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The Radiobiology Behind Dose
Fractionation

Bill McBride
Dept. Radiation Oncology
David Geffen School Medicine
UCLA, Los A...
Objectives
•
•
•

•

•
•

To understand the mathematical bases behind survival curves
Know the linear quadratic model form...
Relevance of Radiobiology to Clinical
Fractionation Protocols
Conventional treatment:
Tumors are generally irradiated with...
In theory, knowing relevant radiobiological parameters
one day may predict the response for
• Dose given in a single or a ...
The First Radiation Dosimeter

prompted the use of dose fractionation
WMcB2009

www.radbiol.ucla.edu
In general, history has shown
repeatedly that single high
doses of radiation do not allow
a therapeutic differential
betwe...
How to modify a treatment
schedule

WMcB2009

www.radbiol.ucla.edu
Modeling Radiation Responses
Assumes that ionizing ‘hits’ are random events in space
Which are fitted by a Poisson Distrib...
This Gives a Survival Curve Based on a Model
where one hit will eliminate a single target
•

When there is single lethal h...
Mean Inactivation Dose (Do)
•
•
•
•

Virus D0 approx. = 1500 Gy
E. Coli D0 approx. = 100 Gy
Mammalian bone marrow cells D0...
Puck and Marcus, J.E.M.103, 563, 1956
First in vitro mammalian survival curve

Eukaryotic Survival Curves are
Exponential,...
Two Component Model
single
lethal
hits

n
1.0

D0 =

1

reciprocal
initial slope

S.F.
0.1

• Two Component Model
(or sing...
1
limiting slope/
low dose rate

S.F.

Multi-fraction survival curves can be
considered linear if sublethal damage is
repa...
Linear Quadratic Model
•
1.0

αD

S.F. = e-αD
Single lethal hits

βD2

S.F. 0.1

Cell kill is the result of single lethal ...
• Over 90% of radiation oncologists use the LQ model:
– it is simple and has a microdosimetric underpinning
α/β is large (...
Thames et al Int J Radiat Oncol Biol Phys 8: 219, 1982.

•The slope of an isoeffect curve changes
with size of dose per fr...
Response to Fractionation Varies
With Tissue
1

1

Acute Responding
Acute
Tissues α/β = 10Gy

S.F.

Late Responding
Tissue...
Sensitivity
Fractionation
the

of Tissue to Dose
can be estimated by
α/β ratio

WMcB2009

www.radbiol.ucla.edu
What are α/β ratios for human
cancers?
In fact, for some tumors e.g. prostate, breast, melanoma, soft tissue
sarcoma, and ...
What total dose (D) to give if
the dose/fx (d) is changed
New
Dnew (dnew + α/β )

Old
= Dold (dold + α/β )

So, for late r...
Biologically Effective Dose (BED)
S.F. = e-E = e-(αD+βD2)
E = nd(α + βd)
E/α = nd(1+d/α/β)

Biologically
Effective Dose

T...
α/β=3Gy; 1.5Gy/fx
α/β=30Gy; 1.5Gy/fx

80

2.0Gy/fx

70

α/β=30Gy; 4Gy/fx

60

D new

α/β=3Gy; 4Gy/fx

50
40
30
20

20

30
...
Does this Matter?

Prescribed Dose:
25 fractions of 2Gy = 50Gy
Hot spot: 110%
Physical dose: 55Gy
Biological dose: 60.5Gy
...
The Linear Quadratic Formulation

• Does not work well at high dose/fx
• Assumes equal effect per fraction

WMcB2009

www....
HT29 cells

N.B. Survival curves may
deviate from L.Q. at low and
high dose!!!!
• Certain cell lines, and tissues, are
hyp...
The Linear Quadratic Formulation
• Does not work well at low or high dose/fx
• Assumes equal effect per fraction

WMcB2009...
4Rs OF DOSE FRACTIONATION
• Assessed by varying the
time between 2 or more
doses of radiation

700R

1500R

Repopulation

...
4Rs OF DOSE FRACTIONATION
These are radiobiological mechanisms that
impact the response to a fractionated course of
radiat...
Repair
•

•
•
•

“Repair” between fractions should be complete - N.B. we are
dealing with tissue recovery rather than DNA ...
Regeneration in Normal Tissues
•
•

The lag time to regeneration varies with the tissue
In acute responding tissues,
– Reg...
Repopulation in Tumor Tissue
Rat rhabdosarcoma

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

T3

local contr...
Other Sources of Heterogeneity
•

Biological Dose
– Cell cycle
– Hypoxia/reoxygenation
– Clonogenic “stem cells” (G.F.)
•
...
• Heterogeneity within and between between
tumors in dose-response characteristics, often
resulting in large error bars fo...
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)
Tumo...
Definitions
• Conventional fractionation
– Daily doses (d) of 1.8 to 2 Gy
– Dose per week of 9 to 10 Gy
– Total dose (D) o...
Definitions
• Accelerated fractionation
– Shorter overall treatment time
– Dose per fraction of 1.8 to 2 Gy
– More than 10...
TCP
or NTC

Tumor control
Late responding tissue
complications

Complication-free cure

TCP
or
NTC

Accelerated
Fractionat...
Conventional

70 Gy - 35 fx - 7 wks

Hyperfractionated

81.6 Gy - 68 fx - 7 wks

Very accelerated
with reduction of dose

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

Very accelerated
CHA...
EORTC hyperfractionation trial in
oropharynx cancer (N = 356)
Oropharyngeal Ca T2-3, N0-1

80.5 Gy - 70 fx - 7 wks
LOCAL C...
Very Accelerated: CHART (N = 918)
Dische 1997

54 Gy - 36 fx - 12 days

control: 66 Gy - 33 fx - 6.5 wks

Loco-regional co...
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/seve...
Moderately Accelerated

Overgaard 2000

DAHANCA 6: only glottic, (N = 694)
DAHANCA 7: all other sites, + nimorazole (N = 7...
Moderately Accelerated
CAIR: 7-day-continuous accelerated irradiation (N = 100)
Skladowski 2000

66-72 Gy - 33-36 fx - 5 w...
RTOG 90-03, Phase III comparison of
fractionation schedules in Stage III and IV
SCC of oral cavity, oropharynx, larynx,
hy...
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
Acute

Fu 2000

Maximum toxicity
Conventional
Hyperfract
Concom Acc +
per patient
boost
split
...
Toxicity of RT in HNSCC
Acute effects in accelerated or hyperfractionated RT
Author

Regimen

Grade 3-4 mucositis
Cont
Exp...
Altered fractionation in head and
neck cancer: meta-analysis
Randomized trials 1970-1998 (no postop RT)
15 trials included...
Conclusions for HNSCC
•
•
•

•
•

Hyperfractionation increases TCP and protects late responding tissues
Accelerated treatm...
Conclusions for HNSCC
• The benefit derived from altered fractionation is consistent
with can be of benefit but should be ...
Other Major Considerations
• Not all tumors will respond to hyper or accelerated
fractionation like HNSCC, especially if t...
Questions:
The Radiobiology Behind Dose Fractionation

WMcB2009

www.radbiol.ucla.edu
Modeling of radiation responses are based
on
1. Random events occurring in cell nuclei
2. Random events in space as define...
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-res...
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
s...
If Dq for a survival curve is 2Gy, what dose
is equivalent to a single dose of 6Gy given in
2 fractions, assuming complete...
A whole body dose of 7 Gy of x‑rays would produce severe,
potentially lethal hematologic toxicity. Assuming that the Do of...
If 90% of a tumor is removed by surgery,
what does this likely represent in term of
radiation dose given in 2 Gy fractions...
What is true for the α/β ratio
1. It is unitless
2. It is a measure of the shoulder of the
survival curve
3. It measures t...
The alpha component in the linear quadratic
formula for as radiation survival curve
represents
1. Unrepairable DNA double ...
Which parameter is most relevant for
standard clinical regimens in RT
1. The α/β ratio
2. Do
3. Alpha
4. Beta
5. The extra...
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 G...
The extrapolation number N for a multifraction survival curve, allowing complete
repair between fractions and no repopulat...
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 d...
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 pe...
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 ...
If the effDo for a multifraction survival curve is
3.5 Gy, what dose would cure 37% of a
series of 1cm diameter tumors (10...
If the effDo for a multifraction survival curve is
3.5 Gy, what dose would cure 69% of a
series of 1cm diameter tumors (10...
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....
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...
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 G...
The α/β ratio for mucosal tissues is closest
to
1. 2 Gy
2. 4 Gy
3. 6 Gy
4. 8 Gy
5. 10 Gy

WMcB2009

www.radbiol.ucla.edu
Which of the following human tumors Is
thought to have an α/β ratio of 1-2 Gy
1. Oropharyngeal Ca
2. Prostate Ca
3. Gliobl...
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 th...
It is decided to treat a patient with hypofractionation at 3
Gy/fraction instead of the conventional schedule of 60 Gy
in ...
A standard treatment for HNSCC tumors is 70 Gy delivered at 2
Gy/fraction. Hyperfractionation is being attempted with a fr...
A standard treatment for HNSCC tumors is 70 Gy delivered at 2
Gy/fraction. Hyperfractionation is being attempted with a fr...
Which of the following sites is the least
suitable for b.i.d. treatment
1. Head and neck
2. Brain
3. Lung
4. Prostate

WMc...
The rationale behind accelerated
fractionation is
1. To spare late responding normal tissue
2. To combat encourage tumor
r...
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...
DAHANCA 6 and 7 clinical trials with 6668Gy given in 6 compared to 7 weeks
1. Was a hyperfractionation trial
2. Treated 6 ...
RTOG 90-03, which compared hyperfractionation,
accelerated fractionation with a split, and
accelerated fractionation with ...
Answers
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NA...
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Radiobiology behind dose fractionation

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Radiobiology behind dose fractionation

  1. 1. 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
  2. 2. 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
  3. 3. 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
  4. 4. 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
  5. 5. The First Radiation Dosimeter prompted the use of dose fractionation WMcB2009 www.radbiol.ucla.edu
  6. 6. 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
  7. 7. How to modify a treatment schedule WMcB2009 www.radbiol.ucla.edu
  8. 8. 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
  9. 9. 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 1.0 • S.F.= e-1 = 0.37 This is the mean lethal dose D0 0.37 • D10 = 2.3 xD0 • In general, S.F. = e-D/D0 S.F. 0.1 or LnS.F. = -D/D0 0.01 0.001 or S.F. = e-αD , i.e. D0 = 1/α D0 D 10 DOSE Gy Where α is the slope of the curve and D0 the reciprocal of the slope How many logs of cells would be killed by 23 Gy if D0 = 1 Gy? WMcB2009 www.radbiol.ucla.edu
  10. 10. 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
  11. 11. 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 single lethal hits n 1.0 0.1 0.01 Accumulation of sub-lethal damage 0.001 dose WMcB2009 www.radbiol.ucla.edu
  12. 12. Two Component Model single lethal hits n 1.0 D0 = 1 reciprocal initial slope S.F. 0.1 • Two Component Model (or single target, single hit + multi-target (n), single hit) • S.F.=e-D/1D0[1-(1-e-D/nD0)n]Extrapolation Number Single hit 0.01 Accumulation of sublethal damage 0.001 Accumulate d damage D0 = n reciprocal final slope DOSE Gy WMcB2009 www.radbiol.ucla.edu
  13. 13. 1 limiting slope/ low dose rate S.F. 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 •The resultant slope is the effective D0 •e D 0 is often 2.5 - 5.0Gy and e D 10 5.8 - 11.5Gy .1 •S.F. = e-D/eD0 3 fractions Single dose .01 0 4 8 12 16 Dose (Gy) 20 •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% 24 WMcB2009 www.radbiol.ucla.edu
  14. 14. Linear Quadratic Model • 1.0 αD S.F. = e-αD Single lethal hits βD2 S.F. 0.1 Cell kill is the result of single lethal hits plus accumulated damage from 2 independent sublethal events S.F. = e-(αD+βD2) Single lethal hits plus accumulated damage 0.01 • The generalized formula is E = αD + βD2 • 0.001 α/β in Gy DOSE Gy For a fractionated regimen E= nd(α + βd) = D (α + βd) Where d = dose per fraction and D = total dose ∀ α/β is dose at which death due to single lethal lesions = death due to accumulation of sublethal lesions i.e. αD = βD2 and D = α/β in Gy WMcB2009 www.radbiol.ucla.edu
  15. 15. • Over 90% of radiation oncologists use the LQ model: – it is simple and has a microdosimetric underpinning α/β is large (> 6 Gy) when survival curve is almost exponential and small (1-4 Gy) when shoulder is wide – the α/β value quantifies the sensitivity of a tissue/tumor to fractionated radiation. • But: – Both α and β vary with the cell cycle. At high doses, S phase and hypoxic cells become more important. – The α/β 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
  16. 16. 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 • α/β 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 α/β ratio Reciprocal total dose for an isoeffect Slope = β Intercept = α Dose per fraction WMcB2009 www.radbiol.ucla.edu
  17. 17. Response to Fractionation Varies With Tissue 1 1 Acute Responding Acute Tissues α/β = 10Gy S.F. Late Responding Tissues - α/β = 2Gy 0 4 8 12 Dose (Gy) Fractionated Acute Effects Single Dose Late Effects α/β = 2Gy α/β is high (>6Gy) when survival curve is almost exponential and low (1-4Gy) when shoulder is wide .01 Fractionated Late Effects .1 .1 S.F. Single Dose Acute Effects α/β = 10Gy .01 16 0 4 8 12 16 Dose (Gy) 20 Fractionation spares late responding tissues WMcB2009 www.radbiol.ucla.edu
  18. 18. Sensitivity Fractionation the of Tissue to Dose can be estimated by α/β ratio WMcB2009 www.radbiol.ucla.edu
  19. 19. What are α/β ratios for human cancers? In fact, for some tumors e.g. prostate, breast, melanoma, soft tissue sarcoma, and liposarcoma α/β ratios may be moderately low Prostate – Brenner and Hall IJROBP 43:1095, 1999 • comparing implants with EBRT ∀ α/β 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 α/β 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 α/β = 4.0Gy (1.0-7.8) • Breast appearance α/β = 3.6Gy; induration α/β If fractionation sensitivity of a cancer is similar to = 3.1Gy dose-limiting healthy tissues, it may be possible to give fewer, larger fractions without compromising effectiveness or safety WMcB2009 www.radbiol.ucla.edu
  20. 20. What total dose (D) to give if the dose/fx (d) is changed New Dnew (dnew + α/β ) Old = Dold (dold + α/β ) 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 α/β for late responding tissues can make a big difference in estimated D! WMcB2009 www.radbiol.ucla.edu
  21. 21. Biologically Effective Dose (BED) S.F. = e-E = e-(αD+βD2) E = nd(α + βd) E/α = nd(1+d/α/β) Biologically Effective Dose Total dose Relative Effectiveness 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) Normalized total dose2Gy = BED/RE = BED/1.2 for α/β of 10Gy = BED/1.67 for α/β of 3Gy www.radbiol.ucla.edu WMcB2009
  22. 22. α/β=3Gy; 1.5Gy/fx α/β=30Gy; 1.5Gy/fx 80 2.0Gy/fx 70 α/β=30Gy; 4Gy/fx 60 D new α/β=3Gy; 4Gy/fx 50 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
  23. 23. Does this Matter? Prescribed Dose: 25 fractions of 2Gy = 50Gy Hot spot: 110% Physical dose: 55Gy Biological dose: 60.5Gy “Double Trouble” www.radbiol.ucla.edu WMcB2009
  24. 24. The Linear Quadratic Formulation • Does not work well at high dose/fx • Assumes equal effect per fraction WMcB2009 www.radbiol.ucla.edu
  25. 25. 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 www.radbiol.ucla.edu WMcB2009
  26. 26. The Linear Quadratic Formulation • Does not work well at low or high dose/fx • Assumes equal effect per fraction WMcB2009 www.radbiol.ucla.edu
  27. 27. 4Rs OF DOSE FRACTIONATION • Assessed by varying the time between 2 or more doses of radiation 700R 1500R Repopulation Redistribution Repair WMcB2009 www.radbiol.ucla.edu
  28. 28. 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
  29. 29. 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
  30. 30. 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
  31. 31. Repopulation in Tumor Tissue Rat rhabdosarcoma Human SCC head and neck T2 70 Total Dose (2 Gy equiv.) 55 T3 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 Treatment breaks are often “bad” Withers, H.R., Taylor, J.M.G., and Maciejewski, B. WMcB2009 www.radbiol.ucla.edu Acta Oncologica 27:131, 1988
  32. 32. Other Sources of Heterogeneity • Biological Dose – Cell cycle – Hypoxia/reoxygenation – Clonogenic “stem cells” (G.F.) • • • • S.F hypoxic oxic 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
  33. 33. • Heterogeneity within and between between tumors in dose-response characteristics, often resulting in large error bars for α/β 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
  34. 34. Altered Fractionation or How to optimally distribute dose over time WMcB2009 www.radbiol.ucla.edu
  35. 35. 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
  36. 36. 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
  37. 37. 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 α/β ratio and there is no therapeutic advantage to be gained with respect to late complications WMcB2009 www.radbiol.ucla.edu
  38. 38. TCP or NTC Tumor control Late responding tissue complications Complication-free cure TCP or NTC Accelerated Fractionation Hyperfractionation Dose www.radbiol.ucla.edu WMcB2009
  39. 39. 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
  40. 40. 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
  41. 41. EORTC hyperfractionation trial in oropharynx cancer (N = 356) Oropharyngeal Ca T2-3, N0-1 80.5 Gy - 70 fx - 7 wks LOCAL CONTROL Years Horiot 1992 control: 70 Gy - 35-40 fx - 7-8 wks p = 0.02 SURVIVAL p = 0.08 Years WMcB2009 www.radbiol.ucla.edu
  42. 42. Very Accelerated: CHART (N = 918) Dische 1997 54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx - 6.5 wks Loco-regional control conventional CHART Favourable outcome with CHART: www.radbiol.ucla.edu Survival conventional CHART well differentiated tumors larynx carcinomas WMcB2009
  43. 43. 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
  44. 44. 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 Local control DAHANCA 6 DAHANCA 7 Nodal control DAHANCA 6 + 7 Disease-specific survival DAHANCA 6 + 7 5 fx/wk 6 fx/wk 73% 56% 81% p=0.04 68% p=0.009 Overall survival Late effects (edema, fibrosis) n.s. n.s. 87% 65% . 89% n.s. 72% p=0.04 WMcB2009 www.radbiol.ucla.edu
  45. 45. 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 SURV IV AL Probability CAIR CONTROL log-rank p=0.00001 Follow-up (months) WMcB2009 www.radbiol.ucla.edu
  46. 46. 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
  47. 47. RTOG 90-03, loco-regional control Fu 2000 WMcB2009 www.radbiol.ucla.edu
  48. 48. RTOG 90-03, survival Fu 2000 WMcB2009 www.radbiol.ucla.edu
  49. 49. 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% WMcB2009 www.radbiol.ucla.edu
  50. 50. 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
  51. 51. 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) WMcB2009 www.radbiol.ucla.edu
  52. 52. 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
  53. 53. 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
  54. 54. Other Major Considerations • Not all tumors will respond to hyper or accelerated fractionation like HNSCC, especially if they have a low α/β 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!!! • 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
  55. 55. Questions: The Radiobiology Behind Dose Fractionation WMcB2009 www.radbiol.ucla.edu
  56. 56. 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 WMcB2009 www.radbiol.ucla.edu
  57. 57. 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 WMcB2009 www.radbiol.ucla.edu
  58. 58. 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 WMcB2009 www.radbiol.ucla.edu
  59. 59. 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 WMcB2009 www.radbiol.ucla.edu
  60. 60. 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 WMcB2009 www.radbiol.ucla.edu
  61. 61. 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 WMcB2009 www.radbiol.ucla.edu
  62. 62. What is true for the α/β 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 WMcB2009 www.radbiol.ucla.edu
  63. 63. 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 WMcB2009 www.radbiol.ucla.edu
  64. 64. Which parameter is most relevant for standard clinical regimens in RT 1. The α/β ratio 2. Do 3. Alpha 4. Beta 5. The extrapolation number WMcB2009 www.radbiol.ucla.edu
  65. 65. 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 WMcB2009 www.radbiol.ucla.edu
  66. 66. 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 WMcB2009 www.radbiol.ucla.edu
  67. 67. 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 WMcB2009 www.radbiol.ucla.edu
  68. 68. 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 WMcB2009 www.radbiol.ucla.edu
  69. 69. 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 WMcB2009 www.radbiol.ucla.edu
  70. 70. 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 WMcB2009 www.radbiol.ucla.edu
  71. 71. If the effDo for a multifraction survival curve is 3.5 Gy, what dose would cure 69% of a series of 1cm diameter tumors (109 clonogens). 1. 56 Gy 2. 64 Gy 3. 72 Gy 4. 80 Gy WMcB2009 www.radbiol.ucla.edu
  72. 72. If a tumor has an effective Do of 3.5 Gy,what is the S.F. after 70 Gy? 1. 2 x 10-11 2. 2 x 10-9 3. 2 x 10-7 4. 2 x 10-5 5. 2 x 10-3 WMcB2009 www.radbiol.ucla.edu
  73. 73. If 16 x 2 Gy fractions reduce survival by 10-4, what dose would be needed to reduce survival to 10-10? 1. 50 Gy 2. 60 Gy 3. 64 Gy 4. 70 Gy 5. 80 Gy WMcB2009 www.radbiol.ucla.edu
  74. 74. If 16 x 2 Gy fractions reduce survival by 10-4, what is the effective D0? 1. 2.0 Gy 2. 2.3 Gy 3. 3.0 Gy 4. 3.5 Gy 5. 3.8 Gy WMcB2009 www.radbiol.ucla.edu
  75. 75. The α/β ratio for mucosal tissues is closest to 1. 2 Gy 2. 4 Gy 3. 6 Gy 4. 8 Gy 5. 10 Gy WMcB2009 www.radbiol.ucla.edu
  76. 76. Which of the following human tumors Is thought to have an α/β ratio of 1-2 Gy 1. Oropharyngeal Ca 2. Prostate Ca 3. Glioblastoma 4. Colorectal Ca WMcB2009 www.radbiol.ucla.edu
  77. 77. 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 (αD + βD2), accurately represents cell survival for this tissue, what is the value of α/β? 1. 1 Gy 2. 2 Gy 3. 4 Gy 4. 10 Gy 5. 20 Gy WMcB2009 www.radbiol.ucla.edu
  78. 78. 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 α/β for late damage = 3 Gy? 1. 40 Gy 2. 48 Gy 3. 50 Gy 4. 55.4 Gy 5. 75 Gy WMcB2009 www.radbiol.ucla.edu
  79. 79. 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 α/β of 3 Gy. 1. 42 Gy 2. 58 Gy 3. 70 Gy 4. 83 Gy 5. 117 Gy WMcB2009 www.radbiol.ucla.edu
  80. 80. 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 α/β of 3 Gy for late responding tissue and 12 Gy for tumor, what would be the therapeutic gain. 1. 6% 2. 12% 3. 18% 4. 24% WMcB2009 www.radbiol.ucla.edu
  81. 81. Which of the following sites is the least suitable for b.i.d. treatment 1. Head and neck 2. Brain 3. Lung 4. Prostate WMcB2009 www.radbiol.ucla.edu
  82. 82. The rationale behind accelerated fractionation is 1. To spare late responding normal tissue 2. To combat encourage tumor reoxygenation 3. To exploit redistribution in tumors 4. To combat accelerated repopulation in tumors WMcB2009 www.radbiol.ucla.edu
  83. 83. The CHART regimen for HNSCC of 54Gy in 36 fractions over 12 days compared with 66 Gy in 33 fractions in 6.5 weeks, overall showed 1. Superior locoregional control, no increase in overall survival, increased late effects 2. Superior locoregional control that translated into an increase in overall survival, no change in late effects 3. No change in locoregional control and overall survival, decreased late effects 4. Superior locoregional control, no increase in overall survival, increased acute effects WMcB2009 www.radbiol.ucla.edu
  84. 84. 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 WMcB2009 www.radbiol.ucla.edu
  85. 85. 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 WMcB2009 www.radbiol.ucla.edu
  86. 86. 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 WMcB2009 www.radbiol.ucla.edu

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