1. Radiobiology for the Radiologist, Hall, 7th ed
Chap 5. Fractionated Radiation
and the Dose-Rate Effect
2012.04.10
Dahoon Jung
Korea Cancer Center Hospital

2. Overview
• Operational Classifications of Radiation Damage
– Potentially Lethal Damage Repair
– Sublethal Damage Repair
• Mechanism of Sublethal Damage Repair
• Repair and Radiation Quality
• The Dose-Rate Effect
• Examples of the Dose-Rate Effect In Vitro and In Vivo
• The Inverse Dose-Rate Effect
• The Dose-Rate Effect Summarized
• Brachytherapy or Endocurietherapy
– Intracavitary Brachytherapy
– Interstital Brachytherapy
– Permanent Interstitial Implants
• Radiolabeled Immunoglobulin Therapy for Human Cancer
– Radionuclides
– Tumor Target Visualization
– Targeting
– Clinical Results
– Dosimetry

3. Operational Classifications of
Radiation Damage
• Radiation damage to mammalian cells can
operationally be devided.
– (1) Lethal damage
• Irreversible and irreparable
• Leads irrevocably to cell death
– (2) Potentially lethal damage (PLD)
• Can be modified by postirradiation environmental
conditions
– (3) Sublethal damage (SLD)
• Can be repaired in hours unless additional SLD is
added.

4. • <Potentially Lethal Damage Repair>
– Potentially lethal : under ordinary
circumstances, it causes cell death.
– Repaired if cells are incubated in a balanced
salt solution.
– Drastic, does not mimic a physiologic
condition

7. • PLD is repaired, and the fraction of cells
surviving a given dose of x-rays is
enhanced if postirradiation conditions are
suboptimal for growth.
– Cells do not have to attempt the complex
process of mitosis while their chroomosomes
are damaged.

8. • <Sublethal Damage Repair>
• SLD is the operational term
– Increase in cell survival that is
observed if a given radiation dose
is split into two fractions separated
by a time interval.
– The increase in survival in a split-
dose experiment results from the
repair of sublethal radiation
damage.

9. • Shows the results of a parallel
experiment in which cells were
exposed to split doses and
maintained at their normal
growing temperature of 37.
• “Age-response function”

10. • 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.

11. • Fig 5.4 is a combination of 3 processes
occurring simultaneously.
– 1. the prompt repair of SLD.
– 2. Reassortment
• Progression of cells through the cell cycle.
– 3. Repopulation
• Increase of surviving fraction resulting from cell
division.

12. • “Four Rs” of radiobiology
– Repair
– Reassortment
– Repopulation
– Reoxygenation
• The dramatic dip in the split-dose curve at 6
hrs caused by reassortment.
• The increase in survival by 12 hrs because of
repopulation are seen only for rapidly growing
cells.

13. • In neither case, there is a
dramatic dip in the curve at 6
hrs.
– Because the cell cycle is long.
• More repair in small 1-day
tumors than in large hypoxic 6-
day tumors.
– Repair is an active process
requiring oxygen and nutrients.

14. • In general, there is a good correlation between
the extent of repair of SLD and the size of the
shoulder of the survival curve.
– The accumulation and repair of SLD.
• The time course of the increase in cell survival
that results from the repair of SLD is charted in
Fig. 5.6B.

16. Mechanism of Sublethal Damage
Repair
• Te repair of SLD is simply the repair of double-
strand breaks.
– Rejoin and repair of double-strand breaks.
• The component of cell killing that results from
single-track damage is the same whether the
dose is given in a single exposure of
fractionated.
• The same is not true of multiple-track damage.

17. Repair and Radiation Quality
• The shoulder on the acute
survival curve and the amount of
SLD repair indicated by a split-
dose experiment vary with the
type of radiation used.
• The effect of dose fractionation
with x-rays and neutrons is
compared in Fig 5.7

18. The Dose-Rate Effect
• For x- or r-rays, dose rate is one of the principal
factors that determine the biologic
consequences of a given absorbed dose.
– Lowered dose rate and extended exposure time
generally occur reduced biologic effect.
• The classic dose-rate effect results from the
repair of SLD that occurs during a long radiation
exposure.

19. • Continuous low-dose-rate(LDR)
irradiation may be considered to
be an infinite number of infinitely
small fractions.
– No shoulder, shallower than for single
acute exposures.

20. Examples of the Dose-rate Effect In
Vitro and In Vivo
• Survival curves for HeLa cells
cultured in vitro and exposed to r-
rays at high and low dose rates.
• The magnitude of the dose-rate
effect from the repair of SLD varies
enormously among different types
of cells.
• HeLa cells have small initial
shoulder.

21. • Chinese hamster cells
– Broad shoulder, large dose-rate
effect.
• There is a clear-cut
difference in biologic effect,
at least at high doses,
between dose rates of 1.07,
0.30, and 0.16 Gy/min.

22. • The differences between HeLa and
hamster cells reflect differences in the
apoptosis.

23. • At LDR, the survival
curves “fan out”.
– Variant range of repair
times of SLD.

24. • Response of mouse
jejunal crypt cells
irradiated with r-rays from
cesium-137 over a wide
range of dose rates.

25. The Inverse Dose-Rate Effect
• Decreasing the dose rate
results in increased cell
killing.

26. • In HeLa cell, such dose in
1.54 to 0.37 Gy/h is
almost as damaging as
an acute exposure.
• At higher dose rates, they
are “frozen” in the phase
of the cycle they are in at
the start of the irradiation.

27. The Dose-Rate Effect Summarized

28. Brachytherapy of
Endocuriethrerapy
• Brachy ; (Gr) short range
• Endo ; (Gr) within
• Intracavitary irradiation
• Interstitial brachytherapy
• Developed early before teletherapy.

29. • <Intracavitary Brachytherapy>
• LDR ;
– Always temporary
– Usually takes 1 to 4 days (50 cGy/h)
– m/c uterine cervix
– Radium  Cs-137  Ir-192
• HDR ;
– Radiobiologic advantage
– Sparing of late-responding normal tissues.

30. • <Interstitial Brachytherapy>
• Temporary or permanent
• The maximum dose
– Depends on the volume of tissue irradiated
– On the dose rate and geometric distribution
• Paterson and Ellis

31. The variation of total dose with dose
rate is much larger for late- than for
early-responding tissues because of
the lower a/b characteristic of such
tissues.

32. • In the 1990s, Mazeron and
his colleagues in Paris
published two papers that
show clearly that a dose-rate
effect is important in
interstitial implants.
– Substantially higher incidence
of necrosis in patients treated
at the higher dose rates.
– Dose rate makes little or no
difference to local control
provided that the total dose is
high enough.

33. • Correlation between the
proportion of recurrent tumors
and the dose rate.

34. • The relatively short half-life of
iridium-192 (70 days) means
that a range of dose rates is
inevitable.
• It is important to correct the total
dose for the dose rate because
of the experience of Mazeron
and his colleagues.
– Small source size
– Lower photon energy
(radiation protection ↑)

35. • <Permanent Interstitial Implants>
• Encapsulated sources with relatively short half-lives can
be left in place permanently.
• Iodine-125 has been used most widely to date for
permanent implants.
• The total prescribed dose is usually about 160 Gy at the
periphery of the implanted volume, with 80 Gy delivered
in the first half-life of 60 days.

36. • The success of the implant in sterilizing the tumor
depends critically on the cell cycle of the clonogenic cells.
– Prostate ca. (slow growing)
• A major advantage of a radionuclide such as iodine-125
is the low energy of the photons emitted (about 30 keV).

37. Photon Energy, keV
Radionuclide Average Range Half-Life HVL, mm Lead
Conventional
Cesium-137 662 - 30 y 5.5
Iridium-192 380 136-1060 74.2 d 2.5
New
Iodine-125 28 3-35 60.2 d 0.025
Gold-198 412 - 2.7 d 2.5
Americium-241 60 - 432 y 0.125
Palladium-103 21 20-23 17 d 0.008
Samarium-145 41 38-61 340 d 0.06
Ytterbium 169 100 10-308 32 d 0.1

38. Radiolabeled Immunoglobulin
Therapy for Human Cancer
• Radiotherapy for cancer using an antibody
to deliver a radioactive isotope to the
tumor.
• Ferritin is an iron-storage protein that is
synthesized and secreted by a broad
range of malignancies.

39. • <Radionuclides>
• Early studies used iodine-131.
– Requires large amounts of radioactivity(about 1,000
MBq)
• Recent years, yttrium-90
– Pure ß-emission of relatively high energy(0.9MeV)
• More recently, rhenium-188, rhenium-
186, phosphorus-32 have been used.

40. • <Targeting>
• The ability to target tumors with antiferritin
mirrors the vascularity of the tumor nodules.

41. • <Clinical Results>
• The most promising results have been in the
treatment of unresectable primary
hepatoma.(Johns Hopkins, iodine-131 labeled
antiferritin + doxorubicin and 5-FU)
– 48% partial remission
– 7% complete remission

42. • Thank you for listening.