Time, Dose and Fractionation (TDF) in Radiobiology

Ji-Hong Hong, M.D., Ph.D.

Ref: Eric J. Hall, Radiobiology for the Radiologist, 5th Edition

Historical observation

Single dose:Sterilization

skin damage

Multiple smaller:

Sterilization

no skin damage

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

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

Clinical observation

A: skin necrosis, B: cure of skin carcinoma, C; moist desquamation. D: dry desquamation E; erythema

Strandquist plot

Ellis Nominal Standard Dose

Weakness:

1. Time factor is not right.

2. Only consider acute responding tissues.

Total dose = (NSD)T0.11N0.24

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.

Time factorCompensation of time factor for acute responding tissue by extra dose

Animal model of acute vs. late responding tissues

Clinical model of acute vs. late responding tissue

Time factor: accelerated repopulation

Clinical evidence of accelerated repopulation

Dose increase = 0.6 Gy/day

1. Tumor regrowth in post-C/T or surgery.

2. Continuous Hyperfractionated Accelerated Radiation Therapy (CHART)

Clinical evidence of (accelerated) repopulation

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:

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

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!!!

Expand the difference of early vs. late tissues by

fractionation

A: Fractionation protects late responding tissues damage than acute responding tissues

Dose-response for acute and late responding tissue

Late responding tissues

Acute responding tissues

Decreasing fraction size

Increasing total dose

Same acute reactions, different late reactions

Treated with X-ray

Treated with neutron

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

S = e –D-D2

S = (e –d-d2 )n -lnS = n(d + d2)

-lnS/nd = + d

-lnS/D = + d

Calculation of

Linear-Quadrate concept

How to obtain an ratio

Set same biological endpoint achieved by different fractionated treatment schema

Calculation of

Calculation of

1 ----- = ------ + -------- d nd -lnS -lnS

d= 0, Intercept = ---- = 0.013 Gy –1

-lnS

Slope = ---- = 0.00129 Gy –2

-lnS

= 10.1 Gy

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!!!!

Calculation of Biological Effective Dose (BED)

Calculation of Biological Effective Dose (BED)

Model calculation

35 F x 2 Gy/7 week 70 F x 1.15 Gy/7 week

Assumptions: complete repair between fractions

Concomitant boost

([30 F x 1.8 Gy] + {12 F x 1.5 Gy]/6 week

Where is the time factor?

CHART protocol

36 F x 1.5 Gy/12 days

The conversion of dose by ratio

D1 x (1 + d1D2 x (1 + d2

D1 (1 + d2(d2

D2 (1 + d1(d1

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.

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.

Fractionation schedule

• 1.8-2 Gy/day

• 5 day/week.

• Total dose is usually higher than 6.000 cGy for gross solid tumor.

Conventional treatment

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

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.

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.

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.

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

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.

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

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?

Models of microvascular endothelial engagement in tumor response to single-dose or fractionated

radiotherapy

Cancer cell, 2005: 8: 89-91

?

?

?

Tumor control probability (TCP) and normal tissue complication probability (NTCP) in

radiotherapy

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

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

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)

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

TCP with doses

0102030405060708090100

54 56 58 60 62 64 66 68 70 (Gy)

)

TCP (%)