The document summarizes key factors related to radiation pathology of tissues, tissue radiosensitivity, and the effects of time, dose, and fractionation of radiation therapy. It discusses how the sensitivity of tissues depends on the type of cells, their proliferation rate, and how they are organized. It also describes Casarett's and Michalowski's classifications of tissue radiosensitivity. Finally, it explains the rationale for fractionating radiation doses, such as allowing for repair of sublethal damage and reoxygenation of tumors.

1. Radiation Pathology Of
Tissues,Tissue Radiosensitivity,
Time, Dose and Fractionation
By Dr. Deepa Gautam
1st yr Resident, Radiotherapy
2070/11/12

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. 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. 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. 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. 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. 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. 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

10. Small lymphocyte , an exception
 one of the most sensitive mammalian cells
 does not usually divide
 dies of interphase (apoptotic) death

11. Michalowski’s Classification
 Classified tissues as
◦ Hierarchical (H) type
◦ Flexible (F)Type

12. 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

13. 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

17. Time , Dose and Fractionation

18. 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

19. 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

20. 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.

21. 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

22. 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)

23. 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

24. 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

25. 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.

27. 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.

28. 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

30. 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

31. Types of Fractionation
 Conventional Fractionation
 Altered Fractionation
◦ Hyperfractionation
◦ Accelerated fractionation
◦ Hypofractionation

32. 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

33. 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.

34. 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.

35.  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

36. 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

37. 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).

38. 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.

39. 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.

41. 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

42. 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

43.  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

44.  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

45. 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.

46. Thank you