The Radiobiology Behind Dose

Fractionation

Bill McBride
Dept. Radiation Oncology
David Geffen School Medicine
UCLA, Los Angeles, Ca.
wmcbride@mednet.ucla.edu

WMcB2009

www.radbiol.ucla.edu
 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

WMcB2009

www.radbiol.ucla.edu
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?

WMcB2009

www.radbiol.ucla.edu
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

WMcB2009

www.radbiol.ucla.edu
 The First Radiation Dosimeter

prompted the use of dose fractionation

WMcB2009

www.radbiol.ucla.edu
 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

WMcB2009

www.radbiol.ucla.edu
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
1.0 • This is the mean lethal dose D0
0.37 • D10 = 2.3 xD0
S.F.
0.1 • In general, S.F. = e-D/D0
or LnS.F. = -D/D0
or S.F. = e-aD , i.e. D0 = 1/a
0.01
Where a is the slope of the curve and D0 the
reciprocal of the slope

0.001
D0
How many logs of cells would be killed
D10 by 23 Gy if D0 = 1 Gy?
DOSE Gy
WMcB2009

www.radbiol.ucla.edu
 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
1.0
lethal
hits

0.1

0.01
Accumulation of
sub-lethal
damage
0.001

dose

WMcB2009

www.radbiol.ucla.edu
 Two Component Model

n single • Two Component Model

lethal (or single target, single hit +
1.0 hits
multi-target (n), single hit)
1D 0 = • S.F.=e-D/1D0[1-(1-e-D/nD0)n]
S.F. reciprocal
0.1 initial slope Extrapolation
Number
Single hit Accumulated
damage

0.01
Accumulation
of sublethal nD 0 =
reciprocal
damage final slope
0.001

DOSE Gy

WMcB2009

www.radbiol.ucla.edu
 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?

WMcB2009

www.radbiol.ucla.edu
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

WMcB2009

www.radbiol.ucla.edu
 Does this Matter?

Prescribed Dose:
25 fractions of 2Gy = 50Gy
Hot spot: 110%
Physical dose: 55Gy
Biological dose: 60.5Gy

“Double Trouble”
WMcB2009

www.radbiol.ucla.edu
 Linear Quadratic Model

• Cell kill is the result of single lethal hits

1.0 plus accumulated damage from 2
aD independent sublethal events

bD2 S.F. = e-aD

S.F. 0.1 Single lethal hits
S.F. = e-(aD+bD2)
Single lethal hits plus
0.01 accumulated damage
• 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
0.001  a/b is dose at which death due to single lethal
a/b in Gy lesions = death due to accumulation of sublethal
lesions i.e. aD = bD2 and D = a/b in Gy
DOSE Gy

WMcB2009

www.radbiol.ucla.edu
• 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
WMcB2009

www.radbiol.ucla.edu
 The Linear Quadratic Formulation

• Does not work well at high dose/fx

• Assumes equal effect per fraction

WMcB2009

www.radbiol.ucla.edu
 N.B. Survival curves may
HT29 cells
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

Lambin et al. Int J Radiat Biol 63:639 1993 WMcB2009

www.radbiol.ucla.edu
 1
Multi-fraction survival curves can be
limiting slope/ considered linear if sublethal damage is
low dose rate repaired between fractions
S.F.
they have an extrapolation number (n) = 1.0

5 fractions •The resultant slope is the effective D0

•eD0 is often 2.5 - 5.0Gy and eD10 5.8 - 11.5Gy
.1 •S.F. = e-D/eD0
•If S.F. after 2Gy = 0.5, eD0 = 2.9Gy; eD10 =
3 fractions 6.7Gy and 30 fractions of 2 Gy (60Gy) would
reduce survival by (0.5)30 = almost 9 logs (or
60/6.7)
Single dose •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%
.01
0 4 8 12 16 20 24
Dose (Gy)

WMcB2009

www.radbiol.ucla.edu
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
Slope = b
for an isoeffect
Douglas and Fowler Rad Res 66:401, 1976
Showed and easy way to arrive at an a/b ratio
Intercept = a

Dose per fraction

WMcB2009

www.radbiol.ucla.edu
 Response to Fractionation Varies With Tissue
1 1

Acute Responding
S.F. S.F. Fractionated
Tissues a/b = 10Gy
Late Effects

.1
.1 Fractionated
Late Responding
Tissues - a/b = 2Gy Acute Effects

Single Dose Single Dose

a/b is high (>6Gy) when survival Late Effects Acute Effects
curve is almost exponential and low a/b = 2Gy a/b = 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

WMcB2009

www.radbiol.ucla.edu
 80 a/b=3Gy; 1.5Gy/fx
a/b=30Gy; 1.5Gy/fx
70 2.0Gy/fx
a/b=30Gy; 4Gy/fx
60
D new
50 a/b=3Gy; 4Gy/fx

40

30

20
20 30 40 50 60 70 80
D old

Note how badly late responding tissues respond to increased dose/fraction

WMcB2009

www.radbiol.ucla.edu
Sensitivity of Tissue to Dose Fractionation
can be estimated by the a/b ratio

WMcB2009

www.radbiol.ucla.edu
 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 WMcB2009

www.radbiol.ucla.edu
 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!

WMcB2009

www.radbiol.ucla.edu
 Biologically Effective Dose (BED)
2)
S.F. = e-E = e-(aD+bD

E = nd(a + bd)

E/a = nd(1+d/a/b)
Biologically Relative
Effective Dose Total dose Effectiveness
35 x 2Gy = B.E.D.of 84Gy10 and 117Gy3

NOTE: 3 x 15Gy = B.E.D.of 113Gy10 and 270Gy3

Normalized total dose2Gy
Equivalent to 162 Gy in 2Gy Fx -unrealistic! = BED/RE
(Fowler et al IJROBP 60: 1241, 2004) = BED/1.2 for a/b of 10Gy
= BED/1.67 for a/b of 3Gy
WMcB2009

www.radbiol.ucla.edu
 4Rs OF DOSE FRACTIONATION
700R 1500R

• Assessed by varying the

time between 2 or more
doses of radiation
Repopulation

Redistribution
Repair

WMcB2009

www.radbiol.ucla.edu
 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

WMcB2009

www.radbiol.ucla.edu
 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?

WMcB2009

www.radbiol.ucla.edu
 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

WMcB2009

www.radbiol.ucla.edu
 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
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” Acta Oncologica 27:131, 1988

WMcB2009

www.radbiol.ucla.edu
 Altered Fractionation

or

How to optimally distribute dose over

time

WMcB2009

www.radbiol.ucla.edu
 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

WMcB2009

www.radbiol.ucla.edu
 TCP Tumor control
Late responding tissue
or NTC complications

Complication-free cure

TCP Accelerated
Hyperfractionation
Fractionation
or NTC

Dose WMcB2009

www.radbiol.ucla.edu
 Other Sources of Heterogeneity
• Biological Dose
– Cell cycle S.F
– Hypoxia/reoxygenation hypoxic

oxic
– Clonogenic “stem cells” (G.F.) 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
WMcB2009

www.radbiol.ucla.edu
• 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

WMcB2009

www.radbiol.ucla.edu
 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

WMcB2009

www.radbiol.ucla.edu
 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

WMcB2009

www.radbiol.ucla.edu
 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

WMcB2009

www.radbiol.ucla.edu
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

WMcB2009

www.radbiol.ucla.edu
 EORTC hyperfractionation trial in oropharynx
cancer (N = 356)
Oropharyngeal Ca T2-3, N0-1
Horiot 1992

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

WMcB2009

www.radbiol.ucla.edu
 Very Accelerated: CHART (N = 918)
Dische 1997

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

WMcB2009
larynx carcinomas
www.radbiol.ucla.edu
 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

WMcB2009

www.radbiol.ucla.edu
 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 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 + 7 65% 72% p=0.04

Overall survival n.s.

Late effects (edema, fibrosis) n.s.

WMcB2009

www.radbiol.ucla.edu
 Moderately Accelerated
CAIR: 7-day-continuous accelerated irradiation (N = 100)
Skladowski 2000

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

OVERALL SURVIVAL

CAIR
Probability

CONTROL

log-rank p=0.00001

Follow-up (months)
WMcB2009

www.radbiol.ucla.edu
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
WMcB2009

www.radbiol.ucla.edu
 RTOG 90-03, loco-regional control
Fu 2000

WMcB2009

www.radbiol.ucla.edu
 RTOG 90-03, survival
Fu 2000

WMcB2009

www.radbiol.ucla.edu
 RTOG 90-03, adverse effects Fu 2000
Acute
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 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%

WMcB2009

www.radbiol.ucla.edu
 Toxicity of RT in HNSCC

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%

WMcB2009

www.radbiol.ucla.edu
 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)

WMcB2009

www.radbiol.ucla.edu
 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?

WMcB2009

www.radbiol.ucla.edu
 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!
WMcB2009

www.radbiol.ucla.edu
 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.
WMcB2009

www.radbiol.ucla.edu
 Questions:
The Radiobiology Behind Dose Fractionation

WMcB2009

www.radbiol.ucla.edu
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

WMcB2009

www.radbiol.ucla.edu
 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.

WMcB2009

www.radbiol.ucla.edu
 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.
WMcB2009

www.radbiol.ucla.edu
 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.

WMcB2009

www.radbiol.ucla.edu
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.

WMcB2009

www.radbiol.ucla.edu
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 2.5-

5.0Gy and the eD10 will be 2.3 times this.

WMcB2009

www.radbiol.ucla.edu
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 non-
repairable 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.
WMcB2009

www.radbiol.ucla.edu
 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

WMcB2009

www.radbiol.ucla.edu
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).

WMcB2009

www.radbiol.ucla.edu
 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

WMcB2009

www.radbiol.ucla.edu
119. The extrapolation number N for a multi-
fraction 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

www.radbiol.ucla.edu
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

www.radbiol.ucla.edu
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.

WMcB2009

www.radbiol.ucla.edu
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.

WMcB2009

www.radbiol.ucla.edu
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

WMcB2009

www.radbiol.ucla.edu
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%

WMcB2009

www.radbiol.ucla.edu
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.

WMcB2009

www.radbiol.ucla.edu
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

WMcB2009

www.radbiol.ucla.edu
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.

WMcB2009

www.radbiol.ucla.edu
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.

WMcB2009

www.radbiol.ucla.edu
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.

WMcB2009

www.radbiol.ucla.edu
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 )

WMcB2009

www.radbiol.ucla.edu
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

WMcB2009

www.radbiol.ucla.edu
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

WMcB2009

www.radbiol.ucla.edu
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%

WMcB2009

www.radbiol.ucla.edu
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

WMcB2009

www.radbiol.ucla.edu
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.

WMcB2009

www.radbiol.ucla.edu
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
WMcB2009

www.radbiol.ucla.edu
137. DAHANCA 6 and 7 clinical trials with 66-
68Gy 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…

WMcB2009

www.radbiol.ucla.edu
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 loco-
regional control and late effects
– Accelerated fractionation with a split to be
equivalent to hyperfractionation in terms of loco-
regional control
– There to be no advantage to altered fractionation
– Accelerated fractionation to be superior to
hyperfractionation

#1 – The lead investigator was K. Fu.

WMcB2009

www.radbiol.ucla.edu