Abeloff's Clinical Oncology, 4th Edition

Part I – Science of Clinical Oncology

Section D – Preventing and Treating Cancer

Chapter 29 – Basics of Radiation Therapy

Ricky A. Sharma,Katherine A. Vallis,
W. Gillies McKenna

SUMMARY OF KEY POINTS

Historical Perspective

  

   

X-rays were discovered by Wilhelm Conrad Roentgen in 1895.

  

   

Radioactivity was discovered and named by Henri Becquerel, Marie Curie, and Pierre Curie.

  

   

Over the past 3 decades, major advances have been made in conformal external beam radiation therapy, brachytherapy, stereotactic irradiation, proton therapy, systemic targeted radionuclide therapy, and chemoradiation treatments.

Radiation Oncology Physics

  

   

Several different types of ionizing radiation are used to treat patients; most cause low linear energy transfer (LET).

  

   

Therapeutic x-rays (photons) and γ-rays are produced by linear accelerators or by radioactive decay.

  

   

Radiation interacts with matter via several processes, of which the most important in clinical radiation therapy is Compton scatter.

  

   

Megavoltage photons from linear accelerators have a skin-sparing effect, with the maximum dose deposited at depth.

Biological Effects of Radiation

  

   

Direct and indirect damage to DNA in cells, particularly double-strand breaks, is believed to be the dominant form of radiation-induced cell kill.

  

   

Irradiation causes diverse cellular responses that induce molecular mechanisms for DNA damage repair, cell cycle arrest, and cell death.

  

   

The most commonly applied model of cell survival probability is the linear quadratic model, which uses α/β ratios to describe the surviving fractions.

  

   

Cells may repair sublethal and potentially lethal damage after exposure to radiation.

  

   

The radiosensitivity of cells changes as they progress through different stages of the cell cycle; cells are most radiosensitive in G2 and M phases.

  

   

The response of cells to radiation is highly oxygen dependent, an effect expressed by the oxygen enhancement ratio (OER).

  

   

Radiosensitizers, particularly systemic cytotoxic chemotherapy, aim to improve the therapeutic ratio by enhancement of tumor cell killing relative to normal tissues.

Clinical Application of Radiobiologic Principles

  

   

Fractionation of radiation and altered fractionation schedules, such as accelerated hyperfractionated radiation therapy, make use of differences in the responses of normal and malignant tissues to irradiation in order to achieve higher therapeutic ratios.

  

   

Radiation has varied effects on normal tissues, ranging from early effects such as skin erythema to late effects such as carcinogenesis.

Process in Radiation Treatment

  

   

Process in treatment planning and quality control is essential to the safe and effective delivery of clinical radiation therapy.

  

   

Three-dimensional conformal treatment planning and delivery has permitted escalation of dose and improved sparing of normal tissues.

  

   

Radiation therapy is used in more than half of all patients with cancer, either as an adjuvant or neoadjuvant treatment in combination with surgery, as a definitive treatment alone or in combination with chemotherapy, as an organ-sparing therapy, or to palliate symptoms.

New Modalities in Radiation

  

   

Brachytherapy delivers extremely high-dose radiation to tumor tissue with a much lower dose to surrounding normal tissues.

  

   

Systemic targeted radionuclide therapy has been a significant advance in the treatment of hematologic malignancies and is being investigated for the treatment of solid cancers.

  

   

Intensity-modulated radiation therapy (IMRT) uses multiple radiation beam intensities to try to improve the therapeutic ratio.

  

   

Proton therapy has radiobiologic advantages over photon therapy, and it may be used to deliver high doses of radiation to tumors in close proximity to normal structures.

HISTORICAL PERSPECTIVE

In the closing years of the nineteenth century, many physicists were investigating the nature of electricity. It was known that if an electrical potential was placed across two separated platinum electrodes, a spark would leap between them. The British physicist William Crookes demonstrated that if the two electrodes were placed within a glass vessel that was then evacuated, as the vacuum increased the spark would at first be replaced by a glow that filled the whole vessel. As the vacuum was increased still further, a dark space would appear at the cathode electrode and would expand as the vacuum dropped until it filled the whole tube. The walls of the vessel would then begin to fluoresce. On November 8, 1895, while passing electricity through a high-vacuum Crookes tube, Wilhelm Conrad Roentgen noted the fluorescence of a nearby piece of paper painted with barium platinocyanide. Because he had wrapped the Crookes tube in heavy opaque paper before beginning the experiment, he realized that this fluorescence of the paper could have been caused by a new, invisible type of ray that the tube was now emitting that was affecting both the shielded walls of the tube and the nearby piece of paper. Hence, the “x-ray” was discovered.[1]

Roentgen proceeded to study the intensity and the attenuation of x-rays. He proposed the inverse square law to describe the loss of intensity of the x-rays with the inverse square of the distance between the tube and the plate.[2] He also noted that he could see the shadow of the bones in his hand when it was placed between the Crookes tube and the fluorescent paper. This led to the first human x-ray film on December 22, 1895, when Roentgen placed his wife's hand between the x-ray tube and a photographic plate ( Fig. 29-1 ).[2] Because the x-ray tube was a simple apparatus to replicate, many experiments using x-rays took place worldwide within a short time. This widespread experimentation resulted in rapid advances in the new field, particularly for diagnostic purposes in hospitals.

 
 

Figure 29-1  First radiograph of his wife's hand, exposed by W.C. Roentgen on December 22, 1895.

 

 

“Radioactivity” was discovered within a few years of the production of the first x-rays. As the Crookes tubes produced x-rays, the walls of the tube would fluoresce. Other substances were also known to fluoresce spontaneously, and it was thought that these substances might also produce x-rays. This possibility was investigated by Henri Becquerel,[3] who observed the darkening of photographic plates by uranium salts. From this phenomenon, he concluded that x-rays were emitted spontaneously and continuously from the salts. He reported the results of his experiments with uranium to Pierre and Marie Curie, who coined the term radioactivity to describe it. They set out to isolate in purer form the radioactive substances within uranium salts, and they reported the discovery of radium in 1898.[4]

The biologic effects of ionizing radiation were recognized very early. Unfortunately, scientists and other workers performing early radiation experiments experienced significant toxic effects. Initially, these side effects were primarily erythema of the skin from exposure to x-rays; the carcinogenic properties of x-rays became evident in later years. For example, Pierre Curie performed an experiment on himself in which he noted skin radiation changes and epilation after exposure to radium for only a few hours.[5] Reading of this, Alexander Graham Bell wrote to a colleague suggesting that if radium “sealed up in fine glass tube” were inserted “into the very heart” of a cancer, it might cause the tumor to regress.[6] Around this time, physicians at St. Louis Hospital in Paris began using radiation to treat patients with cancer. The first reported cure with radiation involved a patient with basal cell epithelioma in 1899.[7]

Hope that further cures for cancer lay in radiation therapy was soon replaced by skepticism when recurrences and toxicities were noted. The early treatments often involved very large single exposures aimed at the complete eradication of tumors. These large exposures, together with the fact that the first x-ray machines were capable of producing only low-energy x-rays with poor tissue penetration, resulted in extensive skin toxicities and other complications. Therefore, only superficial sites were treated by the direct application of radium, with impressive results.[8] Eventually, physicians started to insert radium directly into deep-seated tumors, in the first forms of brachytherapy. Cervical cancer was treated using this method, with dramatic responses.[9] In fact, external beam radiation therapy might have been abandoned had it not been for the work of Claude Regaud and Henri Coutard, who used smaller doses of radiation in several treatments delivered over several weeks to overcome the acute toxicity induced by a large single fraction of radiation therapy.[10] Based on these pioneering studies, radiation oncology became a recognized medical field in 1922, when Coutard and Hautant reported that advanced laryngeal cancer could be cured without severe toxicities using fractionated treatments.[11] By 1934, Coutard had developed a fractionation scheme that remains the basis of radiation fractionation today.

In parallel with advances in the delivery of treatment, advances in measurements were achieved when the skin erythema dose (the dose of x-rays required to cause a light skin reaction) was replaced by a unit called the roentgen in 1928.[12] The roentgen, which was roughly the exposure received by placing 1 gram of radium at a distance of 1 yard for 1 hour, expressed the radiation exposure and allowed reproducible measurement and standardization of treatment dosages in different departments. It was calibrated by measurement of the ionization of air using ionization chambers. When higher-energy beams were developed, the size of the ionization chamber necessary to measure their effect became impossibly large, and the roentgen was replaced by a new unit, the rad (an abbreviation for radiation absorbeddose). The rad was a measure of the energy deposited per unit mass by all types of ionizing radiation. Biologic effects in tissue exposed to ionizing radiation depend on the energy deposited in the tissue rather than the amount of ionization that the radiation produces in air. One rad was defined as the deposition of 100 ergs per gram of absorbing material. As a general rule, the absorbed dose in soft tissue from 1 roentgen of intermediate-energy x-rays or gamma rays was roughly equivalent to 1 rad. With metric conversion to standard SI (Système International), the rad was replaced by the gray (Gy), a unit named after the British radiobiologist L.H. Gray. One gray is equal to 1 joule of energy absorbed per kilogram of mass. Energy absorbed is dependent on the material used; the material used for radiation therapy definitions is water. For materials with significantly higher atomic numbers than water (e.g., bone), the ratio of mass energy absorption coefficient depends on the energy of the radiation (see later section on Interactions of X-Rays with Matter). Clinical doses often are communicated as centiGray (cGy), equivalent to the older term 1 rad (i.e., 1 G = 100 rad = 1 joule/kg).

RADIATION ONCOLOGY PHYSICS

To understand the role of radiation therapy in curing and palliating disease, a full understanding of the particles and processes involved in the production and delivery of radiation is required. This section provides an introduction to the physical properties of radiation that are fundamental to the clinical applications of radiation.

Types of Radiation

Electromagnetic radiation is energy that is transmitted at the speed of light through oscillating electric or magnetic fields. A photon has wavelength l, frequency n, and energy E = hn, where h is Planck's constant (6.626 × 10-34 Joule seconds). The electromagnetic spectrum ranges from wavelengths of 105 m for AM radio waves to 10-12 m for x-rays and cosmic rays. Although electromagnetic radiation conventionally is described as waves, it also is valid to describe radiation in terms of photons (“packets of energy”). Because energy varies inversely with wavelength, x-rays have a much greater energy than do radio waves. This higher energy gives x-rays the property of being deeply penetrating, which makes it possible to use them therapeutically to treat internal tumors.

Clinical types of radiation therapy include teletherapy (e.g., treatment from a cobalt-60 source), external beam x-rays (from a linear accelerator), and brachytherapy (using a source of radiation inserted or implanted into the patient). X-rays and gamma rays differ only in terms of their production: gamma rays are produced within the nucleus from natural radioactive decay and x-rays are produced outside of the nucleus. In practice, x-rays are produced by machines such as linear accelerators (see the section on Radiation Production from Linear Accelerators) and gamma rays used in radiation therapy are produced by the decay of radioactive substances. There is no difference in their treatment effects. Radiation sources used in brachytherapy and systemic radionuclide therapy (see the section on Systemic Targeted Radionuclide Therapy) include radioactive nuclei that decay and emit positively charged alpha (α) particles, positively charged beta (β+) particles, or negatively charged beta (β-) particles (electrons), which may occur with emission of a gamma ray. Clinically, a and b particles do not penetrate deeply, so gamma rays and x-rays are used in external beam radiation therapy to deposit doses at depth.

X-rays, gamma rays, and electrons are termed low linear energy transfer (LET) radiation and must be distinguished from high LET radiation such as alpha particles or fast neutrons. LET is defined as energy transferred per unit track length of radiation, equivalent to how often a type of radiation causes ionizations in the tissue it is traveling through. The x-rays, gamma rays, and electrons commonly used in therapy are low-LET radiation, and are, therefore, sparsely ionizing, producing relatively few ionizations in the paths they travel through in the tissue. This is in contrast to high LET radiation such as neutrons ( Fig. 29-2 ), discussed in more detail in the final section of this chapter.

 
 

Figure 29-2  Computer simulations of sections of charged-particle tracks produced by different types of radiation passing through a strand of chromatin. Each cross represents a single ionization of either the chromatin or the surrounding medium. Right track, low-linear-energy transfer (LET) 100 keV electron, typical of those produced by 250-kV x-rays. Center track, high-LET, high-energy iron ion that produces a dense column of ionization. Note the high-energy secondary delta ray coming out of the track. Left track, medium LET 3 MeV proton. The scale bar represents 50 nm.  (From Cox JD, Ang KK [eds]: Radiation Oncology: Rationale, Technique, Results, 8th ed. St. Louis, Mosby, 2003, p 44.)

 



Radiation Production

Radiation Production by Radioactive Decay

The nucleus contains protons and neutrons that usually have stable configurations. When these configurations are not stable, they undergo spontaneous disintegration to attempt to reach a more stable state. The disintegration of radioactive species is called radioactive decay. 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.

The first radioactive species isolated by the Curies was polonium, with radium discovered shortly thereafter.[5] Since that time, many other radioactive species have been discovered and produced artificially. Today, the main use of radioactive species is in brachytherapy and systemic radionuclide therapy, although cobalt-60 units still are used for teletherapy. Radium was the most important implantation source used for more than 5 decades in the twentieth century. However, many properties of radium make it undesirable as a radioactive source for therapy. During its decay, radium produces radon gas, which is colorless and odorless but highly radioactive. Moreover, radium has a very long half-life (the time it takes for a radioactive substance to decay to half of its original strength). These qualities make it a significant hazard in the case of contamination. Hence, more suitable isotopes have replaced radium in clinical applications ( Table 29-1 ). Cesium-137 is widely used for gynecologic brachytherapy implants. It has a lower-energy gamma ray than radium (i.e., it is less penetrating and easier to shield), and it has no gaseous daughter nuclei. Palladium-103, iridium-192, and iodine-125 are used for implantation in the body for brachytherapy treatments (see the section on New Modalities later in this chapter). Many of the isotopes used in brachytherapy emit low-energy gamma rays, resulting in a steep fall-off of dose for the surrounding normal tissues and posing no significant risk of radiation exposure for people in the patient's environment. Other isotopes such as strontium-90 or yttrium-90 emit β- particles (electrons). The advantage of this type of radiation is that it deposits a dose very superficially, for example sparing the outer layers of the walls of arteries during intravascular brachytherapy.


Table 29-1   -- Therapeutic Isotopes

Isotope

Half-life Average

Energy (keV)

Photon

 

 

 226Ra

1620 y

830

 137Cs

30 y

662

 198Au

2.7 d

412

 192Ir

73.8 d

370

 125I

60 d

28

 103Pd

16.97 d

21

Isotope

Half-life

Maximum Energy (keV)

Beta

 

 

 32P

14.3 d

1710

 90Sr/90Y

28.5 y/2.7 d

550/2280

 188W/188Re

69.4 d/17 h

350/2120

 186Re

3.8 d

1070

 62Zn/62Cu

9.3 h/9.7 min

660/2930

 133Xe

5.2 d

360

 131I

8.0 d

600

 89Sr

50.5 d

1495

 166Ho

26.8 h

1850

From Cox JD, Ang KK (eds): Radiation Oncology: Rationale, Technique, Results, 8th ed. St. Louis, Mosby, 2003, p 6.

keV, kiloelectron volt.

 

 

 

Historically, cobalt-60 is a very important radioisotope because of its use in teletherapy. Cobalt machines were the first practical megavoltage machines, pioneered by the Canadian physicist H.E. Johns.[13]The radioactive decay of cobalt-60 releases gamma rays with energy of approximately 1.2 megavolts (MeV). Because the depth of penetration in tissue increases with increasing x-ray energy, this development allowed the delivery of higher doses of radiation therapy without having to limit the dose due to skin toxicity. This advance drove attempts to generate high-energy x-rays. For example, in the 1930s, St. Bartholomew's Hospital in London had a machine that produced 1-MeV rays using an x-ray tube 30 feet long. These machines, however, had low output and small field sizes and were mechanically unreliable. Cobalt 60 machines were simple in design and highly reliable, so they revolutionized the practice of radiation therapy and were used for decades. Their skin-sparing effect made it possible, for the first time, to administer safely the doses of radiation required for treatment without the desquamating skin toxicity that had been the hallmark of kilovoltage radiation therapy. Over the past 3 decades, cobalt machines in the United States have been replaced largely by modern linear accelerators, which have the advantages of producing more sharply defined beams of a variety of different energies and the ability to deliver electrons or x-rays for therapeutic purposes. Linear accelerators also can be used with devices such as computer-controlled multileaf collimators, allowing dose delivery with much greater precision (see the section on Radiation Production from Linear Accelerators). Today, cobalt 60 is used primarily for palliative teletherapy or for stereotactic teletherapy to small malignant lesions in the brain and benign lesions such as acoustic neuromas or arteriovenous malformations. For sterotactic radiation therapy or radiosurgery, more than 200 narrow beams of gamma rays from a source such as cobalt 60 may be focused on one point, allowing tightly conformed doses of radiation therapy to be delivered as a single fraction or as multiple fractions. Alternatively, a linear accelerator may be used for x-ray production. The treatment requires extremely accurate immobilization of the patient, usually with a head frame or special mask. Lesions must meet stringent criteria to be considered amenable for stereotactic radiation therapy.[14]

Radiation Production from Linear Accelerators

Two processes can produce x-rays when electrons are directed at target atoms. The electrons can ionize the atoms by depositing sufficient energy so that an inner shell electron is ejected. The vacancy in the inner shell is filled by an electron from an outer shell, with the release of a photon called a characteristic x-ray. An alternative 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.

Although some centers continue to deliver external beam radiation therapy to skin cancers using a vacuum tube producing x-rays with a maximum energy of about 300 keV, most centers use linear accelerators for general radiation therapy. Modern linear accelerators (Figs. 29-3 and 29-4 [3] [4]) use microwaves (with a frequency of ∼3000 MHz) to accelerate electrons to very high energies. These electrons strike a target (usually tungsten) to produce a beam of x-rays, mainly by bremsstrahlung effects. The x-ray beam is “flattened” with a filter, so that the beam is uniform, and shaped with the collimators so that the field size is appropriate.

 
 

Figure 29-3  Block diagram representing the mechanism of a typical medical linear accelerator.  (From Leibel SA, Phillips TL [eds]: Textbook of Radiation Oncology. Philadelphia, WB Saunders, 1998, p 110.)

 



 
 

Figure 29-4  Schematic diagram showing the basic components of the treatment head of a modern linear accelerator. A, Components in place for x-ray therapy. B, Components in place for electron therapy.  (From Leibel SA, Phillips TL [eds]: Textbook of Radiation Oncology. Philadelphia, WB Saunders, 1998, p 100.)

 



Another type of radiation therapy produced by linear accelerators is the electron beam. To produce an electron beam with a linear accelerator, the electrons strike a thin scattering foil that spreads out the electron beam to an area large enough to be used for treatment. Electrons are used to treat areas of superficial depth, for example, as definitive treatment of skin cancer or as a boost to the tumor bed of breast cancer.

Interaction of X-rays with Matter

X-rays can interact with matter via several different processes. The probability of each interaction type depends on the composition of the matter and the energy of the x-rays. These interactions cause some photons (x-rays) to be removed from the forward-moving x-ray beam, causing an effect called attenuation, which, in basic terms, is the loss of intensity and subsequent decrease in the deposition of dose as the beam reaches greater depths. Five possible interactions of x-rays with matter include (1) coherent scattering; (2) the photoelectric effect; (3) Compton scatter; (4) pair production; and (5) photodisintegration. The interactions most relevant to radiation therapy are illustrated in Figure 29-5 .

 
 

Figure 29-5  The first step in the absorption of a photon of x-rays or gamma rays is the conversion of the energy of the photon into the kinetic energy of an electron or electron-positron pair. At higher energies, when the energy of the incident photon greatly exceeds the binding energy of the bound electrons in the atoms of the absorber, Compton scatter dominates. Part of the photon energy is given to the electron as kinetic energy, whereas the photon is deflected and has reduced energy. At lower energies, when the binding energy of the bound electrons of the atoms of the absorber is not small compared to the photon energy, the photoelectric effect is most important. The photon disappears completely as it interacts with a bound electron. The electron is ejected with kinetic energy equal to the photon energy, less the energy required to overcome the electron bond. The vacancy caused by the removal of the electron must be filled by an electron dropping from an outer orbit, giving rise to a photon of characteristic radiation. At sufficiently high photon energies, the photon might interact with the powerful nuclear forces to produce an electron-positron pair. The first 1.02 MeV of photon energy is used to create the rest mass of the pair, and the remainder is distributed equally between them as kinetic energy.  (From Cox JD, Ang KK [eds]: Radiation Oncology: Rationale, Technique, Results, 8th ed. St. Louis, Mosby, 2003, p 5.)

 



Coherent Scattering

Also called classic scattering, coherent scattering occurs to low-energy x-rays. In coherent scattering, a photon is scattered from an electron, with a resultant change in direction but no change in energy. Only a negligible amount of coherent scattering occurs in therapeutic and diagnostic irradiation. Coherent scattering is important in processes such as x-ray crystallography.

Photoelectric Effect

The photoelectric effect first was described by Albert Einstein, and it was this contribution to physics that led to his Nobel Prize in 1921. In the photoelectric effect, a photon interacts with a tightly bound inner shell electron in the target tissue. Complete absorption of the photon's energy occurs, with the ejection of the electron from the orbit. The probability of a photoelectric interaction is highly dependent on the atomic number (Z) of the material through which the photon is passing. The photoelectric effect is very important in diagnostic radiology; it is the process that is the basis for the radiographic contrast between tissues (e.g., between bone and fat) in plain x-ray films and computed tomography (CT) scanning. With the exception of skin cancer treatment with superficial x-rays, the photoelectric effect is undesirable in radiation therapy. With higher energy x-rays delivered by linear accelerators, the contribution of the photoelectric effect is small to negligible.

Compton Scatter

Compton scatter is the most important interaction for energies within the range generally used for radiation therapy. In Compton scatter, a photon transfers energy to an electron of the target tissue, causing the ejection of this electron. In contrast to the photoelectric effect, however, the energy of the photon is not completely absorbed. Instead, it is scattered at an angle relative to the forward direction of the original photon. This secondary photon interacts with tissue again and again, ionizing and depositing dose with each interaction. These interactions and subsequent ionizations are responsible for the biologic effects on tissues during radiation therapy.

In contrast to the photoelectric effect, Compton interactions are less dependent on the atomic number (Z) of the tissue because these interactions tend to be with the loosely bound outer electrons in atoms, where the energy binding the electron to the atom is much less dependent on Z. This results in a fairly even probability of interaction (and, hence, a fairly even deposition of dose) throughout the different biologic tissues with which the x-rays interact in a patient.

Pair Production

Pair production occurs at high energies. It is the interaction of a photon with a nucleus, with the spontaneous disappearance of the photon and the production of an electron and a positron (a positively charged electron). Pair production becomes the predominant effect in biologic tissues at about 25 MeV. Because 25 MeV is above the range that is typically used in therapy, pair production plays only a small role in most cases.

Photodisintegration

At very high energies, x-rays can deposit so much dose into the nucleus of the target tissue that partial disintegration of the nucleus occurs, with emission of neutrons from the nucleus. Although this has little importance in the clinical interactions used in most radiation therapy, the production of neutrons is important when planning shielding around high-energy linear accelerators to protect patients and personnel from unnecessary exposure to radiation.

Deposition of Dose

As an x-ray beam passes through tissue, the region of rapidly increasing dose is known as the build-up region. This rapid increase occurs because of forward-moving photons interacting with electrons of the target tissue via the processes described previously. Because these electrons also are propelled forward but have a shorter course than the photons, there is an area at depth at which the number of electrons entering the plane of interaction from superficial interactions is exactly equal to the amount leaving the plane from interactions in that plane. This plane is termed the Dmax, as it represents the depth of the maximum number of ionization events ( Fig. 29-6 ). Beyond this point, as more interactions between the photon beam and tissue occur, fewer photons are available to travel forward and deposit dose at greater depths. This process is called attenuation. How a photon beam is attenuated (i.e., how much dose it deposits at depth) depends on qualities both within the beam and within the target tissue. The most substantial effect on depth dose from the photon beam itself is the beam's energy ( Fig. 29-7 ).

 
 

Figure 29-6  A, Simplified explanation of the phenomenon behind skin sparing. Assume that x-rays interact with tissue and liberate electrons that can have subsequent ionizations along their tracks. In this example, the electrons have a range of 4 mm and an average of five interactions (red lines) for each millimeter of tissue traversed. B, We can then count the number of electron interactions and plot them on a graph. Note that the number of interactions increases with each millimeter of tissue until 4 mm of depth, where the number of interactions (20 in this case) reaches a maximum. If there were no attenuation of beam by tissue, this maximum number of interactions would continue to be observed at all depths. In reality, the intensity of the beam is attenuated by the tissue and, after the point of maximum dose, the number of interactions at greater depths will begin to decrease.  (From Lichter AS: Radiation therapy. In Abeloff M [ed]: Clinical Oncology, 2nd ed. London, Churchill Livingstone, 2000, pp 423–470.)

 

 

 

 
 

Figure 29-7  Percentage depth-dose curves for a variety of radiation types used in clinical radiation therapy. These include x-rays and γ-rays (110 kV to 18 MV) and various energies of electrons (6 MeV to 20 MeV). The inset shows the pattern of absorption at shallow depths and provides an illustration of the skin-sparing effect of photons.

 

 

Linear accelerators typically produce beam energies ranging from 4 to 18 MeV, and the dose deposited at depth increases with beam energy. Therefore, an 18-MeV beam would show more skin sparing and it would have a higher Dmax than a 4-MeV beam. The depth dose is also affected by 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. In other words, a dose given at a 10-cm depth 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. Lung, for example, because it is less dense than soft tissue, allows more photon transmission. Additionally, the inverse square law must be taken into account, particularly with regard to the distance from the source to the skin. All of these factors must be taken into consideration when determining the dose being delivered to structures within the patient.

Electrons differ from photons in that electrons travel only a relatively short distance within tissue. They are very light particles compared with the nuclei of the target tissue with which they interact. Hence, they lose a large fraction of their energy as they travel through tissue, leading to much less skin sparing and the deposition of the majority of the dose superficially. Consequently, they are very useful for treatments in which the target of the radiation lies close to the surface of the patient, such as skin cancer, or close to the source of the electrons, such as brachytherapy implants.

BIOLOGIC EFFECTS OF RADIATION

Basic understanding of the physical properties of a radiation beam must be coupled with an understanding of how radiation interacts with biologic tissues to cause damage. Through the interaction processes described earlier, radiation deposits energy as it travels through a patient. These interactions set secondary electrons in motion that go on to produce further ionizations. This ultimately results in the breaking of chemical bonds and damage to molecules and structures within cells. If these broken bonds and subsequent damage occur to cells’ critical structures, the most significant effect of the accumulation of radiation damage will be cell killing.

This section describes the complexities of this process. It should be noted that the deposition of radiation dose and the damage it induces are random, and its complexity depends on the type of radiation and the tissue being irradiated.

Interactions with Biologic Materials

Cellular kill occurs when critical targets within the cell are damaged by radiation and the cell is unable to repair that damage. Therefore, a radiation dose deposited near critical structures is statistically more likely to incur a biologic effect. A number of biologic molecules or structures are potential targets for radiation damage, and lively debate continues within the field as to whether there are multiple targets within the cell. Many circumstantial data indicate that DNA is a critical target for the biologic effects of radiation. Measurement of DNA damage after radiation closely correlates with cell lethality. [15] [16]Cells that are inhibited from repairing DNA damage or that are naturally deficient in DNA repair enzymes show a distinct radiosensitivity. [17] [18] 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.[19]

DNA damage can be termed direct or indirect ( Fig. 29-8 ). 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 rare event.[20] More commonly, water molecules surrounding the DNA are ionized by the radiation. The ionization of water creates hydroxyl radicals, hydrogen peroxide, hydrated electrons, and other oxygen free radicals,[21] all of which are highly reactive, capable of interacting with DNA and causing damage. This is termed indirect damage. Eighty percent of a cell is composed of water, suggesting that indirect damage to DNA is common.

 
 

Figure 29-8  Two types of interactions are possible between x-rays and DNA. In the direct interaction, an x-ray interacts with the DNA molecule itself. This interaction is relatively rare. In the indirect interaction, x-rays ionize water, and the reactive species that are created interact secondarily with DNA, causing damage and DNA strand breakage.  (From Lichter AS: Radiation therapy. In Abeloff M [ed]: Clinical Oncology, 2nd ed. London, Churchill Livingstone, 2000, pp 423–470.)

 

 

 

Direct and indirect damage can break bonds in DNA. These broken bonds can result in the loss of a base or of the entire nucleotide, or in complete breakage of one or both of the strands of DNA. Single-strand breaks are repaired relatively easily using the opposite strand as a template. Therefore, single-strand breaks are not strongly related to cell killing, though they might result in mutation if the repair fidelity is not high. Chromosomal aberrations such as nondisjunctions and micronuclei are detectable in surviving irradiated cells, which may contribute to the clonal evolution of cancer. Double-strand breaks, on the other hand, are thought to be the most important lesion in determining cell kill.[22] In double-strand breaks, the chromatin is snapped into two pieces. It has been taught traditionally that in an average cell, 1 Gy of low LET radiation causes damage to over 1000 bases in DNA, approximately 1000 single-strand breaks in DNA, and approximately 40 double-strand breaks. 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. The free radicals produced also are thought to be clustered in discrete areas. Therefore, the multiple broken bonds and resultant DNA damage that occurs could be highly localized. The term locally multiply damaged site, or the cluster hypothesis, refers to this phenomenon, since they both suggest that it is these clustered regions of DNA damage that lead to clinically significant effects. [23] [24]

Most investigators believe that the dominant form of lethal radiation-induced DNA damage is the double-strand break, which ultimately results in cell death if the cell is unable to repair the damage. Cells respond to double-strand DNA damage by invoking mechanisms that sense the damage and mechanisms that actually bring about repair. The earliest detectable event after exposure to ionizing radiation appears to be the phosphorylation of histone H2AX (i.e., the formation of “gamma-H2AX”), a reaction dependent on the ataxia telangiectasia mutated (ATM) protein. [25] [26] Major factors that subsequently determine cellular fate include checkpoint proteins (such as ATM, ATR, CHK1, CHK2 and DNA-PK), cofactors and modulating factors that influence p53 activation, and the success of DNA damage repair ( Fig. 29-9 ).[27]

 
 

Figure 29-9  Ionizing radiation induces nuclear 53BP1 foci. B53P1 is a protein that appears to act as a central mediator of several cellular pathways. A, 53BP1 protein localizes to nuclear foci at sites of double-strand DNA damage caused by ionizing radiation (IR). B,Recruitment of repair and chromatin remodeling factors at IR-induced 53BP1 foci. Bioactive proteins co-localize with 53BP1 at foci, including HDAC4 (shown), BRCA1, and Rad50/NBS.  (Used with permission from Gary Kao, MD, PhD, University of Pennsylvania.)

 



Two main modes by which cells accomplish repair of double-strand DNA breaks are generally recognized: homologous repair (HR) and repair by non-homologous end joining (NHEJ). In HR, either the undamaged homologous chromosome or the sister chromatid of a replicated chromosome is used as the template to fill in missing DNA sequences in the damaged chromosome. Consequently, HR is most efficient in late S or G2 phase, when the sister chromatids have replicated but not yet separated. The requirement for a template to which the damaged chromosome is matched ensures that HR has great fidelity of repair. Human tumor cells commonly arrest in G2 after double-strand DNA damage, a time when repair activities are detectable. It is, therefore, plausible that irradiation-induced G2 checkpoint delay allows more time for cells to accomplish HR and thereby survive radiation.[28] In contrast to HR, repair by NHEJ is less cell-cycle dependent. In NHEJ, the blunt ends of chromosomes severed by radiation or other agents are directly rejoined. Although repair by NHEJ might, in some ways, be more efficient than by HR, NHEJ lacks fidelity (i.e., it is considered mutagenic) because the template-free rejoining of blunt ends lacks the specificity of HR. In NHEJ, it is possible for the ends of different chromosomes to be rejoined, giving rise to chromosomal aberrations or potentially to the expression of dangerous fusion proteins. It is likely, therefore, that mutagenesis associated with radiation may be due in part to NHEJ.[29]

If cells successfully repair DNA damage induced by ionizing radiation, they may resume proliferation. Alternatively, radiation may kill cancer cells by three pathways:

  

1.   

Inducing apoptosis by the intrinsic (p53-dependent) or the extrinsic pathway

  

2.   

Causing permanent cell cycle arrest or terminal differentiation

  

3.   

Inducing “mitotic cell death” from aberrant mitosis, resulting in mitotic catastrophe.

Apoptosis also is known as “programmed cell death.” Dependent on the cell type, radiation damage triggers signaling cascades that may involve proteins such as ceramide, p53, MDM2, BAX, PUMA, NOXA, and FAS. The result is self-destruction of the cell. Cells undergoing apoptosis show very characteristic features as they die, including blebbing and fragmentation of the nucleus.[30] Radiation in the doses typically used clinically induce p53-dependent apoptosis in radiation-sensitive organs such as thymocytes and radiosensitive malignancies such as lymphomas, but apoptosis rarely is induced in tumors of epithelial origin.[31] Epithelial tissues and cancers of epithelial origin are more likely to undergo reversible or permanent cell cycle arrest, in which p53 may act as a survival factor for cells, or p53-independent mitotic cell death.[27]

Permanent cell cycle arrest and terminal differentiation also are effective endpoints by which radiation can effect cell kill. Cell cycle perturbations are seen characteristically after radiation exposure and were among the earliest observed biological effects of radiation.[32] Cells can show checkpoints or arrest in any phase of the cell cycle, although the best-described checkpoints with respect to radiation damage are the G1 and G2 checkpoints. Normal cells and cancer cells that retain normal p53 function arrest in the G1 phase of the cell cycle. This is a p53-mediated event.[27] One of the earliest effects seen after radiation damage in cells with normal p53 function is a rise in the intracellular level of p53 due to protein stabilization and decreased protein turnover. This, in turn, leads to an induction of p21, a potent cyclin-dependent kinase inhibitor, leading to blockage of the cells in the G1 phase of the cell cycle.[33] This is only one of the many known functions of p53. It also is involved in the regulation of gene expression, apoptosis, and angiogenesis, among other important cellular processes.[34] The cell cycle arrest induced by p53 often is transient but in some cases can lead the cell to exit the cell cycle permanently and undergo a process that resembles terminal differentiation. The pathways invoked are consequently reminiscent of cellular senescence, in which cells have lost the ability to cycle and proliferate.[35]

Many cancer cells, typically those with loss or mutation in the p53 protein pathway, have lost the ability to block in G1. These cells retain the ability to block in the G2 phase of the cell cycle. The G2 block is less well described at the molecular level than the G1 block, but it also involves effects that regulate the activity of cyclin-dependent kinases that are specific to the G2 phase of the cycle.[34] G2 arrest is clearly related to cellular repair of radiation-induced DNA damage, in that cells that have lost the ability to arrest in G2 are exquisitely sensitive to DNA damage. Even in cells that re-enter the cycle after a G2 block, cell death can be seen subsequently. Such cell death can take several forms. Some cells fail in cytokinesis and form multinucleate giant cells. Some undergo mitotic catastrophe as they attempt to undergo mitosis. Others undergo delayed cell lysis, which, in some cases, may be a delayed form of apoptosis.

Both tumor cells and normal tissues differ in their sensitivity to radiation. In some cases, this is due to differential sensitivity to induction of apoptosis, but in others it is due to molecular mechanisms that are as yet poorly understood. A number of factors have been correlated with radioresistance, such as the presence of hypoxia, which could contribute to the poor prognosis of some tumors. It has been hypothesized that oxygen helps “fix” damage induced by radiation in such a way that the radiation is more lethal to the cancer cells.[36] The specific molecular pathways involved in this phenomenon have not been fully elucidated (see later section on Oxygen Effect).

Most radiobiologists currently think that radiation primarily causes cell death by double-strand DNA damage and that the inability of cancer cells to repair such damage with fidelity results in their death. Although it is clear that cells that lack the ability to repair some forms of DNA damage are extremely sensitive to radiation damage, it is less clear that altered DNA repair capacity contributes to increased resistance to radiation in common cancers.[17] Nevertheless, identifying proteins required to recognize and repair such DNA damage could provide potential targets for sensitizing cells to increase tumor cell kill by radiation.

Other factors that have been implicated in altered cellular sensitivity to radiation include a number of signal transduction pathways, including some that are known to be altered in cancer. For example, EGFR, Ras, and Raf have been implicated in altered cellular sensitivity to radiation, although the molecular mechanisms underlying their effects still are incompletely described. [37] [38] [39] Considerable interest also exists as to whether components of the tumor microenvironment might contribute to tumor sensitivity. In particular, persistent production of the cytokine transforming growth factor (TGF)-β1 is an early and consistent finding in tissues exposed to low and high doses of ionizing radiation.[40]

Cell Survival Curves

One of the central ideas of radiation biology is that the loss of reproductive integrity in long-term survival assays is important to our understanding of the response of a tumor or a normal tissue to radiation. When cells are exposed to lethal doses of radiation, they might not die immediately or within a few hours of treatment, or even sometimes within a single division of radiation. When cells have been observed by time-lapse cinematophotography after irradiation, it can be seen that some cells survive and go on to form colonies, and some die quickly. Others go through up to several rounds of abortive cell division before finally ceasing to divide and undergoing a variety of possible outcomes that might include terminal differentiation, formation of multinucleate giant cells, mitotic catastrophe, or delayed apoptosis. [41] [42] [43] Radiation biologists believe that it is the proportion of cells capable of forming a colony by sustained cell division that most accurately predicts the effects of a dose of radiation. Cell survival curves have been very important in radiation biology to estimate survival of tumor cells within a population with increasing doses of radiation.

The first cell survival curves were demonstrated in the 1950s, when Puck and colleagues[44] plotted the survival of irradiated HeLa tumor cells ( Fig. 29-10 ). HeLa cells were the first continuously cultured human carcinoma strain, named after the patient who donated cervical cancer tissue. Cell survival curves usually are plotted with dose on a semilogarithmic scale. The most striking feature of these curves for low LET radiation is that the effectiveness of killing per unit dose increases with increasing radiation dose. At low doses, the survival curve starts out as a shallow line, with the surviving fraction being an exponential function of dose. At higher doses, the angle of the curve increases, representing more cell kill per increase in unit dose of radiation. Eventually, at higher doses, the curve tends to straighten again. In contrast, high LET radiation cell survival curves on a semilogarithmic plot are straight throughout, albeit with a steeper slope—i.e., survival is an exponential function of dose throughout. Survival curves contrasting low LET and high LET radiation are shown in Figure 29-11 .

 
 

Figure 29-10  X-ray or gamma ray dose-survival curves for mammalian cells. A, The first such curve, reported in 1956 by Puck and Marcus. Note that the dose is expressed in roentgens (R), which, for cells irradiated on the glass, must be multiplied by approximately 1.4 to give the dose in cGy. B, A range of survival curves for other mammalian cells. The dashed lines encompass the range for “wild-type” cells of various origins. The steepest curves show a range typical of hypersensitive mutants, such as cells from patients with ataxia-telangiectasia (AT).  (From Leibel SA, Phillips TL [eds]: Textbook of Radiation Oncology. Philadelphia, WB Saunders, 1998, p 4.)

 



 
 

Figure 29-11  The survival curve for x-rays (low LET radiation) is characterized by a broad initial shoulder, whereas for neutrons (high LET radiation), the survival curve has little or no shoulder. Consequently, the relative biological effectiveness (RBE) gets larger as the dose gets smaller. When a dose is fractionated, the RBE is larger for a given level of cell killing than if the dose is given in a single exposure because the large shoulder of the x-ray dose-response curve is repeated each time.  (From Cox JD, Ang KK [eds]: Radiation Oncology: Rationale, Technique, Results, 8th ed. St. Louis, Mosby, 2003, p 45.)

 



A number of mathematical models have been devised to attempt to describe the shape of the cell survival curves that are observed experimentally, with an initial shallower slope and eventual bending (the “shoulder”) and a final, steeper slope. These include target models, lethal and potentially lethal damage models, and repair saturation models. Some of these have been based on simple mathematical modeling without any real attempt to model known molecular events involved in cell killing, whereas others have been based on attempts to model some of the known molecular events (e.g., chromosome breaks or DNA repair) that are involved in cell killing. All of the models can describe the shape of the survival curve to a first approximation. None do so perfectly, and none take into account all the events and all of the possible mechanisms involved in cell death. For a more detailed discussion of the limitations of each model, the interested reader is referred to one of the textbooks of radiobiology.[45]

One model that has been most influential on clinical practice is the linear quadratic model, because it is the model that best fits the behavior of cells after exposure to radiation doses within the range used in the clinic.[46] In their original thesis, Kellerer and Rossi proposed that radiation-induced cell killing resulted from two potential events, one with a linear relation to dose (exp[-αD]) and the other having a quadratic relation to dose (exp[-βD[2]]). This was expressed mathematically by the “alpha-beta” equation,

which was shown to fit most experimentally observed survival curves. S represents survival of a cell population after a dose, D ( Fig. 29-12 ). For many cell types, the linear-quadratic model is useful in describing dose responses for a population of cells.

 
 

Figure 29-12  Dose response curves for mammalian cells are adequately fitted by the linear-quadratic relationship, at least over the range of doses of concern in radiation therapy. The form of the equation is  where S is the fraction of cells surviving a dose (D), and α and β are constants. Cell killing by the linear and quadratic term are equal when  This occurs when D = α/β.  (From Cox JD, Ang KK [eds]: Radiation Oncology: Rationale, Technique, Results, 8th ed. St. Louis, Mosby, 2003, p 14.)

 



Derived from this model is the α/β ratio, obtained by manipulating the equation just described. A point on the survival curve can be defined at which the components of cell killing can be seen to be equal to each other—that is, αD = βD[2], or D = α/β. In other words, for a cell population there exists a dose of radiation where the linear (α) and quadratic (β) contributions to cell killing are equal. This dose is the dose equal to the ratio of α and β—the α/β ratio. The α/β ratio is specific to a cellular population and reflects the sensitivity of the cell to the two supposed types of damage. By this formulation, tissues that have an early response to radiation (skin, gut epithelium, and tumor cells) have a high α/β ratio. In other words, their survival curves stay straight for a longer period before the bend, with a higher contribution of single-event or α killing. Late-responding tissues such as spinal cord, kidney, and muscle have survival curves that bend earlier, with resultant lower α/β ratios ( Table 29-2 ). These late-responding tissues have “shoulders” on their survival curves within the range of doses commonly used in radiation therapy.


Table 29-2   -- Ratio of Linear to Quadratic Terms from Multifraction Experiments

Reaction Sites

α : β (Gy)

EARLY REACTIONS

Skin

9–12

Jejunum

6–10

Colon

10-11

Testis

12–13

Callus

9–10

LATE REACTIONS

Spinal cord

1.7–4.9

Kidney

1.0–2.4

Lung

2.0–6.3

Bladder

3.1–7.0

From Cox JD, Ang KK (eds): Radiation Oncology: Rationale, Technique, Results, 8th ed. St. Louis, Mosby, 2003, p 27.

 

 

This formulation led to the concept that altered fractionation schedules could be used to exploit this difference and treat tumor populations more effectively (with regard to damage to late-responding tissues, discussed in more detail later). This concept has resulted in several clinical trials of altered fractionation schemes, such as the concomitant boost technique for head and neck cancer and the CHART (continuous hyperfractionated accelerated radiation therapy) regime for lung cancer. [47] [48] Altered fractionation schemes are described later in this chapter.

Cellular Repair

Cells have complex mechanisms that are responsible for repairing radiation-induced damage. As described earlier, the shoulder on the cell survival curve is thought to relate to the cell's ability to repair DNA damage. One of the clearest demonstrations of the cell's ability to repair radiation damage is a phenomenon called sublethal damage repair. It has been observed that two doses of radiation given separated in time are less effective than the sum of the two doses given at the same time. The implication is that in the time interval between the first dose and the second dose, some of the damage from the first dose is repaired. Consistent with this conclusion is that the more closely the two doses are given in time, the more they resemble the effects of a large single dose, implying that repair has measurable kinetics.

Repair of sublethal damage was first reported in 1959 by Elkind and Sutton,[49] who noted that damage caused by radiation did not always produce cell killing and that this sublethal damage became lethal only when the total amount of damage had accumulated to a sufficient level. Since then, sublethal damage has been demonstrated in virtually every biologic system tested, predominantly by split-dose experimentation ( Fig. 29-13 ). [50] [51] [52] It is important to remember that a correlation exists between cell kill and the production of asymmetric chromosomal aberrations (e.g., dicentrics and rings) from the interactions of double-strand breaks in the DNA. Therefore, sublethal damage repair can be interpreted as the repair of DNA damage that would have formed double-strand breaks by two separate hits (b killing). Because high LET radiation interacts almost without exception by a killing, sublethal repair is not considered relevant to the radiobiology of particle therapy.

 
 

Figure 29-13  A, Increase in cell survival observed when a dose of radiation is delivered in two fractions separated by a time interval adequate for repair of sublethal damage. When the dose is split into two fractions, the shoulder must be expressed each time. B, The fraction of cells surviving a split dose increases as the time interval between the two dose fractions increases. As the time interval increases from zero to two hours, the increase in survival results from the repair of sublethal damage. In cells with a long cell cycle, or cells that are out of cycle, cell survival cannot be further increased by separating the dose by more than two or three hours.  (From Cox JD, Ang KK [eds]: Radiation Oncology: Rationale, Technique, Results, 8th ed. St. Louis, Mosby, 2003, p 24.)

 



Cellular repair of DNA lesions classified as “sublethal” is evidenced by the existence of the shoulder on the cell survival curve. Cells show increased survival with split-dose radiation because the shoulder of the survival curve must be repeated with every fraction. In other words, the shoulder of the survival curve represents the accumulation and repair of sublethal damage. Cells that have a broad shoulder that starts at low doses, with a resultant shallow initial slope, have a propensity for sublethal repair. These tissues, described as late-responding tissues with low α/β ratios, exhibit extensive sublethal repair and are spared preferentially by fractionation ( Fig. 29-14 ).

 
 

Figure 29-14  The dose-response relationship for late-responding tissue is “curvier” than for early-responding tissue. The dose at which cell killing is equal by the linear and quadratic components is α : β. This is about 2 Gy for late-responding tissues and 8 to 10 Gy for early-responding tissues.  (From Cox JD, Ang KK [eds]: Radiation Oncology: Rationale, Technique, Results, 8th ed. St. Louis, Mosby, 2003, p 27.)

 



A second type of cellular recovery after radiation, described in 1966 by Phillips and Tolmach,[53] is potentially lethal damage repair. This type represents radiation damage that may or may not lead to the killing of a cell, dependent on the cell's condition and environment in the period following irradiation. The researchers noted that cells that are not proliferating, either because they are out of the cell cycle due to contact inhibition or are being held in poor conditions that do not favor growth, show less killing after irradiation than the same cells did when dividing rapidly under optimal conditions. They postulated that resting cells had more time to repair DNA damage before re-entering the cell cycle than those cells that were dividing actively, thus potentially contributing to resistance to radiation therapy.

The extent of recovery from both sublethal damage and potentially lethal damage has been correlated with the repair of DNA and with the rejoining of chromosomal breaks. [54] [55] Both processes increase the survival of a cell population with fractionated radiation schedules. This can be manifested clinically either by an increase in normal tissue tolerance or by a decrease in tumor control. The time required for most sublethal/potentially lethal damage repair seems to be approximately 6 hours. If radiation therapy fractions are too closely spaced, unrepaired injury will accumulate between dose fractions, with the result that successive doses become more and more damaging to normal tissues. This factor should be borne in mind when designing fractionated courses of radiation to optimize tumor cell kill.

Dose Rate Effects

There is preferential sparing of late-responding tissues by fractionated radiation therapy due to sublethal damage repair. It should be kept in mind, however, that this sparing is relative to early-responding tissues. In other words, as a radiation dose is split and delivered over more than one treatment, the killing of cells within the tumor also decreases, although not by as much as late-responding tissues. When determining cell survival and toxicity (both early and late) of radiation therapy, other factors are involved. One of the most prominent of these factors is cell repopulation. As the total treatment time to deliver a dose of radiation lengthens, cells within a tissue have the ability to replenish, called repopulation. During a course of fractionated radiation therapy, the effects of sublethal repair and repopulation lead to diminished cell death with protraction of treatment times.

Dose rate effects can occur due to interfraction repopulation. In studies by Fowler and colleagues[56] using pig skin, it was shown that as overall treatment time was lengthened, additional radiation was required to elicit the same effect. Because both fraction size and fraction number were kept constant, this finding was believed to reflect the contribution of repopulation to the effect of the radiation.

Dose rate effects also have been demonstrated during each fraction of radiation. Bedford and Hall[57] demonstrated that the survival of cells increased as dose rate decreased from 7.3 Gy per minute to 0.1 Gy per hour. There also exists a dose rate below which reproduction of cells can continue despite continued radiation delivery. This threshold varies with tissue type, based on factors such as the sensitivity of the stem cells required to repopulate the cell population, the duration of the cell cycle, and the amount of adaptation that cells can undergo in response to radiation.[58]

The response to radiation injury and the survival of cells exposed to radiation are complex. Obviously, cell kill increases as radiation dose increases. Many other factors also contribute to survival, many of which are still not known. Early-responding tissues such as skin, mucosa, bone marrow, and tumor cells are likely to experience acute toxicities, which occur during the radiation course or within a few weeks thereafter. These tissues have stem cells for repopulation, which mature into functional cells. They exhibit rapid cell turnover from these stem cells. The intensity of the toxicity in these tissues reflects the balance between cell killing and the regeneration of cells from surviving stem cells. This balance depends primarily on accumulation of radiation dose. Larger fraction sizes are a factor in determining the severity of acute toxicities, with larger fraction sizes resulting in higher toxicity than smaller fraction sizes. The dependence on fraction size for acute toxicities is much more pronounced than for late effects. Moreover, dose rate has been shown to correlate with tumor cell kill and hence with the development of acute toxicity. One more very important parameter that corresponds with tumor cell kill and acute toxicity is the overall treatment time. As treatment time is extended, the development of acute toxicities decreases. It also has been demonstrated that long treatment times also reduce the likelihood of cure by virtue of reduced tumor cell kill because of the concept of accelerated repopulation, particularly beyond 4 to 6 weeks of treatment.[7]

In contrast to acute toxicities in early-responding tissues, late effects occur in late-responding tissues such as spinal cord, central and peripheral nerve tissue, heart myocytes, and kidney nephrons. Late effects often are of more concern to radiation oncologists than early effects, because they result in irreversible end-organ damage from radiation and, therefore, limit dose. Provided that sufficient time (generally agreed to be more than 6 hours) is allowed between fractions to allow for the complete repair of sublethal damage, classical late effects have no dependence on overall treatment time. An exception occurs if the treatment course is intense enough to cause such severe acute toxicities as to reduce the stem cells of early-responding tissues below a threshold; acute toxicity then can progress to chronic tissue injury, termed consequential late effects. Late-responding tissues usually are characterized by slow cellular turnover, with little repopulation during radiation treatments. Therefore, dose rate and overall treatment time play a minor role in the development of late toxicity. As stated previously, these tissues have a low α/β ratio, with the potential for significant sublethal damage repair between fractions. Hence, late-responding tissues are extremely sensitive to changes in dose per fraction.

Cell Cycle Effects

An important aspect of the effect of radiation on cells depends on their progression through different stages of the cell cycle. [59] [60] With tumor cells, which have a high growth fraction, modulation of this factor is potentially of great importance. The radiosensitivity of cells changes as the cell progresses through the cell cycle, with cells in late G2 and mitosis being the most sensitive. Cells in mid- to late S phase and early G2 phase are the most resistant to radiation. Moderate sensitivity exists for those cells in late G1 and early S phase, and cells in mid G1 are moderately resistant.

These differences in sensitivity allow for preferential killing of cells in those stages that are sensitive to radiation, with a subsequent relative accumulation of cells in the resistant S phase of the cell cycle. This accumulation translates into relative radioresistance of the remaining cells to additional doses of radiation, if reassortment into other phases of the cell cycle through natural progression of cell division does not occur ( Fig. 29-15 ).

 
 

Figure 29-15  A, Cell survival curves for populations of Chinese hamster cells irradiated in different phases of the cell cycle. B, Graphic illustration of how these radiosensitivity differences translate into age response patterns.

 

 

Radiation also disrupts progression through the cell cycle. Doses of radiation cause blocks in the G2- to M-phase transition and in the G1- to S-phase transition. These delays are governed by cell cycle “checkpoint” genes, which are responsive to DNA damage and transmit feedback addressing the readiness of the cell to progress to the next phase of the cell cycle. The radiation-induced G1 block is p53 dependent.[27] Because most tumors in adults are mutant or otherwise deficient in p53, the G2 block might be the more important block in tumor response to radiation. The G2 block is dose dependent, averaging 1 to 2 hours per Gy with increasing doses.[60] The G2 delay also varies in time, depending on where the cell was in its cycle when it was irradiated. The delay is longest for cells irradiated in S and early G2 phase and shortest for cells irradiated in G1 phase.[60]

These variations in sensitivity with cell cycle changes could be related to the propensity of the DNA to be damaged or repaired in the various phases of the cell cycle. In late S and early G2 phases, repair of double-strand breaks by homologous repair is most efficient, compared with the G1 and early S phases (when a homologous chromosome is not available) and late G2 phase (when the chromatin is highly condensed and less accessible to repair).[61] Similarly, DNA is uncoiled at the beginning of the S phase, perhaps leading to increased susceptibility to radiation damage in this phase. The preferential susceptibility with respect to the cell cycle reiterates the importance of splitting the total radiation doses into fractions.

Fractionation

The biologic basis of fractionation in radiation therapy makes use of the “four Rs of radiobiology”—repair of sublethal damage, reassortment (redistribution) of cells within the cell cycle, repopulation, andreoxygenation.[45] Dividing the total dose into a number of smaller fractions allows for normal tissue sparing because of the repair of sublethal damage between fractions. Fractionating the therapy also allows for reassortment of tumor cells into radiosensitive phases of the cell cycle, with reoxygenation of the tumor cells causing them to be more radiosensitive. If too much time is allowed between fractions, repopulation or proliferation of the tumor cells can occur. Although this theory forms the basis for fractionated therapy, the reality is much more complex. Tumor populations and normal tissue represent a heterogeneous group of cells, all responding to the radiation and the fractionation scheme differently. Some general characteristics are presented in the following paragraphs.

Early-responding tissues include those tissues that are rapidly dividing and repopulating; these tissues are responsible for the acute toxicity seen with radiation therapy. The severity of acute toxicity reflects the rate of cell killing of early-responding tissues counteracted by regeneration by those tissues’ surviving stem cells. This balance is based mainly on total treatment time. Prolonging overall treatment time spares the patient from the severity of acute toxicity, with short, intense treatment courses leading to severe acute toxicity. Severe acute toxicity can progress to consequential late effects.[62]

Late-responding tissues are responsible for the late toxicity from radiation therapy. These tissues are composed primarily of terminally differentiated cells with no stem cell population. Usually, therefore, there is no turnover of cells within a radiation treatment course and no opportunity for regeneration during treatment. In contrast to early-responding tissues, the overall treatment time has little importance in determining late toxicity. Instead, late toxicity depends mainly on total dose and dose per fraction.

These differences are seen by observing the dose-response relationships of the two types of tissue. Late-responding tissues have dose-response relationships that are more curved (i.e., with a larger shoulder) than those of early-responding tissues. In terms of the linear quadratic model, this translates into a higher α/β ratio for early effects (generally thought to be at ∼10 Gy), compared with the ratio for late effects (thought to be at ∼2 Gy). This has different consequences for each type of tissue. For early effects, the α/β ratio is large, meaning that the survival curve has an initial slope and no bend until higher doses. For late effects, the α/β ratio is small, with a short initial slope and a bend at low doses.[63] This creates a discrepancy between the two curves so that at certain doses, early-responding tissues (including many tumors) will be killed preferentially compared with late-responding tissues (see Fig. 29-14 ). As fraction upon fraction of radiation is given at these doses, the killing of tumor cells is much greater than that of cells of many normal organs, which are late responding. However, as fraction size increases, cells in late-responding tissues are killed in greater numbers. This explains the observation that late-responding tissues exhibit a much more marked change in survival with changes in dose per fraction. In other words, late-responding tissues are preferentially spared by dose fractionation.

The reason for the difference in these curves is not completely understood, although some possible explanations have been presented. The first deals with cell cycle-specific sensitivity. Cells are sensitive to radiation during mitosis and G2 phase and resistant to radiation during S and early G1 or G0 phases. Although this resistance eventually is overcome with high doses, late-responding tissues have many quiescent cells, hence incurring radioresistance as these cells rest in G0. On the other hand, tumor cells and early-responding cells reassort themselves into sensitive phases of the cell cycle, leading to radiosensitivity at smaller doses.

Another explanation of the differences in the dose-response curves relates to repair of DNA damage. Late-responding tissues have a greater capacity for sublethal repair than do early responding tissues, hence the lower α/β ratio and the shallower survival curve at low doses. Although late-responding tissues have a higher repair capacity than early-responding tissues, the repair kinetics themselves do not differ systematically between the two types of tissues.[64] Therefore, there is a minimum limit of time that is needed between fractions so that repair in late tissues can be completed. If this is not allowed, severe toxicity can result. This has been noted in studies that used fractionation schedules in which the interval between doses was less than 4.5 hours.[65] Although the explanation that these toxicities were due solely to incomplete repair has been questioned, most protocols now stipulate a minimum of 6 hours between fractions to allow for sufficient repair to take place.

Provided that sufficient recovery occurs between each fraction and the next, late radiation effects classically show no dependence on treatment course duration. In contrast, overall treatment time has a large effect on both acute toxicity in early-responding tissues and the cure of tumors. This implies that the tumors that show a decrease in curability with longer treatment times have rapid regeneration in response to the cell killing that occurs with radiation.

Altered Fractionation Schemes

All of the factors described so far must be taken into consideration when a fractionation scheme is being designed. The “standard” fractionation schedule differs in many parts of the world. In the United States, 1.8 to 2.0 Gy per day is the conventional fractionation. The standard of five fractions per week delivering a total dose of 9 to 10 Gy per week has evolved not as a biologically designed, optimal method for administration of radiation but rather from considerations such as the convenience of patients and staff, the availability of equipment, and financial constraints. Outside the United States, the same nonmedical constraints have dictated the development of other fractionation regimens that may employ fewer fractions over a shorter time.

In the 1990s, more attention was paid to attempts to alter the customary fractionation protocols to provide schemes that could improve the therapeutic outcome, through either increased tumor sterilization or decreased normal tissue toxicity. These attempts were undertaken based on the knowledge that the effects of radiation on acutely reacting tissues (e.g., skin and mucosa) are different from those on late-reacting tissues (e.g., nerve and connective tissue).

The reactions in early-reacting tissues, which determine the patient's tolerance to treatment during the course of radiation, are time dependent. 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 important in terms of breaks (days off) from treatment, particularly weekends, during which time a mucosal or skin reaction can heal substantially. Late-reacting tissues are not sensitive to overall treatment time, but they are very sensitive to fraction size. It is clear from a number of clinical studies that, given the same total dose, late reactions are worse when large fractions are used than with smaller ones.[66] This is understandable based on 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, early-reacting tissues are extremely 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 bone metastases for the rapid relief of pain ( Fig. 29-16 ). Although a few large fractions preferentially damage late-reacting tissues, a larger number of smaller fractions preferentially spares them.

 
 

Figure 29-16  Influence of fraction size on complications in early- vs. late-reacting tissues. The α/β ratio for the early tissue (blue curve) was set at 10 in this example; the α/β ratio for the late tissue (red curve) was 2.5. The tissues were presumed to have equal reactions to 40 Gy delivered at 2 Gy per fraction. Note that for equal reactions, the early-reacting tissue is far less dependent on fraction size. For large daily fractions, the late-reacting tissue will require substantial dose reduction to maintain equal clinical effects. Conversely, if fraction size is reduced, the late-reacting tissue will tolerate substantially higher doses of radiation.  (From Lichter AS: Radiation therapy. In Abeloff M [ed]: Clinical Oncology, 2nd ed. London, Churchill Livingstone, 2000, pp 423–470.)

 

 

 

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 potential gains. When the aims are to take advantage of the sparing of late tissue damage and avoid having treatment last for too many days or weeks, treatment has been given with multiple fractions per day. Several alternative fractionation schemes are presented in Table 29-3 . These schemes can be categorized according to two basic strategies: hyperfractionation and accelerated fractionation. In hyperfractionation, the fraction number is increased without altering the total treatment time. Although the dose per fraction is reduced, the total dose administered is larger, which allows for the safe escalation of dose with respect to late normal tissue toxicity, because the individual fraction sizes are quite small. An example of hyperfractionation is the treatment of head and neck cancer with 1.15 Gy twice daily (11.5 Gy per week). Following this schedule, instead of a typical 7-week course of treatment delivering 63 Gy at standard fractionation, 80.5 Gy is delivered in the same time period.[67] Several single-arm retrospective studies have reported results with hyperfractionated treatment of head and neck cancer that suggest benefit in terms of local control. [68] [69] A large randomized trial in T2 and T3 oropharyngeal carcinoma showed a statistically significant (approximately 35%) increase in local control in the hyperfractionated group.[67] Although not all studies have shown an advantage for hyperfractionated regimes compared to conventional fractionation, overall the literature suggests that an advantage may exist for hyperfractionation in terms of local control of head and neck cancer (in the absence of concomitant chemotherapy).


Table 29-3   -- Schematic Representation of Altered Fractionation Protocols

 

Week

1

2

3

4

 

 

 

Fx. No.

Fx. Size

Total

ACCELERATED

AM

|||||

|||||

|||||

|||||

|[*]

 

 

42

1.6 Gy

67.2 Gy

FRACTIONATION[*]

PM

|||||

|||||

|||||

|||||

|

 

 

 

 

 

 

Week

1

2

3

4

5

6

7

Fx. No.

Fx. Size

Total

HYPERFRACTIONATION

AM

|||||

|||||

|||||

|||||

|||||

|||||

|||||

70

1.15 Gy

80.5 Gy

 

PM

|||||

|||||

|||||

|||||

|||||

|||||

|||||

 

 

 

 

Week

1

2

3

4

5

6

7

Fx. No.

Fx. Size

Total

ACCELERATED

AM

|||||

|||||

|||||

|||||

|||||

|||||

 

40

1.8 Gy

69 Gy

BOOST

PM

 

 

 

 

|||||

|||||

 

 

1.5 Gy

 

*

May include a break after two weeks to reduce acute toxicity.

 

In accelerated fractionation, the overall time of therapy (i.e., total number of days/weeks) is reduced. The number of fractions, fraction size, and total dose may or may not be reduced. The theoretical advantage is that a reduction in overall treatment time could counteract accelerated repopulation in the tumor. Based on the principles discussed previously, late effects should be similar to conventional fractionation, because the fraction size is standard (or reduced) and the total dose is not increased. An example of accelerated fractionation is the British experience of continuous hyperfractionated accelerated radiation therapy (CHART) to treat non-small-cell lung cancer using 1.5 Gy three times daily for 12 consecutive days, delivering 54 Gy in 36 treatments in 1.5 weeks.[48] Another example of accelerated fractionation is the widely recognized scheme called the “concomitant boost” schedule for head and neck cancer, in which the first 36 Gy is given in four weeks at 1.8 Gy per fraction, and while that larger field continues to a total of 54 Gy, a smaller boost field is added as a second daily treatment for the last 2 to 3 weeks, bringing the total dose to 72 Gy in 6 rather than 8 weeks.[70] The results of a large randomized trial in patients with head and neck cancer showed a local control advantage for this technique.[47] To date, no overall survival benefit has been demonstrated for any altered fractionation schedule other than CHART.

One practical difficulty with hyperfractionated or accelerated schemes is the increased toxicity that can be seen in patients receiving concomitant chemotherapy (see the section on Radiosensitizers, Radioprotectors, and Concomitant Systemic Therapies). Combining chemo- and radiation therapy is becoming increasingly routine in the treatment of many cancers, for example, head and neck cancer and cervical cancer. Furthermore, these schemes, especially those that involve separation of doses in time, require the patient to come to the clinic more than once daily, which tends to be inconvenient for most patients. Therefore, many clinicians feel that these strategies must show an unequivocal benefit on overall survival to be worthwhile. Nevertheless, because of its simplicity and convenience, the concomitant boost technique has become an established and accepted technique worldwide for patients with many cancers, particularly head and neck cancer.

Oxygen Effect

Many agents have been observed to modify the responses of cells and tissues to radiation. One of the most extensively studied chemical modifiers is oxygen. The response of cells to ionizing radiation is strongly oxygen dependent, with well-oxygenated cells showing as much as threefold greater sensitivity to the killing effects of ionizing radiation than the same cells under hypoxic conditions.[45]

The effect of oxygen has been known for nearly a century. In 1912, Swartz noted a reduction of radiation effect if blood flow to an exposed area was reduced.[71] Although many suspected the modifying properties of oxygen, the oxygen effect was not demonstrated quantitatively until 1955.[72] This important discovery by Gray and Tomlinson had significant implications, because it became clear that tumors have a much higher proportion of hypoxic cells than do normal tissues. Many attempts have been made to circumvent this “built-in” radioresistance of tumor cells, but tumor hypoxia continues to be a problem in therapeutic radiation oncology.

The oxygen enhancement ratio (OER) is the ratio of hypoxic to aerated doses needed to achieve the same biologic effect. For x-rays, the oxygen enhancement ratio usually is between 2 and 3, becoming more pronounced at higher doses ( Fig. 29-17 ). In other words, the presence of oxygen in cells increases cell killing by radiation. The mechanism behind oxygen's radiosensitizing effect is thought to lie in the process of indirect damage, which is DNA damage resulting from the production of free radicals from water molecules. These free radicals break chemical bonds and produce chemical changes, initiating the chain of events that result in the expression of biological damage. After DNA damage from free radicals occurs, the damaged targets usually are quickly repaired by a reduction reaction involving reducing species such as thiols and intracellular glutathione, which restores the target to its original condition. Oxygen inhibits this repair of free radical-induced damage by forming irreversible peroxides in the injured biomolecules, thus “fixing” the radiation damage.

 
 

Figure 29-17  Cells irradiated in the presence of molecular oxygen are more sensitive to killing by x-rays than cells that are hypoxic (deficient in oxygen). The ratio of doses that produce the same level of biological damage in the absence of oxygen and in the presence of oxygen is known as the oxygen enhancement ratio (OER). At high doses, the OER has a value of about 3; its value seems to be smaller (close to 2) at doses below 2 Gy.  (From Cox JD, Ang KK [eds]: Radiation Oncology: Rationale, Technique, Results, 8th ed. St. Louis, Mosby, 2003, p 34.)

 



Consistent with this explanation of oxygen's effect is the fact that oxygen need not be present at the time of radiation for sensitization to occur, but it must be present shortly thereafter. Oxygen could be added after the radiation to sensitize cells, provided the delay is no longer than 5 msec.[73] Also consistent with this theory is the fact that high-linear-energy transfer radiation has a lower oxygen enhancement ratio than does low linear energy transfer radiation.

The concentration of oxygen required for radiosensitization is remarkably small. Air has an oxygen concentration of approximately 155 mm Hg. Hypoxic resistance occurs at concentrations between 0 mm Hg and 20 mm Hg. By the time a 20-mm Hg concentration of oxygen is reached, the cell survival curve is similar to the curve obtained under fully oxygenated conditions. This is less than half of the partial pressure of oxygen normally found in tissues (∼40 mm Hg). A concentration as small as 5 mm Hg results in a radiosensitivity halfway between hypoxic and fully oxygenated conditions. In practice, this means that hypoxia is not a major consideration for normal tissues; the minimum oxygen concentration to which most tissues will be exposed is at the level of venous blood (around 40–50 mm Hg), well above the borderline for the oxygen sensitizing effect. Some normal tissues (e.g., cartilage or skin) might contain borderline hypoxic cells.[74]

Although the oxygen tension of normal tissues is similar to that of venous blood (40 mm Hg), the oxygen tension within the cells themselves is heterogeneous. Some normal tissues contain a small percentage of cells that are borderline radiobiologically hypoxic. This percentage is amplified greatly in tumor tissues due to both chronic hypoxia and acute hypoxia. Chronic hypoxia (also termeddiffusion-limited hypoxia) results from the propensity of tumors to outgrow their blood supplies. Tomlinson and Gray calculated the distance to which oxygen could diffuse in respiring tissues to be 100 to 180 mm.[72] Cells beyond this distance would be expected to be dead or dying, producing the observed areas of necrosis seen in tumors, but those on the fringe of this distance would make up a large hypoxic region of cells. Acute hypoxia, also known as perfusion-limited hypoxia, results from the transient closing of blood vessels within the tumors themselves. Other possible causes include changes in overall blood flow or decreases in red blood cell delivery. Like chronic hypoxia, acute hypoxia can create a substantial hypoxic population of cells within a tumor.[74]

These populations of hypoxic cells within tumors can significantly limit the efficacy of radiation therapy. Although cells within these hypoxic parameters retain properties of clonogenicity, they are protected from the killing effects of radiation because of the absence of oxygen to fix the radiation damage. Therefore, the presence of even a small population of hypoxic cells could limit the overall success of radiation therapy in clinical situations. It has been estimated that hypoxic fractions account for up to 50% of tumors, with 15% of all tumor cells, on average, being hypoxic ( Fig. 29-18 ).[75]

 
 

Figure 29-18  Microscopic photo of a leiomyosarcoma of the extremity stained with EF-5, displaying the heterogenicity of hypoxia within the tumor. Green color corresponds to capillaries within the tumor. Red areas correspond to areas of hypoxia, which are at a notable distance from the blood supply.  (Used with permission from Sydney Evans, VMD, University of Pennsylvania.)

 



Given that tumors contain hypoxic cells that greatly limit the success of radiation, how are clinical successes with radiation obtained? The answer might lie in the reoxygenation of tumor cells after radiation that has been observed in rodent tumors. [76] [77] Reoxygenation occurs with both the chronic and acute mechanisms of hypoxia. In terms of chronic hypoxia, reoxygenation involves shrinking the tumors during a course of radiation therapy. As cells die from exposure to radiation, surviving cells that previously were beyond the range of oxygen diffusion are brought closer to a blood supply and then reoxygenate. This process is fairly slow, taking place over a period of days, depending on the rate of tumor regression. Reoxygenation also occurs in terms of the mechanism responsible for acute hypoxia. Assuming that blood flow resumes in areas of acute hypoxia, reoxygenation could take place within minutes or hours.

The process of reoxygenation is thought to be important in the practice of radiation oncology and again suggests the importance of using a protracted, fractionated course of radiation therapy. If human tumors reoxgenate as efficiently as animal tumors do, using multiple fractions could be sufficient to deal with the problem of hypoxic cell populations. Attempts at increasing the partial pressures of oxygen in tumors and using oxygen-mimetic chemicals to increase the sensitivity of tumor cells to radiation have yielded mixed results. A number of pharmacologic agents (e.g., 5-fluoro-etanidazole and pimonidazole) are being studied to allow more accurate assessment of the role of hypoxia in human tumors and cancer management.[78]

Radiosensitizers, Radioprotectors, and Concomitant Systemic Therapies

Although oxygen may be the most effective radiosensitizer, there are limitations to achieving levels of oxygen sufficient for sensitizing all tumor cells. Chemicals have been developed, therefore, to try to sensitize hypoxic tumor cells to kill by radiation. All have a similar electron affinity for the electrons produced by the ionization of biomolecules. The nitroimidazoles, including metronidazole, misonidazole, and etanidazole, represent molecules with such characteristics. Although these compounds are efficient radiosensitizers in animal model studies, clinical trials have shown them to have limited efficacy in humans,[74] for several possible reasons. As laboratory studies have continued to show encouraging results, diffusion into tissues seems to be the limiting quality in these compounds, just as it is for oxygen itself. In addition, severe side effects—most notably peripheral neuropathy—have been noted with some of these compounds at the drug concentrations required to produce radiosensitizing effects on tumors.[78] An additional problem is that in animal models (particularly rodent models), tumors grow rapidly and consequently might have more hypoxia. Also, tumors in animal models are more uniform than human cancers. The design adopted for the clinical trials of these compounds, particularly patient selection, also has been debated.

In response to the lack of efficacy seen with hypoxic cell radiosensitizers, other approaches have emerged to attack the hypoxia problem encountered in tumors. Tirapazamine is a prodrug that is activated to a cytotoxic molecule preferentially under hypoxic conditions.[79] Data suggest a synergistic effect when this compound is given with radiation. Clinical progress with tirapazamine has been slow, perhaps because of the severe nausea or muscle cramping experienced by some patients.[80] Clinical trials are underway with this drug and other prodrugs, such as AQ4N, which is selectively and irreversibly converted to AQ4 in hypoxic tumor cells where it acts as an inhibitor of topoisomerase II.[81]

Compounds that interact with DNA also may act synergistically with radiation. In 1960, it was found that pyrimidines could be halogenated and incorporated into DNA because the van der Waal's radius of chlorine, bromine, or iodine was similar to the size of a methyl group side chain on uridine and because a halogenated uridine would be recognized by DNA polymerase. Therefore, halogenated pyrimidines (e.g., uridine with a bromine atom replacing the methyl group [BUDR] or an iodine replacing the methyl group [IUDR]) could be substituted in DNA for a normal thymine.[82] DNA containing substituted halogenated pyrimidines is more susceptible to DNA double-strand breaks when exposed to ultraviolet light or ionizing radiation.[83] Although this finding relates to cell kill in preclinical models, in clinical trials to date, these compounds have not been shown to be efficacious.[84] It has been postulated that insufficient halogenated pyrimidines are incorporated into the DNA of tumor cells, resulting in inadequate radiosensitization.

Although the therapeutic ratio can be improved with radiosensitization, a therapeutic benefit in terms of the relative sparing of normal tissues could also be attained using radioprotectors. The most abundant radioprotectors are sulfhydryl-containing compounds. Cysteine was the first of these to be shown to protect against the effects of radiation, by Pratt and colleagues in 1948.[85] Since then, many other compounds have been found to be effective radioprotectors, the most efficient of which has a free SH group separated from the rest of the molecule. The mechanisms of the radioprotection afforded by sulfhydryl-containing molecules include free radical scavenging and hydrogen donation to facilitate DNA repair ( Fig. 29-19 ). The radioprotector most commonly used clinically today is WR-2721 (amifostine), developed at the Walter Reed Institute of Research. It is converted to the active metabolite WR-1065 inside the cell and acts as a free radical scavenger. Given intravenously or subcutaneously, it has been demonstrated to be efficacious in reducing toxicity in head and neck cancers and lung cancer and its application is being tested in the treatment of other malignancies.[86]

 
 

Figure 29-19  Chemical protectors: competition model. There is a dual action to chemical radioprotection: (1) thiols and sulfhydryl compounds act as repair compounds; (2) they compete with free radicals (scavenging effect).  (From Leibel SA, Phillips TL [eds]: Textbook of Radiation Oncology. Philadelphia, WB Saunders, 1998, p 50.)

 



Currently, the most widely used radiosensitizers are chemotherapeutic agents. Originally, the rationale for the combination of chemo- and radiation therapy was to attack two different problems, termedspatial cooperation. Whereas radiation would address local control issues, chemotherapy was thought to treat micrometastases located beyond the tumor bed. However, evidence of increased local control in patients receiving combined treatment is now considered evidence of chemotherapy's radiosensitizing effects, which have been demonstrated in many tumors. Examples include the use of platinum agents in lung cancer, head and neck cancer, cervical cancer, rectal cancer, and bladder cancer; mitomycin-C in anal cancer; and 5-FU in esophageal, gastric, and pancreatic cancers ( Table 29-4 ). [87] [88] [89] [90] [91]Although some of the improved outcomes in these studies are due to the elimination of micrometastases, improved local control from radiosensitization has been shown to be an important component. Recently a multicenter European–Canadian trial of patients with glioblastoma multiforme has reported improved local control and a significant improvement in overall survival with a combined modality approach using concomitant and adjuvant temozolamide chemotherapy with high-dose radiation therapy.[92]


Table 29-4   -- Example of Chemotherapy Agents That Sensitize Tissues to the Effects of Radition

Drug

Proposed Mechanism Enhancement

Clinical Use

5-Fluorouracil

Inhibits thymidylate synthase

Head and neck, gastrointestinal, bladder, anus

Platinum agents

DNA cross-linking and adduct formation

Head and neck, gynecologic, bladder, lung, anus

Mitomycin C

DNA cross-linking and adduct formation

Anus, bladder

Gemcitabine

Inhibits ribonucleotide reductase

Pancreas, head and neck, lung, bladder

Paclitaxel

Inhibits microtubule polymerization

Lung, gynecologic malignancies, head and neck

Temozolamide

Alkylation and methylation of DNA

Glioblastoma multiforme

 

 

Over the past decade, the emphasis of drug development in oncology has shifted toward new classes of molecularly targeted agents, particularly antibodies and small molecule inhibitors. It is increasingly apparent that many of these agents can act as radiation-specific sensitizers or protectors. Potential targets for radiosensitization include the following:

  

   

Signal transduction pathways, for which targeting agents are in clinical trials (see later discussion)

  

   

Pathways clearly involved in sensitivity to drugs and radiation, for which agents currently are in preclinical trials

  

   

Investigation of the molecular mechanisms involved in the most highly conserved cellular responses to cytotoxic stress

The first large-scale-example of the clinical benefit that can be obtained by combining a molecularly targeted agent with radical radiation therapy is provided by cetuximab, an IgG1 monoclonal antibody directed against the ligand binding domain of the epidermal growth factor receptor (EGFR; see Chapters 34 and 72 ). Cetuximab enhances the cytotoxic effects of radiation in preclinical models of squamous cell carcinoma. [93] [94] An international multicenter randomized controlled trial has demonstrated in the treatment of locoregionally advanced head and neck cancer that, compared to high-dose radiation therapy alone, concomitant high-dose radiation therapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiation therapy.[95]

CLINICAL APPLICATION OF RADIOBIOLOGIC PRINCIPLES

The goal of all investigations into the physical aspects and biologic principles behind radiation therapy is to attempt to increase the therapeutic index, which is defined as the tumor response for a fixed level of normal tissue damage.[96] Or, to restate it another way, the goal is to increase tumor cell kill and hence tumor control while maintaining normal tissue toxicity within a tolerable range. When discussing normal tissue toxicity, late effects that translate into end-organ damage usually are considered the dose-limiting toxicity.

All organs have a threshold for normal tissue toxicity. These thresholds, though, often lack rigidity and are poorly defined, because they depend on the interaction of many factors. The most important factors in terms of normal tissue tolerance and toxicity are total dose delivered and the volume of the organ exposed to this dose. It is not as simple to calculate this relationship for normal tissue as it is for tumors. When speaking in terms of tumor cure, the fraction of cells surviving determines the success of treatment, because a single surviving cell might suffice for regrowth of the tumor. For normal tissues, the tolerance depends heavily on the ability of stem cells to maintain a sufficient number of mature cells for proper organ function. This statement is an oversimplification, because the tolerance of an organ also depends on its structural organization, which some radiobiologists have termed functional subunits. [45] [74] [97] For example, consider the kidney and the spinal cord. If radiation permanently damages a number of nephrons, the end-organ function might not be affected as long as enough nephrons remain to maintain function. The functional subunits of the kidney, then, are said to be arranged in parallel. On the other hand, if one section of the spinal cord is damaged, the entire cord distal to the lesion will be disrupted. Organs such as the spinal cord, in which damage to one portion of the organ affects the function of the entire organ, have what is called serial functional subunits.

Functional subunits have yet to be described for many organs, and the use of functional subunits to describe radiation tolerance of many organs remains theoretical. It is clear, however, that as the irradiated volume of an organ increases, the complications also increase. Although the volume of the organ that is exposed to radiation is important, this exposure might not be observed as toxicity if the total dose delivered remains below the dose that would damage the normal tissue in question. The concept of a threshold for total dose exposure becomes important as we attempt to escalate dose to increase tumor control. Clinical and preclinical data are consistent with the view that increased dose kills more cells, though few clinical trials have demonstrated this directly. Retrospective data have confirmed a dose response in the treatment of many clinical sites, including head and neck, Hodgkin's disease, high-grade glioma, non-small-cell lung cancer, prostate cancer, breast cancer, and cervical cancer. [98] [99] [100] [101] [102] [103]

Therefore, the total dose to the tumor and the volume of normal tissue treated must be considered when designing a radiation treatment course. Success might be possible in any tumor, regardless of size and histology, if sufficiently high doses are used. Clinically, however, this consideration must be balanced against the toxicity that would result to normal tissue. To increase the therapeutic ratio, many of the radiobiologic and physical principles of radiation have been used, including tumor localization, choosing the optimal energy and radiation modality, manipulating the dose rate, fractionation schemes, and the use of radiosensitizers and radioprotectors or targeted therapies. All depend on accurate localization of the tumor and the precise delivery of radiation.

Effects of Radiation on Normal Tissue

The effects of radiation on normal tissue limit the doses of therapeutic radiation that can be administered safely. For some clinical presentations—for example, a responsive tumor (e.g., lymphoma) located in radiation-tolerant tissues such as the low neck—cure is possible without a major risk of serious complications. In other situations—such as the setting of advanced prostate cancer, where rectal complications can occur—cure is possible, but the risk of long-term complications cannot be dismissed. In still other situations—such as damage to normal brain tissue while treating high-grade gliomas—cure might not be possible without the risk of severe disability. Finally, an increase in the control rate in many clinical situations might be possible only at the expense of more complications unless ways can be found to increase the tumor dose without substantially increasing the dose to surrounding normal tissues. The latter concept underlies the increased use of interstitial implantation techniques and three-dimensional conformal dose delivery, discussed in detail later in this chapter.

It should be remembered that complication risk and chances of cure trade off against one another. Complications are an inherent risk of any medical treatment, and one must weigh the risks of failure to control the tumor against the advantage of local control associated with a complication. Consideration also should be given to whether a complication can be managed with other types of treatment, for example surgical transposition of the ovaries to reduce the chances of radiation menopause in a young female patient undergoing radiation treatment to the pelvis. Understanding the effects of radiation on normal tissues is critical to the proper use of this treatment modality in the context of a patient's treatment as a whole.

Acute Effects on Normal Tissues

The acute effects of radiation result from direct damage to parenchymal cells of organs that are sensitive to radiation. Traditionally, an acute effect has been defined as an effect seen during treatment and up to 3 months from the conclusion of therapy. A detailed discussion of this subject is beyond the scope of this chapter; it has been reviewed in other textbooks. [7] [104] Table 29-5 summarizes the acute effects of radiation and their management.


Table 29-5   -- Acute Effects of Radiation

Organ

Symptom/Sign

Management

Systemic

Lethargy, fatigue

Symptomatic

Skin

Erythema, dry desquamation, pruritus, moist desquamation

Observation; low-dose topical corticosteroids for pruritus; avoidance of occlusive dressings or clothing; aqueous creams

Oral mucous membranes/teeth

Mucositis, ulceration

Dental consultation pretreatment; rinse with sodium bicarbonate; fluoride treatment; viscous xylocaine and oral analgesics for pain; watch for and treat candidiasis

Esophagus

Esophagitis

Systemic analgesics; consider diagnosis of opportunistic inflection

Lung

Pneumonitis, cough

Observation in mild cases; prednisone in severe cases

Liver

Radiation hepatitis

Symptomatic management; prednisone in severe cases

Bowel

Cramping, diarrhea, nausea, vomiting

Antidiarrheal agents; sulcralfate; antiemetics; low-residue diet

Bladder

Frequency, urgency, dysuria, hematuria

Analgesia; antimuscarinics for bladder instability; alpha1-blockers for obstructive symptoms in men

Rectum

Proctitis, bleeding, tenesmus

Symptomatic; corticosteroid suppositories

Hematopoietic

Lymphopenia, thrombocytopenia, anemia, cytopenia

Supportive; transfusions; aggressive treatment of infections

Form Lichter AS: Radiation therapy. In Abeloff M (ed): Clinical Oncology, 2nd ed. London, Churchill Livingstone, 2000, pp 423–470.

 

 

 

Late Effects on Normal Tissues

Late effects are those that occur more than 3 months from the end of therapy. Virtually any organ or tissue that is treated can express a syndrome of late radiation damage. The mechanism of late tissue damage is likely to be multifactorial. Some radiobiologists believe that it is due to slow dropout of small vasculature, leading to organ cell loss, fibrosis, and eventual late organ failure.[105] Evidence for this viewpoint is supplied by morphologic studies of irradiated tissues, where decreased vascularity can be observed in virtually every tissue type.[105] Others believe that late damage is due in large part to direct damage to parenchymal cells. This theory is plausible, as organs have widely differing sensitivities to radiation, but there is little evidence to suggest that blood vessels in one part of the body are more or less radiosensitive than in any other part. Thus, if vascular damage were a final common pathway, then most organs should share similar radiation tolerance doses, and they do not.[106] In all likelihood, late damage represents a combination of vascular damage and direct organ cell depletion. [107] [108] Table 29-6 provides a summary of organ tolerances to radiation.


Table 29-6   -- Approximate Organ Tolerance Doses in Radiation Therapy Estimated from Preclinical and Clinical Data

Organ

Toxicity

Tolerance Dose (cGy)[*]

Brain

Necrosis

6000

Eye

Cataract

600

 

Keratitis

5000

 

Retinal damage

4500

Pituitary

Hypopituitarism

4500

Spinal cord

Paralysis

5000 (5-cm segment)

Skin

Necrosis

6000 (10 × 10 cm)

Salivary gland

Xerostomia

4000

Thyroid

Hypothyroidism

4500

Lung

Pneumonitis

2000

Heart

Peri-/paracarditis

4500

Esophagus

Stricture

6000

Liver

Hepatitis

3000

Stomach

Ulcer/hemorrhage

5000

Kidney

Nephritis

2000

Rectum

Ulcer/hemorrhage

6000

Ovary

Sterility/menopause

600

Testis

Sterility

200

Bladder

Contracture

6500

From Lichter AS: Radiation therapy. In Abeloff M (ed): Clinical Oncology, 2nd ed. London, Churchill Livingstone, 2000, pp 423–470.

*

Dose to whole organ at 200 cGy per fractron, 5% complication level.

 

 

Carcinogenesis

Because radiation causes damage to DNA and some of the damage is misrepaired, it is not difficult to conceive that a radiation-damaged piece of DNA could be misrepaired with a small but nonlethal mistake. Alternatively, a base in the DNA strand could be damaged in a manner that is nonlethal, but alters the base sequence. Such a change in the sequence of DNA bases is called a mutation, and some mutations can lead to malignant transformation of the cell. Thus, radiation would be expected to be a carcinogen, and decades of research have confirmed this fact. In fact, radiation probably is the most thoroughly studied carcinogen. Its ability to induce malignancy was first seen in the pioneers of clinical radiation research, many of whom lost limbs or their lives to multiple aggressive skin cancers caused by repeated exposure to x-rays. Over the years, a number of radiation-exposed populations have been studied, including radium watch dial painters and patients exposed to radiation for benign diseases. Five well-known examples of the latter are tuberculosis victims examined with multiple fluoroscopies over the course of many years, patients with postpartum mastitis whose breasts were irradiated, patients with ankylosing spondylitis who received spinal irradiation, children who received scalp irradiation for tinea capitis, and children treated with radiation to reduce thymic enlargement. [109] [110] [111] [112] [113]Two of the largest and most carefully studied populations exposed to ionizing radiation have been the survivors of the atomic bomb explosions from Japan during World War II and the survivors of the Chernobyl nuclear accident in the former Soviet Union in 1986. [114] [115] [116]

Several basic principles of radiation-induced carcinogenesis have been elucidated by studying these populations:

  

   

Radiation-induced cancer appears several years after exposure, often 4 to 10 years later for radiation-induced leukemias and 10 to 30 years later for solid malignancies.[117]

  

   

Leukemia is the most common primary tumor associated with previous radiation exposure, with relative risks of 30 or greater over that of the general population. The incidence of leukemia peaks 6 to 8 years after radiation exposure, after which time the incidence tails off.[118]

  

   

Not all cancers can be associated with previous radiation exposure. Whereas thyroid and breast cancer are commonly associated, pancreatic and rectal carcinomas appear to have little association with previous radiation induction. No discernible pattern of organ sensitivity has been deduced.[119]

  

   

Radiation induction of cancer is age sensitive. For example, radiation of breast tissue during the teens and 20s is more commonly associated with subsequent breast cancer than irradiation after age 50 years.[120]

  

   

The age distribution of radiation-induced cancers is similar to the naturally occurring incidence pattern. This finding suggests that radiation facilitates the appearance of malignancy rather than being entirely causative of the problem.[121]

  

   

There is a relationship between radiation dose and cancer induction. Cancers are induced with increased frequency as dose increases up to a point, after which increasing dose decreases the appearance of malignancy in both experimental and clinical situations ( Fig. 29-20 ).[74] This is likely due to the amount of DNA damage being caused; at lower doses, cells can survive while sustaining nonlethal mutations, whereas at high doses, lethal mutations dominate. This finding implies that a high-dose therapeutic course of radiation should not induce large numbers of cancers in survivors. This appears to be the case, although it should be emphasized that cancer induction from high dose radiation treatment has been clearly documented.[122]

 
 

Figure 29-20  Relationship between dose and viable mutations. As the dose increases, the number of mutations increases. As dose increases, however, survival of cells decreases. The composite, labeled “surviving cells with mutations,” has a characteristic shape. Mutations increase up to a relatively low dose level and then begin to decrease. High-dose therapeutic radiation produces a very small number of secondary induced cancers.  (From Lichter AS: Radiation therapy. In Abeloff M [ed]: Clinical Oncology, 2nd ed. London, Churchill Livingstone, 2000, pp 423–470.)

 

 

 

Although low doses of radiation can cause cancer, it is not known whether any dose is so low as not to be dangerous—i.e., whether a threshold for adverse effects exists below which small doses of radiation have no biologic effects. Our information on radiation carcinogenesis comes from dosage data in the tens and hundreds of centigrays (cGy). We have little or no data from doses in the 1- or 2-cGy range, and even fewer data in the tenths of cGy range, which are the doses associated with many diagnostic x-ray exposures and with some population exposures relating to emissions from nuclear facilities, working with tracer doses of radionuclides, or visiting a patient with a radioactive implant in the hospital.[123] If a safe threshold were determined, it would make the public health aspects of radiation protection much less problematic. Currently, a conservative approach to radiation exposure is followed in most developed countries, although rules vary locally. In general, it is assumed that any radiation exposure is associated with risk in a linear fashion. Furthermore, population protection levels are calculated with an even more conservative concept of person-cGy, which implies that the same cancer risk will occur if one person is exposed to 1000 cGy that will occur if 1000 persons are each exposed to 1 cGy. From a biologic point of view, this type of calculation seems illogical, but it forms the basis of estimates for the amount of radiation to which the general population can be exposed with safety.[124] Overall, it is prudent to eliminate as much unnecessary radiation exposure as possible. On the other hand, medically necessary radiation in the form of diagnostic or therapeutic radiation can be more life saving compared to the risk of exposure and usually can be justified under even the most stringent estimates of carcinogenic risk of radiation.

PROCESS IN RADIATION TREATMENT

Radiation therapy is an important component of many patients’ treatment regimens. It often is combined with surgery or chemotherapy for optimal treatment of cancer. After the patient has been evaluated and the decision to use radiation has been made, perhaps the most important step in a radiation treatment course is the design of the radiation treatment itself.

Treatment Planning

Successful treatment planning is imperative to the success of a radiation treatment course. Formulation of the management plan for an individual patient involves discussion among radiation oncologists, radiologists, pathologists, surgeons, physicians, nurses, and radiographers. The basis for the prescription of radiation therapy takes into account diagnostic studies, the limitations of radiologic studies, evaluation of tumor extent (staging), knowledge of pathologic characteristics of the disease, a clear definition of the goal of therapy, and consideration of appropriate and alternative treatment modalities. The optimal dose of irradiation depends on the volume to be treated, the anatomic location, the histologic type of the tumor, the stage, and the potential regional spread. The dose-limiting factor usually is one or more normal structures in the region. The patient's general condition must be evaluated initially, with periodic assessment of treatment tolerance during irradiation. The goal is to identify the full extent of the tumor and areas of possible spread. Several considerations must be taken into account when determining the volume to be treated. These considerations include the tumor histology; the extent of gross disease; regions of microscopic spread but no gross disease; whether the treatment is being given postoperatively or in an undisturbed tumor bed; and the tolerances of adjacent structures. A plan must then be devised to treat this entire region to the dose desired for each region while keeping the volume of normal tissue below its tolerance dose.

The process of designing a radiation field starts with simulation, which is used to map out the extent of disease and its relationship to other organs when the patient is in the treatment position. Once simulation has been performed, the treatment position cannot be altered without the risk of inaccurate treatment delivery. Initially conventional simulators were fluoroscopy units designed to mimic the geometry of the treatment machines. Fluoroscopy was used to outline the boundaries of the field, with plain film x-rays being taken to include the general outline of the area to be treated. Although fluoroscopic simulators still are in use, many three-dimensional (3-D) treatment planning systems now are available to permit more accurate or more conformal delivery of radiation treatment. 3-D treatment planning systems use CT data (in some cases, augmented by fusion with other radiologic modalities) to simulate radiation delivery. This can be accomplished in a variety of ways:

  

   

The field can be set up by transferring CT data onto conventional simulation films.

  

   

CT images can be transferred to a computer-based treatment planning system. The fields are designed using the CT-based planning system, with verification (i.e., checking the treatment position) performed by taking x-ray films on a conventional simulator.

  

   

The third and most efficient method is to use a CT simulator to set up the radiation fields. The CT simulator combines the processes of obtaining CT images and field design. CT images of the patient are transferred directly to a computer system that allows the physician to outline the tumor volume and critical structures on individual CT slices. This, in effect, produces an accurate 3-D recreation of both the tumor that is to be treated and normal tissues that are to be avoided during the delivery of radiation.

  

   

Additional data from magnetic resonance imaging (MRI) scanning or positron emission tomographic imaging can be fused with images obtained in the CT simulator in order to improve the accuracy of planning.

After the image data sets are obtained in any type of simulation, careful review of the clinical data must be done to delineate the tissue to be treated. The volume to be treated is defined as the target volumeand is created by adding three components together.[125] First, the gross tumor volume (GTV) is delineated. The gross tumor volume consists of all known detectable disease, including any abnormal regional lymph nodes. This volume refers to the total volume of tumor detectable by diagnostic procedures such as CT or MRI scanning and endoscopic procedures. The clinical tumor volume (CTV) encompasses the gross tumor volume plus regions considered to harbor potential microscopic disease and other areas at risk for spread, such as draining lymphatic regions. The planning target volume(PTV) includes a margin around the clinical target volume to allow for internal target motion, other anatomic motion during treatment (e.g., respiration), and variations in treatment set-up. Finally, a margin must be added to account for the physical characteristics of radiation such as the penumbra (the edge of the beam where dose falls off rapidly). After a complete surgical resection with no residual detectable tumor and clear surgical margins, a GTV cannot be defined and the radiation oncologist will proceed directly to outline a CTV. Examples of 3-D treatment planning are shown in Figure 29-21 .

 
 

Figure 29-21  A, Transverse CT scan of a male pelvis with simulated organs shown. B, Three-dimensional surfaces of the prostate (green), rectum (blue), and bladder (yellow) reconstructed from outlines drawn on CT images. C, Digitally reconstructed radiographs (DRRs) of conventional anteroposterior and lateral fields. Prostate is shown in red, seminal vesicles in blue, rectum in green, and bladder in yellow.  (From Cox JD, Ang KK [eds]: Radiation Oncology: Rationale, Technique, Results, 8th ed. St. Louis, Mosby, 2003.)

 



The planning process also involves choosing the number of radiation beams required, the energy of these beams, the angles, and the weighting (i.e., proportion of total energy deposition) of these beams needed to deliver the required radiation dose to the tumor with optimal sparing of normal tissues. Beams also may be modified to improve the delivery of dose. After the plan has been designed by radiation physicists, digitally reconstructed radiographs are produced from CT data to represent the treatment fields. Beam's eye views also are valuable to the radiographers delivering the treatment, since they offer a radiographic representation of the orientation of each beam. The availability of 3-D treatment planning has allowed for much more complex plans in the attempt to increase the therapeutic ratio via the design of radiation fields, as the doses to the tumor and normal organs can be evaluated accurately and three dimensionally. This evaluation process allows assessment of the possible toxicity that could result from the radiation treatment via the evaluation of a dose volume histogram, which shows the dose delivered throughout the volume of the tumor and each normal organ in the radiation field. Although usually it is unacceptable to treat an entire organ beyond its tolerance, there are circumstances when portions of an organ may be treated to close to or even beyond tolerance. A consideration is whether the organ in question is considered to have a serial or parallel structure (see previous discussion). In an organ with a serial structure, failure of any component of the organ will cause failure of the entire organ. An example of this might be the spinal cord, where taking any segment of the cord beyond cord tolerance will cause failure of everything downstream. In a parallel organ, however, such as the lung or kidney, the patient might be able to tolerate loss of part of the organ's function, provided certain volume considerations are not exceeded ( Fig. 29-22 ).

 
 

Figure 29-22  Dose-volume histogram. The percentage of the volume of a structure receiving a percentage dose level or more is illustrated in this cumulative histogram. For the tumor, 100% of the volume receives 100% of the dose, which is the desirable situation. For normal structures, lesser doses are given. In this example, 40% of the liver received 40% or more of the dose, and 20% of the spinal cord received approximately 17% or more of the dose. A small portion of the liver received more than 90% of the prescribed dose, while no portion of the spinal cord received more than 20% of the prescribed dose. This plot is quite useful in presenting a large amount of complex three-dimensional dose-volume information in a fashion that can be assimilated quickly.  (From Lichter AS: Radiation therapy. In Abeloff M [ed]: Clinical Oncology, 2nd ed. London, Churchill Livingstone, 2000, pp 423–470.)

 

 

 

Normal tissues can be shielded within radiation beams in various ways. The first shields or blocks were manually placed pieces of lead or depleted uranium that were inserted in the radiation field to shield the structures below them. Following the discovery of a low-melting-point alloy of lead with similar beam attenuating properties, it became possible to create complex blocks that followed the divergent properties of the beam to shield organs defined on the simulation films more accurately.[126] Blocks were custom made for each patient, taking into account the divergence of the beam from its source. A newer method of shielding available in modern linear accelerators involves the use of a multileaf collimator (MLC). The MLC system uses 1- or 0.5-cm “leaves” that actually are partitioned jaws of the collimator in the head of the treatment machine. These leaves can be moved in from the edges of the field to block the radiation field and effectively shape the beam as desired ( Fig. 29-23 ).

 
 

Figure 29-23  Traditionally, radiation fields have been shaped by molding blocks made from a low-melting-point lead alloy (left). The same shape can be created within seconds using a multileaf collimator (right). Multiple pairs of thin leaves are each driven by their own motor. The desired shape of the field is entered into a computer that drives the leaf motors and creates the desired shape.  (From Lichter AS: Radiation therapy. In Abeloff M [ed]: Clinical Oncology, 2nd ed. London, Churchill Livingstone, 2000, pp 423–470.)

 

 

 

Once treatment planning is completed, including verification of the treatment position if required, the patient begins the course of radiation therapy. Each day, the patient is positioned by treatment radiographers in the exact position in which the simulation and verification were done. To aid in positioning, immobilization devices are often used, such as foam knee supports, vacuumed bags for limbs, body casts, or perspex/thermoplastic head masks (“shells”). These are made prior to simulation and are kept for use throughout the entire radiation course. For young children (generally less than 4 years of age) or for any patient unable to keep still when left alone in the treatment room, general anesthesia may be required for simulation and for each fraction of radiation therapy. Most modern radiation treatments are isocentric, meaning that there is one point around which the treatment machine (“gantry”), the couch, and the collimator in the head of the treatment machine rotate. Laser lights in the simulator and the treatment room are used to assist in the positioning of the patient relative to the isocenter. The reproducibility of the patient's treatment position is monitored on a daily or weekly basis by the use of portal images taken from the treatment machine while the patient is in the treatment position. Because treatment machines produce megavoltage radiation, the quality of these images is inferior to those produced by diagnostic machines, which produce radiation in the kilovoltage range (see the section on Photoelectric Effect).

Clinical Use of Radiation Therapy

Radiation is employed to treat cancer in most parts of the body. It can be used as definitive treatment (with or without chemotherapy) where radiation is the sole curative modality ( Table 29-7 ). This type of definitive radiation therapy is used in place of a surgical procedure, and it is often referred to as “organ sparing” or “organ preserving.” Examples include the treatment of laryngeal cancer, cervical cancer, and localized bladder cancer. [87] [127] [128] Brachytherapy also is used in this context (see later discussion). If the cancer is not eradicated completely by radiation therapy, or if it recurs, subsequent surgical resection is described as salvage.


Table 29-7   -- Postulated Inter-relationship of Biological Dose, Tumor Size, and Control by Irradiation

Total Dose (Gy)[*]

Histology

Size

Control (%)

50

Squamous

Subclinical (<106 cells)

95+

 

Adenocarcinoma

 

 

60

Squamous

<2 cm

85

 

 

>4 cm

50

65

Squamous

2–4 cm

70

70

Squamous

2–4 cm

90

 

Adenocarcinoma

>4 cm

60

75+

Squamous

>4 cm

90

From Cox JD, Ang KK (eds): Radiation Oncology Rationale, Technique, Results, 8th ed. St. Louis, Mo, Mosby, 2003, p 33.

*

Approximation based on a minimum tumor dose of 2 Gy per fraction and five fractions per week.

 

Radiation also can be used prior to surgical excision (“neoadjuvant radiation therapy”) or after a definitive surgical procedure (“adjuvant radiation therapy”), either to reduce the morbidity of surgery or to increase the likelihood of local and regional control. [129] [130] The aim of combining treatments usually is to improve the chances of cure and to preserve organ function. Clinical examples of these strategies include the treatment of breast cancer and soft tissue sarcoma.

As described earlier in this chapter, chemosensitization of tissues to radiation can have a synergistic effect on tumor cell kill, thus increasing the therapeutic index. Such effects have been demonstrated in the treatment of head and neck cancer, small cell lung cancer, non-small-cell lung cancer, cervical cancer, bladder cancer, anal cancer, pancreatic cancer, glioblastoma multiforme, and esophageal cancer. [87] [88] [89] [90] [91] [92] [131] The most prominent examples of the importance of combining concomitant chemotherapy with definitive radiation therapy are improvements in survival that have been demonstrated by the addition of cisplatin to radical radiation therapy for locally advanced cervical cancer and locally advanced head and neck cancer. [87] [88] [89] According to two large multicenter phase III trials studying postoperative radiation treatment of locally advanced head and neck cancer, concomitant cisplatin chemotherapy improves local control and progression-free survival, but it is associated with increased morbidity. [90] [132] The reader interested in the use of cisplatin or cetuximab in combination with high-dose radiation therapy for head and neck cancer is referred to Chapter 72 . The risk of severe or fatal toxicity to normal tissues should be considered carefully when planning clinical trials of chemosensitization combined with novel approaches to radiation therapy, because fatalities have been reported. [133] [134]

Worldwide, radiation therapy is the most widespread method employed to palliate symptoms related to tumor spread or growth. [7] [135] The most common example of this clinical use is the treatment of bone metastases with hypofractionated (i.e., a small number of large fractions) courses of radiation therapy to provide rapid relief of pain. Although the feasibility depends on the dose previously delivered and normal tissues within the field, retreatment with radiation should always be discussed with the patient's radiotherapist to provide rapid palliation. Radiation remains the main treatment modality for the relief of symptoms in patients with progressive and incurable cancers. It often is employed to stop bleeding, to relieve obstruction (e.g., of airway, gut lumen), and to relieve pain. Some of the most gratifying experiences in radiation oncology come from the ability to relieve symptoms in patients with progressive cancer and to diminish their reliance on major opioids for analgesia. Further examples of improving a patient's quality of life with radiation therapy are early intervention for spinal cord compression caused by multiple myeloma or treatment of painful bone metastasis from prostate cancer. Radiation oncology in this manner epitomizes Osler's dictum, “To cure sometimes, to relieve often, to comfort always—this is our work.”

NEW MODALITIES IN RADIATION

In addition to research directed at increasing the therapeutic ratio in radiation therapy, many of the largest advances in radiation oncology have resulted from improvements in the technology used to deliver radiation. Although it is not feasible to cover all the recent major advances in radiation therapy in this section, the basic principles are described for four modalities that have been adopted as important radiation treatments by large cancer centers.

Brachytherapy

Derived from ancient Greek word for “short distance” (brachy), the term brachytherapy refers to the placement of radioactive seeds or sources inside or next to a tumor. It is also known as sealed source radiation therapy or endocurietherapy. The seeds/sources deliver radiation directly to the tumor, potentially sparing surrounding healthy tissue better than external beam therapy or teletherapy.[135] If brachytherapy is used as an alternative to surgery, for example, in prostate or cervical cancer, it is described as “organ sparing.” The radioactive sources are referred to as sealed sources, as opposed to systemic targeted radionuclide therapy (see the section on Systemic Targeted Radionuclide Therapy), in which the radioactivity is unsealed. Thin needles or hollow applicators often are used to insert sealed sources into the tumor. Interstitial, intracavitary, and intravascular brachytherapy currently are practiced.

Interstitial Brachytherapy

In interstitial brachytherapy, sealed sources are inserted into tissue, for example, the oral cavity, skin, or anus. The most common sealed source is iridium 192 wire. Iridium wire can be arranged using either the Manchester or the Paris systems; the latter was designed specifically to take advantage of the new nuclide. [136] [137] [138] The aim is to treat all parts of the target volume within 10% of the prescription dose. This form of brachytherapy can be further subdivided into two types: permanent, in which sealed sources remain inside the body; and temporary, in which the seeds are removed from the body after the treatment. Cancers treated with temporary implants include soft tissue sarcoma and squamous cell carcinoma of the oral cavity. In the treatment of prostate cancer, radioactive seeds (e.g., iodine 125) about the size of a grain of rice stay within the treatment area permanently. Some migration of the seeds may occur with time.

Intracavitary Brachytherapy

Intracavitary brachytherapy places the sources inside a pre-existing body cavity. The most common applications of this method are gynecologic, particularly for cervical cancer, although it also can be used in other cavitary structures such as the nasopharynx or rectum. The move to reduce the medical staff's radiation exposure led to the introduction of remote afterloading brachytherapy devices, in which hollow tubes are connected to a safe containing a small radioactive source welded to a wire that is driven out by a stepping motor to predetermined positions to deliver radiation treatment. The motor is engaged only when all staff have left the shielded room that holds the patient for the duration of the treatment. Over 50 different types of intracavitary applicators exist for remote afterloading.[136] Althoughhigh-dose-rate (HDR) brachytherapy, often using iridium 192, may be performed as an outpatient procedure, low-dose-rate (LDR) brachytherapy with cesium 137 requires hospital admission because of the length of continuous treatment.

Intravascular Brachytherapy

Intravascular brachytherapy places a catheter with the sealed sources inside a blood vessel, usually an artery. The most well-established application of this method uses strontium 90 as a treatment for coronary artery stenosis in ischemic heart disease. More recently, glass or resin microspheres containing yttrium 90 have been developed to treat hepatocellular carcinoma or liver metastases.[139]

Systemic Targeted Radionuclide Therapy

Systemic targeted radionuclide therapy involves the delivery of radioisotopes specifically to cancer cells. This can be achieved through the design of radiolabeled pharmaceuticals targeted against cell surface molecules that are differentially expressed in cancer compared to normal cells. The radiobiologic effects of these agents depend on the physical characteristics of the radionuclide, such as half-life and the nature of the particulate radiations that are emitted, and on the abundance and distribution of the target molecule within the tumor.[140] An important example of systemic radiation therapy is the use of 131I-NaI to treat thyroid cancer and nonmalignant hyperthyroidism.[141] The success of this treatment is due to the selective uptake and concentration of iodine by the thyroid. This treatment has been used for over half a century, and hundreds of thousands of patients have received this therapy worldwide. Radioiodine therapy is remarkably safe; the only common side effect is hypothyroidism. An overview of long-term safety data suggests that the risk of developing thyroid cancer or other primary malignancies is not increased by radioiodine therapy.[7]

Delivering radioisotopes to cancers of other organs with similar precision has proved more challenging. The discovery of monoclonal antibodies (mAb) in the mid-1970s (see Chapter 34 ) gave rise to much optimism that, if directed against tumor-associated antigens, they could be used to deliver radioisotopes specifically to tumors. After years of development and research, this treatment modality, called radioimmunotherapy (RIT), has come to fruition. The CD20 differentiation antigen, expressed by more than 95% of B cell lymphomas, is targeted by mAbs conjugated to iodine 131(131I-tositumomab; Bexxar [GlaxoSmithKline]) and ytrrium 90-90Y-ibritumomab tiuxetan; Zevalin [Biogen Idec Inc]). Both agents are approved for use in the treatment of relapsed low-grade or follicular B cell lymphoma, with an overall response rate of about 80%.[142] These drugs often are effective even in tumors that are resistant to treatment with a naked anti-CD20 antibody, rituximab. Other indications for RIT in the treatment of non-Hodgkin's lymphoma, such as in the adjuvant setting after chemotherapy and as preparation for stem cell transplantation, are being explored in clinical trials.[143]

In contrast to the successful treatment of hematologic malignancies, RIT of the common solid malignancies has been severely limited by toxicity to the bone marrow, poor tumor penetration, the significantly lower radiosensitivity of these malignancies compared to NHL, and the development of an immune response to the mAbs, which has restricted the ability to administer repeated treatments. Numerous phase I and II trials of radiolabeled antibodies directed against a variety of tumor-associated antigens have been conducted.[144] A few patients have achieved complete response, but more often partial or minor responses are reported. Some encouraging results have been reported in the setting of minimal residual disease, because small tumor deposits and micrometastases accumulate disproportionately high amounts of radioimmunoconjugates compared to larger tumors. Several research strategies are being pursued in an effort to improve the RIT of solid tumors. [145] [146]

An important development in the field of systemic targeted radiation therapy has been the recognition that small peptides that are natural ligands of surface receptors might be used as vehicles for radioisotope delivery. This form of treatment has been called peptide receptor radiation therapy.[147] The low molecular weight of peptides results in efficient tumor penetration. Peptides are rapidly eliminated from the blood by renal excretion, which results in lower bone marrow toxicity and permits dose escalation. Peptide-directed radiation therapy using radiolabeled octreotide (a synthetic analogue of somatostatin) has been tested extensively in tumors that express somatostatin receptors.[148]

In general, β-emitters have been use for systemic radiation therapy. Since β particles have a track length of a few millimeters, not every cell within a tumor need be directly targeted. Adjacent cells will be irradiated through the so-called “crossfire” effect. Unfortunately, the crossfire effect also may result in the irradiation of normal cells and contributes to toxicity. For this reason there has been recent interest in isotopes that emit α-particles or Auger electrons. [149] [150] These have much shorter track lengths and, therefore, if they can be accurately delivered to malignant tissue, are less likely to cause serious normal tissue damage.

Radioimmunotherapy now plays a central role in the treatment of non-Hodgkin's lymphoma. With further advances in the field, molecularly targeted radiotherapeutic agents are likely to be increasingly important in the treatment of cancer.

Intensity-Modulated Radiation Therapy

Radiation therapy is the earliest example of a targeted therapy for cancer: it aims to deliver a dose to tumor and to diminish the dose to adjacent normal structures. The concept of conformal radiation is not new. The first report of field shaping to conform to the shape of the tumor was published in 1959.[151] Remarkably, automated computer-driven treatment planning also was reported in the 1950s.[152] A great advance was made in the 1970s in making the computer and the conformal planning more three-dimensional by virtue of the development of the beam's-eye view display.[153] The beam's-eye view display is reconstructed from x-ray or CT data and provides a view from the source of the radiation beam. This technological advance, coupled with the development of the diagnostic CT scanner, led to the prospect of anatomy definition that had not been possible in radiation treatment planning and resulted in significant improvement in defining tumor volumes and critical structures.[154] In the late 1980s, 3-D radiation treatment planning systems began to be used more widely.[155] Significant additional technological advancements in 3-D treatment planning systems continue to be made to improve radiation therapy, particularly with regard to the integration of CT and MRI into the planning, verification and monitoring processes.

The goal of 3-D conformal radiation therapy is to shape the area of high dose to the tumor volume while minimizing the dose to the surrounding tissues. The high dose is delivered to the tumor volume using a set of fixed radiation beams, with normal tissue surrounding the tumor volume shielded from receiving the full dose of radiation. This shielding classically has been done with blocks made from Cerrobend, a lead alloy, which stop the transmission of photons to those areas desired to be shielded. The development of the linear accelerator offered the ability to deliver shaped uniform beams from multiple angles as it rotated around the patient. The introduction of the multileaf collimator, whereby the machine shaped the beams rather than requiring additional beam-shaping devices such as Cerrobend blocks, made conformal radiation therapy significantly easier and more widely available.

Because the leaves in a multileaf collimator are computer driven, it also is possible to move the leaves continuously during treatment. Treatment has thus become four-dimensional (i.e., in time and space), and allows the use of beams that are deliberately nonuniform to deliver varying doses to varying parts of the treatment field. The CT simulator allows the treatment to be simulated in virtual time rather than in real time, allowing the physicist and physician, assisted by sophisticated computer software, to evaluate dozens or hundreds of treatment plans to optimize the dose to the tumor. This technology forms the basis for intensity-modulated radiation therapy (IMRT).[156] IMRT involves variation in the intensity of the x-ray output from a linear accelerator and the use of multiple shaped treatment fields. Although the treatment can be delivered by standard modern linear accelerators, the planning process is significantly more labor intensive than conventional radiation therapy and requires the use of more sophisticated modeling software for optimization.[157]

Several IMRT delivery techniques are available, such as combining photon and electron beams, including serial tomotherapy, or using a conventional multileaf collimator ( Fig. 29-24 ). [156] [157] In tomotherapy, radiation is delivered in narrow slit beams, analogous to the techniques used for CT imaging systems.[157] Treatment is delivered to a narrow slice of the patient in an arc-type rotation. As the machine rotates around the patient, delivering radiation in an arcing manner, “beamlets” of varying intensity of radiation delivered are created by dynamic movement of the machine's multileaf collimator. In areas to which more dose is to be delivered, the leaves of the multileaf collimator are out of the field longer compared with those areas that require less deposition of dose. The end result of these interactions in serial adjoining axial slices is the conformal treatment that is desired. IMRT also can be done using static field techniques, where the beam moves to various fixed positions around the patient, but the multileaf collimator is used to vary the intensity of different parts of the beam during treatment of each field.

 
 

Figure 29-24  Advanced form of 3-D IMRT, which is based on the use of optimized nonuniform radiation beam intensities incident on the patient. Shown are a 3-D view of the patient, the PTV, spinal cord, parotid glands, and the nine intensity-modulated beams (with gray levels reflecting the intensity value) used to generate the IMRT dose distribution.

 

 

In these highly evolved treatments, optimization of these plans would not be possible without specialized computer software.[158] An important concept used for most IMRT is that of inverse planning, in contrast to the forward planning that is used for most conventional treatment planning. In forward treatment planning, the beam orientation, shape, size, modifiers, and so on are defined first, followed by the calculation of dose that results from this design. Changes to achieve better dose distribution are made by modifying the beam weighting, adding or subtracting beams, and so forth, until the desired dose distribution is achieved. In inverse treatment planning, the desired dose distribution is stated first, followed by computer optimization to adjust beam intensities to attempt to achieve that dose distribution.Optimization includes stating the dose that the tumor bed or areas at risk should receive, as well as limits of dose that normal tissues will be permitted to receive. These parameters are based on maximizing the probability of tumor control and minimizing the toxicity profiles of the various normal tissues and organs. Because normal tissues have different tolerances, different organs will have different thresholds. After the computer optimizes the dose distribution, the physician may choose what is deemed to be an optimal plan ( Fig. 29-25 ).

 
 

Figure 29-25  Typical head-and-neck IMRT treatment plan showing conformal avoidance of the spinal cord and parotid glands, while simultaneously delivering multiple dose prescriptions (66.5 Gy and 54.3 Gy) to the two target volumes. A, Transverse cross-section. White line corresponds to the position of the coronal cross-section. B, Coronal cross-section. White line corresponds to the position of the transverse cross-section. C, DVHs of the target volumes and selected critical structures. Vertical bars indicate the prescription doses and highlight the increased dose heterogeneity often encountered as a consequence of conformal avoidance.

 

 

Many clinical studies have verified that IMRT provides superior dose distribution over conventional 3D conformal radiation, although most of these studies have reported on small numbers of patients. [159] [160] [161] [162] [163] Since the goal of IMRT is to increase the therapeutic ratio, delivering a higher tumor dose relative to normal tissues, IMRT can be used to escalate the tumor volume to a higher dose while maintaining normal tissue toxicity at a tolerable level. Among the cancer sites investigated using IMRT to escalate total dose are non-small-cell lung cancer, head and neck cancer, intracranial tumors, and prostate cancer. [159] [160] [161] [162] [163] Alternatively, IMRT can be used to deliver conventional doses to the tumor bed, resulting in lower dose to normal tissues, with hopes of reducing toxicity. It is anticipated that favorable dose distributions should result in decreased toxicity, although no definitive study has yet demonstrated the clinical impact of IMRT in reducing toxicity to normal tissues. Because the dose distributions made possible by IMRT's planning and treatment delivery are superior to conventional conformal 3D plans, improvements in clinical outcomes are expected, although the long-term safety of IMRT remains to be demonstrated.

As with all technological advances, a number of potentially difficult problems with IMRT exist and need to be addressed. [164] [165] With IMRT, it is much more difficult than with 3-D conformal therapy to verify that treatment has been delivered correctly to the patient and to keep a long-term record of that treatment. If there is organ motion—which is inevitable for every organ below the calvarium—then there is a possibility that the dose delivered may differ significantly from the dose planned and recorded, as planning was performed on static images. Finally, as more beams are added to the treatment and the daily treatment time increases, then, although less normal tissue will be treated to tolerance doses, the volume of normal tissue that receives some dose of radiation (e.g., scattered radiation), in fact, increases, as does the total-body dose of radiation. It remains to be seen how significant these problems will be over the longer term.

Particle Radiation Therapy

Particle beam therapy utilizes subatomic particles instead of x-rays or gamma rays to deliver the dose of radiation. The development and application of particle radiation therapy has been motivated by two main factors. One is the physical property that allows for precise dose localization and superior depth dose distribution with heavy charged particles such as protons. The other is the potential radiobiologic advantage of high-linear-energy-transfer (LET) particles. High-LET radiation deposits more dose along its path than conventional x-rays, which are low LET. This offers advantages for several potential reasons. Firstly, high-LET radiation is more damaging to hypoxic cells. Secondly, there is less repair of damage induced by high linear energy transfer radiation. Thirdly, damage from high-LET radiation is less cell cycle dependent.[74]

Neutron Therapy

Neutron radiation therapy first was applied in the late 1930s to attempt to increase killing of hypoxic cells.[166] Because there was little understanding of the high-LET and resultant high relative biologic effectiveness of neutrons, there were severe radiation sequelae with treatment.[167] It was not until the 1960s that clinical trials in neutron therapy were resumed, with adjustments in dose compensating for the high-LET and relative biologic effectiveness of neutrons.[168] Early trials failed to confirm the efficacy of neutron therapy, but because of the potential advantages of high-LET radiation, neutron therapy has been used widely in the attempt to control various tumors ( Fig. 29-26 ). Approximately 30,000 patients have received neutron therapy worldwide, with mixed results.

 
 

Figure 29-26  Survival curves for various types of clonogenic mammalian cells irradiated with 300-kV x-rays or 15 MeV d+ ➙ T neutrons. Curve 1, Mouse hematopoietic stem cells. Curve 2, Mouse lymphocytic leukemia (Ly. leuk.) L5178Y cells. Curve 3, Tlg cultured cells of human kidney origin. Curve 4, Rat rhabdomyosarcoma cells. Curve 5, Mouse intestinal crypt stem cells. The variation in radiosensitivity between different cell lines is markedly less for neutrons than for x-rays.  (From Cox JD, Ang KK [eds]: Radiation Oncology: Rationale, Technique, Results, 8th ed. St. Louis, Mosby, 2003, p 46.)

 



The most quoted site said to show an advantage for neutrons over conventional photons was unresectable salivary gland carcinomas. Early single-institution studies indicated a therapeutic advantage of neutron therapy over photon therapy, prompting a phase III RTOG/MRC trial that showed a significant local control advantage of neutrons over photons (56% vs. 17%), but with no overall survival advantage due to distant metastases.[169] This advantage also has been shown more recently in both major and minor salivary gland tumors.[170]

Neutron therapy also has been investigated in soft tissue, osteogenic, and chondrogenic sarcomas. These tumors are thought to be radioresistant to conventional x-rays and responsive to neutron therapy.[171] Phase II data and single-institutional data show the possibility of an advantage in unresectable sarcomas, though this has never been tested in a large-scale randomized clinical trial. [172] [173]

Results of neutron therapy in head and neck cancer and in non-small-cell lung cancer have not been as encouraging. Phase III data from head and neck neutron therapy trials indicate higher toxicity with no definite advantage in terms of local control, regional control, or survival with neutrons. [174] [175] [176] Similarly, the results of studies done with neutrons in patients with non-small-cell lung cancer are inconclusive, showing no definite advantage with neutrons over conventional photons.[171]

Two randomized clinical trials have compared neutron therapy with photon therapy in patients with prostate cancer. [177] [178] These studies show an advantage of neutrons in terms of locoregional control, with one study showing an overall survival advantage. Neither study showed an advantage in terms of disease-specific survival.

There are no active clinical studies involving neutron therapy. It is used selectively in certain specialist centers for inoperable tumors (e.g., salivary gland tumors, selected sarcomas) in which there is some evidence for its effectiveness and in which the dose distribution is superior to conventional radiation therapy. Given its potential for causing late toxicity[179] and because neutron therapy often produces dose distributions that are less desirable than charged particle therapy, interest in neutron therapy has waned.

Proton Therapy

Although protons have a slightly higher linear energy transfer than x-rays, they are not generally considered high-linear-energy transfer particles. Most of their their advantage over x-rays is achieved in their physical dose distribution. When a heavy, charged particle, such as a proton, passes through tissue, the dose it deposits increases slowly with depth, then reaches a sharp increase at its maximum depth of penetration. This is called the Bragg peak ( Fig. 29-27 ). The maximum depth of penetration can be adjusted by varying the energy of the proton beam or by adding or removing compensating material placed in the path of the beam. In clinical use, the Bragg peak often is spread out in depth using specialized filters to achieve the dose deposition pattern desired, but still with the desirable sharp dose fall-off at the deep edge of the beam. Using multiple beams or varying compensators, it is possible to design a 3-D dose deposition that is precisely confined to the tumor volume with minimal dose to the surrounding normal tissue.

 
 

Figure 29-27  Depth-dose distributions for a proton beam compared with other photon beams. The dose for the proton beam is limited for the entrance tissues, reaches a Bragg peak at the desired depth, then displays an extremely sharp fall-off.

 

 

Most patients treated with proton therapy have had tumors in close proximity to critical structures.[180] The precise dose deposition patterns of protons made it possible to treat these tumors without crossing the threshold of critical toxicity of the surrounding normal structures ( Fig. 29-28 ).

 
 

Figure 29-28  A, Proton beam arrangement compared with a complex IMRT plan of nine beams for the treatment of malignant melanoma. Note the full coverage of the target volume with sparing of normal tissues. B, Proton beam arrangement compared with an IMRT plan for treatment of a pediatric meningioma. C, Treatment of a thoracic paraspinal chordoma requiring contouring of the dose distribution around the spinal cord, while continuing to provide full coverage to the target volume, more easily attained with proton beams than with a complex IMRT plan.  (Used with permission from Anthony Lomax, PhD, Paul Scherrer Institute, Switzerland.)

 



Uveal melanoma is a malignancy that had been difficult to treat with photons on account of toxicity to normal structures of the eye. Surgical enucleation traditionally has been the treatment of choice. Proton therapy has become an alternative treatment for uveal melanomas. Massachusetts General Hospital has reported a 10- and 15-year actuarial local control rate of 95%, using 70 Gy-equivalent doses. Enucleation was avoided in the great majority of patients, with only 2% to 10% (depending on size of the primary tumor) requiring subsequent enucleation. [180] [181] This high rate of control also has been reported by the group at the Paul Sherrer Institute in Switzerland, with a 10-year local control rate of 95%.[182] Again, subsequent enucleation rate was low (8%), with a 15-year overall eye retention rate of 84%.[183] With these outcome data, all patients could be considered for what is basically organ-sparing treatment in the form of proton beam therapy.

Tumors of the paranasal sinuses also have been treated using proton beam therapy, with the precision of proton beams allowing dose escalation up to 76 Gy-equivalent. Using a combination of photons and protons after partial resection or biopsy, local control rates for T3-T4 tumors have been reported up to 85%, again with low toxicity. [180] [184]

More commonly occurring tumors have also been treated with proton beam radiation therapy, with the high precision allowing for dose escalation in diseases that are difficult to control with conventional doses. A phase II study in 23 patients with glioblastoma multiforme was undertaken at the Massachusetts General Hospital with dose escalation up to 90 Gy-equivalent using proton beams. Such doses cannot be achieved with photons due to toxicity to critical brain structures. Median survival was 20 months, with a 3-year actuarial survival of 18%. Recurrence was seen in only one patient treated at the 90 Gy-equivalent dose level, but radiation necrosis was observed in 7 of the 23 patients treated.[185]

Meningiomas are another type of CNS tumor that has been treated with protons. In a study of 46 patients with partially resected, biopsied, or recurrent meningiomas, a combination of photons and protons was used to deliver a median dose of 59 Gy-equivalent to the macroscopic tumor volume. The recurrence-free rates at 5 and 10 years were 100% and 88%, respectively. Eight patients, however, developed severe ophthalmologic, neurologic, or otologic long-term toxicity from radiation therapy.[186]

Prostate cancer is the only tumor in which dose escalation with protons has been tested against conventional radiation in a randomized trial.[187] Patients with T3 or T4 prostate cancer who received 50.4 Gy via photons to a pelvic field were randomized to receive either an additional 16.8 Gy with photons or 25.2 Gy equivalent with protons. There was no difference in overall survival, disease-specific survival, or local control between the two groups. Additionally, there was an increase in toxicity in the proton arm, owing to the higher dose delivered to the rectum.[188] This study was done in the 1970s, prior to the recognition of the importance of volume considerations in determining rectal toxicity. More recent studies have demonstrated that sparing of the rectum during prostate irradiation can be achieved with proton therapy.[189]

The role of proton therapy is currently being studied in patients with prostate cancer, hepatocellular carcinoma, and non-small-cell lung cancer, and in combination with stereotactic radiosurgery (see previous discussion). [180] [190] [191] [192] Proton therapy provides a further example of the application of technological advances in the field of radiation oncology ( Box 29-1 ). Because it represents the optimal therapeutic ratio available in terms of dose delivery for many cancers, its availability as a standard treatment modality is anticipated to become more widespread.

Box 29-1 

TREATMENT STRATEGIES FOR CHORDOMA OF THE BASE OF SKULL

Tumors of the skull base are difficult to treat because of their location. The base of the skull involves and is surrounded by critical structures such as the brain stem, the optic chiasm, the optic nerves, the cranial nerve roots, the arterial circle of Willis, and the cervical spinal cord. Two primary malignant tumors that arise in the skull base are chordomas and chondrosarcomas, both of which can cause debilitating morbidity or even death due to the position in which they arise. Both types of tumor are difficult to treat, either with surgery or conventional radiation therapy, without the risk of leaving the patient with significant disability. These tumors require high doses of radiation if local control is to be achieved, and retreatment with radiation usually is not feasible without significant risk of morbidity.

Using a combination of 3-D conformal x-ray therapy and charged particle therapy (protons), a more desirable dose distribution can be achieved than that obtained using conformal megavoltage photon radiation alone. The Bragg peak (see Fig. 29-27 ) can be used to allow a steep fall-off of dose within a few millimeters of critical organs. In two reported series of patients with chordomas arising in this anatomic region, the application of this novel combination of radiation modalities has resulted in local control rates of 65% to 70%.[*] In these small series, median tumor dose was 70 Gy-equivalent (physical dose ×1.1—the relative biologic effectiveness for protons). A low incidence of long-term toxicities was reported.

*  Austin-Seymour M, Munzenrider J, Goitein M, et al: Fractionated proton radiation therapy of chordoma low-grade chondrosarcoma of the base of the skull. J Neurosurg 1989;70:13–17; and Fagundes MA, Hug EB, Liebsch NJ, et al: Radiation therapy for chordomas of the base of skull cervical spine: patterns of failure outcome after relapse. Int J Radiat Oncol Biol Phys 1995;33:579–584.

CONCLUSIONS

Radiation therapy has progressed rapidly since the discovery of x-rays over 100 years ago. Understanding of the physical and biologic properties of radiation has led to great advances in the field of radiation therapy, making it possible to cure hundreds of thousands of patients worldwide and spare thousands more from the mutilating consequences of surgery. With the advent of computers and conformal 3-D treatment planning, the field of radiation oncology has advanced further in recent decades. The therapeutic index has been increased by dose escalation and more accurate shielding of normal tissues. Recent innovations such as systemic targeted radionuclide therapy, novel approaches to brachytherapy, and dose escalation with IMRT offer hope for further improvements in radiation treatments for patients with cancer. Clinical studies investigating these modalities and the strategic development of combination treatments, particularly with cytotoxic chemotherapy and molecular biology-based targeted therapies, will ensure continued advancement of the field of radiation oncology in years to come.

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