Principles of Radiobiology

What is Radiobiology?

Radiobiology is the study of the effects of radiation on biological systems.

How does radiation damage cells?

Radiation damages cells by causing breaks within the structure of DNA. There are two primary mechanisms by which this damage occurs.

Direct Radiation Damage

Radiation impacts sufficient energy to DNA bonds to directly cause breaks.

Indirect Radiation Damage

Indirect damage occurs when radiation interactions outside of the DNA to produce free radicals which in turn damage DNA.

    • A free radical is an atom or molecule carrying an unpaired electron in an outer shell.
    • Hydroxide (OH-) is the most common free radical produced by radiation within the body. Hydroxide is produced in the body through interaction of water (H2O).

DNA Strand Breaks

What is DNA?

DNA (deoxyribonucleic acid) is shaped like a double helix. Each side of the helix is known as a "strand."

DNA Composition

Backbone comprised of deoxyribose (a sugar) and a phosphate group bound together by covalent bonds.

Nucleobases (base pairs) encode genetic information. The four bases are Cytosine (C), Guanin (G), Adenine (A), and Thymine (T). Importantly, only C-G and A-T pairs are allowed.

Single Strand Breaks

Single strand breaks occur when only one strand is damaged. This type of DNA damage in considered sub-lethal because they can generally be repaired.

When multiple single strand breaks occur close together on the same strand, the damage may be non-repairable (i.e. lethal).

Double Strand Breaks

Double strand breaks occur when both strands are broken within a few base pairs. This type of DNA damage in generally non-repairable and may result in cell death, sterilization (inability to reproduce), or mutation.

Factors Influencing Radiosensitivity

Law of Bergonie and Tribondeau

The law of Bergonie and Tribondeau states: The radiosensitivity of  a cell is directly proportional to reproductive rate and is inversely proportional to its degree of differentiation. 

This means that radiosensitivity increases with:

  • Increased rate of cell division
  • Low degree of specialization (stem cells are very radiosensitive)
  • Higher metabolic rate
  • Increased oxygenation
  • Increased length of time they are actively proliferating

Cell Cycle Stage

The cell cycle is the series of distinct phases leading to duplication of DNA and, ultimately, cell division. The cell cycle is of interest because the radiosensitivity of a cell is dependent upon its stage in the cell cycle.

G1: First growth phase

The cell is performing normal functions and growing.

S: Synthesis phase

During the S phase, the cell replicates its DNA. S phase is the least radiosensitive phase of the cell cycle because the cell contains two copies of its DNA.

G2: Second growth phase

The cell is again performing normal functions and continues to grow.

M: Mitosis phase

The cell divides into two cells in a process called mitosis. Mitosis is the most radiosensitive phase both because mitosis is sensitive to disruption and because the cell is well oxygenated during this phase.

Key Point: Radiosensitivity of the mitosis phase is 10-100 times greater than in non-dividing phases! The synthesis phase is the least radiosensitive phase.

Temporal Aspects of Radiation Damage

Although radiation absorption is essentially instantaneous (~10-15 s), radiation damage accumulation from single strand breaks depends both on the temporal rate of damage and on the rate at which the cell repairs sublethal damage.

If DNA damage cannot be repaired, cell death may take between weeks and month depending on the type of cell. This is the reason for the delay in late effects described in the linear quadratic model.

Tissue Responses

Radiation Effects

Acute and Chronic Effects

Acute effects occur shortly after radiation exposure. Examples include inflammation and erythema.

Chronic effects occur after a delay period. Examples include alopecia and fibrosis.

Data from ICRP 103 and ICRP 60

Exposed PopulationExcess Relative Risk of Cancer per Sv
Entire population5.5% - 6.0%
Adults only4.1% - 4.8%

 Stochastic (Probabilistic) Effects

Stochastic effects are those in which the probability of effect increases with dose and the effect is binary. Because of their probabilistic nature, there is no dose threshold for stochastic effects.

Examples of stochastic effects

  • Cancer induction
  • Cell death

Non-Stochastic Effects

Non-stochastic effects are those in which the magnitude of effect increases with increased dose. Non-stochastic effects have a minimum dose, a threshold dose, below which the effect is not observed.

Examples of non-stochastic effects

  • Erythema (skin reddening)
  • Cataract induction

Total Body Exposure Responses

Total body exposure responses are non-stochastic effects. The magnitude effect is dependent upon absorbed dose.

Exposure Response Phases

1. Prodromal Phase: Minutes to days after exposure

Prodromal phase is marked by the emergence of initial symptoms. This often includes nausea, vomiting, diarrhea and general low-level symptoms.

2. Latent Phase: Days to a week after exposure

During the latent phase, symptoms which began in the prodromal phase are temporarily reduced or eliminated.

3. Manifest illness: Days to weeks after exposure

 In this phase, the primary symptoms, outlined in the table at right, occur.

4. Death or recovery

SyndromeDose RangeSigns/SymptomsSurvival
Hematopoietic Syndrome1-6Gy
  • Drop in blood cell count.
  • Infections due to low blood cells
  • Poor wound healing
  • Moderate fever
  • Possible headache
  • Short-term cognitive impairment
  • Alopecia (after 3 Gy)
  • 50-95%
  • Recovery in 6-8 weeks
Gastrointestinal Syndrome6-30Gy
  • Symptoms associated with Hematopoietic Syndrome
  • Nausea
  • Vomiting
  • Loss of appetite
  • Abdominal pain
  • Death is common without exotic treatments such as bone marrow transplant
  • 0-50%
  • >99% fatality above 8Gy
  • Cause of death is generally gastrointestinal infection
  • Survival time of 2 days to 2 weeks
Neurovascular Syndrome>30Gy
  • Symptoms associated with Gastrointestinal Syndrome
  • Dizziness
  • Headache
  • Seizures
  • Tremor
  • Ataxia
  • Loss of consciousness
  • 0% survival
  • Survival time 1-2 days

Organ Responses

Parallel and Serial Organs

Organs vary in their sensitivity not only to the amount of radiation dose they receive, but also to the distribution of that dose. Organs may be divided into sub-units. Each sub-unit may be functional or non-functional following radiation damage. Sub-units may be as small as cells or as large as lobes of the liver.

Serial Organs are organs in which disabling any sub-unit causes the entire organ to fail.

Parallel Organs are organs in which many or all of the sub-units must be disabled to cause organ failure.

Serial OrgansParallel Organs
Spinal CordLungs
Brain StemLiver
Optic StructuresKidneys

Organ Specific Exposure Responses

OrganToxicityDose Threshold
Skin (Hair)Epilation (hair loss)3Gy
SkinErythema (skin reddening)6Gy
SkinDry Desquamation (sores)12Gy
SkinWet Desquamation (oozing sores)25Gy
SkinRadionecrosis (loss of skin)50Gy
EyesCataract5Gy
Whole bodyDeath3-5Gy

Therapeutic Ratio

Therapeutic ratio is the ratio of normal tissue tolerance to a lethal tumor dose. Much of conventional fractionated radiotherapy centers on attempting to optimize therapeutic ratio.

Key Point: Tumors with therapeutic ratio >1 are said to be radiosensitive.

Clinical Radiobiology

Linear Quadratic Model (LQM)

The linear quadratic model is the most commonly used model of cell survival used in radiation therapy. LQM is clinically useful in determining the efficacy of a given fractionation scheme.

  • D is the dose administered
  • S(D) is the fraction of cells to survive a given dose.
  • αD is the probability of cell death arising from a single "double hit" producing a double strand break.
  • βD2 is the probability of cell death arising from multiple "single hits," each generating single strand breaks, close enough together to cause a double strand break.

LQM Assumptions

  • DNA hits, events that damage DNA, are random with probability proportional to dose.
  • Double strand breaks are required for cell sterilization (i.e. death or, equivalently, inability to reproduce)
  • There are two methods of producing a double strand break
    1. A single hit damages both DNA strands (αD)
    2. Two hits in close proximity, each breaking a single strand, produce a double strand break (βD2)

Alpha/Beta Ratio

Alpha/Beta ratio relates the relative importance of single and double strand breaks in causing cell death. In effect, alpha/beta ratio indicates how resistant a cell is to radiation damage.

High alpha/beta ratios (around 10) indicate that single hit damage does not readily accumulate to lethal effects and there is little increase in cell killing per unit dose for higher total doses. That is, high alpha/beta ratios indicate a linear plot on the cell survival plot.

Low alpha/beta ratios (1-3) indicate that the accumulation of multiple single hits produces increased lethality for higher doses. Cell survival plots for low alpha/beta ratio cells have a greater curvature.

Data from Technical Basis of Radiation Therapy, 5th Edition Table 1

Tissue TypeAlpha/Beta
Tumor and Early Effects10
Late Complications3
Late CNS Effects2
Prostate1.5

Alpha/Beta radio impacts the curvature of the cell survival curve for radiotherapy.

Key Point: High alpha/beta ratio tumors benefit from fractionation because it reduces normal tissue toxicity without significant reduction in tumor lethality.

Fractionation

Fractionation is the division of a treatment dose into several discrete treatments (fractions). Fractionation allows the oncology team to leverage the differences in alpha/beta ratio between tumors (~10) and normal tissue (~3) to improve the therapeutic ratio.

Common Fractionation Schemes

Standard Fractionation

  • 1.8 - 2Gy per fraction
  • 1 treatment per day, Monday - Friday
  • Assuming 109 tumor cells and an expected kill ratio of 50% per 2Gy fraction, 30 fractions is sufficient to reduce the number of expected surviving cells to less than 1.

BID (Hyperfractionation)

  • 2 fractions delivered per day (separated by at least 6 hours)
  • 1.2Gy per fraction
  • Reduced late effects such as those to the central nervous system
  • Early effects, such as those to the skin or GI tract, are unchanged

HypoFractionation

  • >2Gy per fraction
  • Up to 1 fraction per day
  • Increases late effected
  • Decreases early effects

Radiosurgery

  • 1-5 fractions with doses ranging between 8 and 90 Gy per fraction
  • Such high dose fractions potentially invalidate the linear quadratic model and are currently not well understood.
  • Radiosurgery focuses on avoiding dose to normal tissue rather than on improving therapeutic ratio. As a result, it is commonly used only for small lesions and special cases such as trigeminal neuralgia.

Factors in Fractionated Radiotherapy (The Five Rs)

1. Repair

Sublethal damage is repaired in both tumors and healthy cells. Differences in repair rate may be exploited.

2. Repopulation

Cell division and population growth occurs, albeit to an inhibited degree, between fractions.

3. Reoxygenation

Tumors often have poor vasculature and, as a result, are anoxic. This lack of oxygen makes tumor cells more radioresistant. Fractionation allows time for some tumor cells to die which improves oxygenation of the remaining cells. This effect increases radiosensitivity during subsequent fractions.

4. Redistributions

The distribution of cells in a given cell cycle stage changes with fractionation.

5. Recruitment

Tumor cells that were previously in non-dividing cells may become dividing cells during the course of treatment. That is, a cell irradiated one day in the radioresistant S phase may be irradiated in the radiosensitive M phase on a subsequent fraction.

Key Point: 100% kill is not required for long-term survival without recurrence. Rather, it may be sufficient to eradicate the metastatic spread and bring the tumor into partial remission.

Evaluating Fractionation Schemes

Biologically Effective Dose (BED)

Biologically effective dose allows for simple assessment of the biological effect of a particular dose and fractionation scheme, given the alpha/beta ratio of the tissue in question. Two fractionation schemes are equally effective when their BED values are equal.

  • is the number of fractions delivered
  • d is the dose per fraction
  • α/β is the alpha over beta value derived from the linear quadratic model
Equivalent Dose (EQD)

Equivalent dose, often notated EQDwhere x is the reference dose per fraction, is used to find an equivalent fractionation scheme to a reference scheme. Because standard 2Gy per fraction is most common, EQD2 is most often used.

Key Point: Because of the differences in alpha/beta ratio, an EQD2 cannot be found both for tumor control and normal tissue toxicity simultaneously. Often, the new fractionation scheme will be limited by normal tissue tolerances.

Relative Biological Effectiveness

Relative biological effectiveness (RBE) is the ratio of absorbed dose required to produce an effect under reference conditions to the absorbed dose required to produce the same effect under another set of conditions. RBE is a useful concept because the effect of a given dose is determined not just by the absorbed dose but also by the type of radiation and the circumstances under which the radiation is delivered.

  • Deval is the dose which is being evaluated
  • Dref is the reference dose
  • NOTE: Doses here are isoeffective dose

Key Point: A positive RBE indicates that the dose under investigation is more effective than the reference dose.

Factors influencing RBE

  • Linear Energy Transfer (LET)
  • Radiation quality
  • Fractionation
  • Dose rate
  • Biological system in question
  • Biological conditions

Oxygen Enhancement Ratio (OER)

Oxygen is a radiosensitizer which improves the RBE compared to anoxic conditions. Oxygen enhancement ratio is a special care of BRE measuring the impact of oxygenation on radiosensitivity.

  • OER for photons, X-rays and gamma rays, is typically between 2.5 and 3
  • Neutrons have a low OER, typically around 1.5

Key Point: High LET particles, such as protons and alpha particles, produce more radiation damage per unit path length. This increases the probability of double strand breaks for a given absorbed dose in increases RBE.

Knowledge Test

1. A 5.6cm3 tumor contains approximately how many cells?

Question 1 of 3

2. Which of the following is not a reason to use hypofractionation?

Question 2 of 3

3. Which of the following is not a true  statement regarding the law of Bergonie and Tribondeau?

Question 3 of 3


 

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