The Radiobiology Behind Dose
Fractionation
Bill McBride
Dept. Radiation Oncology
David Geffen School Medicine
UCLA, Los Angeles, Ca.
wmcbride@mednet.ucla.edu
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Objectives
• To understand the mathematical bases behind survival curves
• Know the linear quadratic model formulation
• Understand how the isoeffect curves for fractionated radiation
vary with tissue and how to use the LQ model to change dose
with 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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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 convenntional 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?
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In theory, knowing relevant radiobiological parameters
one day may predict the response for
• Dose given in a single or a small number of fractions
• SBRT, SRS, SRT, HDR or LDR brachytherapy, protons,
cyberknife, gammaknife
• Non-uniform dose distributions optimized by IMRT
• e.g. dose “painting” of radioresistant tumor subvolumes
• Combination therapies with chemo- or biological agents
• Different RT options when tailored by molecular and
imaging theragnostics
• If you know the molecular profile and tumor phenotype, can you
predict the best delivery method?
• Biologically optimized treatment planning
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The First Radiation Dosimeter
prompted the use of dose fractionation
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Modeling Radiation Responses
Assumes that ionizing ‘hits’ are random events in space
Which are fitted by a Poisson Distribution
P of x = e-m.mx/x!
where m = mean # hits, x is a hit
P survival
(when x = 0)
100 targets 100 hits m=1 e-1=0.368
100 targets 200 hits m=2 e-2=0.137
100 targets 300 hits m=3
e-3=0.05
N.B. Lethal hits in DNA are not really randomly
distributed, e.g. condensed chromatin is more
sensitive, but it is a reasonable approximation
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This Gives a Survival Curve Based on a Model where one
hit will eliminate a single target
1.0
0.37
•
When there is single lethal hit per target
•
•
S.F.= e-1 = 0.37
This is the mean lethal dose D0
D10 = 2.3 xD0
S.F.
•
0.1
0.01
0.001
In general, S.F. = e-D/D0
or LnS.F. = -D/D0
or S.F. = e-aD , i.e. D0 = 1/a
Where a is the slope of the curve and D0 the
reciprocal of the slope
D0
D10
DOSE Gy
How many logs of cells would be killed
by 23 Gy if D0 = 1 Gy?
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Puck and Marcus, J.E.M.103, 563, 1956
First in vitro mammalian survival curve
Eukaryotic Survival Curves are Exponential, but have
a ‘Shoulder’
Two component model
n
single
lethal
hits
1.0
0.1
0.01
Accumulation of
sub-lethal
damage
0.001
dose
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Two Component Model
• Two Component Model
single
lethal
hits
n
1.0
(or single target, single hit +
multi-target (n), single hit)
1D 0 =
reciprocal
initial slope
S.F.
0.1
• S.F.=e-D/1D0[1-(1-e-D/nD0)n]
Single hit
0.01
Accumulation
of sublethal
damage
nD 0
Extrapolation
Number
Accumulated
damage
=
reciprocal
final slope
0.001
DOSE Gy
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Mean Inactivation Dose (Do)
•
•
•
•
Virus D0 approx. = 1500 Gy
E. Coli D0 approx. = 100 Gy
Mammalian bone marrow cells D0 = 1 Gy
Generally, for mammalian cells D0 = 1-1.5 Gy
Why the differences?
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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.
SBRT/SRS often aims at TISSUE ABLATION
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Does this Matter?
Prescribed Dose:
25 fractions of 2Gy = 50Gy
Hot spot: 110%
Physical dose: 55Gy
Biological dose: 60.5Gy
“Double Trouble”
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Linear Quadratic Model
•
1.0
aD
S.F. = e-aD
Single lethal hits
bD2
S.F. 0.1
Cell kill is the result of single lethal hits
plus accumulated damage from 2
independent sublethal events
S.F. = e-(aD+bD2)
Single lethal hits plus
accumulated damage
0.01
0.001
a/b in Gy
DOSE Gy
•
The generalized formula is E = aD + bD2
•
For a fractionated regimen E= nd(a + bd) = D (a + bd)
Where d = dose per fraction and D = total dose

a/b is dose at which death due to single lethal
lesions = death due to accumulation of sublethal
lesions i.e. aD = bD2 and D = a/b in Gy
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• Over 90% of radiation oncologists use the LQ model:
– it is simple and has a microdosimetric underpinning
 a/b is large (> 6 Gy) when survival curve is almost
exponential and small (1-4 Gy) when shoulder is
wide
– the a/b value quantifies the sensitivity of a
tissue/tumor to fractionated radiation.
• But:
– Both a and b vary with the cell cycle. At high doses,
S phase and hypoxic cells become more important.
– The a/b ratio varies depending upon whether a cell
is quiescent or proliferative
– The LQ model best describes data in the range of 1 6Gy and should not be used outside this range
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The Linear Quadratic Formulation
• Does not work well at high dose/fx
• Assumes equal effect per fraction
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HT29 cells
N.B. Survival curves may
deviate from L.Q. at low and
high dose!!!!
• Certain cell lines, and tissues, are
hypersensitive at low doses of 0.050.2Gy.
• The survival curve then plateaus over
0.05-1Gy
• Not seen for all cell lines or tissues, but
has been reported in skin, kidney and
lung
• At high dose, the model probably does
not fit data well because D2 dominates the
equation
Lambin et al. Int J Radiat Biol 63:639 1993
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1
limiting slope/
low dose rate
S.F.
Multi-fraction survival curves can be
considered linear if sublethal damage is
repaired between fractions
they have an extrapolation number (n) = 1.0
5 fractions
.1
•The resultant slope is the effective D0
•eD0 is often 2.5 - 5.0Gy and eD10 5.8 - 11.5Gy
•S.F. = e-D/eD0
3 fractions
Single dose
.01
0
4
8
12
16
Dose (Gy)
20
•If S.F. after 2Gy = 0.5, eD0 = 2.9Gy; eD10 =
6.7Gy and 30 fractions of 2 Gy (60Gy) would
reduce survival by (0.5)30 = almost 9 logs (or
60/6.7)
•If a 1cm tumor had 109 clonogenic cells, there
would be an average of 1 clonogen per tumor
and cure rate would be about 37%
24
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Thames et al Int J Radiat Oncol Biol Phys 8: 219, 1982.
•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
• a/b 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
Douglas and Fowler Rad Res 66:401, 1976
Showed and easy way to arrive at an a/b ratio
Reciprocal
total dose
for an isoeffect
Slope = b
Intercept = a
Dose per fraction
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Response to Fractionation Varies With Tissue
1
1
Acute Responding
Tissues a/b = 10Gy
S.F.
.1
Late Responding
Tissues - a/b = 2Gy
0
4
8
12
Dose (Gy)
Fractionated
Late Effects
.1
Fractionated
Acute Effects
Single Dose
Late Effects
a/b = 2Gy
a/b is high (>6Gy) when survival
curve is almost exponential and low
(1-4Gy) when shoulder is wide
.01
S.F.
Single Dose
Acute Effects
a/b = 10Gy
.01
16
0
4
8
12
16
Dose (Gy)
20
Fractionation spares late responding tissues
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a/b=3Gy; 1.5Gy/fx
a/b=30Gy; 1.5Gy/fx
80
2.0Gy/fx
70
a/b=30Gy; 4Gy/fx
60
D new
a/b=3Gy; 4Gy/fx
50
40
30
20
20
30
40
50
60
70
80
D old
Note how badly late responding tissues respond to increased dose/fraction
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Sensitivity of Tissue to Dose Fractionation
can be estimated by the a/b ratio
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What are a/b ratios for human cancers?
In fact, for some tumors e.g. prostate, breast, melanoma, soft tissue sarcoma,
and liposarcoma a/b ratios may be moderately low
Prostate
– Brenner and Hall IJROBP 43:1095, 1999
• comparing implants with EBRT
 a/b ratio is 1.5 Gy [0.8, 2.2]
– Lukka JCO 23: 6132, 2005
• Phase III NCIC 66Gy 33F in 45days vs 52.5Gy 20F in 28 days
• Compatible with a/b ratio of 1.12Gy (-3.3-5.6)
Breast
– Owen, J.R., et al. Lancet Oncol, 7: 467-471, 2006 and Dewar et al JCO, ASCO
Proceedings Part I. Vol 25, No. 18S: LBA518, 2007.
• UK START Trial
– 50Gy in 25Fx c.w. 39Gy in 13Fx; or 41.6Gy in 13Fx [or 40Gy in 15Fx (3 wks)]
• Breast Cancer a/b = 4.0Gy (1.0-7.8)
• Breast appearance a/b = 3.6Gy; induration a/b = 3.1Gy
If fractionation sensitivity of a cancer is similar to dose-limiting healthy
tissues, it may be possible to give fewer, larger fractions without
compromising effectiveness or safety
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What total dose (D) to give if the dose/fx
(d) is changed
New
Dnew (dnew + a/b )
Old
= Dold (dold + a/b )
So, for late responding tissue, what total dose in 1.5Gy
fractions is equivalent to 66Gy in 2Gy fractions?
Dnew (1.5+2) = 66 (2 + 2)
Dnew = 75.4Gy
NB: Small differences in a/b for late responding tissues can make a
big difference in estimated D!
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Biologically Effective Dose (BED)
2)
S.F. = e-E = e-(aD+bD
E = nd(a + bd)
E/a = nd(1+d/a/b)
Biologically
Effective Dose
Total dose
Relative
Effectiveness
35 x 2Gy = B.E.D.of 84Gy10 and 117Gy3
NOTE: 3 x 15Gy = B.E.D.of 113Gy10 and 270Gy3
Equivalent to 162 Gy in 2Gy Fx -unrealistic!
(Fowler et al IJROBP 60: 1241, 2004)
Normalized total dose2Gy
= BED/RE
= BED/1.2 for a/b of 10Gy
= BED/1.67 for a/b of 3Gy
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4Rs OF DOSE FRACTIONATION
• Assessed by varying the
time between 2 or more
doses of radiation
700R
1500R
Repopulation
Redistribution
Repair
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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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Repair
• “Repair” between fractions should be complete - N.B. we are
dealing with tissue recovery rather than DNA repair
– Correction for incomplete repair is possible (Thames)
• In general, time between fractions for most tissues should be >6
hours
• Some tissues, such as CNS, recover slowly making b.i.d. treatment
inadvisable
• Bentzen - Radiother Oncol 53, 219, 1999
– CHART analysis HNC showed that late morbidity was less than
would be expected assuming complete recovery between
fractions
– Is the T1/2 for recovery for late responding normal tissues 2.54.5hrs?
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Regeneration in Normal Tissues
• The lag time to regeneration varies with the tissue
• In acute responding tissues,
– Regeneration has a considerable sparing effect
• In human mucosa, regeneration starts 10-12 days into a 2Gy Fx
protocol and increases tissue tolerance by at least 1Gy/dy
– Prolonging treatment time has a sparing effect
– As treatment time is reduced, acute responding tissues become
dose-limiting
• In late responding tissues,
– Prolonging overall treatment time beyond 6wks has little effect, but
prolonging time to retreatment may increase tissue tolerance
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Repopulation in Tumor Tissue
Rat rhabdosarcoma
Human SCC head and neck
T2 T3
70
Total
Dose
(2 Gy equiv.)
55
local control
no local control
40
Treatment Duration
Hermens and Barendsen, EJC 5:173, 1969
4 weeks to start of accelerated repopulation.
Thereafter T1/2 of 4 days = loss of 0.6Gy per day
Withers, H.R., Taylor, J.M.G., and Maciejewski, B.
Treatment breaks are often “bad”
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Acta Oncologica 27:131, 1988
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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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TCP
or NTC
Tumor control
Late responding tissue
complications
Complication-free cure
TCP
or NTC
Accelerated
Fractionation
Hyperfractionation
Dose
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Other Sources of Heterogeneity
•
Biological Dose
– Cell cycle
– Hypoxia/reoxygenation
– Clonogenic “stem cells” (G.F.)
•
•
•
•
S.F
hypoxic
oxic
Dose
Number
Intrinsic radiosensitivity
Proliferative potential
Differentiation status
Phillips, J Natl Cancer Inst 98:1777, 2006
•
Physical Dose
– Need to know more about the importance of dose-volume constraints
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• Heterogeneity within and between between
tumors in dose-response characteristics, often
resulting in large error bars for a/b values
• In spite of this, the outcome of clinical studies of
altered fractionation generally fit the models,
within the constraints of the clinical doses used
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Definitions
• Conventional fractionation
– Daily doses (d) of 1.8 to 2 Gy
– Dose per week of 9 to 10 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 a/b ratio and there is no therapeutic
advantage to be gained with respect to late complications
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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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Hyperfractionated
Barcelona (586), Brazil (112), RTOG 90-03 (1113), EORTC 22791 (356),
Toronto (331)
Very accelerated
CHART (918), Vancouver (82), TROG 91-01 (350),GORTEC 94-02 (268)
Moderately accelerated
RTOG 90-03 (1113), DAHANCA (1485), EORTC 22851 (512) CAIR (100),
Warsaw (395)
Other
EORTC 22811 (348), RTOG 79-13 (210)
7623 patients in 18 randomized phase III trials !!
HNSCC only will be discussed
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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
LOCAL CONTROL
Years
Horiot 1992
control: 70 Gy - 35-40 fx - 7-8 wks
p = 0.02
SURVIVAL
p = 0.08
Years
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Very Accelerated: CHART (N = 918)
Dische 1997
54 Gy - 36 fx - 12 days
control: 66 Gy - 33 fx - 6.5 wks
Loco-regional control
conventional
CHART
Favourable outcome with CHART:
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Survival
conventional
CHART
well differentiated tumors
larynx carcinomas
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CHART: Morbidity
Dische 1997
54 Gy - 36 fx - 12 days
control: 66 Gy - 33 fx - 6.5 wks
P = 0.04
P = 0.003
Moderate/severe subcutaneous
fibrosis and oedema
Mucosal ulceration and
deep necrosis
P = 0.04
P = 0.009
Laryngeal oedema
Moderate/severe dysphagia
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Moderately Accelerated
Overgaard 2000
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
Local control
DAHANCA 6
DAHANCA 7
Nodal control
DAHANCA 6 + 7
Disease-specific survival
DAHANCA 6 + 7
5 fx/wk
6 fx/wk
73%
56%
81% p=0.04
68% p=0.009
Overall survival
Late effects (edema, fibrosis)
n.s.
n.s.
87%
65%
.
89% n.s.
72% p=0.04
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Moderately Accelerated
CAIR: 7-day-continuous accelerated irradiation (N = 100)
Skladowski 2000
66-72 Gy - 33-36 fx - 5 wks
68.4-72 Gy - 38-40 fx - 5.5 wks
control: 70-72 Gy - 35-36 fx - 7 wks
control: 66.6-72 Gy - 37-40 fx - 7.5-8 wks
OVERALL SURVIVAL
Probability
CAIR
CONTROL
log-rank p=0.00001
Follow-up (months)
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RTOG 90-03, Phase III comparison of fractionation schedules
in Stage III and IV SCC of oral cavity, oropharynx, larynx,
hypopharynx (N = 1113)
Fu 2000
Conventional
70 Gy - 35 fx - 7 wks
Hyperfractionated
81.6 Gy - 68 fx - 7 wks
Accelerated with split
67.2 Gy - 42 fx - 6 weeks (including 2-week split)
Accelerated with
Concomitant boost
72 Gy - 42 fx - 6 wks
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RTOG 90-03, loco-regional control
Fu 2000
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RTOG 90-03, survival
Fu 2000
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RTOG 90-03, adverse effects
Acute
Fu 2000
Maximum toxicity
Conventional
Hyperfract
Concom Acc +
per patient
boost
split
Grade 1
15%
4%
4%
7%
Grade 2
57%
39%
36%
41%
Grade 3
35%
54%
58%
49%
Grade 4
0%
1%
1%
2%
Late
Maximum toxicity
per patient
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Conventional
11%
50%
19%
8%
1%
Hyperfract
8%
56%
19%
9%
0%
Concom Acc +
boost
split
7%
16%
44%
50%
29%
20%
8%
7%
1%
1%
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Toxicity of RT in HNSCC
Acute effects in accelerated or hyperfractionated RT
Author
Regimen
Horiot (n=356)
HF
Horiot (n=512)
Acc fx + split
Dische (n=918)
CHART
Fu (n=536)
Acc fx(CB)
Fu (n=542)
Acc fx + split
Fu (n=507)
HF
Skladowski (n=99) Acc fx 26%
Grade 3-4 mucositis
Cont
Exp
49%
67%
50%
67%
43%
73%
25%
46%
25%
41%
25%
42%
56%
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Altered fractionation in head and neck
cancer: meta-analysis
Randomized trials 1970-1998 (no postop RT)
15 trials included (6515 patients)
Bourhis, Lancet 2006
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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Conclusions for HNSCC
• Hyperfractionation increases TCP and protects late responding tissues
• Accelerated treatment increase TCP but also increases acute toxicity
• What should be considered standard for patients treated with radiation
only?
– Hyperfractionated radiotherapy
– Concomitant boost accelerated radiotherapy
• Fractions of 1.8 Gy once daily when given alone, cannot be considered
as an acceptable standard of care
• TCP curves for SSC are frustratingly shallow … selection of tumors?
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Conclusions for HNSCC
• The benefit derived from altered fractionation is consistent
with can be of benefit but should be used with care
• 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
• Start treatment on a Monday and finish on a Friday, and
consider working Saturdays
• Never change a winning horse!
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Other Major Considerations
• Not all tumors will respond to hyper or accelerated
fractionation like HNSCC, especially if they have a low
a/b ratio.
• High single doses or a small number of high dose per
fractions, as are commonly used in SBRT or SRS
generally aim at tissue ablation. Extrapolating based on a
linear quadratic equation to total dose is fraught with
danger.
• Addition of chemotherapy or biological therapies to RT
always requires caution and preferably thoughtful preconsideration!!!
• Don’t be scared to get away from the homogeneous field
concept, but plan it if you intend to do so.
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Questions:
The Radiobiology Behind Dose Fractionation
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109. A basic assumption in modeling of
radiation responses is that lethal ionizing
events are
– Random events occurring in cell nuclei
– Random events in space as defined by the
Poisson distribution
– A Gaussian distribution
– Logarithmic dose response curves
#2 – This mathematical assumption is the basis of the
log linear survival curve
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110. D0 is
– Is a measure of the shoulder of a survival
curve
– Is the mean lethal dose for the linear
portion of the dose-response curve
– Represents the slope of the log linear
survival curve
– Is constant at all levels of radiation effect
#3 – It is the mean lethal dose which is also 1/slope.
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111. Dq is
– The inverse of the terminal slope of the
survival curve
– A measure of the inverse of the initial slope
of the survival curve
– A measure of the shoulder of the survival
curve
– A measure of the intercept of the terminal
portion of the survival curve on the y axis
#3 – The terminal slope is extrapolated back to the x
axis.
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112. If Dq for a survival curve is 2Gy, what dose
is equivalent to a single dose of 6Gy given in
2 fractions, assuming complete repair and no
repopulation between fractions.
– 4 Gy
– 6 Gy
– 8 Gy
– 10 Gy
#3 – When dose is fractionated Dq is repeated, so it is
6+2Gy.
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113. If hematopoietic bome marrow stem cells have a
Do of 1Gy, and there is no shoulder on the survival
curve, what fraction will survival a lethal dose of
6.9Gy?
1. 0.0001
2. 0.001
3. 0.01
4. 0.37
#2 – If Do is 1Gy, D10 is 2.3Gy i.e. 3xD10.
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114. If 90% of a tumor is removed by surgery,
what does this likely represent in term of
radiation dose given in 2 Gy fractions?
– 1-2 Gy
– 3-4 Gy
– 6-10 Gy
– 10-20 Gy
– 20-30 Gy
#2 – The eDo for fractionated radiation is around 2.55.0Gy and the eD10 will be 2.3 times this.
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115. What is true for the a/b ratio
– It is unitless
– It is a measure of the shoulder of the
survival curve
– It measures the sensitivity of a tissue to
changes in size of dose fractions
– It is the ratio where the number of nonrepairable lesions equals that for repairable
lesions
#3 – Low a/b ratios reflect the sensitivity of late
responding tissues to fractionation and high a/b ratios
the lack of sensitivity of acute responding tissues.
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116. The alpha component in the linear
quadratic formula for a survival curve can be
thought of as representing
– Unrepairable DNA double strand breaks
– Lethal single track events
– Multiply damaged sites in DNA
– Damage that can not be altered by hypoxia
#2 – The beta component may be thought of as
representing intertrack accumulated damage
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117. Which parameter contributes most to cell
killing in standard clinical fractionated
regimens in RT
– The a/b ratio
– Do
– Alpha
– Beta
– The extrapolation number
#3 – Single lethal hits predominate at low doses (2Gy).
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118. If cells have a Do of 2 Gy, assuming no shoulder,
what dose is required to kill 95% of the cells?
– 6 Gy
– 12 Gy
– 18 Gy
– 24 Gy
– 30 Gy
#1 – 3xDo or e-3 = 0.05
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119. The extrapolation number N for a multifraction survival curve, allowing complete
repair between fractions and no repopulation
is
–1
–<1
– >1
– Dependent on the size of the dose per
fraction
#1 – It is a straight log-linear curve with the slope
extrapolating to the x/y intersect at 1.0.
WMcB2009
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120. The extrapolation number N for a single
dose neutron survival curve is
–1
–<1
– >1
– Dependent on the size of the dose per
fraction
#1 – It is a straight log-linear curve with the slope
extrapolating to the x/y intersect at 1.0.
WMcB2009
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121. The extrapolation number N for a low dose
rate survival curve is
–1
–<1
– >1
– Dependent on the size of the dose per
fraction
#1 – It is a straight log-linear curve with the slope
extrapolating to the x/y intersect at 1.0.
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122. The inverse of the slope of a multifraction
survival curve (effDo) for x-rays is generally
within the range
– 1.0-1.5 Gy
– 1.5-2.5 Gy
– 2.5-5.0 Gy
– 5.0-10.0 Gy
#3 – This obviously has a lot of assumption, but is not a
bad ‘ball-park’ figure to remember.
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123. If the effDo for a multifraction survival curve
is 3.5 Gy, what dose would cure 37% of a
series of 1cm diameter tumors (109
clonogens).
– 56 Gy
– 64 Gy
– 72 Gy
– 80 Gy
#3 – The eD10 would be about 8Gy (2.3x3.5Gy), so
72Gy would reduce survival to on average 1 surviving
cell or e-1 and would give 37% cure. Or TCP= e-m.SF
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124. If the effDo for a multifraction survival curve is
3.5 Gy, what dose would cure 87% of a series of
1cm diameter tumors (109 clonogens).
– 56 Gy
– 64 Gy
– 72 Gy
– 80 Gy
#3 – 2 more eDo doses would reduce survival from 1 to
e-2 or 0.135 cells/tumor. TCP = e-0.135 = 87%
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125. If a tumor has an effective Do of 3.5 Gy, what is
the S.F. after 70 Gy?
– 2 x 10-11
– 2 x 10-9
– 2 x 10-7
– 2 x 10-5
– 2 x 10-3
#2 – The eD10 would be about 8Gy (2.3x3.5Gy), so
70Gy would reduce survival to about 2 x 10-9.
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126. If 16 x 2 Gy fractions reduce survival by 10-4, what
dose would be needed to reduce survival to 10-10?
– 50 Gy
– 60 Gy
– 64 Gy
– 70 Gy
– 80 Gy
#5 – 16 + 16+ 8 x 2Gy = 80Gy
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127. If 16 x 2 Gy fractions reduce survival by 10-4, what
is the effective Do?
– 2.0 Gy
– 2.3 Gy
– 3.0 Gy
– 3.5 Gy
– 3.8 Gy
#4 – The eD10 would be about 8Gy, so eDo would be
3.5Gy.
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128. The a/b ratio for mucosal tissues is
closest to
– 1 Gy
– 3 Gy
– 5 Gy
– 10 Gy
#4 – Acute responding tissues have a high a/b ratio.
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129. Which of the following human tumors has
recently been thought to have an a/b ratio of
1-2 Gy
– Oropharyngeal Ca
– Prostate Ca
– Glioblastoma
– Colorectal Ca
#2 –Several studies have suggested this and therefore
that hypofractionation may be of value.
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130. If tissue tolerance is 60Gy at 2 Gy/fraction and 40
Gy at 4Gy/fraction, what is its a/b ratio?
– 1 Gy
– 2 Gy
– 4 Gy
– 10 Gy
– 20 Gy
#2 – Dnew (dnew + a/b ) = Dold (dold + a/b )
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131. It is decided to treat a patient with hypofractionation
at 3 Gy/fraction instead of the conventional schedule
of 60 Gy in 2 Gy fractions. What total dose should be
delivered in order for the risk of late normal-tissue
damage to remain unchanged assuming an a/b for
late damage of 3 Gy?
– 40 Gy
– 48 Gy
– 50 Gy
– 55.4 Gy
– 75 Gy
#3 – Dnew (3 + 3 ) = 60 (2 + 3 ) = 50Gy
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132. Hyperfractionation using a fraction size of 1.2 Gy is
replacing a standard 70Gy in 2Gy fractions for HNSCC.
Assume full repair of sublethal damage between
fractions and an a/b of 3 Gy, what total dose should be
used to maintain the same level of late complications?
– 42 Gy
– 58 Gy
– 70 Gy
– 83 Gy
– 117 Gy
#4 – Dnew (1.2 + 3 ) = 70 (2 + 3 ) = 83Gy
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133. A standard treatment of 70 Gy in 2 Gy/fraction is
changed to 83Gy in 1.2 Gy. Assuming no proliferation
and complete repair between fractions, an a/b of 3 Gy
for late responding tissue and 12 Gy for tumor, what
would be the therapeutic gain.
– 6%
– 12%
– 18%
– 24%
#2 – The response of the tumor is not going to change
much, so you can guess 83/70 = 12%
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134. Which of the following sites is the least
suitable for b.I.d. treatment
– Head and neck
– Brain
– Lung
– Prostate
#2 – The brain does not respond well to b.i.d. treatment
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135. The rationale behind accelerated
fractionation is
– To spare late responding normal tissue
– To combat encourage tumor reoxygenation
– To exploit redistribution in tumors
– To combat accelerated repopulation in
tumors
#4 – The idea is to get the dose in during the lag time
before accelerated repopulation starts.
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136. The CHART regimen for HNSCC of 54Gy in 36
fractions over 12 days compared with 66 Gy in 33
fractions in 6.5 weeks, overall showed
– Superior locoregional control, no increase in
overall survival, increased late effects
– Superior locoregional control that translated into
an increase in overall survival, no change in late
effects
– No change in locoregional control and overall
survival, decreased late effects
– Superior locoregional control, no increase in
overall survival, increased acute effects
#3 – The aim of this trial was not to increase response
but to decrease normal tissue reactions, unlike a later
NSCLC CHART trial
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137. DAHANCA 6 and 7 clinical trials with 6668Gy given in 6 compared to 7 weeks
– Was a hyperfractionation trial
– Involved treating patients 6 days a week
– Showed no increase in local control
– Showed no increase in disease-specific
survival
#2 – with better outcomes…
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138. RTOG 90-03 compared hyperfractionation,
accelerated fractionation with a split, and accelerated
fractionation with a boost. It showed
– Hyperfractionation to be superior in terms of locoregional control and late effects
– Accelerated fractionation with a split to be
equivalent to hyperfractionation in terms of locoregional control
– There to be no advantage to altered fractionation
– Accelerated fractionation to be superior to
hyperfractionation
#1 – The lead investigator was K. Fu.
WMcB2009
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