7. radiobiology behind dose fractionation

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www.r www.r adbiol adbiol .ucla.ed .ucla.ed u WMcB2009 The Radiobiology Behind Dose The Radiobiology Behind Dose Fractionation Fractionation Bill McBride Bill McBride Dept. Radiation Oncology Dept. Radiation Oncology David Geffen School Medicine David Geffen School Medicine UCLA, Los Angeles, Ca. UCLA, Los Angeles, Ca. [email protected] [email protected]

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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
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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
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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
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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
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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
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NOTE: 3 x 15Gy = B.E.D.of 113Gy10 and 270Gy3
Normalized total dose2Gy
(Fowler et al IJROBP 60: 1241, 2004)
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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
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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
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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
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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)
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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)
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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
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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
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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
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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)
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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:
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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
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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
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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
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Answers