Time, Dose and Fractionation       (TDF) in Radiobiology             Ji-Hong Hong, M.D., Ph.D.Ref: Eric J. Hall, Radiobiol...
Historical observationSingle dose:Sterilization skin damageMultiple smaller:Sterilizationno skin damage
Influence of 4Rs in Radiation Therapy•   Repair: favor lower α/β or high Dq value (late >    early > tumor)•   Reoxygenati...
4 Rs and TDF                   Tumor            Early     Late responding                                 responding      ...
Clinical observationStrandquist plot A: skin necrosis, B: cure of skin carcinoma, C; moist desquamation. D: dry desquamati...
Ellis Nominal Standard Dose       Total dose = (NSD)T0.11N0.24Weakness:2. Time factor is not right.3. Only consider acute ...
Acute vs. late responding tissues• Acute responses: occurring during or within short  time after RT.  – Such as mucositis,...
Time factorCompensation of time factor for acute responding tissue by extradose
Animal model of acute vs. late    responding tissues
Clinical model of acute vs. late      responding tissue
Time factor: accelerated repopulation
Clinical evidence of accelerated repopulation          Dose increase = 0.6 Gy/day
Clinical evidence of (accelerated)              repopulation1. Tumor regrowth in post-C/T or   surgery.2. Continuous Hyper...
Q & A for time factor• Q1: Will prolong total treatment time reduce late  complications?  – A:• Q2: Will prolong total tre...
Fractionation factor• Question 1:  – 3 Gy/per fx. x 10 = 2 Gy/per fx. x 15 (????)                                    Repea...
Fractionation factorQ2: Does fractionation scheme bring same effects to early-and late responding tissueA: see next slide ...
Expand thedifference of earlyvs. late tissues by   fractionationA: Fractionation protectslate responding tissuesdamage tha...
Dose-response for acute and late responding tissueIncreasingtotal dose                                             Late re...
Same acute reactions, different late reactionsTreated with X-rayTreated with neutron
How to evaluate the effects of fractionation  on acute vs. late responding tissues ?  For example:  3 Gy x 10 fx.   Vs. 2 ...
Calculation of α/βLinear-Quadrate concept       S=e   –αD-βD2       S=   (e –αd-βd )n -lnS = n(αd + β d2)                ...
How to obtain an α/β ratioSet same biological endpoint achieved by differentfractionated treatment schema
Calculation of α/β
Calculation of α/β 1        α               β----- = ------   + -------- d nd     -lnS         -lnSd= 0,        αIntercept...
α/β ratio      Q: Does α/β ratio means the      radiosensitivity of a tissue?      A: No, it is nothing to do with      ra...
Calculation of Biological Effective Dose                (BED)
Calculation of Biological Effective Dose                (BED)
Model calculation35 F x 2 Gy/7 week         70 F x 1.15 Gy/7 week Assumptions: complete repair between fractions
Concomitant boost([30 F x 1.8 Gy] + {12 F x 1.5 Gy]/6 week    Where is the time factor?
CHART protocol36 F x 1.5 Gy/12 days
The conversion of dose by α/β ratioD1 x (1 + d1/α/β) = D2 x (1 +d2/α/β)D1      (1 +d2/α/β)      (α/β + d2)−− = −−−−−−−−−−−...
Calculation     D1         (1 + d2/α/β)         (α/β + d2)     −− = −−−−−−−−−−−              = −−−−−−−−−     D2    (1 + d1...
Summary• The total treatment time should be shorten  to prevent repopulation of tumor, but  tolerance of acute responding ...
Fractionation schedule
Conventional treatment• 1.8-2 Gy/day• 5 day/week.• Total dose is usually higher than 6.000  cGy for gross solid tumor.
HypofractionationDose > 2 Gy/per fraction.• Palliative:  – Short term: > 2 Gy/day, usually 3 Gy/day. Total dose is    lowe...
Hyperfractionation•Decrease of fraction size   – < 1.8 Gy/fraction, usually 1.15-1.6 Gy.•Increase fraction number.   – Usu...
Accelerated fractionation•Same fraction size, 1.8 – 2 Gy, same fractionnumber.•Shorten total treatment time.   –Eg. bid (t...
Some limitation•“Consequential” late damage.  –Late damage developed out of the very  severe effects.  –Clinical example: ...
Mixed typeCHART (Continuous hyperfractionated, acceleratedradiotherapy)•150 cGy/Fx. 3 fx./day, W1-7, total dose = 54 Gy.•T...
Mixed typeARCON-Accelerated Hyperfractionated Radiation Therapywhile Breathing Carbogen and with the addition ofNicotinami...
Singe-dose vs. fractionated dose                               “Target-Switching” model                               (dos...
Singe-dose vs. fractionated dose • Accumulated vs. single dose • Interaction between previous events and   subsequent radi...
Models of microvascular endothelial engagementin tumor response to single-dose or fractionated                radiotherapy...
Tumor control probability (TCP) andnormal tissue complication probability     (NTCP) in radiotherapy
Tumor control probability (1)• Assumption  – 1 cm3 = 109 tumor cells  – Survival fraction of 2 Gy = 0.5 = ½  – No repopula...
Tumor control probability (2)• Calculation  – 1 cm3 = 109 tumor cells  – After     •   28 treatment (2 Gy x 28) = 4 cells ...
Poisson distribution         an e-aPn = -------------           n!(Pn =the probability of finding n survival cells)(a = ex...
TCP with dosesDose (Gy)     56        58        60        62        64        66  Cell      (1/2)28   (1/2)29   (1/2)30   ...
TCP with dosesTCP (%) 100  90  80  70  60  50  40  30  20  10                                                   )   0     ...
Upcoming SlideShare
Loading in...5
×

06 time,dose,fractionation

1,881

Published on

Published in: Health & Medicine, Technology
0 Comments
4 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
1,881
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
191
Comments
0
Likes
4
Embeds 0
No embeds

No notes for slide
  • Figure 1. Models of microvascular endothelial engagement in tumor response to single-dose or fractionated radiotherapy Endothelial damage appears to be induced by both the high treatment doses (&gt;8.10 Gy) of single-dose radiotherapy ( A ) and the low-dose (1.8.3 Gy) exposures of fractionated radiotherapy ( B ). The resulting microvascular dysfunction confers conversion of sublethal radiation lesions in tumor cells into lethal lesions via an as yet unknown mechanism. Endothelial apoptosis and microvascular dysfunction contribute significantly to tumor cell lethality and tumor cure by the single-dose approach. Radiation induces translocation of endothelial cell ASMase into glycosphingolipid- and cholesterol-enriched plasma membrane rafts, where it hydrolyses sphingomyelin (SM) to generate the proapoptotic second messenger ceramide, initiating transmembrane signaling of apoptosis. Inhibition of this process by ASMase depletion or by proangiogenic growth factors markedly attenuates the lethal response of tumor cells to this mode of radiotherapy. In contrast, the endothelial cell damage induced by the low-dose exposures of fractionated radiotherapy does not enhance tumor cell death effectively, as the death signaling pathway in endothelium is repressed by concomitant activation of tumor cell HIF-1. ROS generated by waves of hypoxia/reoxygenation occurring after each radiation exposure lead to translation of HIF-1 mRNA transcripts stored in specialized cytosolic stress granules of hypoxic tumor cells. This adaptive response generates VEGF and other proangiogenic factors that attenuate radiation-induced apoptosis in endothelial cells. Genetic inhibition of the HIF-1 response leads to extensive endothelial apoptosis, microvascular dysfunction, enhanced tumor cell death, and tumor growth delay. The mechanism of endothelial damage in this response remains unknown, and a possible involvement of the ASMase pathway has not as yet been assessed. This observation indicates a potential for pharmacologic targeting of HIF-1 to improve the outcome of fractionated radiotherapy via engagement of the endothelial apoptosis component.
  • 06 time,dose,fractionation

    1. 1. Time, Dose and Fractionation (TDF) in Radiobiology Ji-Hong Hong, M.D., Ph.D.Ref: Eric J. Hall, Radiobiology for the Radiologist, 5th Edition
    2. 2. Historical observationSingle dose:Sterilization skin damageMultiple smaller:Sterilizationno skin damage
    3. 3. Influence of 4Rs in Radiation Therapy• Repair: favor lower α/β or high Dq value (late > early > tumor)• Reoxygenation: favor tumor killing• Redistribution (Reassortment): advantage for slow proliferating tissues• Repopulation: tumors and early tissues have advantage
    4. 4. 4 Rs and TDF Tumor Early Late responding responding tissues tissuesRepairReassortmentRepopulationReoxygenation Is there any gain between early responding tissue (or tumor) and late responding tissues
    5. 5. Clinical observationStrandquist plot A: skin necrosis, B: cure of skin carcinoma, C; moist desquamation. D: dry desquamation E; erythema
    6. 6. Ellis Nominal Standard Dose Total dose = (NSD)T0.11N0.24Weakness:2. Time factor is not right.3. Only consider acute responding tissues.
    7. 7. Acute vs. late responding tissues• Acute responses: occurring during or within short time after RT. – Such as mucositis, skin reaction, bowel responses,bone marrow depression. – More related to total dose and time, less related to fraction size.• Late responses: occurring months to years after RT. – Such as fibrosis of tissue, radiation myelopathy, renal damage, usually are irreversible changes when damage is formed. – More related to fraction size and total dose, less related to total time.• The behaviors of tumor are more similar to those of acute responding tissues.
    8. 8. Time factorCompensation of time factor for acute responding tissue by extradose
    9. 9. Animal model of acute vs. late responding tissues
    10. 10. Clinical model of acute vs. late responding tissue
    11. 11. Time factor: accelerated repopulation
    12. 12. Clinical evidence of accelerated repopulation Dose increase = 0.6 Gy/day
    13. 13. Clinical evidence of (accelerated) repopulation1. Tumor regrowth in post-C/T or surgery.2. Continuous Hyperfractionated Accelerated Radiation Therapy (CHART)
    14. 14. Q & A for time factor• Q1: Will prolong total treatment time reduce late complications? – A:• Q2: Will prolong total treatment increase the possibility of repopulation? – A:• Q3: The total treatment time should be as short as possible, but what are the limitations? – A:
    15. 15. Fractionation factor• Question 1: – 3 Gy/per fx. x 10 = 2 Gy/per fx. x 15 (????) Repeated shoulder A: Biological effects 30 Gy/10 fx > 30 Gy/15 fx
    16. 16. Fractionation factorQ2: Does fractionation scheme bring same effects to early-and late responding tissueA: see next slide Q3: Does acute responding tissue have same dose-response curve with the late responding tissues? A: No!!!
    17. 17. Expand thedifference of earlyvs. late tissues by fractionationA: Fractionation protectslate responding tissuesdamage than acuteresponding tissues
    18. 18. Dose-response for acute and late responding tissueIncreasingtotal dose Late responding tissues Decreasing fraction size Acute responding tissues
    19. 19. Same acute reactions, different late reactionsTreated with X-rayTreated with neutron
    20. 20. How to evaluate the effects of fractionation on acute vs. late responding tissues ? For example: 3 Gy x 10 fx. Vs. 2 Gy x 20 Gy Q: Do these treatment doses have same biological effects between acute and late responding tissues ? A: Q: Does any way to describe the differences between acute and late responding tissue in their sensitivity to change fraction size? Α: α/β ratio
    21. 21. Calculation of α/βLinear-Quadrate concept S=e –αD-βD2 S= (e –αd-βd )n -lnS = n(αd + β d2) 2 -lnS/nd = α + β d  -lnS/D = α + β d
    22. 22. How to obtain an α/β ratioSet same biological endpoint achieved by differentfractionated treatment schema
    23. 23. Calculation of α/β
    24. 24. Calculation of α/β 1 α β----- = ------ + -------- d nd -lnS -lnSd= 0, αIntercept = ---- = 0.013 Gy –1 -lnS βSlope = ---- = 0.00129 Gy –2 α/β = 10.1 Gy -lnS
    25. 25. α/β ratio Q: Does α/β ratio means the radiosensitivity of a tissue? A: No, it is nothing to do with radiosensitivity. It is related to the sensitivity to change of fraction size. Q: Do late responding tissues have small α/β ratio and are more sensitive to change of fraction size A: Yes!!!!
    26. 26. Calculation of Biological Effective Dose (BED)
    27. 27. Calculation of Biological Effective Dose (BED)
    28. 28. Model calculation35 F x 2 Gy/7 week 70 F x 1.15 Gy/7 week Assumptions: complete repair between fractions
    29. 29. Concomitant boost([30 F x 1.8 Gy] + {12 F x 1.5 Gy]/6 week Where is the time factor?
    30. 30. CHART protocol36 F x 1.5 Gy/12 days
    31. 31. The conversion of dose by α/β ratioD1 x (1 + d1/α/β) = D2 x (1 +d2/α/β)D1 (1 +d2/α/β) (α/β + d2)−− = −−−−−−−−−−− = −−−−−−−−−D2 (1 +
    32. 32. Calculation D1 (1 + d2/α/β) (α/β + d2) −− = −−−−−−−−−−− = −−−−−−−−− D2 (1 + d1/α/β) (α/β + d1)For example:A treatment protocol gives 40 Gy/20 Fx., if we change thefraction to 3 Gy, how should we adjust the total dose for acuterresponding tissues (α/β = 10) or later responding tissue ((α/β =3)For acute responding tissue40/D2 = (3 + 10) / (2 + 10)  D2 = 37 GyFor late responding tissue
    33. 33. Summary• The total treatment time should be shorten to prevent repopulation of tumor, but tolerance of acute responding tissue is the limitation.• The reduction of fraction size is to protect normal late responding tissues, but the fraction number is increased.
    34. 34. Fractionation schedule
    35. 35. Conventional treatment• 1.8-2 Gy/day• 5 day/week.• Total dose is usually higher than 6.000 cGy for gross solid tumor.
    36. 36. HypofractionationDose > 2 Gy/per fraction.• Palliative: – Short term: > 2 Gy/day, usually 3 Gy/day. Total dose is lower than curative dose. Eg. 3 Gy x 10 Fx.• Curative – For organs with parallel functional structure such as lung and liver. If the dose can be conformed to tumor, hypofractionation is considered. Eg. Proton treatment in hepatoma and lung cancer. – Sterotactic Radiosurgery: single dose – Some Europe countries used large fraction size, their results were also acceptable in some literature. However, large fraction size is less used in the USA for curative attempt.
    37. 37. Hyperfractionation•Decrease of fraction size – < 1.8 Gy/fraction, usually 1.15-1.6 Gy.•Increase fraction number. – Usually treat more than 1 fraction/per day.•Purpose: Spare normal tissue (late complication tissue)when using smaller fraction size. – If treated with similar dose as conventional treatment, complications are expected to decrease. – If treated with the increased total dose, tumor control probability is expected to increase but same possibility of late complications.
    38. 38. Accelerated fractionation•Same fraction size, 1.8 – 2 Gy, same fractionnumber.•Shorten total treatment time. –Eg. bid (twice per day), or > 5 fractions/per week•Purpose: reduce tumor repopulation during RT.•Limitation: Severe acute reaction.
    39. 39. Some limitation•“Consequential” late damage. –Late damage developed out of the very severe effects. –Clinical example: skin reactions, G-I reactions•Incomplete repair between fractions –Especially for CNS.
    40. 40. Mixed typeCHART (Continuous hyperfractionated, acceleratedradiotherapy)•150 cGy/Fx. 3 fx./day, W1-7, total dose = 54 Gy.•Total treatment time: 12 days.•Results: –Increased acute toxicity. –Late complications: not increased except spinal cord. –similar or slightly better local control for different types of tumor.•Implication: Reduce repopulation
    41. 41. Mixed typeARCON-Accelerated Hyperfractionated Radiation Therapywhile Breathing Carbogen and with the addition ofNicotinamide-Accelerated to overcome proliferation.-Hyperfractionated to spare normal tissues.-Carbogen breathing to overcome chronic hypoxia.-Nicotinamide to overcome acute hypoxia.
    42. 42. Singe-dose vs. fractionated dose “Target-Switching” model (dose-dependent “target”)• Threshold dose in radiobiological effects – Apopotisis of tumor and endothelial cell death – Cytokine gene expression • 1 Gy in lung, 7 Gy in brain. Nature Medicine, 2005: 11:477
    43. 43. Singe-dose vs. fractionated dose • Accumulated vs. single dose • Interaction between previous events and subsequent radiation • enhancement ? adaptation? • Other radiobiological factors – Repopulation, reassortment, re- oxygneation, repairQ: What are the differences betweensingle-dose and fractionated treatment?
    44. 44. Models of microvascular endothelial engagementin tumor response to single-dose or fractionated radiotherapy ? ? ? Cancer cell, 2005: 8: 89-91
    45. 45. Tumor control probability (TCP) andnormal tissue complication probability (NTCP) in radiotherapy
    46. 46. Tumor control probability (1)• Assumption – 1 cm3 = 109 tumor cells – Survival fraction of 2 Gy = 0.5 = ½ – No repopulation during treatment, each dose has same killing effect• Calculation – 2 Gy x 2 = ½ x ½ – 2 Gy x 3 = ½ x ½ x ½ ........... 2 Gy x 10 = (1/2)10 = 1/1024 = (10)-3 2 Gy x 30 = (1/2)30 = (10)-9 2 Gy x 31 = (1/2)31 = (10)-9 x ½
    47. 47. Tumor control probability (2)• Calculation – 1 cm3 = 109 tumor cells – After • 28 treatment (2 Gy x 28) = 4 cells • 29 treatment (2 Gy x 29) =2 cells • 30 treatment (2 Gy x30) = 1 cell • 31 treatment (2 Gy x 31) = 0.5 cell • 32 treatment (2 Gy x 32) = 0.25 cell
    48. 48. Poisson distribution an e-aPn = ------------- n!(Pn =the probability of finding n survival cells)(a = expected number)Eg: n =1, a=1 11e-1P1 = ------------- = 37% 1!(P1 =the probability of finding 1 survival cells)(1 = expected number)
    49. 49. TCP with dosesDose (Gy) 56 58 60 62 64 66 Cell (1/2)28 (1/2)29 (1/2)30 (1/2)31 (1/2)32 (1/2)33 killingSurviving 4 2 1 0.5 0.25 0.125 cells TCP 0.018 0.135 0.375 0.61 0.78 0.88
    50. 50. TCP with dosesTCP (%) 100 90 80 70 60 50 40 30 20 10 ) 0 54 56 58 60 62 64 66 68 70 (Gy)
    1. A particular slide catching your eye?

      Clipping is a handy way to collect important slides you want to go back to later.

    ×