Physics 300: WK 1

Radiobiology

What is radiobiology?

• Study of the effects of ionising radiation on biological tissues and living organisms

• Combines radiation physics, radiation chemistry, biology and mathematical models

• Examines:

  • Events following radiation energy absorption

  • Tissue damage produced

  • How tissue compensates for damage

What is the role of radiobiology in radiotherapy?

• Provides the scientific basis for radiotherapy

• Explains tumour and normal tissue responses to radiation

• Helps develop new treatment strategies

• Helps determine treatment schedules

How do X-rays and gamma rays interact with tissue?

• Produce secondary electrons

• Secondary electrons cause further ionisation and excitation

• Damage can then occur through:

  • Direct action

  • Indirect action

• X-rays and gamma rays are indirectly ionising radiation

What is direct action of radiation?

• Secondary electrons interact directly with critical targets

• Causes direct damage to molecules such as DNA (deoxyribonucleic acid)

What is indirect action of radiation?

• Radiation ionises water

• Produces free radicals, especially hydroxyl radicals (•OH)

• Free radicals then damage critical targets such as DNA

• Responsible for around two-thirds of biological damage from low LET (Linear Energy Transfer) radiation

Which types of radiation are directly vs indirectly ionising?

• Indirectly ionising:

  • X-rays

  • Gamma rays

  • Neutrons

• Directly ionising:

  • Electrons

  • Beta particles

  • Protons

  • Alpha particles

  • Carbon ions

What are the stages of radiation interaction and their time scales?

• Physical: 10⁻¹⁶–10⁻¹² seconds → ionisation of atoms

• Chemical: 10⁻¹²–10⁻² seconds → DNA damage

• Biological: seconds–hours → DNA repaired, misrepaired or unrepaired

• Clinical: hours–years → cell death, mutation, carcinogenesis, early/late effects

What DNA damage does 1 Gy (Gray) of low LET radiation typically produce?

• About 10⁵ ionisations

• 1000 base damages

• About 1000 SSBs (Single-Strand Breaks)

• About 40 DSBs (Double-Strand Breaks)

What is the difference between SSBs and DSBs?

• SSB (Single-Strand Break):

  • Usually readily repaired

  • Opposite strand can act as a template

• DSB (Double-Strand Break):

  • Much more difficult to repair

  • May result in cell death

• Incorrect repair can result in mutation

What are the three classifications of radiation damage?

• Lethal damage

  • Irreversible

  • Irreparable

  • Leads to cell death

• SLD (Sublethal Damage)

  • Can be repaired within hours

  • Additional SLD can combine to become lethal

• PLD (Potentially Lethal Damage)

  • Can be modified by environmental conditions after irradiation

What is Acute Radiation Syndrome?

• Response following a high acute total-body radiation dose

• Generally associated with doses above 1 Gy

• Main syndromes:

  • Haematopoietic/bone marrow

  • Gastrointestinal

  • Central nervous system

What is haematopoietic syndrome?

• Usually around 1–10 Gy

• Damages bone marrow stem cells

• ↓ White blood cells, platelets and red blood cells

• Can cause:

  • Infection

  • Bleeding

  • Anaemia

• Recovery may be possible with treatment

What is gastrointestinal syndrome?

• Occurs above approximately 10 Gy

• Nausea, vomiting and prolonged diarrhoea

• Loss of intestinal villi and breakdown of mucosal barrier

• Causes:

  • Dehydration

  • Electrolyte imbalance

  • Infection/sepsis

• Very high doses → death may occur within 1–2 weeks

What is CNS (Central Nervous System) syndrome?

• Around >20–50 Gy

• Severe nausea and vomiting

• Disorientation and loss of coordination

• Respiratory distress

• Seizures and coma

• Caused by brain oedema/dysfunction of critical CNS cells

• Death usually within hours–days

What does a cell survival curve show?

• Relationship between:

  • Radiation dose

  • Surviving fraction of cells

• Most commonly described using the LQ (Linear Quadratic) model

What is the Linear Quadratic model?

• Describes cell survival after radiation

• Has two components:

  • Linear component (αD) → proportional to dose

  • Quadratic component (βD²) → proportional to dose²

• Equation:

  • SF(D) = exp(−αD − βD²)

• α = initial slope/linear cell killing

• β = curvature/quadratic cell killing

What factors affect the cell survival curve?

• LET (Linear Energy Transfer)

• Oxygen concentration

• Cell cycle

• Dose rate

What is LET (Linear Energy Transfer)?

• Amount of energy deposited along the radiation track

• High LET:

  • More ionisations per centimetre

  • More biological damage

  • More DSBs and complex damage

  • Damage is harder to repair

How do high and low LET radiation differ on a survival curve?

• Low LET:

  • Less steep curve

  • Broader shoulder

  • More repair

• High LET:

  • Steeper curve

  • Small/no shoulder

  • Less repair

What is RBE (Relative Biological Effectiveness)?

• Compares biological effectiveness of different types of radiation

• RBE = dose of reference radiation ÷ dose of test radiation

• Both doses must produce the same biological effect

How does oxygen affect radiosensitivity?

• Oxygen is a radiosensitiser

• Oxygen makes cells more sensitive to radiation

• Enhances free-radical damage

• Reduces free-radical recombination

• Inhibits repair of free-radical damage

Why is tumour hypoxia a problem in radiotherapy?

• Tumour cells are often hypoxic (low oxygen)

• Hypoxic cells are more radioresistant

• Therefore, they are harder to kill with radiation

How do hypoxic and oxic cells differ on a survival curve?

• Hypoxic:

  • Less steep

  • Broader shoulder

  • Better repair/more radioresistant

• Oxic:

  • Steeper

  • Smaller/no shoulder

  • Less repair/more radiosensitive

How does cell-cycle phase affect radiosensitivity?

• Radiosensitivity varies throughout the cell cycle

• Most sensitive: M (Mitosis) and G2

• Less sensitive: G1 and S

• G1/S cells have more time to repair before mitosis

• Sensitivity order shown in the slides:

  • M > G2 > G1 > early S > late S

How does dose rate affect cell survival?

• Lower dose rate:

  • More time to repair SLD (Sublethal Damage)

  • Less biological damage

• Higher dose rate:

  • More biological damage

  • More complex damage

What is the main goal of radiotherapy?

• Deliver enough radiation to control/eradicate the tumour

• Minimise irradiation of surrounding normal tissues

• Maximise TCP (Tumour Control Probability)

• Minimise NTCP (Normal Tissue Complication Probability)

What are TCP and NTCP?

• TCP (Tumour Control Probability):

  • Probability of controlling the tumour

  • Want this high

• NTCP (Normal Tissue Complication Probability):

  • Probability of complications in normal tissue

  • Want this low

• Typical treatment:

  • TCP > 0.5

  • NTCP < 0.05

What is fractionation?

• Dividing the total radiation dose into multiple smaller doses/fractions

• Same total physical dose can have different biological effects depending on fraction size

• More fractions → less damage, particularly to normal tissue

What are the 4 Rs of radiotherapy?

• Repair

• Redistribution (reassortment)

• Reoxygenation

• Repopulation

What is Repair in fractionated radiotherapy?

• Mammalian cells repair radiation damage between fractions

• Mainly involves repair of SLD (Sublethal Damage)

• Allows normal tissue to repair before next fraction

• Most repair occurs around 2–6 hours after radiation

What is Redistribution in fractionated radiotherapy?

• Cells have different radiosensitivities throughout cell cycle

• Some tumour cells may initially be in resistant G1/S phases

• Between fractions they progress through the cell cycle

• May enter radiosensitive G2/M phases before the next fraction

• Therefore → greater tumour cell killing

What is Reoxygenation in fractionated radiotherapy?

• Tumours contain hypoxic, radioresistant cells

• Between fractions, surviving tumour cells can become reoxygenated

• Compressed blood vessels may reopen

• More oxygen → cells become more radiosensitive to the next fraction

• Oxygen can diffuse approximately 150 μm (micrometres)

What is Repopulation in fractionated radiotherapy?

• Normal tissues can repopulate between fractions

• Helps reduce acute side effects

• BUT surviving tumour cells can also repopulate

• Tumour repopulation can partially counteract radiotherapy cell killing

Overall, why is fractionation beneficial?

• Spares normal tissue through:

  • Repair of sublethal damage

  • Repopulation

• Increases tumour damage through:

  • Reoxygenation

  • Redistribution into radiosensitive cell-cycle phases

What are early (acute) radiation effects?

• Appear within days–weeks

• Mainly affect rapidly dividing tissues

• Examples:

  • Skin

  • Gastrointestinal epithelium

  • Mucosa

  • Bone marrow

• Often repairable

• Usually reversible

What are late (chronic) radiation effects?

• Appear months–years after radiotherapy

• Mainly affect slowly proliferating tissues

• Examples:

  • Lung

  • Spinal cord

  • Liver

  • CNS (Central Nervous System)

  • Bone

  • Cartilage

• Damage is never completely repaired

What are radioprotectors?

• Chemical agents that reduce normal cell response to radiation

• Scavenge free radicals

• Can donate hydrogen atoms to assist chemical repair of DNA damage

• Reduce normal tissue complications

• Examples:

  • Cysteine

  • Cysteamine

  • Amifostine

What are radiosensitisers?

• Chemical agents that increase tumour cell response to radiation

• Increase tumour cell killing

• Generally promote direct and indirect effects of radiation

What is the α/β (alpha/beta) ratio?

• Dose in Gy (Gray) where cell killing from the linear and quadratic components is equal

• High α/β:

  • More linear survival curve

• Low α/β:

  • More curved survival curve

What α/β ratios are associated with different tissues?

• Early responding tissues + most tumours:

  • High α/β ≈ 10 Gy

• Late responding tissues:

  • Low α/β ≈ 3 Gy

What is BED (Biologically Effective Dose)?

• Used to compare the biological effects of different fractionation schedules

• Requires the α/β ratio of the tissue

• Formula:

  • BED = nd[1 + d/(α/β)]

• n = number of fractions

• d = dose per fraction

How do you calculate BED?

Example from the lecture:

• Total dose = 60 Gy

• n = 30 fractions

• d = 2 Gy/fraction

• α/β = 10 Gy

• BED = 30 × 2[1 + (2/10)]

• BED = 72 Gy

What happens to the required total dose if dose per fraction increases while keeping the same BED?

• Fewer fractions are required

• Example from slides:

  • 60 Gy / 30 fractions at 2 Gy/fraction

  • Equivalent BED with 3 Gy/fraction ≈ 18.5 fractions

  • Total physical dose ≈ 55.5 Gy