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
• 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.
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.
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 doserate is much larger for late- than forearly-responding tissues because ofthe lower a/b characteristic of suchtissues.
• 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, keVRadionuclide Average Range Half-Life HVL, mm Lead Conventional Cesium-137 662 - 30 y 5.5 Iridium-192 380 136-1060 74.2 d 2.5New 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