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Effect of External Magnetic Fields on Biological Effectiveness of Proton Beams
Journal Pre-proof Effect of external magnetic fields on biological effectiveness of proton beams Taku Inaniwa, PhD, Masao Suzuki, PhD, Shinji Sato, BS, Masayuki Muramatsu, PhD, Akira Noda, PhD, Yoshiyuki Iwata, PhD, Nobuyuki Kanematsu, PhD, Toshiyuki Shirai, PhD, Koji Noda, PhD PII:
S0360-3016(19)33964-1
DOI:
https://doi.org/10.1016/j.ijrobp.2019.10.040
Reference:
ROB 26018
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 25 June 2019 Revised Date:
25 September 2019
Accepted Date: 23 October 2019
Please cite this article as: Inaniwa T, Suzuki M, Sato S, Muramatsu M, Noda A, Iwata Y, Kanematsu N, Shirai T, Noda K, Effect of external magnetic fields on biological effectiveness of proton beams, International Journal of Radiation Oncology • Biology • Physics (2019), doi: https://doi.org/10.1016/ j.ijrobp.2019.10.040. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Effect of external magnetic fields on biological effectiveness of proton beams Taku Inaniwa, PhD1*, Masao Suzuki, PhD2, Shinji Sato, BS1, Masayuki Muramatsu, PhD1, Akira Noda, PhD1, Yoshiyuki Iwata, PhD1, Nobuyuki Kanematsu, PhD1, Toshiyuki Shirai, PhD1, and Koji Noda, PhD3
1
Department of Accelerator and Medical Physics, National Institute of Radiological Sciences, QST,
Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan 2
Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological
Sciences, QST, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan 3
QST, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
Short running title: Magnetic effects on biological effectiveness
*Corresponding author and author responsible for statistical analyses: Dr. Taku Inaniwa Department of Accelerator and Medical Physics, National Institute of Radiological Sciences, QST, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan
Tel: +81-43-251-3170 Fax: +81-43-251-1840 E-mail: [email protected]
Funding: This work was partially supported by a Grant-in Aid for Scientific Research [No. 17K09074] from the Japan Society for Promotion of Science (JSPS).
Disclosures
Dr. Inaniwa reports grants from the Japan Society for Promotion of Science (JSPS), during the conduct of the study; personal fees from TOSHIBA Corporation, personal fees from Mitsubishi Electric Corporation, personal fees from Elekta, Inc., personal fees from Osaka Heavy Ion Therapy Center, outside the submitted work; In addition, Dr. Inaniwa has a patent Magneto Particle Therapy issued.
Mr. Sato reports personal fees from TOSHIBA Corporation, personal fees from Mitsubishi Electric Corporation, personal fees from Elekta Inc., personal fees from Hitachi Corporation, outside the submitted work.
Dr. Iwata reports personal fees from Mitsubishi Electric Corporation, personal fees from Toshiba Corporation, personal fees from Sumitomo Heavy Industries, Ltd., outside the submitted work; In addition, Dr. Iwata has a patent Magneto Particle Therapy issued.
Dr. Kanematsu reports personal fees from Osaka Heavy Ion Therapy Center, personal fees from Elekta Inc., personal fees from Mitsubishi Electric Corporation, personal fees from Toshiba Corporation, outside the submitted work.
Dr. Shirai reports personal fees from Elekta, Inc., personal fees from Mitsubishi Electric Corporation, personal fees from TOSHIBA Corporation, outside the submitted work.
Dr. Noda has a patent Magneto Particle Therapy issued.
Acknowledgments: The authors thank Drs. S. Hojo and T. Wakui of the cyclotron operation section of NIRS, QST for their support in performing experiments.
Effect of external magnetic fields on biological effectiveness of proton beams
1
ABSTRACT
Background and Purpose
The purpose is to verify experimentally whether application of magnetic fields longitudinal and
perpendicular to a proton beam alters the biological effectiveness of the radiation.
Methods and Materials
Proton beams with linear energy transfer (LET) of 1.1 and 3.3 keV/µm were irradiated onto human
cancer and normal cells under the longitudinal (perpendicular) magnetic field of BL (BP) = 0, 0.3, or 0.6 T. Cell survival curves were constructed to evaluate the effects of the magnetic fields on the
biological effectiveness. The ratio of dose that would result in a survival fraction of 10% without the
magnetic field Dwo to the dose with the magnetic field Dw, R10 = Dwo / Dw, was determined for each cell line and magnetic field.
Results
For cancer cells exposed to the 1.1- (3.3-) keV/µm proton beams, R10s were increased to 1.10±0.07 (1.11±0.07) and 1.11±0.07 (1.12±0.07) by the longitudinal magnetic fields of BL = 0.3 and 0.6 T, respectively. For normal cells, R10s were increased to 1.13±0.06 (1.17±0.06) and 1.17±0.06 (1.30±0.06) by the BLs. In contrast, R10s were not changed significantly from 1 by the perpendicular magnetic fields of BP = 0.3 and 0.6 T for both cancer and normal cells exposed to 1.1- and 3.3-keV/µm proton beams.
2
Conclusions
The biological effectiveness of proton beams was significantly enhanced by the longitudinal
magnetic fields of BL = 0.3 and 0.6 T, while the biological effectiveness was not altered by the perpendicular magnetic fields of the same strengths. This enhancement effect should be taken into
account in MRI guided proton therapy with a longitudinal magnetic field.
3
1. INTRODUCTION
The good soft-tissue contrast of MRI is useful in radiotherapy to monitor the anatomical
changes in real time. In fact, MRI guidance has been successfully used in x-ray therapy (MRXT) as
a means to increase the targeting accuracy of radiation beams (1). Due to the dose distribution with
steep gradients, the targeting accuracy of charged-particle therapy will benefit even more from MRI
guidance than for x-ray therapy. When the MRI guidance is combined with charged-particle therapy
(MRPT), the trajectory of charged particles is deflected by the MRI magnetic fields. A number of
studies has investigated the influence of the MRI magnetic field on patient dose distribution using
computer simulations (2, 3, 4, 5, 6, 7). Recently, the technical feasibility of MRPT has been
experimentally verified by integrating a C-shaped MR scanner with a 0.22-T perpendicular magnetic
field into a proton research beam line (8). The influence of magnetic fields on biological
effectiveness of charged-particle beams has also been studied by several authors. Nagle et al. (9)
investigated the effects of the magnetic field perpendicular to proton beams on cell survival, and
concluded that the perpendicular magnetic field had no influence on cell-inactivation efficiency of
proton beams. Takatsuji et al. (10) reported that the frequency of chromosome aberrations was
increased by the application of magnetic fields longitudinal to proton and helium-ion beams. −−− et
al (11, 12) investigated the effects of the magnetic fields both perpendicular and longitudinal to
carbon-ion beams on cell survival using human cancer and normal cell lines. They reported that the
4
cell-inactivation efficiency of carbon-ion beams was significantly increased by the longitudinal
magnetic fields, while the efficiency was unchanged by the perpendicular magnetic fields. The most
commonly used ion species in charged particle-therapy has been protons rather than carbon ions. In
addition, the magnetic field direction considered for MRPT has been both longitudinal and
perpendicular to the treatment beams (5, 6). It is thus beneficial to investigate the effects of the
longitudinal as well as the perpendicular magnetic fields on biological effectiveness of proton
beams.
In this study, proton beams with a low and a high linear energy transfer (LET) were irradiated
onto human cancer and normal cell lines under longitudinal and perpendicular magnetic fields. The
effects of external magnetic fields on biological effectiveness of proton beams were evaluated by
cell survival. Experimental conditions except for the ion species, e.g., cell lines, magnetic field
strengths, and dose monitor calibration, were the same as those used by −−− et al (11, 12) for
carbon-ion beams.
2. MATERIALS AND METHODS
2.1 Beam Irradiation Devices
All experiments were performed in the C8 research beam line of the cyclotron facility at −−−−
5
(13), where all instruments indispensable for broad beam delivery are installed including a scatterer,
wobbler magnets, and a dose monitor. Figure 1 shows the experimental setup. Either a solenoid
magnet with a 10.5-cm-diameter and a 16.8-cm-length bore (11) or a dipole magnet with
25-cm-diameter iron poles and an 8.3-cm gap distance (12) was set at the isocenter to produce
homogeneous magnetic fields longitudinal and perpendicular to the proton beams, respectively. The
magnetic field strengths of the solenoid and the dipole magnets, BL and BP, at the isocenter could be controlled by the electromagnet current up to 0.6 T and 0.67 T, respectively. The field homogeneity
over a central circular area of 3.5 cm in diameter was ≤ 0.2% for any BLs and BPs. A Markus ion chamber (Type 23343, PTW, Freiburg, Germany), a radiochromic film (Gafchromic EBT3, Ashland,
Wayne, NJ), and a plastic culture dish of 3.5 cm in diameter (Falcon 353001 Cell Culture Dish,
Corning Inc., Corning, NY) were set up on the isocenter at right angle to the beam direction by
attaching them to flat polymethyl methacrylate (PMMA) holders for both magnets (Figure 1(a)). A
pristine proton beam of 70 MeV was provided by an AVF-930 cyclotron (Sumitomo Heavy
Industries, Ltd., Tokyo, Japan). An 8-cm-diam irradiation field with the dose uniformity of ≤ ±5%
was formed by a 100-µm thick aluminum scatterer and wobbler magnets. The dose uniformity over
the central circular region of 3.5 cm in diameter was ≤ ±2%. The dose-averaged LET of the beam at
the surface of the cell sample was 1.1 keV/µm, while it was increased to 3.3 keV/µm by putting a
PMMA block of 30.5 mm in thickness in front of the dish. These LET values were determined by a
6
Geant4-based Monte Carlo simulation (14) of a 70-MeV proton beam impinging on a PMMA
phantom at the corresponding residual ranges of 33.1 and 2.6 mm in PMMA, respectively.
The applied dose was controlled with a dose monitor, which was calibrated against the
calibrated Markus ion chamber in the absence of the magnetic fields for each LET beam. The dose
deviation between the prescribed and delivered doses measured with the Markus ionization chamber
was 0.3% in standard deviation for both LET beams. The proton beam rotates around the central axis
(CAX) under the longitudinal magnetic fields, and it deflects horizontally under the perpendicular
magnetic fields. However, the macroscopic dose within uniform radiation field is unaffected by the
uniform magnetic fields (detailed discussions in section 4). The dose delivered to the cells under BL and BP of ≤ 0.6T should thus be controlled to an accuracy of 0.3% throughout the experiments. To confirm the adequate field formation and to confirm the cell culture dish was correctly placed at the
center of the radiation fields, a radiochromic film was exposed to the low- and high-LET beams
under BL and BP of 0, 0.3, and 0.6 T prior to cell irradiation experiments. Two days after the irradiation, the optical density distribution of the radiochromic films was measured by a flat-bed
scanner (ES-10000G, Seiko Epson Corp., Nagano, Japan). The dose distribution of the proton field
was determined from the film optical density based on the calibration procedures described by Yonai
et al. (15) for each LET beam. The film irradiation experiment was repeated on every experimental
day for each LET beam for each magnetic field condition. Dose rates were ∼5 Gy/min and ∼9
7
Gy/min for the 1.1- and 3.3-keV/µm beams, respectively.
2.2 Cell irradiation
Human cancer and normal cells with different origins were utilized in this study. For cancer
cells, human undifferentiated carcinoma cells from the mouth floor purchased from the JCRB Cell
Bank in the National Institutes of Biomedical Innovation, Health and Nutrition (Cell name,
HSGc-C5; Cell No., JCRB1070) were used. For normal cells, normal human skin fibroblasts
purchased from the RIKEN BioResource Center Cell Bank (Cell name, NB1RGB; Cell No.,
RCB0222) were used. The cell culturing methods were the same as those used by −−− et al (11, 12).
The cells were cultured in the 3.5-cm diameter plastic culture dish containing 2ml Eagle’s minimum
essential medium (MEM) 2 days before the irradiation. The MEM was removed 30 min before the
irradiation.
For cell irradiations under the longitudinal magnetic fields, the culture dish was set at the
isocenter within the bore of the solenoid magnet facing the beam by bottom side. For cell
irradiations under the perpendicular magnetic field, the culture dish was also set at the isocenter
within the gap of the dipole magnet facing the beam by bottom side, but was intendedly shifted in
the horizontal direction up to 9.8 mm depending on the applied magnetic field strength to make up
for the magnetical beam deflection. The cells on the dish were then exposed to the 1.1- and
8
3.3-keV/µm proton beams under the magnetic fields BL and BP of 0, 0.3, or 0.6 T. To measure the radiation dose-response curves for the cells, delivered dose levels were varied from 1 to 7 Gy for
each condition. A clonogenic cell survival was detected with a colony-forming assay as a
reproductive cell death. Survival of cells unirradiated by proton beams was also measured after a
2-min application of BL and BP of each strength, and was used for control. The temperature within the bore (gap) of the solenoid (dipole) magnet was monitored by a thermometer, and was kept at
22.5 ± 2.0 ℃ throughout the experiments. Within 30 min after the irradiations, the graded numbers of
the single cells dispersed by trypsin were inoculated in triplicate onto plastic culture dishes in order
to form 60-70 colonies per dish. After a 14-day incubation, the colonies were fixed and stained by
the solution containing 20% methanol and 0.2% crystal violet. Any colony organized into more than
50 cells was detected as a survivor.
A complete set of the cell irradiation experiments was repeated three times on different days. To
examine effects of the magnetic fields on cell viability, plating efficiencies of the unirradiated cells
in the absence of the magnetic fields were compared with the efficiencies in the presence of the
magnetic fields of different BL and BP values. To examine effects of the magnetic fields on cell-inactivation efficiency of the proton beams, dose-response curves were constructed for all
independent cell irradiation experiments. Dose-response curves were fitted by a linear quadratic
(LQ) model. The ratio of dose that would result in a survival fraction of 10% without the magnetic
9
field Dwo to the dose with the magnetic field Dw, R10=Dwo/Dw, was determined for each cell line and magnetic field for each set of the experiments. For the uncertainty of R10, the uncertainty of surviving rate (given by statistical error of surviving colonies), the uncertainty of the dose delivered
to the cells (estimated to be 0.3%), and the fitting uncertainty by the LQ model were considered. The
assumption of R10=1 was tested to investigate whether the external magnetic fields alter the biological effectiveness of the proton beams. p < 0.05 was considered statistically significant.
3
RESULTS
3.1 Cell viability
The plating efficiencies of the unirradiated HSGc-C5 and NB1RGB cells in the presence of the
longitudinal magnetic fields of BL = 0.3 and 0.6 T were within the range between 77 and 86% and between 29 and 47%, respectively, and had no statistically-significant difference with the efficiencies
in the absence of the magnetic field (p>0.30 and p>0.43 for the cells, respectively). Similarly, the
plating efficiencies of the unirradiated cells in the presence of the perpendicular magnetic field of BP = 0.3 and 0.6 T were within the range between 82 and 89% and between 33 and 41%, respectively,
and had no statistically-significant difference with the efficiencies in the absence of the magnetic
field (p>0.67 and p>0.37 for the cells, respectively). Neither longitudinal nor perpendicular magnetic
10
fields of ≤ 0.6 T affected the viability of these cell lines.
3.2 Effect of longitudinal magnetic field on cell-inactivation efficiency of proton beams
Figures 2 and 3 show the dose-response curves of HSGc-C5 and NB1RGB cells under the
longitudinal magnetic fields. The R10 values determined from the dose-response curves for each set of experiments are shown in Table 1. The LQ parameters determined for the dose-response curves of
HSGc-C5 and NB1RGB cells are shown in table S1 and S2, respectively. In HSGc-C5 cells, R10s were 1.10 and 1.11 for BL = 0.3 T for 1.1- and 3.3-keV/µm beams, respectively. However, no further increase in R10 was observed for BL = 0.6 T. In NB1RGB cells, R10s were 1.13 and 1.17 for BL = 0.3 T for 1.1- and 3.3-keV/µm beams, respectively. R10s were further increased for the higher magnetic field of BL = 0.6 T up to 1.17 and 1.30 for the 1.1- and 3.3-keV/µm beams, respectively.
3.3 Effect of perpendicular magnetic field on cell-inactivation efficiency of proton beams
Figures 4 and 5 show the dose-response curves for HSGc-C5 and NB1RGB cells under the
perpendicular magnetic fields. The R10 values determined from the dose-response curves for each set of experiments are shown in Table 1. The LQ parameters determined for the dose-response curves of
HSGc-C5 and NB1RGB cells are shown in table S3 and S4, respectively. For HSGc-C5 cells
exposed to a 1.1-keV/µm proton beam, the mean R10 value was 2-3% lower than 1. However, there
11
was no significant change in R10 values from 1 (p >> 0.05) for both HSGc-C5 and NB1RGB cells irradiated by 1.1- and 3.3-keV/µm proton beams under the perpendicular magnetic field of BP ≤ 0.6 T.
4
DISCUSSION
The 70-MeV proton beam under the perpendicular magnetic fields of BP ≤ 0.6 T deflected in the horizontal direction up to 9.8 mm. The dose variation due to the deflection was compensated for
by intendedly shifting the cell culture dish in the horizontal direction according to the applied
magnetic field strength. In contrast, the proton beam under the longitudinal magnetic field of BL ≤ 0.6 T rotated around the CAX up to 1.3º. The dose increase within the central circular region of 3.5
cm in diameter due to the focusing effect of the proton beam under the solenoid magnetic field was
at most 0.07%. For 70-MeV protons, the local dose increase by the electron return effect would be
small even for BP = 0.6 T (16). Taken together, the effect of the magnetic fields on dose delivered to the cells was insignificant regardless of BL and BP throughout the experiments. A significant increase in R10 from 1, i.e., a significant enhancement in cell-inactivation efficiency of proton beams, was observed for NB1RGB cells under the longitudinal magnetic field
of BL = 0.3 and 0.6 T. An increase (not significant) in R10 from 1 was observed also for HSGc-C5
12
cells under the longitudinal magnetic fields. For instance, R10s were 1.12 and 1.30 for HSGc-C5 and NB1RGB cells, respectively, for 3.3-keV/µm proton beams with BL = 0.6 T. No significant change in R10 from 1 was observed under the perpendicular magnetic field of BP = 0.3 and 0.6 T. These results were consistent with the previous studies for proton beams. Takatsuji et al. (10) observed ∼15% increase in yield of chromosome aberrations for human peripheral blood lymphocytes exposed to a
4.9-MeV proton beam of 2.0 Gy dose by applying a longitudinal magnetic field of 1.1 T. Nugle et al.
(9) reported that important biological outcomes, e.g., survival and DNA damage repair, following a
130-MeV proton-beam irradiation were not differently affected by the application of a perpendicular
magnetic field of 1.01 T. The results of this study are also consistent with previous studies for
carbon-ion beams (11, 12). For carbon-ion beams with a LET of 50 keV/µm, R10s significantly increased to 1.29 and 1.36 for HSGc-C5 and NB1RGB cells, respectively, for BL = 0.6 T (11), while they were 0.99 and 1.00 for the cell lines for BP = 0.6 T (12). One of the most straightforward hypotheses for the mechanisms by which the enhancement in cell-inactivation efficiency of proton
beams occurs was the modification of the radiation track structure by the intense longitudinal
magnetic fields via Lorentz force. However, an in-silico study has invalidated the hypothesis as the
external magnetic fields of several tesla do not modify the radiation track structure significantly (17).
Mohajer et al. (18) provided other hypotheses for the mechanisms: (i) one or more steps in the DNA
damage response are modified by the magnetic field; (ii) the yield or lifetime of intercellular reactive
13
oxygen species responsible for indirect DNA damage are influenced by the magnetic field; and (iii)
the intercellular signaling stimulating the non-targeted radiation-induced effects are affected by the
magnetic field. However, these hypotheses are all unlikely as a responsible mechanism, since they
should be independent on the magnetic field direction with respect to the radiation. The observed
enhancement in cell-inactivation efficiency of the proton beams are likely to be due to some physical
kinematics of electrons, recoiled ions, or reactive oxygen species caused by the external magnetic
field. The mechanisms for the observed results are still incompletely understood and require further
investigation.
For x rays, the influence of the perpendicular magnetic fields on cell survival has been
investigated by several authors for various cell lines and magnetic field strengths (19, 20, 21). All
these studies concluded that cell survival levels following x-ray irradiation were unaffected by the
perpendicular magnetic fields. These results have promoted the clinical application of MR-guided
x-ray therapy. To the best knowledge of the present authors, this is the first report investigating the
effects of the longitudinal as well as the perpendicular magnetic fields on cell inactivation efficiency
of proton beams. The results herein suggest that these effects should be taken into account in MRPT
with a longitudinal magnetic field.
The increase in cell-inactivation efficiency of proton beams by the longitudinal magnetic field
possibly be used to increase the tumor control probability. However, at the same time, it might
14
increase the toxicity in critical organs.
5
CONCLUSION
Cell-inactivation efficiency of proton beams were significantly enhanced by applying the
longitudinal magnetic fields of BL = 0.3 and 0.6 T, while there was no significant change in cell-inactivation efficiency by the perpendicular magnetic fields of the same strength. The
mechanisms underlying the observed results are still incompletely understood. However, this
enhancement effect should be taken into account in MRPT with a longitudinal magnetic field.
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characterization of gafchromic EBT3 and EBT-XD films for clinical carbon ion beams. Radiat.
Protec. Dosim. 2018; 180: 314-8.
16. Lühr A, Burigo L N, Gantz S, Schellhammer S M, Hoffmann A L. Proton beam electron return
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17. Bug M U, Gargioni E, Guatelli S, Incerti S, Rabus H, Schulte R, Rosenfeld A B. Effect of a
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in the presence of a uniform 20-kilogauss magnetic field. Int. J. Radiat. Biol. 1980; 38: 285-92.
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18
Figure Legends
Figure 1. (a) Schematic drawing of the experimental setup in the C8 research beam line and
photographs with (b) the solenoid and (c) the dipole magnets. A proton beam was delivered in the
z-axis direction. The cell dish and dosimeters were set at the isocenter (z=0) within the bore of the
solenoid magnet or within the gap of the dipole magnet perpendicularly to the beam direction. All
dimensions are given in mm.
Figure 2. Dose-response curves of the HSGc-C5 cells irradiated by (a) 1.1- and (b) 3.3-keV/µm
proton beams for BL of 0 (black), 0.3 (red), and 0.6 T (green). Symbols and curves are the measured and LQ-model-fitted survival fractions, respectively.
Figure 3. Dose-response curves of the NB1RGB cells irradiated by (a) 1.1- and (b) 3.3-keV/µm
proton beams for BL of 0 (black), 0.3 (red), and 0.6 T (green). Symbols and curves are the measured and LQ-model-fitted survival fractions, respectively.
Figure 4. Dose-response curves of the HSGc-C5 cells irradiated by (a) 1.1- and (b) 3.3-keV/µm
proton beams for BP of 0 (black), 0.3 (red), and 0.6 T (green). Symbols and curves are the measured and LQ-model-fitted survival fractions, respectively. In both figures, the curves for three
19
magnetic-field strengths overlapped each other.
Figure 5. Dose-response curves of the NB1RGB cells irradiated by (a) 1.1- and (b) 3.3-keV/µm
proton beams for BP of 0 (black), 0.3 (red), and 0.6 T (green). Symbols and curves are the measured and LQ-model-fitted survival fractions, respectively. In both figures, the curves for three
magnetic-field strengths overlapped each other.
20
Table 1. The R10 values for HSGc-C5 and NB1RGB cells irradiated by the 1.1- and 3.3-keV/µm proton beams under the longitudinal and perpendicular magnetic fields, BL and BP, of 0.3 and 0.6 T. Values in brackets are the p values of the t-test for R10=1. Magnetic field
R10 HSGc-C5
BL = 0.3 T
BL = 0.6 T
BP = 0.3 T
BP = 0.6 T
NB1RGB
1.1-keV/µm
3.3-keV/µm
1.1-keV/µm
3.3-keV/µm
1.10±0.07
1.11±0.07
1.13±0.06
1.17±0.06
(0.101)
(0.084)
(0.010)
(0.002)
1.11±0.07
1.12±0.07
1.17±0.06
1.30±0.06
(0.077)
(0.054)
(0.001)
(< 0.001)
0.97±0.08
0.99±0.07
0.99±0.05
1.00±0.05
(0.376)
(0.446)
(0.421)
(0.489)
0.98±0.08
0.99±0.07
0.99±0.05
1.00±0.05
(0.399)
(0.471)
(0.408)
(0.473)
S0360-3016(19)33964-1
DOI:
https://doi.org/10.1016/j.ijrobp.2019.10.040
Reference:
ROB 26018
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 25 June 2019 Revised Date:
25 September 2019
Accepted Date: 23 October 2019
Please cite this article as: Inaniwa T, Suzuki M, Sato S, Muramatsu M, Noda A, Iwata Y, Kanematsu N, Shirai T, Noda K, Effect of external magnetic fields on biological effectiveness of proton beams, International Journal of Radiation Oncology • Biology • Physics (2019), doi: https://doi.org/10.1016/ j.ijrobp.2019.10.040. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Effect of external magnetic fields on biological effectiveness of proton beams Taku Inaniwa, PhD1*, Masao Suzuki, PhD2, Shinji Sato, BS1, Masayuki Muramatsu, PhD1, Akira Noda, PhD1, Yoshiyuki Iwata, PhD1, Nobuyuki Kanematsu, PhD1, Toshiyuki Shirai, PhD1, and Koji Noda, PhD3
1
Department of Accelerator and Medical Physics, National Institute of Radiological Sciences, QST,
Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan 2
Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological
Sciences, QST, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan 3
QST, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
Short running title: Magnetic effects on biological effectiveness
*Corresponding author and author responsible for statistical analyses: Dr. Taku Inaniwa Department of Accelerator and Medical Physics, National Institute of Radiological Sciences, QST, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan
Tel: +81-43-251-3170 Fax: +81-43-251-1840 E-mail: [email protected]
Funding: This work was partially supported by a Grant-in Aid for Scientific Research [No. 17K09074] from the Japan Society for Promotion of Science (JSPS).
Disclosures
Dr. Inaniwa reports grants from the Japan Society for Promotion of Science (JSPS), during the conduct of the study; personal fees from TOSHIBA Corporation, personal fees from Mitsubishi Electric Corporation, personal fees from Elekta, Inc., personal fees from Osaka Heavy Ion Therapy Center, outside the submitted work; In addition, Dr. Inaniwa has a patent Magneto Particle Therapy issued.
Mr. Sato reports personal fees from TOSHIBA Corporation, personal fees from Mitsubishi Electric Corporation, personal fees from Elekta Inc., personal fees from Hitachi Corporation, outside the submitted work.
Dr. Iwata reports personal fees from Mitsubishi Electric Corporation, personal fees from Toshiba Corporation, personal fees from Sumitomo Heavy Industries, Ltd., outside the submitted work; In addition, Dr. Iwata has a patent Magneto Particle Therapy issued.
Dr. Kanematsu reports personal fees from Osaka Heavy Ion Therapy Center, personal fees from Elekta Inc., personal fees from Mitsubishi Electric Corporation, personal fees from Toshiba Corporation, outside the submitted work.
Dr. Shirai reports personal fees from Elekta, Inc., personal fees from Mitsubishi Electric Corporation, personal fees from TOSHIBA Corporation, outside the submitted work.
Dr. Noda has a patent Magneto Particle Therapy issued.
Acknowledgments: The authors thank Drs. S. Hojo and T. Wakui of the cyclotron operation section of NIRS, QST for their support in performing experiments.
Effect of external magnetic fields on biological effectiveness of proton beams
1
ABSTRACT
Background and Purpose
The purpose is to verify experimentally whether application of magnetic fields longitudinal and
perpendicular to a proton beam alters the biological effectiveness of the radiation.
Methods and Materials
Proton beams with linear energy transfer (LET) of 1.1 and 3.3 keV/µm were irradiated onto human
cancer and normal cells under the longitudinal (perpendicular) magnetic field of BL (BP) = 0, 0.3, or 0.6 T. Cell survival curves were constructed to evaluate the effects of the magnetic fields on the
biological effectiveness. The ratio of dose that would result in a survival fraction of 10% without the
magnetic field Dwo to the dose with the magnetic field Dw, R10 = Dwo / Dw, was determined for each cell line and magnetic field.
Results
For cancer cells exposed to the 1.1- (3.3-) keV/µm proton beams, R10s were increased to 1.10±0.07 (1.11±0.07) and 1.11±0.07 (1.12±0.07) by the longitudinal magnetic fields of BL = 0.3 and 0.6 T, respectively. For normal cells, R10s were increased to 1.13±0.06 (1.17±0.06) and 1.17±0.06 (1.30±0.06) by the BLs. In contrast, R10s were not changed significantly from 1 by the perpendicular magnetic fields of BP = 0.3 and 0.6 T for both cancer and normal cells exposed to 1.1- and 3.3-keV/µm proton beams.
2
Conclusions
The biological effectiveness of proton beams was significantly enhanced by the longitudinal
magnetic fields of BL = 0.3 and 0.6 T, while the biological effectiveness was not altered by the perpendicular magnetic fields of the same strengths. This enhancement effect should be taken into
account in MRI guided proton therapy with a longitudinal magnetic field.
3
1. INTRODUCTION
The good soft-tissue contrast of MRI is useful in radiotherapy to monitor the anatomical
changes in real time. In fact, MRI guidance has been successfully used in x-ray therapy (MRXT) as
a means to increase the targeting accuracy of radiation beams (1). Due to the dose distribution with
steep gradients, the targeting accuracy of charged-particle therapy will benefit even more from MRI
guidance than for x-ray therapy. When the MRI guidance is combined with charged-particle therapy
(MRPT), the trajectory of charged particles is deflected by the MRI magnetic fields. A number of
studies has investigated the influence of the MRI magnetic field on patient dose distribution using
computer simulations (2, 3, 4, 5, 6, 7). Recently, the technical feasibility of MRPT has been
experimentally verified by integrating a C-shaped MR scanner with a 0.22-T perpendicular magnetic
field into a proton research beam line (8). The influence of magnetic fields on biological
effectiveness of charged-particle beams has also been studied by several authors. Nagle et al. (9)
investigated the effects of the magnetic field perpendicular to proton beams on cell survival, and
concluded that the perpendicular magnetic field had no influence on cell-inactivation efficiency of
proton beams. Takatsuji et al. (10) reported that the frequency of chromosome aberrations was
increased by the application of magnetic fields longitudinal to proton and helium-ion beams. −−− et
al (11, 12) investigated the effects of the magnetic fields both perpendicular and longitudinal to
carbon-ion beams on cell survival using human cancer and normal cell lines. They reported that the
4
cell-inactivation efficiency of carbon-ion beams was significantly increased by the longitudinal
magnetic fields, while the efficiency was unchanged by the perpendicular magnetic fields. The most
commonly used ion species in charged particle-therapy has been protons rather than carbon ions. In
addition, the magnetic field direction considered for MRPT has been both longitudinal and
perpendicular to the treatment beams (5, 6). It is thus beneficial to investigate the effects of the
longitudinal as well as the perpendicular magnetic fields on biological effectiveness of proton
beams.
In this study, proton beams with a low and a high linear energy transfer (LET) were irradiated
onto human cancer and normal cell lines under longitudinal and perpendicular magnetic fields. The
effects of external magnetic fields on biological effectiveness of proton beams were evaluated by
cell survival. Experimental conditions except for the ion species, e.g., cell lines, magnetic field
strengths, and dose monitor calibration, were the same as those used by −−− et al (11, 12) for
carbon-ion beams.
2. MATERIALS AND METHODS
2.1 Beam Irradiation Devices
All experiments were performed in the C8 research beam line of the cyclotron facility at −−−−
5
(13), where all instruments indispensable for broad beam delivery are installed including a scatterer,
wobbler magnets, and a dose monitor. Figure 1 shows the experimental setup. Either a solenoid
magnet with a 10.5-cm-diameter and a 16.8-cm-length bore (11) or a dipole magnet with
25-cm-diameter iron poles and an 8.3-cm gap distance (12) was set at the isocenter to produce
homogeneous magnetic fields longitudinal and perpendicular to the proton beams, respectively. The
magnetic field strengths of the solenoid and the dipole magnets, BL and BP, at the isocenter could be controlled by the electromagnet current up to 0.6 T and 0.67 T, respectively. The field homogeneity
over a central circular area of 3.5 cm in diameter was ≤ 0.2% for any BLs and BPs. A Markus ion chamber (Type 23343, PTW, Freiburg, Germany), a radiochromic film (Gafchromic EBT3, Ashland,
Wayne, NJ), and a plastic culture dish of 3.5 cm in diameter (Falcon 353001 Cell Culture Dish,
Corning Inc., Corning, NY) were set up on the isocenter at right angle to the beam direction by
attaching them to flat polymethyl methacrylate (PMMA) holders for both magnets (Figure 1(a)). A
pristine proton beam of 70 MeV was provided by an AVF-930 cyclotron (Sumitomo Heavy
Industries, Ltd., Tokyo, Japan). An 8-cm-diam irradiation field with the dose uniformity of ≤ ±5%
was formed by a 100-µm thick aluminum scatterer and wobbler magnets. The dose uniformity over
the central circular region of 3.5 cm in diameter was ≤ ±2%. The dose-averaged LET of the beam at
the surface of the cell sample was 1.1 keV/µm, while it was increased to 3.3 keV/µm by putting a
PMMA block of 30.5 mm in thickness in front of the dish. These LET values were determined by a
6
Geant4-based Monte Carlo simulation (14) of a 70-MeV proton beam impinging on a PMMA
phantom at the corresponding residual ranges of 33.1 and 2.6 mm in PMMA, respectively.
The applied dose was controlled with a dose monitor, which was calibrated against the
calibrated Markus ion chamber in the absence of the magnetic fields for each LET beam. The dose
deviation between the prescribed and delivered doses measured with the Markus ionization chamber
was 0.3% in standard deviation for both LET beams. The proton beam rotates around the central axis
(CAX) under the longitudinal magnetic fields, and it deflects horizontally under the perpendicular
magnetic fields. However, the macroscopic dose within uniform radiation field is unaffected by the
uniform magnetic fields (detailed discussions in section 4). The dose delivered to the cells under BL and BP of ≤ 0.6T should thus be controlled to an accuracy of 0.3% throughout the experiments. To confirm the adequate field formation and to confirm the cell culture dish was correctly placed at the
center of the radiation fields, a radiochromic film was exposed to the low- and high-LET beams
under BL and BP of 0, 0.3, and 0.6 T prior to cell irradiation experiments. Two days after the irradiation, the optical density distribution of the radiochromic films was measured by a flat-bed
scanner (ES-10000G, Seiko Epson Corp., Nagano, Japan). The dose distribution of the proton field
was determined from the film optical density based on the calibration procedures described by Yonai
et al. (15) for each LET beam. The film irradiation experiment was repeated on every experimental
day for each LET beam for each magnetic field condition. Dose rates were ∼5 Gy/min and ∼9
7
Gy/min for the 1.1- and 3.3-keV/µm beams, respectively.
2.2 Cell irradiation
Human cancer and normal cells with different origins were utilized in this study. For cancer
cells, human undifferentiated carcinoma cells from the mouth floor purchased from the JCRB Cell
Bank in the National Institutes of Biomedical Innovation, Health and Nutrition (Cell name,
HSGc-C5; Cell No., JCRB1070) were used. For normal cells, normal human skin fibroblasts
purchased from the RIKEN BioResource Center Cell Bank (Cell name, NB1RGB; Cell No.,
RCB0222) were used. The cell culturing methods were the same as those used by −−− et al (11, 12).
The cells were cultured in the 3.5-cm diameter plastic culture dish containing 2ml Eagle’s minimum
essential medium (MEM) 2 days before the irradiation. The MEM was removed 30 min before the
irradiation.
For cell irradiations under the longitudinal magnetic fields, the culture dish was set at the
isocenter within the bore of the solenoid magnet facing the beam by bottom side. For cell
irradiations under the perpendicular magnetic field, the culture dish was also set at the isocenter
within the gap of the dipole magnet facing the beam by bottom side, but was intendedly shifted in
the horizontal direction up to 9.8 mm depending on the applied magnetic field strength to make up
for the magnetical beam deflection. The cells on the dish were then exposed to the 1.1- and
8
3.3-keV/µm proton beams under the magnetic fields BL and BP of 0, 0.3, or 0.6 T. To measure the radiation dose-response curves for the cells, delivered dose levels were varied from 1 to 7 Gy for
each condition. A clonogenic cell survival was detected with a colony-forming assay as a
reproductive cell death. Survival of cells unirradiated by proton beams was also measured after a
2-min application of BL and BP of each strength, and was used for control. The temperature within the bore (gap) of the solenoid (dipole) magnet was monitored by a thermometer, and was kept at
22.5 ± 2.0 ℃ throughout the experiments. Within 30 min after the irradiations, the graded numbers of
the single cells dispersed by trypsin were inoculated in triplicate onto plastic culture dishes in order
to form 60-70 colonies per dish. After a 14-day incubation, the colonies were fixed and stained by
the solution containing 20% methanol and 0.2% crystal violet. Any colony organized into more than
50 cells was detected as a survivor.
A complete set of the cell irradiation experiments was repeated three times on different days. To
examine effects of the magnetic fields on cell viability, plating efficiencies of the unirradiated cells
in the absence of the magnetic fields were compared with the efficiencies in the presence of the
magnetic fields of different BL and BP values. To examine effects of the magnetic fields on cell-inactivation efficiency of the proton beams, dose-response curves were constructed for all
independent cell irradiation experiments. Dose-response curves were fitted by a linear quadratic
(LQ) model. The ratio of dose that would result in a survival fraction of 10% without the magnetic
9
field Dwo to the dose with the magnetic field Dw, R10=Dwo/Dw, was determined for each cell line and magnetic field for each set of the experiments. For the uncertainty of R10, the uncertainty of surviving rate (given by statistical error of surviving colonies), the uncertainty of the dose delivered
to the cells (estimated to be 0.3%), and the fitting uncertainty by the LQ model were considered. The
assumption of R10=1 was tested to investigate whether the external magnetic fields alter the biological effectiveness of the proton beams. p < 0.05 was considered statistically significant.
3
RESULTS
3.1 Cell viability
The plating efficiencies of the unirradiated HSGc-C5 and NB1RGB cells in the presence of the
longitudinal magnetic fields of BL = 0.3 and 0.6 T were within the range between 77 and 86% and between 29 and 47%, respectively, and had no statistically-significant difference with the efficiencies
in the absence of the magnetic field (p>0.30 and p>0.43 for the cells, respectively). Similarly, the
plating efficiencies of the unirradiated cells in the presence of the perpendicular magnetic field of BP = 0.3 and 0.6 T were within the range between 82 and 89% and between 33 and 41%, respectively,
and had no statistically-significant difference with the efficiencies in the absence of the magnetic
field (p>0.67 and p>0.37 for the cells, respectively). Neither longitudinal nor perpendicular magnetic
10
fields of ≤ 0.6 T affected the viability of these cell lines.
3.2 Effect of longitudinal magnetic field on cell-inactivation efficiency of proton beams
Figures 2 and 3 show the dose-response curves of HSGc-C5 and NB1RGB cells under the
longitudinal magnetic fields. The R10 values determined from the dose-response curves for each set of experiments are shown in Table 1. The LQ parameters determined for the dose-response curves of
HSGc-C5 and NB1RGB cells are shown in table S1 and S2, respectively. In HSGc-C5 cells, R10s were 1.10 and 1.11 for BL = 0.3 T for 1.1- and 3.3-keV/µm beams, respectively. However, no further increase in R10 was observed for BL = 0.6 T. In NB1RGB cells, R10s were 1.13 and 1.17 for BL = 0.3 T for 1.1- and 3.3-keV/µm beams, respectively. R10s were further increased for the higher magnetic field of BL = 0.6 T up to 1.17 and 1.30 for the 1.1- and 3.3-keV/µm beams, respectively.
3.3 Effect of perpendicular magnetic field on cell-inactivation efficiency of proton beams
Figures 4 and 5 show the dose-response curves for HSGc-C5 and NB1RGB cells under the
perpendicular magnetic fields. The R10 values determined from the dose-response curves for each set of experiments are shown in Table 1. The LQ parameters determined for the dose-response curves of
HSGc-C5 and NB1RGB cells are shown in table S3 and S4, respectively. For HSGc-C5 cells
exposed to a 1.1-keV/µm proton beam, the mean R10 value was 2-3% lower than 1. However, there
11
was no significant change in R10 values from 1 (p >> 0.05) for both HSGc-C5 and NB1RGB cells irradiated by 1.1- and 3.3-keV/µm proton beams under the perpendicular magnetic field of BP ≤ 0.6 T.
4
DISCUSSION
The 70-MeV proton beam under the perpendicular magnetic fields of BP ≤ 0.6 T deflected in the horizontal direction up to 9.8 mm. The dose variation due to the deflection was compensated for
by intendedly shifting the cell culture dish in the horizontal direction according to the applied
magnetic field strength. In contrast, the proton beam under the longitudinal magnetic field of BL ≤ 0.6 T rotated around the CAX up to 1.3º. The dose increase within the central circular region of 3.5
cm in diameter due to the focusing effect of the proton beam under the solenoid magnetic field was
at most 0.07%. For 70-MeV protons, the local dose increase by the electron return effect would be
small even for BP = 0.6 T (16). Taken together, the effect of the magnetic fields on dose delivered to the cells was insignificant regardless of BL and BP throughout the experiments. A significant increase in R10 from 1, i.e., a significant enhancement in cell-inactivation efficiency of proton beams, was observed for NB1RGB cells under the longitudinal magnetic field
of BL = 0.3 and 0.6 T. An increase (not significant) in R10 from 1 was observed also for HSGc-C5
12
cells under the longitudinal magnetic fields. For instance, R10s were 1.12 and 1.30 for HSGc-C5 and NB1RGB cells, respectively, for 3.3-keV/µm proton beams with BL = 0.6 T. No significant change in R10 from 1 was observed under the perpendicular magnetic field of BP = 0.3 and 0.6 T. These results were consistent with the previous studies for proton beams. Takatsuji et al. (10) observed ∼15% increase in yield of chromosome aberrations for human peripheral blood lymphocytes exposed to a
4.9-MeV proton beam of 2.0 Gy dose by applying a longitudinal magnetic field of 1.1 T. Nugle et al.
(9) reported that important biological outcomes, e.g., survival and DNA damage repair, following a
130-MeV proton-beam irradiation were not differently affected by the application of a perpendicular
magnetic field of 1.01 T. The results of this study are also consistent with previous studies for
carbon-ion beams (11, 12). For carbon-ion beams with a LET of 50 keV/µm, R10s significantly increased to 1.29 and 1.36 for HSGc-C5 and NB1RGB cells, respectively, for BL = 0.6 T (11), while they were 0.99 and 1.00 for the cell lines for BP = 0.6 T (12). One of the most straightforward hypotheses for the mechanisms by which the enhancement in cell-inactivation efficiency of proton
beams occurs was the modification of the radiation track structure by the intense longitudinal
magnetic fields via Lorentz force. However, an in-silico study has invalidated the hypothesis as the
external magnetic fields of several tesla do not modify the radiation track structure significantly (17).
Mohajer et al. (18) provided other hypotheses for the mechanisms: (i) one or more steps in the DNA
damage response are modified by the magnetic field; (ii) the yield or lifetime of intercellular reactive
13
oxygen species responsible for indirect DNA damage are influenced by the magnetic field; and (iii)
the intercellular signaling stimulating the non-targeted radiation-induced effects are affected by the
magnetic field. However, these hypotheses are all unlikely as a responsible mechanism, since they
should be independent on the magnetic field direction with respect to the radiation. The observed
enhancement in cell-inactivation efficiency of the proton beams are likely to be due to some physical
kinematics of electrons, recoiled ions, or reactive oxygen species caused by the external magnetic
field. The mechanisms for the observed results are still incompletely understood and require further
investigation.
For x rays, the influence of the perpendicular magnetic fields on cell survival has been
investigated by several authors for various cell lines and magnetic field strengths (19, 20, 21). All
these studies concluded that cell survival levels following x-ray irradiation were unaffected by the
perpendicular magnetic fields. These results have promoted the clinical application of MR-guided
x-ray therapy. To the best knowledge of the present authors, this is the first report investigating the
effects of the longitudinal as well as the perpendicular magnetic fields on cell inactivation efficiency
of proton beams. The results herein suggest that these effects should be taken into account in MRPT
with a longitudinal magnetic field.
The increase in cell-inactivation efficiency of proton beams by the longitudinal magnetic field
possibly be used to increase the tumor control probability. However, at the same time, it might
14
increase the toxicity in critical organs.
5
CONCLUSION
Cell-inactivation efficiency of proton beams were significantly enhanced by applying the
longitudinal magnetic fields of BL = 0.3 and 0.6 T, while there was no significant change in cell-inactivation efficiency by the perpendicular magnetic fields of the same strength. The
mechanisms underlying the observed results are still incompletely understood. However, this
enhancement effect should be taken into account in MRPT with a longitudinal magnetic field.
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18
Figure Legends
Figure 1. (a) Schematic drawing of the experimental setup in the C8 research beam line and
photographs with (b) the solenoid and (c) the dipole magnets. A proton beam was delivered in the
z-axis direction. The cell dish and dosimeters were set at the isocenter (z=0) within the bore of the
solenoid magnet or within the gap of the dipole magnet perpendicularly to the beam direction. All
dimensions are given in mm.
Figure 2. Dose-response curves of the HSGc-C5 cells irradiated by (a) 1.1- and (b) 3.3-keV/µm
proton beams for BL of 0 (black), 0.3 (red), and 0.6 T (green). Symbols and curves are the measured and LQ-model-fitted survival fractions, respectively.
Figure 3. Dose-response curves of the NB1RGB cells irradiated by (a) 1.1- and (b) 3.3-keV/µm
proton beams for BL of 0 (black), 0.3 (red), and 0.6 T (green). Symbols and curves are the measured and LQ-model-fitted survival fractions, respectively.
Figure 4. Dose-response curves of the HSGc-C5 cells irradiated by (a) 1.1- and (b) 3.3-keV/µm
proton beams for BP of 0 (black), 0.3 (red), and 0.6 T (green). Symbols and curves are the measured and LQ-model-fitted survival fractions, respectively. In both figures, the curves for three
19
magnetic-field strengths overlapped each other.
Figure 5. Dose-response curves of the NB1RGB cells irradiated by (a) 1.1- and (b) 3.3-keV/µm
proton beams for BP of 0 (black), 0.3 (red), and 0.6 T (green). Symbols and curves are the measured and LQ-model-fitted survival fractions, respectively. In both figures, the curves for three
magnetic-field strengths overlapped each other.
20
Table 1. The R10 values for HSGc-C5 and NB1RGB cells irradiated by the 1.1- and 3.3-keV/µm proton beams under the longitudinal and perpendicular magnetic fields, BL and BP, of 0.3 and 0.6 T. Values in brackets are the p values of the t-test for R10=1. Magnetic field
R10 HSGc-C5
BL = 0.3 T
BL = 0.6 T
BP = 0.3 T
BP = 0.6 T
NB1RGB
1.1-keV/µm
3.3-keV/µm
1.1-keV/µm
3.3-keV/µm
1.10±0.07
1.11±0.07
1.13±0.06
1.17±0.06
(0.101)
(0.084)
(0.010)
(0.002)
1.11±0.07
1.12±0.07
1.17±0.06
1.30±0.06
(0.077)
(0.054)
(0.001)
(< 0.001)
0.97±0.08
0.99±0.07
0.99±0.05
1.00±0.05
(0.376)
(0.446)
(0.421)
(0.489)
0.98±0.08
0.99±0.07
0.99±0.05
1.00±0.05
(0.399)
(0.471)
(0.408)
(0.473)