Time, Dose, and Fractionation

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

2. 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

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 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

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

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 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

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: 1013-15; 2004.

17. 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

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. 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

22. 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

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. 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

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. 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

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 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

31. 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

32. 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