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IMPROVING
THERAPEUTIC RATIO
       RADIOBIOLOGICAL
          BACKGROUND



               DR ARNAB BOSE
               Dept. of Radiotherapy
               NRS Medical College, Kolkata
Introduction
   Radiobiology is a branch of science concerned with the
    action of ionizing radiation on biological tissues and living
    organisms

   Objective of this presentation -
    To understand why ionising radiation can be used to
    treat malignant cells
    To know the type of radiation that does this best
    To identify factors of significance to the success of this
    process
Introduction
   The interaction of radiation with a cell is a matter of
    chance [probability]. If an interaction occurs, the
    damage may not be expressed, in fact damage is more
    frequently repaired
   The initial deposition of energy occurs very quickly
   The radiation is deposited in the cell randomly

    Expression of damage occurs after a latent period,
    ranging from hours to years or even generations

   The DNA is the sensitive target in the cell
Cell Cycle
   The cell proliferation cycle is defined by two well defined
    time periods: Mitosis (M), where division takes place &
    the period of DNA synthesis (S).
   The S and M portions of the cell cycle are separated by
    two periods (gaps) G1 and G2 when, respectively, DNA
    has not yet been synthesized or has been synthesized
    but other metabolic processes are taking place.
   The time between successive divisions (mitoses) is
    called the cell cycle time.
Radiobiology
Cell Cycle
   In general, the G2/M phases are the most radiosensitive
    and late S phase is most radioresistant.
   Transition through the cell cycle is governed by cyclins
    and cyclin-dependent kinases (cdk).
    List of important checkpoints: G1 →S governed by p53,
    Rb, Cyclin D1/Cdk4/6, and Cyclin E/Cdk2 S governed by
    Cyclin A/Cdk2 G2 →M governed by Cyclin B/A/Cdk1
   For a typical mammalian cell, a single fraction of
    radiation (1–2 Gy) results in >1,000 base damage, 1,000
    SSB, and 40 DSBs. DSBs are the most relevant in terms
    of cell-killing
Cell Death
   Cell death of non-proliferating (static) cells is defined as
    the loss of specific function, while for stem cells and
    other cells capable of many divisions it is defined as the
    loss of reproductive integrity (reproductive death).
   A surviving cell that maintains its reproductive integrity
    and proliferates almost indefinitely is said to be
    clonogenic.
    When cells are exposed to ionizing radiation the
    standard physical effects between radiation and the
    atoms or molecules of the cells occur first and the
    possible biological damage to cell functions follows later.
Classification of Radiations in
Radiobiology
   For use in radiobiology and radiation protection the
    physical quantity that is useful for defining the quality of
    an ionizing radiation beam is the linear energy transfer
    (LET).
   The ICRU defines the LET as follows:
    “LET of charged particles in a medium is the quotient dE/
    dl, where dE is the average energy locally imparted to
    the medium by a charged particle of specified energy in
    traversing a distance of dl.”
   Unit usually used for the LET is keV/µm.
   Typical LET values for commonly used radiations are:
     250 kVp X rays: 2 keV/µm. Cobalt-60 gamma rays: 0.3
    keV/µm. 3 MeV X rays: 0.3 keV/µm. 1 MeV electrons:
    0.25 keV/µm.
    LET values for other, less commonly used radiations are:
    14 MeV neutrons: 12 keV/µm. Heavy charged particles:
    100–200 keV/µm. 1 keV electrons: 12.3 keV/µm. 10 keV
    electrons: 2.3 keV/µm.
    X rays and gamma rays are considered low LET
    (sparsely ionizing) radiations, while energetic neutrons,
    protons and heavy charged particles are high LET
    (densely ionizing) radiations. The demarcation value
    between low and high LET is at about 10 keV/µm.
Cell Damage by Radiation
    The biological effects of radiation result mainly from
     damage to the DNA, which is the most critical target
     within the cell

    When directly ionizing radiation is absorbed in biological
     material, the damage to the cell may occur in one of
     two ways:
4.      Direct
5.      Indirect.
Direct Action
   In direct action the radiation interacts directly with the
    critical target in the cell. The atoms of the target itself
    may be ionized or excited through Coulomb interactions,
    leading to the chain of physical and chemical events that
    eventually produce the biological damage.

    Direct action is the dominant process in the interaction
    of high LET particles with biological material.
Indirect Action
   In indirect action the radiation interacts with other
    molecules and atoms (mainly water, since about 80% of
    a cell is composed of water) within the cell to produce
    free radicals, which can, through diffusion in the cell,
    damage the critical target within the cell.

   In interactions of radiation with water, short lived yet
    extremely reactive free radicals such as H2O+ (water ion)
    and OH• (hydroxyl radical) are produced.
   The free radicals in turn can cause damage to the target
    within the cell.
   A free radical is a molecule or atom, which is not
    combined to anything (free) and carries an unpaired
    electron in its outer shell. It is in a state associated with a
    high degree of chemical reactivity.
   If the water molecule is ionised
     H2O = H2O+ + e-
    (H2O is the water molecule ; H2O+ is an ion radical )
   Ion meaning it is electrically charged, because it has lost
    an electron and a radical because it has an unpaired
    electron in the outer shell, making it very reactive.
   Ion radicals have a short life, usually no more than
    10-10 s, before they decay to form free radicals
   Free radicals are not charged, but do have an unpaired
    electron in the outer shell.
   The water ion radical can, for example, do the following:
    H2O+ + H2O = H3O+ + OH*
(H2O+, H3O+ are the ion radicals H2O is a water molecule)
   OH* is a highly reactive hydroxyl radical, with 9
    electrons, therefore one is unpaired.
   Hydroxyl radicals (OH*), are highly reactive and can go
    on to react with DNA. It is estimated that 2/3 of the x-ray
    damage to mammalian DNA is by hydroxyl radicals
Radiobiology
Types of DNA Damage
    DNA damage to the cell can come in several forms:
    1. Base damage/single-strand breaks (SSBs) – repaired
     via base excision repair, not a major contributor to
     radiosensitivity.
    2. Double-strand breaks (DSBs) – repaired via
     homologous recombination repair (in late S/G2, a DNA
     template is available) which is accurate, or non
     homologous end-joining which is error-prone. DSBs are
     a major contributor to radiosensitivity; ~40 DSBs are
     required to kill cell.
    3.Chromosome aberrations – result from unrepaired or
     misrepaired DSBs. Symmetric chromosome damage
     (e.g., translocations) tends to be nonlethal, whereas
     asymmetric damage (e.g., rings) tends to be lethal due
     to the loss of large amounts of DNA.
Radiobiology
Radiobiology
Radiobiology
DNA Damage Repair
Cell Survival Curve
   A cell survival curve describes the relationship between
    the surviving fraction of cells (i.e. the fraction of
    irradiated cells that maintain their reproductive integrity
    (clonogenic cells)) and the absorbed dose.
   Cell survival as a function of radiation dose is graphically
    represented by plotting the surviving fraction on a
    logarithmic scale on the ordinate against dose on a
    linear scale on the abscissa.
   The type of radiation influences the shape of the cell
    survival curve.
   Densely ionizing radiations exhibit a cell survival curve
    that is almost an exponential function of dose, shown by
    an almost straight line on the log–linear plot.
   For sparsely ionizing radiation, however, the curves
    show an initial slope followed by a shoulder region and
    then become nearly straight at higher doses.
Linear Quadratic Model
   During the 1980s the linear-quadratic model has gained
    wide acceptance as a mathematical description of
    biological response to irradiation. The dose range where
    the LQ model is well supported by data is roughly 1–5Gy
    per fraction. Extrapolations made outside this range
    should be done with extreme caution
   It is mainly used for the calculation of treatment
    parameters of schedules supposed to be isoeffective.
   The simplest adequate mathematical description of
    these data is provided by a linear-quadratic function:
   There is a hypothesis considering two types of radiation
    damage

   The first type of damage, responsible for the linear
    component, is assumed to result from a single event.
    This damage is lethal for the cell if it is not or
    insufficiently repaired. The probability to produce such a
    damage is proportional to dose,                 while its
    probability to be repaired insufficiently is assumed to be
    dose independent within the range of clinically relevant
    doses.
   The second type of damage, responsible for the
    quadratic component, is by itself not lethal for the cell. It
    is a so-called sublethal damage.
   Only the combination of two such lesions can yield a
    lethal event for the cell. The probability to produce a
    single sublethal damage is again proportional to dose.
    The probability to produce two of such lesions is
    proportional to the square of dose, i.e.              Again
    the probability of insufficient repair is assumed to be
    dose independent within the range of clinically relevant
    doses.
   Typically, survival curves are continuously bending, with
    a slope that steepens as the dose increases. The ratio α/
    β gives the relative importance of the linear dose term
    and the quadratic dose term for those cells, and controls
    the shape of the survival curve. When α/β is large, the
    linear term predominates, so a plot of log (SF) against d
    is relatively straight, while if α/β is small, the quadratic
    term is more important, giving a plot with greater
    curvature. For cells whose survival curves have a lower
    α/β ratio, doubling the dose leads to more than doubling
    of the effect on log (SF). Such cells will be particularly
    sensitive to changes in fraction size when radiation is
    given as fractionated schedule.
   The earlier multitarget single
    hit model described the slope
    of the survival curve by D0
    (the dose to reduce survival to
    37% of its value at any point
    on the final near exponential
    portion of the curve) and the
    extrapolation number n (the
    point of intersection of the
    slope on the log survival axis).
    Dq was the quasi-threshold
    dose. However, this model
    does not have any current
    biological basis.
   The linear quadratic model
    assuming that there are two
    components to cell kill by
    radiation
    where
   S(D) is the fraction of cells
    surviving a dose D; alpha is a
    constant describing the initial
    slope of the cell survival curve;
    beta is a smaller constant
    describing the quadratic
    component of cell killing.
   The ratio       gives the dose
    at which the linear and
    quadratic components of cell
    killing are equal (8 Gy in the
    example shown)
   High α/β [straighter curve], characteristic of cell with little
    repair capability e.g. tumour cells [from 5 - 20 Gy]
   Low α/β [more curved], characteristic of high repair
    potential e.g. late responding normal tissue [1-4 Gy]
   This difference in cell survival curves provides rationale
    for fractionated radiation therapy treatment and explains
    therapy treatment and explains radiobiological
    advantage
   The biological equivalent dose (BED) refers to the
    effective total absorbed dose (in Gy) for a given
    fractionation scheme if it were given by standard
    fractionation (1.8–2.0 Gy/day).
   BED = nd[1+d/(a(alpha)b(beta))], where n = number of
    fractions and d = the dose per fraction.
Radiobiology
    In the past few decades great efforts have been made
     to apply radiobiological concepts to design safer and
     more effective therapeutic strategies

     Withers (1975) suggested four basic mechanisms that
      contribute to the diverse reactions of different tissues to
      irradiation:
     Re distribution of cells in the cell cycle
     Re oxygenation of hypoxic cells in the tumor
     Repair of cellular radiation damage
     Re population of surviving cells during radiotherapy
    treatment
Re distribution
   The radio sensitivity of cells varies considerably when
    they transit through the cell cycle
   Radiation-induced partial synchrony is a consequence
    from selective killing of cells in a sensitive phase of the
    cell cycle as well as by progression delay in late G2-
    phase
   Cells surviving irradiation are preferentially those which
    were in relatively resistant phases during fractionated
    radiotherapy
Radiobiology
Re distribution
   Redistribution of surviving cells within the mitotic cycle
    results in self-sensitization of proliferating cell
    populations
   This process, however, only affects cells that divide
    frequently during the 4 to 8 weeks commonly taken to
    administer a course of curative radiotherapy, but there is
    little or no such an effect in slowly or non-proliferating
    tissues
    Assuming a proliferating tumor surrounded by non-
    proliferating normal tissue, small doses per fraction and
    time intervals sufficient for redistribution, should result in
    an improved therapeutic differential
Re oxygenation
   Hypoxic cells are about 2.5 to 3.0 times more resistant to
    X-irradiation than euoxic cells
    In tumors, hypoxic cells arise because of imbalances
    between the rate of production of new cells and the
    vascularization of the tumor
   Cells are well oxygenated to a distance of about 100 mm
    from a capillary. At greater distances partial oxygen
    pressure is so low that cells die and later become
    necrotic. At intermediate distances, the oxygen
    concentration is high enough to keep cells viable but at
    the same time low enough to increase their resistance to
    X-rays
   These chronically hypoxic cells might limit radio curability
    of the tumor
   Oxygen “fixes” the free radical damage to DNA caused
    by X-rays. For this effect to be observed, oxygen must
    be present in the target at the time of irradiation or
    microseconds afterwards. Generally, at least 2% oxygen
    concentration results in maximum radiosensitization.
   In addition to rendering cells more radioresistant, both
    chronic and acute hypoxia also contribute to malignant
    and metastatic progression.
Re oxygenation
   Irradiation preferentially sterilizes cells that are
    adequately oxygenated. If a mixed population is
    irradiated, a biphasic dose response curve results which
    is steep at low doses but shallower at higher doses due
    to preferential survival of the more resistant hypoxic cells
   Between fractions hypoxic cells may be re oxygenated
    which increases radio curability of the tumor

   There had been many attempts to overcome hypoxia by
    specific radio sensitizers, by improving oxygenation
    pharmacologically or by irradiation under hyperbaric
    oxygen pressure or by breathing carbogen
Radiobiology
Oxygen Enhancement Ratio
   The ratio of doses without and with oxygen (hypoxic versus well
    oxygenated cells) to produce the same biological effect is called
    the oxygen enhancement ratio (OER).

   OER =     Dose to produce a given effect without oxygen
              Dose to produce the same effect with oxygen

   The OER for X rays and electrons is about three at high doses
    and falls to about two for doses of 1–2 Gy.

   The OER decreases as the LET increases and approaches
    OER = 1 at about LET = 150 keV/mm,
OER and LET
Relative Biological Effectiveness
   The relative biological effectiveness (RBE) compares the
    dose of test radiation to the dose of standard radiation to
    produce the same biological effect. The standard
    radiation has been taken as 250 kVp X rays for historical
    reasons, but is now recommended to be 60Co g rays.
    RBE = Dose from standard radiation to produce a given biological effect
                Dose from test radiation to produce the same biological effect

   The RBE varies not only with the type of radiation but
    also with the type of cell or tissue, biologic effect under
    investigation, dose, dose rate and fractionation.
   In general, the RBE increases with the LET to reach a
    maximum RBE of 3–8 (depending on the level of cell kill)
    at LET ª 200 keV/m and then decreases because of
    energy overkill
RBE and LET
Repair
   The influence of repair of molecular injury on cell survival
    and the response of tissue to irradiation can be inferred
    from in vitro survival curves and from changes in the
    total dose required to produce a certain level of injury as
    a function of changes in dose per fraction, i.e. from
    isoeffect curves

   Fractionation responses can be modeled in terms of two
    types of radiation-induced cellular injury,
    one resulting in a logarithmic decline in target cell
    survival that is linear with dose , and
    another in which the decline increases proportionally to
    the square of the dose
Repair
   The linear component is assumed to reflect cell kill from
    a single molecular event, while the quadratic component
    might be due to two independent so-called sub lethal
    events that have to interact to become lethal for the cell

   Sub lethal events may be repaired with half-times in the
    order of 20 minutes to some hours

   If a dose is split into two fractions with a time interval of
    several hours then a substantial portion of sub lethal
    damage induced by the first fraction is already repaired
    when the second fraction is given
Repair
   Thus the likelihood for interaction of two sub lethal
    damages is diminished, resulting in less cell kill due to
    the quadratic component , as compared to the same
    dose given in a single session
   Thus not only total dose but also the number of
    fractions or the dose per fraction, respectively,
    determine the magnitude of the radiation effect.
   If radiation dose is
    delivered in a series of
    equal fractions (F),
    separated by a time
    interval that allows
    complete SLD repair, the
    effective dose survival
    curve becomes an
    exponential function of
    dose Shoulder of the
    survival curve is repeated
    many times; the effective
    survival curve is a straight
    line from the origin through
    point on the single-dose
    survival curve
    corresponding to the daily
    dose (F)
   D0 (the reciprocal of the
    slope), has a value close
    to 3 Gy for human cells
   In mammalian cells 3 types of radiation damage
    described :
     Lethal damage
     Sub lethal damage
     Potentially lethal damage

   Lethal Damage - Irreversible and irreparable
                        Leads to cell death
   Potentially Lethal Damage - Component of radiation
                  damage that can be modified by post
    irradiation environmental conditions
   Sub lethal Damage -
    Under normal circumstances can be repaired in hours
    usually considered to be complete within 24 h
    If additional sub lethal damage added within this time
    then can interact to form lethal damage

   Sub lethal damage repair observed as an increase in
    survival if a dose of radiation is split into 2 equal
    fractions separated by a time interval fractions
If dose is split into 2
 fractions separated by a
 time interval more cells
 survive than for the
 same total dose given
 in a single fraction,
 because the shoulder of
 the curve must be
 repeated each time.
    As time interval between 2 F
    increases see rapid increase
    in SF, usually complete within
    2 h in culture but longer in
    vivo, particularly for some
    late responding tissues
     As time interval increases
    may see dip in SF due to
    movement of surviving cells
    through the cell cycle; only
    observed in cycling cells
   If time interval exceeds the
    cell cycle, see increase in SF
    due to proliferation
   Conventional fractionation is explained as follows:
    division of dose into multiple fractions spares normal
    tissues through repair of sublethal damage between
    dose fractions and repopulation of cells. The former is
    greater for late reacting tissues and the latter for early
    reacting tissues.
    Concurrently, fractionation increases tumour damage
    through reoxygenation and redistribution of tumour cells.
   A balance is achieved between the response of tumour
    and early and late reacting normal tissues, so that small
    doses per fraction spare late reactions preferentially, and
    a reasonable schedule duration allows regeneration of
    early reacting tissues and tumour reoxygenation to likely
    occur.
   The current standard fractionation is based on five daily
    treatments per week and a total treatment time of
    several weeks. This regimen reflects the practical
    aspects of dose delivery to a patient, successful
    outcome of patient treatments and convenience to the
    staff delivering the treatment.

   Conventional fractionation consists of daily fractions of
    1.8 to 2.0 Gy, 5 days per week; the total dose is
    determined by the tumor being treated and the tolerance
    of critical normal tissues in the target volume (usually 60
    to 75 Gy).
   Hyperfractionation uses an increased total dose, with the
    size of dose per fraction significantly reduced and the
    number of fractions increased; overall time is relatively
    unchanged
   In accelerated fractionation, overall time is significantly
    reduced; the number of fractions, total dose, and size of
    dose per fraction are unchanged or somewhat reduced,
    depending on the overall time reduction
    Accelerated hyperfractionation has features of both
    hyperfractionation and accelerated fractionation.
   Hypofractionation uses decreased number of fractions
    with increased fraction size
   Concomitant boost is an additional dose delivered 1 or
    more times per week to selected target volumes (i.e.,
    gross tumor volume) through smaller field(s), along with
    the conventional dose to larger irradiated volumes.
   To achieve an increase in tolerance of late-responding
    tissues through dose fractionation, the time interval
    between the dose fractions must be long enough (6
    hours) to allow cellular repair to approach completion.
Radiobiology
   Dose-rate effect refers to repair of SLD that occurs
    during long radiation exposure. Smaller doses per
    fraction lead to a repeat of the shoulder on the survival
    curve. Continuous low-date irradiation (such as I-125
    seeds) would be considered an infinite number of
    infinitely small fractions leading to a survival curve with
    no shoulder and far shallower compared to acute
    exposures.
   The inverse-dose effect occurs when decreasing dose
    rate actually increases cell killing. This is because higher
    dose rates (HDRs) would cause arrest in radioresistant
    phases of the cell cycle
   Together with the total dose and fractionation
    schedule, target volume is a major variable in
    radiotherapy. For a given fractionation regimen,
    higher doses can usually be given when volumes at
    the same site are small rather than large
   Volume is also an important determinant of normal
    tissue response to a given dose, first because larger
    volumes provide less opportunity for tissues to draw
    on their ‘functional reserve’ and second because
    larger irradiated volumes make it more likely that a
    critical volume element will exceed some upper
    dose limit
Re population
   Early reacting tissues like skin and mucosa counteract
    cell depletion by repopulation, usually after a delay that
    depends on the degree of denudation. Cells in late
    reacting tissues proliferate very slowly if at all.
    Prolongation of treatment time might spare acute normal
    tissue damage but not late reactions
   Proliferation of surviving tumor cells during treatment is
    one of the main factors that determine the outcome of
    fractionated radiotherapy
   An increase in the number of viable tumor cells between
    fractions or during treatment interruptions is assumed to
    result in a failure to control the tumor. Irradiation
    treatment should be performed in as short a time as
    possible
Radiobiology
   Radiation kills cells randomly, which means that each
    tumour cell has the same probability of surviving
    irradiation, that probability depending on the given dose.
   SF2 is the probability of any cell surviving a single dose
    of 2 Gy, the most commonly used fraction size.
   Generally, after F fractions, the final survival probability
    will be (SF2)F.
Radiobiology
The End

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Radiobiology

  • 1. IMPROVING THERAPEUTIC RATIO RADIOBIOLOGICAL BACKGROUND DR ARNAB BOSE Dept. of Radiotherapy NRS Medical College, Kolkata
  • 2. Introduction  Radiobiology is a branch of science concerned with the action of ionizing radiation on biological tissues and living organisms  Objective of this presentation - To understand why ionising radiation can be used to treat malignant cells To know the type of radiation that does this best To identify factors of significance to the success of this process
  • 3. Introduction  The interaction of radiation with a cell is a matter of chance [probability]. If an interaction occurs, the damage may not be expressed, in fact damage is more frequently repaired  The initial deposition of energy occurs very quickly  The radiation is deposited in the cell randomly  Expression of damage occurs after a latent period, ranging from hours to years or even generations  The DNA is the sensitive target in the cell
  • 4. Cell Cycle  The cell proliferation cycle is defined by two well defined time periods: Mitosis (M), where division takes place & the period of DNA synthesis (S).  The S and M portions of the cell cycle are separated by two periods (gaps) G1 and G2 when, respectively, DNA has not yet been synthesized or has been synthesized but other metabolic processes are taking place.  The time between successive divisions (mitoses) is called the cell cycle time.
  • 6. Cell Cycle  In general, the G2/M phases are the most radiosensitive and late S phase is most radioresistant.  Transition through the cell cycle is governed by cyclins and cyclin-dependent kinases (cdk).  List of important checkpoints: G1 →S governed by p53, Rb, Cyclin D1/Cdk4/6, and Cyclin E/Cdk2 S governed by Cyclin A/Cdk2 G2 →M governed by Cyclin B/A/Cdk1  For a typical mammalian cell, a single fraction of radiation (1–2 Gy) results in >1,000 base damage, 1,000 SSB, and 40 DSBs. DSBs are the most relevant in terms of cell-killing
  • 7. Cell Death  Cell death of non-proliferating (static) cells is defined as the loss of specific function, while for stem cells and other cells capable of many divisions it is defined as the loss of reproductive integrity (reproductive death).  A surviving cell that maintains its reproductive integrity and proliferates almost indefinitely is said to be clonogenic.  When cells are exposed to ionizing radiation the standard physical effects between radiation and the atoms or molecules of the cells occur first and the possible biological damage to cell functions follows later.
  • 8. Classification of Radiations in Radiobiology  For use in radiobiology and radiation protection the physical quantity that is useful for defining the quality of an ionizing radiation beam is the linear energy transfer (LET).  The ICRU defines the LET as follows: “LET of charged particles in a medium is the quotient dE/ dl, where dE is the average energy locally imparted to the medium by a charged particle of specified energy in traversing a distance of dl.”  Unit usually used for the LET is keV/µm.
  • 9. Typical LET values for commonly used radiations are: 250 kVp X rays: 2 keV/µm. Cobalt-60 gamma rays: 0.3 keV/µm. 3 MeV X rays: 0.3 keV/µm. 1 MeV electrons: 0.25 keV/µm. LET values for other, less commonly used radiations are: 14 MeV neutrons: 12 keV/µm. Heavy charged particles: 100–200 keV/µm. 1 keV electrons: 12.3 keV/µm. 10 keV electrons: 2.3 keV/µm.  X rays and gamma rays are considered low LET (sparsely ionizing) radiations, while energetic neutrons, protons and heavy charged particles are high LET (densely ionizing) radiations. The demarcation value between low and high LET is at about 10 keV/µm.
  • 10. Cell Damage by Radiation  The biological effects of radiation result mainly from damage to the DNA, which is the most critical target within the cell  When directly ionizing radiation is absorbed in biological material, the damage to the cell may occur in one of two ways: 4. Direct 5. Indirect.
  • 11. Direct Action  In direct action the radiation interacts directly with the critical target in the cell. The atoms of the target itself may be ionized or excited through Coulomb interactions, leading to the chain of physical and chemical events that eventually produce the biological damage.  Direct action is the dominant process in the interaction of high LET particles with biological material.
  • 12. Indirect Action  In indirect action the radiation interacts with other molecules and atoms (mainly water, since about 80% of a cell is composed of water) within the cell to produce free radicals, which can, through diffusion in the cell, damage the critical target within the cell.  In interactions of radiation with water, short lived yet extremely reactive free radicals such as H2O+ (water ion) and OH• (hydroxyl radical) are produced.  The free radicals in turn can cause damage to the target within the cell.
  • 13. A free radical is a molecule or atom, which is not combined to anything (free) and carries an unpaired electron in its outer shell. It is in a state associated with a high degree of chemical reactivity.  If the water molecule is ionised H2O = H2O+ + e- (H2O is the water molecule ; H2O+ is an ion radical )  Ion meaning it is electrically charged, because it has lost an electron and a radical because it has an unpaired electron in the outer shell, making it very reactive.  Ion radicals have a short life, usually no more than 10-10 s, before they decay to form free radicals
  • 14. Free radicals are not charged, but do have an unpaired electron in the outer shell.  The water ion radical can, for example, do the following: H2O+ + H2O = H3O+ + OH* (H2O+, H3O+ are the ion radicals H2O is a water molecule)  OH* is a highly reactive hydroxyl radical, with 9 electrons, therefore one is unpaired.  Hydroxyl radicals (OH*), are highly reactive and can go on to react with DNA. It is estimated that 2/3 of the x-ray damage to mammalian DNA is by hydroxyl radicals
  • 16. Types of DNA Damage  DNA damage to the cell can come in several forms: 1. Base damage/single-strand breaks (SSBs) – repaired via base excision repair, not a major contributor to radiosensitivity. 2. Double-strand breaks (DSBs) – repaired via homologous recombination repair (in late S/G2, a DNA template is available) which is accurate, or non homologous end-joining which is error-prone. DSBs are a major contributor to radiosensitivity; ~40 DSBs are required to kill cell. 3.Chromosome aberrations – result from unrepaired or misrepaired DSBs. Symmetric chromosome damage (e.g., translocations) tends to be nonlethal, whereas asymmetric damage (e.g., rings) tends to be lethal due to the loss of large amounts of DNA.
  • 21. Cell Survival Curve  A cell survival curve describes the relationship between the surviving fraction of cells (i.e. the fraction of irradiated cells that maintain their reproductive integrity (clonogenic cells)) and the absorbed dose.  Cell survival as a function of radiation dose is graphically represented by plotting the surviving fraction on a logarithmic scale on the ordinate against dose on a linear scale on the abscissa.
  • 22. The type of radiation influences the shape of the cell survival curve.  Densely ionizing radiations exhibit a cell survival curve that is almost an exponential function of dose, shown by an almost straight line on the log–linear plot.  For sparsely ionizing radiation, however, the curves show an initial slope followed by a shoulder region and then become nearly straight at higher doses.
  • 23. Linear Quadratic Model  During the 1980s the linear-quadratic model has gained wide acceptance as a mathematical description of biological response to irradiation. The dose range where the LQ model is well supported by data is roughly 1–5Gy per fraction. Extrapolations made outside this range should be done with extreme caution  It is mainly used for the calculation of treatment parameters of schedules supposed to be isoeffective.  The simplest adequate mathematical description of these data is provided by a linear-quadratic function:
  • 24. There is a hypothesis considering two types of radiation damage  The first type of damage, responsible for the linear component, is assumed to result from a single event. This damage is lethal for the cell if it is not or insufficiently repaired. The probability to produce such a damage is proportional to dose, while its probability to be repaired insufficiently is assumed to be dose independent within the range of clinically relevant doses.
  • 25. The second type of damage, responsible for the quadratic component, is by itself not lethal for the cell. It is a so-called sublethal damage.  Only the combination of two such lesions can yield a lethal event for the cell. The probability to produce a single sublethal damage is again proportional to dose. The probability to produce two of such lesions is proportional to the square of dose, i.e. Again the probability of insufficient repair is assumed to be dose independent within the range of clinically relevant doses.
  • 26. Typically, survival curves are continuously bending, with a slope that steepens as the dose increases. The ratio α/ β gives the relative importance of the linear dose term and the quadratic dose term for those cells, and controls the shape of the survival curve. When α/β is large, the linear term predominates, so a plot of log (SF) against d is relatively straight, while if α/β is small, the quadratic term is more important, giving a plot with greater curvature. For cells whose survival curves have a lower α/β ratio, doubling the dose leads to more than doubling of the effect on log (SF). Such cells will be particularly sensitive to changes in fraction size when radiation is given as fractionated schedule.
  • 27. The earlier multitarget single hit model described the slope of the survival curve by D0 (the dose to reduce survival to 37% of its value at any point on the final near exponential portion of the curve) and the extrapolation number n (the point of intersection of the slope on the log survival axis). Dq was the quasi-threshold dose. However, this model does not have any current biological basis.
  • 28. The linear quadratic model assuming that there are two components to cell kill by radiation where  S(D) is the fraction of cells surviving a dose D; alpha is a constant describing the initial slope of the cell survival curve; beta is a smaller constant describing the quadratic component of cell killing.  The ratio gives the dose at which the linear and quadratic components of cell killing are equal (8 Gy in the example shown)
  • 29. High α/β [straighter curve], characteristic of cell with little repair capability e.g. tumour cells [from 5 - 20 Gy]  Low α/β [more curved], characteristic of high repair potential e.g. late responding normal tissue [1-4 Gy]  This difference in cell survival curves provides rationale for fractionated radiation therapy treatment and explains therapy treatment and explains radiobiological advantage  The biological equivalent dose (BED) refers to the effective total absorbed dose (in Gy) for a given fractionation scheme if it were given by standard fractionation (1.8–2.0 Gy/day).  BED = nd[1+d/(a(alpha)b(beta))], where n = number of fractions and d = the dose per fraction.
  • 31. In the past few decades great efforts have been made to apply radiobiological concepts to design safer and more effective therapeutic strategies  Withers (1975) suggested four basic mechanisms that contribute to the diverse reactions of different tissues to irradiation:  Re distribution of cells in the cell cycle  Re oxygenation of hypoxic cells in the tumor  Repair of cellular radiation damage  Re population of surviving cells during radiotherapy treatment
  • 32. Re distribution  The radio sensitivity of cells varies considerably when they transit through the cell cycle  Radiation-induced partial synchrony is a consequence from selective killing of cells in a sensitive phase of the cell cycle as well as by progression delay in late G2- phase  Cells surviving irradiation are preferentially those which were in relatively resistant phases during fractionated radiotherapy
  • 34. Re distribution  Redistribution of surviving cells within the mitotic cycle results in self-sensitization of proliferating cell populations  This process, however, only affects cells that divide frequently during the 4 to 8 weeks commonly taken to administer a course of curative radiotherapy, but there is little or no such an effect in slowly or non-proliferating tissues  Assuming a proliferating tumor surrounded by non- proliferating normal tissue, small doses per fraction and time intervals sufficient for redistribution, should result in an improved therapeutic differential
  • 35. Re oxygenation  Hypoxic cells are about 2.5 to 3.0 times more resistant to X-irradiation than euoxic cells  In tumors, hypoxic cells arise because of imbalances between the rate of production of new cells and the vascularization of the tumor  Cells are well oxygenated to a distance of about 100 mm from a capillary. At greater distances partial oxygen pressure is so low that cells die and later become necrotic. At intermediate distances, the oxygen concentration is high enough to keep cells viable but at the same time low enough to increase their resistance to X-rays  These chronically hypoxic cells might limit radio curability of the tumor
  • 36. Oxygen “fixes” the free radical damage to DNA caused by X-rays. For this effect to be observed, oxygen must be present in the target at the time of irradiation or microseconds afterwards. Generally, at least 2% oxygen concentration results in maximum radiosensitization.  In addition to rendering cells more radioresistant, both chronic and acute hypoxia also contribute to malignant and metastatic progression.
  • 37. Re oxygenation  Irradiation preferentially sterilizes cells that are adequately oxygenated. If a mixed population is irradiated, a biphasic dose response curve results which is steep at low doses but shallower at higher doses due to preferential survival of the more resistant hypoxic cells  Between fractions hypoxic cells may be re oxygenated which increases radio curability of the tumor  There had been many attempts to overcome hypoxia by specific radio sensitizers, by improving oxygenation pharmacologically or by irradiation under hyperbaric oxygen pressure or by breathing carbogen
  • 39. Oxygen Enhancement Ratio  The ratio of doses without and with oxygen (hypoxic versus well oxygenated cells) to produce the same biological effect is called the oxygen enhancement ratio (OER).  OER = Dose to produce a given effect without oxygen Dose to produce the same effect with oxygen  The OER for X rays and electrons is about three at high doses and falls to about two for doses of 1–2 Gy.  The OER decreases as the LET increases and approaches OER = 1 at about LET = 150 keV/mm,
  • 41. Relative Biological Effectiveness  The relative biological effectiveness (RBE) compares the dose of test radiation to the dose of standard radiation to produce the same biological effect. The standard radiation has been taken as 250 kVp X rays for historical reasons, but is now recommended to be 60Co g rays.  RBE = Dose from standard radiation to produce a given biological effect Dose from test radiation to produce the same biological effect  The RBE varies not only with the type of radiation but also with the type of cell or tissue, biologic effect under investigation, dose, dose rate and fractionation.  In general, the RBE increases with the LET to reach a maximum RBE of 3–8 (depending on the level of cell kill) at LET ª 200 keV/m and then decreases because of energy overkill
  • 43. Repair  The influence of repair of molecular injury on cell survival and the response of tissue to irradiation can be inferred from in vitro survival curves and from changes in the total dose required to produce a certain level of injury as a function of changes in dose per fraction, i.e. from isoeffect curves  Fractionation responses can be modeled in terms of two types of radiation-induced cellular injury, one resulting in a logarithmic decline in target cell survival that is linear with dose , and another in which the decline increases proportionally to the square of the dose
  • 44. Repair  The linear component is assumed to reflect cell kill from a single molecular event, while the quadratic component might be due to two independent so-called sub lethal events that have to interact to become lethal for the cell  Sub lethal events may be repaired with half-times in the order of 20 minutes to some hours  If a dose is split into two fractions with a time interval of several hours then a substantial portion of sub lethal damage induced by the first fraction is already repaired when the second fraction is given
  • 45. Repair  Thus the likelihood for interaction of two sub lethal damages is diminished, resulting in less cell kill due to the quadratic component , as compared to the same dose given in a single session  Thus not only total dose but also the number of fractions or the dose per fraction, respectively, determine the magnitude of the radiation effect.
  • 46. If radiation dose is delivered in a series of equal fractions (F), separated by a time interval that allows complete SLD repair, the effective dose survival curve becomes an exponential function of dose Shoulder of the survival curve is repeated many times; the effective survival curve is a straight line from the origin through point on the single-dose survival curve corresponding to the daily dose (F)  D0 (the reciprocal of the slope), has a value close to 3 Gy for human cells
  • 47. In mammalian cells 3 types of radiation damage described : Lethal damage Sub lethal damage Potentially lethal damage  Lethal Damage - Irreversible and irreparable Leads to cell death  Potentially Lethal Damage - Component of radiation damage that can be modified by post irradiation environmental conditions
  • 48. Sub lethal Damage - Under normal circumstances can be repaired in hours usually considered to be complete within 24 h If additional sub lethal damage added within this time then can interact to form lethal damage  Sub lethal damage repair observed as an increase in survival if a dose of radiation is split into 2 equal fractions separated by a time interval fractions
  • 49. If dose is split into 2 fractions separated by a time interval more cells survive than for the same total dose given in a single fraction, because the shoulder of the curve must be repeated each time.
  • 50. As time interval between 2 F increases see rapid increase in SF, usually complete within 2 h in culture but longer in vivo, particularly for some late responding tissues  As time interval increases may see dip in SF due to movement of surviving cells through the cell cycle; only observed in cycling cells  If time interval exceeds the cell cycle, see increase in SF due to proliferation
  • 51. Conventional fractionation is explained as follows: division of dose into multiple fractions spares normal tissues through repair of sublethal damage between dose fractions and repopulation of cells. The former is greater for late reacting tissues and the latter for early reacting tissues.  Concurrently, fractionation increases tumour damage through reoxygenation and redistribution of tumour cells.  A balance is achieved between the response of tumour and early and late reacting normal tissues, so that small doses per fraction spare late reactions preferentially, and a reasonable schedule duration allows regeneration of early reacting tissues and tumour reoxygenation to likely occur.
  • 52. The current standard fractionation is based on five daily treatments per week and a total treatment time of several weeks. This regimen reflects the practical aspects of dose delivery to a patient, successful outcome of patient treatments and convenience to the staff delivering the treatment.  Conventional fractionation consists of daily fractions of 1.8 to 2.0 Gy, 5 days per week; the total dose is determined by the tumor being treated and the tolerance of critical normal tissues in the target volume (usually 60 to 75 Gy).
  • 53. Hyperfractionation uses an increased total dose, with the size of dose per fraction significantly reduced and the number of fractions increased; overall time is relatively unchanged  In accelerated fractionation, overall time is significantly reduced; the number of fractions, total dose, and size of dose per fraction are unchanged or somewhat reduced, depending on the overall time reduction  Accelerated hyperfractionation has features of both hyperfractionation and accelerated fractionation.  Hypofractionation uses decreased number of fractions with increased fraction size
  • 54. Concomitant boost is an additional dose delivered 1 or more times per week to selected target volumes (i.e., gross tumor volume) through smaller field(s), along with the conventional dose to larger irradiated volumes.  To achieve an increase in tolerance of late-responding tissues through dose fractionation, the time interval between the dose fractions must be long enough (6 hours) to allow cellular repair to approach completion.
  • 56. Dose-rate effect refers to repair of SLD that occurs during long radiation exposure. Smaller doses per fraction lead to a repeat of the shoulder on the survival curve. Continuous low-date irradiation (such as I-125 seeds) would be considered an infinite number of infinitely small fractions leading to a survival curve with no shoulder and far shallower compared to acute exposures.  The inverse-dose effect occurs when decreasing dose rate actually increases cell killing. This is because higher dose rates (HDRs) would cause arrest in radioresistant phases of the cell cycle
  • 57. Together with the total dose and fractionation schedule, target volume is a major variable in radiotherapy. For a given fractionation regimen, higher doses can usually be given when volumes at the same site are small rather than large  Volume is also an important determinant of normal tissue response to a given dose, first because larger volumes provide less opportunity for tissues to draw on their ‘functional reserve’ and second because larger irradiated volumes make it more likely that a critical volume element will exceed some upper dose limit
  • 58. Re population  Early reacting tissues like skin and mucosa counteract cell depletion by repopulation, usually after a delay that depends on the degree of denudation. Cells in late reacting tissues proliferate very slowly if at all. Prolongation of treatment time might spare acute normal tissue damage but not late reactions  Proliferation of surviving tumor cells during treatment is one of the main factors that determine the outcome of fractionated radiotherapy  An increase in the number of viable tumor cells between fractions or during treatment interruptions is assumed to result in a failure to control the tumor. Irradiation treatment should be performed in as short a time as possible
  • 60. Radiation kills cells randomly, which means that each tumour cell has the same probability of surviving irradiation, that probability depending on the given dose.  SF2 is the probability of any cell surviving a single dose of 2 Gy, the most commonly used fraction size.  Generally, after F fractions, the final survival probability will be (SF2)F.