Tolerância tecidos

normais e reirradiação

Isabel Bravo – 29 Janeiro 2011

 Radiobiology is of great importance for
radiotherapy. It allows the optimization of a
radiotherapy schedule for individual
patients in regard to:
• Total dose and number of fractions
• Overall time of the radiotherapy course
• Tumour control probability (TCP) and normal
tissue complication probability (NTCP)

Isabel Bravo – Jan 2011

 Radiobiology: normal tissues
• Sparing of normal tissues is essential for good
therapeutic outcome
• The radiobiology of normal tissues may be
even more complex 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 more
important

Isabel Bravo – Jan 2011

Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
Isabel Bravo – Jan 2011
 Different tissue types
• Serial organs (e.g. • Parallel organs (e.g.
spine) lung)

Isabel Bravo – Jan 2011

 Different tissue types
• Serial organs (e.g. • Parallel organs (e.g.
spine) lung)

Effect of radiation on the organ is different

Isabel Bravo – Jan 2011

 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 to
whole organ failure (e.g. spinal cord)

Isabel Bravo – Jan 2011

 Classification of radiation
effects in normal tissues
• Early or acute reactions • Late reactions
– Erythema – Telangectesia
– Nausea – Spinal cord injury,
– Vomiting paralysis
– Tiredness – Fibrosis
– Fistulas
• Occurs typically during • Occurs later than 6
course of RT or within 3 months after
months irradiation

Isabel Bravo – Jan 2011

 Classification of radiation
effects in normal tissues
• Early or acute • Late reactions
reactions

Late effects can be a result

of severe early reactions:
consequential radiation injury

Isabel Bravo – Jan 2011

 Late effects
• Often termed complications

• Can occur many years after treatment

• Can be graded:
» RTOG / EORTC
» CTCAE v3
» WHO

Isabel Bravo – Jan 2011

 A comment on vascularisation
• Blood vessels play a very important role
in determining radiation effects both for
tumours and for normal tissues.
• Vascularisation determines oxygenation
and therefore radiosensitivity
• Late effects may be related to vascular
damage

Isabel Bravo – Jan 2011

 Radiobiological models
• Many models exist
• Based on clinical experience, cell experiments
or just the beauty or simplicity of the
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.

Isabel Bravo – Jan 2011

 LQ Model

• α Lethal cell kill

• β Sub-lethal damage

Isabel Bravo – Jan 2011

Isabel Bravo – Jan 2011
 Biological effectiveness
E/α = BED = (1 + d / (α/β)) * D = RE * D

• BED = biologically effective dose, the dose

which would be required for a certain effect at
infinitesimally small dose rate (no beta kill)

• RE = relative effectiveness

Isabel Bravo – Jan 2011

 BED useful to compare the effect of
different fractionation schedules

• Need to know α/β ratio of the tissues

concerned.

• α/β typically lower for normal tissues than

for tumour

Isabel Bravo – Jan 2011

 What does the α/β-ratio tell?

• “α“
• linear component
• no or little repair
• less sensitive to fractionation
• “β”
• exponential component
• potential for repair
• more sensitive to fractionation
• “α/β“
• high: less potential for repair = less sensitive to
fractionation
• low: more potential for repair = more sensitive to
fractionation
Isabel Bravo – Jan 2011
 α/β ratios
• Large α/β ratios • Small α/β ratio
• α/β = 10 to 20 • α/β = 2
– Early or acute – Late reacting
reacting tissues tissues, e.g. spinal
– Most tumours cord
– potentially prostate
cancer

Isabel Bravo – Jan 2011

 • Reoxygenation
• Redistribution
• Repair
• Repopulation (or Regeneration)
• Radiosensitivity

Isabel Bravo – Jan 2011

Isabel Bravo – Jan 2011
 Time, dose and fractionation
• Need to optimize fractionation schedule
for individual circumstances
• Parameters:
Total dose
Dose per fraction
Time between fractions
Total treatment time

Isabel Bravo – Jan 2011

 Use of the LQ model in
external beam radiotherapy:
• Calculate ‘equivalent’ fractionation
schemes
• Determine radiobiological parameters
• Determine the effect of treatment breaks
– e.g. Do we need to give extra dose for the
long weekend break?

Isabel Bravo – Jan 2011

 Normal tissue tolerance

The tolerance doses is critically dependent on:

• the total dose
• the fractionation schedule
• 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

Isabel Bravo – Jan 2011

 What are these tolerance doses?

Isabel Bravo – Jan 2011

 • What is the “pathology” of radiation damage
• LQ-model
• pathophysiology
• mechanisms of repair
• How is radiation damage evaluated and
categorized?
• RTOG-EORTC, LENT-SOMA, CTCAE vs. 3.0
• Radiation damage of specific organs
• Which factors might influence radiation
damage?

Isabel Bravo – Jan 2011

 Pathophysiology of radiation damage

Isabel Bravo – Jan 2011

 Pathophysiology of radiation damage

Isabel Bravo – Jan 2011

 Normal tissue tolerance
• 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 to

predict radiosensititvity?
Isabel Bravo – Jan 2011
 Normal tissue tolerance
Linear Quadratic model

Isabel Bravo – Jan 2011

 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

Isabel Bravo – Jan 2011

 Linear Quadratic model

Effect of fractionation
• fractionation
• sublethal damage repair
• single dose/hypofractionation
• no or minor repair
• Repair
• “fast”: 10-20 min
• “slow”: > 2 h
• intercellular repair: hours
– days
• “half-time” of repair: 2
hours

Isabel Bravo – Jan 2011

 What are the α/β-values?

Early responding α/β(Gy)

• Jejunal mucosa 13
• Colonic mucosa 7
• Skin epithelium 10
• Bone marrow 9

Human tumors 6-25

Late responding α/β(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
Isabel Bravo – Jan 2011
 Linear Quadratic model
What do we have?
an α/β- value for different tissues

What do we want?
• calculate an isoeffective dose-fractionation
schedule
• predict normal tissue tolerance probability
(NTCP)

What do we need?
• the „endpoint“ (=side effect)

Isabel Bravo – Jan 2011

 QUANTEC
Quantitative Analyses of Normal
Tissue Effects in the Clinic

Isabel Bravo – Jan 2011

 QUANTEC
1. Clinical Significance
2. Endpoints
3. Challenges Defining Volumes
4. Review of Dose / Volume Data
5. Factors Affecting Risk
6. Mathematical / Biological Models
7. Special Situations
8. Recommended Dose / Volume Limits
9. Future Toxicity Studies
10. Toxicity Scoring

Isabel Bravo – Jan 2011