D201 Tolerância tecidos normais e reirradiação

8/7/2019 D201 Tolerncia tecidos normais e reirradiao

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Tolerncia tecidos

Isabel Bravo 29 Janeiro 2011


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Radiobiology is of great importance forradiotherapy. It allows the optimization of a

radiotherapy schedule for individual

patients in regard to:

Isabel Bravo Jan 2011

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:


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)


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


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,


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


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


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


. 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


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


et a ce

Sub-lethal damage


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Biological effectivenessE/ = BED = (1 + d / (/)) * D = RE * D


= 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


.

/ 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


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


reacting tissues

Most tumours

tissues, e.g. spinal

cord

potentially prostate

cancer


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Reoxygenation

Redistribution


Repopulation (or Regeneration)

Radiosensitivity


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Time, dose and fractionation Need to optimize fractionation schedule

for individual circumstances


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


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


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



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




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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)


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



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


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



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


. ac ors ec ng s6. Mathematical / Biological Models

7. Special Situations

8. Recommended Dose / Volume Limits

9. Future Toxicity Studies

10. Toxicity Scoring

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D201 Tolerância tecidos normais e reirradiação