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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Modeling Radiation Responses

Assumes that ionizing hits are random events in space
Which are fitted by a Poisson Distribution P of x = e-m.mx/x!
where m = mean # hits, x is a hit

P survival (when x = 0) 100 targets 100 hits m=1 e-1=0.368 100 targets 200 hits m=2 e-2=0.137 100 targets 300 hits m=3 e-3=0.05

N.B. Lethal hits in DNA are not really randomly distributed, e.g. condensed chromatin is more sensitive, but it is a reasonable approximation
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This Gives a Survival Curve Based on a Model where one hit will eliminate a single target

1.0

When there is single lethal hit per target

0.37

S.F.
0.1

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

0.01

0.001

D0 D10 DOSE Gy
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

Eukaryotic Survival Curves are Exponential, but have a Shoulder

Two component model
n
1.0

single lethal hits

0.1

0.01

Accumulation of sub-lethal damage

0.001

dose

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Two Component Model

n
1.0

single lethal hits

1D 0 =

Two Component Model

(or single target, single hit + multi-target (n), single hit)

S.F.
0.1

reciprocal initial slope

S.F.=e-D/1D0[1-(1-e-D/nD0)n]
Single hit Extrapolation Number Accumulated damage

0.01

Accumulation of sublethal damage DOSE Gy

nD 0

reciprocal final slope

0.001

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S.F.

limiting slope/ low dose rate

Multi-fraction survival curves can be considered linear if sublethal damage is repaired between fractions
they have an extrapolation number (n) = 1.0

5 fractions .1 3 fractions

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%

Single dose

.01
0 4 8 12 16 Dose (Gy) 20 24

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Linear Quadratic Model

1.0

aD bD2

Cell kill is the result of single lethal hits plus accumulated damage from 2 independent sublethal events S.F. = e-aD Single lethal hits

S.F. 0.1

0.01

0.001

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

S.F. = e-(aD+bD2) Single lethal hits plus accumulated damage

a/b in Gy
DOSE Gy

a/b is dose at which death due to single lethal lesions = death due to accumulation of sublethal lesions i.e. aD = bD2 and D = a/b in Gy

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 Over 90% of radiation oncologists use the LQ model: it is simple and has a microdosimetric underpinning a/b is large (> 6 Gy) when survival curve is almost exponential and small (1-4 Gy) when shoulder is wide the a/b value quantifies the sensitivity of a tissue/tumor to fractionated radiation. But: Both a and b vary with the cell cycle. At high doses, S phase and hypoxic cells become more important. The a/b ratio varies depending upon whether a cell is quiescent or proliferative The LQ model best describes data in the range of 1 6Gy and should not be used outside this range
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Thames et al Int J Radiat Oncol Biol Phys 8: 219, 1982.

The slope of an isoeffect curve changes with size of dose per fraction depending on tissue type Acute responding tissues have flatter curves than do late responding tissues a/b measures the sensitivity of tumor or tissue to fractionation i.e. it predicts how total
dose for a given effect will change when you change the size of dose fraction

Douglas and Fowler Rad Res 66:401, 1976 Showed and easy way to arrive at an a/b ratio

Reciprocal total dose for an isoeffect

Slope = b

Intercept = a Dose per fraction

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Response to Fractionation Varies With Tissue

1 1

S.F.

Acute Responding Tissues a/b = 10Gy

S.F.

Fractionated Late Effects

.1

Late Responding Tissues - a/b = 2Gy

.1

Fractionated Acute Effects

.01

a/b is high (>6Gy) when survival curve is almost exponential and low (1-4Gy) when shoulder is wide

Single Dose Late Effects a/b = 2Gy

.01

Single Dose Acute Effects a/b = 10Gy

8 12 Dose (Gy)

16

12 16 Dose (Gy)

20

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

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What total dose (D) to give if the dose/fx (d) is changed

New Dnew (dnew + a/b ) Old = Dold (dold + a/b )

So, for late responding tissue, what total dose in 1.5Gy fractions is equivalent to 66Gy in 2Gy fractions? Dnew (1.5+2) = 66 (2 + 2) Dnew = 75.4Gy

NB: Small differences in a/b for late responding tissues can make a big difference in estimated D!

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Biologically Effective Dose (BED)

S.F. = e-E = e-(aD+bD
2)

E = nd(a + bd)
E/a = nd(1+d/a/b)

Biologically Effective Dose

Total dose

Relative Effectiveness
Normalized total dose2Gy = BED/RE = BED/1.2 for a/b of 10Gy = BED/1.67 for a/b of 3Gy
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35 x 2Gy = B.E.D.of 84Gy10 and 117Gy3 NOTE: 3 x 15Gy = B.E.D.of 113Gy10 and 270Gy3

Equivalent to 162 Gy in 2Gy Fx -unrealistic! (Fowler et al IJROBP 60: 1241, 2004)

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80 70

a/b=3Gy; 1.5Gy/fx a/b=30Gy; 1.5Gy/fx

2.0Gy/fx

a/b=30Gy; 4Gy/fx

60

D new
50 40 30 20

a/b=3Gy; 4Gy/fx

20

30

40

50

60

70

80

D old

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

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Does this Matter?

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

Double Trouble
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The Linear Quadratic Formulation

Does not work well at high dose/fx

Assumes equal effect per fraction

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HT29 cells

N.B. Survival curves may deviate from L.Q. at low and high dose!!!!
Certain cell lines, and tissues, are hypersensitive at low doses of 0.050.2Gy. The survival curve then plateaus over 0.05-1Gy Not seen for all cell lines or tissues, but has been reported in skin, kidney and lung At high dose, the model probably does not fit data well because D2 dominates the equation

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

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The Linear Quadratic Formulation

Does not work well at low or high dose/fx
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
700R 1500R

Repopulation

Redistribution Repair

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4Rs OF DOSE FRACTIONATION

These are radiobiological mechanisms that impact the response to a fractionated course of radiation therapy
Repair of sublethal damage
spares late responding normal tissue preferentially

Redistribution of cells in the cell cycle

increases acute and tumor damage, no effect on late responding normal tissue

Repopulation
spares acute responding normal tissue, no effect on late effects, danger of tumor repopulation

Reoxygenation
increases tumor damage, no effect in normal tissues

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Repair
Repair between fractions should be complete - N.B. we are dealing with tissue recovery rather than DNA repair Correction for incomplete repair is possible (Thames) In general, time between fractions for most tissues should be >6 hours Some tissues, such as CNS, recover slowly making b.i.d. treatment inadvisable Bentzen - Radiother Oncol 53, 219, 1999 CHART analysis HNC showed that late morbidity was less than would be expected assuming complete recovery between fractions Is the T1/2 for recovery for late responding normal tissues 2.54.5hrs?

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Regeneration in Normal Tissues

The lag time to regeneration varies with the tissue In acute responding tissues,
Regeneration has a considerable sparing effect In human mucosa, regeneration starts 10-12 days into a 2Gy Fx protocol and increases tissue tolerance by at least 1Gy/dy Prolonging treatment time has a sparing effect As treatment time is reduced, acute responding tissues become dose-limiting

In late responding tissues,

Prolonging overall treatment time beyond 6wks has little effect, but prolonging time to retreatment may increase tissue tolerance

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Repopulation in Tumor Tissue

Rat rhabdosarcoma Human SCC head and neck
T2 T3 70 Total Dose (2 Gy equiv.) 55

local control

no local control

40 Treatment Duration Hermens and Barendsen, EJC 5:173, 1969

4 weeks to start of accelerated repopulation. Thereafter T1/2 of 4 days = loss of 0.6Gy per day
Withers, H.R., Taylor, J.M.G., and Maciejewski, B. Acta Oncologica 27:131, 1988
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Treatment breaks are often bad

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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
S.F hypoxic

oxic Dose

Phillips, J Natl Cancer Inst 98:1777, 2006

Physical Dose Need to know more about the importance of dose-volume constraints
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 Heterogeneity within and between between tumors in dose-response characteristics, often resulting in large error bars for a/b values In spite of this, the outcome of clinical studies of altered fractionation generally fit the models, within the constraints of the clinical doses used

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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

Tumor control Late responding tissue complications

Complication-free cure

TCP or NTC

Accelerated Fractionation

Hyperfractionation

Dose
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Conventional
70 Gy - 35 fx - 7 wks

Hyperfractionated
81.6 Gy - 68 fx - 7 wks

Very accelerated with reduction of dose

54 Gy - 36 fx - 12 days

Moderately accelerated
72 Gy - 42 fx - 6 wks

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Hyperfractionated
Barcelona (586), Brazil (112), RTOG 90-03 (1113), EORTC 22791 (356), Toronto (331)

Very accelerated
CHART (918), Vancouver (82), TROG 91-01 (350),GORTEC 94-02 (268)

Moderately accelerated
RTOG 90-03 (1113), DAHANCA (1485), EORTC 22851 (512) CAIR (100), Warsaw (395)

Other
EORTC 22811 (348), RTOG 79-13 (210)

7623 patients in 18 randomized phase III trials !!

HNSCC only will be discussed
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EORTC hyperfractionation trial in oropharynx cancer (N = 356)

Oropharyngeal Ca T2-3, N0-1
Horiot 1992

80.5 Gy - 70 fx - 7 wks LOCAL CONTROL

p = 0.02

control: 70 Gy - 35-40 fx - 7-8 wks SURVIVAL

p = 0.08

Years

Years

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Very Accelerated: CHART (N = 918)

Dische 1997

54 Gy - 36 fx - 12 days

control: 66 Gy - 33 fx - 6.5 wks

Loco-regional control

Survival

conventional CHART

conventional CHART

Favourable outcome with CHART:

well differentiated tumors larynx carcinomas

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CHART: Morbidity
Dische 1997

54 Gy - 36 fx - 12 days
P = 0.04

control: 66 Gy - 33 fx - 6.5 wks

P = 0.003

Moderate/severe subcutaneous fibrosis and oedema Mucosal ulceration and deep necrosis

P = 0.04

P = 0.009

Laryngeal oedema

Moderate/severe dysphagia

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Moderately Accelerated
DAHANCA 6: only glottic, (N = 694) DAHANCA 7: all other sites, + nimorazole (N = 791)

Overgaard 2000

66-68 Gy - 33-34 fx - 6 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)

control: 66-68 Gy - 33-34 fx - 7 wks 5 fx/wk 6 fx/wk

73% 56%
87% 65% n.s. n.s. .

81% p=0.04 68% p=0.009

89% n.s. 72% p=0.04

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Moderately Accelerated
CAIR: 7-day-continuous accelerated irradiation (N = 100)
Skladowski 2000

66-72 Gy - 33-36 fx - 5 wks 68.4-72 Gy - 38-40 fx - 5.5 wks

control: 70-72 Gy - 35-36 fx - 7 wks control: 66.6-72 Gy - 37-40 fx - 7.5-8 wks

OVERALL SURVIVAL

CAIR

Probability

CONTROL

log-rank p=0.00001

Follow-up (months)

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RTOG 90-03, Phase III comparison of fractionation schedules in Stage III and IV SCC of oral cavity, oropharynx, larynx, hypopharynx (N = 1113)
Fu 2000

Conventional
70 Gy - 35 fx - 7 wks

Hyperfractionated
81.6 Gy - 68 fx - 7 wks

Accelerated with split

67.2 Gy - 42 fx - 6 weeks (including 2-week split)

Accelerated with Concomitant boost

72 Gy - 42 fx - 6 wks
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RTOG 90-03, loco-regional control

Fu 2000

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RTOG 90-03, survival

Fu 2000

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RTOG 90-03, adverse effects Acute

Fu 2000

Maximum toxicity Conventional Hyperfract Concom Acc + per patient boost split Grade 1 15% 4% 4% 7% Grade 2 57% 39% 36% 41% Grade 3 35% 54% 58% 49% Grade 4 0% 1% 1% 2%

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

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

Randomized trials 1970-1998 (no postop RT) 15 trials included (6515 patients)
Bourhis, Lancet 2006

Survival benefit: 3.4% (36% 39% at 5 years, p = 0.003) Loco-regional control benefit: 7% (46.5% 53% at 5 years, p < 0.0001)

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Conclusions for HNSCC

Hyperfractionation increases TCP and protects late responding tissues Accelerated treatment increase TCP but also increases acute toxicity What should be considered standard for patients treated with radiation only? Hyperfractionated radiotherapy Concomitant boost accelerated radiotherapy Fractions of 1.8 Gy once daily when given alone, cannot be considered as an acceptable standard of care TCP curves for SSC are frustratingly shallow selection of tumors?

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Conclusions for HNSCC

The benefit derived from altered fractionation is consistent with can be of benefit but should be used with care In principle, tumors should be treated for an overall treatment time that is as short as possible consistent with acceptable acute morbidity, but with a dose per fraction that does not compromise late responding normal tissues, or total dose. Avoid treatment breaks and treatment prolongation wherever possible and consider playing catch-up if there are any Start treatment on a Monday and finish on a Friday, and consider working Saturdays Never change a winning horse!
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Other Major Considerations

Not all tumors will respond to hyper or accelerated fractionation like HNSCC, especially if they have a low a/b ratio. High single doses or a small number of high dose per fractions, as are commonly used in SBRT or SRS generally aim at tissue ablation. Extrapolating based on a linear quadratic equation to total dose is fraught with danger. Addition of chemotherapy or biological therapies to RT always requires caution and preferably thoughtful preconsideration!!! Dont 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 nonrepairable 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 multifraction 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 4. Dependent on the size of the dose per fraction

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The extrapolation number N for a low dose rate survival curve is 1. 1 2. < 1 3. >1 4. Dependent on the size of the dose per 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

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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

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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? 1. 50 Gy 2. 60 Gy 3. 64 Gy 4. 70 Gy 5. 80 Gy

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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

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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

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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

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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. 1 Gy 2. 2 Gy 3. 4 Gy 4. 10 Gy 5. 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 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

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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. 1. 42 Gy 2. 58 Gy 3. 70 Gy 4. 83 Gy 5. 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. 1. 6% 2. 12% 3. 18% 4. 24%

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

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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

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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 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

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DAHANCA 6 and 7 clinical trials with 6668Gy 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

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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 locoregional control 3. There to be no advantage to altered fractionation 4. Accelerated fractionation to be superior to hyperfractionation
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Answers
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. NA 2 2 4 1 5 2 4 2 4 4 3 2 1 3 2 1 2 3 3 1 3 1 2 5 1 3 1 3 3

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