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X- or -radiation is sparsely ionizing; most damage can be
repaired
4 nm

Repairable Sublethal Damage

2 nm

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4Rs OF DOSE FRACTIONATION

These are radiobiological mechanisms that impact the

response to a fractionated course of radiation therapy

• Repair of sublethal damage

– spares late responding normal tissue preferentially
• Redistribution of cells in the cell cycle
– increases acute and tumor damage, no effect on late responding normal
tissue
• Repopulation
– spares acute responding normal tissue, no effect on late effects,
– danger of tumor repopulation
• Reoxygenation
– increases tumor damage, no effect in normal tissues

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In general, history has shown repeatedly that single

high doses of radiation do not allow a therapeutic
differential between tumor and critical normal tissues.

Dose fractionation does.

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

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Relevance of Radiobiology to Clinical Fractionation
Protocols
Conventional treatment:
Tumors are generally irradiated with 2Gy dose per fraction delivered
daily to a more or less homogeneous field over a 6 week time period to
a specified total dose

The purpose of conventional dose fractionation is to increase dose to the

tumor while PRESERVING NORMAL TISSUE FUNCTION
• Deviating from conventional fractionation protocol impacts outcome
• How do you know what dose to give; for example if you want to change dose
per fraction or time? Radiobiological modeling provide the guidelines. It uses
– Radiobiological principles derived from preclinical data
– Radiobiological parameters derived from clinical altered fractionation
protocols
• hyperfractionation, accelerated fractionation, some hypofractionation schedules

The number of non-homogeneous treatment plans (IMRT) and extreme hypofractionated

treatments are increasing. Do existing Isabel
models cope?
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Radiobiology 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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Radiobiological models
• Many models exist
• Based on clinical experience, cell experiments
or 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

• α Lethal cell kill

• β Sub-lethal damage

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It is hypothesized that the lethal lesions are

large double strand breaks with Multiply
4 nm Damaged Sites (MDS) that can not be
repaired. They are more likely to occur at the
end of a track

Unrepairable Multiply Damaged Site

Single lethal hit

2 nm Also known as  - type killing

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At high dose, intertrack repairable Sublethal
Damage may Accumulate forming
unrepairable, lethal MDS

Also known as  - type killing

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Linear Quadratic model

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Two Component Model

• Two Component Model

n single (or single target, single hit +
lethal multi-target (n), single hit)
1.0 hits
1D0 =
reciprocal
• S.F.=e-D/1D0[1-(1-e-D/nD0)n]
S.F.
0.1 initial slope
Single hit Extrapolation
Number
Accumulated
damage

0.01
Accumulation
of sublethal nD0 =
reciprocal
damage final slope
0.001

DOSE Gy

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Linear Quadratic model

single-hit injury (e –αD)

= exponential curve
(linear in half-log cell surv. curve)

• multi-hit (cumulative)
injury (e –βD2)
= continuously bending curve
related by a coefficient “ β“
to the square of the dose

• α/β = dose, at which single

and multi-hit mechanisms
contribute equally to cell killing

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The linear quadratic model

1
0 2 4 6 8 10
Probability of cell survival

0.1

0.01

cell kill (low a/b)

cell kill (high a/b)

0.001
Dose (Gy)

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The linear quadratic model

1
0 2 4 6 8 10
Alpha determines
initial slope
Probability of cell survival

0.1

Beta determines
0.01 curvature
cell kill (low a/b)
cell kill (high a/b)

0.001
Dose (Gy)
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.
•The slope of an isoeffect curve
changes with size of dose per
fraction depending on tissue
type

• Acute responding tissues have

flatter curves than do late
responding tissues

•  measures the sensitivity of

tumor or tissue to fractionation i.e.
it predicts how total dose for a given
effect will change when you change
the size of dose fraction

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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
– breast cancer
cancer

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Sensitivity of Tissue to Dose
Fractionation can be estimated by
the  ratio

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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 α/β
1
0 2 4 6 8 10
Probability of cell survival

0.1

0.01 cell kill (low a/b)

cell kill (high a/b)
fractionated (low a/b)
fractionated (low a/b)

0.001
Dose (Gy)

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Response to Fractionation Varies With Tissue

1 1

Acute Responding
S.F. S.F. Fractionated
Tissues  = 10Gy
Late Effects

.1
.1 Fractionated
Late Responding
Tissues -  = 2Gy Acute Effects

Single Dose Single Dose

/ is high (>6Gy) when survival Late Effects Acute Effects
curve is almost exponential and low  = 2Gy  = 10Gy
.01 (1-4Gy) when shoulder is wide
.01
0 4 8 12 16 0 4 8 12 16 20
Dose (Gy) Dose (Gy)

Fractionation spares late responding tissues

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Impact of fraction size on tumor and

normal tissues response
• Radiobiological data show that both tumores and acutely
tissues are less sensitive to change in fraction size then
late responding tissues.

• The sensitivity to changes in fraction size for each tissue

can be quantified with the use of the α/β ratio which
marks the shape of the fractionation response.

• Dose per fraction is the dominant factor in determining

late effects.
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Impact of fraction size on tumor and

normal tissues response
• A high α/β ratio (7 - 20 Gy), as in acutely responding
tissues and in tumors, indicates a more linear survival
response of the target cells.

• A low α/β ratio (0,5 – 6 Gy), as in late responding

tissues, defines a survival curve of the target cells that is
significantly curved.

• Therefore, the effects of fractionation are relatively larger

in the latter than in the former tissues.
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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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• Reoxygenation
• Redistribution
• Repair
• Repopulation (or Regeneration)
• Radiosensitivity

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Repopulation/
Regeneration
• Normal tissue repopulation 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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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 in Tumor Tissue

Rat rhabdosarcoma Human SCC head and neck

T2 T3

70
Total local control
Dose
(2 Gy equiv.)
55 no local control

40
Treatment Duration
4 weeks to start of accelerated repopulation.
Thereafter T1/2 of 4 days = loss of 0.6Gy per day

Treatment breaks are often “bad”

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The 5 Rs of radiotherapy: Influence on

time between fractions, t, and overall
treatment time, T

• Reoxygenation • Need minimum T

• Redistribution
• Repair
• Repopulation (or
Regeneration)
• Need minimum t
• Need minimum t for
normal tissues
• Need to reduce T for
tumour

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The 5 Rs of radiotherapy: Influence on

time between fractions, t, and overall
treatment time, T

• Reoxygenation • Need minimum T

• Need minimum t
• Redistribution
Cannot achieve •allNeed
at once -
minimum t for
• RepairOptimization of schedule
normal tissues
for individual circumstances
• Need to reduce T for
• Repopulation (or
Regeneration) tumour

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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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Altered Fractionation

or

How to optimally distribute

dose over time
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Players
• Total dose (D)
• Dose per fraction (d)
• Interval between fractions (t)
• Overall treatment time (T)
• Tumor type
• Acute reacting normal tissues
• Late reacting normal tissues
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Definitions
• Conventional fractionation
– Dose per week of 9 to 10 Gy
– Daily doses (d) of 1.8 to 2 Gy
– Total dose (D) of 40 to 70 Gy

• Hyperfractionation
– The number of fractions (N) is increased
– T is kept the same
– Dose per fraction (d) less than 1.8 Gy
– Two fractions per day (t)

Rationale: Spares late responding tissues

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Definitions
• Accelerated fractionation
• Shorter overall treatment time
– Dose per fraction of 1.8 to 2 Gy
– More than 10 Gy per week
Rationale: Overcome accelerated tumor repopulation

• Hypofractionation
– Dose per fraction (d) higher than 2.2 Gy
– Reduced total number of fractions (N)
Rationale: Tumor has low  ratio and there is no therapeutic
advantage to be gained with respect to late complications

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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
– breast cancer
cancer

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Conventional

70 Gy - 35 fx - 7 wks

Hyperfractionated
81.6 Gy - 68 fx - 7 wks

Very accelerated
with reduction of dose
54 Gy - 36 fx - 12 days

Moderately accelerated

72 Gy - 42 fx - 6 wks

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EORTC hyperfractionation trial in oropharynx cancer (N
= 356)
Oropharyngeal Ca T2-3, N0-1

80.5 Gy - 70 fx - 7 wks control: 70 Gy - 35-40 fx - 7-8 wks

SURVIVAL p = 0.08
LOCAL CONTROL p = 0.02

Years Years

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Very Accelerated: CHART (N = 918)

54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx - 6.5 wks

Loco-regional control Survival

conventional conventional
CHART CHART

Favourable outcome with CHART: well differentiated tumors

larynx carcinomas
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Moderately Accelerated
DAHANCA 6: only glottic, (N = 694)
DAHANCA 7: all other sites, + nimorazole (N = 791)

66-68 Gy - 33-34 fx - 6 wks control: 66-68 Gy - 33-34 fx - 7 wks

Actuarial 5-year rates 5 fx/wk 6 fx/wk

Local control
DAHANCA 6 73% 81% p=0.04
DAHANCA 7 56% 68% p=0.009
Nodal control
DAHANCA 6 + 7 87% . 89% n.s.
Disease-specific survival
DAHANCA 6 + 65% 72% p=0.04
7
n.s.
n.s.
Overall survival
Late effects (edema, fibrosis)
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Altered fractionation in head and neck cancer:
meta-analysis
Randomized trials 1970-1998 (no postop RT) Bourhis, Lancet 2006
15 trials included (6515 patients)

Survival benefit: 3.4% (36% 39% at 5 years, p = 0.003)

Loco-regional control benefit: 7% (46.5% 53% at 5 years, p < 0.0001)

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% Loss of local control/day

“CONVENCIONAL”

Larynx 2.5 Maciejewski et al, 1983

Oropharynx 2.3 Wang, 1988
Head & neck 2.0 Bataini et al, 1989
Head & neck 1.7 Mendenhall et al, 1989
Larynx 2.9 Taylor et al, 1991
Head & neck 1.0 Pajak et al, 1991
Larynx 1.7 Barton et al, 1992
Larynx 1.6 Robertson et al, 1996
Head & neck 1.2 Roberts et al, 1994
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% Loss of local control/day

“CERVIX CA”

1.1 Fyles et al, 1992

0.3 Lanciano et al, 1993
1.4 Girinsky et al, 1993
0.7 Petereit et al, 1995
0.5 Pedersen et al, 1994
0.8

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Conclusions for HNSCC

• Benefits from altered fractionation
• In principle, tumors should be treated for an overall
treatment time that is as short as possible consistent with
acceptable acute morbidity, but with a dose per fraction
that does not compromise late responding normal tissues,
or total dose.

• Avoid treatment breaks and treatment prolongation

wherever possible – and consider playing “catch-up” if
there are any

• working Saturdays

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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 gaps
– e.g. Do we need to give extra dose for the
long weekend break?

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Relevance of Radiobiology to Clinical Fractionation
Protocols
Conventional treatment:
Tumors are generally irradiated with 2Gy dose per fraction delivered
daily to a more or less homogeneous field over a 6 week time period to
a specified total dose
The purpose of conventional dose fractionation is to increase dose to the
tumor while PRESERVING NORMAL TISSUE FUNCTION
• Deviating from conventional fractionation protocol impacts outcome
• How do you know what dose to give; for example if you want to change dose
per fraction or time? Radiobiological modeling provide the guidelines. It uses
– Radiobiological principles derived from preclinical data
– Radiobiological parameters derived from clinical altered fractionation
protocols
• hyperfractionation, accelerated fractionation, some hypofractionation schedules

The number of non-homogeneous treatment plans (IMRT) and extreme

hypofractionated treatments are increasing. Do existing models cope?

Isabel Bravo 50
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• Know the linear quadratic model formulation and how to use the
LQ model to change dose and dose per fraction

• Understand the 4Rs of radiobiology as they relate to clinical

fractionated regimens and the sources of heterogeneity that
impact the concept of equal effect per fraction

• Know the major clinical trials on altered fractionation and their

outcome

• Recognize the importance of dose heterogeneity in modern

treatment planning

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

Isabel Bravo 52