Radiation Biology & Radiation Therapy

Transcription

1 Radiation Biology & Radiation Therapy for Medical Students 2nd Semester st & 2 nd Sessions Professor of Medical Physics mmortazavi@sums.ac.ir

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3 LET & RBE

4 LET Linear energy transfer (LET) represents the amount of energy transferred from radiation to a medium (for example, tissues) per unit length of the path traveled by the radiation (sometimes referred to as 'track'). The commonly used unit is kev/µm. LET is defined as: The linear energy transfer (LET) of a medium for charged particles is the quotient of de/dl, where de is the energy lost by a charged particle due to electronic collisions in traversing a distance dl. Since energy transfer to the medium is principally via ionization produced, LET is related to the density of ionization along the track. LET gives an indication of the radiation quality. Radiation Cobalt-60 gamma radiation kev X-radiation MeV protons MeV protons MeV α particles 166 LET (kev/µm)

5 incident radiation Linear Energy Transfer air dispersion of energy tissue high LET ( ) greater radiotoxicity low LET (, x, ~ ) LET = linear energy transfer

6 Radiation quality

7 Typical Linear Energy Transfer Values

8 Relative Biologic Effectiveness The RBE of some test radiation (r) compared with x-rays is defined by the ratio D 250kVp /D r,where D 250kVp and D r are, respectively, the doses of x-rays and the test radiation required for equal biological effect.

9 Relative Biologic Effectiveness

10 The optimal LET LET of about 100 kev/μm is optimal in terms of producing a biologic effect. At this density of ionization, the average separation in ionizing events is equal to the diameter of DNA double helix which causes significant DSBs. DSBs are the basis of most biologic effects. The probability of causing DSBs is low in sparsely ionizing radiation such as x-rays that has a low RBE.

11 LET

12 The Ionization Process Radiation causes ionizations of atoms, which will affect molecules, which may affect cells, which may affect tissues, which may affect organs, which may affect the whole body.

13 Absorption Mechanisms Radiation can be classified as directly ionizing or indirectly ionizing Direct absorption - by primary radiation charged particles Indirect absorption - by secondary radiation photons, neutrons

14 Ionization

15 Cellular Effects

16 Ionizing radiation burn Large red patches of skin on the back and arm from multiple prolonged fluoroscopy procedures.

17 Energy Absorption For Humans LD 50/60 = 4 Gy (4 J/kg) If a 70 kg person receives a dose of 4 Gy, they ve absorbed an equivalent of 280 J. What is the caloric equivalent of 280 J? J = 1 cal, thus 280/4.186 = 67 calories What would be the temperature rise in the body from this energy deposition? Would we expect this to be fatal?

18 Direct and Indirect Ionization Direct Ionization: charged particles direct disruption of atomic and molecular structures charged particles are directly ionizing (if sufficiently energetic) Indirect Ionization: Gamma-rays, x-rays, uncharged particles Gamma- and x-rays 1st transfer energy to electrons Neutrons first transfer energy to recoil protons (H 1 ) or nuclear fragments

19 Water Molecule

20 Indirect Action Chain of Events Ion Formation: H 2 O H 2 O + + e - H 2 O + is an Ion Radical Radical Formation: H 2 O + H + + OH Hydroxyl Radical

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22 Time Scale of Events Initial ionization: s Ion radical lifetime: s Free radical lifetime: 10-5 s Breakage of bonds and expression of biological effects: hours, days, months, years cell killing: hours to days oncogenic (cancer): years mutation in germ cell: generations

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24 Direct Action vs Indirect Action

25 Direct vs Indirect Action Indirect Action: Electrons interact with water to form OH radicals (2/3 of x-ray biological damage). can be modified by sensitizers or protectors Direct Action: Electron directly interacts with target molecule (High LET damages by direct action). cannot be modified by sensitizers or protectors

26 Chromatid breaks Generally, chromatid breaks and chromatid exchanges can be induced by radiation in the S and G- 2 phases of the cell cycle, when the chromosome has split into 2 chromatids.

27 Chromosome breaks Chromosome breaks can be induced by radiation in the G-1 phase of the cell cycle, before the chromosome splits into 2 chromatids.

28 Factors Affecting Radiation Effects on Cells Total energy absorbed by the cell LET, RBE, W R Dose Rate Oxygen Chemical Modifiers Radioprotectors Radiosensitizers Rate of Cell Division Cell Differentiation Age Sex Different Species

29 Bergonie and Tribondeau s law By 1906 Bergonie and Tribondeau realized that cells were most sensitive to radiation when they are: Rapidly dividing Undifferentiated Have a long mitotic future

30 LD 50/30 for various species Species LD50/30 Gy (rad) Pig 2.5 (250) Dog 2.75 (275) Guinea pig 3 (300) Monkey 4.25 (425) Opossum 5.1 (510) Mouse 6.2 (620) Goldfish 7 (700) Hamster 7 (700) Rat 7.1 (710) Rabbit 7.25 (725) Gerbil 10.5 (1050) Turtle 15 (1500) Newt 30 (3000)

31 Organism Guinea Pig Pig Dog Goat Monkey Man Mouse Rat Rabbit Fish Frog Yeast (haploid) Bacteria Yeast (dipliod) M. radiodurans (air) Comparative Radiosensitivity of Living Organisms LD 50 in Gy (X-rays) Factors that Influence LD50 Biological and Physical Deinococcus radiodurans 15,000 Gy with 37% viability

32 Rapair Lethal Damage Sublethal Damage Potentially Lethal Damage

33 Biological Effects of Radiation Cells are undamaged. Cells are damaged, repair damage and operate normally. Cells are damaged, repair damage and operate abnormally. Cells die as a result of damage. Whatever the source and amount of ionizing radiation, it will have some biological effect on living organisms. Atoms become ionized when the radiation displaces electrons. These altered atoms will affect the molecules to which they belong and therefore the biological cells to which the molecules belong. The biological effect on the cell may be direct or indirect. If the radiation interacts with the cell DNA, the cell is considered to be directly affected. If the radiation interacts with the water within the cell to create radicals, which have the capability to form toxic substances such as hydrogen peroxide the cell is said to be indirectly affected. The results of these interactions depend on the sensitivity of the cell type and on the amount and type of radiation the cell receives. Living cells are not equally sensitive to radiation. Rapidly reproducing cells, such as those of a fetus, are more sensitive than those cells which have a longer time to repair damage before reproducing. Cells damaged by radiation respond one of four ways: (1) The cells are not damaged (2) Less active cells that receive small amounts of radiation are able to complete the normal repair of damage (3) Incomplete or incorrect repair of damage may cause the cell to operate abnormally or causes future generations of cells to have mutations (4) Large amounts of damage cause the cell to die

34 Cell Death and Survival Curves

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37 There are a number of assays used for in vitro survival curves. Some look at cell metabolism or membrane integrity as a measure of viability. The most quantitative are those that are based directly on plating or cloning efficiencies. Essentially, a known number of single cells are plated onto dishes and left for 2-4 weeks, depending on how fast the cells grow, until they can form a visible colony. As mentioned in the previous slide, we define a colony as one containing at least 50 cells. The fraction of cells plated that form colonies define cloning efficiency. Radiation exposure reduces that number, and dividing the cloning efficiency seen after irradiation by that of the unirradiated, yields a surviving fraction. Colony = >50 cells Small colonies? From: Hall Radiobiology for the Radiologist

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40 Effect of LET on cell survival Survival curves for cultured cells of human origin exposed to 250-kV X-rays, 15-MeV neutrons, and 4-MeV alpha-particles. As the LET of the radiation increases, the survival curve changes: the slope of the survival curves gets steeper and the size of the initial shoulder gets smaller. A more common way to represent these data is on the next slide.

41 RBE for different cells and tissues Even for a given total dose or dose per fraction, the RBE varies greatly according to the tissue or endpoint studied. Survival curves for various types of clonogenic mammalian cells irradiated with 300 kv X-rays or 15-MeV neutrons. Note that the variations in radiosensitivity among different cell lines is markedly less for neutrons than for X-rays.

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43 LD 50/ Gy: LD 50/30 for Adult Humans without Medical Intervention

44 Stochastic Effect That Occurs On A Random Basis, Independent of the Size of Dose. The Effect Typically Has No Threshold and is Based on Probabilities, With The Chances Of Seeing The Effect Increasing With Dose. If it Occurs, The Severity Of A Stochastic Effect Is Independent Of The Dose Received. Cancer Is A Stochastic Effect.

45 Non-stochastic Effects Effects That Can Be Related Directly To The Radiation Dose Received. The Effect Is More Severe With A Higher Dose. It Typically Has A Threshold, Below Which The Effect Will Not Occur. These Are Sometimes Called Deterministic Effects. For Example, A Skin Burn From Radiation Is A Non-stochastic Effect That Worsens As The Radiation Dose Increases. The image shows severe radiation burns on the back of a man. The man was one of three woodsmen who found a pair of canisters in the mountains of the country of Georgia (formally part of the USSR). The men did not know the canisters were intensely radioactive relics that were once used to power remote generators. Since the canisters gave off heat, the men carried them back to their campsite to warm themselves on a cold winter night.

46 Stochastic vs Non-Stochastic Effects

47 Factors which may Influence Radiation Somatic & Genetic Damages Total Absorbed Dose Potential of Ionizing Tissues Area (Volume) Irradiated Type of Tissue irradiated

48 Dose Response Models LNT

49 Typical dose-survival curves for mammalian cells exposed to x rays and fast neutrons

50 Three periods of gestation 1. Preimplantation 0-9 days (in humans) 2. Organogenesis 10 days - 6 weeks 3. Fetal Period 6 weeks to term

51 Acute Radiation Syndrome

52 Acute Radiation Syndrome Signs and symptoms experienced by individuals exposed to acute whole body irradiation. Data collected largely through Japanese atomic bomb survivors at Hiroshima and Nagasaki. Limited number of accidents at nuclear installations. Clinical radiotherapy. Well-characterized animal data base. LD50/60 dose of human is ~4.5 Gy. Lethal Dose (LD 100) is 8 Gy (~10 Gy).

53 Prodromal Radiation Syndrome Early symptoms that appear after exposure to whole body radiation: gastrointestinal: nausea, vomiting, diarrhea, anorexia neuromuscular: easy fatigability Effect is dose dependent: Varies in time of onset Severity Duration

54 Hematopoietic syndrome Cause of death at doses 2-10 Gy. Peak incidence of death occurs at about 30 days post-irradiation, and continues for up to 60 days. Suppresses normal bone marrow and spleen functions. Symptoms associated with hematopoietic syndrome are: chill, fatigue, hemorrhages, ulceration, infection and anemia. Death is possible unless receive medical interventions such as bone marrow transplant.

55 Gastrointestinal syndrome Occurs at dose Gy of gamma-rays or its equivalence. Death usually occurs within 3 to 10 days. Symptoms due largely to depopulation of the epithelial lining of the GI tract by radiation. No human has survived radiation dose >10 Gy. Clinical symptoms include nausea, vomiting, and prolong diarrhea, dehydration, loss of weight, complete exhaustion, and eventuallydeath.

56 Cerebrovascular syndrome Identified at doses >50 Gy of gamma-rays. Death occurs within hours from cardiovascular and neuromuscular complications. Clinical manifestations include severe nausea, vomiting within minutes of exposure, disorientation, loss of muscular co-ordination, respiratory distress, seizures, coma and death.

57 Radiation-induced Mutagenesis Radiation DOES NOTproduce new, unique mutations, but increases the incidence of the same mutations that occur spontaneously. Mutation incidence in humans is DOSE and DOSE-RATE dependent. A dose of 1 rem (10 msv) per generation increases background mutation rate by 1%. Information on the genetic effects of radiation comes almost entirely from animal and IN VITRO studies. Children of A-bomb survivors from Hiroshima and Nagasaki fail to show any significant genetic effects of radiation.

58 Radiation Carcinogenesis Cancer is a stochastic late effect. No threshold, an all or none effect. Severity is not dose related. Probability of carcinogenesis is dose dependent. Leukemia has the shortest latency period of ~5 years. Solid tumors have a latency period of ~20 to 30 years. Total cancer risk for whole body irradiation is one death per 10 4 individuals exposed to 1 rem.

59 Cancer Treatment

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61 Radiation Therapy

62 Radiation Therapy 1. Cells can be killed by ionizing radiation. 2. Most important target appears to be nuclear DNA. 3. Radiation damage to DNA results in nonviable offspring. 4. Rapidly dividing cell populations are the most sensitive to ionizing radiation (e.g. tumors, epithelial cells, hemopoietic cells.

63 TCP & NTCP Curves At a high enough dose we would have a high probability of curing every tumor. Unfortunately, we must also irradiate some normal tissue and its response usually limits the dose that can be used

64 The physical goal of radiation therapy Deliver a high dose to all parts of the tumor while minimizing the dose to surrounding normal tissue.

65 What is achievable? This ideal dose distribution is not physically achievable, but we attempt to satisfy it through two general strategies: Brachytherapy and Teletherapy

66 Treatment of Cancer Radiation is very effective in the treatment of certain cancers. The choice is basically do you administer the radiotherapy externally or internally.

67 Some cancers are considered more responsive to radiation therapy Certain types of cancer are considered more responsive to radiation therapy. In these cancers radiation can sometimes successfully stop growth without permanently damaging the surrounding normal tissue. If these tumors can be treated early, before metastasis the cure rate is high. Cancers in this category: skin and lip head and neck breast cervical and endometrium prostate Hodgkin's disease and local extranodal lymphoma Seminoma of testis and dysgerminoma of ovary Medulloblastoma, pineal germinoma,and ependymoma Retinoblastoma Choroidal melanoma

68 Some cancers are considered limited responsive to radiation therapy Other tumors with limited response to radiation that may be curable with combined therapies include: Wilms tumor Rhabdomyosarcoma colorectal cancer soft tissue carcinoma embryonal carcinoma of testis Most other malignant cancers are not considered curable with radiation because they are difficult to detect early enough and/or they have a much higher growth rate. Tumors found in especially sensitive tissue cannot be treated with the large dose of radiation necessary to kill the tumor. Also, radiation alone is not usually successful against highly metastatic tumors. In some instances, a limited number of cures are obtained following surgery, radiation, or a combination of the two.

69 External Beam Therapy External beam therapy (EBT) is a method for delivering a beam of high-energy photons to the location of the patient's tumor. The beam is generated outside the patient and is targeted at the tumor site. These high-energy photons can destroy the cancer cells and careful treatment planning allows the surrounding normal tissues to be spared.

70 Teletherapy In teletherapy an external source at a distance of about one meter from the patient is used to irradiate the tumor. A series of daily fractions, each about 2 Gy, is used. It takes about one minute to deliver the actual treatment.

71 Teletherapy 1. Any anatomical site can be treated. 2. Large fields (even the whole body!) can be accommodated. 3. Treatment is quick and convenient. 4. Usually done as an outpatient procedure. 5. Noninvasive. 6. Can be performed on patients who are not well. 7. No significant radiation dose to staff, No radiation to family members, etc. 8. The physical disadvantages can be largely overcome.

72 Dose in Teletherapy To understand the dose distribution from an external photon beam, we need to consider: 1. Dose is due mainly to electrons. 2. Electrons have finite range. 3. Attenuation of primary photons. 4. Inverse square law. 5. Compton scattered photons.

73 Simple Model for Dose Near the Surface

74 Maximum Dose Surface Dose Dose at Beam Exit

75 Buildup region The dose region between the surface (depth z = 0) and depth z = z max in megavoltage photon beams is referred to as the dose buildup region and results from the relatively long range of energetic secondary charged particles (electrons and positrons) that are first released in the patient by photon interactions (photoelectric effect, Compton effect, pair production) and then deposit their kinetic energy in the patient.

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77 Modifying dose at the skin surface and at depth In radiation therapy, bolus is a material which has properties equivalent to tissue when irradiated. It is widely used in practice for modifying dose at the skin surface and at depth A specific thickness of bolus can be applied to the skin to alter the dose received at depth in the tissue and on the skin surface. A typical example of this is the application of a defined thickness of bolus to a chest wall for post-mastectomy chest wall treatment, to increase the skin dose. When a full bolus is applied, bolus thickness equal to the depth of the build-up region removes the skin-sparing effect of a megavoltage x-ray beam.

78 Dose distribution

79 Multi Beams Consider what happens if you use two beams entering the patient from opposite directions. The resulting dose distribution will be the sum of the contributions from the two fields. Plotting the dose along the central axis of this opposing pair of fields we get something that looks like

80 SINGLE BEAMS A single beam may be used to treat a tumour which is near enough to the body surface for sufficient dose to be received without overdosing overlying and underlying tissues within the treatment beam Most tumours require a different method...

81 Multi-beam treatments Used if a high dose is required to kill tumours deeper in the body Several beams used Beams only overlap in the tumour area Tumour receives fatal dose but healthy cells receive a lower, safer dose. Each of these beams delivers 1/3 of the required dose.

82 Before treatment can begin, scans are taken to accurately locate the tumor.

83 Then computers are used to help plan the best route for each beam

84 Sensitive areas such as the eyes and spinal cord must be avoided. eyes brain tumour

85 Two beams from opposite directions

86 Now we can get more dose in a deep-seated tumor than in the overlying normal tissue. This idea can be extended to more complex arrangements ranging from standard 3, 4 or more field geometries to quite complex individualized plans that incorporate beam modifiers.

87 Fractionation Sterilization Endpoint Experiments 1920 s-30 s Single Fraction Severe Skin Effects Multiple Smaller Fractions Less Severe Skin Effects

88 Isoeffect Curves Each isoeffect curve represents a different clinical acute toxicity endpoint. Examples A = skin necrosis, E = skin erythema.

89 Brachytherapy Brachytherapy is not a new treatment method. Throughout this century, several types and routes of implantation of radioactive seeds have been used to treat cancer. Radioactive Iodine seeds were widely used during the 1970s and 1980s.

90 Brachytherapy Brachytherapy sources can be divided into permanent and temporary groups. Permanent sources tend to have lower energy and shorter half-lives. The advantage of these lower energies is enhanced safety. The disadvantage is that anatomical adjustments cannot be made once the sources are placed.

91 Brachytherapy In brachytherapy radiation sources are placed adjacent to or within the target volume. The sources may be implanted permanently or temporarily. Temporary implants may be performed at high dose rate (HDR, treatment time of minutes) or low dose rate (LDR, treatment time of days).

92 Temporary seed placement is shown here.

93 Brachytherapy The isotopes used most commonly in brachytherapy are Cs-137, Ir-192, and I-125. Radionuclide Half Life Energy

94 Brachytherapy In brachytherapy radioactive seeds or sources are placed in or near the tumor itself, giving a high radiation dose to the tumor while reducing the radiation exposure in the surrounding healthy tissues. The term "brachy" is Greek for short distance.

95 Brachytherapy

96 Temporary Brachytherapy Currently, temporary implants consist primarily of 192Ir and 137Cs.

97 67 year old male with metastatic prostate cancer.

98 Iridium 192 is used for high dose rate treatment of prostate cancer. During the implantation, hollow needles are inserted transperineally. The needles are then connected to an automated remote-controlled loading machine. The total irradiation time is usually only 5-10 minutes. HDR Brachytherapy

99 Linear accelerator (Linac) An electron linear accelerator uses microwaves propagating in a special waveguide to accelerate the electrons. The largest linac accelerates electrons to 2 GeV, but medical accelerators operate in the 4-25 MeV range.

100 Linear Accelerator Linacs consist of four major components a modulator, an electron gun, a radio-frequency (RF) power source, and an accelerator guide. The electron beam produced by a linac can be used for treatment or can be directed toward a metallic target to produce x-rays. The modulator amplifies the AC power supply, rectifies it to DC power, and produces highvoltage DC pulses that are used to power the electron gun and RF power source. The electron gun injects electrons into the accelerator guide in pulses of the appropriate duration, velocity, and position to maximize acceleration. The RF power source, either a magnetron or a klystron, supplies high-frequency electromagnetic waves (3,000 MHz), which accelerate the electrons injected from the electron gun down the accelerator guide.

101 Linear Accelerator

102 Linear Accelerator The electron beam is focused onto a metal target (usually tungsten). An ionization chamber measures the radiation output in real time and is the means by which the dose to the patient is controlled.

103 At high energies the bremsstrahlung beam is forward peaked, so a metal flattening filter is used to produce a more uniform beam A set of moveable collimators allow the user to define rectangular beams of dimensions from 4 to 40 cm. Linear Accelerator

104 Proton Beam Radiotherapy This form of external beam irradiation involves directing radiation through the front of the eye in order to reach the intraocular tumor. When compared to lowenergy eye-plaque radiation therapy, it is easier to treat tumors that are surrounding the optic nerve with protons.

105 Proton Therapy Protons can produce excellent dose distributions with a single field. However, these installations are an order of magnitude more expensive than photon facilities and it is questionable whether they are justified when modern conformal photon techniques can produce competitive results.

106 Thank you for your attention!