06 time,dose,fractionation
TRANSCRIPT
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Time, Dose and Fractionation (TDF) in Radiobiology
Ji-Hong Hong, M.D., Ph.D.
Ref: Eric J. Hall, Radiobiology for the Radiologist, 5th Edition
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Historical observation
Single dose:Sterilization
skin damage
Multiple smaller:
Sterilization
no skin damage
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Influence of 4Rs in Radiation Therapy
• Repair: favor lower or high Dq value (late > early > tumor)
• Reoxygenation: favor tumor killing• Redistribution (Reassortment): advantage for slow
proliferating tissues• Repopulation: tumors and early tissues have adva
ntage
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4 Rs and TDF
Tumor Early responding
tissues
Late responding tissues
Repair
Reassortment
Repopulation
Reoxygenation
Is there any gain between early responding tissue (or tumor) and late responding tissues
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Clinical observation
A: skin necrosis, B: cure of skin carcinoma, C; moist desquamation. D: dry desquamation E; erythema
Strandquist plot
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Ellis Nominal Standard Dose
Weakness:
1. Time factor is not right.
2. Only consider acute responding tissues.
Total dose = (NSD)T0.11N0.24
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Acute vs. late responding tissues• Acute responses: occurring during or within short time aft
er RT.– Such as mucositis, skin reaction, bowel responses,bone marrow d
epression.– More related to total dose and time, less related to fraction size.
• Late responses: occurring months to years after RT.– Such as fibrosis of tissue, radiation myelopathy, renal damage, us
ually are irreversible changes when damage is formed.– More related to fraction size and total dose, less related to total ti
me.
• The behaviors of tumor are more similar to those of acute responding tissues.
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Time factorCompensation of time factor for acute responding tissue by extra dose
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Animal model of acute vs. late responding tissues
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Clinical model of acute vs. late responding tissue
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Time factor: accelerated repopulation
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Clinical evidence of accelerated repopulation
Dose increase = 0.6 Gy/day
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1. Tumor regrowth in post-C/T or surgery.
2. Continuous Hyperfractionated Accelerated Radiation Therapy (CHART)
Clinical evidence of (accelerated) repopulation
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Q & A for time factor
• Q1: Will prolong total treatment time reduce late complications? – A:
• Q2: Will prolong total treatment increase the possibility of repopulation?– A:
• Q3: The total treatment time should be as short as possible, but what are the limitations? – A:
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Fractionation factor
• Question 1: – 3 Gy/per fx. x 10 = 2 Gy/per fx. x 15 (????)
Repeated shoulder
A: Biological effects 30 Gy/10 fx > 30 Gy/15 fx
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Fractionation factorQ2: Does fractionation scheme bring same effects to early- and late responding tissueA: see next slide
Q3: Does acute responding tissue have same dose-response curve with the late responding tissues?A: No!!!
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Expand the difference of early vs. late tissues by
fractionation
A: Fractionation protects late responding tissues damage than acute responding tissues
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Dose-response for acute and late responding tissue
Late responding tissues
Acute responding tissues
Decreasing fraction size
Increasing total dose
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Same acute reactions, different late reactions
Treated with X-ray
Treated with neutron
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How to evaluate the effects of fractionation on acute vs. late responding tissues ?
For example:3 Gy x 10 fx. Vs. 2 Gy x 20 Gy
Q: Do these treatment doses have same biological effects between acute and late responding tissues ? A:Q: Does any way to describe the differences between acute and late responding tissue in their sensitivity to change fraction size?
ratio
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S = e –D-D2
S = (e –d-d2 )n -lnS = n(d + d2)
-lnS/nd = + d
-lnS/D = + d
Calculation of
Linear-Quadrate concept
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How to obtain an ratio
Set same biological endpoint achieved by different fractionated treatment schema
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Calculation of
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Calculation of
1 ----- = ------ + -------- d nd -lnS -lnS
d= 0, Intercept = ---- = 0.013 Gy –1
-lnS
Slope = ---- = 0.00129 Gy –2
-lnS
= 10.1 Gy
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ratio Q: Does ratio means the radiosensitivity of a tissue?A: No, it is nothing to do with radiosensitivity. It is related to the sensitivity to change of fraction size.
Q: Do late responding tissues have small ratio and are more sensitive to change of fraction size
A: Yes!!!!
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Calculation of Biological Effective Dose (BED)
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Calculation of Biological Effective Dose (BED)
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Model calculation
35 F x 2 Gy/7 week 70 F x 1.15 Gy/7 week
Assumptions: complete repair between fractions
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Concomitant boost
([30 F x 1.8 Gy] + {12 F x 1.5 Gy]/6 week
Where is the time factor?
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CHART protocol
36 F x 1.5 Gy/12 days
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The conversion of dose by ratio
D1 x (1 + d1D2 x (1 + d2
D1 (1 + d2(d2
D2 (1 + d1(d1
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Calculation
D1 (1 + d2(d2
D2 (1 + d1(d1For example:
A treatment protocol gives 40 Gy/20 Fx., if we change the fraction to 3 Gy, how should we adjust the total dose for acuter responding tissues ( = 10) or later responding tissue (( = 3)
For acute responding tissue40/D2 = (3 + 10) / (2 + 10) D2 = 37 Gy
For late responding tissue40/D2 = (3 + 3) /(2 + 3) D2 = 33 Gy.
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Summary
• The total treatment time should be shorten to prevent repopulation of tumor, but tolerance of acute responding tissue is the limitation.
• The reduction of fraction size is to protect normal late responding tissues, but the fraction number is increased.
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Fractionation schedule
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• 1.8-2 Gy/day
• 5 day/week.
• Total dose is usually higher than 6.000 cGy for gross solid tumor.
Conventional treatment
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Dose > 2 Gy/per fraction.• Palliative:
– Short term: > 2 Gy/day, usually 3 Gy/day. Total dose is lower than curative dose. Eg. 3 Gy x 10 Fx.
• Curative – For organs with parallel functional structure such as lung and liv
er. If the dose can be conformed to tumor, hypofractionation is considered. Eg. Proton treatment in hepatoma and lung cancer.
– Sterotactic Radiosurgery: single dose – Some Europe countries used large fraction size, their results wer
e also acceptable in some literature. However, large fraction size is less used in the USA for curative attempt.
Hypofractionation
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Hyperfractionation
•Decrease of fraction size– < 1.8 Gy/fraction, usually 1.15-1.6 Gy.
•Increase fraction number.– Usually treat more than 1 fraction/per day.
•Purpose: Spare normal tissue (late complication tissue) when using smaller fraction size.
– If treated with similar dose as conventional treatment, complications are expected to decrease.
– If treated with the increased total dose, tumor control probability is expected to increase but same possibility of late complications.
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Accelerated fractionation
•Same fraction size, 1.8 – 2 Gy, same fraction number.•Shorten total treatment time.
–Eg. bid (twice per day), or > 5 fractions/per week
•Purpose: reduce tumor repopulation during RT.•Limitation: Severe acute reaction.
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Some limitation
•“Consequential” late damage.–Late damage developed out of the very severe effects.–Clinical example: skin reactions, G-I reactions
•Incomplete repair between fractions–Especially for CNS.
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Mixed typeCHART (Continuous hyperfractionated, accelerated radiotherapy)•150 cGy/Fx. 3 fx./day, W1-7, total dose = 54 Gy.•Total treatment time: 12 days.•Results:
–Increased acute toxicity.
–Late complications: not increased except spinal cord.
–similar or slightly better local control for different types of tumor.
•Implication: Reduce repopulation
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Mixed type
ARCON -Accelerated Hyperfractionated Radiation Therapy while Breathing Carbogen and with the addition of Nicotinamide-Accelerated to overcome proliferation.-Hyperfractionated to spare normal tissues.-Carbogen breathing to overcome chronic hypoxia.-Nicotinamide to overcome acute hypoxia.
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Singe-dose vs. fractionated dose
• Threshold dose in radiobiological effects– Apopotisis of tumor a
nd endothelial cell death
– Cytokine gene expression
• 1 Gy in lung, 7 Gy in brain.
“Target-Switching” model(dose-dependent “target”)
Nature Medicine, 2005: 11:477
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Singe-dose vs. fractionated dose
• Accumulated vs. single dose
• Interaction between previous events and subsequent radiation
• enhancement ? adaptation?
• Other radiobiological factors– Repopulation, reassortment, re-oxygneation, repair
Q: What are the differences between single-dose and fractionated treatment?
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Models of microvascular endothelial engagement in tumor response to single-dose or fractionated
radiotherapy
Cancer cell, 2005: 8: 89-91
?
?
?
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Tumor control probability (TCP) and normal tissue complication probability (NTCP) in
radiotherapy
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Tumor control probability (1)
• Assumption– 1 cm3 = 109 tumor cells– Survival fraction of 2 Gy = 0.5 = ½– No repopulation during treatment, each dose has same
killing effect
• Calculation– 2 Gy x 2 = ½ x ½– 2 Gy x 3 = ½ x ½ x ½........... 2 Gy x 10 = (1/2)10 = 1/1024 = (10)-3
2 Gy x 30 = (1/2)30 = (10)-9
2 Gy x 31 = (1/2)31 = (10)-9 x ½
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Tumor control probability (2)
• Calculation– 1 cm3 = 109 tumor cells– After
• 28 treatment (2 Gy x 28) = 4 cells
• 29 treatment (2 Gy x 29) =2 cells
• 30 treatment (2 Gy x30) = 1 cell
• 31 treatment (2 Gy x 31) = 0.5 cell
• 32 treatment (2 Gy x 32) = 0.25 cell
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Poisson distribution an e-a
Pn = ------------- n!
(Pn =the probability of finding n survival cells)(a = expected number)
Eg: n =1, a=1 11e-1
P1 = ------------- = 37% 1!
(P1 =the probability of finding 1 survival cells)(1 = expected number)
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TCP with doses
Dose (Gy) 56 58 60 62 64 66
Cell killing
(1/2)28 (1/2)29 (1/2)30 (1/2)31 (1/2)32 (1/2)33
Surviving cells
4 2 1 0.5 0.25 0.125
TCP 0.018 0.135 0.375 0.61 0.78 0.88
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TCP with doses
0102030405060708090100
54 56 58 60 62 64 66 68 70 (Gy)
)
TCP (%)