Proton Beam Radiotherapy: Physics and Biology

This book offers a comprehensive, practical guide to understanding the physical and biological characteristics of proton beam radiotherapy. The application of proton beams to the treatment of solid cancers has expanded exponentially over the last decade due to their physical properties, which make it possible to administer higher doses of radiation to lesions with only a minimum dose to the surrounding healthy tissues. Accordingly, understanding the basic aspects of proton beam radiotherapy is a primary concern not only for medical physicists and radiation biologists, but also for all physicians involved in cancer treatment using proton beams.

The major aspects discussed include the technique’s development background, the generation and delivery system for proton beams, physical characteristics, biological consequences, dosimetry, and future prospects in both medical physics and radiation biology in terms of effective cancer treatment. Gathering contributions from experts who provide clear and detailed information on the basics of proton beams, the book will greatly benefit not only radiological technicians, medical physicists, and physicians, but also scientists in cancer radiotherapy.

• Language: English
• Publisher: Springer
• Release date: Jan 24, 2020
• ISBN: 9789811374548

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Part IHistory of Proton Radiotherapy and Overview

© Springer Nature Singapore Pte Ltd. 2020

K. Tsuboi et al. (eds.)Proton Beam Radiotherapyhttps://doi.org/10.1007/978-981-13-7454-8_1

Discovery of the Proton and Its Intrinsic Powers

Kiyoshi Yasuoka¹  

(1)

Faculty of Medicine, Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki, Japan

Kiyoshi Yasuoka

Email: [e-mail]

Abstract

Following the discovery of X-rays by Wilhelm Conrad Roentgen during the late nineteenth century, the field of radiation physics experienced a rush of scientific discovery. During this period, Ernest Rutherford identified α-particles, whereas Geiger and Marsden observed that an α-particle deflects at an angle of more than 90° when it strikes a thin gold foil. Several years later, Rutherford considered that his new atomic structure could explain this deflection and determined the proton to be a constituent of the atomic nucleus. In 1946, Robert R. Wilson proposed that protons could be therapeutically used in the medical field and introduced Particle Beam Therapy. The proton’s intrinsic powers now enable the treatment of deep-seated cancers, such as liver cancers. Image-guided proton therapy was used as early as 1988 for the essential treatment of deep-seated cancers.

Keywords

ProtonRadiation physicsParticle beam therapyDeep-seated cancerIGPT

1 Introduction

People have long been interested in the vastness of the universe as well as in the minute world that exists within materials and human bodies. In ancient times, people drew the numerous constellations seen in the night-sky and imagined romantic stories about them. The invention of the telescope in the early seventeenth century opened up a field of scientific research regarding the universe. New technology has led to the development of more powerful telescopes that are able to see long distances into space using optical lenses and mirrors along with a parabolic antenna for radio waves. The first optical microscope was developed in the late sixteenth century to observe the minute world that exists within materials and living things, and enabled research into small structures including biological cells and bacteria. In the late nineteenth century, a rush of scientific discovery arrived in the field of radiation physics. First, Wilhelm Conrad Roentgen discovered X-rays using a cathode ray tube (CRT) in 1895. Then, Antoine Henri Becquerel detected radioactivity in 1896 using a photographic plate and uranium salts of phosphorescent materials. This was followed by the identification of electrons for the first time using a CRT in 1897 by Sir J. J. Thomson. Two years later, in 1899, Ernest Rutherford discovered α-particles in the radiation emitted from uranium salts, following which, in 1909, Geiger and Marsden observed that an α-particle deflects at an angle of more than 90° when it strikes a gold foil. The following year, Geiger showed that the largest possible deflection of a particle passing through a thin gold foil was less than 1°. It was very difficult to understand that the large deflection angle of the α-particles after they struck thin gold foil was a result of the sum of multiple small deflections. In the same year, Sir J. J. Thomson proposed a theory to explain this strange behavior of α-particles. His atomic structure model suggested that an atom consists of a number of negative charges accompanied by an equal number of positive charges uniformly distributed in a sphere. Using this model, he hypothesized that the large deflections would not take place without the positively- and uniformly-charged sphere being very much smaller than the size of the whole atom. Building on the knowledge gained from experimental work and theories, Ernest Rutherford suggested a simple atomic structure model that was able to explain the large deflection behavior. He described that, according to his model, an atom contains negative charges uniformly distributed in a sphere surrounding positive charges at its central point. He determined that the large deflection must have been caused by a single collision. This idea successfully explained how α-particles exhibited large deflections while passing through thin gold foils. This came to be known as the Rutherford Scattering Experiment, which led to the discovery of the atomic nucleus in 1911. During that year, Rutherford published a new atomic model showing that an atom consists of electrons orbiting around a very small nucleus in which most of the atomic mass and charge is concentrated. He needed eight more years to uncover the detailed structure of the atomic nucleus.

2 Constituent Particles of the Atomic Nucleus

Ernest Rutherford [1] had suggested that the use of highly energetic charged particles could be a promising technique to study the matter existing inside an atom. It is well known today that energetic particles (radiation) are used in the ultimate microscope, nanoscope, picoscope, femtoscope, or quantum-scope to investigate and visualize the matter existing within materials and living things at an atomic or subatomic level. The scale down to which these tools can work is proportional to an inverse of the energy of the charged particles. How are energetic particles obtained? There are two sources of energetic particles: a naturally radioactive substance and an accelerator which artificially energizes particles. Rutherford was the first researcher to propose the development of a particle accelerator to enable further research regarding the atomic nucleus. This was the beginning of research into nuclear and high energy physics that would lead to the application of particle accelerators to the medical field years later. In the decade following 1910, right after Rutherford’s discovery of the atomic nucleus, however, only naturally radioactive sources were available for the generation of energetic particles. Therefore, he used radium to generate energetic α-particles.

In 1919, Rutherford set up an apparatus consisting of radium placed inside a metal box containing a silver window plate. A zinc-sulfide scintillation screen was placed outside the box. The experiment was performed by changing the gas inside the box; air, oxygen, carbon dioxide, nitrogen, and their dried gases were used. In all cases, the α-particles emitted from the radium source were stopped before they reached the screen. This experiment led to a much greater surprise; the α-particles passing through the dried air in the box gave rise to unexpected long-range bright scintillations on the screen. All the background noise of α-particles, fast nitrogen and oxygen atoms, electrons, and water vapor in the air were completely excluded by fact of their measured ranges. The bright scintillations with unexpectedly long ranges were equal to those of fast hydrogen atoms. The particles or atoms that hit the screen had the same range and energy as fast hydrogen atoms. Which elements of dried air could cause such long-range scintillations? The anomalous effect did not take place in the presence of oxygen and carbon dioxide gases but only took place in the presence of pure nitrogen gas. The number of long-range scintillations was compared between the dried air and the dried nitrogen. The ratio was the same number as the value expected from nitrogen gas. At this stage, Rutherford came to the unavoidable conclusion that "the long-range atoms arising from the collision of α-particles with nitrogen are not nitrogen atoms but probably atoms of hydrogen, or atoms of mass 2." The fast α-particles broke apart the nitrogen nucleus. This was the first evidence that the hydrogen atom is a constituent of the nitrogen nucleus. Rutherford later named the hydrogen atom the proton. He had determined that the proton particle is one of the constituents of the atomic nucleus. The name proton is derived from the Greek word protos meaning primal or original. In 1910, protons were thought to be the most elementary of particles, although it is now well known that atomic molecules contain even more fundamental components called quarks. Rutherford also predicted the existence of other constituent particles in the nitrogen nucleus. These particles, named neutrons, were discovered in 1932 by James Chadwick, a student of Ernest Rutherford. For all of these reasons, Ernest Rutherford is known as the Father of the Proton.

3 A Particle-Based Surgical Knife (Quantum Knife)

In 1946, 27 years following the discovery of the proton, a very important article titled Medical Use of Protons was published by Robert R. Wilson. Neutrons, X-rays, and artificial activities were in use before Wilson proposed that protons could be therapeutically used in the medical field. After Gustav Ising’s description of the principle of a linear particle accelerator in 1924, many types of accelerators had been developed for use in nuclear and high-energy physics laboratories. In 1930, Robert J. Van de Graaff had invented an electrostatic generator to produce very high electric voltages. It was used to accelerate charged particles like electrons; however, it was not able to generate high currents. Two physicists, Ernest O. Lawrence and M. Stanley Livingstone, invented the cyclotron accelerator in 1931, which was successful in accelerating mercury ions to 80 keV. In 1932, Sir John D. Cockcroft and Ernest T. S. Walton invented an electronic circuit to generate high DC voltages from low-voltage inputs using a voltage multiplier and ultimately constructed the Cockcroft and Walton (C&W) accelerator. The C&W accelerator was the first artificial nucleus disintegrator. They were able to accelerate protons up to 700 keV. Thus, the proton, which was discovered as a constituent of atomic nucleus in 1918, became a tool used to observe the matter inside materials and living things. Cockcroft and Walton succeeded in producing the first nuclear reaction ⁷Li(p,⁴He)⁴He, the first splitting of the atom, by using protons extracted from the artificial accelerator. This was the first proton beam.

Major nations of the world were involved in World War II, and novel, extreme technologies were used in the war, including radar and microwaves. These technologies were also applied in the development of the accelerator. In 1945, Edwin M. McMillan and Vladimir Veksler considered independently a principle of phase stability during multiple accelerations of charged particles traveling in an orbit within a circular accelerator. They had solved the problem of how to synchronize a circular cycle of the particle in orbit with a high radio frequency in acceleration. This technique resulted in the construction of a synchrotron accelerator.

Robert R. Wilson was a graduate student under Ernest Lawrence, and he received his doctorate for his work on the development of the cyclotron accelerator at the Berkeley Laboratory (later LBL). He also became an accelerator physicist. After World War II, he resumed his work on the accelerator and constructed electron synchrotrons. During the rapid development of the synchrotron, he considered the application of the energetic accelerators to the medical field. The article Radiological Use of Fast Protons, [2] published in 1946, was written to inform medical and biological workers of his detailed calculations about the physical properties and possible therapeutic uses of protons, deuterons, and α-particles. He introduced Particle Beam Therapy and is known as the Father of Proton Therapy. He invented a particle-based surgical knife, which only excises tumor tissues without any damage to normal tissues. Although it may seem magical, it is one of the scientific properties of protons. Once the protons receive enough energy and form a beam of high enough intensity, the beam can become a powerful and potentially high-quality surgical knife for the excision of various kinds of tumors.

During 1967–1978, Wilson was the first director of the Fermi National Accelerator Laboratory (Fermilab), Batavia, a laboratory for the study of high-energy physics, located in the western suburbs of Chicago, Illinois, USA. It is a 15-story high-rise called Robert R. Wilson Hall, with a library, an auditorium, a cafeteria, experimental rooms, and offices for employees and visiting scientists.

4 Noninvasive Surgical Knife for Use in Treating Deep-Seated Cancers

Until the early 1980s, most patients referred for proton therapy had shallow-seated cancers, such as ocular diseases and/or head and neck cancers, because the required proton beam energy for treatment was as low as 160 MeV or less. At that time, the Particle Radiation Medical Science Center (PARMS), the former facility of the Proton Medical Research Center (PMRC) at the University of Tsukuba, started proton beam therapy using a high energy 250 MeV proton beam extracted from a proton booster at 500 MeV in KEK (the National Laboratory for High Energy Physics). This converted to a therapeutic energy beam was able to travel as far as 38 cm in water. Thus, PARMS provided the first proton beam application for cancers in deep-seated organs such as the liver, and this new technique enabled the treatment of a variety of deep-seated cancers.

During the time when tumors were located in shallow tissues, precise positioning of the patient was not considered to be important for conventional X-ray therapy or proton beam therapy. Patient positioning had usually been assessed using X-ray films. However, because it was not a real-time positioning system, it took a long time to determine the correct position. The accuracy of positioning using this method was unsatisfactory. When the first treatment for deep-seated cancers, such as liver cancers started at PARMS, a more precise measurement system was required. Thus, for these treatments, Image-Guided Proton Therapy (IGPT) was developed at PARMS [3]. It was the first IGPT setup in the world (Fig. 1), and consisted of a radioscopy system incorporating an X-ray tube, an image intensifier device, and a TV camera. The imaging data was recorded onto video discs. During the period between 1982 and 1987, X-ray images were real-time still pictures, because the X-ray intensity was not high enough to monitor a moving image inside a patient. In 1988, however, the IGPT was improved using a high-intensity X-ray tube to allow observation of a real-time moving image. Development of the improved IGPT led to the development of a new generation of more precise proton irradiation systems using a respiration gate, which made it possible to expose proton beams to a patient only during exhalation [4]. Initially, the sensor consisted of a strain gauge attached to the patient’s body, but it was later improved through the use of advanced laser techniques. The respiration gate made therapeutic proton beam technology applicable to a moving target and increased its precision. It resulted in shortening treatment times because efficiency of beam delivery becomes considerably high when the respiration gate is used. The gate can be used to identify the moment at which acceleration of the proton beam has to be started and the moment until which it has to be held, allowing the patient to be exposed to the proton beam only during exhalation.

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Fig. 1

Development of the IGPT at PARMS

References

1.

Rutherford E (1919) Collision of α particles with light atoms. IV. An anomalous effect in nitrogen. Phil Mag 90(S1):31–37

2.

Wilson RR (1946) Radiological use of fast protons. Radiology 47(5):487–491Crossref

3.

Tsujii H et al (1989) Field localization and verification system for proton beam radiotherapy in deep-seated tumors. Jap J Radiol 49(5):622–629

4.

Ohara K et al (1989) Irradiation synchronized with respiration gate. Int J Radiat Oncol Biol Phys 17:853–857Crossref

© Springer Nature Singapore Pte Ltd. 2020

K. Tsuboi et al. (eds.)Proton Beam Radiotherapyhttps://doi.org/10.1007/978-981-13-7454-8_2

Early History of Biology and Clinical Application of Proton Beam Therapy

Koji Tsuboi¹  

(1)

Tumor Therapy Center, Tsukuba Central Hospital, University of Tsukuba, Tsukuba, Ibaraki, Japan

Koji Tsuboi

Email: [e-mail]

Abstract

Protons were discovered by Rutherford E in 1919. Following the invention and development of cyclotron invented by Lawrence EO in 1931, Wilson RR proposed the medical use of accelerated high energy protons in 1946. To realize his proposal, Lawrence JH, Tobias CA, and Larsson B made great contributions to the biological analyses of proton beams, and the first proton therapy was performed in 1954. They used proton beams to the pituitary gland to suppress the pituitary function in hormone-dependent breast cancer patients. In addition to this, development of X-ray computed tomography, the large-field passive beam delivery system, and the three-demensional treatment planning system formed the basis of the proton therapy system known today. After the first hospital-based proton center with an accelerator dedicated to medical use was built in Loma Linda University in 1990, the number of proton centers has been increasing exponentially to date. Recently, the technology of spot-scanning beam enabled intensity-modulated proton therapies, which is a highly specialized proton therapy, delivering a precise dose of protons to the target, making this method the mainstay of current proton therapy.

Keywords

Proton beamCyclotronBragg peakHistory of proton therapyRelative biological effectiveness

1 Discovery of Proton and Invention of Cyclotron

In 1919, Rutherford E discovered that the nuclei of nitrogen could be disintegrated by the impact of α-particles emitted from a radioactive source, proving the presence of hydrogen nucleus in other nuclei [1]. This is regarded as the discovery of protons. He proposed to give the hydrogen nucleus a special name as a particle. The British Association for the Advancement of Science accepted Rutherford’s suggestion that the hydrogen nucleus be named the proton, following Prout’s word protyle [2].

Construction of the world’s first cyclotron was completed in 1931 by American physicist Lawrence EO (Fig. 1) and his associate in Berkeley [3]. After improvements in the size and power of the cyclotron, the construction of a 184-inch cyclotron which could generate up to 340 MeV protons was completed at Berkeley in 1947 [4]. This invention enabled the use of high energy particle beams, leading not only to the discovery of many new elements but also to medical innovations, including particle radiotherapy and generation of radioisotopes for diagnostic use.

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Fig. 1

Ernest O Lawrence

2 Proposal for The Medical Use of Protons

Following the development of cyclotron by Lawrence EO, Wilson RR (Fig. 2), a former student of Lawrence EO, was involved in the design of the Harvard Cyclotron Laboratory (HCL) in 1946. He came up with an idea that accelerated protons of 125 MeV could penetrate the human body exactly up to 12 cm and stop completely on attaining the Bragg peak ionization. He then proposed the medical use of accelerated high energy protons [5]. This is the origin of the current proton therapy.

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Fig. 2

Robert R Wilson

3 The Early Applications in Biological Systems and Animals

Protons generated by cyclotrons were investigated for their biological effectiveness. At this time, Berkeley Radiation Laboratory played an important role and conducted extensive studies on protons to realize Wilson’s idea, mainly in animal experiments conducted by Lawrence JH (Fig. 3), who was Lawrence EO’s brother, and Tobias CA (Fig. 4) [6–10]. The initial series of animal experiments were performed on the rat pituitary gland [11], followed by the monkey pituitary gland [12]. They focused on the pituitary gland because the position of the pituitary was easily identified by the bony structure of sella turcica on the plain skull roentgenogram. It has been mentioned that the first animal treated with proton was a dog with breast cancer [7]. The pituitary of the dog was removed with radiosurgery using proton beams, and she lived for at least 2 years after the treatment. In addition, the pioneering biological experiments using protons were performed by Tobias CA and his associates in which the relative biological effectiveness (RBE) per unit of ionization of the high energy proton beams was found to be close to 200 kv X-rays [6]. Inspired by these results reported from Berkeley, the biomedical program in Uppsala University, Sweden was initiated in 1954 using 185 MeV proton beams under the leadership of Larsson B (Fig. 5) [13]. After extensive radiobiological studies during 1957–1968, they concluded that the biological effectiveness of 185 MeV protons is equivalent to ⁶⁰Co γ-rays [14]. They also initiated a series of radiosurgical experiments using proton beams on animal brain and spinal cord, using rabbit and goat [15–17]. It is also noteworthy that they found that the biological effect plotted as a function of dose peaked about 2 mm beyond the physical Bragg peak position by using root tips of bean and onion seedling with an endpoint of abnormal metaphases [18]. In this way, extensive biological study with protons of high energies in various endpoints was conducted by these pioneers, and their radiobiological works were extensively reviewed by Ueno Y et al. [19]. They summarized that RBEs of high energy protons were almost equal when compared with γ-rays. More recently, Paganetti H et al. [20] reviewed RBE values of in vitro and in vivo systems, and according to them, the experimental in vivo and clinical data indicate that continued employment of a generic RBE value, and for that value to be 1.1, is reasonable. Later, a fixed value of generic RBE of 1.1 for clinical applications was recommended in a joint International Commission on Radiation Units and Measurements - International Atomic Energy Agency (ICRU-IAEA) Report [21]. The timeline is summarized in Table 1.

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Fig. 3

John H Lawrence

../images/428187_1_En_2_Chapter/428187_1_En_2_Fig4_HTML.png

Fig. 4

Cornelius A Tobias

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Fig. 5

Börje Larsson

Table 1

Timeline of early history of proton beam therapy (1946–2000)