Fig. 1.1
Artistic description of BNCT. The 10B atom, previously charged into the tumor cell, undergoes nuclear reaction when it absorbs a thermal neutron. The short-range, high linear energy transfer (LET) reaction fragments and destroys the tumor cell. Courtesy Prof. Dr. Angela Bracco, NuPECC Chair
When talking about gamma radiation and X-rays, it should always be remembered that they come from different sources, with gamma radiation resulting from nuclear decay. Both consist of extremely small wavelength photons and are capable of causing ionization when going through biological environments; therefore, they are called ionizing radiation. From all the techniques used in internal or external radiotherapy, they are the most common techniques, mainly because of economic factors.
Figure 1.2 shows the different types of radiation: X-rays, gamma rays, electrons, protons, neutrons, negative pi meson, carbon ions, and neon [3]. Currently, X-rays are most commonly used due to the low price of linear accelerators (linacs). In hadron therapy, the protons and carbons ions stand over the others. Neon has been widely used in initial research using charged particles.
Fig. 1.2
Types of radiation used in various radiotherapy techniques. Courtesy National Institute of Radiological Sciences (NIRS)
Radiation may kill cancer cells, breaking the DNA molecules and preventing cell replication. X-rays can break DNA or pass through its structure; however, protons are more lethal and carbon ions are two to three times more efficient than X-rays (Fig. 1.3) [4].
Fig. 1.3
Schematic representation of DNA breaks by type of radiation. Courtesy National Institute of Radiological Sciences (NIRS)
As shown in Fig. 1.4, the highest density of secondary electrons is produced by carbon ions, leading to a greater break of clustered DNA [5].
Fig. 1.4
Proton and carbon track structure in nanometric resolution compared with the schematic representation of a DNA molecule. Courtesy Prof. Dr. Ugo Amaldi
The biological system has the ability to fix injuries that occur in DNA. However, if DNA is exposed to a high local dose of radiation, the repair fails to correct the damage at the most effective dose compared to ionizing radiation. Thus, the impact of radiation on the microscopic level, see Fig. 1.5 where 53BP1 protein and RPA, both related to DNA repair, are made fluorescent by immunostaining [6].
Fig. 1.5
Repair of DNA after irradiation. 53BP1 and RPA proteins exhibit fluorescence. Reproduced from [15]
Jakob et al. [7] provided the image shown in Fig. 1.5, employing a 9.5 MeV 12C beam to irradiate a monolayer of cells, which was visualized using a microscope.
1.2 Cancer: Statistical Considerations
Cancer can be defined as the uncontrolled growth and proliferation of a group of cells. In 1982, 1.2 million new cancer cases were diagnosed in Europe. Three years later, 750,000 deaths were attributed to cancer, with death from cancer occurring in approximately 20 % of cases. In developed countries, about 30 % of the population is diagnosed with cancer, and about half die of this disease. This corresponds to about a million deaths per year. Certainly, the prognosis of individual cases varies and depends on the tumor type, stage, diagnosis, general health of the patient. In Europe, 45 % of patients have survived without symptoms for a period of 5 years or more.
In Russia, there are 2.3 million patients with cancer, with 450,000 new cases each year. Hadron therapy is the recommended treatment for 50,000 of these patients annually, but the capacity for this treatment by hospitals that have hadron therapy is 1,000 patients per year. Therefore, about 30–40 new protontherapy centers and 10–15 new carbon ion therapy centers should be built in Russia [8].
As a cause of death in developed countries, cancer ranks third after heart disease and stroke; it ranks second in the United States after heart disease. In 2000, studies showed that there were 10 million new cases of cases, with 6 million deaths, and 22 million people living with cancer worldwide [9]. These numbers represent an increase of 22 % in incidence and mortality from the year 1990 [9]. The number of new cancer cases worldwide was projected to be 12.3 to 15.4 million in 2010 and 2020, respectively [9]. In 2008, a total of 1,437,180 new cases and 565,650 cancer deaths were estimated to occur in the United States alone [9].
There are several approaches to the treatment of a malignant tumor:
(1)
Surgery (direct removal of tissues affected by cancer): This is an invasive method and not always possible; it accounts for 22 % of treatment success.
(2)
Chemotherapy (administered drugs that prevent mitosis and cause cell death [apoptosis]). Chemotherapy causes severe side effects due to the nonspecific action of drugs in body cells.
(3)
Immunotherapy (treatment of disease by inducing, enhancing or suppressing an immune response): Immunotherapy uses the body’s own immune system to help fight cancer.
(4)
Hormone therapy (drugs for inhibiting the activity of hormones that influence tumor growth): It is used in treatment of breast and prostate cancer, particularly with orally administration without side effects.
(5)
Cell therapy, genetic treatments, and novel specific targets.
(6)
Radiation therapy (cells are killed by energy deposition): This.has side effects due to damage to healthy tissues (in conventional radiotherapy). Radiation therapy can be administered externally by means of photons (the most widely used energy deposition method) or protons and ions (the method of tomorrow).
Of these approaches, the most important are surgery, radiotherapy, and chemotherapy. Currently, 70 % of cancer patients receive radiotherapy in the course of their treatment. Of those cured, 49 % are cured with surgery, 40 % by radiotherapy, and 11 % by chemotherapy [10]. Figure 1.6 shows the incidence and cancer mortality for all ages and both sexes [10].
Fig. 1.6
Incidence and mortality data for all ages and both sexes. Courtesy International Agency for Research on Cancer, World Health Organization. Dr. Nicolas Gaudin, Head, Communications Group
Photons with high energy, which reached the megavoltage (MV) range around the year 1950, contributed significantly to the improvement of therapeutic outcomes, as shown in Table 1.1 [11].
Table 1.1
Improved survival of several types of cancers with the advent of megavoltage therapy
5-year survival rate (%) | ||
|---|---|---|
Type of cancer | kV X-rays | MV X-rays |
Hodgkin disease | 30–35 | 70–75 |
Cervical cancer | 35–45 | 55–65 |
Prostate cancer | 5–15 | 55–60 |
Nasopharynx cancer | 20–25 | 45–50 |
Bladder cancer | 0–5 | 25–35 |
Ovarian cancer | 15–20 | 50–60 |
Retinoblastoma | 30–40 | 80–85 |
Seminoma of the testis | 65–70 | 90–95 |
Embryonal cancer of the testis | 20–25 | 55–70 |
Cancer of the tonsil | 25–30 | 40–50 |
Fig. 1.7
Carbon ions have the most balanced properties of ion species in terms of both physical and biological dose distribution. Courtesy National Institute of Radiological Sciences (NIRS)
Protons and carbon ions are the most widely used particles in the treatment of cancer worldwide. The ion beam deposits most of its energy at the end of its range, resulting in a Bragg peak (discovered by Sir William Bragg, an English physicist, in 1904). Forty-two years later, Robert R. Wilson recognized the advantage of this peak in cancer research, publishing the essential work on protons and heavy ions for the treatment of human cancer [12]. This was the first study on the application of charged particles for use in the medical field. During World War II, Wilson participated in the construction of the atomic bomb in Los Alamos; after the war, he returned to Berkeley where he wrote a paper on the potential benefits of high-energy protons in cancer therapy. It was Wilson who proposed that carbon ions could be greater than the proton beam. He became the director of the Fermi Laboratory, where he led the application of therapy by fast neutrons in more than 3100 patients. Compared with conventional photon therapy, particle beam therapy has minor complications and a better cure rate, and it does not affect the tissue surrounding the tumor.
1.3 Conventional Radiotherapy
The first linear accelerator (linac) was proposed in 1928 by Rolf Wideroe. In a linac (Fig. 1.8), the particles are accelerated in a straight line for a steady electric field or a field that varies with time. The best system to accelerate charged particles is to use radiofrequency (RF) fields, as high acceleration voltages can be achieved by employing RF resonant cavities compared with those obtained with similar-dimension electrostatic accelerators. Most linear accelerators proposed for hadron therapy are based on acceleration through RF fields [13].
Fig. 1.8
Simplified diagram of a linear accelerator
Linear accelerators are used worldwide, treating nearly 20,000 cancer patients (for each 10 million inhabitants) in developed countries. The linacs (Fig. 1.9) replaced low-energy X-rays and gamma radiation from radioactive cobalt because they deposited the dose (energy per mass unit) at greater depths. They are extremely attractive from an economic point of view because they have a very low price compared to the circular accelerators used in hadron therapy.
Fig. 1.9
Conventional radiotherapy: linear accelerators dominate. Courtesy Prof. Dr. Ugo Amaldi
As can be seen in Fig. 1.10 showing 8-MeV X-ray beams, after an initial increase of the dose absorbed, an exponential decay occurs; then, the maximum absorbed dose is reached at 2–3 cm deep in soft tissues. At a depth of 25 cm, the dose is only a third of the maximum dose.
Fig. 1.10
Qualitative depth dependence of the deposited dose for each radiation type, with a narrow Bragg peak at the end. Courtesy Prof. Dr. Ugo Amaldi and CERN
To increase the dose to the tumor, it is necessary to adjust the dose to the target. To irradiate deep tumors, multiple beams are directed to the center of the tumor (crossfire technique). A gantry is used for positioning the beam in the tumor. The technique of intensity modulated radio therapy (IMRT) uses 6–10 input ports; the beams may not be coplanar and their intensities vary via the irradiation field with the use of variable multileaf collimators, controlled by computers.
It was always necessary a high precision and greater biological effectiveness of the applied dose. High accuracy is achieved with increasing photon energy, leading to a shallow decay of the dose with a minor lateral spread. High effectiveness can be obtained by the application of hyperbaric oxygen, drugs, and heat as radiation-sensitizer agents. The high accuracy combined with the high control rate of tumor in conventional radiotherapy using X-rays has brought important results for the high energy employed in hadron therapy.
1.4 Status of Protontherapy
The history of protontherapy can be divided into two periods. In the first period, Ernest Orlando Lawrence created a system called Cyclotron in 1929, which accelerated particles to high energies without the use of high voltage, [14]. The first cyclotron was about 15 cm and fit in the palm of a hand, as shown in Fig. 1.11.
Fig. 1.11
Ernest Orlando Lawrence (1901–1958), with the first cyclotron that he built shown in the palm of his hand
Berkeley cyclotrons of 11, 27, and 37 in diameter were then built (Fig. 1.12). The latter cyclotron was used successfully in 1938 to treat 24 patients with fast neutrons. From then until 1943, a total of 226 patients were treated by fast neutrons using a 60-in cyclotron 60. However, due to side effects in healthy tissues, Stone emphasized that the technique should not be used for cancer therapy [15].
