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

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

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 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

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.

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

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 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

/ 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.

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

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

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 ( 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.

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

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 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 ( 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

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 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 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 ( 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

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 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.

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

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 ( 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 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