Radiation therapy

Radiation therapy (or radiotherapy [RT]) is the medical use of ionizing radiation as part of cancer treatment to control malignant cells (not to be confused with radiology, the use of radiation in medical imaging and diagnosis).

RT may be used for curative or adjuvant cancer treatment. It is used as palliative treatment when cure is not possible and the aim is for local disease control or symptomatic relief, or as therapeutic treatment when the therapy has survival benefit and it can be curative.

RT is commonly used for the treatment of malignant tumors, and may be used as the primary therapy. It is also common to combine RT with surgery, chemotherapy, hormone therapy, or some mixture of the three.

Most common cancer types can be treated with RT in some way. The precise treatment intent (curative, adjuvant, neoadjuvant, therapeutic, or palliative) will depend on the tumor type, location, and stage, as well as the general health of the patient.

The radiation fields may also include the draining lymph nodes if they are clinically or radiologically involved with tumor, or if there is thought to be a risk of subclinical malignant spread. It is necessary to include a margin of normal tissue around the tumor to allow for uncertainties in daily set-up and internal tumor motion. These uncertainties can be caused by internal movement (for example, respiration and bladder filling) and movement of external skin marks relative to the tumor position.

To spare normal tissues (such as skin or organs which radiation must pass through in order to treat the tumor), shaped radiation beams are aimed from several angles of exposure to intersect at the tumor, providing a much larger absorbed dose there than in the surrounding, healthy tissue.

Electromagnetic radiation is energy that is transmitted at the speed of light through oscillating electric and magnetic fields. A photon has a wavelength λ, frequency v, and energy E=hv, where h is Planck’s constant (6.6 × 10 ⁻³⁴ Joule seconds).

The electromagnetic spectrum ranges from wavelengths of 10 ⁵ m for AM radio waves to 10 ⁻¹² m for gamma rays and cosmic rays ( Fig. 25-1 ).

Electromagnetic spectrum.

Although electromagnetic radiation is conventionally described as waves, it is also valid to describe radiation in terms of photons, or particles with packets of energy.

Because energy varies inversely with wavelength, x-rays have a much greater energy than do radio waves. This high energy gives x-rays the property of being deeply penetrating, and hence, they are able to be used therapeutically to treat deep-seated tumors.

Radiation used clinically consists of teletherapy, external beam radiation (from an outside source), and brachytherapy (using a source of radiation inserted or implanted into the patient).

The electromagnetic radiation used in external beam radiation therapy consists of x-rays and gamma rays. They differ only in terms of their production, as gamma rays are produced within the nucleus from natural radioactive decay, and x-rays are produced outside of the nucleus.

In practice, almost all x-rays are produced by machines (linear accelerators), and gamma rays used in radiation therapy are produced by the decay of radioactive substances. The vast majority of forms of radiation used in the clinic today, whether external beam radiation or brachytherapy, are from x-rays, gamma rays, or electrons.

The nucleus contains protons and neutrons that usually have stable configurations. When these configurations are not stable, they undergo spontaneous transformations to attempt to reach a more stable state.

These disintegrations of isotopes into a more stable state are called radioactive decay, and the species that undergo these transformations are called radioactive. With these disintegrations, energy is released as a photon (gamma ray), which can be used for radiation therapy.

The type of radioactive decay and type of particle emitted depend on the nuclear composition of the radioactive species.

Regardless, the energy released as these decays occur is in the form of gamma rays, and it is these that are (usually) used clinically to deliver radiation dose.

Cobalt-60 is a very important radioisotope that is used in external beam RT (teletherapy). Cobalt machines were the first practical megavoltage machines and were pioneered by the Canadian physicist, Herbert Johns.

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  The radioactive decay of Cobalt-60 releases 1.2-megavolt (MeV) gamma rays, which represents a major advance in external beam radiation treatment.

The depth of penetration in tissue increases with increasing x-ray energy, but with x-ray energies up to 250 kilovolts (keV), the maximal dose is always deposited at the skin surface, and thus x-ray doses have always been limited by skin tolerance.

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  This follows from the physics of x-ray interaction with matter, which is discussed in more detail in subsequent sections.

At energies up to 250 keV, x-rays interact with matter via the photoelectric effect, whereby they interact with the tightly bound electrons close to the nucleus of an atom to cause ionization.

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  This process begins to occur as soon as the photon interacts with matter (i.e., at the skin surface).

Cobalt-60 machines were simple in design and mechanically highly reliable, and they revolutionized the practice of RT. By their skin-sparing effect, doses of radiation required for treatment could be given safely for the first time without the desquamating skin toxicity that was the hallmark of kilovoltage radiotherapy.

In time, Cobalt machines in the United States were largely replaced by linear accelerators, which have the advantage of producing more sharply defined beams of a variety of different energies and which can produce both electrons and x-rays.

Linear accelerators can also be used with devices such as computer-controlled multileaf collimators, allowing much more precise dose delivery. Cobalt machines remain the workhorses of cancer treatment in much of the less developed world, however.

Most radiotherapy is delivered with beams of x-rays that were produced by directing highly accelerated electrons into a target.

Two processes can produce x-rays when electrons are directed onto target atoms.

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  The electrons can ionize these atoms by depositing sufficient energy so that an inner shell electron is ejected. The vacancy in the inner shell is filled by an outer shell electron with the release of a photon called a characteristic x-ray. Characteristic x-rays are of low energy and of little utility in therapy.

  
  
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  Another way of producing x-rays involves the interaction of an electron with the electromagnetic field of a nucleus. This interaction decelerates the electron, with the conservation of energy leading to the production of bremsstrahlung (braking energy) x-rays.

Before 1950, external beam radiation therapy was accomplished by accelerating electrons in a vacuum tube to hit a target, producing bremsstrahlung x-rays, with a maximum energy of about 300keV. As just stated, these x-rays are low in energy compared with what is used today, with disadvantages of poor penetration and the deposition of dose maximally at the skin.

The modern radiation therapy treatment machine is called a linear accelerator.

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  These machines use microwaves (with a frequency of 3000 MHz) to accelerate electrons to very high energies.

  
  
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  These electrons strike an x-ray target (usually tungsten) to produce a beam of (mainly bremsstrahlung) x-rays.

  
  
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  This x-ray beam is flattened with a flattening filter, so that the beam is uniform throughout, and collimated by the collimator, so that the size of the beam can be selected.

  
  
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  This high-energy beam is directed at the target volume within the patient, which is made up of the tumor and surrounding tissue that is to be treated ( Fig. 25-2 ).

  
  

  
  

  
  

  

  
  

  
  

  Linear accelerator.

  
  

The absorbed dose from an x-ray beam is the measure of the energy deposited by the beam and absorbed by the target.

The unit of absorbed dose is the Gray (Gy), named after the British radiobiologist L.H. Gray.

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  It is defined as the Joules of energy absorbed in a kilogram of tissue (J/kg). Clinical doses are often communicated as centiGray (cGy), equal to the older term of rad.

Because the amount of radiation absorbed by the target is assumed to be closely related to the observed biologic effects, how and where the dose is deposited is obviously very important.

As stated previously, x-rays in the megavoltage energy range, such as those used in radiation therapy, exhibit the phenomenon of skin sparing, whereby the dose deposited in tissue is relatively low at the surface but increases rapidly over the first few millimeters. The region of rapidly increasing dose is known as the build-up region. This rapid increase occurs because of the forward-moving photons interacting with electrons of the target tissue via the interactions described previously.

Linear accelerators typically produce beam energies ranging from 6 to 18 MeV, and the dose at depth increases with beam energy.

Therefore, an 18 MeV photon beam would deliver more dose to a given depth in a patient than would a 6 MeV photon beam.

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  An 18 MeV beam would also show more skin sparing (i.e., it would have a greater D _max ).

Another aspect that affects the depth dose is the size of the field of radiation used to treat the patient. With a larger field size, there is greater scattering of photons within the field during the interactions with electrons.

This scatter effect leads to more interactions, which translates into a higher deposition of dose at depth.

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  In other words, the dose at 10 cm depth within a patient from a photon beam that has a field size of 20 cm × 20 cm would be higher than the same photon beam with a field size of 5 cm × 5 cm.

Many other factors go into the calculation of dose delivered at varying depths in a patient, including scatter from the collimators in the machine, blocks to shield normal tissue, and wedges and compensators (which are used to shape the photon beam).

Another main modifier in the target tissue that affects dose at depth is the density of the tissue being treated.

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  Lung, for example, being less dense than soft tissue, allows more photon transmission.

Cell killing occurs when critical targets within the cell are damaged by radiation. Therefore, radiation that deposits dose near critical structures is more likely to incur a biologic effect.

A number of biologic molecules or structures are potential targets for radiation damage, and there is still lively debate within the field as to whether there are multiple targets within the cell.

Many circumstantial data indicate that DNA is the critical target for the biologic effects of radiation, although this speculation remains without definitive proof. Measurement of DNA damage after radiation closely correlates with cell lethality.

Cells that are inhibited from repairing DNA damage or that are naturally deficient in DNA repair enzymes show a distinct radiosensitivity ^.

Also, experiments in which the nucleus was irradiated selectively show that radiation caused cell death at a higher rate than did radiation of the cytoplasm.

DNA damage can be termed direct or indirect. If radiation is absorbed by the DNA itself, the atoms of the DNA can become ionized and damaged.

This is termed the direct effect of radiation. Because the width of DNA is 1 to 4 nm and there is relatively little DNA in the cell, direct damage must be a relatively infrequent event.

More commonly, water molecules surrounding the DNA are ionized by the radiation. The ionization of water creates hydroxyl radicals, peroxide, hydrated electrons, and oxygen radicals. All of these species are highly reactive free radicals. These radicals, in turn, interact with the DNA and cause damage. This is termed indirect damage.

Eighty percent of a cell is composed of water, making indirect damage a much more common event.

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  Direct and indirect damage work to cause broken bonds in the DNA backbone.

  
  
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  These broken bonds can result in the loss of a base or of the entire nucleotide, or in complete breaking of one or both of the strands of DNA. Single-strand breaks are easily repaired using the opposite strand as a template.

  
  
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  Therefore, single-strand breaks show little relation to cell killing, although they might result in mutation if the repair is incorrect.

  
  
  
  
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    Double-strand breaks, on the other hand, are thought to be the most important lesion in DNA produced by radiation. Double-strand breaks, as the name implies, results in the chromatin being snapped into two pieces.

    
    
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    These double-strand breaks can result in mutations or, most important, in cell killing. Because x-rays are sparsely ionizing, there can be random stochastic processes in regions within the cell where ionization events are much more densely clustered than in other areas.

    
    
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    The free radicals produced are also thought to be clustered in discrete areas.

    
    
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    Therefore, the multiple broken bonds and resultant DNA damage that occurs could be highly localized. The term locally multiply damaged site , coined by John Ward, or the cluster hypothesis described by Goodhead refers to this phenomenon, and Ward suggests that it is these clustered regions of DNA damage that lead to clinically significant effects.

  
  

Most investigators believe that the dominant form of lethal radiation-induced DNA damage is the double-strand break, which ultimately results in mitotic death. In surviving irradiated cells, chromosomal aberrations such as nondisjunctions and micronuclei are detectable.

Radiation controls cancer cells through at least three main effects:

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  Inducing apoptosis.

  
  
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  Causing permanent cell cycle arrest or terminal differentiation.

  
  
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  Inducing cells to die of mitotic catastrophe.

  
  
  
  
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    Apoptosis is also known as “programmed cell death.” The triggering of cell death is a process frequently seen in normal development, differentiation, immune responses, menstruation, neuronal development, and tissue turnover, and it also can be triggered by several noxious stimuli, including ionizing radiation. In this case, radiation damage triggers signaling cascades that invoke pre-existing mechanisms by which the cell self-destructs. Cells undergoing apoptosis show very characteristic features as they die, including dramatic blebbing and fragmentation of the nucleus. Radiation with doses typically used in the clinic often induces apoptosis in lymphomas and other malignancies of hematopoetic origin. In contrast, apoptosis is far less commonly seen in tumors of epithelial origin, such as head and neck squamous cell cancers. Tumors that commonly undergo apoptosis often have a brisk clinical response to radiation therapy.

    
    
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    All of these factors must be taken into consideration when a fractionation scheme is being designed. Although the “standard” fractionation schedule differs in many parts of the world, 1.8 to 2.0 Gy per day is considered the conventional fractionation schedule in the United States. Most regimens that deviate from this norm use more than one fraction in a day. This reduces both the size of the fraction and the total treatment time, to take advantage of the radiobiologic principles as they apply to early-responding tissues (and tumors) and to late-responding tissues as described previously.

  
  

The standard of five fractions per week and 9 to 10 Gy of dose per week has evolved not as a biologically designed, optimal method of administration of radiation but rather from considerations such as the convenience of patients and staff, the availability of equipment, and financial concerns.

Outside of the United States, the same nonmedical constraints have often dictated other fractionation regimens that usually employ fewer fractions over a shorter time period because of limited availability of high-energy treatment machines or trained radiation oncologists.

In the 1990s, more attention was paid to attempts to alter the customary fractionation protocols toward schemes that would improve the biologic outcome from treatment, either through increased tumor sterilization or decreased normal tissue toxicity, or both.

These attempts were undertaken because of the knowledge that the effects of radiation on acutely reacting tissues (e.g., skin and mucosa) are different from those on late-reacting tissues. Early-reacting tissues, which determine the patient’s tolerance to treatment, are time dependent in their reactions.

Because these tissues proliferate rapidly, prolonging the total time of therapy allows proliferation to take place and thus lessens the severity of the overall reaction. This is especially true about breaks (days off) from treatment, during which a mucosal or skin reaction can heal substantially in just a few days. Late-reacting tissues do not proliferate during a 6- to 7-week course of treatment, and their reaction is thus not sensitive to overall treatment time.

Late-reacting tissues are very sensitive to fraction size, however. It is now clear from a number of clinical studies that for the same total dose, late reactions are worse when large fractions are used compared with smaller ones. This is understandable from the shape of the cell survival curves for early- and late-reacting tissue. Late-reacting tissues have low α/β ratios, and their survival curves bend at higher doses, causing a substantial difference in cell kill with large rather than small fractions.

With little proliferation to make up the difference, the tissues become fraction-size dependent. If large fractions are used, the total dose must be lowered to achieve the same effect on long-term toxicity.

Clinical examples of this effect are found most often in palliative regimens, in which 20 Gy in five fractions or 30 Gy in 10 fractions are given to spinal metastases and equate with 50 Gy in 25 fractions for spinal cord tolerance.

Many Canadian and European centers give fewer numbers of larger fractions for curative treatment as well, reducing total dose for the sake of not amplifying late toxicity. It becomes clear that a few large fractions preferentially damage late-reacting tissues, whereas larger numbers of smaller fractions preferentially spare them.

The other side of this coin is tumor proliferation. If many small fractions are used and the time it takes to deliver a course of radiation is protracted, tumor proliferation could negate any gains. When the aims are to both take advantage of the sparing of late tissue damage and avoid having treatment last for too many days, treatment has been given with multiple fractions per days.