The Radiobiology Behind Dose Fractionation

www.radbiol.ucla.edu
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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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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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How to modify a treatment schedule

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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
Modeling Radiation Responses
N.B. Lethal hits in DNA are not really randomly
distributed, e.g. condensed chromatin is more
sensitive, but it is a reasonable approximation
Assumes that ionizing ‘hits’ are random events in space

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This Gives a Survival Curve Based on a Model where one
hit will eliminate a single target
• 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
• In general, S.F. = e-D/D
0
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
DOSE Gy
1.0
0.1
0.01
0.001
D0
S.F.
D10
0.37
How many logs of cells would be killed
by 23 Gy if D0 = 1 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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Puck and Marcus, J.E.M.103, 563, 1956
First in vitro mammalian survival curve
1.0
0.1
0.01
0.001
Accumulation of
sub-lethal
damage
single
lethal
hits
n
dose
Two component model
Eukaryotic Survival Curves are Exponential, but have
a ‘Shoulder’

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DOSE Gy
1D0 =
reciprocal
initial slope
nD0 =
reciprocal
final slope
S.F.
Two Component Model
• Two Component Model
(or single target, single hit +
multi-target (n), single hit)
• S.F.=e-D/1D0[1-(1-e-D/nD0)n]
Single hit Accumulated
damage
1.0
0.1
0.01
0.001
Accumulation
of sublethal
damage
single
lethal
hits
n
Extrapolation
Number

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24
20
16
12
8
4
0
0
.01
.1
1
Dose (Gy)
S.F.
Single dose
limiting slope/
low dose rate
3 fractions
5 fractions
Multi-fraction survival curves can be
considered linear if sublethal damage is
repaired between fractions
they have an extrapolation number (n) = 1.0
•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
•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%

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S.F. = e-aD
Single lethal hits
S.F. = e-(aD+bD2)
Single lethal hits plus
accumulated damage
• Cell kill is the result of single lethal hits
plus accumulated damage from 2
independent sublethal events
• 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
S.F.
1.0
0.1
0.01
0.001
DOSE Gy
a/b in Gy
aD
bD2
Linear Quadratic Model

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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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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
Reciprocal
total dose
for an isoeffect
Dose per fraction
Intercept = a
Slope = b
Douglas and Fowler Rad Res 66:401, 1976
Showed and easy way to arrive at an a/b ratio

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Response to Fractionation Varies With Tissue
16
12
8
4
0
0
.01
.1
1
Dose (Gy)
S.F.
Late Responding
Tissues - a/b = 2Gy
Acute Responding
Tissues a/b = 10Gy
a/b is high (>6Gy) when survival
curve is almost exponential and low
(1-4Gy) when shoulder is wide
20
16
12
8
4
0
0
.01
.1
1
Dose (Gy)
S.F.
Single Dose
Late Effects
a/b = 2Gy
Single Dose
Acute Effects
a/b = 10Gy
Fractionated
Late Effects
Fractionated
Acute Effects
Fractionation spares late responding tissues

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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 Old
Dnew (dnew + a/b ) = 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)
Biologically
Effective Dose Total dose
Relative
Effectiveness
S.F. = e-E = e-(aD+bD2)
E = nd(a + bd)
E/a = nd(1+d/a/b)
35 x 2Gy = B.E.D.of 84Gy10 and 117Gy3
NOTE: 3 x 15Gy = B.E.D.of 113Gy10 and 270Gy3
Normalized total dose2Gy
= BED/RE
= BED/1.2 for a/b of 10Gy
= BED/1.67 for a/b of 3Gy
Equivalent to 162 Gy in 2Gy Fx -unrealistic!
(Fowler et al IJROBP 60: 1241, 2004)

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80
70
60
50
40
30
20
20
30
40
50
60
70
80
a/b=30Gy; 4Gy/fx
a/b=3Gy; 4Gy/fx
a/b=3Gy; 1.5Gy/fx
a/b=30Gy; 1.5Gy/fx
2.0Gy/fx
D old
D new
Note how badly late responding tissues respond to increased dose/fraction

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Prescribed Dose:
25 fractions of 2Gy = 50Gy
Hot spot: 110%
Physical dose: 55Gy
Biological dose: 60.5Gy
Does this Matter?
“Double Trouble”

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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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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 0.05-
0.2Gy.
• 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
HT29 cells
Lambin et al. Int J Radiat Biol 63:639 1993

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The Linear Quadratic Formulation
• Does not work well at low or high dose/fx
• Assumes equal effect per fraction

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Redistribution
Repair
Repopulation
700R 1500R
4Rs OF DOSE FRACTIONATION
• Assessed by varying the
time between 2 or more
doses of radiation

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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 2.5-
4.5hrs?

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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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Human SCC head and neck
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.
Acta Oncologica 27:131, 1988
Total
Dose
(2 Gy equiv.)
Treatment Duration
local control
no local control
70
55
40
T2 T3
Repopulation in Tumor Tissue
Hermens and Barendsen, EJC 5:173, 1969
Treatment breaks are often “bad”
Rat rhabdosarcoma

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Other Sources of Heterogeneity
• Biological Dose
– Cell cycle
– Hypoxia/reoxygenation
– Clonogenic “stem cells” (G.F.)
• Number
• Intrinsic radiosensitivity
• Proliferative potential
• Differentiation status
• Physical Dose
– Need to know more about the importance of dose-volume constraints
Dose
oxic
hypoxic
S.F
Phillips, J Natl Cancer Inst 98:1777, 2006

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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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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
– 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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TCP
or NTC
Dose
Hyperfractionation
Accelerated
Fractionation
Tumor control
Late responding tissue
complications
Complication-free cure
TCP
or NTC

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Conventional
70 Gy - 35 fx - 7 wks
Very accelerated
with reduction of dose
54 Gy - 36 fx - 12 days
Moderately accelerated
72 Gy - 42 fx - 6 wks
Hyperfractionated
81.6 Gy - 68 fx - 7 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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Oropharyngeal Ca T2-3, N0-1
Years
LOCAL CONTROL SURVIVAL
Years
Horiot 1992
80.5 Gy - 70 fx - 7 wks control: 70 Gy - 35-40 fx - 7-8 wks
p = 0.02
p = 0.08
EORTC hyperfractionation trial in oropharynx
cancer (N = 356)

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Loco-regional control Survival
conventional
CHART
conventional
CHART
54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx - 6.5 wks
Dische 1997
Favourable outcome with CHART: well differentiated tumors
larynx carcinomas
Very Accelerated: CHART (N = 918)

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54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx - 6.5 wks
CHART: Morbidity
Dische 1997
Moderate/severe subcutaneous
fibrosis and oedema
P = 0.04
Moderate/severe dysphagia
P = 0.04
Mucosal ulceration and
deep necrosis
P = 0.003
Laryngeal oedema
P = 0.009

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DAHANCA 6: only glottic, (N = 694)
DAHANCA 7: all other sites, + nimorazole (N = 791)
Overgaard 2000
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
Overall survival
Late effects (edema, fibrosis)
Moderately Accelerated
5 fx/wk 6 fx/wk
73% 81% p=0.04
56% 68% p=0.009
87% 89% n.s.
65% 72% p=0.04
n.s.
n.s.

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Skladowski 2000
OVERALL SURVIVAL
CONTROL
CAIR
log-rank p=0.00001
Follow-up (months)
Probability
66-72 Gy - 33-36 fx - 5 wks control: 70-72 Gy - 35-36 fx - 7 wks
68.4-72 Gy - 38-40 fx - 5.5 wks control: 66.6-72 Gy - 37-40 fx - 7.5-8 wks
CAIR: 7-day-continuous accelerated irradiation (N = 100)
Moderately Accelerated

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Conventional
Accelerated with split
70 Gy - 35 fx - 7 wks
67.2 Gy - 42 fx - 6 weeks (including 2-week split)
72 Gy - 42 fx - 6 wks
Hyperfractionated
81.6 Gy - 68 fx - 7 wks
Accelerated with
Concomitant boost
Fu 2000
RTOG 90-03, Phase III comparison of fractionation schedules
in Stage III and IV SCC of oral cavity, oropharynx, larynx,
hypopharynx (N = 1113)

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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
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%
Fu 2000
Acute
Maximum toxicity Conventional Hyperfract Concom Acc +
per patient boost split
Grade 1 11% 8% 7% 16%
Grade 2 50% 56% 44% 50%
Grade 3 19% 19% 29% 20%
Grade 4 8% 9% 8% 7%
Grade 5 1% 0% 1% 1%
Late

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Acute effects in accelerated or hyperfractionated RT
Author Regimen Grade 3-4 mucositis
Cont Exp
Horiot (n=356) HF 49% 67%
Horiot (n=512) Acc fx + split 50% 67%
Dische (n=918) CHART 43% 73%
Fu (n=536) Acc fx(CB) 25% 46%
Fu (n=542) Acc fx + split 25% 41%
Fu (n=507) HF 25% 42%
Skladowski (n=99) Acc fx 26% 56%
Toxicity of RT in HNSCC

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Altered fractionation in head and neck
cancer: meta-analysis
Bourhis, Lancet 2006
Randomized trials 1970-1998 (no postop RT)
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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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 pre-
consideration!!!
• 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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Modeling of radiation responses are based
on
1. Random events occurring in cell nuclei
2. Random events in space as defined by
the Poisson distribution
3. A Gaussian distribution
4. Logarithmic dose response curves

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D0 is
1. Is a measure of the shoulder of a survival
curve
2. Is the mean lethal dose of the linear
portion of the dose-response curve
3. Represents the slope of the log linear
survival curve
4. Is constant at all levels of radiation effect

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Dq is
1. A measure of the inverse of the terminal
slope of the survival curve
2. A measure of the inverse of the initial
slope of the survival curve
3. A measure of the shoulder of the survival
curve
4. A measure of the intercept of the terminal
portion of the survival curve on the y axis

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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.
1. 4 Gy
2. 6 Gy
3. 8 Gy
4. 10 Gy

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A whole body dose of 7 Gy of x-rays would produce severe,
potentially lethal hematologic toxicity. Assuming that the Do of
the hematopoietic stem cells is 1 Gy and that these cells have
a negligible capacity to repair sublethal radiation damage,
what is the surviving fraction of these stem cells after this dose
of radiation?
1. 0.0001
2. 0.001
3. 0.025
4. 0.067
5. 0.1167

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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. 1-2 Gy
2. 3-4 Gy
3. 6-7 Gy
4. 9-12 Gy
5. 20-30 Gy

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What is true for the a/b ratio
1. It is unitless
2. It is a measure of the shoulder of the
survival curve
3. It measures the sensitivity of a tissue to
changes in size of dose fractions
4. It is the ratio where the number of non-
repairable lesions equals that for
repairable lesions

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The alpha component in the linear quadratic
formula for as radiation survival curve
represents
1. Unrepairable DNA double strand breaks
2. Lethal single track events
3. Multiply damaged sites in DNA
4. Damage that can not be altered by
hypoxia

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Which parameter is most relevant for
standard clinical regimens in RT
1. The a/b ratio
2. Do
3. Alpha
4. Beta
5. The extrapolation number

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If cells have a Do of 2 Gy, assuming no shoulder,
what dose is required to kill 95% of the cells?
1. 6 Gy
2. 12 Gy
3. 18 Gy
4. 24 Gy
5. 30 Gy

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The extrapolation number N for a multi-
fraction survival curve, allowing complete
repair between fractions and no repopulation
is
1. 1
2. < 1
3. >1
4. Dependent on the size of the dose per
fraction

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The extrapolation number N for a single
dose neutron survival curve is
1. 1
2. < 1
3. >1
fraction

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The extrapolation number N for a low dose
rate survival curve is
1. 1
2. < 1
3. >1
fraction

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The inverse of the slope of a multifraction
survival curve (effDo) is generally within the
range
1. 1.0-1.5 Gy
2. 1.5-2.5 Gy
3. 2.5-5.0 Gy
4. 5.0-10.0 Gy

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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).
1. 56 Gy
2. 64 Gy
3. 72 Gy
4. 80 Gy

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If the effDo for a multifraction survival curve
is 3.5 Gy, what dose would cure 69% of a
series of 1cm diameter tumors (109
clonogens).
1. 56 Gy
2. 64 Gy
3. 72 Gy
4. 80 Gy

WMcB2009
If a tumor has an effective Do of 3.5 Gy,what is the
S.F. after 70 Gy?
1. 2 x 10-11
2. 2 x 10-9
3. 2 x 10-7
4. 2 x 10-5
5. 2 x 10-3

WMcB2009
If 16 x 2 Gy fractions reduce survival by 10-4, what
dose would be needed to reduce survival to 10-10?
1. 50 Gy
2. 60 Gy
3. 64 Gy
4. 70 Gy
5. 80 Gy

WMcB2009
If 16 x 2 Gy fractions reduce survival by 10-4, what
is the effective D0?
1. 2.0 Gy
2. 2.3 Gy
3. 3.0 Gy
4. 3.5 Gy
5. 3.8 Gy

WMcB2009
The a/b ratio for mucosal tissues is closest
to
1. 2 Gy
2. 4 Gy
3. 6 Gy
4. 8 Gy
5. 10 Gy

WMcB2009
Which of the following human tumors Is
thought to have an a/b ratio of 1-2 Gy
1. Oropharyngeal Ca
2. Prostate Ca
3. Glioblastoma
4. Colorectal Ca

WMcB2009
The TD5/5 for a certain tissue irradiated at 2
Gy/fraction is 60 Gy whereas at 4 Gy/fraction it is 40
Gy. Assuming that the linear quadratic
equation, -lnSF= N (aD + bD2), accurately represents
cell survival for this tissue, what is the value of a/b?
1. 1 Gy
2. 2 Gy
3. 4 Gy
4. 10 Gy
5. 20 Gy

WMcB2009
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 according to the linear-quadratic model with
a/b for late damage = 3 Gy?
1. 40 Gy
2. 48 Gy
3. 50 Gy
4. 55.4 Gy
5. 75 Gy

WMcB2009
A standard treatment for HNSCC tumors is 70 Gy delivered at 2
Gy/fraction. Hyperfractionation is being attempted with a fraction
size of 1.2 Gy. What total treatment dose should be used to
maintain the same complication rate for the late responding
normal tissues. Assume full repair of sublethal damage between
fractions and an a/b of 3 Gy.
1. 42 Gy
2. 58 Gy
3. 70 Gy
4. 83 Gy
5. 117 Gy

WMcB2009
A standard treatment for HNSCC tumors is 70 Gy delivered at 2
Gy/fraction. Hyperfractionation is being attempted with a fraction
size of 1.2 Gy. What total treatment dose should be used to
maintain the same complication rate for the late responding
normal tissues. 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.
1. 6%
2. 12%
3. 18%
4. 24%

WMcB2009
Which of the following sites is the least
suitable for b.i.d. treatment
1. Head and neck
2. Brain
3. Lung
4. Prostate

WMcB2009
The rationale behind accelerated
fractionation is
1. To spare late responding normal tissue
2. To combat encourage tumor
reoxygenation
3. To exploit redistribution in tumors
4. To combat accelerated repopulation in
tumors

WMcB2009
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
1. Superior locoregional control, no increase in overall
survival, increased late effects
2. Superior locoregional control that translated into an
increase in overall survival, no change in late effects
3. No change in locoregional control and overall survival,
decreased late effects
4. Superior locoregional control, no increase in overall
survival, increased acute effects

WMcB2009
DAHANCA 6 and 7 clinical trials with 66-
68Gy given in 6 compared to 7 weeks
1. Was a hyperfractionation trial
2. Treated 6 days a week
3. Showed no increase in local control
4. Showed no increase in disease-specific
survival

WMcB2009
RTOG 90-03, which compared hyperfractionation,
accelerated fractionation with a split, and
accelerated fractionation with a boost showed
1. Hyperfractionation to be superior in terms of
loco-regional control and late effects
2. Accelerated fractionation with a split to be
equivalent to hyperfractionation in terms of loco-
regional control
3. There to be no advantage to altered fractionation
4. Accelerated fractionation to be superior to
hyperfractionation

WMcB2009
Answers
1. NA
2. 2
3. 2
4. 4
5. 1
6. 5
7. 2
8. 4
9. 2
10. 4
11. 4
12. 3
13. 2
14. 1
15. 3
16. 2
17. 1
18. 2
19. 3
20. 3
21. 1
22. 3
23. 1
24. 2
25. 5
26. 1
27. 3
28. 1
29. 3
30. 3

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