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BASICS RADIOBIOLOGY FOR RADIOTHERAPY

BASICS RADIOBIOLOGY FOR RADIOTHERAPY

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BASICS RADIOBIOLOGY FOR RADIOTHERAPY

  1. 1. TOPIC 2 BASICS RADIOBIOLOGY FOR RADIOTHERAPY (2 hours) 122/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  2. 2. 2.1 Introduction 2.2 Radiation Chemistry 2.3 Volume Definition 2.3.1 Gross Tumour Volume (GTV) 2.3.2 Clinical Target Volume (CTV) 2.3.3 Planning Target Volume (PTV) 2.3.4 Treated Volume (TV) 2.3.5 Irradiated Volume (Iv) 2.3.6 Organs At Risk (Oar) 222/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  3. 3. 2.4 5 Rs 2.4.1 Repair 2.4.2 Repopulation 2.4.3 Reoxygenation 2.4.4 Redistribution 2.4.5 Radiosensitivity 2.5 Biological Effect of Ionizing Radiation 2.5.1 Dose Response Curve 2.5.2 Cell Survival Curve 2.5.3 Systemic Effects 2.5.4 Oxygen Effect 2.5.5 LET 2.5.6 Relative Biological Effectiveness (RBE) 322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  4. 4. 2.1 Introduction 422/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  5. 5. INTERACTIONS between Ionizing radiation and living systems radiation physics + biology Radiation oncology 2.1 Introduction 522/3/2017 ACTION Of ionizing radiation on biological tissues radiation physics + biology Radiobiology
  6. 6. 2.1 Introduction 622/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak Radiobiology allows the optimization of a radiotherapy schedule for individual patients in regards to: Total dose and number of fractions Overall time of the radiotherapy course Tumour control probability (TCP) and normal tissue complication probability (NTCP)
  7. 7. 2.2 Radiation Chemistry 722/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  8. 8. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 8 2.2 Radiation Chemistry Radiation may impact the DNA directly, causing ionization of the atoms in the DNA molecule (“direct hit”). It is a fairly uncommon occurrence due to the small size of the target; the diameter of the DNA helix =2 nm. Dominant process in the interaction of high LET particles such as neutrons or alpha particles with biological material. 1) DIRECT ACTION
  9. 9. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 9 2) INDIRECT ACTION 2.2 Radiation Chemistry The radiation interacts with non-critical target atoms or molecules, usually water. This results in the production of free radicals, which are atoms or molecules that have an unpaired electron and thus are highly reactive These free radicals can then attack critical targets such as the DNA. Damage from indirect action is much more common than damage from direct action
  10. 10. • Indirect action: Electrons produce free radicals which break chemical bonds and produce chemical changes • Direct Action: Photon ejects an electron which produce a biological damage on the DNA 2.2 Radiation Chemistry
  11. 11. 2.2 Radiation Chemistry
  12. 12. 2.2 Radiation Chemistry
  13. 13. 2.3 Volume Definition 2.3.1 Gross Tumour Volume (GTV) 2.3.2 Clinical Target Volume (CTV) 2.3.3 Planning Target Volume (PTV) 2.3.4 Treated Volume (TV) 2.3.5 Irradiated Volume (Iv) 2.3.6 Organs At Risk (Oar) 1322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  14. 14. •Volume definition is a prerequisite for meaningful 3-D treatment planning and for accurate dose reporting. •ICRU reports No. 50 and 62 define and describe several target and critical structure volumes that aid in the treatment planning process and that provide a basis for comparison of treatment outcomes. •The following volumes have been defined as principal volumes related to 3-D treatment planning: gross tumour volume (GTV), clinical target volume (CTV), internal target volume (ITV) and planning target volume (PTV) 2.3 Volume Definition
  15. 15. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 15
  16. 16. GTV – Gross Tumour Volume CTV – Clinical Target Volume PTV – Planning Target Volume OAR – Organ at Risk TV – Treated Volume IV – Irradiated Volume 2.3 Volume Definition
  17. 17. The gross palpable, visible and demonstrable extent and location of the malignant growth (ICRU Report No. 50) 2.3.1 Gross Tumour Volume (GTV)
  18. 18. •This is determined by physical examination by the oncologist and the results of radiological investigations relevant to the site of the tumour. •As the term suggests, tumours have a length, breadth and depth, and the GTV must therefore be identified using orthogonal 2D or 3D imaging (computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, etc.), diagnostic modalities (pathology and histological reports, etc.) and clinical examination. 2.3.1 Gross Tumour Volume (GTV)
  19. 19. Part VIII.3.7 Operational Considerations – Planning of physical treatment Slide 19 Gross Tumour Volume (GTV) – Gross palpable or visible/demonstrable extent and location of tumour GTV
  20. 20. •“The clinical target volume (CTV) is the tissue volume that contains a demonstrable GTV and/or sub-clinical microscopic malignant disease, which has to be eliminated. This volume thus has to be treated adequately in order to achieve the aim of therapy, cure or palliation” (ICRU Report No. 50) 2.3.2 Clinical Target Volume (CTV)
  21. 21. •Usually determined by the radiation oncologist, often after other relevant specialists such as pathologists or radiologists have been consulted. •This volume may not be defined separately but considered when defining the planning target volume (PTV) (e.g. CTV = GTV + 1 cm margin) 2.3.2 Clinical Target Volume (CTV)
  22. 22. Part VIII.3.7 Operational Considerations – Planning of physical treatment Slide 22 Clinical Tumour Volume (CTV) CTV Contains a GTV and/or sub-clinical microscopic malignant disease, which has to be eliminated CTV
  23. 23. •“The planning target volume (PTV) is a geometrical concept, and it is defined to select appropriate beam arrangements, taking into consideration the net effect of all possible geometrical variations, in order to ensure that the prescribed dose is actually absorbed in the CTV” (ICRU Report No. 50) 2.3.3 Planning Target Volume (PTV)
  24. 24. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 24 • The PTV includes the internal target margin (ICRU Report No. 62) and an additional margin for the set-up uncertainties, machine tolerances and intratreatment variations • It fully encompasses the GTV and CTV (e.g : PTV = CTV + 1 cm). 2.3.3 Planning Target Volume (PTV)
  25. 25. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 25 • In practice, it is often the result of a compromise between two contradictory issues: making sure that the CTV will receive the prescribed dose while at the same time ensuring that OARs will not receive an excessive dose. 2.3.3 Planning Target Volume (PTV)
  26. 26. Part VIII.3.7 Operational Considerations – Planning of physical treatment Slide 26 Planning Target Volume (PTV) • Contains a CTV and a margin to account for variation is size, shape and position relative to treatment beams PTV
  27. 27. •The volume of tissue enclosed by an isodose surface selected and specified by the clinician as being appropriate to achieve the aim of treatment. •For example, this may be the volume encompassed within the 95% isodose surface (with 100% in the centre of the PTV) for a curative treatment plan. 2.3.4 Treated Volume (TV)
  28. 28. •The TV should not be significantly larger than the PTV. The use of 3D treatment planning and shaping the radiation fields to the shape of the PTV using conformal radiation delivery techniques ensures that the TV encloses the PTV with as narrow a margin as possible. This ensures minimal irradiation of surrounding OARs while coverage of the PTV is assured. 2.3.4 Treated Volume (TV)
  29. 29. Part VIII.3.7 Operational Considerations – Planning of physical treatment Slide 29 Treated volume Treated volume – Volume enclosed by an isodose surface selected as appropriate to achieve purpose of treatment Treated Volume
  30. 30. •The tissue volume receiving a radiation absorbed dose that is considered significant in relation to normal tissue tolerance. •This concept is not often considered in practice but may be useful when comparing one or more competing treatment plans. •Clearly, it would be preferable to accept the plan with the smallest IV, all else being equal. 2.3.5 Irradiated Volume (Iv)
  31. 31. Part VIII.3.7 Operational Considerations – Planning of physical treatment Slide 31 Irradiated volume Irradiated volume – The volume that receives a dose that is significant in relation to normal tissue tolerance Irradiated Volume
  32. 32. •Organs adjacent to the PTV which are non-target; do not contain malignant cells •The aim should therefore be to minimise irradiation of OARs as they are often relatively sensitive to the effects of ionising radiation and, if damaged, may lead to substantial morbidity. •The OARs to be considered will vary greatly according to the anatomical region being treated, the size of the PTV and the location of the PTV in these regions. 2.3.6 Organs At Risk (Oar)
  33. 33. •The following are examples of the most common OARs that must be considered: 1. Brain: lens of eye, optic chiasm, brain stem 2. Head & neck: lens of eye, parotid glands 3. Thorax: spinal cord, lungs 4. Abdomen: spinal cord, large bowel, small bowel, kidneys 5. Pelvis: bladder, rectum, femoral heads, large bowel, small bowel 2.3.6 Organs At Risk (Oar)
  34. 34. Part VIII.3.7 Operational Considerations – Planning of physical treatment Slide 34 Organs at Risk (OAR) • Normal tissues whose radiation sensitivity could significantly influence treatment planning and/or the dose prescription OARs • Lung • Spinal cord
  35. 35. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 35
  36. 36. 2.4 Biological Factors (5 Rs) 2.4.1 Repair 2.4.2 Repopulation 2.4.3 Reoxygenation 2.4.4 Redistribution 2.4.5 Radiosensitivity 3622/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  37. 37. Repair Repopulation Reoxygenation Redistribution Radiosensitivity •The biological factors that influence the response of normal and neoplastic tissues to fractionated radiotherapy 2.4 Biological Factor (5 Rs)
  38. 38. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 38
  39. 39. 2.4.1 Repair 3922/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  40. 40. •All cells repair radiation damage •Repair is very effective because DNA is damaged significantly more due to ‘normal’ other influences (e.g. temperature, chemicals) than due to radiation •The half time for repair, tr, is of the order of minutes to hours 2.4.1 Repair
  41. 41. •It is essential to allow normal tissues to repair all repairable radiation damage prior to giving another fraction of radiation. •This leads to a minimum interval between fractions of 6 hours •Spinal cord seems to have a particularly slow repair - therefore, breaks between fractions should be at least 8 hours if spinal cord is irradiated. 2.5.1 Repair
  42. 42. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 42
  43. 43. 2.4.2 Repopulation 4322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  44. 44. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 44 • In both tumours and normal tissues, proliferation of surviving cells may occur during the course of fractionated treatment. • Furthermore, as cellular damage and cell death occur during the course of the treatment, the tissue may respond with an increased rate of cell proliferation. • The effect of this cell proliferation during treatment, known as repopulation or regeneration (increase the number of cells during the course of the treatment and reduce the overall response to irradiation) 2.4.2 Repopulation
  45. 45. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 45 • This effect is most important in early-responding normal tissues (e.g., skin, gastrointestinal tract) or in tumours whose stem cells are capable of rapid proliferation; it will be of little consequence in late-responding, slowly proliferating tissues (e.g., kidney), which do not suffer much early cell death and hence do not produce an early proliferative response to the radiation treatment. • Repopulation is likely to be more important toward the end of a course of treatment, when sufficient damage has accumulated (and cell death occurred) to induce a regenerative response. 2.4.2 Repopulation
  46. 46. •The repopulation time of tumour cells appears to vary during radiotherapy - at the commencement it may be slow (e.g. due to hypoxia), however a certain time after the first fraction of radiotherapy (often termed the “kick-off time”, Tk) repopulation accelerates. •Repopulation must be taken into account when protracting/prolong radiation e.g. due to scheduled (or unscheduled) breaks such as holidays. 2.4.2 Repopulation
  47. 47. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 47
  48. 48. 2.4.3 Reoxygenation 4822/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  49. 49. •Oxygen is an important enhancement for radiation effects (“Oxygen Enhancement Ratio” (OER) •The tumor may be hypoxic (in particular in the center which may not be well supplied with blood) •One must allow the tumor to re-oxygenate, which typically happens a couple of days after the first irradiation 2.4.3 Reoxygenation
  50. 50. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 50 • The response of tumours to large single doses of radiation is dominated by the presence of hypoxic cells within them, even if only a very small fraction of the tumour stem cells are hypoxic. • Immediately after a dose of radiation, the proportion of the surviving cells that is hypoxic will be elevated. However, with time, some of the surviving hypoxic cells may gain access to oxygen and hence become reoxygenated and more sensitive to a subsequent radiation treatment. • Reoxygenation can result in a substantial increase in the sensitivity of tumours during fractionated treatment. 2.4.3 Reoxygenation
  51. 51. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 51
  52. 52. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 52
  53. 53. 2.4.4 Redistribution 5322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  54. 54. •Cells have different radiation sensitivities in different parts of the cell cycle •Highest radiation sensitivity is in early S and late G2/M phase of the cell cycle G1 G1 S (synthesis) M (mitosis)G2 2.4.4 Redistribution
  55. 55. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 55 • Variation in the radiosensitivity of cells in different phases of the cell cycle results in the cells in the more resistant phases being more likely to survive a dose of radiation. • Two effects can make the cell population more sensitive to a subsequent dose of radiation. 1. Some of the cells will be blocked in the G2 phase of the cycle, which is usually a sensitive phase. 2. Some of the surviving cells will redistribute into more sensitive parts of the cell cycle. • Both effects will tend to make the whole population more sensitive to fractionated treatment as compared with a single dose. • .
  56. 56. •The distribution of cells in different phases of the cycle is normally not something which can be influenced - however, radiation itself introduces a block of cells in G2 phase which leads to a synchronization •One must consider this when irradiating cells with breaks of few hours. 2.4.4 Redistribution
  57. 57. 2.4.5 Radiosensitivity 5722/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  58. 58. •For a given fractionation course (or for single-dose irradiation), the haemopoietic system shows a greater response than the kidney, even allowing for the different timing of response. •Similarly, some tumours are more radioresponsive than others to a particular fractionation schedule, and this is largely due to differences in radiosensitivity. 2.4.5 Radiosensitivity
  59. 59. Muscle Bones Nervous system Skin Liver Heart Lungs Bone Marrow Spleen Thymus Lymphatic nodes Gonads Eye lens Lymphocytes (exception to the RS laws) Low RSMedium RSHigh RS 2.4.5 Radiosensitivity
  60. 60. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 60
  61. 61. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 61
  62. 62. 2.5 Biological Effect of Ionizing Radiation 2.5.1 Dose Response Curve 2.5.1.1 Deterministic 2.5.1.2 Stochastic Effect 2.5.1.3 Sigmoid Curve 2.5.1.4 Cell Survival Curve 2.5.2 LET 2.5.3 OER 2.5.4 RBE 62Dr. Nik Noor Ashikin Bt Nik Ab Razak
  63. 63. 2.5 Biological Effect of Ionizing Radiation 6322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  64. 64. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 64 2.5 Biological Effect of Ionizing Radiation
  65. 65. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 65 2.5 Biological Effect of Ionizing Radiation
  66. 66. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 66 2.5 Biological Effect of Ionizing Radiation
  67. 67. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 67 2.5 Biological Effect of Ionizing Radiation
  68. 68. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 68 2.5 Biological Effect of Ionizing Radiation
  69. 69. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 69 2.5 Biological Effect of Ionizing Radiation
  70. 70. Module Medical IX. 70 Biological effects of radiation in time perspective Time scale Fractions of seconds Seconds Minutes Hours Days Weeks Months Years Decades Generations Effects Energy absorption Changes in biomolecules (DNA, membranes) Biological repair Change of information in cell Cell death Organ Clinical death changes Mutations in a Germ cell Somatic cell Leukaemia or Cancer Hereditary effects
  71. 71. 2.5 Biological Effect of Ionizing Radiation 71 Dose to the tumor determines probability of cure Dose to normal structures determines probability of side effects and complications Dose to patient, staff and visitors determines risk of radiation detriment to these groups What matters in the end is the biological effect! 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 2.5 Biological Effect of Ionizing Radiation
  72. 72. 2.5 Biological Effect 7222/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak Biological Effect Stochastic Effects (carcinogenic and genetic effects) Deterministic Effects (tissue reactions)
  73. 73. 2.5.1 Dose Response Curve 7322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  74. 74. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 74 2.5.1.3 Sigmoid Curve (non-threshold) DOSE RESPONSE CURVE Line 3: Non linear dose response Line 1: No level of radiation can be considered safe. Diagnostic Imaging Line 2: Threshold is assumed, response expected at lower doses. (Radiotherapy) Stochastic Effect
  75. 75. 2.5.1.1 Deterministic Effect 7522/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  76. 76. 2.5.1.1 Deterministic Effect DETERMINISTIC EFFECTS/ (High Dose) erythema skin breakdown cataracts death Have a dose threshold Due to cell killing (high dose given over short period) Severity of harm is dose dependent Specific to particular tissues Acute effect/ short term effect/ early effect
  77. 77. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 77
  78. 78. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 78
  79. 79. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 79 2.5.1.1 Deterministic Effect
  80. 80. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 80
  81. 81. Acute radiation syndrome (ARS)  ARS is the most notable deterministic effect of ionizing radiation  Signs and symptoms are not specific for radiation injury but collectively highly characteristic of ARS  Combination of symptoms appears in phases during hours to weeks after exposure - prodromal phase - latent phase - manifest illness - recovery (or death)
  82. 82. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 82
  83. 83. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 83
  84. 84. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 84
  85. 85. 2.5.1.2 Stochastic Effect 8522/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  86. 86. 2.5.1.2 Stochastic Effect STOCHASTIC EFFECT (low dose) Eg: -cancer induction (Somatic effect) -hereditary effects Severity (example cancer) independent of the dose Due to cell changes and proliferation towards a malignant disease No dose threshold - applicable also to very small doses Probability of effect increases with dose Late effect / Chronic effect)
  87. 87. 2.5 Biological Effect2.5.1.2 Stochastic Effect
  88. 88. Phases of cancer induction and manifestation Initia tion Muta te d Cells Elimia tion Re pa ra tion Progre ssion Pre-c a nce r Norma l Cells Promotion Minima l Ca nc er Clinic a l Ca ncer Spre a ding
  89. 89. 2.5.1.3 Sigmoid Curve (non-threshold) 9022/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  90. 90. Dose Repairing cell structures is still possible No repairing: a low dose means a great damage Practically all the cells are dead dose 2.5.1.3 Sigmoid Curve (non-threshold)
  91. 91. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 92 2.5.1.3 Sigmoid Curve (non-threshold) LD 50/60 amount of radiation that will cause 50% of exposed individuals to die within 60 days
  92. 92. 2.5.1.4 Cell Survival Curve 9322/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  93. 93. Biological Effects At Cellular Level Possible mechanisms of cell death: • Physical death • Functional death • Death during interphase • Mitotic delay • Reproductive failure Cellular effects of ionizing radiation are studied by cell survival curves %survivalcells(semilogarithmic) Dose n = targets Dq D0 (threshold) (radiosensitivity) 2.5.1.4 Cell Survival Curve
  94. 94. • Do = 37% dose slope - Dose required to reduce the number of clonogenic cells to 37% of their former value • Dq = Quasi threshold dose - Dose at which straight portion extrapolated backward cuts the dose axis • n = extrapolation number - Extrapolating the straight portion of the survival curve until it cuts the “surviving fraction” axis  Radiosensitive cells are characterized by curves with steep slope D0 and/or small shoulder (low n) Loge n = Dq / D0 %survivalcells(semilogarithmic) Dose n = targets Dq D0 (threshold) (radiosensitivity) 2.5.1.4 Cell Survival Curve
  95. 95. 2.5.2 LET 9622/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  96. 96. 2.5.2 LET 9722/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak LET the linear rate of energy absorption by absorbing medium as charged particle traverses the medium (dE/dl, KeV/mm) defining the quality of an ionizing radiation beam
  97. 97. Photon Proton Helium Carbon Oxygen Neon
  98. 98. gamma rays deep therapy X-rays soft X-rays alpha-particle HIGH LET Radiation LOW LET Radiation Separation of ion clusters in relation to size of biological target 4 nm The Spatial Distribution of Ionizing Events Varies with the Type of Radiation and can be defined by LET
  99. 99. http://dmco.ucla.edu/McBride_Lab WMcB2008 • A dose of 1 Gy will give 2x103 ionization events in 10-10 g (the size of a cell nucleus). This can be achieved by: – 1MeV electrons •700 electrons which give 6 ionization events per m. – 30 keV electrons •140 electrons which give 30 ionization events per m. – 4 MeV protons •14 protons which give 300 ionization events per m. • The biological effectiveness of these different radiations vary! -ray ’-ray excitation ionization  particle excitation and ionization
  100. 100. http://dmco.ucla.edu/McBride_Lab WMcB2008 Repairable Sublethal Damage X- or -radiation is sparsely ionizing; most damage can be repaired 4 nm 2 nm
  101. 101. http://dmco.ucla.edu/McBride_Lab WMcB2008 Single lethal hit Also known as  - type killing 4 nm 2 nm Unrepairable Multiply Damaged Site It is hypothesized that the lethal lesions are large double strand breaks with Multiply Damaged Sites (MDS) that can not be repaired. They are more likely to occur at the end of a track
  102. 102. http://dmco.ucla.edu/McBride_Lab WMcB2008 At high dose, intertrack repairable Sublethal Damage may Accumulate forming unrepairable, lethal MDS Also known as  - type killing
  103. 103. 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak 104 2.5.2 LET
  104. 104. 2.5.3 Oxygen Enhancement Ratio 10522/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  105. 105. 2.5.3 Oxygen Enhancement Ratio 106 1 • Oxygen is a powerful oxidizing agent and therefore acts as a radiosensitizer if it is present at the time of irradiation (within msecs). • Its effects are measured as the oxygen enhancement ratio (O.E.R.) 2 • The presence or absence of molecular oxygen within a cell influences the biological effect of ionizing radiation: the larger the cell oxygenation above anoxia, the larger is the biological effect until saturation of the effect of oxygen occurs, especially for low LET radiations 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  106. 106. 2.5.3 Oxygen Enhancement Ratio 107 3 • The effect is quite dramatic for low LET (sparsely ionizing) radiations, while for high LET (densely ionizing) radiations it is much less pronounced 4 • The ratio of doses without and with oxygen (hypoxic vs. well- oxygenated cells) to produce the same biological effect is called the oxygen enhancement ratio (OER). • O.E.R. = D(anox)/D(ox) 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  107. 107. 22/3/2017 108 2.5.3 Oxygen Enhancement Ratio
  108. 108. 2.5.3 Oxygen Enhancement Ratio 109 5 • For densely ionizing radiation, such as low-energy α-particles, the survival curve does not have an initial shoulder 6 • In this case, survival estimates made in the presence and absence of oxygen fall along a common line; the OER is unity – in other words, there is no oxygen effect 22/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  109. 109. http://dmco.ucla.edu/McBride_Lab WMcB2008 Oxygen Enhancement Ratio (OER) Dose required to produce a specific biological effect in the absence of oxygen Dose required for the same effect in its presence= OER varies with level of effect but can be 2.5 - 3 fold 1) Culture Cells ( 3) Count cells in hemocytometer 4) irradiate under oxic or hypoxic conditions 0 Gy 2Gy 4Gy 6Gy 5) Plate cells and grow for about 12 days . . . . . .. . 6) Count colonies Dose (Gy) S.F. 0 2 4 6 8 10 1.0 0.1 0.01 oxic hypoxic Physical Dose = Biological Dose 2) Suspend Cells trysinization)
  110. 110. http://dmco.ucla.edu/McBride_Lab WMcB2008 • Hypoxic areas occur almost solely in tumors and are more radioresistant than oxic areas. • Hypoxia contributes to treatment failure • Reoxygenation occurs between radiation dose fractions giving a rationale for dose fractionation • The oxygen effect is greater for low LET than high LET radiation Giacca and Brown Pimonizadole (oxygen mimetic) staining colorectal carcinoma The effects of hypoxia were first discovered in 1909 by Schwarz who showed that strapping a radium source on the arm gave less of a skin reaction than just placing it there. This was used to give higher doses to deep seated tumors. Clinical Relevance of Hypoxia
  111. 111. 2.5.4 Relative Biological Effectiveness (RBE) 11222/3/2017 Dr. Nik Noor Ashikin Bt Nik Ab Razak
  112. 112. 2.5.4 RBE 113 1 • Equal doses of different LET radiation DO NOT produce equal biological effects 2 •A term relating the ability of radiations with different LETs to produce a specific biologic response is relative biological effectiveness (RBE)
  113. 113. 2.5.4 RBE 114 3 • RBE is defined as the comparison of a dose of some test radiation to the dose of 250 kV x- rays that produces the same biologic response 4 •250 kV x-rays or 1.17/1.33 MeV 60Co as the standard radiation
  114. 114. RBE is end-point dependent Fractionated doses of dense vs. sparse ionizing beam: The RBE of high LET beam becomes larger when the fraction number is increasing. 2.5.4 RBE
  115. 115. The ICRP 1991 standard values for relative effectiveness Radiation Energy WR (also RBE or Q) x-rays, gamma rays, electrons, positrons, muons 1 neutrons < 10 keV 5 10 keV - 100 keV 10 100 keV - 2 MeV 20 2 MeV - 20 MeV 10 > 20 MeV 5 protons > 2 MeV 2 alpha particles, nuclear fission products, heavy nuclei 20 Weighting factors WR (also termed RBE or Q factor, to avoid confusion with tissue weighting factors Wf) used to calculate equivalent dose according to ICRP report 92 2.5.4 RBE
  116. 116. http://dmco.ucla.edu/McBride_Lab WMcB2008 ACUTE RESPONDING TISSUES (responses seen during standard therapy) Gut Skin Bone Marrow Mucosa LATE RESPONDING TISSUES (responses seen after end of therapy) Brain Spinal Cord Kidney Lung Bladder Tissue Type Matters Dose (Gy) Surviving Fraction 2016128400 .01 .1 1 Late Responding Tissues Acute Responding Tissues and Many Tumors Physical Dose = Biological Dose
  117. 117. Example • To achieve 50% survival fraction, 250 kV x-ray needs 2 Gy, but the tested particle needs 0.66 Gy only RBE = D250/Dt 2 = 2 / 0.66 = 3 RBE at survival fraction of 0.5 for the tested particle is 3. 2.5.4 RBE
  118. 118. 2.5.4 RBE
  119. 119. http://dmco.ucla.edu/McBride_Lab WMcB2008 Questions on Interaction of Radiation with Biological Matter: what is biological dose? Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca. wmcbride@mednet.ucla.edu
  120. 120. http://dmco.ucla.edu/McBride_Lab WMcB2008 1.The lifetime of radicals in target molecules is about – 10-3 secs – 10-6 secs – 10-9 secs – 10-12 secs #2 – free radicals are highly unstable and reactive
  121. 121. http://dmco.ucla.edu/McBride_Lab WMcB2008 2.Electromagnetic radiation is considered ionizing if it has a photon energy greater than – 1.24 eV – 12.4 eV – 124 eV – 1.24 keV #3 – this is sufficient to break bonds in biological molecules
  122. 122. http://dmco.ucla.edu/McBride_Lab WMcB2008 3.The S.I. unit of absorbed dose is – Becquerel – Sievert – Gray – Roentgen #3 The International System (IS) unit is the Gray, named after the radiobiologist Louis “Hal” Gray who was based in London
  123. 123. http://dmco.ucla.edu/McBride_Lab WMcB2008 4.Which of the following are not charged particles? – Electrons – Neutrons – Protons – Heavy ions – Alpha particles #2 – which is why they are called NEUTRons
  124. 124. http://dmco.ucla.edu/McBride_Lab WMcB2008 5. Which of the following is NOT a characteristic of the indirect action of ionizing radiation – Production of diffusible free radicals – Production of reactive oxygen species – Involvement of anti-oxidant defenses – Causes a change in redox within a cell favoring reduction of constituents #4 the free radicals produced makes ionizing radiation an oxidative stress overall
  125. 125. http://dmco.ucla.edu/McBride_Lab WMcB2008 6. Which of the following is true about the oxygen enhancement ratio – Is the same at all levels of cell survival – Can be measured by the dog-leg in a cell survival curve after single high dose irradiation of tumors – Is the ratio of doses needed for an isoeffect in the absence to the presence of oxygen – Is low for cells in S cell cycle phase compared to cells in G2/M phase #3 responses should be compared by the doses needed for a particular isoeffect. The OER varies with the level of effect eg survival
  126. 126. http://dmco.ucla.edu/McBride_Lab WMcB2008 7. Which of the following is true about Linear Energy Transfer – It is a measure of the biological effectiveness of ionizing radiation – Shows an inverse correlation with the oxygen enhancement ratio – Is maximal at a relative biological effectiveness of 150 keV/micrometer – Is measured in keV/micrometer #4 LET is an average value imparted per unit path length. Because the radiations vary in energy, the LET is not biologically very useful
  127. 127. http://dmco.ucla.edu/McBride_Lab WMcB2008 8.The Relative Biological Effectiveness of a radiation is – Assessed by the dose required for to produce the same effect as 250kVp X-rays – Is the ratio of the dose required of 250 kVp X-rays to that of the test radiation for a given isoeffect – Is directly related to Linear Energy Transfer – Is about 3 for alpha particle radiation #2 - again, measured by isoeffective doses – classically relative to 250kVp x-rays, but often more recently 60Co has been used
  128. 128. http://dmco.ucla.edu/McBride_Lab WMcB2008 9. Which of the following radiobiological phenomena occurring between dose fractions has little or no effect on normal tissue radiation responses? – Repair – Redistribution of cells in the cell cycle – Repopulation – Reoxygenation #4 – Normal tissues are generally considered to be well oxygenated

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