Therapeutic radiation

28 Therapeutic radiation


Principles, effects, and complications






Historical perspective


In November 1895, Wilhelm Conrad von Roentgen discovered a new type of ray that was generated from a stream of electrons in a cathode gas discharge tube and had the ability to pass though tissues with different degrees of penetration. Because the composition of the rays was unknown, they were called X-rays. His subsequent presentation to the Wurzburg Society on the ability of his rays to generate an image of structures inside the body gave birth to diagnostic radiology. The following year, in France, Henri Becquerel discovered that fluorescent materials made of uranium also emitted constant radiation.1 Marie and Pierre Curie used ionization to measure becquerel rays and quantify radiation intensity against uranium. Marie Curie first used the word “radioactivity” in 1898. The couple isolated two new radioactive elements from pitchblende, polonium, named for Marie’s native Poland, and radium, Latin for ray. Today, these pioneers’ names are in constant use as measures of radioactivity.2


The earliest oncologic brachytherapy procedure was in 1902, when a radium applicator was used to treat a tumor of the palate and pharynx. Within a few years, there were clinical studies of effectiveness, and radium tubes were inserted directly into tumors, and by the 1920s, radium had become the standard of care in oncology,3 as well as the treatment for many benign conditions. The use of Roentgen’s rays to palliate advanced cancer was first described in 1903,4 and this was the forerunner of external-beam radiation treatment.


Until the 1950s, most radiation machines were very similar to diagnostic radiology ones, and generated X-rays at potentials of up to 300 kV. Superficial therapy (50–150 kV) could treat to a depth of 5 mm, and thus was useful for superficial skin cancers. Orthovoltage (or deep) therapy (150–500 kV) provided greater penetration, but was not capable of treating much more than 3 cm below the skin, with 100% of the dose at the skin. At this range of energy, interaction between radiation and matter is strongly dependent on the atomic number (Z) of the attenuating material – in other words, in this process, known as the photoelectric effect, tissue such as bone, which has a high Z, attenuates more radiation; fat and soft tissue (lower Z) attenuate less; and air (for example, in the lungs) hardly at all, thus producing the contrast necessary for diagnostic imaging. Unfortunately, this higher absorbed dose in bone resulted in many more problems from osteoradionecrosis (ORN).


The development in Canada of the cobalt-60 unit in 1951 introduced the new era of megavoltage (MV) radiotherapy to the world, allowing greater penetration of tissue and, with maximal dose not achieved until a depth of 0.5 cm, resulting in better skin-sparing and improved dose homogeneity. Since then, computer-controlled megavoltage linear accelerators have been developed, providing increasing penetration and skin-sparing, and a rapid accumulation of technologies to verify, deliver, and record increasing precise RT.



Introduction


Radiation therapy (RT) requires an understanding of physics. A multidisciplinary team, including radiation oncologists, physicists, dosimetrists and radiotherapists, is required for the delivery of radiation. Delivery of radiation can be achieved using different modalities, including kilovoltage, orthovoltage, megavoltage, electron therapy using a linear accelerator, proton therapy, and brachytherapy.


RT is the use of ionizing radiation to treat malignant tumors and some benign disorders. Nearly two-thirds of cancer patients receive RT as part or all of their treatment. Radiation oncology is the discipline of medicine that addresses the causes, prevention, and treatment of human cancer with special emphasis on the role of ionizing radiation.4 Radiation oncologists work in a multiprofessional context with radiation therapists, nursing, dosimetry and medical physics, along with dieticians, social workers, and counselors. Radiation therapists are the technologists who deliver the RT. Unlike their counterparts in diagnostic radiology, they spend not only considerable time on the technical components of treatment (treatment delivery, quality assurance, and verification), but also interact with and support cancer patients throughout the duration of their therapy. The radiation oncologist is also part of a multidisciplinary team, with specialized surgical and medical oncologists, along with diagnostic radiology and pathologists, which advocates for the best evidence-based care for their cancer patients. However, outside the immediate team, it is rare for other physicians to know much about the process, rationale, and issues around RT, and even less about the risks and causes of toxicity, let alone the technology involved. This chapter is designed as a primer, or virtual elective in the topic, and aims to help improve communication and understanding between plastic surgeons and radiation oncologists so that they can better appreciate some of the common issues that they have to deal with. This chapter starts with a brief description of the basics of radiation technology, modalities, medical physics, and radiobiology. It then outlines practical applications, with a description of RT planning and process, and clinical treatment issues. The final section describes specific toxicity syndromes.



Radiation technology


RT has always been totally dependent on technology. Although much of the equipment that has been the mainstay of RT is being replaced by newer technology, some of it remains in effective and efficient use. For example, kilovoltage therapy can be effectively used for very superficial treatments. It delivers 100% of the prescribed dose at the skin, has rapid fall-off below the skin, and a tight penumbra (edge). In the 50–150-kV range, penetration provides useful coverage only to a depth of 5 mm; orthovoltage therapy (150–500 kV) provides better penetration, but is not capable of treating much more than 3 cm below the skin. With kV energies, skin dose becomes the rate-limiting step. At the orthovoltage range of energy, interaction between radiation and matter is strongly dependent on the atomic number (Z) of the attenuating material – in other words, in this process, known as the photoelectric effect, tissue such as bone, which has a high Z, attenuates more radiation; fat and soft tissue (lower Z) attenuate less; and air (for example, in the lungs) hardly at all, thus producing the contrast necessary for diagnostic imaging. Unfortunately, this higher absorbed dose in bone resulted in many more problems from ORN.


Megavoltage radiotherapy allows even greater penetration of tissue, resulting in better skin-sparing and improved dose homogeneity. Cobalt units deliver MV radiation, and have a 60Co source that generates gamma (γ) rays with average megavoltage energy of 1.3 MV. 60Co has a half-life of 5.26 years, and, because of this decay and subsequent drop in output, the source needs to be replaced every few years. Maximum dose (Dmax) is not achieved until 0.5 cm beyond the surface of the skin and the intrinsic scatter of the beam and ionized particles means that the penumbra, or dose fall-off at the edge of a beam, is not very tight. Despite this, cobalt is still the most prevalent and important external-beam radiotherapy modality in the world. Although affluent countries have mostly replaced their cobalt units with linear accelerators, cobalt still provides an excellent low-maintenance, reliable, safe, and effective alternative in many low- and middle-income countries.


The linear accelerator, or linac, produces high-frequency electromagnetic waves to accelerate charged particles – electrons – to a very high energy through an accelerator tube and a beam transport system. When the electrons hit a target at the end of this, they produce megavoltage X-ray beams that have sharper edges and can penetrate deep tissue. Typical photon energies produced by linacs are 4, 6, 10, and 18 MV that result in increasing maximum depth doses. The machines can also be set so that the high-energy electrons exit the accelerator without hitting the target to produce electron beams, which are less penetrating than photons, with a faster fall-off, that can be used for superficial treatments. Most linacs can produce a range of electron energies from 4 to 17 MeV.



Particle therapy


Electrons are the most commonly used particle therapy. As described above, they deposit their energy superficially, sparing structures deeper in the body, with fairly steep dose distribution curves. Electrons produce more side scatter than photons and have wider penumbras. They are typically used to treat skin cancers and “boosts” to breast tumor cavities. They are also used to spare sensitive organs that may otherwise reach maximum tolerance, for example, protecting the spinal cord when treating posterior neck nodes.


Other particle therapies are less commonly available. Protons have similar biologic activity as photons; their advantage is that they have a unique shape to their dose distribution, with low steady-dose deposition until near the end of their clearly defined range when the dose peak then falls sharply to nearly zero. This is the Bragg peak phenomenon, which allows very precise dose distribution, protection of critical structures, and dose intensification. Protons are ideal for treating structures in the base of skull, such as the clivus, especially for chordomas, where the necessary dose is far above the tolerance of the sensitive optic chiasm and other sensitive structures in that region, and would otherwise cause severe toxicity. Another indication for protons is to deliver pediatric craniospinal irradiation for cancers such as medulloblastoma, because the proton dose distribution significantly reduces the exit dose through structures anterior to the spine (kidneys, bowel, lungs) when compared to conventional treatment with photons. The most common use of protons currently is in the treatment of prostate cancer, allowing the prostate to receive a higher dose of radiation, but causing less damage to the rectum and bladder. Many new proton facilities are opening, but they are expensive and cumbersome to construct and maintain, requiring a cyclotron or a synchrotron to accelerate protons, and a large space.


Neutron RT offers the advantage of high linear energy transfer, a property that allows the delivery of 20–100 times more energy along their path than photons, thus being biologically more effective in treating radioresistant tumors such as sarcomas and salivary gland tumors. Their use requires a careful balance of risk and benefit as they can lead to more severe long-term side-effects, due to relatively high effective entrance and exit doses.5


Carbon, neon, and heavier ions hold promise as they combine the radiobiological advantages of neutrons with the dose distribution and Bragg peak of protons, but are only available in very specialized units.



Brachytherapy


Brachytherapy is a method of delivering radiation treatment over very short distances using radioactive sealed sources. There are three main ways of delivering this type of radiation: (1) an applicator can be used to deliver dose to the surface of a thin tumor, for example, an eye plaque used to treat ocular melanoma; (2) intracavitary – inserting the sealed source into the cavity of an organ, e.g., in the treatment of cervical cancer, a combination (tandem) apparatus is used consisting of a cylindrical rod inserted into the cervical os and through the cervical canal into the uterus, with two ovoids placed in the lateral fornices; and (3) interstitial, when the source is either implanted directly into the tumor or postoperative bed, for example, for postoperative treatment of sarcoma, or when radioactive gold seeds are implanted directly into an organ, e.g., in the treatment of early-stage prostate cancer. Brachytherapy is often used in conjunction with external beam, usually to increase the total dose to a smaller volume at the site of greatest risk of recurrence. For example, after partial mastectomy, the whole breast receives external-beam treatment followed by implantation of a source to provide a boost to the tumor bed.


Originally, following the work done by Marie Curie and others, radium needles were used, until the importance of radioprotection was realized. In the modern era, artificially produced radionuclides are used, most commonly those derived from cesium (137Cs), iridium (192Ir), iodine (131I), palladium (103Pd), and gold (198Au). The activity of these radionuclides is still calculated relative to that of radium. To protect health professionals and the patient, the process of using high-energy sources, such as 137Cs and 192Ir, has evolved considerably, most notably with the use of after-loading. This means that the empty cylinders (for intracavity) or catheters and trocars (for interstitial brachytherapy) are inserted in the operating room, and loaded with inert metal “dummy” sources that are easily visible on radiologic imaging; this is done to verify the position and calculate the dose distribution. The patient is not treated until in a shielded room, either as an inpatient, when treatment is delivered over several days, or in a brachytherapy suite, when the treatment is a short one, such as when high dose rate is used. The radioactive sources are housed in a shielded safe in a remote-controlled after-loading unit, which looks very much like a small heating furnace. After a final verification of positioning, the applicator, catheters, cylinders, or trocars are connected with tubes to the after-loading unit, and, after all personnel have left the room, the active sources, which look like small beads, are remotely loaded through a pressurized system. The unit is programmed to control the position of the sources and the duration of the sources in any position to achieve the prescribed dose in a homogeneous fashion over the three-dimensional dose distribution. When protracted treatments are used, for example, with low-dose-rate brachytherapy, or when a high dose rate is given just in short pulses of time, the units can be paused, and the active sources retract temporarily into the safe within the after-loading unit, making it possible for personnel to enter the room to provide care.


Low-energy radionuclides such as 131I, 103Pd, and 198Au do not pose the same concerns for health workers, and thus are used as permanent implants in the form of seeds, most commonly for prostate cancer.



Physics


An explanation of RT techniques and dosimetry requires a basic understanding of physics. The photon generated by the linac is a very high-energy X-ray that does not have any charged particles in it. However, when it enters the body, it passes through tissue faster than the speed of light. As it goes through the skin and enters the tissue, it uses the Compton process to deposit energy. This means that it interacts with biological tissue by colliding with an electron on the more loosely bound outer shell of an atom (Fig. 28.1). The photon continues along its path, but the electron is knocked off, like a billiard ball, at an angle that depends on the speed and angle with which it was hit. The electron travels (scatters) a distance that is proportional to the energy with which it was hit, meaning that higher photon energies propel electrons more in a forward direction than lower energies can do, before the electron is deposited, and the dose absorbed into the tissues. This triggers downstream free radical interactions, and these can cause DNA single-strand or double-strand breaks, or other injuries, including damage to basepairs and protein cross-links. The chromosomal aberrations that result from double-strand breaks mean that the cancerous cell cannot repair or duplicate at the end of its life cycle, and this is the principal cause of cell death.



If all of these electron energy deposits are added up, then a distribution curve showing absorbed dose and depth can be plotted (Fig. 28.2A) that shows that skin absorbed dose is less than 40%, and 100% or Dmax occurs some distance into the skin at a depth that is consistent with the energy of the photon beam. The commonest energy used is 6 MV, and this has a Dmax of 1.5 cm beyond skin. The dose then falls off at a steady rate that is just less than 5%/cm, meaning that 50% of the dose has been deposited approximately 11 cm into the body. If a tumor is situated centrally, this means that there is too much of a gradient of dose across it. To overcome this heterogeneity within the target volume, a second beam can enter the body (assuming a diameter of 20 cm) from the opposite side, again depositing its maximal energy at 1.5 cm, then attenuating at <5%/cm. The energy deposits from each side are added, a homogeneous distribution is achieved across the target volume (Fig. 28.2B), and the skin does not receive a therapeutic dose, unless bolus is used (Fig. 28.2C). This explains the technique of parallel-opposed pairs (of beams). Similarly, assuming the example, above used opposing anterior and posterior beams, then the addition of right and left lateral beams (four-field box technique) would give an even tighter homogeneous distribution to the target volume, and, since the entrance and exit doses are shared between four beams, further skin dose reduction. This is the basis for using multiple fields, or beams, from different angles, to “focus” (a misleading term, since the beam does not focus on a spot, as light does through a lens) and deposit maximal dose to a target.



In conventional RT, most beams are delivered with uniform intensity across the field. Beam-modifying devices are accessories such as shielding blocks, wedges, and compensators, which are placed in the head of the machine to differentially absorb dose proportionally to the thickness of the device (i.e., more dose is absorbed through thicker regions, and less through thin), and thus reduce hot or cold spots in tissues that have nonsquare shapes. In modern linacs, blocking is done by a system of multileaf collimators (MLCs), which are narrow strips of metal in the head of the linac that act like miniblocks. Their shape can be programmed for shielding (Fig. 28.3). Three-dimensional conformal therapy uses multiple beams to be shaped in such a way that a significant amount of normal tissue can be excluded.



MLCs can also be programmed to move dynamically in and out of the beam, so that the amount of time in each position is adjusted to allow a variable amount of dose through each leaf, compensates for irregular shapes with great precision, and can control the dose to specified targets within a volume. This is the basis for IMRT, which involves identifying doses for individual or multiple target volumes and constraints for normal organs that need to be protected from the effect of radiation, and then using a sophisticated RT planning program that modulates the intensity across multiple individual beams or arcs with dynamic MLC, using an inverse planning system. This allows the creation of a very conformal plan that can even have convex and concave shapes to avoid a critical structure, for example, avoiding the spinal cord in a way that conventional beams would not be able to do (Fig. 28.4). It is also possible to “dose paint” so that different areas receive different doses at the same time, and also to reduce volumes, adapting to reduction in the tumor size. A similar result is obtained with tomotherapy, which uses principles of CT scanning to deliver intensity-modulated beams slice by slice. An advantage of IMRT over this system is that IMRT is delivered on a normal linac rather than a dedicated machine.



With the move to increasing high precision in RT delivery, consistent reproducibility of treatment position has become increasingly important. Electronic portal imaging (digital MV X-rays taken on the RT machine) can take both orthogonal views of the target, e.g., anterior and lateral beams, and beam’s eye view images. The utility of this is enhanced when there are recognizable and stable landmarks, for example, some part of the bony anatomy. However, when the target is somewhat mobile, then fiducial markers, such as seeds placed in the prostate gland, can greatly help to match up the target. The cone beam CT uses kV three-dimensional imaging to verify positioning for IGRT.


Stereotactic techniques have been used in structures such as the brain for many years. A linac-based process involves the use of multiple very small beams that cover a small target (2–5 cm) to a large dose of RT, delivering a therapeutically radical equivalent dose in just a few, or even just one, fraction. It has primarily been used on central nervous system tumors, including benign conditions such as arteriovenous malformations or schwanommas, immobilizing the head in a frame. The gamma knife uses a 60Co source with similar principles. With the advent of IGRT, this principle is now applied to sterotactic body RT for sites elsewhere in the body, such as lung, liver, and paraspinal tumors. Large doses, for example 5 Gy, are given in five fractions twice a week to a total of 25 Gy, which is the equivalent of an ablative dose, but with much greater precision, and far less toxicity. It is well tolerated even by frail and ill patients.


Intraoperative RT is not a modern idea. It is used to treat small areas (4–10 cm) of the body that are at high risk for recurrence after the tumor has been removed. It is especially used to treat the retroperitoneum while the patient is asleep. Electrons are used most commonly, and electron-shaping cones that are attached to the head of the machine are positioned into the wound and lined up against the tissue at risk for residual disease by the radiation oncologist and surgeon together. Personnel then leave the room, the beam is switched on, and the dose is delivered in less than 2 minutes, the cones are removed, and the surgeon can close the wound.



Radiobiology


Radiation injury can be viewed from two perspectives: the radiation effect on tumor cells, and the radiation toxicity on normal cells. The therapeutic ratio is a dose–response relationship between tumor control and normal tissue complications, and helps balance the two perspectives. In an ideal world, the curves representing tumor response and normal tissue complications would be well separated (Fig. 28.5A). Far too often, they are so close together that it is not possible to achieve a high enough dose to eradicate the tumor without causing harmful complications (Fig. 28.5B). Usually in clinical practice there is some degree of compromise, and traditionally, a 5% risk of normal tissue complications is accepted (Fig. 28.5C), taking into account the specific risks of the situation.



Radiation toxicity is expressed during mitosis of normal cells. Acute toxicity occurs during treatment or shortly afterwards. It is related to the total dose, the size of the volume irradiated, and radiosensitizing drugs such as chemotherapy. It occurs in cells with a rapid turnover, such as oral mucosa or skin epithelium, where cell division is necessary to maintain function. Even though these cells may be affected within a few days of starting fractionated treatment, their damage does not become manifest for at least 2 weeks as the progenitor stem cells do not have as rapid a turnover. Examples are skin erythema and desquamation, oral mucositis, and esophagitis. These reactions usually start to heal 2 weeks after the completion of treatment. Even quite brisk reactions can heal fast (Figs 28.6, 28.7). Acute toxicity is reversible, and does not predict for permanent damage. The exception is if there is consequential damage, i.e., there is persistent injury due to the destruction of the basement membrane zone with complete depletion of stem cells due to very high dose, and usually an additional factor such as chemotherapy, infection, or trauma. This can be found in chronic ulcers in the skin, bladder, or gastrointestinal tract. Delayed acute toxicity occurs 6 weeks to 6 months after the completion of treatment; it is also reversible. As with acute toxicity, it is dose-, volume-, and drug-related. Examples are radiation pneumonitis and L’Hermitte’s syndrome (a transient demyelination syndrome of the spinal cord, which does not predict subsequent radiation myelitis).




Late toxicity occurs 6 months or later after the completion of X-ray therapy (XRT). It represents damage that is expressed at the end of the life cycle of parenchymal cells that have slow cell renewal and a relative inability to repopulate from stem cells. It occurs in organs that have less dependence on cell turnover and have both proliferative and functional cell populations, primarily connective and nervous tissue. Examples are the endothelium of blood vessels, and osteoblasts and chondroblasts of bone. These injuries are characterized by fibrosis, often over many years, and are not reversible, thus of serious consequence. It is therefore essential to factor these risks into dose limitations. They are strongly correlated with fraction size.


A method of quantifying the risk of permanent tissue damage is the concept of TD5/5, which is the total dose, given in standard fraction sizes, that produces a 5% risk of damage to a specified organ at 5 years.6 These figures have been updated to reflect modern conformal treatments7 and provide a guide for constraining the dose to an organ at risk during the treatment-planning process, as well as for guiding informed consent.


Ionizing radiation kills cells by damaging DNA either directly or indirectly. A direct hit can cause lethal double-strand breaks, or, more commonly, the damage is caused by the release of oxygen-derived free radicals from water associated with absorption of energy into the cellular tissue. Cell death can take several forms. Lethal chromosome damage can result in apoptosis, which is a type of programmed cell death associated with activation of the tumor suppressor gene p53. Apoptosis is rapid, inducing no inflammatory response, and although it has been described in many different tissues, only certain types of tumors, for example, hemopoietic ones, undergo apoptotic death. The commonest mechanism is senescence, in which cells survive and continue to function, but lose their capacity to reproduce and proliferate.


All organized tissues mount repair in response to injury. Radiation injury prompts the body to respond in a similar way as it does to other trauma, for example, surgery. However, there are three important differences. Firstly, radiation delivers a repetitive, daily injury during the course of fractionated treatment. Secondly, the injury caused by the release in the tissue of free radicals affects all cellular and extracellular components within the volume of tissue irradiated. Thirdly, radiation causes damage to the DNA.


Response to radiation injury causes a signal transduction pathway that is mediated by the ataxia telangectasia mutated (ATM) gene to instigate DNA repair and to regulate cell cycle checkpoints, giving the cells additional time to repair. A cascade of cytokines is an immediate response, and may lead to both radiosensitization and protection.8 Interleukin-1 and 6, and tumor necrosis factor-α cause an inflammatory response and coagulation effect. Transforming growth factor-β (TGF-β) is one of the most widely studied radiation-induced cytokines, and plays multiple roles. It causes fibroblast differentiation as well as stimulating the production of collagen. It is involved in the synthesis and regulation of extracellular matrix molecules. Following radiation, the extracellular matrix is both quantitatively and qualitatively modified – degrading progresses are altered and production of collagen synthesis increases. TGF-β also down-regulates thrombomodulin activity in endothelium, leading to platelet aggregation, and, from the platelets, release of more TGF-β, thus setting up a self-perpetuation production of TGF-β that contributes to the chronicity of radiation injury. However, it is primarily the sustained activity of TGF-β-driven myofibroblasts that causes the fibrotic reactions to radiation. Fibrosis is not an endpont, but a dynamic process of fibroblast activity. In traumatic wounds, remodeling happens over years, but this capacity to remodel in lost in irradiated tissue and instead there is self-perpetuating reactive fibrosis.9


Irradiated skin and soft tissue are susceptible to minimal trauma, creating a problem for surgical intervention. Radiation causes delayed wound healing, with decreased wound-breaking strength because of the damage to the microvasculature and the decreased cellular elements.9 These problems are related to the total dose, the dose per fraction, the timing of the surgery, and the extent of the surgery. The optimal time to operate on irradiated skin is the window provided once the acute reaction has resolved and before the development of excessive fibrosis, generally 3–10 weeks after completion of XRT (Fig. 28.8).



Feb 21, 2016 | Posted by in General Surgery | Comments Off on Therapeutic radiation
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