Radiation Protection in Radiotherapy

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Radiation Protection inRadiotherapy
IAEA Training Material on Radiation Protection in
Radiotherapy

• Part 3
• Biological Effects
• Lecture 2 High Doses in Radiation Therapy

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Overview

• Radiobiology is of great importance for
  radiotherapy. It allows the optimization of a
  radiotherapy schedule for individual patients in
  regards to
• 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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Objectives

• To understand the radiobiological background of
  radiotherapy
• To be familiar with the concepts of tumour
  control probability and normal tissue
  complication probability
• To be aware of basic radiobiological models which
  can be used to describe the effects of radiation
  dose and fractionation

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Contents

• 1. Basic Radiobiology
• 2. The linear quadratic model
• 3. The four R s of radiotherapy
• 4. Time and fractionation

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1. Basic Radiobiology

• The aim of radiotherapy is to kill tumor cells
  and spare normal tissues
• In external beam and brachytherapy one inevitably
  delivers some dose to normal tissue

Brachytherapy sources
Beam 2
Beam 1
Beam 3
patient
tumor
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Basic Radiobiology target

• The aim of radiotherapy is to kill tumour cells -
  they may be in a bulk tumor, in draining lymph
  nodes and/or in small microscopic spread.
• Tumour radiobiology is complex - the response
  depends not only on dose but also on individual
  radiosensitivity, timing, fraction size, other
  agents given concurrently (e.g. chemotherapy),
• Several pathways to tumour sterilization exist
  (e.g. mitotic cell death, apoptosis ( programmed
  cell death), )

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Survival curves
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Radiobiology tumor

• Irradiation kills cells
• Different mechanisms of cell kill
• Different radio-sensitivity of different tumours
• Reduction in size makes tumour
• better oxygenated
• grow faster

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Radiobiology micrometastasis

• Tumours may spread first through adjacent tissues
  and lymph nodes nearby
• Need to irradiate small deposits of clonogenic
  cells early
• Less dose required as each fraction of radiation
  reduces the number of cells by a certain factor

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The target in radiotherapy

• The bulk tumour
• may be able to distinguish different parts of the
  tumour in terms of radiosensitivity and
  clonogenic activity
• Confirmed tumour spread
• Potential tumour spread

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Reminder

• Palpable tumour (1cm3) 109cells !!!
• Large mass (1kg) 1012 cells - need three orders
  of magnitude more cell kill
• Microscopic tumour, micrometastasis around 106
  cell - need less dose

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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 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

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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 greater the pain for the patient
• the more chance that a whole organ fails
• Rule of thumb - 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)

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Classification of radiation effects in normal
tissues

• Early or acute reactions
• Skin reddening, erythema
• Nausea
• Vomiting
• Tiredness
• Occurs typically during course of RT or within 3
  months

• Late reactions
• Telangectesia
• Spinal cord injury, paralysis
• Fibrosis
• Fistulas
• Occurs later than 6 months after irradiation

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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 (compare ICRP report
  86)
• Can occur many years after treatment
• Can be graded - lower grades more frequent

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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

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Summary of radiation effects

• Target in radiotherapy is bulk tumour and
  confirmed and/or suspected spread
• Need to know both effects on tumour and normal
  tissues
• Normal tissues need to be considered as a whole
  organ
• Radiation effects are complex - detailed
  discussion of radiation effects is beyond the
  scope of the course
• Models are used to reduce complexity and allow
  prediction of effects...

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There is considerable clinical experience with
radiotherapy, however, new techniques are
developed and radiotherapy is not always
delivered in the same fashion

• Radiobiological models can help to predict
  clinical outcomes when treatment parameters are
  altered (even if they may be too crude to
  describe reality exactly)

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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.

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2. The Linear Quadratic Model

• Cell survival
• single fraction S exp(-(aD ßD2))
• (n fractions of size d S exp(- n (ad ßd2))
• Biological effect
• E - ln S aD ßD2
• E n (ad ßd2) nd (a ßd) D (a ßd)

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Biological effectiveness

• E/a BED (1 d / (a/ß)) 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

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Quick question???

• What is the physical unit for the a/b ratio?

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BED useful to compare the effect of different
fractionation schedules

• Need to know a/b ratio of the tissues concerned.
• a/b typically lower for normal tissues than for
  tumour

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The linear quadratic model
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The linear quadratic model
Alpha determines initial slope
Beta determines curvature
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Rule of thumb for a/b ratios

• Large a/b ratios
• a/b 10 to 20
• Early or acute reacting tissues
• Most tumours

• Small a/b ratio
• a/b 2
• Late reacting tissues, e.g. spinal cord
• potentially prostate cancer

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The effect of fractionation
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Fractionation

• Tends to spare late reacting normal tissues - the
  smaller the size of the fraction the more sparing
  for tissues with low a/b
• Prolongs treatment

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A note of caution

• This is only a model
• Need to know the radiobiological data for
  patients
• Important assumptions
• There is full repair between two fractions
• There is no proliferation of tumour cells - the
  overall treatment time does not play a role.

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3. The 4 Rs of radiotherapy

• R Withers (1975)
• Reoxygenation
• Redistribution
• Repair
• Repopulation (or Regeneration)

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Reoxygenation

• Oxygen is an important enhancement for radiation
  effects (Oxygen Enhancement Ratio)
• The tumour may be hypoxic (in particular in the
  center which may not be well supplied with blood)
• One must allow the tumour to re-oxygenate, which
  typically happens a couple of days after the
  first irradiation

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Redistribution

• Cells have different radiation sensitivities in
  different parts of the cell cycle
• Highest radiation sensitivity is in early S and
  late G2/M phase of the cell cycle

M (mitosis)
G2
G1
S (synthesis)
G1
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Redistribution

• The distribution of cells in different phases of
  the cycle is normally not something which can be
  influenced - however, radiation itself introduces
  a block of cells in G2 phase which leads to a
  synchronization
• One must consider this when irradiating cells
  with breaks of few hours.

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Repair

• All cells repair radiation damage
• This is part of normal damage repair in the DNA
• Repair is very effective because DNA is damaged
  significantly more due to normal other
  influences (e.g. temperature, chemicals) than due
  to radiation (factor 1000!)
• The half time for repair, tr, is of the order of
  minutes to hours

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Repair

• It is essential to allow normal tissues to repair
  all repairable radiation damage prior to giving
  another fraction of radiation.
• This leads to a minimum interval between
  fractions of 6 hours
• Spinal cord seems to have a particularly slow
  repair - therefore, breaks between fractions
  should be at least 8 hours if spinal cord is
  irradiated.

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Repopulation

• Cell population also grows during radiotherapy
• For tumour cells this repopulation partially
  counteracts the cell killing effect of
  radiotherapy
• The potential doubling time of tumours, Tp (e.g.
  in head and neck tumours or cervix cancer) can be
  as short as 2 days - therefore one loses up to 1
  Gy worth of cell killing when prolonging the
  course of radiotherapy

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Repopulation

• The repopulation time of tumour cells appears to
  vary during radiotherapy - at the commencement it
  may be slow (e.g. due to hypoxia), however a
  certain time after the first fraction of
  radiotherapy (often termed the kick-off time,
  Tk) repopulation accelerates.
• Repopulation must be taken into account when
  protracting radiation e.g. due to scheduled (or
  unscheduled) breaks such as holidays.

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Repopulation/ Regeneration

• Also normal tissue repopulate - this is an
  important mechanism to reduce acute side effects
  from e.g. the irradiation of skin or mucosa
• Radiation schedules must allow sufficient
  regeneration time for acutely reacting tissues.

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The 4 Rs of radiotherapy Influence on time
between fractions, t, and overall treatment time,
T

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

• Need minimum T
• Need minimum t
• Need minimum t for normal tissues
• Need to reduce T for tumour

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The 4 Rs of radiotherapy Influence on time
between fractions, t, and overall treatment time,
T

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

• Need minimum T
• Need minimum t
• Need minimum t for normal tissues
• Need to reduce T for tumor

Cannot achieve all at once - Optimization of
schedule for individual circumstances
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4. Time, dose and fractionation

• Need to optimize fractionation schedule for
  individual circumstances
• Parameters
• Total dose
• Dose per fraction
• Time between fractions
• Total treatment time

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Extension of LQ model to include time

• E - ln S n d (a ßd) - ?T
• ? equals ln2/Tp with Tp the potential doubling
  time
• note that the ?T term has the opposite sign to
  the a ßd term indicating tumour growth instead
  of cell kill

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The potential doubling time

• the fastest time in which a tumour can double its
  volume
• depends on cell type and can be of the order of 2
  days in fast growing tumours
• can be measured in cell biology experiments
• requires optimal conditions for the tumour and is
  a worst case scenario

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Extension of LQ model to include time

• E - ln S n d (a ßd) - ?T
• Including Tk ("kick off time") which allows for a
  time lag before the tumour switches to the
  fastest repopulation time
• BED (1 d / (a/ß)) nd - (ln2 (T - Tk)) / aTp

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Evidence for kick off time
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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?

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Calculation of equivalent fractionation schemes

• Assume two fractionation schemes are identical in
  biological effect if they produce the same BED
• BED (1d1/(a/ß))n1d1 (1d2/(a/ß))n2d2
• This is obviously only valid for one
  tissue/tumour type with one set of alpha, beta
  and gamma values
• Example at the end of the lecture

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Brachytherapy

• Typically not a homogenous dose distribution
• Low dose rate treatment possible
• High dose rate treatments are typically given
  with larger fractions than external beam
  radiotherapy
• Pulsed dose rate somewhere in between

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LQ model can be extended to brachytherapy

• HDR with short high dose fractions can be handled
  very similarly to external beam radiotherapy
• However, the dose inhomogeneities inherent in
  brachytherapy (compare parts 6 and 11 of the
  course) make a good calculation difficult.

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LDR brachytherapy

• An extension of the LQ model to cover low dose
  rates with significant repair occurring during
  treatment
• Mathematics developed by R Dale (1985)
• Too complex for present course

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Brachytherapy

• LQ model allows BED calculation for brachytherapy
• comparison possible for external beam and
  brachytherapy
• adding of biologically effective doses possible
• Brachytherapy has the potential to minimize the
  dose to normal structures - probably still the
  most important factor is good geometry of an
  implant

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However, caution is necessary

• All models are just models
• The radiobiological parameters are not well known
• Parameters for a population of patients may not
  apply to an individual patient

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A note on different radiation qualities

• Not only in radiation protection is there a
  different effectiveness of different radiation
  types - however
• The effect of concern is different
• The Relative Biological Effectiveness (RBE
  values) is different - e.g. for neutrons in
  therapy RBE is about 3
• The effect of fractionation may be VERY different

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Adapted from Marco Zaider (2000)
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Comparison of dose response of neutrons and
photons
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Summary

• Radiobiology is essential to understand the
  effects of radiotherapy
• It is also important for radiation protection of
  the patient as it allows minimization of the
  radiation effects in healthy tissues
• There are models which allow to estimate the
  effect of a given radiotherapy schedule
• Caution is necessary when applying a model to an
  individual patient - clinical judgement should
  not be overruled

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Where to Get More Information

• Other sessions
• References
• Steel G (ed) Radiobiology, 2nd ed. 1997
• Hall E Radiobiology for the radiologist, 3rd ed.
  Lippincott, Philadelphia 1988
• Withers R. The four Rs of radiotherapy. Adv.
  Radiat. Biol. 5 241-271 1975

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Any questions?
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Question

• Please calculate the dose per fraction in a five
  fraction treatment for a palliative radiotherapy
  treatment which results in the same biologically
  effective dose to the tumour as a single fraction
  of 8Gy (assume a/b 20Gy (tumour) or 2Gy (spinal
  cord)).

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Answer (part 1)

• Assuming no time effects (i.e. time between
  fractions is large enough to allow full repair
  and the overall treatment time is short enough to
  prohibit significant repopulation during the
  treatment) the biologically effective dose (BED)
  of the treatment schedules can be calculated as
• BED nd (1 d/(a/b)) with n number of
  fractions, d dose per fraction and a/b the
  alphabeta ratio
• BED (tumour, single fraction) 1 8 (1 8/20)
  11.2Gy

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Answer (part 2)

• to get a similar BED in five fractions for the
  tumour, one needs to deliver 2Gy per fraction
  (BED 11Gy)
• BED (spinal cord, single fraction) 1 8 (1
  8/2) 40Gy
• to get a similar BED in five fractions for the
  spinal cord, one needs to deliver 3.1Gy per
  fraction (BED 39.5Gy)
• This example illustrates how much more sensitive
  late reacting normal tissue is to fractionation.
  The single dose of 8Gy is nearly 4 times more
  toxic to spinal cord than to a tumour.