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Time, Dose, and Fractionation. Gary M. Freedman M.D. Fox Chase Cancer Center.

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The 4 R’s of fractionationThe radiobiological rationale behind dose fractionationThe effect of tissue type on the response to dose fractionationEffect of tissue/tumor types on / ratiosQuantitation of multi-fraction survival curvesBED and isoeffect dose calculations

The 4 R’s of fractionationThe radiobiological rationale behind dose fractionationThe effect of tissue type on the response to dose fractionationEffect of tissue/tumor types on / ratiosQuantitation of multi-fraction survival curvesBED and isoeffect dose calculations

The 4 R’s of fractionationThe radiobiological rationale behind dose fractionationThe effect of tissue type on the response to dose fractionationEffect of tissue/tumor types on / ratiosQuantitation of multi-fraction survival curvesBED and isoeffect dose calculations

Repair of Sublethal Damage

- Tends to improve cell survival.
- Repair occurs during interval between fractions.
- Needs 2 hour interval for maximal effect.

Reassortment of cells within the cell cycle

- Tends to reduce cell survival.
- Cells move to more radiosensitive phase in the cell cycle between fractions.
- M and G2 most sensitive phases.
- Late S most resistant phase.

Reoxygenation

- Tends to reduce cell survival.
- Pool of hypoxic cells diminishes after each fraction.
- Oxic cells more sensitive.

Repopulation

- Tends to increase cell survival.
- Occurs when fraction interval length greater than cell cycle doubling time.

The 4 R’s of fractionationThe radiobiological rationale behind dose fractionationThe effect of tissue type on the response to dose fractionationEffect of tissue/tumor types on / ratiosQuantitation of multi-fraction survival curvesBED and isoeffect dose calculations

Fractionation

Sterilization Endpoint Experiments 1920’s-30’s

- Single Fraction Severe Skin Effects
- Multiple Smaller Fractions Less Severe Skin Effects

Isoeffect Curves

- Each isoeffect curve represents a different clinical acute toxicity endpoint.
- Examples A = skin necrosis, E = skin erythema.

Mechanisms for Early vs. Late Responding Tissues

- Late responders may have high percentage of resting G0 cells.
- Tumors and acute tissues may cycle fast enough so that proliferation > cell kill.

M

G2

G1

G0

S

Proliferation and Treatment Time

- Normal tissues are not all the same!
- Treatment time effects tumor and acute responding tissue rather than late side effects.
- Accelerated repopulation occurs if treatment time too long.
- For head and neck cancer, need extra 60 cGy / day after day 28 to maintain same tumor control.

Tissue Type and Fractionation

- Late responding tissues have larger shoulder, more curved shape of dose-response curve. Greater repair and survival at lower dose per fractions.
- Early tissues have smaller shoulder, less curved shape.

The 4 R’s of fractionationThe radiobiological rationale behind dose fractionationThe effect of tissue type on the response to dose fractionationEffect of tissue/tumor types on / ratiosQuantitation of multi-fraction survival curvesBED and isoeffect dose calculations

/ Ratios

- / equal killing occurs at lower dose for late responding tissues.
- Early / about 10
- Late / about 3

Normal Tissue /

Brenner Int J Radiat Oncol Biol Phys 60: 1013-15; 2004.

Multifraction Effects: Cell Type

- Early responding tissues less sensitive to fractionation than late responding tissues.
- Different cell survival curves, same fraction sizes.

Late Tissue

Surviving Fraction

Early Tissue

Hyperfractionation

- Increases differences seen between acute and late effects compared with standard 2 Gy fraction size.
- Reduces late effects more than acute/tumor effects (because fractionation affects late effects more).

Multifraction Effects: Fraction Size

- Fewer large fractions result in more severe late effects than more smaller fractions.
- Same cell survival curves, different fraction sizes.

Small Fraction

Surviving Fraction

Large Fraction

Standard Regimen

70 Gy / 35 Fx / 7 wks

Biologic Effective Dose = (Total Dose) x (relative effectiveness).

BED = D ( 1 + d/ / )

BED3 = 70 ( 1 + 2/3 ) = 116

BED10= 70 ( 1 + 2/10 ) = 84

Proposed BID Regimen

BED10= 84 = X ( 1 + 1.2/10 )

X = 75 Gy

BED3 = 75 ( 1 + 1.2/3 ) = 105

Would expect less late effects

But, 75 Gy / 62 Fx = 6 weeks

Therefore, also shortening treatment time!

Hyperfractionation studies usually increase total dose as well.

Hyperfractionation80.5 GY / 70 Fx / 7 wks

1.15 Gy BID

5 yr local control 59%

Complications equal

BED3 = 80.5 ( 1 + 1.15/3 ) = 111

BED10= 80.5 ( 1 + 1.15/10 ) = 90

70 Gy / 35 Fx / 7 wks

2 Gy daily

5 yr local control 40%

BED3 = 70 ( 1 + 2/3 ) = 116

BED10= 70 ( 1 + 2/10 ) = 84

EORTCHead and Neck CancerAccelerated Fractionation

- Reduces treatment time to decrease effects of repopulation.
- Increases acute effects. May require a break or reduced dose for patient tolerance.
- No affect on late effects because total dose and fraction size the same.

72 GY / 45 Fx / 5 wks

1.6 Gy TID, 2 wk break

15% improvement in local control (expected)

Complications Increased (unexpected)

BED3 = 72 ( 1 + 1.6/3 ) = 110

BED10= 72 ( 1 + 1.6/10 ) = 84

70 Gy / 35 Fx / 7 wks

2 Gy daily

BED3 = 70 ( 1 + 2/3 ) = 116

BED10= 70 ( 1 + 2/10 ) = 84

EORTCHead and Neck CancerTreatment Time

- Danish Head and Neck Trials
- Same total dose.
- Same dose per fraction.
- Shorter time increased acute effects (expected).
- No change in late effects (expected).

RTOG 90-03

- Improved local control (expected) with hyperfractionation and accelerated fractionation without split.
- Increased acute effects (expected).
- No increase in late effects (expected).

Fu Int J Radiat Oncol Biol Phys 48: 7 – 16; 2000.

54 GY / 36 Fx / 2 wks

1.5 Gy TID

Local control the same (unexpected)*.

Severe acute effects (expected).

Late complications same (expected).

Myelopathy increased (unexpected).

BED3 = 54 ( 1 + 1.5/3 ) = 81

BED10= 54 ( 1 + 1.5/10 ) = 62*

(*BED formula doesn’t account for large difference in treatment time)

70 Gy / 35 Fx / 7 wks

2 Gy daily

BED3 = 70 ( 1 + 2/3 ) = 116

BED10= 70 ( 1 + 2/10 ) = 84

UKCHARTFractionation Summary

- Fraction size and total dose determine late effects.
- Fraction size, total dose and overall treatment time determine acute effects/tumor control.
- Decreasing treatment time increases risks of acute effects, but lowers tumor repopulation.
- BED calculations break down with large differences in total treatment time (tumor cell proliferation).

Clinical Trial Design

- Will hypofractionation of the prostate to shorten treatment time increase late effects?
- Answer: Not if total dose lower.
- Will it increase tumor control?
- Answer: Not if prostate tumor is a slow cycler (probably not).
- Answer: Depends on if it is acute or late responding tissue.

Biological Effect DoseIf / Prostate Tumor = 10

Standard Radiation:

76 Gy in 38 fractions in 2.0 Gy per fraction

BED4 = 76 ( 1 + 2/4 ) Rectum

= 114

BED10 = 76 ( 1 + 2/10 ) Tumor

= 91

Hypofractionated Radiation:

70.2 Gy in 26 fractions in 2.7 Gy per fraction

BED4 = 70.2 ( 1 + 2.7/4 ) Rectum

= 118

BED10 = 70.2 ( 1 + 2.7/10 ) Tumor

= 89

= X (1 + 2/10) = 74 Gy @ 2 Gy / Fx

Biological Effect DoseIf / Prostate Tumor = 1.5

Standard Radiation:

76 Gy in 38 fractions in 2.0 Gy per fraction

BED4 = 76 ( 1 + 2/4 ) Rectum

= 114

BED1.5 = 76 ( 1 + 2/1.5 ) Tumor

= 177.3

Hypofractionated Radiation:

70.2 Gy in 26 fractions in 2.7 Gy per fraction

BED4 = 70.2 ( 1 + 2.7/4 ) Rectum

= 118

BED1.5 = 70.2 ( 1 + 2.7/1.5 ) Tumor

= 197

= X (1 + 2/1.5) = 84 Gy @ 2 Gy / Fx

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