IT FORMS THE BASIS OF FRACTIONATION AND DETERMINES THE SUCCESS AND FAILURE OF RADIOTHERAPY. IT IS ALSO IMPORTANT FOR THE EXAM (MD OR DNB).

1. 4R’s OF RADIOBIOLOGY IN
RADIOTHERAPY
Dr. SWARNITA SAHU
SENIOR RESIDENT
RADIATION ONCOLOGY
BLK-MAX SUPERSPECIALITY HOSPITAL,NEW
DELHI

2. • CLINICAL SIGNIFICANCE:
Success OR failure of standard clinical
radiation.
Basis of fractionated radiotherapy
• DNB EXAM:
Long or short question.

4. 4 R’s Of Radiobiology
R- epair- few hours.
R- eassortment- few hours.
R- eoxygenation- hours to days.
R- epopulation- 5 to 7 weeks.

5. TYPE OF RADIATION IN
RADIOTHERAPY?
IONISING RADIATION
Sufficient energy to dislodge orbital electrons.

7. EFFECT OF RADIATION

9. RADIATION DAMAGES
LETHAL DAMAGE
POTENTIALLY LETHAL DAMAGE
SUBLETHAL DAMAGE

10. LETHAL DAMAGE
Irreversible
Irreparable
leads to cell death .

11. POTENTIALLY LETHAL DAMAGE
 CAUSES CELL DEATH – under ordinary circumstances
 REPAIRED : if post radiotherapy conditions are
manipulated.
1)cells incubated in balanced salt solution.
2)mitosis is delayed by suboptimal growth condition.

12. SUBLETHAL DAMAGE
 Under normal circumstances can be repaired in hours unless
additional sublethal damage is added .
HOURS
REPAIRED

13. REPAIR
 Base excision repair
 Nucleotide excision repair
 DNA Double strand break repair
Non homologous end-joining
Homologous recombination repair
 Others
Crosslink repair
Mismatch repair
Single strand annealing

14. CLINICAL APPLICATION
 REPAIR IN BETWEEN THE FRACTIONS
BENEFITS NORMAL TUMOR CELLS
TISSUES RESISTANT

16. • RADIOSENSITIVE: G2-M
• RADIORESISTANT: S PHASE

17. • A asynchronous population of cells (Different phases)
RADIATION
• More cells are killed in the sensitive phase (than in the resistant
phases) 6 HRS
The surviving population of cells progresses around cell cycle.
[ S (resistant) to G2-M (sensitive) phase]

18. CLINICAL APPLICATION
RE-ASSORTMENT MAKES
TUMOR SENSITIVE TO
RADIOTHERAPY

21. HYPOXIA
CHRONIC ACUTE
limited diffusion distance of
oxygen.
Temporary closing of the tumor
blood vessel owing to malformed
vasculature

22. REOXYGENATION
(hrs to days)
• A modest dose of xrays to a mixed population of
aerated and hypoxic cells results in significant killing
of aerated cells but little killing of hypoxic cells.
• Consequently the viable cell population
immediately after irradiation is dominated by
hypoxic cells.
• If sufficient time is allowed before the next radiation
dose, the process of reoxygenation restores the
proportion of hypoxic cells to about 15%.
• If the process is repeated many times,the tumor cell
population is depleted ,despite the resistance of
hypoxic cells to killling by x-rays.
• In other words ,if reoxygenation is efficient between
dose fractions, the presence of hypoxic cells does
not have a significant effect on the outcome of a
multifraction regimen.

23. WHY OXYGEN IS IMPORTANT
OXYGEN FIXATION HYPOTHESIS
Oxygen FIXES (Ii.e. makes
permanent) the damage
produced by free radicals.

24. MECHANISM OF REOXYGENATION
 FAST COMPONENT
 In few hours.
 First component of reoxygenation.
 In acutely hypoxic cells.
 As soon as the blood vessel
reopens.
 SLOW COMPONENT
Over a period of days
Chronically hypoxic cells.
Dose of radiation
Tumor cells get killed and removed from population
Tumor shrinks in size and restructuring or revascularisation
occurs

25. CLINICAL SIGNIFICANCE
If all the cells of the human tumors
reoxygenate , use of multifraction
course of radiotherapy, extending
over a period of time can deal
effectively with any hypoxic cells of
human tumors.

27. REPOPULATION
 It is the increase in cell division that is seen in normal and
malignant cells at some point after radiation is delivered.
.
 In normal tissues, repopulation occurs in different speeds
depending on the the tissue.
 Early responding tissues (mucosa, skin) begin repopulation at
about 4 weeks.
 Late responding tissue (spinal cord, bladder) only begin
repopulation after a conventional course of radiation has been
completed and therefore repopulation has minimal effect on these
tissues.

28. ACCELERATED REPOPULATION
Treatment with any cytotoxic agents ,including
radiation ,can trigger surviving cells(clonogens)in a
tumor to divide faster than before. This is known as
accelerated repopulation.

29. Study by Withers and his collegues on head and
neck cancers illustrated that-
 Clonogen repopulation in the rapidly growing human cancer cells accelerates at
about 28 days after the initiation of radiotherapy in a fractionated regimen.
 A dose increment of about 0.6 Gy per day is required to compensate for this
repopulation.
 Such a dose increment is consistent with a 4-day clonogen doubling rate,
compared with a median of about 60 days for unperturbed growth.
 CONCLUSION (for head and neck cancers and other fast growing tumors)-
 Better to delay initiation of treatment than to introduce delays during
treatment.
 If overall treatment time is too long ,the effectiveness of later dose fractions is
compromised because the surviving clonogens in the tumor have triggered into
rapid repopulation.

30. SUMMARY
 REASSORTMENT AND REOXYGENATION
 REPAIR AND REPOPULATION
FRIENDS OF TUMOR RADIOTHERAPY
FOES OF TUMOR RADIOTHERAPY
But FRIENDS OF NORMAL TISSUE.

31. TAKE HOME MESSAGE
BASIS OF FRACTIONATION
 REPAIR of sublethal damage in NORMAL healthy cells.
 REPOPULATION of NORMAL healthy cells.
 REASSORTMENT of TUMOR cells.
 REOXYGENATION of TUMOR cells.
THESE ARE THE RADIOBIOLOGICAL MECHANISMS THAT
IMPACT THE RESPONSE OF A FRACTIONATED COURSE OF
RADIATION THERAPY.

32. 5th R OF RADIOBIOLOGY
 Radiosensitivity of the living tissues varies with
maturation & metabolism. Radiosensitive cells are-
1)Stem cells
2)Younger tissues
3)High metabolic activity
4)High proiferation and growth rate

33. • Response of tissue is determined by amount of energy
deposited per unit mass(dose in Gy).
• Two identical doses may not produce identical responses
due to other modifying factors
Physical Factors Biological Factors
-linear energy transfer -oxygen effect
-relative biologic effectiveness -age
-fractionation. -recovery
-chemical agents