Gamma rays are radiation produced by the decay of radioactive isotopes, either natural or man-made, whereas x-rays, or photons, are artificially produced when charged particles strike a target. Photons are typically produced in a linear accelerator in which electrons are accelerated to hit a tungsten target to emit the photons. When that tungsten target is removed from the path of the beam, electron beams are generated; funnellike applicators and collimators can be inserted to help shape the beam. Gamma rays have well-defined energies characteristic of the isotope that emits them, whereas x-rays have a broader spectrum that is determined by the energy of the machine that produced them. Protons are heavy charged particles that are accelerated to strike a target and that deliver their energy at a specific point in the tissue. Radiation dose delivered to the body is expressed in gray (Gy) or for protons in Gy (relative biologic effectiveness), abbreviated Gy(RBE).

For photons, the energy of electromagnetic radiation determines the ability of radiation to penetrate tissue, with higher energies allowing deeper penetration. Higher energies scatter their radiation dose in a more forward direction. In high-energy machines, the maximum dose is deposited below the skin surface. For this reason, a low-energy machine operating at peak energy of 140,000 volts would be preferable in treating superficial tumors such as skin cancer because the maximum dose is deposited in the skin, and the dose decreases exponentially to less than 25% of the maximum dose at a depth of 4 cm. For tumors deeper in the body, a more penetrating beam from a linear accelerator, such as one operating at a peak energy of 10 million to 15 million volts (10-15 MV) is preferable. A 15-MV beam deposits its maximum energy at a depth of 2.8 cm and is still able to deliver 50% of its maximum dose at a depth of 20 cm. Unlike the higher energy photons, electrons deposit their maximum dose at or near the surface, penetrate to a predictable depth with a relatively constant dose, and then decrease rapidly. Protons, on the other hand, deliver their energy at the end of their Bragg peak. Like photons, the ability of the proton beam to penetrate deeper in the body depends on its energy. The main difference, however, lies in the exit dose. Photons continue to deliver small amounts of energy over a range. Therefore tissues beyond the target will also receive dose from photon irradiation. Because almost all of the energy in protons is delivered at the end of the Bragg peak, virtually no dose is delivered to tissues beyond that point.

In some situations, it is preferable to deliver radiation to the tumor from an internal source. This technique is known as brachytherapy, meaning short-distance therapy. Radiation dose is determined by the ability of the radiation to penetrate tissue and the distance from the source of the radiation. Like visible light, the intensity of the radiation decreases in proportion to the square of the distance from the source (1/d²). Because doubling the distance from the source of radiation will decrease the intensity by 75% and tripling the distance will decrease the intensity by 89%, it is reasonable to consider placing the source of radiation within the tumor to minimize the dose that would be delivered to the surrounding normal tissue.

Radioactive isotopes produce radiation with a decreasing dose rate as time passes, a process known as radioactive decay. Every isotope has a half-life, defined as the time required for the dose rate to decrease by 50%. Depending on the half-life, certain isotopes are used for either high–dose rate (HDR) brachytherapy or low-dose rate (LDR) brachytherapy. For HDR, an applicator or catheter is inserted into the target structure, and the radioactive isotope is inserted for a specific amount of time (usually a few minutes) and then removed. The procedure can be repeated as often as needed to deliver the adequate total dose. In LDR, the isotope is left in the applicator for several hours to days or may be inserted directly into the target organ and left there permanently.

Radiation causes its effects in tissue by producing ionizations within the cell. The target in cells is the DNA molecule, and the ionizations will produce breaks in the DNA strand. Nonmalignant, healthy cells can repair this damage if it is confined to a single strand because the opposite strand serves as a template for repair. However, if two strand breaks occur on opposite chains in close proximity, the two ends of the chromosome may drift apart. These fragmented chromosomes may adhere to other chromosomes or they may sort out randomly when the cell divides, resulting in the daughter cells to be missing critical segments of DNA or have excess and unregulated copies of other genes, either of which may be fatal to the cell. Thus the damaged cells are observed to die a mitotic death; the lethal effect of radiation is not expressed until the cell replicates.

Radiobiologic research is ongoing to identify factors that affect the survival of cells and methods to selectively increase radiation effects on tumor cells. The easiest method to assay the effect of radiation is to deliver a dose of radiation to a suspension of single cells and then measure the percentage of surviving cells. The technique uses a suspension with a known concentration of cells. A sample is placed on a culture plate and the colonies are counted. At the same time a similar-sized sample is radiated and plated and the number of colonies counted. The ratio of the number of colonies developing on the two plates is the surviving fraction.

Because a Gy represents a specific amount of energy transferred to tissue, each Gy in theory should have an equal physical effect on the cell. However, the biologic effect is less for the first Gy than it is for the 101st Gy, suggesting that cells are capable of accumulating a certain amount of damage that is not lethal. Interestingly, if the radiation dose is split up and delivered over several fractions with time between fractions for cells to repair the damage, each fraction of radiation will kill the same proportion of the surviving cells. If the cells are allowed to completely repair the damage from the first dose, the second dose of radiation will have the same effect on the surviving cells as it would have if they had never been radiated the first time. This effect demonstrates the importance of uninterrupted radiation treatments. In vitro studies have shown normal cells to repair radiation-induced damage more efficiently than tumor cells, and attempts to deliver two doses of radiation per day, known as hyperfractionation, may increase the efficacy of treatment.

Oxygen is known to enhance the effects of radiation both in vivo and in vitro. Cells are more sensitive when radiated under oxygenated conditions than when they are hypoxic. Normal tissues are always oxygenated, but experimental measurements in tumors have shown that these cells pile up around a capillary and consume the available oxygen, limiting diffusion into the deeper tissues. This scenario results in well-oxygenated, relatively sensitive cells adjacent to the capillary and necrotic material at a distance away from the capillary. Between these two areas is a region of viable but hypoxic cells that are more resistant to radiation. In vitro studies show that hypoxic cells require 1.5 to three times as much radiation to achieve the same cell kill.

Current efforts are being taken to develop substances that act like oxygen in cells but are not metabolized like oxygen. Ideally, these substances will help to deal with the problem of hypoxic tumor cells without affecting the sensitivity of normal cells. In vitro work showed that these compounds, known as radiosensitizers, sensitized hypoxic tumor cells to the effects of radiation. However, clinical trials were limited by toxicity. Similarly, efforts to develop drugs that protect normal cells from the effects of radiation are underway. Although these trials also have failed to show in vivo benefit, efforts continue to develop a new generation of sensitizers and protectors. More importantly, chemotherapy and hormonal therapies have been observed to affect tumor sensitivity in vivo, and these agents form the basis of many current combined modality trials.

The delivery of radiation to a tumor requires a physician to perform five functions: (1) identify and locate the structures to be treated, (2) identify those adjacent structures that need to be protected, (3) prescribe the appropriate dose of radiation for the tumor based on its size and histology, (4) consider the tolerance of tissue within the target that may be affected by treatment, and (5) consider the tolerance of tissues between the skin and the target (transit volume). Although a complex but solvable problem, most clinical situations require some compromise on one or more issues. The clinician must select those compromises that will minimize effects on normal tissue while maximizing the probability of tumor control, known as the therapeutic ratio.

Modern equipment and computer software allow for sophisticated three-dimensional conformal radiation treatment (3D-CRT) and intensity modulated radiation therapy (IMRT). Both of these techniques have become the standard of care in most radiation oncology centers. Patients undergo computed tomography (CT)-based simulation in which a series of axial images are obtained of the target and the adjacent critical structures. Often fiducial markers are placed prior to simulation in the target organ to improve target localization during the treatments. The target or targets, depending on other areas at risk for tumor involvement, bony structures, and sensitive normal tissues, are defined on the CT imaging. Today’s treatment machines are able to deliver radiation from a wide range of angles to specifically shape dose intensities to conform around the target.