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

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time dose and fractionation

Time, Dose, and Fractionation

Gary M. Freedman M.D.

Fox Chase Cancer Center

slide2

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
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
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
Reoxygenation
  • Tends to reduce cell survival.
  • Pool of hypoxic cells diminishes after each fraction.
  • Oxic cells more sensitive.
repopulation
Repopulation
  • Tends to increase cell survival.
  • Occurs when fraction interval length greater than cell cycle doubling time.
slide7

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
Fractionation

Sterilization Endpoint Experiments 1920’s-30’s

  • Single Fraction  Severe Skin Effects
  • Multiple Smaller Fractions  Less Severe Skin Effects
isoeffect curves
Isoeffect Curves
  • Each isoeffect curve represents a different clinical acute toxicity endpoint.
  • Examples A = skin necrosis, E = skin erythema.
tissue type
Early Responding

Tumor

Skin

Mucosa

Intestinal Epithelium

Late Responding

Spinal Cord

Tissue Type
mechanisms for early vs late responding tissues
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
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
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.
slide14

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
/ Ratios
  • / equal killing occurs at lower dose for late responding tissues.
  • Early / about 10
  • Late / about 3
normal tissue
Normal Tissue /

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

slide17

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

multifraction effects cell type
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
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
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

hyperfractionation1
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.

Hyperfractionation
eortc head and neck cancer
80.5 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 Cancer
accelerated fractionation
Accelerated 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.
eortc head and neck cancer1
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 Cancer
treatment time
Treatment 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
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.

uk chart
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

UKCHART
fractionation summary
Fractionation 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
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.
slide30

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

biological effect dose if prostate tumor 10
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 dose if prostate tumor 1 5
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