Effects of Radiation PDF

Biological Effects of Radiation and its role in radiation therapy Irene Polycarpou What is radiation therapy? High energy beams Radiation therapy is a form of curative method making use of high energy beams of radiation. High energy...

Biological Effects of Radiation and its role in radiation therapy Irene Polycarpou What is radiation therapy? High energy beams Radiation therapy is a form of curative method making use of high energy beams of radiation. High energy beams irradiate the cancer cells.  Importance of radiotherapy in Cancer - Radiation therapy remains consistently one of the most effective treatments against cancer. - About 50% of all patients will receive radiation therapy at some point during their treatment. - The global use of radiotherapy is increasing due to the aging of the population in North America, Europe and China, and the increased diagnosis and need for treatment which requires a corresponding increase in support, education and training.  Importance of radiotherapy in Cancer - Surgery, with a longer history than radiotherapy, is also the main form of treatment in many types of cancer and leads to good therapeutic results in early non-metastatic malignancies. - Radiation therapy is a good alternative to surgery for the long-term control of many cancers such as lung, cervix, bladder, prostate and skin that often achieves good results. - Chemotherapy is the third most important cancer treatment. There are now several options in chemotherapy drugs that primarily target proliferating cells. - New treatment options are targeted drugs that can specifically kill cancer cells. Cancer type and percentage of patients receiving radiotherapy Ionizing Radiation -Ionizing radiation is so named because its reaction with neutral atoms or molecules causes those atoms or groups of atoms to become ions or electrically charged entities. -The forms of ionizing radiation associated with cancer treatment are X-rays, gamma rays, and particle radiation. These forms of radiation are either directly or indirectly ionizing. Structure of an atom  Ionizing radiation -Direct ionizing radiation (eg, a beam of protons, alpha or beta particles) causes immediate disruption of the atomic or molecular structure of the tissue through which it passes. -In contrast, indirect ionizing radiation (eg, electromagnetic waves and neutron beams) delivers energy as it passes through tissue, which leads to the production of fast-moving particles that in turn cause tissue damage. -Among the biochemical and molecular effects of ionizing radiation is the ability to cause breaks in the double-stranded DNA molecule in the cell nucleus.  43 How does radiotherapy works? Radiation induce damage of tumour cell DNA, preventing cell division and causing cell death. DNA can be damaged directly by radiation. This kills some cancer cells immediately after treatment. Radiation can also form free radicals from water molecules in the body, which then damage the DNA of cancer cells (indirectly method). Directly ionizing radiation causes direct disruption of the atomic or molecular structure of the tissue through which it passes. In contrast, indirectly ionizing radiation gives up energy as it passes through tissues, which results in the production of fast-moving particles that in turn cause damage to tissues.  44 Direct or indirect damage of DNA Direct and indirect actions of radiation In the direct reaction, the radiation interacts directly with DNA resulting in damage. In the indirect reaction, radiation interacts with other molecules in the cell, particularly water, to produce free radicals such as hydrogen atoms (H+), hydroxyl radicals (HO+), and radical superoxide anion (O2−), which in turn they cause DNA damage. Direct and indirect actions of radiation Why is DNA the main target of ionizing radiation? -Ionized molecules are very reactive and can affect all components of the cell. -BUT the cell contains many copies of RNA and proteins and these also have short half-lives (degraded and synthesized quickly). -DNA is found in only two copies, does not degrade, is very large (and thus a large target), and is central to cell function. Chromatin: DNA and proteins that make up chromosomes Euchromatin: not condensed chromatin Heterochromatin: condensed chromatin Linear Energy transfer, LET -Linear Energy transfer (LET) refers to the amount of energy deposited by ionizing radiation in matter. -Units are energy per unit length. -LET is commonly used to distinguish between types of ionizing radiation. Photons and electrons have a lower LET than protons and alpha particles. -Small length units (µm) for LET reflect its application in energy deposition at subcellular dimensions. Linear Energy transfer, LET Why are neutrons described as "high LET" radiation when they are uncharged particles? -Neutrons do not interact with orbital electrons in the tissues through which they pass and do not Low LET: Electrons directly produce ionization. produced by an X-ray -However, they interact with atom nuclei, ejecting protons and other particles. -This indirect production of hit particles confers a high LET and results in DNA damage involving High LET: Electrons produced by many adjacent base pairs. a neutron beam - This is why the same dose of radiation delivered via a neutron beam will cause more cell death than the same dose delivered with X-rays Linear Energy transfer, LET Schematic comparison between energy deposition for high and low LET beams in relation to radiobiology. -Circles indicate ionizing events. -The increased density of ionization events occurring with a higher LET beam results in greater biological (DNA) damage. Biological response: As LET increases, cell survival decreases. Why? Because high LET causes more severe DNA damage that cannot be repaired by the cell's mechanisms. Relative biological effectiveness, RBE - It is defined as the ratio of radiation doses required to produce the same degree of biological damage. Low LET (reference dose) RBE= High LET (tested dose) Reference dose=250 kVp X-rays RBE= Low LET 250 kVp X-rays Dose from another source that can produce the same biological response  RBE= Low LET 250 kVp X-rays Dose from another source that can produce the same biological response kVp stands for peak kilovoltage. This is the highest voltage (measured in thousands of volts) that the x-ray machine will produce during an exposure. For example, if 60 kVp is selected, 60 kilovolts (60,000 volts) is the maximum power of the X-rays produced in this exposure. Relative biological effectiveness, RBE Generally RBE increases with higher LET but up to a point. Why? Οverkill: The dose required for cells to die due to DNA damage is shown on the red line. Anything above this dose is not needed and thus we consider it to be a "waste" of radiation and reduce the efficiency of the treatment. Relative biological effectiveness, RBE Generally RBE increases with higher LET but up to a point. Why? The Radiation weighting factor (WR) is a quantitative measurement of the effect of each radiation on the tissue. Each tissue is affected differently by radiation and this is determined by the Tissue weighting factor (WT) WT = Risk of damage to the organ Risk of damage to the organism  9 The success of radiotherapy depends on the amount of dose administered to the area of tumor. Tissue weighting factor (WT) -Different tissues have different radiosensitivities. Cells that divide frequently (eg, hematopoietic cells) are more affected than cells that divide infrequently (eg, connective and adipose tissue). -Metabolic factors such as oxygen concentration in the irradiated volume are also important. -The International Commission on Radiological Protection (ICRP) has set reference values ​for certain instruments taking into account the "average person". Some important terms… Absorbed dose: It is the amount of energy absorbed by the radiation beam per unit mass of absorbing material. The unit of absorbed dose is measured in Gray (Gy). Equivalent dose: It is the result of multiplying the Absorbed dose by the Radiation weighting factor (WR) as different radiations affect the tissue differently. The unit of absorbed dose is REM. Equivalent dose = Absorbed dose Χ Radiation Weighting Factor WR Effective dose: It is the result of multiplying the Equivalent Dose by the Tissue Weighting Factor (WT) as different tissues react differently to radiation. Effective dose = Equivalent dose Χ Tissue Weighting Factor WT  28 Radiation Dose Biological effect depends on: – Intensity, energy and type of radiation – Exposure time – Area exposed and depth of energy deposition Absorbed, Equivalent and Effective Dose Are quantities used to specify the dose received and the biological effectiveness of that dose Absorbed Dose The amount of radiation absorbed per unit mass of material Unit: gray, 1Gy = 1J/kg Physical, measurable quantity Equivalent Dose The biological effects of radiation depends on the type of radiation. Equal dose of Alpha particles & Gamma rays does not affect tissue the same way. To account for the difference of the biological effects of radiation, we use the quantity EQUIVALENT DOSE. Equivalent dose is the product of absorbed dose and the radiation weighting factor WR for the type of radiation use. Equivalent dose reflects the biological damage from different types of radiation Equivalent Dose Same equivalent dose  different effects in different parts of the body due to the different radiosensitivity of organs and tissues To account for the difference of the biological effects of radiation AND the radiosensitivity of different areas, we use the quantity EFFECTIVE DOSE. Effective dose is the product of equivalent dose and the tissue weighting factor WT for the type of tissues. Effective Dose A measure of harm whatever the source of radiation and whatever the area irradiated or exposed Correlates to radiation risk Annual whole body dose limit for workers: effective dose 20mSv Rem 35 Intensity-modulated radiation therapy, or IMRT -It is a type of cancer treatment in which cancer cells are irradiated directly from different directions. -The patient receives higher and more efficient doses of radiation, limiting damage to surrounding tissues. Thus the negative side effects are reduced. -How does it work? First the patient has a computed tomography (CT) scan to visualize the tumor in 3D. Advanced computer programs are then used to calculate and deliver radiation directly to the tumor from different angles. At the beginning of each treatment session, a radiation therapist places the patient on a treatment table, placing marks on the skin to guide where to deliver radiation therapy. Treatment sessions are painless. Intensity-modulated radiation therapy, or IMRT Distribution of the dose. The higher dose is delivered only to the site of the tumor. Intensity-modulated radiation therapy, or IMRT -Which types of cancer are irradiated in this way? Prostate, breast, head and neck, lung and brain. Can you think of why? Because they are close to important organs and tissues. Unit 1 Revision 1. Radiotherapy is very important in the treatment of cancer. 2. About 50% of patients are expected to need radiotherapy at some point during their treatment. 3. Ionizing radiation is used in cancer treatment to cause damage to DNA. 4. Radiation affects DNA directly and indirectly 5. There are various units of measurement of radiation that take into account the effect on tissue. 6. Important terms: absorbed dose, equivalent dose, effective dose. Are there specific regions of DNA that when hit confer more sensitivity to radiotherapy? No or they haven't been discovered yet. Damage to the whole DNA molecule has the same role in causing death... «Effect of radiation on tumor» A tumor is a mass of malignant cells that grow out of control. In the area of ​thetumor, a microenvironment is formed by various cells. In this microenvironment there are special conditions such as hypoxia (limited oxygen), lack of blood supply and therefore limited nutrients. These particular conditions affect the effectiveness of chemotherapeutic and radiotherapeutic methods....  Hypoxia Hypoxia is a condition in which oxygen is not available in sufficient amounts at the tissue level. This may be due to insufficient oxygen supply to the tissues either due to low blood supply or due to low oxygen content in the blood. Why is the tumor environment hypoxic? During tumor growth and progression, cancer often has limited access to nutrients and oxygen. Most solid tumors do have areas that are permanently or transiently hypoxic due to abnormal vasculature and poor blood supply In the microenvironment of a tumor there are various types of cells such as immune cells but also supportive structural tissue. The tumor trains these cells to allow it to grow and help it grow! Also, connective tissue prevents treatments from effectively reaching their target.... How does hypoxia develop in the tumor and how does this affect radiotherapy? ❖ The oxygen concentration in most normal tissues is a constant 5%–7%. ❖ When oxygen concentrations fall to 3% or below, the tissue is considered hypoxic. ❖ Below this value, oxygen deprivation leads to the activation of molecular pathways that serve to change the behavior or "phenotype" of the cell. ❖ Many of these pathways are activated to allow the cell or tissue to adapt to the stress associated with oxygen deprivation. ❖ For example, these pathways can increase the capacity for anaerobic glycolysis (to maintain energy production) and stimulate angiogenesis (growth of new blood vessels) to increase tissue oxygen supply.  So how does hypoxia affect the effectiveness of radiotherapy? - Hypoxia causes the disease to relapse after radiation because the hypoxic cells are already close to death and will not be as affected by the damage to their DNA. -Also the hypoxic cells will produce the Hif factor which will allow them to survive under these harsh conditions.  Effects of ionizing radiation on the tumor microenvironment. -The widespread use of radiotherapy in solid tumors relies on its ability to damage macromolecules, especially DNA, thereby causing tumor growth inhibition and cancer cell death. - Radiotherapy affects the patient's immune system both negatively and positively. How? Negative: it destroys the immune cells that are exposed to it. Positive: radiotherapy can activate the patient's immune system to cause cancer cells to die. How is this possible? -Causes immunogenic death due to the release of antigens from tumor cells. -Causes changes in the immunophenotype of cancer cells to be recognized by immune cells. -Modifies the tumor microenvironment to make the tumor more accessible to treatments.  Damage to endothelial cells Hypoxia Side effects Activation of Immune cells  Dose fractionation Radiation therapy is usually divided or "fractionated" over a course of treatment lasting several weeks. Fractionation in radiotherapy is the process of dividing a radiation dose into multiple 'fractions’. This practice seeks to maximize the destruction of malignant cells while minimizing damage to healthy tissue.  Dose fractionation The mechanisms that apply in fractionation are: -Redistribution -Re-oxygenation -Repair Dose fractionation Redistribution The radiosensitivity of cells depends on their stage in the cell cycle. Cells are most sensitive to radiation in the M phase and G2 phase of their cycle and most resistant in the S phase. Why? So how does Redistribution lead to a better result? Since a group of malignant cells are at different points in their cell cycle, delivering the entire radiation dose in a single fraction is ineffective against a percentage of cancer cells. Dividing the total radiation dose into multiple fractions maximizes the chance of irradiating cells when they are in the most radiosensitive period of their cell cycle. Dose fractionation Re-oxygenation When cancer cells are hypoxic they are less sensitive to the indirect effects of radiation. Fractionated radiotherapy allows cells closest to oxygen sources to be killed first, and the time between fractions allows relatively hypoxic cells to improve their oxygen supply. These cells are then more sensitive to subsequent doses of radiation. Dose fractionation Repair Fractionation increases the destructive effect on cancer cells while minimizing damage to healthy cells due to the different ability of normal and malignant cells to repair DNA damage. Healthy cells have a greater ability to repair DNA damage than malignant cells. Therefore, partitioning the total radiation dose gives healthy cells the opportunity to repair this lethal damage between fractions. Meanwhile, malignancies with impaired DNA repair pathways are less able to recover from radiation damage to their DNA. Dose fractionation Repair Important Points -Radiation therapy is usually divided or 'fractionated' over a course of treatment lasting several weeks. -The mechanisms that apply to fractionation are Redistribution, Re-oxygenation and Repair During radiation, healthy tissue is exposed to radiation because: The tumor microscopically spreads to neighboring areas which must be irradiated to kill all the cancer cells. There are normal structures within the tumor such as soft tissue and blood vessels that are exposed during treatment At the entry and exit points of radiation there is normal tissue exposed to clinically relevant doses. For this reason, the effect of radiation on normal tissues must be considered together with the therapeutic value of the treatment. Normal tissue is affected by radiation... Normal tissue absorbs 60% of the dose... Early vs Chronic effects The early effects of tissue radiation are seen shortly after treatment while the chronic effects after months or years. The time interval of 90 days was set to separate early vs late effects. The early side effects of radiation are usually found in tissues with high proliferative activity, e.g. bone marrow, skin or intestinal mucosa. The main consequence of this effect is the progressive depletion of cells, i.e. hypoplasia. This is usually accompanied by inflammation. In order for the area to heal, the cells that survive must start proliferating again, or stem cells can reach the area that can differentiate and replace the damaged cells. Early vs Chronic effects Early: Chronic: Dermatitis, hair loss, Infertility, differences etc. in proliferative in immunity, damage to blood vessels, tissues... cancer... Effect of radiotherapy on blood cells Radiotherapy can cause changes in the number of blood cells, especially if it is given to large areas of the body or if bones containing the bone marrow where these cells are produced are irradiated, such as the pelvis, legs and trunk.  Effect of radiotherapy on blood cells Which cells are affected? 1. White Blood Cells (WBCs) White blood cells help the body fight infections. After radiotherapy, levels of neutrophils are measured, which are particularly useful in fighting infections caused by bacteria. A low number of neutrophils (neutropenia) leaves the body vulnerable to infections. 2. Red blood cells. Red blood cells carry oxygen to tissues. The ability of red blood cells to carry oxygen is measured by the amount of hemoglobin they contain. If the hemoglobin level is low or the red blood cells decrease after radiation therapy, the patient develops anemia. The body works much harder to deliver oxygen to the tissues, and patients experience exhaustion and shortness of breath. Platelets. Platelets help blood clot. A low blood platelet count (thrombocytopenia) after radiotherapy can cause bleeding. Platelets are pieces of very large cells in the bone marrow called megakaryocytes. They help form blood clots to slow or stop bleeding and to help wounds heal. What are the consequences for patients if the blood cells are affected by radiotherapy? -Infection: can occur due to a low number of white blood cells and, in particular, neutrophils. Even a mild infection can delay treatment. The doctor can wait until the infection and increase the blood cell count before treatment is continued. The doctor may also recommend drugs to increase the production of white blood cells in the body. -Anemia. It results from a low red blood cell count. The most common symptoms of anemia are fatigue and shortness of breath. In some cases, the fatigue becomes so severe that the cancer treatment must be temporarily stopped or the dose reduced. Anemia can be relieved with a blood transfusion or with drugs to increase the body's production of red blood cells. -Bleeding. A low number of platelets in the blood can cause bleeding. The patient may bleed profusely from a small incision or spontaneously from the nose or gums. Rarely, dangerous internal bleeding can occur. A low platelet count can also be treated with a platelet transfusion. A side effect is appearance of secondary tumors (ie radiation carcinogenesis). Radiation-induced secondary cancer A large percentage of patients receiving chemotherapy or radiotherapy develop secondary cancers some years later... Children and young adults are likely to survive longer after cancer treatment, increasing their risk of developing a secondary cancer caused by radiation radiation- induced secondary malignancies (RISM). The underlying causes of the carcinogenic effect of radiation is the fact that it causes double strand breaks (DSB) in DNA. If cells are not driven to death and continue to divide with these lesions, they can accumulate mutations and develop into cancer cells. The type of radiation determines the likelihood of secondary cancer development Recent studies have shown that malignancies were lower in proton beam therapy compared to photons (5.2% vs. 7.5%). Why? Acute Radiation Syndrome (ARS) (sometimes known as radiation toxicity or radiation sickness) is an acute illness caused by irradiation of the entire body (or most of the body) from a high dose of penetrating radiation in a very short period of time (usually a matter of minutes). Chernobyl nuclear accident Happened in April 1986 in the Chernobyl nuclear power plant in the former Soviet Union Because of the radiation, the health of hundreds of thousands of people was affected Increase in cancer resulting in thousands of subsequent deaths Increase in Leukemia and lymphomas BUT A publication in Science in 2021 showed that 130 children of people exposed to radiation during the Chernobyl accident had no genetic effects... Important Points 1. Normal tissue is affected by radiotherapy due to exposure of normal cells to it. 2. The effects of radiation therapy can be early or chronic. 3. Radiation can affect normal blood cells and cause side effects such as anemia or bleeding in patients. 4. Radiotherapy can cause secondary cancers to appear years after it is given. 5. Dose and site of exposure, co-administration of chemotherapy, age of the patient, years since administration, and many other factors affect the risk of developing other cancers. 6. The most common form of secondary cancer that occurs after radiotherapy is leukemia but also several solid tumors. 7. People affected by the atomic bombings of Japan and the Chernobyl accident form a study group on the long-term side effects of radiation.