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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
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
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.
• <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
Chap 5 fractionated radiation and the dose rate effect
Chap 5 fractionated radiation and the dose rate effect
• 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.
• <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.
• 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”
• 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.
• 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.
• “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.
• 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.
• 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.
Chap 5 fractionated radiation and the dose rate effect
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.
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
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.
• 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.
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.
• 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.
• The differences between HeLa and
  hamster cells reflect differences in the
  apoptosis.
• At LDR, the survival
  curves “fan out”.
  – Variant range of repair
    times of SLD.
• Response of mouse
  jejunal crypt cells
  irradiated with r-rays from
  cesium-137 over a wide
  range of dose rates.
The Inverse Dose-Rate Effect
• Decreasing the dose rate
  results in increased cell
  killing.
• 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.
The Dose-Rate Effect Summarized
Brachytherapy of
            Endocuriethrerapy
•   Brachy ; (Gr) short range
•   Endo ; (Gr) within
•   Intracavitary irradiation
•   Interstitial brachytherapy
•   Developed early before teletherapy.
• <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.
• <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
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.
• 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.
• Correlation between the
  proportion of recurrent tumors
  and the dose rate.
• 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 ↑)
• <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.
• 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).
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
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.
• <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.
• <Targeting>
• The ability to target tumors with antiferritin
  mirrors the vascularity of the tumor nodules.
• <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
• Thank you for listening.

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Chap 5 fractionated radiation and the dose rate effect

  • 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.