Radiosensitivity & Fractionation ResponsesPS Lin

Adaptive responseBystander effectsAbscopal effect Abscopal effect Beams-eye-viewplanningConformity/homogeneity(a point or a pixel)Temporal effect smallDose additive Cells-eye-viewperspectiveCellular geometric positionExperience treatment regimens(fx size, dose rate, total dose,Intrinsic properties)Current model is based onphysical consideration &direct rad-target interaction Targeted vs non-TargetedNdBEDIn-field vs out-of-field effects biologic penumbraGenomic instabiity

ND

Fertil/Malaise IJROBP 11: 1699, 1985.

D = mean inactivation dose

SF2

SF2SF2 = SF after single dose (one fx)(SF2)n = SF after n doses (n fxs) 50% (0.5) 3.12x10-2 3.05x10-5SF2 =1 fx5 fx15 fx 60% (0.6) 7.78x10-2 4.71x10-4 70% (0.7) 1.68x10-1 4.75x10-3

Single target, single hit

Multi-target, single hit

Total dose recovery Dq = Dq1 + Dq2 + Dq3Dq = (fx-dose single fx dose)/ total # fx -1)

Dq = (DF DS)/ (F-1)Isoeffective doses

Application with Do Dose required for each log (decade) of cell killing:

D10 = 2.3 x Do Eq 1Do = commonly in the range of 0.75 to 2 GyeDo = commonly in the range of 3 to 5 GyDecade of cell killing for a given dose:

Decade of killing = Total dose/ D10 = Total dose/Do x 2.3Eq 2 SF of tumor cells after a given dose:

SF = Total # of clonogen/# of decade kill Eq 3

The Linerar-Quadratic model

Type A damage, always lethal

Single (ionizing event) it non-repairable damage, thus independentof dose rate, exposure time, and fractionationStraight line survival curve, slop of the curve at very low dose,low dose rate, or multiple small fxSurvival = a linear exponential function of dose ( proportional to dose)

= initial slop of the survival curveUnits = 1/Gy

Type B damage, always lethal

Two (ionizing events) hits, repairable, thus dose rate, fractionation, and exposure time dependent Cell death is a quadratic function of dose = degree of downward curvature of the survival curveUnits = 1/Gy2Recovery ratio for 2 equal split-dose:

RR = exp(2d2); or ln(RR) = 2 d2

)1. At this specific dose, killing due to single hit = killing due totwo or more hits, orkilling mediated by function is equal to that of by function---- not the dose where = or simply survival mechanism = 3. Is a fractionation sensitivity or dose rate factorfor different tissues2. At this point curve significantly increase bending: eg.late reacting tissues with smaller values (more curvythan early reacting tissues4. May be obtained from a reciprocal dose plot (spaghetti plot),Hall Fig 18.28, 2006.

5. Units = Gy

)RE

Fundamentals for using BED as a quantitative toolTo estimate normal tissue tolerance after changing fx-size: use more thanone values, including value < 3 GyMake sure check PTV not to have unacceptable hot-spots in critical normaltissue avoiding double-/treble-trouble should consider 2D-BED in relationship with anatomical structuresBEDnew is meaningful when compared to a reference BEDre essentially all fractionation schemes can be normalized and comparedFor some tumor types, repopulation of clonogen should be consideredSome histological classes of tumors may require the use of different valuesMixed modalities or combination radiotherapy may also be assessed For tumors with high values, total dose is predictive of local control, butfor tumors with low values, total dose and fx-size togetherdetermine the outcomeNo volume effect is incorporated in the BED concept, developing conceptsincluding integrated BED, EUD, and BED dose-volume histograms

Formulating isoeffective fx schemes: BED1 = BED2: (n1d1 RE1) = n2d2 (RE2)Must determine each tissue type separately (one value at a time, cannot be mixed)BED whole = BED p1 + BED p2 + BED p3 + (P1, p2, p3, ..= different fx size and fx number)BED (not physical dose) is considered to be biologically additive:***To determine d, using ad2 + bd + c = 0

d = [-b + (b2 4 ac) ] / 2a

Note: adding different modality physical doses isnot meaningful, but Nag S, Gupta N, IJROBP 46: 507, 2000.t*

DMF (normal tissue dose modifying factor): to obtain more realisticequivalent normal tissue effectsDMF: generally for HDR is ,

Exp: using HDR alone to treat prostate cancer;plan: bid 5-6 fx /3 days, dose escalating studyDMF values depend on the technique used.If no DMF correction is applied, all treatments is expected to produce highrectal toxicities

DMF: HDR may be > 1; e.g., 2

Exp: RTOG 92-07, high incidence of esophageal fistulae(depends on the dose to the esophageal mucosa)

EBRT: 50 Gy in 25 fx; HDR 15 Gy in 3 fx22

Cervical Cancer: External beam: 45 Gy, 1.8Gy/fx,whole pelvic HDR: 30Gy, 6 Gy/fx; to point M (mid-well) Total BED10 = BEDEBR + BEDHDR

= 1.8 Gy x25(1+ 0.18) + 30Gy(1+0.6) = 101 Gy10

LQED2 = BED / RE (for a 2 Gy fx)

= 101 Gy / (1+0.2)

= 84 GyNo normal tissue modifying factor applied

For tissue with values of 10 or 3 Gy:DEq10 = EQD210 = BED / 1.2; or = nd ( 1 + 0.1d) / 1.2DEq3 = EQD23 = BED/ 1.67; or = nd (1 + 0.33d) / 1.67OrEQD2 = D d + 2 + Nd RERErefCovert a dose into the isoeffective dose in 2 Gy fxs:(DEq or EQD2)Exp: for a tissue with = 2Gy, irradiated with 4 fx of 5 Gy

DEq = 20 1 + 5/2 1 + 2/2= 35 Gy (biological equivalent in 2 Gy fx)= 5 + 22 + 220= 35 Gy**Nd (d + )/ (2 + )

Considering clonogen proliferation during treatment:BED = nd( 1+ d/[]) {(0.693/)[(T-Tko)/Tpot]} 0.693/ = daily BED equivalent of repopulation, Gy/day (T Tko)/ Tpot = effective repopulation days (Teff)T = total treatment days, Tko = repopulation kick-off dayTpot = potential doubling time*{ } = BED equivalent of the total repopulation occurring in T-Tko days

Must pay attention when adding compensation dose to restore themissing BED not the physical dose and Teff

BED calculation with hot-spot factor(% of prescription point dose factor)BED = Nd (HSF) (1 + (d x HSF)/) Exp: for 30 fx of 2 Gy; = 3 GyBED (conventional) = 30 x 2 Gy x 1.67 = 100 Gy If physical dose at hot spot is relative to 120 % at prescription point:

Then; BEDHSF = 30 x 2 Gy x 1.2 x [1 + (2x1.2)/3] = 129.6 GyNote: BEDHSF >> BED, in this case almost 10% greater

and be careful on the double trouble and even

more critical in treble trouble situations.

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