Chap 5. Fractionated Radia-tion and the Dose-Rate Effect

2012.04.10Dahoon Jung

Korea Cancer Center Hospital

Radiobiology for the Radiologist, Hall, 7th ed

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 Radi-ation 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 environmen-

tal conditions

– (3) Sublethal damage (SLD)• Can be repaired in hours unless additional SLD

is added.

• <Potentially Lethal Damage Repair>– Potentially lethal : under ordinary cir-

cumstances, it causes cell death.– Repaired if cells are incubated in a bal-

anced 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 condi-tions are suboptimal for growth.– Cells do not have to attempt the com-

plex process of mitosis while their chroomosomes are damaged.

• <Sublethal Damage Re-pair>

• 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 paral-lel experiment in which cells were exposed to split doses and maintained at their normal growing tempera-ture of 37.

• “Age-response function”

• If the increase in radiosensitivity in moving from late S to the G2/M pe-riod exceeds the effect of repair of SLD, the surviving fraction falls.

• Fig 5.4 is a combination of 3 pro-cesses 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 grow-ing 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 hy-poxic 6-day tumors.– Repair is an active process

requiring oxygen and nutri-ents.

• In general, there is a good correlation be-tween 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 sur-vival 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 expo-sure 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 indi-cated by a split-dose exper-iment vary with the type of radiation used.

• The effect of dose fractiona-tion 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 bio-logic 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 frac-tions.– 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 differ-ence in biologic effect, at least at high doses, be-tween 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 je-junal crypt cells irradi-ated with r-rays from cesium-137 over a wide range of dose rates.

The Inverse Dose-Rate Ef-fect

• Decreasing the dose rate results in in-creased 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 Endocuri-ethrerapy

• 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 irradi-

ated– On the dose rate and geometric distribu-

tion

• 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 charac-teristic 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 inci-

dence 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 pro-portion 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 col-leagues.– 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 clono-genic cells.– Prostate ca. (slow growing)

• A major advantage of a radionuclide such as io-dine-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 Ther-apy for Human Cancer

• Radiotherapy for cancer using an an-tibody to deliver a radioactive iso-tope 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 antifer-

ritin 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 la-beled antiferritin + doxorubicin and 5-FU)– 48% partial remission– 7% complete remission

• Thank you for listening.