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

2. The 4 R’s of fractionation The radiobiological rationale behind dose fractionation The effect of tissue type on the response to dose fractionation Effect of tissue/tumor types on / ratios Quantitation of multi-fraction survival curves BED and isoeffect dose calculations

3. Repair of Sublethal Damage
Tends to improve cell survival.
Repair occurs during interval between fractions.
Needs 2 hour interval for maximal effect.

4. 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.

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

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

7. The 4 R’s of fractionation The radiobiological rationale behind dose fractionation The effect of tissue type on the response to dose fractionation Effect of tissue/tumor types on / ratios Quantitation of multi-fraction survival curves BED and isoeffect dose calculations

8. Fractionation Sterilization Endpoint Experiments 1920’s-30’s
Single Fraction  Severe Skin Effects
Multiple Smaller Fractions  Less Severe Skin Effects

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

10. Tissue Type Early Responding Tumor Skin Mucosa Intestinal Epithelium
Late Responding
Spinal Cord

11. 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

12. 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.

13. 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.

14. The 4 R’s of fractionation The radiobiological rationale behind dose fractionation The effect of tissue type on the response to dose fractionation Effect of tissue/tumor types on / ratios Quantitation of multi-fraction survival curves BED and isoeffect dose calculations

15. / Ratios
/ equal killing occurs at lower dose for late responding tissues.
Early / about 10
Late / about 3

16. Normal Tissue /
Brenner Int J Radiat Oncol Biol Phys 60: ; 2004.

17. The 4 R’s of fractionation The radiobiological rationale behind dose fractionation The effect of tissue type on the response to dose fractionation Effect of tissue/tumor types on / ratios Quantitation of multi-fraction survival curves BED and isoeffect dose calculations

18. 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

19. 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).

20. 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

21. Hyperfractionation 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 ( /10 )
X = 75 Gy
BED3 = 75 ( /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.

22. 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 ( /3 ) = 111
BED10= 80.5 ( /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

23. 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.

24. EORTC Head and Neck Cancer
72 GY / 45 Fx / 5 wks
1.6 Gy TID, 2 wk break
15% improvement in local control (expected)
Complications Increased (unexpected)
BED3 = 72 ( /3 ) = 110
BED10= 72 ( /10 ) = 84
70 Gy / 35 Fx / 7 wks
2 Gy daily
BED3 = 70 ( 1 + 2/3 ) = 116
BED10= 70 ( 1 + 2/10 ) = 84

25. 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).

26. 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.

27. UK CHART 70 Gy / 35 Fx / 7 wks 2 Gy daily 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 ( /3 ) = 81
BED10= 54 ( /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

28. 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).

29. 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.

30. The 4 R’s of fractionation The radiobiological rationale behind dose fractionation The effect of tissue type on the response to dose fractionation Effect of tissue/tumor types on / ratios Quantitation of multi-fraction survival curves BED and isoeffect dose calculations

31. Biological Effect Dose If / 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 ( /4 ) Rectum
= 118
BED10 = 70.2 ( /10 ) Tumor
= 89
= X (1 + 2/10) = Gy / Fx

32. Biological Effect Dose If / 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 ( /4 ) Rectum
= 118
BED1.5 = 70.2 ( /1.5 ) Tumor
= 197
= X (1 + 2/1.5) = Gy / Fx