Principles of proton beam therapy

Introduction

The potential of physical characteristics of protons for cancer treatments was first recognized by Wilson in 1946. During the following four decades or so, proton accelerators at various physics laboratories around the world were adapted for clinical purposes. Examples of such facilities include the University of California Berkeley; the Harvard Cyclotron Laboratory in Cambridge, Massachusetts; Uppsala University, Sweden; Dubna, Russia; and Chiba, Japan. Physics laboratory-based particle therapy facilities are designed for physics applications and, as such, are not suitable for clinical applications. This led to the establishment of hospital-based proton therapy facilities. The first among these was at the Loma Linda University Medical Center, California, in 1990, followed by Massachusetts General Hospital-Harvard University in 1999, the MD Anderson Cancer Center (MDACC) in Houston, and the University of Florida in Jacksonville, both in 2006. Since then, the number of proton therapy centers in the United States and around the world has grown dramatically. According to the Particle Therapy Co-Operative Group (PTCOG) website ( http://www.ptcog.ch ), as of March 2018, there were approximately 27 proton therapy facilities in operation in the United States and nearly 70 around the world. As of December 2016, 150,000 patients worldwide had been treated with protons.

Along with the rapid growth in the number of proton centers, the technology has continued to evolve. Whereas up until the last decade most of the proton treatments were carried out using passively scattered beams, the new treatment centers are now being equipped almost exclusively with scanning beam systems. These systems provide much greater flexibility to optimally shape dose distributions. Accelerators and gantries continue to become more compact and have greater functionality and lower cost. The treatment delivery control systems are becoming more sophisticated, allowing proton therapy systems to deliver superior treatments more efficiently.

Furthermore, ongoing research over the last dozen years is resulting in improved understanding of the sensitivity of protons to inter- and intrafractional anatomy variations, range uncertainties, setup uncertainties, and the unique biological effects of protons. This knowledge is being incorporated into the development of intensity-modulated proton therapy (IMPT) methods to optimize biologically effective proton dose distributions to achieve higher and higher therapeutic ratios. Accuracy of dose distributions is being improved with the introduction of Monte Carlo techniques and made practical with the development of fast Monte Carlo methods. Clinical trials, many of them randomized protons versus photons, are being conducted to evaluate the relative clinical and cost-effectiveness of protons.

In principle, protons have a much greater therapeutic potential than has been realized to date. Although the technology has improved substantially and we have made significant strides in improving our understanding of physical, biological, and clinical aspects of proton therapy in the recent past, considerable additional research and development are needed to maximally exploit the potential of proton therapy. Sections later describe the principles underlying proton therapy, the current state of the art and its limitations, ongoing research and development to advance the state of the art, and the long-term promise of radiotherapy with protons.

Physical characteristics of protons

The rationale for the use of protons to treat cancers is built upon their unique physical characteristics. These characteristics allow the production of radiation dose distribution patterns that conform more tightly to the shape of the tumor target and avoid normal tissues to a greater extent. The physical characteristics of protons also lead to biological effects that are, in general, quite different from those of the traditional radiation treatment modalities. Taken together, the physical and biological properties of protons offer a substantially higher therapeutic ratio.

Protons interact with matter primarily through Coulomb interactions with atomic electrons, Coulomb interactions with nuclei, and nuclear interactions. As a proton traverses the medium, it slows down continuously. The energy deposited by it per unit distance (called the linear energy transfer, or LET) increases until all of its energy is depleted, and it comes to essentially an abrupt stop. Thus, in a uniform medium, for example, a water phantom, a monoenergetic beam of protons leads to the formation of the characteristic Bragg curve ( Fig. 2.1 ). Because protons are much heavier than electrons, Coulomb interactions with electrons do not deflect them appreciably from their original path. However, Coulomb scattering from nuclei, although it occurs much less frequently, leads to larger-angle scattering and contributes to a substantial lateral spreading of proton beams. It leads to the widening of proton beam penumbra, especially when the protons have slowed down near the end of their range. Interactions of protons with nuclei occur with even lower probability and mainly at higher energies and lead to large-angle scattering and the production of secondary particles, including neutrons.

These properties of protons have a profound impact on the biological and clinical effects. Protons ionize more densely than photons. The density of ionization increases with increasing LET as they slow down as a function of depth. This, in turn, causes continuously increasing biological damage (e.g., more complex and clustered DNA damage), thus continuously increasing relative biological effectiveness (RBE) as a function of depth. The RBE is a complex function with physical and biological parameters. It is briefly dealt with in the section on Proton Biological Characteristics. More details can be found in Chapter 1 and in the literature, including some cited at the end of this chapter. The variations in RBE can be exploited to enhance the biologically effective dose differential between the target and normal tissues.

In addition, protons have a lower entrance dose compared with photons (except in the entrance buildup region, see Fig. 2.1 ) and virtually no dose beyond the end of their range. Thus theoretically, they can be used to produce considerably more “compact” dose distributions (smaller “low-dose bath”). Such dose distributions can, in general, spare large volumes of normal tissues for the same target dose (see the section on Proton Therapy Planning and Plan Evaluation and Chapter 5 for more details.). Recent recognition of additional value of such compact dose distributions is their potential to mitigate radiation-induced lymphopenia (RIL), which is widely recognized to be a significant prognostic indicator of adverse outcomes.

It should be noted that although sharp falloff of dose at the end of the range of protons is critical to the improved patterns of dose distributions, it also has potential negative ramifications. It renders proton dose distributions, compared with photon dose distributions, more vulnerable to intrafractional changes in anatomy due respiratory motion and other physiological functions, and to interfractional variations in anatomy because of such factors as weight gain or loss, tumor shrinkage, setup variations, and so on. Special efforts are required to minimize uncertainties thus introduced and to address residual uncertainties.

Proton biological characteristics

A common misconception about proton therapy is an inherent assumption that, for the same physical dose delivered to a tissue, the biological and clinical effects of protons and photons are identical except that protons are 10% more biologically effective. In other words, the RBE of protons is a constant of 1.1. In reality, as protons interact with the tissues in the body (and matter in general), they traverse very differently and in a more complex manner. As a consequence, they have very different biological and clinical effects. They should be considered a different form of drug, perhaps many different forms of drug, depending on their physical parameters and the dose delivered. It is crucial that practitioners of proton therapy understand and appreciate these differences to apply proton therapy more effectively.