Conventional radiotherapy is mainly applied by using X-rays, electron beams, or gamma rays in daily routine practice. However, there are other forms of radiotherapy used in the management of cancers, such as particle therapy. Particle therapy is sometimes also referred to as hadron therapy. Particle therapy is a form of external beam radiotherapy using neutrons, protons, or positive ions. The beam’s primary distinguishing physical characteristic from X-rays is the mass of the particles. Dr. Robert R. Wilson, a physicist who worked with particle accelerators, proposed for the first time the medical use of charged particles in medicine in 1946. 1 In the 1950s, for the first time, proton beams were used to treat malignant diseases. In the 1970s, heavier positive ions were used in medical treatments in the United States.
Particle beams have different physical dose distribution characteristics and biological effects than conventional radiotherapy beams. Charged particles include protons as well as the nuclei of ions such as carbon, silicon, helium, and neon. The most readily available type of particle therapy globally is proton therapy. The number of proton centers operating globally is approximately 50. These centers are usually hospital based. Other charged particle therapy centers are fewer in number and are usually located within physics research laboratories, although recent constructions in Japan (Gunma, Saga, and Kanagawa) and Europe (Wiener Neustadt) have focused on stand-alone clinical facilities. 2
26.2 Physical Characteristics and Biological Effects of Charged Particles
The term “particle therapy” encompasses a broad range of particles. Used colloquially, it typically refers to pions, neutrons, and protons, as well as heavier ions such a helium, carbon, and neon. Electrons are technically charged particles. They are generated by conventional linear accelerators. Their low mass, approximately 1/2000th of that of a proton, limits their use to the treatment of relatively superficial tumor volumes. Neutrons are uncharged particles, and although they possess mass, a neutron beam does not have the discrete range of a charged particle beam. Charged particle therapy can be divided into those using (a) protons and (b) heavy ions with masses heavier than protons.
A charged particle deposits energy that is approximately inversely proportional to the square of the particle’s velocity when it enters a medium. As the particle slows, the probability of causing ionization increases and resultant accumulation of ionization at the end of the particle’s path causes a dose peak known as a “Bragg” peak. The process can be compared to a stone skipping across a pond that deposits a small amount of energy in the pond with each skip, only to reach a point at the end of its range where it drops into the pond and deposits its remaining energy in one region. The particle’s energy beyond this point reduces rapidly, and there is almost no ionization after this point. ▶ Fig. 26.1 a shows a comparison of the “Bragg” peak and the dose distribution of high-energy X-ray beams in a medium. This favorable dose profile of charged particles causes deposition of the radiation at the tumor and not beyond it where normal structures are present, which is advantageous compared with X-rays for suitable targets. However, this effective part of a pure particle beam is quite narrow and is not adequate to treat a tumor. As shown in ▶ Fig. 26.1 b, the narrow Bragg peak can be broadened by modulating the energy levels of beams of protons and carbon ions. This creates a dose plateau, a “spread-out Bragg peak” (SOBP), to provide uniform dose across the tumor volumes, although it raises the amount of radiation dose deposited along the entrance path. Several different techniques exist to create the SOBP through either scattering or creation of a scanning beam. Each technique has advantages and disadvantages. The reduction of entrance and exit doses due to the Bragg peak causes a decrease in integral dose delivered by the charged particle beam in relation to X-rays. Integral dose is a main concern when considering the risk of secondary malignancies related to radiation therapy, especially in pediatric patients when they are treated with intensity-modulated radiotherapy (IMRT). Other than superior dose distribution characteristics, another advantage of certain charged particles is to increase the biological effectiveness of the radiation. The dense ionization tracks created by beams of heavier particles result in a higher probability of causing unrepairable DNA damage and may lead to better tumor control, although this effect differs according to the mass and charge of the particle; protons have the lowest and neutrons, carbon, argon, and neon particles have the highest relative biological effectiveness.
Fig. 26.1 (a) Comparison of the depth–dose relationship for high-energy X-rays and charged particles. As the particle slows, the probability of causing ionization increases and the resultant accumulation of ionization at the end of the particles path causes a dose peak known as a “Bragg” peak. The particles energy beyond this point reduced considerably, and there is almost no exposure after this point. (b) Comparison of broadened Bragg peak for different charged particles (protons and carbon ions) with high-energy X-rays (photons). (Reproduced with permission from Durante and Loeffler 2010. 6)
Beside these physical advantages, biological characteristics of charged particles are slightly superior to photons. The linear energy transfer (LET), which is defined as deposition of energy per micron of water, is higher for charged particles compared with protons. The relative biological effectiveness (RBE) is defined as the ratio of X-ray and particle doses producing the same biological effect. The RBE for proton therapy is accepted as 1.1, and for charged particles it ranges between 3 and 5, although these number vary along the length of the track of the charged particles and with the target tumor or tissue. Heavy particles with high LET are more effective than X-rays for killing cells due to the high proportion of direct damage to DNA, and because they are less dependent on the cell cycle and oxygen, which is very important for hypoxic tumors. 2
Technical issues regarding treatment delivery are quite complex for particle therapy and are beyond the scope of this chapter. Although most of the centers use fixed beams, using a classic linear accelerator–type rotating gantry is very complex and expensive. However, there is great enthusiasm to erect new charged particle facilities worldwide despite their very high costs. Efforts are ongoing regarding reducing the size and cost of heavy ion therapy gantries. 3 There are concerns about cost-effectiveness, and the majority of these centers are located in developed countries. 4
26.3 Use of Charged Particles in Clinical Practice
Although charged particles have several advantages through their physical and biological characteristics, their use in multimodality treatment is still relatively rare. There have been very few randomized controlled trials as of this writing, and current knowledge is mainly based on phase I/II dose escalation studies. There is not enough evidence to suggest charged particles to replace conventional X-rays, although results from single-institution reports are promising. In 2016, access to charged particle facilities remains low despite recent construction in Europe, Asia, and North America, in comparison of availability of treatment in existing photon centers.
26.4 Current Results of Charged Particles in Management of Chordomas
Clival chordomas are locally aggressive low-grade tumors, and surgery is the mainstay of the management. Even with optimal management, a very high recurrence rate remains. Different pathologic subtypes (classic, chondroid, dedifferentiated subtypes) exist. The chondroid subtype has the most favorable and dedifferentiated subtype the worst outcome. Due to the complex anatomical localization, complete surgical excision is not usually executed. Thus, local radiotherapy is routinely considered for the majority of patients unless the tumor is small and has been excised with tumor-free surgical margins. Distant failure is a relatively rare event in these low-grade tumors. Due to the high conformal nature of both protons and ion beams, superior radiobiological characteristics of ion beams have led to the use of these methods alongside conventional radiotherapy with photons. 5,6 All the major data in the literature regarding patients, treatment characteristics, and outcomes and toxicity by using charged particles are summarized in ▶ Table 26.1.
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