Radiation Therapy
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http://www.news-medical.net Radiation therapy (in North America), or radiotherapy (in the UK and Australia) also called radiation oncology, and sometimes abbreviated to XRT, is the medical use of ionizing radiation as part of cancer treatment to control malignant cells (not to be confused with radiology, the use of radiation in medical imaging and diagnosis). Radiotherapy may be used for curative or adjuvant cancer treatment. It is used as palliative treatment (where cure is not possible and the aim is for local disease control or symptomatic relief) or as therapeutic treatment (where the therapy has survival benefit and it can be curative). Total body irradiation (TBI) is a radiotherapy technique used to prepare the body to receive a bone marrow transplant. Radiotherapy has several applications in non-malignant conditions, such as the treatment of trigeminal neuralgia, severe thyroid eye disease, pterygium, pigmented villonodular synovitis, prevention of keloid scar growth, and prevention of heterotopic ossification. The use of radiotherapy in non-malignant conditions is limited partly by
worries about the risk of radiationinduced cancers. Radiotherapy is used for the treatment of malignant tumors (cancer), and may be used as the primary therapy. It is also common to combine radiotherapy with surgery,chemotherapy, hormone t herapy or some mixture of the three. Most common cancer types can be treated with radiotherapy in some way. The precise treatment intent (curative, adjuvant, neoadjuvant, therapeutic, or palliative) will depend on the tumour type, location, and stage, as well as the general health of the patient. Radiation therapy is commonly applied to the cancerous tumour. The radiation fields may also include the draining lymph nodes if they are clinically or radiologically involved with tumour, or if there is thought to be a risk of subclinical malignant spread. It is necessary to include a margin of normal tissue around the tumour to allow for uncertainties in daily set-up and internal tumor motion. These uncertainties can be caused by internal movement (for example, respiration and bladder filling) and movement of external skin marks relative to the tumour position.
To spare normal tissues (such as skin or organs which radiation must pass through in order to treat the tumour), shaped radiation beams are aimed from several angles of exposure to intersect at the tumour, providing a much larger absorbed dose there than in the surrounding, healthy tissue. Radiation therapy has been in use as a cancer treatment for more than 100 years, with its earliest roots traced from the discovery of x-rays in 1895 by Wilhelm Röntgen. The field of radiation therapy began to grow in the early 1900s largely due to the groundbreaking work of Nobel Prize-winning scientist Marie Curie, who discovered the radioactive elements polonium and radium. This began a new era in medical treatment and research. Radium was used in various forms until the mid-1900s when cobalt and caesium units came into use. Medical linear accelerators have been used to as sources of radiation since the late 1940s. With Godfrey Hounsfield’s invention of computed tomography (CT) in 1971, three-dimensional planning became a possibility and created a shift from 2-D to 3-D radiation delivery; CT-based
planning allows physicians to more accurately determine the dose distribution using axial tomographic images of the patient's anatomy. Orthovoltage and cobalt units have largely been replaced by megavoltage linear accelerators, useful for their penetrating energies and lack of physical radiation source. The advent of new imaging technologies, including magnetic resonance imaging (MRI) in the 1970s and positron emission tomography (PET) in the 1980s, has moved radiation therapy from 3-D conformal to intensitymodulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT). These advances have resulted in better treatment outcomes and fewer side effects.
Radiation therapy works by damaging the DNA of cells. The damage is caused by a photon, electron, proton, neutron, or ion beam directly or indirectly ionizing the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA.
In the most common forms of radiation therapy, most of the radiation effect is through free radicals. Because cells have mechanisms for repairing DNA damage, breaking the DNA on both strands proves to be the most significant technique in modifying cell characteristics. Because cancer cells generally are undifferentiated and stem cell-like, they reproduce more, and have a diminished ability to repair sublethal damage compared to most healthy differentiated cells. The DNA damage is inherited through cell division, accumulating damage to the cancer cells, causing them to die or reproduce more slowly. One of the major limitations of radiotherapy is that the cells of solid tumors become deficient in oxygen. Solid tumors can outgrow their blood supply, causing a lowoxygen state known as hypoxia. Oxygen is a potent radiosensitizer, increasing the effectiveness of a given dose of radiation by forming DNA-damaging free radicals. Tumor cells in a hypoxic environment may be as much as 2 to 3 times more resistant to radiation damage than those in a normal oxygen environment. Much research has been devoted to overcoming this problem
including the use of high pressure oxygen tanks, blood substitutes that carry increased oxygen, hypoxic cell radiosensitizers such as misonidazole and metronidazole, and hypoxic cytotoxins, such as tirapazamine. There is also interest in the fact that high-LET (linear energy transfer) particles such as carbon or neon ions may have an antitumor effect which is less dependent of tumor oxygen because these particles act mostly via direct damage. The photons and the electrons present in the radiation source ionizes the water molecules producing free radicals (OH radicals), which in turn ionizes the atom present in the DNA molecule. Generally normal cells have excellent repair mechanisms but cancer cells are have diminished ability to repair the damages and hence continue to produce cells with the damage. These cells, which have the damaged DNA, will either die or reproduce slowly. Read more: Radiotherapy Mechanism | Medindia http://www.medindia.net/ patients/patientinfo/Radiotherapy_ Mechanism.htm#ixzz2Xo4g8ZT1
Biologic Basis The exact mechanism of cell death due to radiation is still an area of active investigation. A large body of evidence supports doublestranded breaks of nuclear DNA as the most important cellular effect of radiation. This breakage leads to irreversible loss of the reproductive integrity of the cell and eventual cell death. Radiation damage can be directly ionizing; however, in clinical therapy, damage is most commonly indirectly ionizing via free-radical intermediaries formed from the radiolysis of cellular water. Radiation can also affect the processes of the cell cycle necessary for cell growth, cell senescence, and apoptosis (programmed cell death). Many of these processes are only now beginning to be elucidated and manipulated in order to make radiation therapy more effective. The therapeutic mechanism for radiation is based on the intrinsic ability of cells to repair damage and the ability of the radiation oncologist to take advantage of any geometric separation between malignant and nonmalignant tissues.
Cell survival after exposure can be expressed in terms of a logarithmic curve of survival versus dose. The curve forms an initial shoulder followed by a logarithmic decline in survival, which varies with the dose (see the image below). Sublethal damage, which must be overcome with each fraction of radiation therapy, is thought to cause the initial shoulder.
Radiation therapy, general principles. Cell survival, single fraction. Repeated small doses of radiation are less damaging to a sensitive cell than a single fraction containing an equivalent total dose (see the image below). Manipulation of the cellular environment can alter the shape of the survival curve.
Skin – Erythema, 10.6; desquamation, 11.2 Oral mucosa – Mucositis, 10.8 Values for α/β in early-responding tumor tissue are as follows:
[5] "Second Cancers Caused by Cancer Treatment," American Cancer Society, 30 Jan 12. [6] U. Schneider et al., "The Impact of IMRT and Proton Radiotherapy on Secondary Cancer Incidence," Strahlenther. Onkol. 182 647 (2006) Radiation therapy involves administration of ionizing radiation from an external source, from a source placed inside the body (brachytherapy), or through the use of radioactive drugs (systemic). The ionizing radiation, which forms ions in the cells of the tissues it passes through thereby killing the cells or altering their DNA, comes in two major types: photons (the most common source and comes from cobalt, cesium, or a linear accelerator) and particles (electrons, protons, neutrons, α particles, and β particles). Electron and most particle beams are used for tumors close to the body surface because they do not go deeply into tissues. On the other hand, proton beams are a newer application that causes little damage to tissues they pass through but kill cells at the end of their path, possibly resulting in fewer side effects. [1] How does the ionizing radiation kills cells and damage DNA?
Radiation therapy, general principles. Effect of fractionation. Besides being related to intrinsic cellular radiosensitivity, cell survival is also related to oxygen tension, the position of the cell in the mitotic cycle, and dose rate. These features are responsible for the 4 Rs of radiobiology— namely, R epair,R edistribution, R epopulating, and R eoxygenation. Several models have been used to conceptualize radiation-induced cell death and to explain the cell survival curve. The cell survival curve can be interpreted to follow a linear-quadratic model, according to which the surviving fraction is equivalent toe(αD - βD2), where α and β represent the alpha and beta components, respectively (see the image below).
Radiation therapy, general principles. Composition of cell survival curve. In the linear-quadratic model, 2 components of cell injury are present. The linear alpha component is responsible for the initial shoulder on the cell survival curve and is caused by repairable damage to the target. The quadratic beta component represents irreparable damage. The linear component is proportional to the dose, whereas the quadratic component is proportional to the dose squared. Early-responding tissues and tumors have a relatively larger alpha component and a larger α/β ratio; late-responding tissues have smaller α/β ratios. This difference between tumor and lateresponding tissues is useful in designing therapeutic schemes that use multiple daily fractions rather than the conventional oncedaily treatments. Values for α/β in early-responding normal tissue are as follows:
Nasopharynx - 16 Oropharynx - 16 Vocal cord - 13 Tonsil - 7 Skin (squamous or carcinoma) 8.5 Values for α/β in late responding normal tissue are as follows: Skin – Telangiectasia, 2.7; fibrosis, 1.7 Spinal cord – Myelitis, 3.3 Cartilage – Fibrosis, 4.5 [1] "Radiation Therapy Principles," American Cancer Society, September 2011. [2] Y. Z. Fang, S. Yang and G. Wu, "Free Radicals, Antioxidants, and Nutrition," Nutrition 18, 872 (2002). [3] R. J. Brooker, Genetics: Analysis and Principles, 4th Ed (McGraw-Hill, 2011). [4] M. Diehn et al., "Association of Reactive Oxygen Species Levels and Radioresistance in Cancer Stem Cells," Nature 458, 780 (2009).
When the cells are ionized, free radicals and reactive oxygen species (ROS) form. Free radicals are simply atoms, molecules, or ions with unpaired electrons, and ROS is a subset of free radicals that involve oxygen. These agents are very chemically reactive due to their free electron. [2] Due to this high reactivity, free radicals and ROS are likely to attack the covalent bonds of the DNA and other cells they encounter, and these reactions typically occur in chains. Enough injury in the cell will result in apoptosis, or programmed cell death. At the same time, if enough DNA is damaged, the cells will be unable to replicate. Thus, when the radiation targets the tumor cells, the affected cells will die or be unable to proliferate, effectively reducing or eliminating the cancer. [3]
worries about the risk of radiationinduced cancers. Radiotherapy is used for the treatment of malignant tumors (cancer), and may be used as the primary therapy. It is also common to combine radiotherapy with surgery,chemotherapy, hormone t herapy or some mixture of the three. Most common cancer types can be treated with radiotherapy in some way. The precise treatment intent (curative, adjuvant, neoadjuvant, therapeutic, or palliative) will depend on the tumour type, location, and stage, as well as the general health of the patient. Radiation therapy is commonly applied to the cancerous tumour. The radiation fields may also include the draining lymph nodes if they are clinically or radiologically involved with tumour, or if there is thought to be a risk of subclinical malignant spread. It is necessary to include a margin of normal tissue around the tumour to allow for uncertainties in daily set-up and internal tumor motion. These uncertainties can be caused by internal movement (for example, respiration and bladder filling) and movement of external skin marks relative to the tumour position.
To spare normal tissues (such as skin or organs which radiation must pass through in order to treat the tumour), shaped radiation beams are aimed from several angles of exposure to intersect at the tumour, providing a much larger absorbed dose there than in the surrounding, healthy tissue. Radiation therapy has been in use as a cancer treatment for more than 100 years, with its earliest roots traced from the discovery of x-rays in 1895 by Wilhelm Röntgen. The field of radiation therapy began to grow in the early 1900s largely due to the groundbreaking work of Nobel Prize-winning scientist Marie Curie, who discovered the radioactive elements polonium and radium. This began a new era in medical treatment and research. Radium was used in various forms until the mid-1900s when cobalt and caesium units came into use. Medical linear accelerators have been used to as sources of radiation since the late 1940s. With Godfrey Hounsfield’s invention of computed tomography (CT) in 1971, three-dimensional planning became a possibility and created a shift from 2-D to 3-D radiation delivery; CT-based
planning allows physicians to more accurately determine the dose distribution using axial tomographic images of the patient's anatomy. Orthovoltage and cobalt units have largely been replaced by megavoltage linear accelerators, useful for their penetrating energies and lack of physical radiation source. The advent of new imaging technologies, including magnetic resonance imaging (MRI) in the 1970s and positron emission tomography (PET) in the 1980s, has moved radiation therapy from 3-D conformal to intensitymodulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT). These advances have resulted in better treatment outcomes and fewer side effects.
Radiation therapy works by damaging the DNA of cells. The damage is caused by a photon, electron, proton, neutron, or ion beam directly or indirectly ionizing the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA.
In the most common forms of radiation therapy, most of the radiation effect is through free radicals. Because cells have mechanisms for repairing DNA damage, breaking the DNA on both strands proves to be the most significant technique in modifying cell characteristics. Because cancer cells generally are undifferentiated and stem cell-like, they reproduce more, and have a diminished ability to repair sublethal damage compared to most healthy differentiated cells. The DNA damage is inherited through cell division, accumulating damage to the cancer cells, causing them to die or reproduce more slowly. One of the major limitations of radiotherapy is that the cells of solid tumors become deficient in oxygen. Solid tumors can outgrow their blood supply, causing a lowoxygen state known as hypoxia. Oxygen is a potent radiosensitizer, increasing the effectiveness of a given dose of radiation by forming DNA-damaging free radicals. Tumor cells in a hypoxic environment may be as much as 2 to 3 times more resistant to radiation damage than those in a normal oxygen environment. Much research has been devoted to overcoming this problem
including the use of high pressure oxygen tanks, blood substitutes that carry increased oxygen, hypoxic cell radiosensitizers such as misonidazole and metronidazole, and hypoxic cytotoxins, such as tirapazamine. There is also interest in the fact that high-LET (linear energy transfer) particles such as carbon or neon ions may have an antitumor effect which is less dependent of tumor oxygen because these particles act mostly via direct damage. The photons and the electrons present in the radiation source ionizes the water molecules producing free radicals (OH radicals), which in turn ionizes the atom present in the DNA molecule. Generally normal cells have excellent repair mechanisms but cancer cells are have diminished ability to repair the damages and hence continue to produce cells with the damage. These cells, which have the damaged DNA, will either die or reproduce slowly. Read more: Radiotherapy Mechanism | Medindia http://www.medindia.net/ patients/patientinfo/Radiotherapy_ Mechanism.htm#ixzz2Xo4g8ZT1
Biologic Basis The exact mechanism of cell death due to radiation is still an area of active investigation. A large body of evidence supports doublestranded breaks of nuclear DNA as the most important cellular effect of radiation. This breakage leads to irreversible loss of the reproductive integrity of the cell and eventual cell death. Radiation damage can be directly ionizing; however, in clinical therapy, damage is most commonly indirectly ionizing via free-radical intermediaries formed from the radiolysis of cellular water. Radiation can also affect the processes of the cell cycle necessary for cell growth, cell senescence, and apoptosis (programmed cell death). Many of these processes are only now beginning to be elucidated and manipulated in order to make radiation therapy more effective. The therapeutic mechanism for radiation is based on the intrinsic ability of cells to repair damage and the ability of the radiation oncologist to take advantage of any geometric separation between malignant and nonmalignant tissues.
Cell survival after exposure can be expressed in terms of a logarithmic curve of survival versus dose. The curve forms an initial shoulder followed by a logarithmic decline in survival, which varies with the dose (see the image below). Sublethal damage, which must be overcome with each fraction of radiation therapy, is thought to cause the initial shoulder.
Radiation therapy, general principles. Cell survival, single fraction. Repeated small doses of radiation are less damaging to a sensitive cell than a single fraction containing an equivalent total dose (see the image below). Manipulation of the cellular environment can alter the shape of the survival curve.
Skin – Erythema, 10.6; desquamation, 11.2 Oral mucosa – Mucositis, 10.8 Values for α/β in early-responding tumor tissue are as follows:
[5] "Second Cancers Caused by Cancer Treatment," American Cancer Society, 30 Jan 12. [6] U. Schneider et al., "The Impact of IMRT and Proton Radiotherapy on Secondary Cancer Incidence," Strahlenther. Onkol. 182 647 (2006) Radiation therapy involves administration of ionizing radiation from an external source, from a source placed inside the body (brachytherapy), or through the use of radioactive drugs (systemic). The ionizing radiation, which forms ions in the cells of the tissues it passes through thereby killing the cells or altering their DNA, comes in two major types: photons (the most common source and comes from cobalt, cesium, or a linear accelerator) and particles (electrons, protons, neutrons, α particles, and β particles). Electron and most particle beams are used for tumors close to the body surface because they do not go deeply into tissues. On the other hand, proton beams are a newer application that causes little damage to tissues they pass through but kill cells at the end of their path, possibly resulting in fewer side effects. [1] How does the ionizing radiation kills cells and damage DNA?
Radiation therapy, general principles. Effect of fractionation. Besides being related to intrinsic cellular radiosensitivity, cell survival is also related to oxygen tension, the position of the cell in the mitotic cycle, and dose rate. These features are responsible for the 4 Rs of radiobiology— namely, R epair,R edistribution, R epopulating, and R eoxygenation. Several models have been used to conceptualize radiation-induced cell death and to explain the cell survival curve. The cell survival curve can be interpreted to follow a linear-quadratic model, according to which the surviving fraction is equivalent toe(αD - βD2), where α and β represent the alpha and beta components, respectively (see the image below).
Radiation therapy, general principles. Composition of cell survival curve. In the linear-quadratic model, 2 components of cell injury are present. The linear alpha component is responsible for the initial shoulder on the cell survival curve and is caused by repairable damage to the target. The quadratic beta component represents irreparable damage. The linear component is proportional to the dose, whereas the quadratic component is proportional to the dose squared. Early-responding tissues and tumors have a relatively larger alpha component and a larger α/β ratio; late-responding tissues have smaller α/β ratios. This difference between tumor and lateresponding tissues is useful in designing therapeutic schemes that use multiple daily fractions rather than the conventional oncedaily treatments. Values for α/β in early-responding normal tissue are as follows:
Nasopharynx - 16 Oropharynx - 16 Vocal cord - 13 Tonsil - 7 Skin (squamous or carcinoma) 8.5 Values for α/β in late responding normal tissue are as follows: Skin – Telangiectasia, 2.7; fibrosis, 1.7 Spinal cord – Myelitis, 3.3 Cartilage – Fibrosis, 4.5 [1] "Radiation Therapy Principles," American Cancer Society, September 2011. [2] Y. Z. Fang, S. Yang and G. Wu, "Free Radicals, Antioxidants, and Nutrition," Nutrition 18, 872 (2002). [3] R. J. Brooker, Genetics: Analysis and Principles, 4th Ed (McGraw-Hill, 2011). [4] M. Diehn et al., "Association of Reactive Oxygen Species Levels and Radioresistance in Cancer Stem Cells," Nature 458, 780 (2009).
When the cells are ionized, free radicals and reactive oxygen species (ROS) form. Free radicals are simply atoms, molecules, or ions with unpaired electrons, and ROS is a subset of free radicals that involve oxygen. These agents are very chemically reactive due to their free electron. [2] Due to this high reactivity, free radicals and ROS are likely to attack the covalent bonds of the DNA and other cells they encounter, and these reactions typically occur in chains. Enough injury in the cell will result in apoptosis, or programmed cell death. At the same time, if enough DNA is damaged, the cells will be unable to replicate. Thus, when the radiation targets the tumor cells, the affected cells will die or be unable to proliferate, effectively reducing or eliminating the cancer. [3]
