Altered fractionation

Introduction
Multi-fraction radiotherapy regimens are largely the result of early
radiobiological studies performed in the 1920-1930s
Regaud and Ferroux - 1927
Sterilization of Rams with single dose of RT extensive scrotal skin damage
multiple fractions over an extended period of time no skin damage
Postulated that testes were tumor-like tissue, while the scrotal skin was a
dose-limiting normal tissue
STRANDQUIST PLOT
33 . 0
T D

Isoeffect curves total dose plotted as a function of overall
treatment time
Dose given as 3-5 # per week
St. lines with a slope of 0.33




A
B
C
D
E
1 3 7 10 20 2
D
o
s
e

i
n

R


Time in days
A - Skin necrosis
B cure for skin carcinoma
C moist desquamation
D dry desquamation
E skin erythema

ELLIS NSD MODEL
Ellis NSD formula
Time factor was a composite of N (no. of #s) & T (overall treatment
time)
Fractionation - twice as important as time
Hence dose is related to time & no. of #s as
D = (NSD) T
0.11
N
0.24

Where NSD (Nominal Stand. Dose) is proportionality constant for
specific level of skin damage
Based on skin rxns and does not anyway predict late effects



Time factor
Compensation of time factor for acute responding tissue by extra
dose
Clinical model of acute vs. late responding
tissue
Prolonging overall time within the normal
radiotherapy range has little sparing effect on
late reactions but a large sparing effect on
early reactions
LQ MODEL
LQ model is derived from cell survival curves.
LQ model is based on fundamental mechanism of interaction of radn with
biological systems.
Basis of LQ theory is that cell is damaged when both strands of DNA are
damaged.
This can be produced either by single ionizing particle
Or it can be accomplished by independent interaction by two separate ionizing
particles
S.F. = e
-oD
Single lethal hits
S.F. = e
-(oD+|D
2
)
Single lethal hits plus
accumulated damage
Linear Quadratic Model
Cell kill is the result of single lethal hits plus
accumulated damage from 2 independent
sublethal events






o/| is dose at which death due to
single lethal lesions = death due to
accumulation of sublethal lesions
i.e. oD = |D
2
and D = o/| in Gy



S.F.
1.0





0.1





0.01




0.001
DOSE Gy
o/| in Gy
oD
|D
2

Biologically effective dose is the quantity by which diff. fractionation
regimens are intercompared
BED = total dose x relative effectiveness

|
|
|
.
|

\
|
+ =
|
o
o
d
nd
E
1
Where
n - no. of #s
d - dose/#

RADIATION RESPONSE
Survival curves of early & late responding cells have
different shapes.
For early effects, / is large; dominates at low
doses- irreparable damage dominates at low doses
For late effects, / is small, the term has an
influence at low doses, (repairable damage)
If fractionation regimen is changed from many small
doses to few large dose fractions leads to severe
late tissue toxicity.
Late reacting tissues are more sensitive to changes
in fractionation pattern than early responding
tissues
Fraction size is the dominant factor in determining late
effects; overall treatment time has little influence.
By contrast, fraction size and overall treatment time both
determine the response of acutely responding tissues
RADIOBIOLOGICAL RATIONALE
FOR FRACTIONATION
Delivery of tumoricidal dose in small dose fractions in conventional
multifraction regimen is based on 4Rs of radiobiology namely
Repair of SLD
Repopulation
Redistribution
Reoxygenation
Radiosensitivity is considered by some authors to be 5
th
R of
radiobiology.

RADIATION DAMAGE CLASSIFICATION
Radiation damage to mammalian cells are divided into three
categories:
Lethal damage :irreversible, irreparable & leads to cell death
Sub lethal damage : can be repaired in hours unless additional sub lethal
damage is added to it
Potentially lethal damage : can be manipulated by repair when cells are
allowed to remain in non-dividing state.
REPAIR
Most important rationale for fractionation
Mammalian cells can repair radn damage in b/w dose fractions.
dose fractionation enable normal tissue to recover b/w #s reducing damage to
normal tissue
Ability of normal tissue to repair radn damage better than tumor forms basis of
fractionation.
small dose /# spares late reactions preferentially & a reasonable schedule
duration allows regeneration of early reacting tissues.
SLD & ITS REPAIR
Initial shoulder in cell survival curve
reflects ability of cells to accumulate
SLD
Ability of cells to recover from SLD
demonstrated by Elkind & Sutton by
split dose experiments.

Redistribution
Increase in survival during 1
st
2hrs in split dose
experiment results from repair of SLD
If interval b/w doses is 6hrs then resistant cells
move to sensitive phases
If interval is more than 6hrs then cells will
repopulate & results in increase of surviving
fraction.
Redistribution
Redistribution of proliferating cell populations throughout the cell cycle
increases cell kill in fractionated treatment relative to a single session treatment.
Cells are most sensitive during M & G
2
phase & are resistant during S phase of
cell cycle .
Redistribution can be a benefit in fractionated course of RT if cells are caught in
sensitive phase after each fraction .
Repopulation
In b/w dose fractions normal cells as well as tumor cells repopulate.
longer a radiotherapy course lasts, more difficult it becomes to control tumor &
may be detrimental
acutely responding normal tissue need to repopulate during course of
radiotherapy .
Thus fractionation must be controlled so as not to allow too much time for
excessive repopulation of tumor cells at the same time not treating so fast that
acute tolerance is exceeded

ACCELERATED REPOPULATION
Treatment with any cytotoxic agent , including rad
n
, triggers surviving cells
(clonogens) in a tumor to divide faster than before
Dose escalation is needed to overcome this proliferation.
e.g. it starts in head & neck cancer 4wks after initiation of fractionated RT
Implication
Treatment should be completed as soon after it is started .
It is better to delay a treatment than to introduce delay during treatment .
Reoxygenation
Cells at the center of tumor are
hypoxic & are resistant to low LET
radiation.
Hypoxic cells get reoxygenated during
a fractionated course of treatment,
making them more radiosensitive to
subsequent doses of radiation.

ADV. OF FRACTIONATION
Acute effects of single dose of radiation can be decreased
Pt.s tolerance improves with fractionated RT
Exploits diff. in recovery rate b/w normal tissues & tumors.
Rad
n
induced redistribution & sensitization of rapidly proliferating cells.
Reduction in hypoxic cells leads to
Reoxygenation
Opening of compressed blood vessels


VARIOUS FRACTIONATION SCHEDULES
Fractionated radiation exploits difference in 4Rs between tumors and normal tissue thereby
improving therapeutic index
Types
Conventional
Altered
Hyper fractionation
Accelerated fractionation
Split course
Hypofractionation

Conventional fractionation
Fraction sizes of 1.8 - 2.2Gy
1 fraction per day
5 fractions per week
Evolved as conventional regimen because it is
Convenient (no weekend treatment)
Efficient (treatment every weekday)
Effective (high doses can be delivered without exceeding either acute or chronic normal tissue
tolerance)
Allows upkeep of machines.
Most tried & trusted method
Both tumoricidal & tolerance doses are well documented



HYPERFRACTIONATIO
N
Rationale
To take maximal adv. of diff. in repair capacity of late reacting normal tissue compared with
tumors.
Radio sensitization through redistribution.
Pure hyper fractionation
total dose & over all t/t same as conventional regimen
in twice as many #s i.e. treating twice daily.
Impure hyper fractionation
total dose is increased.


HYPERFRACTIONATION
EORTC 22791
A hyper fractionated schedule of 80.5Gy/70#(1.15Gy twice/day)/7wks compared with
70Gy/35#/7wks in head & neck cancer.
RESULTS
Increased local tumor control at 5yr from 40 to59%
Reflected in improved survival
No increase in side effects

EORTC 22791
80.5 Gy / 70 # / 1.15
Gy / # /twice daily/ 7
weeks
5 yr LC - 59%
No increased late
effects
70Gy / 35# / 2 Gy / #
5 yr LC - 40%
UNEQUIVOCAL ADVANTAGE OF HYPERFRACTIONATION IN
OROPHARYNGEAL CANCERS
ACCELERATED TREATMENT
Rationale To reduce repopulation in rapidly proliferating tumors by reducing overall treatment
time.

Pure accelerated treatment
same total dose
half the overall time
2 or more #s/day
acute effects become limiting factor.

Impure accelerated treatment dose is reduced or rest period is interposed in the middle of
treatment.
Types of accelerated treatment
Type A: drastic reduction of the overall time with substantial decrease in the
total dose
Type B: duration of treatment is more modestly reduced with total dose kept in
the same range and there is a break in treatment
Type C: duration of treatment is more modestly reduced with total dose kept in
the same range with a concomitant boost phase
CHART Type A
Mount Vernon Hospital, London
treatments 6hrs apart
Total dose of 54Gy can be delivered in 36# over 12 consecutive days
Including weekends.
This schedule was chosen to complete treatment before acute reactions start
appearing i.e. 2wks
Characteristics-
Better local tumor control
Acute reactions are brisk but peak after treatment is completed
Dose/# small hence late effects acceptable
Several myelopathies occuring at 50 Gy because time between
fractions ( 6 hrs) was too short


Split-Course Accelerated
Fractionation Regimen (Type B)
Total dose is delivered in two halves with a gap in b/w.
Purpose of gap is
to allow elderly pts. to recover from acute reactions of treatment
to exclude pts. from further morbidity who have poorly tolerated 1
st
half or disease
progressed despite treatment.
Applied to elderly pts. in radical treatment of Ca bladder, prostate & lung cancer.
Disadv : impaired tumor control due to prolong T/T time that results in tumor
cell repopulation

Concomitant boost ( Type C)
Developed at M.D. Anderson cancer centre

Boost dose to a reduced volume given concomitantly , with t/t of initial layer
volume

54Gy in 30 # over 6 wks & boost dose of 1.5 Gy per # in last 12 # with Inter # interval of 6 hr in last 12#
Last 12 # twice daily 1.8 Gy AM and 1.5 Gy PM
LC 54% vs. 46% in conventional

Concomitant boost
Improved rate of local control
Improved overall survival
Increased rate of early toxicity
No increased rates of late toxicity
Simultaneous Integrated Boost
Nasopharynx
Followed in MSKCC
2.12 Gy x 33 fractions -GTV
1.8 Gy x 33# - intermediate risk areas
1.64 Gy x 33# - low risk areas
Dose painting technique possible with IMRT
2.12 Gy
1.8 Gy
1.64 Gy
GTV
IR-CTV
LR- CTV
SIB
ARCON
Accelerated to overcome repopulation
Hyperfractionated to spare normal tissues
Carbogen breathing to overcome chronic hypoxia
Nicotinamide to overcome acute hypoxia

Spectacular results in advanced laryngeal cancers
Results yet to be published


HYPOFRACTIONATION
The delivery of total dose in fewer numbers of fractions than conventional fractionation
Rationale
Treatment completed in a shorter period of time.( palliative)
Machine time well utilized for busy centers.
Higher dose /# gives better control for larger tumors.
Higher dose /# also useful for hypoxic fraction of large tumor.
Disadv.
Higher potential for late normal tissue complications.
Extreme hypofractionation
Small targets treated with high dose conformal radiotherapy
SBRT - 1 to 5 total radiation treatments using highly conformal dose distributions
Radiosurgery lower number of highly conformal treatment (usually a single fraction)
SBRT
Takes more resources
More technique/ equipment dependent
Takes longer to plan
High MU per treatment
Radiobiologic principles may not apply

Thank you