LET, RBE & OER - dr vandana

OER, LET and RBE Presented By: Dr. Vandana Dept. of Radiotherapy CSMMU, Lucknow

Oxygen Enhancement Ratio (OER) 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow

OER The oxygen enhancement ratio (OER) is the ratio of doses under hypoxic to aerated conditions that produce the same biologic effect. The presence or absence of molecular oxygen dramatically influences the biologic effect of x-rays. Oxygen presence (aerated cells) increases radiation effectiveness for cell killing. Lack of oxygen (hypoxic cells) results in more radio resistant cells. 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow

Nature of the Oxygen Effect 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow Surviving Fraction Cells are much more sensitive to x-rays in the presence of molecular oxygen than in its absence (i.e., under hypoxia). The ratio of doses under hypoxic to aerated conditions necessary to produce the same level of cell killing is called the oxygen enhancement ratio (OER).

Oxygen Effect 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow To produce its effect, molecular oxygen must be present during the radiation exposure or at least during the lifetime of the free radicals generated by the radiation. Oxygen “fixes” (i.e., makes permanent) the damage produced by free radicals. In the absence of oxygen , damage produced by the indirect action may be repaired .

Oxygen Fixation 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow CH 3 functional group CH 2 • free radical, unpaired electron Generally, the free-radical reactions go like this: CH 2 • + O 2 CH 2 O 2  an organic peroxide “fixes” the indirect damage ion pairs free radicals (oxygen has no impact on direct damage)

Radio-sensitivity and O 2 Concentration Most of the change of sensitivity occurs as the oxygen tension increases from 0 to 30 mm Hg. A further increase of oxygen content has little further effect. A relative radio-sensitivity halfway between anoxia and full oxygenation occurs for a pO 2 of about 3 mm Hg, which corresponds to a concentration of about 0.5% oxygen . 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow Fig: The dependence of radio-sensitivity on oxygen concentration

OER Effect OER varies from 2-3, increasing with dose Low-LET radiations oxygen effect is more pronounced High-LET radiations oxygen effect is non-existent (OER = 1) 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow Low-LET radiation

Other Radiations and the OER 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow 0.001 0.01 High-LET radiation Dose, Gy 0.001 0.1 0.01 1.0 1.0 2.0 0 3.0 Dose, Gy  particles OER = 1.0 0.1 1.0 0 6 2 4 OER = 1.6 15 MeV Neutrons Hypoxic Aerated

Linear Energy Transfer (LET) 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow

LET LET can be defined as “ The energy deposited per unit track ” Unit is KeV/  m The linear energy transfer (LET) of charged particles in the medium is the quotient of dE/dx, where dE is the average energy locally imparted to the medium by a charged particle in traversing a distance of dx. 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow

On the following diagram, each dot represents a unit of energy deposited. As you see: Alpha particles impart a large amount of energy in a short distance (densely ionizing) . Beta particles impart less energy than alpha, but are more penetrating. Gamma rays impart energy sparsely and are the most penetrating. dispersion of energy low LET (  , x, ~  ) high LET (  , n, p) air tissue incident radiation greater radiotoxicity LET = linear energy transfer

Typical LET values 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow Radiation Linear Energy Transfer ( keV/ µ m ) Cobalt-60 γ -rays 0.2 250-kV x-rays 2.0 10-MeV protons 4.7 150-MeV proton 0.5 14-MeV neutrons Track Avg. 12 Energy Avg. 100 2.5-MeV α -particles 166 2-GeV Fe ions (space radiation ) 1000

The Optimal LET 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow LET of about 100 keV/ μ m 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 Double Strand Breaks(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.

Effect of LET on cell survival Fig: 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.

09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow Fig. : Oxygen enhancement ratio as a function of linear energy transfer. At low LET, corresponding to x- or γ-rays, the OER is between 2.5 and 3; As the LET increases, the OER falls slowly at first, until the LET exceeds about 60 keV/µm, after which the OER falls rapidly and reaches unity by the time the LET has reached about 200 keV/µm OER and LET

Relative Biologic Effectiveness (RBE) 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow

RBE In comparing different type of radiations , x-rays are used as the standard. Relative Biologic Effectiveness (RBE) of radiation for producing a given biological effect is given as below: Dose in Gy from 250 KeV X-rays Dose in Gy from another radiation source to produce the same biologic response RBE =

RBE The amount or quantity of radiation is expressed in terms of the absorbed dose, a physical quantity with the unit of Gray or Rad. Absorbed dose is a measure of energy absorbed per unit mass of tissue. Equal doses of different types of radiation do not produce equal biologic effects. One gray of neutrons produces a greater biologic effect than 1 gray of X-rays . The key to the difference lies in the pattern of energy deposition. 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow

Factors that determine RBE Biologic system or endpoint Dose level and the number of fractions Dose Rate Radiation quality (LET)

Biologic system or endpoint RBE varies according to the tissue or endpoint studied. It has a marked influence on the RBE values obtained. RBE values are high for tissues that accumulate and repair a great deal of Sub-Lethal Damage (SLD) and low for those that do not repair SLD.

RBE for different cells and tissues Figure below illustrates the difference in intrinsic radiosensitivity among various types of cells: Fig: Survival curves for various types of Clonogenic mammalian cells irradiated with 300 kV X-rays or 15-MeV neutrons. Variation in radiosensitivity among different cell lines is markedly less for neutrons than for x-rays. Cells characterized by x-ray survival curve with a large shoulder, indicating that they can accumulate and repair a large amount of sub-lethal radiation damage, show larger RBE for neutrons. Conversely, cells for which x-ray survival curve has little if any shoulder exhibit smaller neutron RBE values.

End Point LD 50 of X-rays (250-kV) in causing plant deaths is 6 Gy (600 rad) LD 50 of neutrons in causing plant deaths is 4 Gy (400 rad) The RBE of neutrons compared with x-rays is then simply the ratio of 6:4 which is 1.5 . To measure the RBE of some test radiation, one first choose a biological system in which the effect of radiations may be scored quantitatively as well as choose an end point. For Example: If We are measuring the RBE of fast neutrons compared with 250-kV X-rays, using the lethality of plant seedlings as a test system, groups of plants are exposed to a range of either X-rays or neutron doses. Note: LD 50 is dose of radiation that result in death of half of the plants in a group.

Figure: shows survival curves obtained if mammalian cells in culture are exposed to a range of doses of either fast neutrons or 250-kV X-rays. For surviving fraction of .01, RBE =(10 Gy dose of x-rays)/ (6.6 Gy dose of neutrons) = 1.5 For surviving fraction of 0.6, RBE =(3 Gy dose of x-rays)/ (1Gy dose of neutrons) = 3.0 Because the X-rays and neutron survival curves have different shapes, the X-ray survival curve having an initial shoulder and the neutron curve being an exponential function of dose, the resultant RBE depends on the level of dose chosen.

Dose Level and fractionated doses For a surviving fraction of 0.01 the RBE for neutrons relative to X-rays is 2.6 (was 1.5 at single exposure). This is direct consequence of larger shoulder of x-ray curve. The width of the shoulder represents a part of the dose that is “ wasted ”; the larger the number of fractions, the greater the extent of the wastage . Neutrons curve-almost no shoulder. Net result is that neutrons become progressively more efficient than x-rays as the dose per fraction is reduced and the number of fraction is increased. The RBE generally increases as the dose is decreased. The RBE for a fractionated regimen with neutrons is greater than for a single exposure, because a fractionated schedule consists of a number of small doses and the RBE is large for small doses . Fractionation of radiation dose increases cell survival

The lower the dose rate, the higher the survival. RBE as a function of dose rate RBE can vary with the dose rate because the slope of the dose-response curve for sparsely ionizing radiations, such as x- or γ-rays, varies critically with a changing dose rate. In contrast, the biologic response to densely ionizing radiations depends little on the rate at which the radiation is delivered.

RBE as a function of LET Beyond this value for the LET, the RBE again falls to lower values. The LET at which the RBE reaches a peak is much the same (about 100 keV/ μm ) for a wide range of mammalian cells. As the LET increases, the RBE increases slowly at first, and then more rapidly as the LET increases beyond 10 keV/ μm . Between 10 and 100 keV/ μm , the RBE increases rapidly with increasing LET and reaches the maximum at about 100 keV μm.

In the case of sparsely ionizing X-rays the probability of a single track causing a DSB is low, thus X-rays have a low RBE. At the other extreme, densely ionizing radiations (ex. LET of 200 keV/ μm) readily produce DSB, but energy is “wasted” because the ionizing events are too close together. Thus, RBE is lower than optimal LET radiation.

OER & RBE as a function of LET Fig: Variation of OER and RBE as a function of LET of the radiation involved. 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow Variation of the OER and the RBE as a function of LET. The two curves are virtually mirror image of each other. The optimal RBE and the rapid fall of OER occur at about the same LET value, 100 keV/µm

Conclusion OER is the ratio of hypoxic-to-aerated doses OER decreases as LET increases Oxygen must be present during irradiation, or very soon after (microseconds) Only a small of amount O 2 is required (< 5%) LET – energy transferred per unit length of track Densely ionizing radiation – High LET, Sparsely ionizing radiation – Low LET 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow

Optimal LET is 100 keV/ μ m OER reaches unity by an LET of about 200 kev/ μ m Relative biologic effectiveness (RBE) is the ratio D 250 /D r For low LET radiation,  RBE  LET, for higher LET the RBE increases to a maximum, the subsequent drop is caused by the overkill effect. RBE is large for small doses. RBE values are higher for tissues that repair SLD. 09/13/11 Presented by: Dr. Vandana, CSMMU, Lucknow

LET, RBE & OER - dr vandana

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LET, RBE & OER - dr vandana