Tissue radiosensitivity

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Tissue radiosensitivity

  1. 1. Radiation Pathology Of Tissues,Tissue Radiosensitivity, Time, Dose and Fractionation By Dr. Deepa Gautam 1st yr Resident, Radiotherapy 2070/11/12
  2. 2. Radiation Pathology Of Tissues  The response of a tissue or organ to radiation depends primarily on three factors: 1. the inherent sensitivity of the individual cells 2. the kinetics of the population as a whole of which the cells are a part 3. the way in which cells are organized in that tissue  These factors combine to account for the substantial variation in response to radiation characteristic of different tissues.
  3. 3. Radiation Pathology Of Tissues  the amount of radiation needed to destroy the functioning ability of a matured differentiated cell is far greater than that of a dividing cell.  sensitivity or resistance of a tissue or organ depends on the extent to which the tissue involved can continue to function adequately with a reduced number of cells.  the time interval between the delivery of the radiation and its expression in tissue damage is very variable for different populations.  it is determined by the normal lifespan of the mature functional cells and the time taken by a cell "born" in the stem cell compartment to mature to a functional state.
  4. 4. Tissue Radiosentisivity  Radiosensitivity expresses the response of the tumour to irradiation  Bergonie andTribondeau’s Law (1906) : tissues will be more radiosensitive if 1. their cells are undifferentiated 2. they have a greater proliferative capacity 3. they divide more rapidly.
  5. 5. Classification of Tissue Radiosensitivity  Two systems are typically used to classify tissue radiosensitivity in terms of: 1. Population kinetics: Casarett’s Classification 2. Tissue architecture: Michalowski’s Classification
  6. 6. Casarett’s Classification  a classification of mammalian cell radiosensitivity based on histologic observation of early cell death.  divided parenchymal cells divided into four major categories  supporting structures, such as the connective tissue and the endothelial cells of small blood vessels regarded as intermediate in sensitivity between groups II and III of the parenchymal cells.
  7. 7. Casarett’s Classification  Group I: ◦ most sensitive ◦ Cells are rapidly dividing and undifferentiated ◦ eg stem cells, epidermis of the skin and the intestine, primitive cells of the spermatogesis.  Group II: ◦ Relatively sensitive ◦ cells that divide regularly but also mature and differentiate inbetween divisions. ◦ Eg. cells of the hematopoietic series in the intermediate stages of differentiation, more differentiated spermatogonia and spermatocytes
  8. 8. Casarett’s Classification  Group III: ◦ the reverting postmitotic cells, ◦ do not undergo mitosis ordinarily but are capable of dividing with the appropriate stimulus like damage or loss of many of their own kind ◦ relatively resistant ◦ Eg.cells of liver, pancreas, adrenal, thyroid  Group IV: ◦ the fixed postmitotic cells ◦ most resistant to radiation ◦ Highly differentiated and appear to have lost the ability to divide. ◦ Eg. Nerve cells, muscles cells, granulocytes
  9. 9. Small lymphocyte , an exception  one of the most sensitive mammalian cells  does not usually divide  dies of interphase (apoptotic) death
  10. 10. Michalowski’s Classification  Classified tissues as ◦ Hierarchical (H) type ◦ Flexible (F)Type
  11. 11. H-Type  Three distinct types of cells are identified within a tissue 1. Stems cells-capable of uncontrolled proliferation 2. Functional cells-fully differentiated, incapable of further division and die after finite lifespan 3. Intermediate type- maturing partially differentiated cells which are still multiplying to complete the process of differentiation Eg, hematopoietic bone marrow, intestinal epithelium,epidermis
  12. 12. F-Type  No strict hierarchy  Tissues are composed of cells that rarely divide under normal conditions but can be triggered to divide by damage to the tissue  All cells including functional, enter the cell cycle after the damage  eg liver, thyroid, dermis
  13. 13. Time , Dose and Fractionation
  14. 14. Time  It is the overall time to deliver a prescribed dose of radiation  Biologic effects enormously varies with time  Longer the overall duration of treatment, greater is the dose required to produce a particular effect  Hence dose should always be stated in relation with time
  15. 15. Time  For curative purpose the overall treatment time is about 5-6wks  For treatment more than 6 wks , the dose has to be increased  Short duration of treatment is used in palliative treatment eg. 30Gy/10#, 20Gy/5#  Overall treatment time has influence on early but not late responding tissues
  16. 16. Rams Story  Experiments performed in Paris in the 1920s and 1930s.  Rams could not be sterilized with a single dose of x-rays without extensive skin damage  If the radiation were delivered in daily fractions over a period of time, sterilization was possible without skin damage.  The testes as a model of a growing tumor and skin as dose-limiting normal tissue.
  17. 17. Fractionation  The division of total dose into number of separate fractions over a certain period of time  Size of each dose per # depends upon the tumour dose as well as normal tissue tolerance
  18. 18. Radiobiological Rationale for Fractionation  Repair of sublethal damage (few hrs)  Reassortment/Redistribution of cells within cell cycle(few hrs)  Repopulation (5-7 wks)  Reoxygenation (hrs to few days)
  19. 19. Repair Of Sublethal damage  Most important rationale for fractionation  Sublethal damage are repaired in between two dose fractions  Initial shoulder of the curve represents the repair of sublethal damage
  20. 20. Reassortment/Redistribution  Cells may be in different phases of cell cycle during irradiation  A small dose of radiation given over a short period will kill a lot of sensitive cells and less of resistant cells  Surviving cells continue the cycle and may reach sensitive phase when second dose of radiation is given
  21. 21. Repopulation  the process of increase in cell division seen in normal and malignant cells after irradiation  time to onset of repopulation after irradiation and the rate at which it proceeds vary with the tissue  Acute-responding tissues(stem cells, progenitor cells, GI epithelium, oropharyngeal mucosa,skin) begin repopulation early.  Late-responding tissues(Renal tubular epithelium, oligodendrocytes, schwann cells, endothelium, fibroblasts) begin repopulation after completion of conventional course of radiation.
  22. 22. Accelerated Repopulation  the triggering of surviving cells to divide more rapidly as a tumor shrinks after irradiation or treatment with any cytotoxic agent  a marked increase in their growth fraction and doubling time and decrease in cell cycle time, at 4 - 5 wks.  Eg. SCC of head and neck(3-4wks), cervix.  About 0.6 Gy per day is needed to compensate for this repopulation.  So better to delay initiation of treatment than to introduce delays during treatment.
  23. 23. Reoxygenation  the phenomenon by which hypoxic cells become oxygenated after a dose of radiation.  Fast component (hrs)  seen in acute hypoxia  reoxygenation occurs when temporarily closed vessels reopen  Slow component(days)  seen in chronic hypoxia  reoxygenation occurs when the tumor shrinks in size and the surviving cells that were previously beyond the range of oxygen diffusion, come closer to a blood supply
  24. 24. Advantages of Fractionation  Acute effects of single dose of radiation can be minimized  Patient’s tolerance improves with fractionated radiation  Provides time for repair of sublethal damage of normal cells  Provides time for redistribution and sensitization of tumour cells  Provides time for reoxygenation of tumour cells
  25. 25. Types of Fractionation  Conventional Fractionation  Altered Fractionation ◦ Hyperfractionation ◦ Accelerated fractionation ◦ Hypofractionation
  26. 26. Conventional Fractionation  Evolved as conventional regimen because: ◦ Convenient( no weekend treatment) ◦ Efficient (treatment every day) ◦ Effective(high doses can be delivered without exceeding acute or chronic normal tissue tolerance) ◦ Most tried and trusted method  Most common conventional fractionation for curative radiotherapy is 1.8 to 2.2 Gy /# 5 days a wk for 5-8 wks
  27. 27. Hyperfractionation  Keeping the same total dose as in conventional regimen in same overall time but delivering it in twice as many #s as treatment is given twice a day  But in practice,the total dose must be increased because the dose per fraction is decreased with or without increase in overall time  Aim: to decrease late effects ,achieve same or better tumour control with same or slightly increased early effects  shown in randomized clinical trials of head and neck cancer to improve local tumor control and survival with no increase in acute or late effects.
  28. 28. Accelerated Fractionation  In accelerated treatment, to reduce repopulation in rapidly proliferating tumors, conventional doses and number of fractions are used; but because two doses per day are given , the overall treatment time is halved.  In practice the dose must be reduced or a rest interval allowed because acute effects become limiting.
  29. 29.  The time interval between multiple daily fractions should be sufficient enough for repair of sublethal damage  RTOG trials suggested that late effects were worse with intervals less than 4 hrs than those more than 6hrs  So atleast 6hrs interval is required
  30. 30. Hypofractionation  the total dose of radiation is divided into large doses and treatments are given less than once a day.  an external-beam regimen consisting of a smaller number of larger dose fractions, or alternatively high dose rate (HDR) brachytherapy delivered in a limited number of fractions  Eg. ca prostate, ca cervix, palliative RT
  31. 31. The Strandquist Plot  It is the relation between total dose and overall treatment time.  time includes the number of fractions.  Fig: Isoeffect curves relating the total dose to the overall treatment time for ◦ skin necrosis (A) ◦ cure of skin carcinoma (B) ◦ moist desquamation of skin (C) ◦ dry desquamation of skin (D) ◦ skin erythema (E).
  32. 32. Ellis Nominal Standard Dose System  total dose for the tolerance of connective tissue is related to the number of fractions (N) and the overall time (T) by the relation:  Total dose=(NSD)T0.11 N0.34  It enables predictions to be made of equivalent dose regimens, provided that the range of time and number of #s are not too great and do not exceed the range over which the data are available.
  33. 33. Weakness of NSD  the system is based on skin-reaction data, it does not predict late effects  The time correction was a power function (T0.11) that is far from accurate.  The extra dose required to counteract proliferation in a normal tissue irradiated in a fractionated regimen is a sigmoidal function of time and no extra dose is required until some weeks into a fractionated schedule.
  34. 34. Dose  It is a measure of the energy absorbed per unit mass of tissue  Unit is Gray  1Gy=1J/kg  It depends upon: ◦ Radiosensitivity of tumour ◦ Size of treatment volume- smaller the volume, greater dose can be delivered without exceeding normal tissue tolerance ◦ Proximity to dose limiting structure eg. Brainstem, spinal cord, optic nerve
  35. 35. Using The Linear-Quadratic Concept To Calculate Effective Dose  Suggested by Dr. Jack Fowler  This model emphasizes on: ◦ The difference between early and late responding tissues ◦ The fact that it is never possible to match and differentiate two fractionation regimens to be equivalent to both
  36. 36.  Linear portion of the curve(α): loge of the cells killed per Gy  As curve bends, quadratic component of cell killing (β) is the loge of cells killed per Gy2  The ratio of α/β has the dimension of dose and is the dose at which the linear and quadratic components of cell killing are equal
  37. 37.  For a single acute dose D, the biologic effect is given by E=αD+βD2  For n well separated fraction of dose d, the biologic effect is given by E=n(αd+βd2)  May be rewritten as,  But nd equals D(total dose),so E=α(total dose)(relative effectiveness)  If this equation is divided by α, we have  E/α is the biologically effective dose and is the quantity by which different fractionation regimens are compared
  38. 38. The Final Equation  Biologically effective dose=total dose X relative effectiveness Choice of α/β:  α/β is assumed to be 3 Gy for late-responding tissues and 10 Gy for early-responding tissues.  We may substitute other values that seem more appropriate.
  39. 39. Thank you

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