Radiosensitivity & Fractionation Responses

PS Lin

Targeted vs non-Targeted

Current model is based on

physical consideration &
direct rad-target interaction

Beams-eye-view
planning

Nd
Conformity/homogeneity
(a point or a pixel)
Temporal effect small
Dose additive

Abscopal effect

Ge
no

Bystander effects
mic

Adaptive response instabi

i ty

Abscopal effect

In-field vs out-of-field effects

biologic penumbra

Cells-eye-view
perspective

BED

Cellular geometric position

Experience treatment regimens
(fx size, dose rate, total dose,
Intrinsic properties)

ND

Fertil/Malaise IJROBP 11: 1699, 1985.

D = mean inactivation dose

SF2

SF2
SF2 = SF after single dose (one fx)
(SF2)n = SF after n doses (n fxs)
SF2 =

1 fx

5 fx

15 fx

50% (0.5)

3.12x10-2

3.05x10-5

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 + Dq3

Isoeffective doses

Dq = (fx-dose single fx dose)/ total # fx -1)

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

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

D10 = 2.3 x Do

Eq 1

Decade of cell killing for a given dose:

Decade of killing = Total dose/ D10
= Total dose/Do x 2.3

Eq 2

SF of tumor cells after a given dose:

SF = Total # of clonogen/# of decade kill
Do = commonly in the range of 0.75 to 2 Gy
eDo = commonly in the range of 3 to 5 Gy

Eq 3

The Linerar-Quadratic model

Type A damage, always lethal

Single (ionizing event) it non-repairable damage, thus independent
of dose rate, exposure time, and fractionation
Straight line survival curve, slop of the curve at very low dose,
low dose rate, or multiple small fx
Survival = a linear exponential function of dose ( proportional to dose)
= initial slop of the survival curve
Units = 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
Recovery ratio for 2 equal split-dose:
RR = exp(2d2); or

ln(RR) = 2 d2

= degree of downward curvature of the survival curve

Units = 1/Gy2

)
1. At this specific dose, killing due to single hit = killing due to
two or more hits, or
killing mediated by function is equal to that of by
function---not the dose where = or simply survival
mechanism =
2. At this point curve significantly increase bending: eg.
late reacting tissues with smaller values (more curvy
than early reacting tissues
3. Is a fractionation sensitivity or dose rate factor
for different tissues
4. 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 tool

BEDnew is meaningful when compared to a reference BEDre
essentially all fractionation schemes can be normalized and compared
To estimate normal tissue tolerance after changing fx-size: use more than
one values, including value < 3 Gy
Make sure check PTV not to have unacceptable hot-spots in critical normal
tissue avoiding double-/treble-trouble
should consider 2D-BED in relationship with anatomical structures
For some tumor types, repopulation of clonogen should be considered
Some histological classes of tumors may require the use of different values
For tumors with high values, total dose is predictive of local control, but
for tumors with low values, total dose and fx-size together
determine the outcome
No volume effect is incorporated in the BED concept, developing concepts
including integrated BED, EUD, and BED dose-volume histograms
Mixed modalities or combination radiotherapy may also be assessed

Formulating isoeffective fx schemes: Must determine each tissue type separately

(one value at a time, cannot be mixed)

BED1 = BED2: (n1d1 RE1) = n2d2 (RE2)

BED (not physical dose) is considered to be biologically additive:

BED whole = BED p1 + BED p2 + BED p3 +

(P1, p2, p3, ..= different fx size and fx number)

*
To determine d, using ad2 + bd + c = 0
d = [-b + (b2 4 ac) ] / 2a

Note: adding different modality physical doses is

not meaningful, but
*

Nag S, Gupta N, IJROBP 46: 507, 2000.t

DMF (normal tissue dose modifying factor): to obtain more realistic

equivalent normal tissue effects

DMF: generally for HDR is ,<1; e.g., 0.6-0.8

Exp: HDR treatment of the cervix, bladder and rectum may
receive 70% of the prescribed dose
Using BED combined to determine EBRT +HDR dose to obtain
EDQ2 for tumor = 85 Gy; for late effects < 75 Gy

Exp: using HDR alone to treat prostate cancer;

plan: bid 5-6 fx /3 days, dose escalating study

DMF values depend on the technique used.

If no DMF correction is applied, all treatments is expected to produce high
rectal 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 fx

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 Gy

No normal tissue modifying factor applied

Covert a dose into the isoeffective dose in 2 Gy fxs: (DEq or EQD2)

Nd

RE
REref

Nd (d + )/ (2 + )

For tissue with values of 10 or 3 Gy:

DEq10 = EQD210 = BED / 1.2; or = nd ( 1 + 0.1d) / 1.2
DEq3 = EQD23 = BED/ 1.67; or = nd (1 + 0.33d) / 1.67

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)

Or

* EQD2 = D

d+
2+

20

5+2
2+2

= 35 Gy

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 day
Tpot = potential doubling time
{ } = BED equivalent of the total repopulation occurring in T-T ko days
Must pay attention when adding compensation dose to restore the
missing 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 Gy
BED (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 Gy
Note: BEDHSF >> BED, in this case almost 10% greater
and be careful on the double trouble and even
more critical in treble trouble situations.