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Tolerncia tecidos
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Radiobiology is of great importance forradiotherapy. It allows the optimization of a
radiotherapy schedule for individual
patients in regard to:
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Total dose and number of fractions
Overall time of the radiotherapy course
Tumour control probability (TCP) and normal
tissue complication probability (NTCP)
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Radiobiology: normal tissues
Sparing of normal tissues is essential for good
therapeutic outcome
The radiobiology of normal tissues may be
even more com lex as the one of tumours:
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different organs respond differently
there is a response of a cell organization
not just of a single cell
repair of damage is in general moreimportant
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Different tissue types
Serial organs (e.g.
spine)
Parallel organs (e.g.
lung)
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Different tissue types Serial organs (e.g.
spine)
Parallel organs (e.g.
lung)
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Effect of radiation on the organ is different
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Volume effects
The more normal tissue is irradiated in
parallel organs
the more chance that a whole organ fails
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The greater the volume the smaller the
dose should be
In serial organs even a small volume
irradiated beyond a threshold can lead towhole organ failure (e.g. spinal cord)
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Classification of radiation
effects in normal tissues Early or acute reactions
Erythema
Nausea
Late reactions
Telangectesia
Spinal cord injury,
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Vomiting
Tiredness
Occurs typically during
course of RT or within 3
months
paralysis
Fibrosis
Fistulas
Occurs later than 6
months afterirradiation
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Classification of radiation
effects in normal tissues
Early or acute
reactions
Late reactions
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Late effects can be a result
of severe early reactions:
consequential radiation injury
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Late effects Often termed complications
Can occur many years after treatment
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Can be graded:
RTOG / EORTC
CTCAE v3
WHO
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A comment on vascularisation Blood vessels play a very important role
in determining radiation effects both for
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. Vascularisation determines oxygenation
and therefore radiosensitivity
Late effects may be related to vasculardamage
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Radiobiological models Many models exist
Based on clinical experience, cell experiments
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mathematics
One of the simplest and most used is the so
called linear quadratic or alpha/beta model
developed and modified by Thames, Withers,Dale, Fowler and many others.
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LQ Model
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et a ce
Sub-lethal damage
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Biological effectivenessE/ = BED = (1 + d / (/)) * D = RE * D
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= o og ca y e ect ve ose, t e osewhich would be required for a certain effect at
infinitesimally small dose rate (no beta kill)
RE = relative effectiveness
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BED useful to compare the effect of
different fractionation schedules
Need to know / ratio of the tissues
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.
/ typically lowerfor normal tissues than
for tumour
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What does the /-ratio tell?
linear component
no or little repair
less sensitive to fractionation
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exponential component
potential for repair
more sensitive to fractionation
/
high: less potential for repair = less sensitive to
fractionation low: more potential for repair = more sensitive to
fractionation
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/ ratios Large / ratios
/ = 10 to 20
Small / ratio
/ = 2
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reacting tissues
Most tumours
tissues, e.g. spinal
cord
potentially prostate
cancer
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Reoxygenation
Redistribution
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Repopulation (or Regeneration)
Radiosensitivity
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Time, dose and fractionation Need to optimize fractionation schedule
for individual circumstances
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Total dose
Dose per fraction
Time between fractions
Total treatment time
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The tolerance doses is critically dependent on:
the total dose
the fractionation schedule
Normal tissue tolerance
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the volume of normal tissue irradiated TD 5/5 = 5% probability of severe sequelae in
5 years
TD 50/5= 50% probability of severe sequelae
in 5 years
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What are these tolerance doses?
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What is the pathology of radiation damage LQ-model
pathophysiology
mechanisms of repair
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categorized?
RTOG-EORTC, LENT-SOMA, CTCAE vs. 3.0
Radiation damage of specific organs
Which factors might influence radiation
damage?
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Pathophysiology of radiation damage
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Pathophysiology of radiation damage
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we have radiation damage to cells
SSB, DSB and other DNA lesions
we have multiple repair-mechanisms
fast, intermediate, slow
Normal tissue tolerance
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we have different kinds of cell-death
reproductive (mitotic), apoptotic, G1-
arrest
How can we use this knowledge topredict radiosensititvity?
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Linear Quadratic model
Normal tissue tolerance
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What damages can be repaired?
sublethal damage
DNA single strand breaks (SSB)
can be repaired
if not repaired, can be damaged
lethally if hit again (multi-hit)
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lethal damage
DNA double strand break (DSB)
low/no potential for repair
potential lethal damage (PLD)
potential repair in non-proliferating
cells
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Effect of fractionation
fractionation
sublethal damage repair
single dose/hypofractionation
Linear Quadratic model
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no or m nor repa r Repair
fast: 10-20 min
slow: > 2 h
intercellular repair: hours
days
half-time of repair: 2
hours
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What are the /-values?
Early responding /(Gy)
Jejunal mucosa 13
Colonic mucosa 7
Skin epithelium 10
Bone marrow 9
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Human tumors 6-25
Late responding /(Gy)
Spinal cord 1,6 - 5
Kidney 0.5 - 5
Liver 1,4 - 3,5
Lung 2,5 - 6,3
Skin 2,5 - 4,5
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What do we have?
an /- value for different tissues
What do we want?
calculate an isoeffective dose-fractionation
Linear Quadratic model
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schedulepredict normal tissue tolerance probability
(NTCP)
What do we need?
the endpoint (=side effect)
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QUANTEC1. Clinical Significance
2. Endpoints
3. Challenges Defining Volumes
4. Review of Dose / Volume Data
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. ac ors ec ng s6. Mathematical / Biological Models
7. Special Situations
8. Recommended Dose / Volume Limits
9. Future Toxicity Studies
10. Toxicity Scoring