Radiotherapy for Head and Neck Cancer: Radiation Physics, Radiobiology, and Clinical Principles

Characteristics of Radiation

Radiation refers to the propagation of energy through space or a medium ( Fig. 75.1 ), and it can be broadly classified as either particulate or electromagnetic: if the radiant energy is carried off by a particle that has rest mass, the radiation is particulate or corpuscular radiation; examples of particulate radiations are electrons, β-particles, protons, neutrons, and heavy charged particles.

Electron beams, which are produced in a linear accelerator, are widely available for the treatment of superficial lesions in clinical radiation oncology practice. In addition, mixed beams that consist of electron beams and photon beams are used to treat lesions that require higher surface doses. Negatrons (negatively-charged β-particles) from strontium-90 are used in the treatment of restenosis in intravascular coronary brachytherapy. Although other forms of particulate radiation have been employed experimentally in the past, their use has been limited to a few centers. The use of protons is gaining popularity in many centers, specifically for pediatric tumors.

Electromagnetic radiation is a packet of energy (a photon) that propagates through space. It has no rest mass and propagates at the speed of light. This discrete energy (E) is related to its associated frequency (ν) as follows:

where h is Planck's constant, with a value of 6.626 × 10 ³⁴ joule-second (J-s). The energy of a photon is often expressed in electron volts (eV); 1 eV represents the amount of energy required to accelerate an electron through a potential of 1 V. The frequency (v) of a photon is related to its wavelength (λ) as follows:

where c is 3.0 × 108 m/s, the speed of light in a vacuum. The waves of electromagnetic radiation are composed of oscillating electric and magnetic fields that are orthogonal to each other and to the direction of propagation, as shown in Fig. 75.1 . The electromagnetic spectrum spans a broad and continuous range, from radiowaves to x-rays with wavelengths from 106 to 10 ¹³ m. Radiation with wavelengths shorter than that of visible light is classified either as ultraviolet rays, x-rays, or γ -rays ; the boundaries between these regions are not sharply defined. For example, x-rays and γ-rays are indistinguishable except for their origins: one is from the orbital electrons, and the other is from the nucleus, respectively. Different types of electromagnetic radiation interact differently with the same material (see Fig. 75.1 ).

Radiation Production by Radioactive Decay

As previously discussed, radioactivity is the phenomenon in which radioactive materials disintegrate by emitting radiation to achieve nuclear stability. The amount of radioactivity is measured in units of curie (ci), named after the Polish-born French scientist, Marie Curie. A curie is equal to 3.7 × 10 ¹⁰ disintegrations per second. A smaller unit, the millicurie (mci), is routinely used in the field of radiologic physics. The SI unit of radioactivity is the becquerel . It is equal to 1 disintegration/s, typically denoted as the reciprocal of 1 second (s-1). Unstable nuclei decay by emitting α- or β-particles or γ-rays. An α-particle, denoted by the symbol α, is actually a helium atom that has been stripped of its electrons and consists of two protons and two neutrons. A negative β-particle (β ⁻ ) carrying a unit negative charge (−1e) is called a negatron; a positive β-particle (β ⁺ ) carrying a unit positive charge (+1e) is called a positron .

Unstable atoms de-excite by emitting x-rays. An atom is said to be in an excited state if any orbital electron is not in its lowest energy state. When an atom is in an excited state, an electron from the higher energy shell jumps into the vacant position; as a consequence of this transition, an x-ray is emitted. A cascade of x-rays can be emitted after a tightly bound electron is ejected. The process of ejecting an orbital electron is called ionization radiation .

Radiation Production From Linear Accelerators

Another type of radiation is termed bremsstrahlung, German for “braking radiation”; it is an electromagnetic radiation produced by a sudden slowing down or deflection of charged particles, especially electrons, passing through matter near the strong electric fields of atomic nuclei.

Internal bremsstrahlung arises in the radioactive process of β -decay , which consists of the production and emission of electrons by unstable atomic nuclei or the capture by nuclei of one of their own orbiting electrons. These electrons, deflected from their own associated nuclei, emit internal bremsstrahlung. During the deceleration process, the electrons interact with the atomic nuclei, which results in the emission of bremsstrahlung radiation. Before 1950, external beam RT was accomplished in this way, with a maximum energy of about 300 keV. As just stated, these x-rays are low in energy compared with what is used today, and they have the disadvantages of poor penetration and maximal deposition of dose at the skin. Today, other types of radiation are produced in nuclear reactors, cyclotrons, and linear accelerators.

Interaction of X-Rays With Matter

Once high-energy x-rays are successfully produced, they can interact with matter via several different processes. Each interaction type has a probability based 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, an effect called attenuation , which is basically the loss of intensity and subsequent decrease in the deposition of dose as the beam reaches greater depths. The five possible interactions of x-rays with matter are: (1) coherent scattering, (2) the photoelectric effect, (3) the Compton effect, (4) pair production, and (5) photodisintegration. The most important of these interactions in RT are represented in Fig. 75.2 .

Coherent Scattering

Also called classic scattering, coherent scattering occurs when x-rays are of low energy. In coherent scattering, a photon is separated from an electron with a resultant change in direction but no change in energy. The amount of coherent scattering that occurs in therapeutic, and even diagnostic, radiation is negligible. Coherent scattering is important in processes such as x-ray crystallography. It is a dominant process at low-photon energies (those below 10 keV) and in material with a high atomic number. Because of its low photon energy, coherent scattering does not contribute to either diagnostic radiology or RT.

Photoelectric Effect

The photoelectric effect was first described by Albert Einstein, and it was this contribution to physics—not his discoveries regarding relativity—that led to his being awarded the Nobel Prize in 1921. In the photoelectric effect, a photon interacts with a tightly bound inner-shell electron of 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. Thus the photoelectric effect is very important in diagnostic radiology—it is the process that forms the basis for the radiographic contrast between tissues (e.g., between bone [calcium and phosphorus] and fat [carbon and hydrogen]). The photoelectric effect is, in most instances, undesirable in RT. Typically, we do not want bony structures to be shielding underlying tumors. However, with higher-energy x-rays, such as those used in RT, the contribution of the photoelectric effect is relatively small. In comparison, this effect is great with the low-energy radiation used for diagnostic radiology, in which the difference between bone and tissue absorption provides the necessary tissue contrast.

Compton Effect

Compton scattering is the most important interaction of energies within the range used for RT. In Compton scattering, 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 and 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 a dose with each interaction. These interactions and subsequent ionizations are responsible for the biologic effects on tissues during RT.

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

Pair Production

Pair production occurs at high energies as a result of the interaction between a photon and a nucleus, with the spontaneous disappearance of the photon and the production of an electron and a positron. Pair production occurs at higher energies and becomes dominant at ranges above standard treatment, at approximately 25 megaelectron volts (MeV); thus it rarely has a role in treatment.

Photodisintegration

At very high energies, x-rays can deposit so much of a dose into the nucleus of the target tissue that partial disintegration of the nucleus occurs, and neutrons are emitted from the nucleus. Although this process has little importance in the clinical interactions used in RT, the production of neutrons is important in the planning of shielding around high-energy linear accelerators for the sake of protecting patients and personnel from potentially carcinogenic low-dose radiation.

Deposition of Dose

The absorbed dose from an x-ray beam is the measure of the energy deposited by the beam and absorbed by the target. Radiation doses were historically measured by roentgens, a unit of exposure that did not quantify the dose the patient absorbs. In the late 1950s the rad , an abbreviation for “radiation-absorbed dose,” was introduced. The rad is equivalent to the deposition of 100 ergs (10 ⁻⁷ joules) per gram of material.

More recently, an international commission has agreed that radiation doses should be specified in terms of gray (Gy), which corresponds to the deposition of 1 joule/kg of material. Numerically, doses in rad can be converted to equivalent doses in Gy by dividing by 100 (i.e., 100 rad equals 1 Gy). This is closely related to the observed biologic effects, and how and where the dose is deposited is obviously very important. Because the amount of radiation absorbed by the target is assumed to be as previously stated, x-rays in the megavoltage energy range, such as those used in RT, exhibit the phenomenon of skin sparing, whereby the dose deposited in tissue is relatively low at the surface but increases rapidly over the first few millimeters. The region of rapidly increasing dose is known as the build-up region . This rapid increase occurs because of the forward-moving photons interacting with electrons of the target tissue via the previously described processes. Because these electrons are also propelled forward but have a shorter course than the photons, at depth, there is an area at which the number of electrons entering the plane of interaction from superficial interactions is exactly equal to the number leaving the plane from interactions in that plane. This plane is termed the D _max , because it represents the maximum number of ionization events past this point; as more interactions between the photon beam and tissue occur, fewer photons are available to travel forward and deposit the dose at greater depths. This process, as previously described, is called attenuation . How quickly a photon beam is attenuated—that is, how much dose it deposits at depth—depends on qualities both within the beam and within the target tissue. The most substantial effect on the dose delivered at depth from the photon beam is the beam's energy.

Deposition of Energy

As a high-energy photon beam traverses through a medium, the atoms are excited and ionized. Of the two interacting processes, ionization is disruptive to atoms; it changes the molecular integrity and leads to cell death in tissue. The ejected electrons undergo further interactions and deposit their energies to the medium through excitation and ionization. The amount of energy transferred to the electrons at the initial point of interaction is called kerma . The second stage of the energy-transfer process is called the absorbed dose . Not all the energy transferred to the medium at the initial point of interaction is absorbed. Some of the energy is radiated away as bremsstrahlung, and the remaining is called collision kerma. The absorbed dose is the energy retained in the medium along the path of the electrons. If the electron track has an appreciable length, the transfer of energy (kerma) and the absorption of energy (absorbed dose) take place at separate locations.

When a photon beam enters a medium, the initial ionization of atoms takes place at the surface. The energy is directly transferred to the ejected electrons, and, therefore, kerma has a maximum value at the surface. As the beam proceeds farther, the photon intensity decreases as a result of absorption and scatter; hence, kerma decreases as a function of depth into the medium. On the other hand, absorbed dose is initially low at the medium surface, increases to a maximum, and thereafter decreases as a function of depth. The region from the surface to depth of maximum dose is called the build-up region . The position of maximum absorbed dose is called the point of equilibrium , and the region beyond the maximum dose is the region of transient electronic equilibrium .

Linear Accelerators

Linear accelerators typically produce beam energies that range from 6 to 18 MeV, and the dose at depth increases with beam energy. Therefore an 18-MeV photon beam would deliver more dose to a given depth in a patient than would a 6-MeV photon beam. An 18-MeV beam would also have more skin sparing (i.e., it would have a greater D _max ). Another aspect that affects the depth dose is the size of the field of radiation used to treat the patient. With a larger field size, greater scattering of photons within the field occurs 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, the dose at a 10-cm depth within a patient from a photon beam that has a field size of 20 × 20 cm would be higher than the same photon beam with a field size of 5 × 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 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, is less dense than soft tissue and allows more photon transmission. Additionally, the inverse square effect, first noted by Roentgen, must be taken into account. All of these factors must be taken into consideration in the determination of the dose being delivered to structures within the patient. Calculation of the dose given to a tumor or other volumes within a patient is thus complex and requires much more knowledge than simply how much of an x-ray dose the machine is putting out.

As an energy source, electrons differ from photons in that electrons travel only a certain (short) distance within tissue. They are very light particles compared with the nuclei of the target tissue with which they interact. Hence the electrons lose a large fraction of their energy in a single process. This leads to much less skin sparing and to deposition of the majority of the dose in superficial tissues. Consequently, however, they are very useful for treatments in which the target of the radiation lies close to the surface, such as with skin tumors ( Fig. 75.4 ).

Particle Beams

High-energy charged particle beams interact with tissues in a unique way. At first, the charged particles lose energy gradually, but the energy release is intense at the end of the range; this intense energy deposition is called the Bragg peak . This feature provides a means of delivering the maximum dose to a target at a specified depth. Often in clinical practice, the particle beams are modulated to change the energy, and hence the depth, to widen the dose deposition to cover the target; this change is in addition to allowing optimized dose delivery.

In the strictest sense, the electron beams used in conventional RT facilities are a type of particle radiation, but this section is devoted to the heavier charged particles—protons, α-particles, heavy ions, π-mesons, and fast neutrons—used experimentally at a small number of RT centers throughout the world. These particles are of special interest because of their different radiobiologic properties or their better depth-dose characteristics, which allow for higher tumor doses without causing a commensurate increase in the dose to the surrounding healthy tissues.

One particle for which a great amount of clinical work has been done is the fast neutron . Fast neutrons are of clinical interest because of their radiobiologic properties, which occur because of the much greater amount of energy they deposit when they go through tissue. Neutrons are neutral particles that interact with the atomic nuclei to produce “heavy” charged particles such as protons, α-particles, or nuclear fragments that in turn create a dense chain of ionization events as they go through tissue. The distribution of these secondary particles depends on the energy spectrum of the neutron beam, so the biologic properties of the beam depend strongly on its energy spectrum. Neutrons used in therapy are generally produced by accelerating charged particles, such as protons or deuterons, and bombarding them on a beryllium target.

There is considerable interest in using charged particle beams directly for therapeutic purposes, which generally require beams of much higher energy than those used to produce neutrons. The lighter particles, such as protons and α-particles, are of interest because of their extremely favorable depth-dose characteristics. The radiobiologic properties of these beams are similar to those of conventional photon or electron beams. Heavy charged particles combine the favorable depth-dose properties of the proton and α-particle beams with the favorable biologic properties of the neutron beams. Energies are on the order of several hundred MeV per nucleon, rather than the few MeV per nucleon for the recoil fragments produced by neutrons. These highly energetic particles do not deposit much energy in tissue until they reach the end of their path, where they are moving slowly; hence they do not produce much radiation damage in the intervening tissues. However, because of their extremely high cost and general unavailability, these beams are not widely in use.

Interest in proton beams has grown, and the number of RT facilities using this modality in the United States has been rising, with many centers suggesting the use of proton therapy in HNC treatment and other indications. The current literature on proton beam therapy is largely based on dosimetric analyses and retrospective studies at single institutions. Proton beam therapy has a clear dosimetric advantage compared to photons, which may reduce any unnecessary radiation dose to normal tissues, but organs within the target range will receive the entire dose of proton-based radiation, and there are no data regarding what happens during the treatment. Moreover, some studies suggest that proton beams pose an increased risk for toxicities in subsets of patients who received that therapy, such as skin toxicity, temporal lobe necrosis, and neurologic complications. To conclude, protons have potential a dvantages in head and neck cancers, and their exact role has to be defined in prospective studies.

Aspects of External Beam Radiation

A series of technical tasks must be performed to prepare a patient to undergo external beam RT. The purpose of these tasks—simulation, treatment planning, verification, dose delivery, and quality assurance—is to ensure that high radiation doses are delivered to the patient in an accurate and controlled manner. Usually, the processes of simulation, treatment planning, and verification take 1 to 3 days. The setup and treatment planning must be individualized to maximize the dose delivered to the target while minimizing the irradiation of surrounding normal tissue. Any inaccuracy in this process could cause further delay in the initiation of the radiation treatment.

During simulation, the patient setup is assessed for ease of positioning and daily reproducibility. This process involves the use of immobilization devices, anything that can hold a patient in position during treatment, and treatment aids, any kind of support to make the patient comfortable. In most HNC patients, a mask that immobilizes the head and neck is used.

After the patient is immobilized, at least two reference points are marked on the patient with x-ray markers to define a reference plane close to the internal tumor target. The marking of the reference points is aided by the use of lasers. Next, the region of interest on the patient is scanned using computed tomography (CT), often with a dedicated CT-simulator scanner to obtain CT images for image-based treatment planning. The images are scanned to a treatment planning station. The radiation oncologist then outlines the tumor target region and critical surrounding normal structures on the axial images on the basis of the CT scan, and a prescribed dose with appropriate normal tissue margin is provided. On the basis of this information, a medical physicist or a medical dosimetrist designs an individualized treatment plan. The challenge in the plan is to deliver the prescribed dose uniformly to the tumor or tumor bed target while maintaining a very low dose to the critical normal structures. Although these goals are achievable, it takes time to arrive at an optimized, individualized plan.

Apart from delivering the prescribed dose to the target and minimal dose to the surrounding critical structures, the individualized plan must be evaluated for deliverability —that is, the selected beam orientation must be such that the linear accelerator does not collide with the patient or the table, and the technical parameters of the patient's plan must comply with the technical requirements of the delivery machine. Next, the individualized machine-delivery parameters are downloaded into a record verification system database. Patient verification is the process of ascertaining that the individualized plan is correct and deliverable. Correct here means that the patient is easily placed into the treatment position, is relatively comfortable and immobile, the setup is reproducible, and the target is at the appropriate position relative to the isocenter according to the plan. Finally, clearance is sufficient to avoid patient-equipment collision. During verification, orthogonal radiographs or individualized field radiographs are taken, with films or a portal imager, for assessment and for documentation of the setup. In addition, machine parameters are captured in the database. These images can be used to assist in repositioning the patient as necessary.

Typically, the radiation dose is delivered to the patient using a linear accelerator ( Fig. 75.5 ). The radiation beam produced has a forward peak; that is, it has extremely high intensity along the beam axis. It must pass through a conical metallic flattening filter to create a uniform field beam for clinical use. As the clinical beam exits the linac, it is collimated by a pair of jaws or a multileaf collimation (MLC) system (see Fig. 75.5 ). The MLC system is used to shield and protect normal structures, replacing the antiquated and cumbersome lead blocks. In addition, the system is used to modify beam intensity in intensity-modulated RT. The linear accelerator has a gantry that allows the rotation of the treatment head around the patient; hence, the radiation beam can be directed at the target from multiple positions to reduce dose to the normal tissues. Because of the high voltage, moving parts, and high dose, the linac must be properly calibrated and maintained for safe use (see Fig. 75.5 ).

A new intensity-modulated radiotherapy (IMRT) radiation technique has emerged lately: volumetric modulated arc radiotherapy (VMAT). With this technique, the radiotherapy machine rotates around the patient during treatment. The machine continuously reshapes and changes the intensity of the radiation beam as it moves around the body, the treatment is much quicker than regular IMRT. Typically, IMRT plans require 20 to 25 minutes for delivery of the daily treatment, while a VMAT plan can now be delivered in approximately 3 to 5 minutes (approximately 1.5 minutes per gantry rotational arc), which is easier for patients. In dosimetric studies, in comparison with IMRT and 3DCRT, the calculated mean and maximum doses for organs at risk were lower for VMAT, although both VMAT and IMRT techniques have higher critical organ sparing than the 3DCRT. This would suggest that the risk of secondary cancer induction after VMAT is lower than after IMRT or 3DCRT in HNC.

In addition to external beam therapy, radiation oncology departments offer brachytherapy services ( brachy is derived from the Greek word for “short”); in this treatment modality, sealed radioactive sources are implanted near or directly into tumors. The principal advantage of brachytherapy has been its rapid dose fall-off away from the source. Brachytherapy is generally invasive. When the implant requires short-lived radioactive sources, preimplant dosimetry is performed to determine the number of sources required. After this number has been determined, the implants are ordered from the vendors. When the sources arrive, they must be assayed and prepared for implantation. On the day of implantation, a final dosimetry plan is created, and the sources—often in the form of seeds, as used in prostate brachytherapy—are implanted according to the new treatment plan. For cases that involve sources with long half-lives, catheters are provided to the radiation oncologist for implantation. After the implantation, the patient must undergo simulation, and a final treatment plan is generated, similar to the process already described for external beam RT. With advances in computer technology, remote afterloading brachytherapy is now being practiced; in this therapy, radioactive sources are remotely loaded into a patient, and they can be retracted at any time if necessary.

Treatment Planning

Successful treatment planning is imperative to the success of a radiation treatment course. The goal is to identify the full extent of the tumor and areas of possible spread. Several factors must be considered, including tumor histology, extent of the gross disease, regions of microscopic spread without 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 each normal tissue below its tolerance. After the image datasets are obtained in any type of simulation, careful review of the clinical data must be made to delineate the tissue in need of treatment. This volume to be treated is defined as the target volume, and it is created by adding three components together: (1) the gross tumor volume (GTV) is noted; this volume is expanded to create (2) the clinical target volume (CTV) by accounting for the areas at risk for spread, such as adjacent tissues or draining lymphatic regions; and (3) the planning target volume (PTV) is calculated by adding margin to correct for possible variability in daily positioning and patient motion during treatment.

The remainder of the planning process involves choosing the number of radiation beams required, the energy of these beams, and the angles and weighting of the beams needed to deliver the required radiation dose to the tumor with optimal sparing of normal tissues. After these beams are designed, digitally reconstructed radiographs are produced to reflect the designed treatment fields. The availability of a three-dimensional (3D) treatment planning has allowed for greater complexity of plans in the attempt to increase the therapeutic ratio via the designing of radiation fields, because 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 organ.

Once treatment planning is completed, the patient begins the course of RT. The first step is to set up the patient to verify the simulation fields on the actual treatment machine. Each day, the patient is repositioned into the exact position in which the simulation and subsequent treatment planning were done. To aid in the repositioning, immobilization devices are often used that consist of foam body casts or plastic head masks, as previously mentioned. These are made prior to simulation and are kept for use throughout the entire radiation course. Laser lights that converge on the treatment machine's exact isocenter, the point around which the treatment machine rotates, are available within the treatment room and are used to assist in this repositioning. As 3D techniques allow for greater refinement of treatment volumes and the increasing complexity of plans, exact daily repositioning is absolutely imperative.

When planning radiation treatment, the clinician must keep in mind the dosages needed to control gross tumor-positive margins and microscopic disease. The probability of tumor control correlates with both the dose of radiation and the volume of the cancer. Radiation cell kill is basically an exponential function of dosage. As a result, the necessary dosage of radiation is roughly proportional to the number of cells in the tumor (tumor volume). Control of microscopic disease in HNC usually requires a dosage of approximately 50 Gy, whereas positive margins require 60 Gy, and adequate control of large tumors (stages T3 and T4) requires dosages in the range of 70 Gy.

Cell-Cycle Arrest

Radiation triggers signaling cascades that lead to arrest, usually at the G1 and G2 checkpoints in the cell cycle. Cell-cycle perturbations ( Fig. 75.7 ) are seen characteristically after radiation exposure and were among the earliest observed biologic effects of radiation. 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 those cancer cells that retain p53 function are blocked in the G1 phase of the cell cycle. This is a p53-mediated event.

Mitotic Death

Many cancer cells, typically those with loss or mutation in the p53 protein pathway, have lost the ability to stop in G1, although these cells retain the ability to arrest in the G2 phase of the cell cycle. However, even in cells that reenter the cycle after the G2 checkpoint, cell death can still be seen and can take several forms: some cells fail in cytokinesis and form multinucleated giant cells, and some undergo mitotic catastrophe as they attempt to undergo mitosis.

Radiosensitivity

Our main interest in radiobiology is in figuring out ways to improve the treatment toxicity ratio. One of the main concepts is radiation sensitivity , which refers to the relative susceptibility of cells, tissues, tumors, or organisms to radiation. However, tumor regression is not solely a function of tumor cell death but is influenced by many factors, including the amount of extracellular stroma; the propensity of the tumor cells to undergo rapid, rather than delayed, death; and the resorption of radiation-inactivated cells (depopulation). A frequent misconception is that tumors should be more radiosensitive than normal tissues, because they proliferate more rapidly. This misconception may go back 100 years. In 1906, only 11 years after the discovery of x-rays, Bergonie and Tribondeau formulated a “law” for the relationship between cellular radiosensitivity and reproductive capacity. They postulated that cells that have a higher proliferation rate are more radiosensitive than slowly proliferating cells. On a purely cellular basis, it is correct that cells in mitosis at the time of irradiation are more radiosensitive than cells in other phases of the cell cycle. However, many other factors, such as tissue- and host-specific factors, have important influence. In 1906, there was no appreciation of late-occurring normal tissue complications. It is now known that many slowly proliferating or nonproliferating normal tissues, such as the kidney, are highly radiosensitive; they just express radiation injury much later than rapidly proliferating tissues do. Similarly, the proliferation rate of tumors does not predict their RT curability. For example, rapidly proliferating tumors such as glioblastoma multiforme can be highly radioresistant.