Cell, Tissue, and Tumor Kinetics in Response to Irradiation Bill
McBride Dept. Radiation Oncology David Geffen School Medicine UCLA,
Los Angeles, Ca.
[email protected] McBride
*
Radiation Biology is study of the effects of radiation on living
things. For the most part, this course deals with the effects of
radiation doses of the magnitude of those used in radiation
therapy.
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Objectives
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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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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In general, history has shown repeatedly that single high doses of
radiation do not allow a therapeutic differential between tumor and
critical normal tissues.
Dose fractionation does.
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P of x = e-m.mx/x!
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
P survival
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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
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
*
The mathematical bent of early radiobiologists led them to describe
survival curves by the mean lethal dose (D37 or D0), which is the
dose required to cause on average one lethal hit per cell and
result in 37% survival. In practice D10, the dose that would reduce
survival to by one log10, which is 2.3x D0 is easier to use. The
slope of the curve is given by , where D0 is 1/. Bacterial killing
and protein inactivation follow this log-linear curve, although the
D0 values are high compared with mammalian cells.
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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?
Meat, Poultry, Fish,
Shellfish, some vegetables
Eukaryotic Survival Curves are Exponential, but have a
‘Shoulder’
1.0
0.1
0.01
0.001
*
In 1956 Puck and Marcus published the first survival curve for
mammalian cells and noted that the D0 was 100-150cGy. Furthermore,
it had a shoulder region before the logarithmic decline. It is
easiest to think of this as single-hit and multi-hit killing
(another assumption!). At low doses, the rate of deposition of
energy by a charged particle is inversely proportional to its
energy, and as it loses energy through collisions and scattering
the distribution of ionizing events become more dense and the
probability of a lethal lesion being formed by a single track
increases. At higher doses, accumulation of injury from other
tracks (intertrack) becomes a more likely cause of a lethal lesion.
Note that the nature of the chromosomal lesions will go from being
predominantly deletions to more exchange-type (two-hit) lesions.
Note that with doses of around 2Gy, the former will dominate.
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S.F.=e-D/1D0[1-(1-e-D/nD0)n]
damage
single
lethal
hits
n
Extrapolation
Number
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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%
.01
.1
1
24
20
16
12
8
4
0
0
Kellerer and Rossi, 1972
Linear Quadratic Formula
*
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
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
*
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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
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
Showed and easy way to arrive at an ratio
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16
12
8
4
0
0
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
.01
.1
1
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What are a/ ratios for human cancers?
In fact, for some tumors e.g. prostate, breast, melanoma, soft
tissue sarcoma, and liposarcoma a/ ratios may be moderately
low
Prostate
comparing implants with EBRT
Lukka JCO 23: 6132, 2005
Phase III NCIC 66Gy 33F in 45days vs 52.5Gy 20F in 28 days
Compatible with a/ 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/ = 4.0Gy (1.0-7.8)
Breast appearance a/ = 3.6Gy; induration a/ = 3.1Gy
*
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What total dose (D) to give if the dose/fx (d) is changed
New Old
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
*
NOTE: 3 x 15Gy = B.E.D.of 113Gy10 and 270Gy3
Normalized total dose2Gy
(Fowler et al IJROBP 60: 1241, 2004)
*
Note how badly late responding tissues respond to increased
dose/fraction
80
70
60
50
40
30
20
20
30
40
50
60
70
80
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Hot spot: 110%
Physical dose: 55Gy
Biological dose: 60.5Gy
Does this Matter?
Strandquist plot
D = const x T 1-p
Linear on log/log plot
Fowler 1963 in pig skin - Number of Fx important
Ellis formula - nominal standard dose (NSD)
Number of fx important based on pig skin expts.
Dose = (NSD)T0.11.N0.24
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D= NSD x N0.24
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
*
An additional complication has been reported by Joiner et al, who
have shown that certain cell lines show a hypersensitivity zone at
0.05-0.2 Gy that flattens out over 0.05-1 Gy, before showing the
normal shape of survival curve. The basis for this is not well
established but hypersensitivity is thought to be associated with
increased apoptosis and lack of G2 arrest.
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Assumes equal effect per fraction
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4Rs OF DOSE FRACTIONATION
Assessed by varying the time between 2 or more doses of
radiation
Redistribution
Repair
Repopulation
700R
1500R
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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
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
*
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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
*
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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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
Treatment breaks are often “bad”
Rat rhabdosarcoma
Where T = overall treatment time; Tp = effective doubling
time
i.e. S.F. = e-(D+D2)+ln2/Tp(T-Tk)
Where Tk is time of start of regeneration
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Need to know more about the importance of dose-volume
constraints
Phillips, J Natl Cancer Inst 98:1777, 2006
Dose
oxic
hypoxic
S.F
6.psd
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SF2
TCP (%)
Average
In order to cure a tumor, the last surviving clonogen must be
killed, which is a probability function of dose.
TCP = e-(m. SF) or e-m.e-(ad+bD2)
Where m is the initial number of clonogenic cells
TCP=37% when, on average, 1 cell survives
Slope of curve represents radiobiological heterogeneity
DOSE (Gy)
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Heterogeneity within and between between tumors in dose-response
characteristics, often resulting in large error bars for
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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*
Hyperfractionation
T is kept the same
Dose per fraction (d) less than 1.8 Gy
Two fractions per day (t)
Rationale: Spares late responding tissues
*
Conventional empirically developed Fletcher
Radiosensitive tumors can be controlled with low doses (seminoma
and lymphoma), low incidence of normal tissue damage
GBM very radioresistant
Most tumors intermediate sensitivity SCC, adenoca
Tumor size also plays a role
Conformal radiotherapy: dose escalation with sparing of normal
tissues but when done in a conventional way, lengthening OTT
Hyperfractionation: escalate dose, improve tumor control without
increasing risk of late complications.
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Definitions
More than 10 Gy per week
Rationale: Overcome accelerated tumor repopulation
Hypofractionation
Reduced total number of fractions (N)
*
Exceptions of tumors with low a/b: melanoma, prostate,
liposarcoma
Applied in the palliative setting, limited life expectancy, late
side effects not an issue
Moderate hypofractionation used in some countries, total dose
usually lower but OTT also shorter which may compensate for the
expected reduction in local tumor control
A way to escalate dose in trials of CRT? SIB
Accelerated fractionation:early normal tissue reactions are
expected to increase. If interval between fractions is long enough
late normal tissue side effects should be the same or less if
fractionsize is lower than 1.8 or 2 Gy and/or total dose is
decreased
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TCP
Very accelerated
Moderately accelerated
*
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Hyperfractionated
Barcelona (586), Brazil (112), RTOG 90-03 (1113), EORTC 22791
(356), Toronto (331)
Very accelerated
Moderately accelerated
RTOG 90-03 (1113), DAHANCA (1485), EORTC 22851 (512) CAIR (100),
Warsaw (395)
Other
7623 patients in 18 randomized phase III trials !!
HNSCC only will be discussed
*
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Scatter plot of selected altered fractionation schedules tested in
randomised controlled trials according to the dose per fraction
employed and the rate of dose accumulation. The Manchester schedule
is included for comparison. The trial codes and the corresponding
literature references are: 22791: European Organization for
Research and Treatment of Cancer (EORTC) trial, 22851: EORTC trial,
CHART, DAHANCA, Gliwice I and II : CAIR with 2.0 and 1.8 Gy/F,
respectively, GORTEC 9402, Pinto: Radiation Therapy Oncology Group
(RTOG) RTOG 90-03 (HF: hyperfractionation, CB: concomitant boost,
SC: accelerated split-course.
Bernier and Bentzen EJC 39:560, 2003
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EORTC hyperfractionation trial in oropharynx cancer (N = 356)
*
Increase of about 19 %in long term local tumor control
Interfraction interval 4 to 6 hours
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Survival
conventional
CHART
conventional
CHART
54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx - 6.5 wks
Dische 1997
larynx carcinomas
*
12 consecutive days, 3 fractions per day, interval 6 hours, 1.5 Gy,
total dose 54 Gy, total dose is lower to remain within tolerance of
acutely responding tissues
918 patients
OTT reduced by 33 days, total dose is 12 Gy less but LC is the
same.
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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
*
Mucositis occured earlier but settled sooner as well, skin
reactions were less severe.
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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
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
CAIR: 7-day-continuous accelerated irradiation (N = 100)
Moderately Accelerated
OVERALL SURVIVAL
with different dose per fraction
Maciejewski 1996, Skladowski 2000
conventional
67.2 Gy - 42 fx - 6 weeks (including 2-week split)
72 Gy - 42 fx - 6 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)
Hyperfractionated
*
per patient boost split
Fu 2000
per patient boost split
Late
Author Regimen Grade 3-4 mucositis
Cont Exp
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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Bourhis, Lancet 2006
15 trials included (6515 patients)
Survival benefit: 3.4% (36% 39% at 5 years, p = 0.003)
*
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!
*
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:
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Random events occurring in cell nuclei
Random events in space as defined by the Poisson distribution
A Gaussian distribution
Is a measure of the shoulder of a survival curve
Is the mean lethal dose of 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
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Dq is
A measure of 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
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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.
4 Gy
6 Gy
8 Gy
10 Gy
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A whole body dose of 7 Gy of xrays 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?
0.0001
0.001
0.025
0.067
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?
1-2 Gy
3-4 Gy
6-7 Gy
9-12 Gy
20-30 Gy
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
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The alpha component in the linear quadratic formula for as
radiation survival curve represents
Unrepairable DNA double strand breaks
Lethal single track events
Damage that can not be altered by hypoxia
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Which parameter is most relevant for standard clinical regimens in
RT
The ratio
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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?
6 Gy
12 Gy
18 Gy
24 Gy
30 Gy
The extrapolation number N for a multi-fraction survival curve,
allowing complete repair between fractions and no repopulation
is
1
< 1
>1
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The extrapolation number N for a single dose neutron survival curve
is
1
< 1
>1
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The extrapolation number N for a low dose rate survival curve
is
1
< 1
>1
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The inverse of the slope of a multifraction survival curve (effDo)
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
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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).
56 Gy
64 Gy
72 Gy
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).
56 Gy
64 Gy
72 Gy
80 Gy
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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
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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
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If 16 x 2 Gy fractions reduce survival by 10-4, what is the
effective D0?
2.0 Gy
2.3 Gy
3.0 Gy
3.5 Gy
3.8 Gy
2 Gy
4 Gy
6 Gy
8 Gy
10 Gy
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Which of the following human tumors Is thought to have an ratio of
1-2 Gy
Oropharyngeal Ca
Prostate Ca
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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 Gy
2 Gy
4 Gy
10 Gy
20 Gy
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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 normaltissue damage to remain unchanged according to
the linearquadratic model with a/b for late damage = 3 Gy?
40 Gy
48 Gy
50 Gy
55.4 Gy
75 Gy
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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.
42 Gy
58 Gy
70 Gy
83 Gy
117 Gy
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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.
6%
12%
18%
24%
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Which of the following sites is the least suitable for b.i.d.
treatment
Head and neck
To combat encourage tumor reoxygenation
To exploit redistribution in tumors
To combat accelerated repopulation in tumors
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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
www.radbiol.ucla.edu
WMcB2009
DAHANCA 6 and 7 clinical trials with 66-68Gy given in 6 compared to
7 weeks
Was a hyperfractionation trial
Showed no increase in local control
Showed no increase in disease-specific survival
www.radbiol.ucla.edu
WMcB2009
RTOG 90-03, which compared hyperfractionation, accelerated
fractionation with a split, and accelerated fractionation with a
boost 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
www.radbiol.ucla.edu
WMcB2009
Answers