Photon Radiation

The most common form of ionizing radiation used in radiotherapy is the photon, which is a particle that has no mass, travels at the speed of light, and carries the energy present in microwaves, visible light, ultraviolet light, and x-rays. The nature of the interaction of a photon with matter depends upon the energy of the photon. In the kiloelectron volt (keV) range, which is used in most diagnostic x-ray units, photons interact with matter via the photoelectric effect.² A photon interacts with a tightly bound electron, which absorbs most of the energy and is ejected from the atom and is then free to interact with other atoms in the vicinity. This interaction is highly dependent on the atomic number of the material being irradiated. Diagnostic x-ray studies take advantage of this phenomenon, as bone, which is high in calcium, is much more likely to interact with these photons than soft tissue, which is mostly carbon, hydrogen, and oxygen. This differential interaction is the basis of diagnostic x-ray imaging.

At higher energies, which is the energy of most therapeutic radiation, the Compton effect predominates.² A high-energy photon in the megaelectron volt (MeV) range interacts with a loosely held orbital electron, which results in ejection of the electron, and scattering of the photon (with a change in energy of the scattered photon). This interaction is independent of the atomic number of the material being irradiated, but it is dependent on electron density. Thus, images generated from therapeutic energy x-rays are less useful for imaging than diagnostic x-rays, as there is little contrast between bone and soft tissue. However, this energy range is useful in radiation therapy, as it is highly penetrating, and is able to interact equally with all tissues.

There are two main sources of high-energy photons used in radiation therapy. The first source is radioactive decay, which is a natural process that occurs in elements with unstable nuclei and results in the emission of energy as the nucleus gains stability. Cobalt-60, the most common element used in radiation therapy units, undergoes a process known as beta decay to become nickel-60, which results in the emission of a high-energy photon known as a gamma ray (γ-ray). For ⁶⁰Co, the average energy of the photons generated in the radioactive decay is 1.25 MeV. Radiotherapy devices that take advantage of this phenomenon use a shielded radioactive source, and a small opening or openings result in shaping (known as collimation) of the beam to the desired size and shape. As will be discussed later, this is the source of radiation used in devices such as the Gamma Knife.

The other main source of high-energy photons is a linac, which uses microwaves to accelerate electrons to a high energy. These electrons are directed to collide with a high-molecular-weight target, and the resulting interactions between nuclei and electrons result in the production of high-energy photons (X-rays) via a process known as bremsstrahlung, or “braking” radiation. The difference between X-rays and γ-rays is simply the site of origin: X-rays are produced by electron interactions but γ-rays are produced by nuclear decay. Unlike the γ-rays produced by ⁶⁰Co, the energy of the X-rays generated in a linac is based on the characteristics of the machine, and most commercial units offer multiple energy options. These X-rays are produced in the head of the unit (known as the gantry), and can be shaped by a system of controllable leaves, known as a multileaf collimator (MLC), placed between the source of the X-rays and the patient (Fig. 45.1).

FIGURE 45.1 Linear accelerator diagram. Left, A schematic drawing of a linear accelerator. Electrons are generated in the electron gun, and accelerated using microwave energy in the waveguide. The electrons are bent 270 degrees to hit a high-molecular-weight target, which generates high-energy x-rays that are then shaped using the collimator. Right, An actual linear accelerator in clinical use. The gantry is capable of 360-degree rotation to deliver radiation from every angle.

The physical characteristics of photons determine their biological effects. Photons deposit dose in a characteristic pattern, in which there is an initial buildup of energy after entry into the patient, followed by a steady loss of energy as they pass through the tissue according to the law of exponential decay. The energy of the photon is lost in inverse proportion to the square of the distance traveled. Thus, photons spare the skin to some degree, but deposit the majority of their dose upon entrance into tissue, and continue to deposit decreasing amounts of energy as they exit the body (Fig. 45.2). The shape of this depth-dose curve is dependent on the energy of the photon involved. Higher energy photons exhibit greater skin-sparing effect, but have a slower rate of attenuation as they pass through tissue. In general, photons in the 1- to 6-MeV range are used for SRS, as the desired target depth in the cranium is relatively shallow, and higher energies result in unnecessary increased dose delivered beyond the target point.

FIGURE 45.2 Depth-dose curve for photons and protons. The x-axis represents depth in tissue, and the y-axis represents the percentage of the total dose delivered (where 100% is the dose at 14.5 cm deep in tissue, a typical depth for cranial radiosurgery). Photon radiation (here shown as a 6-MeV beam) increases upon entrance into tissue until it reaches a maximum, and then decreases in a manner that is inversely proportional to the square of the distance traveled. Proton radiation (pristine proton peak) shows a low entrance dose, and a very sharp buildup known as the Bragg peak. For larger lesions, a spread-out Bragg peak (SOBP) can be used to ensure that the entire target volume is covered by the high-dose region, although this results in higher entrance dose.

(Image courtesy of Marc Bussiere, MSc.)

Proton Radiation

Another form of ionizing radiation used in SRS involves charged particles, most commonly protons. Proton production starts by stripping the electron from molecular hydrogen gas, and the resulting protons are then accelerated to a therapeutic energy level using alternating magnetic fields in a cyclotron or synchrotron. The physical properties of protons result in a different dose distribution from that of photon radiation. Protons have a defined distance of travel, known as the range, which is dependent on their energy. Protons release their energy primarily at the end of their range, which is known as the Bragg peak, after William Henry Bragg, the Nobel Prize–winning physicist. The consequence of the Bragg peak is that protons deposit relatively lower doses of radiation prior to the end of their range compared to photons, and have no exit dose, that is, no dose delivered past their range (see Fig. 45.2). By modulating the energy of protons, a spread-out Bragg peak (SOBP) can be generated to cover wider areas, with the tradeoff of increased entrance dose. Because of their sharp range and lack of exit dose, protons provide a favorable dose profile for use in SRS. The disadvantage of protons is that their availability is limited to a few centers due to the cost and complexity of maintaining such facilities for clinical use.

Fractionation versus Radiosurgery

Conventional radiotherapy is typically fractionated into daily doses, which is thought to result in reduced effects of radiation on normal tissue. Fractionation allows for DNA repair to occur, which is predicted to favor normal cells that retain the full complement of DNA repair proteins.¹⁹ Furthermore, fractionation allows for reoxygenation of hypoxic areas, resulting in increased sensitivity of malignant cells that were previously hypoxic.²⁰ Additionally, fractionated therapy allows for reassortment of cells in the cell cycle, as cells are most sensitive to radiation during the G2/M phase of the cell cycle and resistant during the late S phase and G1. Thus, giving radiation in daily fractions allows those cells that are in resistant phases of the cell cycle to move to more sensitive phases of the cell cycle during subsequent fractions.²¹ The downside of fractionation is that it allows for repopulation of tumor cells during the therapy. Reoxygenation, reassortment, repair, along with repopulation, are known as the “four Rs” of radiobiology, and explain the radiobiological basis for daily fractionated therapy.

The value of fractionation is more apparent for certain tissues, which typically have high rates of proliferation and show relatively less capability to repair sublethal DNA damage. This concept is quantified as the α/β ratio, which is a radiobiological concept, based on a model of radiation response, that attempts to explain the differential sensitivity of tissues to fractionation.²² Tissues with a high α/β ratio respond quickly to radiotherapy, and are sensitive to smaller fraction sizes. Examples of these so-called “early” responding tissues include the gastrointestinal tract, lymphocytes, and skin. Tissues with a low α/β ratio respond more slowly to radiation, are typically less proliferative, and show a high capacity for DNA repair. Examples of late responding tissues include neural tissue and the lung.

The α/β ratio can be used to calculate a biologically equivalent dose (BED), which attempts to equalize total doses that are given in different fraction sizes. The equation is BED = (number of fractions ∗ fractional dose) ∗ (1 + (fractional dose/α/β ratio)).²² Although there is debate over the validity of this model at the high doses used in radiosurgery, it allows one to approximate the effect of doses delivered in fractionated sessions and those given in radiosurgery. For example, if one assumes a tumor to have a high α/β ratio of 10, a dose of 20 Gy in a single fraction is biologically equivalent to a dose of 40 Gy in 8 fractions, or 50 Gy in 25 fractions. However, for normal brain tissue, which has an α/β ratio closer to 3, the schedule 20 Gy × 1 has a BED of 153.3, while 5 Gy × 8 has a BED of 106.7, and 2 Gy × 25 has a BED of 83.3. Thus, the preceding regimens have the same BED for a tissue with a high α/β ratio, but the larger fraction sizes have a much higher BED for tissues with a low α/β ratio. What this means is that although the tumor control would be predicted to be equivalent for 20 Gy in 1 fraction and 50 Gy in 25 fractions, the radiosurgical dose would produce a more profound effect on normal brain tissue. Although the BED is merely an approximation of biological effect and not a real quantity, it can be useful when considering the dose of radiation to be used when the target is close to critical normal structures such as cranial nerves.

Given these advantages to fractionation, the radiobiological rationale for radiosurgery is not immediately obvious. However, proponents of radiosurgery argue that there are some principles that make SRS radiobiologically favorable. First, radiosurgery relies on precise immobilization and localization of the tumor to be treated, with inclusion of minimal margin of normal tissue. The design of the treatment machine, as outlined later in this chapter, creates a high dose of radiation in a very precisely defined space, with a very rapid dose falloff outside the target volume. Thus, even if critical normal structures are very close to the target tissue, the dose received is much lower than that received in the target itself. Thus, the physics of radiosurgery can compensate for suboptimal radiation biology.

Another potential explanation for the excellent clinical effect of radiosurgical doses in malignant disease lies in the possibility that high radiation doses are required to kill radiation-resistant cells. Emerging data suggest that clonogenic cells within tumors may have an intrinsically higher radioresistance due to increased expression of antioxidant genes.²³ It may be that very high radiation doses are able to overcome this effect, resulting in death of those clonogenic cells, and leading to tumor control.

Finally, as described earlier, at high doses of radiation, the primary mode of cell death may be due to endothelial damage, which may explain why the radiobiological rationale of fractionation may not be applicable when considering the observed clinical efficacy of SRS, especially for such targets as arteriovenous malformations. If radiation-induced apoptosis of the endothelium is a response to high dose per fraction, then fractionation may result in less normal tissue toxicity but also less control of the targeted lesion. All of these mechanisms are speculative and remain to be proved in a rigorous scientific fashion.

The radiobiological concerns outlined here suggest some situations when it may be advantageous to choose fractionated treatment over single-fraction radiosurgery. Given that normal neural tissue, including cranial nerves, are late-responding, with an α/β ratio of approximately 3, they will be more sensitive to large radiation doses compared to small ones. If the target to be treated is in close proximity to one of these structures (e.g., optic nerve sheath meningioma²⁴ or a pituitary tumor very close to the optic chiasm²⁵), it may be more prudent to fractionate treatment to reduce the risk of injury to the cranial nerves. Conversely, for hormone-secreting tumors, there is biological evidence that high-dose radiosurgery is associated with more rapid normalization of hormone levels.²⁶ Thus, the choice between radiosurgery and fractionated treatment must weigh a number of radiobiological and clinical parameters.