This chapter discusses fractionated radiation and the dose-rate effect. It covers operational classifications of radiation damage including potentially lethal damage and sublethal damage. Fractionation allows for repair of sublethal damage through processes like reassortment and repopulation. The dose-rate effect results from increased repair at lower dose rates. Examples are provided for both in vitro and in vivo models. Brachytherapy techniques like intracavitary and interstitial brachytherapy are also summarized.

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.