes considerable damage to the cells, and thus can sometimes cause irreversible damage to the normal tissues. Therefore, this treatment is only used when the other radiation therapies fail. In the following paper, fast neutron therapy is discussed in detail. First, the reactions creating the neutrons are covered. This is followed by the discussion of the gantry and the MLC that are used to apply the dosage on the patient. Next, the dosage used for treatment is discussed. Finally, some advantages and disadvantages of the fast neutron therapy are discussed. University of Washington, Wayne State University and FermiLab are the center of research on the therapy and much of the details are taken from these institutes.

List of Figures

Figure 1: A cyclotron a device that rotates and accelerates a particle by changing the gradient of the magnetic field, thus making the particle speed up spirally. Image taken from (Gagnon) ...................................................................................................................... 7 Figure 2: The icon conical flattening filter used to bring the proton beam to the beryllium sample and the parallel-sided aperture used to collect the neutrons. Image is courtesy of (Kiger, Sakamoto, & Harling) ........................................................... 8 Figure 3: The drawing of an MLC system showing (with the filter and the aperture located inside it) is shown on the left. The University of Washington Clinical Neutron Therapy System (CNTS) is shown on the right. ................................................ 8 Figure 4: A tumor cell targeted by the CNTS system. Note the high resolution of isolating the tumorous cell from the skin around. Image is courtesy of University of Washington. ............................................................................................................ 9 Figure 5: The gantry system holding the MLC ........................................................................... 10 Figure 6:FNT vs X-ray or proton therapy. The FNT produces high-LET electrons capable of performing double-stranded DNA damage while the X-ray therapy only does single-stranded DNA damage. ............................................................................ 11 Figure 7: The comparison of X-ray, neutron and proton therapy. The table is courtesy of (Jones, 2008). .......................................................................................................... 11 Figure 8: The correlation of LET and the RBE. The higher the LET generally represents a higher RBE value. ............................................................................................... 12 Figure 9: A salivary gland tumor treated with NFT. Picture courtesy of (Lennox). .. 14

List of Abbreviation
CNTS FNT LET RBE RT Clinical Neutron Therapy System Fast Neutron Therapy Linear Energy Transfer Relative Biological Effect Radiation Therapy

Table of Content

Abstract .......................................................................................................................................................... 2 List of Figures .............................................................................................................................................. 3 List of Abbreviation .................................................................................................................................. 4 1. Introduction ........................................................................................................................................ 6 Fast Neutron Therapy .............................................................................................................................. 6 1.1. Producing the beam of neutrons ....................................................................................... 7 1.2. Neutron bombardment .......................................................................................................... 8 1.3. Neutron treatment and the dosage amount ............................................................... 10 2. Comparison of neutron vs. other radiation therapies .................................................... 13 2.1. Advantages of FNT ................................................................................................................ 13 2.2. Disadvantages of FNT .......................................................................................................... 13 3. Conclusion ......................................................................................................................................... 15 Bibliography .............................................................................................................................................. 16

1. Introduction and Background

Radiation Therapy (RT) is the medical use of a beam to ionize a cancerous and/or tumor cell and cause DNA breakdown to kill it. To protect the normal tissue, shape- shifting masks are used to reshape the beam onto the targeted cell. Fast Neutron Therapy (FNT) is a specific type of RT. It is classified as high-linear-energy-transfer (high-LET) beam therapy, in which the targeted cells go under single-hit double- stranded DNA damage that effectively kills the cell. This is in contrast to other RT (such as X-ray) that is classified low-linear-energy-transfer (low-LET) in which the targeted cells undergo single-stranded DNA damage, which can readily be repaired, thus limiting the destruction of the cell. The damage is simply done by ionizing the DNA chain and causing them to break apart. In laboratory environment, killing cancerous cells is significantly easier than curing them.

2. Fast Neutron Therapy

2.1. Producing the beam of neutrons
A line of high-energy beam of protons is created using a cyclotron, shown in Figure 1. Deuterons and helium atoms may also be used, however, with the current cyclotrons can create a beam of proton with energy as high as 50.5MeV (Risler, Emery, & Laramore); in practice, a beam of 26MeV protons is used (Goodhead, Berry, Bance, & Gray, 1978).

Figure 1: A cyclotron a device that rotates and accelerates a particle by changing the gradient of the magnetic field, thus making the particle speed up spirally. Image taken from (Gagnon)

This beam is then passed through an iron conical flattening filter, towards a thick beryllium target of thickness 3.8cm (Bewley, Meulders, Octave-Prignot, & Page, 1980) using very high magnetic field gradient. The beryllium-proton reaction creates a scattering of fast neutrons that are then collimated by a parallel-sided aperture. This system is known as MLC. The filter and the aperture is shown in the figure below.

Figure 2: The icon conical flattening filter used to bring the proton beam to the beryllium sample and the parallel-sided aperture used to collect the neutrons. Image is courtesy of (Kiger, Sakamoto, & Harling)

The collimated neutrons have a typical energy of 20MeV (Goodhead, Berry, Bance, & Gray, 1978) and can then be used in the therapy. The diagram below shows an MLC system along with its masking complementary component.

Figure 3: The drawing of an MLC system showing (with the filter and the aperture located inside it) is shown on the left. The University of Washington Clinical Neutron Therapy System (CNTS) is shown on the right.

2.2. Neutron bombardment

The MLC is assembled on top of a gantry to allow a 360 rotation about the patient. The pneumatically controlled wedges shown in Figure 3 are used to shape the beam of the neutron leaving the head. The collimator discussed from

the previous section, is typically a multi-leaf collimator with 40 both steel and plastic leaves (shown on Figure 3 on the right) used to for the conformal shaping of the treatment field (Risler, Emery, & Laramore). In other words, the parallel beam of neutron passes through the field-shaping device (shown on the right) to create the required shape. On the image above, for example, the final field would be a distorted trapezoid. The resolution of the system is therefore dependent on the number of leaves used on the masking.

Figure 4: A tumor cell targeted by the CNTS system. Note the high resolution of isolating the tumorous cell from the skin around. Image is courtesy of University of Washington.

The head of the system would be as far as 150cm from the targeted cells, although it can also be closer as well (Risler, Emery, & Laramore). The figure below shows a typical gantry assembled neutron therapy system. As a safety measure, the treatment room is isolated with a 240cm thick concrete wall that can effectively block 99% of the particle beams (Risler, Emery, & Laramore).

Figure 5: The gantry system holding the MLC

2.3. Neutron treatment and the dosage amount

RT works by bombarding the targeted cell with the radiation of interest (such as X-ray, proton, or neutron). Upon impact, these particles ionize the cells, and cause a flow of electrons in a straight line. These charged particles (i.e. electrons) then pass through the DNA of the tumor and cause DNA breakdown. Figure 6 shows the procedure. X-ray therapy has energy of about 25MeV (Johns & Cunningham, 1978), and therefore usually produces Compton interaction upon falling on human tissue. This interaction then produces relatively high-energy secondary electrons with energy deposit of 1 KeV/m (low-LET) (Johns & Cunningham, 1978). In contract, the neutrons produces charged particles with energy deposit as high as 80 KeV/m (high-LET) (Johns & Cunningham, 1978). Due to its low rate of energy deposit, the electrons from the X-ray therapy typically only ionize a few cells, and only do single-stranded DNA helix damage. Cells can readily repair this DNA breakdown and so the damage is minimal. In contrast, the neutrons produce high-LET electrons that can effectively perform double-stranded DNA damage i.e. completely destroy the DNA beyond repair.

These targeted cells are therefore typically killed. Figure below shows the DNA breakdown in action.

Figure 6:FNT vs X-ray or proton therapy. The FNT produces high-LET electrons capable of performing double- stranded DNA damage while the X-ray therapy only does single-stranded DNA damage.

To compare two different therapy methods, relative biological effect (RBE) is implemented. RBE is defined as the dosage of two therapy methods to obtain the same biological effect. The table below summarizes this ratio (using the X-ray as the basis).

Figure 7: The comparison of X-ray, neutron and proton therapy. The table is courtesy of (Jones, 2008).

We can see that NFT is about 3 times more effective than X-ray, meaning that you require one third of the dosage of X-ray to achieve the same effect. This correlation is a direct result of the property of high-LET property of the neutron. The diagram below shows this correlation.

Figure 8: The correlation of LET and the RBE. The higher the LET generally represents a higher RBE value.

Radiation therapy is generally drastically enhanced in the presence of oxygen. Unfortunately, the tumor/cancerous cells generally have lower oxygen concentration an effect commonly known as tumor hypoxia. Under all other types of therapy then, oxygen is injected into the area to increase the effect of the therapy. FNT however, is known to overcome the tumor hypoxia, thus simplifying the task considerably. The table above also compares the oxygen modification factor (the higher the number, the more the treatment is dependent on the oxygen level). Once again, FNT is shown to have the lowest factor.

3. Comparison of neutron vs. other radiation therapies

3.1. Advantages of FNT
As discussed in the previous sections, the FNTs main advantage is its ability to perform a double-stranded DNA damage, thus they are more effective per unit dose than other RT (such as X-ray) (Lennox). Thus, the cell survival curves for neutron treatment is nearly exponential. The oxygen effect, or tumor hypoxia is also much smaller for the NFT. The cell is also far less dependent to the growth stage under the NFT treatment. Thus, patients with very large tumors, slow-growing tumors, large hypoxia tumors, and tumors resistant to low-LET, should use NFT. Some tumors are labeled radio-resistant (including some types of cancer such as leiomyosarcoma). NFT however, is known to be able to penetrate such cells and still break down their DNA and destroy them. Thus FNT is a local control treatment, meaning the tumor is completely destroyed and does not grow back in the future.

3.2. Disadvantages of FNT

Due to its high-LET, FNT can cause severe damage to the area around the tumor cells. Thus, the larger the tumor is, the larger the dosage is required, and this inevitably results in a larger damage done to the normal tissues. There are also late-effects (up to 18 months after the treatment completion) and they include vascular changes, scarring, irradiated skin and organs, radiation injury to brain and more all of these effects are irreversible (Cohen & Awschalom, 1982).

For cells that are curable by alternative RT methods, it is preferable to not use NFT since the NFT can cause more damage to normal tissues. Some (Jones, 2008) also believe that NFT is only good for very superficial, slow-growing cancers with very little tissue coverage. Other studies have found a 71% survival rate for patients with various different cancers and tumors who all went under NFT treatment (Schartz, Einck, Bellon, & Laramore, 2001). Schartz et al. conclude that FNT is effective for soft tissues cartilaginous sarcomas.

Figure 9: A salivary gland tumor treated with NFT. Picture courtesy of (Lennox).

4. Conclusion
As a result of the high linear energy transport of the neutron beam, the therapy has shown to be superior to other radiation therapy methods for treating very large tumors, especially those who are radio-resistant and/or the tumor cells in areas with low oxygen concentration. NFT has a higher BFE (as high as three times X-ray) - one can achieve the same biological effect with a lower dosage. This can lower the time of treatment as well as the number of dosages applied. The treatment has shown to have a success rate of 71% for the patients that had otherwise no treatment. There have been cases of the treatment to cause irreversible side effects; there is still more research required to understand the entire biological response for such rare cases.

 Bibliography
Bewley, D. K., Meulders, J. P., Octave-Prignot, M., & Page, B. C. (1980). Neutron beams from protons on beryllium. IOP Science , 887-892. Cohen, L., & Awschalom, M. (1982). Fast Neutron Radiation Therapy. Annual Review , 359-90. Gagnon, S. (n.d.). Cyclotron. Retrieved November 26, 2011, from Jefferson Lab: http://education.jlab.org/glossary/cyclotron.html Goodhead, D. T., Berry, R. J., Bance, D. A., & Gray, P. (1978). Fast Neutron Therapy Beam Produced by 26MeV Protons on Beryllium. IOP Science , 144-148. Johns, L. E., & Cunningham, J. R. (1978). The Physics of Radiology. Springfield: Charles C Thomas. Jones, B. (2008, January 17). The neutron-therapy saga: a cautionary tale. Retrieved November 25, 2010, from Medical Physics Web: http://medicalphysicsweb.org/cws/article/opinion/32466 Kiger, W. S., Sakamoto, S., & Harling, O. K. Effects on neutron collimation, beam size, and spectrum on in-phantom performance of realistic epithermal neutron beams on BNCT. In F. Hawthorne, Frontiers in neutron capture therapy. Boston. Lennox, A. J. High-energy neutron therapy for radioresistance cancers. Northern Illinois University Institute for Neutron Therapy at Fermilab. Batavia: Fermi National Accelerator Laboratory. Risler, R., Emery, R., & Laramore, G. R. Routine Operation of the University of Washington Fast Neutron Therapy Facility and Plan for Improvements. Washington: University of Washington. Schartz, D. L., Einck, J., Bellon, J., & Laramore, G. E. (2001). Fast neutron radiotherapy for soft tissue and cartilaginous sarcomas at high risk for local recurrence. Elsevier , 449-456.