Fractionation and Dose Rate Effects

Non-lethal damage

involves a lesion which doesn’t prevent proliferation, but affects the rate of proliferation

Lethal damage

irreparable, irreversible, leads irrevocably to cell death

Sublethal damage

non-lethal cellular injury that can be repaired or accumulated with further dose to become lethal; damage that affects the response to additional exposure to radiation; evidenced by shoulder in multi-exposures, basis for fractionated radiation therapy treatments

Potentially lethal damage

damage that can be modified by post-irradiation environmental conditions; only lethal if cells are stimulated to divide before repair occurs, can have SLD with or without PLD

Factors known to increase survival by affecting PLD

• Incubation in Hanks Balanced Salt Solution for several hours after irradiation (instead of growth media)

• Grow cells in density inhibited state for 6-12 hours following irradiation

• Suboptimal growth conditions (delay of mitosis)

PLD occurs in

transplantable tumors in animals (hypothesized but not proven in humans)

A broad shoulder indicates what for SLD repair?

substantial amount of SLD repair

A narrow shoulder indicates what in regards to SLD repair?

limited SLD repair

High beta in linear quadratic model results in

more bend in survival curve (large shoulder = small alpha/beta ratio)

If the dose delivered in two fractions is separated by a time interval, there is a _____ in cell survival bc the shoulder is expressed each time

increase

Single dose is

linear quadratic

The effective dose-response curve for multifraction regimens approaches an

exponential function of dose

Cell killing correlated with production of

asymmetrical chromosomal aberrations (at least 2 DSB)

DSB can be caused by

single or multiple tracks

Single track component of cell killing is the same whether or not

dose is fractionated

In a single dose, all breaks produced by separate electrons can interact to form

dicentrics

If the same dose is delivered in two fractions a certain time apart, some of those DSBs can be repaired, which leads to

fewer interactions bt broken chromosomes → fewer lethal lesions → more cell survives

Which discriminates better between cell lines of different radiosensitivities?

low dose rate (LDR)

4 Rs of Radbio

1. Repair

2. Reassortment

3. Repopulation

4. Reoxygenation

Repair

prompt repair of sublethal damage, observed as increase in cell survival when a given radiation dose is split into 2 fractions

Reassortment (redistribution)

progression of cells through the cell cycle during the interval between radiation doses

Repopulation

inc of surviving fraction due to cell division when the time interval bt 2 dose fractions exceeds the cell cycle (aka proliferation)

Reoxygenation

oxygen increases radiosensitivity, fractionation of dose allows greater effect

What are the other proposed Rs of Radbio?

• Radiosensitivity

• Reactivation

• Reinforcement

In rapidly dividing cells, there is a dip in cell survival due to

reassortment or cells moving from resistant to sensitive phases of cell cycle

As the fractions get further apart, there is an increase in cell survival due to

proliferation or repopulation bt doses

Survival is a _____ function of dose

exponential

Are dose rate effects the same in cells?

no

The dose rate effect is more dramatic in which: CHO or HeLa cells?

CHO

For some cells, there is a decreased dose rate associated with increased killing. This can be explained based on the

G2 block

The dose-response curve for acute exposures is characterized by

broad initial shoulder

As the dose rate is reduced, the survival curve becomes progressively more shallow as more sublethal damage is _____, but cells are frozen in their positions in the cell cycle and don’t progress

repaired

As the dose rate is further lowered and for a limited range of dose rates, the survival curve steepens again because cells can

progress through cell cycle to pile up at a block in G2 (radiosensitive) but still can’t divide

A further lowering of dose rate below this critical dose rate allows cells to escape the G2 block and divide; cell ______ may then occur during the protracted exposure, and survival curves become shallower as cell birth from mitosis offsets cell killing from the irradiation

proliferation

Factors contributing to dose rate effect

1. Cellular sensitivity of stem cells - cells w broad shoulder are less susceptible to low dose rate → shoulder continuously reconstructed during protracted exposure

2. Duration of cell cycle - long cell cycle is more damaged by a dose rate of continuous irradiation than cells with a short cell cycle

3. Ability of tissues to adapt

Conventional multi-fraction radiotherapy was based on

ram sterilization experiments (couldn’t sterilize them without damage to the skin)

What became a model of a growing tumor? What became the dose-limiting normal tissue?

ram testes, skin

Claudius Regaud

• head of bio section of Radium Institute where Marie Curie led physics & chemistry section

• Served in WWI, organized war hospitals and surgical teams

• Developed first brachytherapy techniques and early fractionation schemes

Increasing time between fractions results in

higher dose needed to cause a given skin reaction (same dose = lesser effect)

Was the nominal standard dose model developed from Strandquist plots accurate?

no bc it didn’t account well enough for proliferation

Early acute response radiation induced normal tissue damage is expressed in

weeks to a few months after exposure

Late response radiation induced normal tissue damage is expressed

months to years after exposure

A large beta means a small a/b ratio, which indicates which response?

late

A small beta indicates a large a/b, which indicates which response?

early (larger alpha means less curvy)

Early responding is impacted more by the

duration of the treatment

Late responding is impacted more by the

dose per fraction

Fewer large doses in late responding results in

worse late effects

Large a/b implies

decreased sensitivity to changes in fraction size

Small a/b suggests

changes in fraction size have dramatic effect on tissue response

Hyper-fractionation results in

reduced late effects if total dose is adjusted to produce equal acute effects (tumor control = same or slightly improved)

Iso-effect curves in small animals are are ______ for a range of late effects than for various acute effects

steeper

Early responding organs

skin, GI mucosa, intestinal epithelium

Early responding result from the death of

a large number of cells

Does early responding resolve?

yes

Early responding has rapidly

dividing tissue

What determines the response for early responding tissues?

fraction size and overall treatment

Late responding tissues

spinal column, kidney, lung, bladder

Late responding effects are

severe and non-reversible (fibrosis, necrosis, vascular effects)

Are late responding effects generally self-renewing?

no

Late responding is ____ limiting

dose

What is the dominant factor in determining late effects?

fraction size (overall treatment time has little influence)

Are tissue dose response curves related to organ function the same as clonogenic survival?

no (clonogenic dose-effect curve is more straight w smaller shoulder and corresponds to proportion of functional cells remaining vs proportion of clonogenic cells remaining)

What is the rationale for using LDR for TBI?

target cells are leukemic; dose-limiting tissue is the lung and LDR spares the lung