OER RADIATION ONCOLOGY ; OXYGEN ENHANCEMENT RATIO

OER

1. OER / RBE / LET Dr ANJALIKRISHNA NP PG RESIDENT RADIOTHERAPY

2. OXYGEN ENHANCEMENT RATIO

3. OXYGEN EFFECT Cells are much more sensitive to radiation in the presence of oxygen The formation of RO2·, an organic peroxide, represents a non restorable form of the target material; that is, the reaction results in a change in the chemical composition of the material exposed to the radiation. This reaction cannot take place in the absence of oxygen. Oxygen fixes ( ie , makes permanent ) the damage produced by free radicals . In the absence of oxygen , damage produced by the indirect action may be repaired .

4. The oxygen fixation hypothesis . About two-thirds of the damage produced by x-rays is by indirect action mediated by free radicals. The damage produced by free radicals in DNA can be repaired under hypoxia but may be “fixed” (made permanent and irreparable) if molecular oxygen is available .

5. 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 . Ie , Oxygen effect is time dependent . O2 needs to be present during radiation . or O2 has to be present within milliseconds after radiation . Radiation - ion pairs - free radicals 0.01 msec. OXYGEN IS NATURAL RADIOSENITIZER .

6. If molecular oxygen is present, DNA reacts with the free radicals (R·). The DNA radical can be chemically restored to its reduced form through reaction with a sulfhydryl (SH) group. SULFHYDRIL group is a natural radio protector which exert their effect by scavenging free radicals . Oxygen and sulfhydryl only acts on indirect action and they do not have any effect on direct action of radiation to DNA .

7. RADIOSENSITIVITY & O2 CONCENTRATION

8. Very little change upto 20 mmHg. Sharp fall in sensitivity and reduces to half at around 3 mmHg. Maximum radio resistance at 1/100 mm of Hg . Oxygen tension in most of tissue is similar at venous blood O2 tension , ie 20-40 mmHg .So , MOST OF THE NORMAL TISSUES HAVE GOOD SENSITIVITY TO RADIATION.

9. EFFECT OF O2 on cell survival curve .

10. So , to get the same surviving fraction , dose of RT to be increased with decreasing oxygen tension . The ratio of RT to get the same SF in hypoxic cells to oxic cells is known as OXYGEN ENHANCEMENT RATIO (OER). OER = DH / DO = D hypoxic/D aerobic Ratio of doses administered under hypoxic to aerated condition needed to achieve the same biological effect is called oxygen enhancement ratio .

11. For sparsely ionizing radiations, such as x- and γ-rays, the OER at high doses has a value of between 2.5 and 3.5. For a densely ionizing radiation, such as low-energy α-particles , the survival curve does not have an initial shoulder; which means that all hits results into cell kill and no sub lethal damage to be fixed by oxygen .we can say , α-particle radiation is as effective for hypoxic cells as for oxic cell . Intermediate value for fast neutrons , the OER for neutrons is about 1.6. For radiations of intermediate ionizing density, such as neutrons, the survival curves have a much reduced shoulder

12. Survival curves for mammalian cells exposed to x-rays in the presence and absence of oxygen are illustrated here;

13. High dose region ; predominant process of cell kill is by accumulation of sublethal damage ( cell killing by multiple hit event –MHE ) which can be repaired ,so oxygen fix it and repair slows down . Low dose region ; cell killing is predominantly by single hit event –SHE ,no sublethal damage to be fixed up by oxygen ; so , in low dose region OER = 2 ( x ray or gamma ray )

14. 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). It has a value close to 3.5 at high doses (A) But may have a lower value of about 2.5 at x-ray doses less than about 2 to 3 Gy (B).

15. OER varies slightly during cell cycle . Cells in G1 phase have a lower OER than those in S, and because G1 cells are more radiosensitive, they dominate the low-dose region of the survival curve. S PHASE > G1 PHASE > G2/M PHASE . OER OF S PHASE = 2.8 - 2.9 OER OF G2/M PHASE = 2.3 -2.4

16. CLINICAL IMPORTANCE Various experimental solid tumors in animals have shown to have hypoxic contents between 10 to 40 %, which limits the radio curability However , it should be remembered that even a minute proportion of hypoxic cells will limit the radiocurability if treated with large single fraction . There are abundant evidences to support the existence of hypoxic cells in human tumour .

17. TUMOR HYPOXIA & DFS IN CA CERVIX

18. HYPOXIA & local tumor control in HEAD & NECK CANCER

19. LINEAR ENERGY TRANSFER Linear energy transfer (LET) is the energy transferred per unit length of the track. The special unit usually used for this quantity is kiloelectron volt per micrometer (keV/ μm ) of unit density material. The LET (L) of charged particles in medium is the quotient of dE /dl. dE is the average energy locally imparted to the medium by a charged particle of specified energy in traversing a distance of dl . L= dE /dl

20. Typical Linear Energy Transfer Values

21. Linear energy transfer (LET) is the average energy deposited per unit length of track. The track average is calculated by dividing the track into equal lengths and averaging the energy deposited in each length. The energy average is calculated by dividing the track into equal energy intervals and averaging the lengths of the track that contain this amount of energy. The method of averaging makes little difference for x-rays or for monoenergetic charged particles, but the track average and energy average are different for neutrons. In the case of either x-rays or monoenergetic charged particles, the two methods of averaging yield similar results. In the case of 14-MeV neutrons, by contrast, the track average LET is about 12 keV/ μm and the energy average LET is about 100 keV/ μm . The biologic properties of neutrons tend to correlate best with the energy average.

22. RELATIVE BIOLOGIC EFFECTIVENESS (RBE) The amount or quantity of radiation is expressed in terms of the absorbed dose, a physical quantity with the unit of gray ( Gy ). Absorbed dose is a measure of the energy absorbed per unit mass of tissue. Equal doses of different types of radiation do not produce equal biologic effects. For example, 1 Gy of neutrons produces a greater biologic effect than 1 Gy of x-rays. The key to the difference lies in the pattern of energy deposition at the microscopic level.

23. OPTIMAL LET

24. why radiation with an LET of about 100 keV/ μm is optimal in terms of producing a biologic effect ? LET of about 100 keV/ μm is optimal in terms of producing a biologic effect . At this density of ionization , the average separation in ionizing events is equal to the diameter of DNA double helix (i.e., about 20 Å or 2 nm) which causes significant DOUBLE STRAND BREAK . DSB are the basis of most biological effects . The probability of causing DSBs is low in sparsely ionizing radiation . The LET at which the RBE reaches a peak is much the same (about 100 keV/ μm ) for a wide range of mammalian cells, from mouse to human, and is the same for mutation as an end point as for cell killing.

25. Variation of relative biologic effectiveness (RBE) with linear energy transfer (LET) for survival of mammalian cells of human origin. The RBE rises to a maximum at an LET of about 100 keV/ μm and subsequently falls for higher values of LET. Curves 1, 2, and 3 refer to cell survival levels of 0.8, 0.1, and 0.01, respectively, illustrating that the absolute value of the RBE is not unique but depends on the level of biologic damage and, therefore, on the dose level.

26. In the case of x-rays, which are more sparsely ionizing, the probability of a single track causing a DSB is low, and in general, more than one track is required. As a consequence, x-rays have a low biologic effectiveness. At the other extreme, much more densely ionizing radiations (e.g., with an LET of 200 keV/ μm ) readily produce DSBs. But energy is “wasted” Because, the ionizing events are too close together. RBE is the ratio of doses producing equal biologic effect , this more densely ionizing radiation has a lower RBE than the optimal LET radiation. The more densely ionizing radiation is just as effective per track but less effective per unit dose.

27. The most biologically effective LET is that at which there is a coincidence between the diameter of the DNA helix and the average separation of ionizing events. Radiations having this optimal LET include neutrons of a few hundred kiloelectron volts as well as low-energy protons and α-particles.

28. RBE depends on the following : Radiation quality (LET) (The type of radiation and its energy, whether electromagnetic or particulate, and whether charged or uncharged) Radiation dose & Number of dose fractions (The shape of the dose– response relationship varies for radiations that differ substantially in their LET). Dose rate (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) Biologic system or end point (RBE values are high for tissues that accumulate and repair a great deal of sublethal damage and low for those that do not)

29. x-rays, which are sparsely ionizing, have a low LET, and consequently exhibit a large OER of about 2.5 .

30. Neutrons, which are intermediate in ionizing density and characteristically show an OER of 1.6.

31. 2.5-MeV α-particles, which are densely ionizing and have a high LET; in this case, survival estimates, whether in the presence or absence of oxygen, fall along a common line, and so the OER is unity.

32. Variation of the oxygen enhancement ratio (OER) and the relative biologic effectiveness (RBE) as a function of the linear energy transfer (LET) of the radiation involved . The rapid increase in RBE and the rapid fall of the OER occur at about the same LET, 100 keV/ μm .