Radiobiology-Radiation Oncology

1. FRACTIONATION AND DOSE RATE
EFFECT
PRESENTOR:- Dr.Veda
MODERATOR :- Dr.Surekha

2. FRACTIONATION
• The five R’s of radiotherapy form the basis for
fractionation .
• The total dose cannot be given in just one fraction,
since this would produce serious adverse reactions
in normal tissues.
• Therefore, it is necessary to divide the total dose
into fractions.
• Normal cells can protect themselves from the
radiation through repair and repopulation during
the interfraction periods
• Tumor cells are sensitized to the radiation through
reoxygenation and redistribution

5.  Rationale for hyperfractionation
• Hyperfractionation employs small-dose fractions to
allow higher total doses to be delivered within the
tolerance of late-responding normal tissues, thus
enabling a higher biologically effective dose to the
tumor.
• The α/β ratio for both tumor cells and acute
responding tissues must be greater than that
for the dose-limiting normal tissue.
Other rationales:-
• Radiosensitization through cell cycle
redistribution
• Lesser dependence on oxygen effect.

7.  Rationale for Accelerated
Fractionation
• Reduction in overalltreatment time decreases
the opportunity for tumor cell regeneration,
thereby increasing the probability oftumor
control for a given total dose.

9. • Split course :
• Refers to a fractionated treatment regimen
that includes a planned interruption in order to
decrease acute side effects.
• It is no better than conventional fractionation
with regard to treatment efficacy.

10. • Concomitant Boost.
• 2 fractions are given daily in the fourth week of
radiotherapy in order to prevent accelerated
repopulation in head and neck cancers.
• The boost dose is given to the primary tumor
site.

12. TIME DOSE PARAMETERS
The parameters that determine normal tissue
tolerance are :-
• Total dose
• Dose per fraction
• fraction frequency
• duration of treatment.
Fraction size and frequency determine rate of
dose accumulation, sometimes referred to as the
weekly dose rate.

13. RADIATION DAMAGE
1)LETHAL DAMAGE
2)POTENTIALLY LETHAL DAMAGE
3)SUBLETHAL DAMAGE

14. POTENTIALLY LETHAL DAMAGE
• Component of radiation damage that can be
modified by manipulation of the post irradiation
conditions is known as PLD.
• Repair can occur if cells are prevented from
dividing for 6hours or more after irradiation
;manifested as an increase in survival .
• Repair can be demonstrated in vitro by keeping
cells in saline or plateu phase for 6 hours after
irradiation and in vivo by delayed removal and
assay of animal tumours or cells of normal tissues.

15. SUBLETHAL DAMAGE
• Occurs under normal circumstances
• Can be repaired in hours .
• If additional SLD is added from a second dose
of radaiation  Lethal damage occurs.

16. • SUBLETHAL DAMAGE REPAIR
• Term that describes the increase in survival if a
dose of radiation is split into two fractions
separated in time.
Half-time:-
• mammalian cells - 1 hour
• longer in late-responding normal tissues in
vivo.

17. • SLD repair occurs in tumors and normal tissues
in vivo as well as in cells cultured in vitro.
• The repair of SLD reflects the repair of DNA
breaks before they can interact to form lethal
chromosomal aberrations.
• SLD repair is significant for x-rays but is almost
nonexistent for neutrons.

18. SURVIVAL OF CHINESE HAMSTER CELLS
EXPOSED TO 2 FRACTIONS OF X-RAYS. At Room temperature

19. At 37 DEGREES CELCIUS

20. • If an asynchronous population of cells is
exposed to a large dose of radiation, more cells
are killed in the sensitive than in the resistant
phases of the cell cycle.
• The surviving population of cells, therefore,
tends to be partly synchronized.
• In Chinese hamster cells, most of the survivors
from a first dose of radiation are located in the S
phase of the cell cycle.

21. • If about 6 hours are allowed to elapse before a
second dose of radiation is given, this cohort
of cells progresses around the cell cycle and is
in G2/M, a sensitive period of the cell cycle at
the time of the second dose.
• If the increase in radiosensitivity in moving
from late S to the G2/M period exceeds the
effect of repair of SLD, the surviving fraction
falls

22. • The pattern of repair -combination of three
processes occurring simultaneously.
• First, there is the prompt repair of sub lethal
radiation damage.
• Second, there is progression of cells through the
cell cycle during the interval between the split
doses, which has been termed reassortment.

23. • Third, there is an increase of surviving fraction
resulting from cell division, or repopulation if
the interval between the split doses is from 10
to 12 hours because this exceeds the length of
the cell cycle of these rapidly growing cells.

24. Repair of sublethal damage in 2 in vivo
mammalian cell systems.

25.  Factors involved in repair of SLD

26. • If a dose is split into two 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 with each
fraction.
• In general, there is a good correlation between
the extent of repair of SLD and the size of the
shoulder of the survival curve.
• Both are manifestations of the same basic
phenomenon: the accumulation and repair of
SLD.

27. • Some mammalian cells are characterized by a
survival curve with a broad shoulder, and split-
dose experiments then indicate a substantial
amount of SLD repair.
• Other types of cells show a survival curve with a
minimal shoulder, and this is reflected in more
limited repair of SLD.
• (α/β) description of the survival curve, it is the
quadratic component(β) that causes the curve to
bend and that results in the sparing effect of a
split dose.
• A large shoulder corresponds to a small α/β ratio

28. THE DOSE RATE EFFECT
• For x- or γ-rays, dose rate is one of the principal
factors that determine the biologic consequences
of a given absorbed dose.
• As the dose rate is lowered and the exposure
time extended, the biologic effect of a given dose
generally is reduced.
• The classic dose-rate effect, which is very
important in radiotherapy, results from the repair
of SLD that occurs during a long radiation
exposure.

30. • Curve A is the survival curve for
single acute exposures of x-rays.
• Curve F is obtained if each dose is
given as a series of small fractions
of size D1 with an interval
between fractions sufficient for
repair of SLD.
• Multiple small fractions
approximate to a continuous
exposure to an LDR.

31. IN VITRO – HeLa Cells
• survival curve for acute
exposures that has a small
initial shoulder, which goes
hand in hand with a
modest dose-rate effect.
• This is to be expected
because both are
expressions of the cell’s
capacity to accumulate
and repair sublethal
radiation damage.
• Apoptosis is an important
form of cell death.

32. IN VIVO-HAMSTER CELLS
• broad shoulder to
their acute x-ray
survival curve .
• show a large dose-
rate effect.
• decrease in cell
killing becomes
even more
dramatic as the
dose rate is
reduced further.
• Apoptosis-rarely
seen

33. Dose survival curves at HDR & LDR for
various cell lines

34. Response of mouse jejunal crypt cells
irradiated with gamma rays.

35. INVERSE DOSE RATE EFFECT
• Decreasing the dose rate results in increased cell
killing .

36. • A range of dose rates can be found for HeLa
cells such that lowering the dose rate leads to
more cell killing.
• At 1.54Gy per hour, cells are “frozen” in the
various phases of the cycle and do not
progress.
• As the dose rate is dropped to 0.37 Gy per
hour, cells progress to a block in G2, a
radiosensitive phase of the cycle.

37. • A range of dose rates can be
found,at least for HeLa cells,
that allows cells to progress
through the cycle to a block
in late G2.
• Under continuous LDR
irradiation, an
asynchronous population
becomes a population of
radiosensitive G2 cells.

38.  SUMMARY OF DOSE RATE EFFECT
• For acute exposures at HDRs,the survival curve
has a significant initial shoulder.
• As the dose rate is lowered and the treatment
time protracted, more and more SLD can be
repaired during the exposure.
• Consequently, the survival curve becomes
progressively more shallow (D0 increases) and
the shoulder tends to disappear.
• A point is reached at which all SLD is repaired
resulting in a limiting slope.

39. • In at least some cell lines,a further lowering of the
dose rate allows cells to progress through the
cycle and accumulate in G2.
• This is a radiosensitive phase and so the survival
curve becomes steeper again.
• This is the inverse dose-rate effect. A further
reduction in dose rate allows cells to pass through
the G2 block and divide.
• Proliferation then may occur during the radiation
exposure if the dose rate is low enough and the
exposure time is long compared with the length of
the mitotic cycle.
• This may lead to a further reduction in biologic
effect as the dose rate is progressively lowered
because cell birth tends to offset cell death.

41. • THANK YOU