The mode of action of radiation

When absorbed by living tissues, ionizing radiation causes excitation and ionization of component atoms or molecules in the path of the beam. Subsequent chemical reactions result in breaking of molecular bonds and can result in apoptotic cell death if molecules critical for cell viability are disrupted. The ‘critical target’ is generally regarded as being nuclear DNA, but other molecules in other parts of the cell (e.g., proteins and lipids) may also be damaged and contribute to radiation-induced cellular injury. The damage to DNA prevents normal cell replication but does not lead to immediate cell death; the radiation damage is manifest when the damaged cells attempt to divide. Hence radiation tumor response and toxicity appear delayed.

Radiation biology

The response of living cells and tissues to radiation depends upon the dose of radiation, how this is applied, and the radiosensitivity of the cell population. Radiosensitivity varies according to a number of factors (Box 15-1), one of the most important being the ‘growth fraction’ of the cell population. Small, rapidly growing tumors tend to respond more favorably to radiation than large, slowly growing tumors. Radiation treatment is unlikely to achieve more than a partial and temporary remission in the latter.

Whilst radiation is a potent means of causing tumor cell death, it is not selective and can be equally damaging to normal tissues; indeed, certain normal tissues may be more sensitive to radiation than many tumors. In order to be of therapeutic benefit, radiation must be employed in such a way as to minimize normal tissue injury whilst achieving maximum tumor cell kill. Various methods may be employed to localize the radiation to the tumor, as outlined later in this chapter.

One way to reduce normal tissue injury is to ‘fractionate’ the treatment. Following exposure to a single dose of radiation a number of changes occur in the exposed cell population, that are often referred to as the four ‘R’s’ of radiation (Box 15-2).

As normal tissues are able to repair and repopulate better than most tumors and as redistribution (around the cell cycle) and re-oxygenation increase tumor sensitivity, by applying the radiation in multiple small doses (fractions) over a long period of time rather than as one large dose, normal tissue injury is reduced and tumor cell kill increased.

The biological effect of radiation depends on the amount of radiation applied and length of time over which it is applied, hence the term ‘biological radiation dose’. The same total dose given in a short time or fewer fractions has greater effect than the same dose given over a longer time in many fractions (applies to both tumor response and toxicity). Fraction size is an important determinant of normal tissue damage. Small fractions minimize normal tissue effects, large fractions increase risk of late tissue effects. Overall treatment time is important in achieving tumor control. Thus by using multiple small fractions of radiation delivered over a long period of time tumor cell kill may be increased whilst normal tissue damage can be limited to some extent.

At the present time most radical (i.e., definitive, with intent to cure) radiation schedules for human patients employ approximately 30 daily treatments over a period of four to six weeks. In animals, where general anesthesia is required for restraint of the patient during treatment and where radiation facilities are less widely available, larger weekly or biweekly fractions may be used in a more palliative approach. However, many centers do use definitive schedules, e.g., Monday–Wednesday–Friday protocols or daily fractions over several weeks.

In brachytherapy, where implants are placed within the tumor volume, fractionation is not required. Instead the total dose is delivered over a period of time, usually three to four days for implants and up to two to three weeks for systemically administered isotopes, e.g., radioactive iodine (¹³¹I) for thyroid tumors in cats.

• X-rays

• gamma-rays

• electrons.

• Teletherapy: radiation is applied in the form of an external beam of X-rays, gamma-rays or electrons that are directed into the tumor

• Brachytherapy: radioactive substances, which emit gamma or beta rays, may be applied to the surface of a tumor, implanted within the tumor or administered systemically to the patient.

External beam methods

Various devices exist for generating and delivering radiation to tissues (Box 15-3).

With external beam radiation, the beam can be collimated to the area of the tumor and several treatment ports employed in order to reduce the amount of entry and exit beam radiation affecting the surrounding normal tissues. The prescription and planning of such treatment is facilitated by three-dimensional computerized treatment planning programs (Fig. 15-3). Multi-leaf collimators allow complex planning and shaping of the radiation field to the defined target volume. Intensity modulated radiotherapy (IMRT) allows multiple differently shaped photon beams to be effectively ‘painted’ onto the tumor, allowing higher doses of radiation to be delivered to the tumor with no increase in the dose delivered to normal tissue. More recent developments in radiotherapy include tomotherapy, which is a form of IMRT that uses a helical delivery system. Stereotactic radiosurgery describes a technique where multiple, highly targeted beams of radiation are delivered in large doses in fewer treatments (usually one to five). Radiosurgery may be delivered by a ‘gamma-knife’ which uses technology similar to IMRT, or a free standing ‘Cyberknife’. Tomotherapy and stereotactic radiosurgery have not been used widely in veterinary medicine to date, although there are some reports of radiosurgery in the treatment of brain tumors.

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