TIME, DOSE &

FRACTIONATION
Dr. Rowshon Ara Begum
As s oc iat e P rofe s sor & H oD ,
Radiat ion On col ogy,
N I CRH, Moh a k h a li , Dh a k a -1 212
F C P S , MP H , M.P h il (Ra diot h e ra p y)
 TIME
•Time factor is overall time to deliver prescribed dose from
beginning of course of radiation until its completion.
•Effect of treatment varies enormously with time. Hence
dose should always be stated in relation to time
•General rule is longer the overall duration of treatment
greater is the dose required to produce a particular effect.
•Local control is lost when treatment time is prolonged and
early toxicity increased when time is too short ,
 TIME DEPENDS ON
1. Intension to treat
.For curative purposes, Overall Treatment Time (OTT) is 5-6
weeks
.Short duration can be use for treatment of small
lesions/aged patients
2. Site of tumor
.Rapidly proliferating tumor has poor LC with increase in
time
 CLINICAL IMPLICATION OF OTT
• Overall treatment time is a very important factor for fast-growing
tumors.
• In head and neck cancer, local tumor control is decreased by about
1.4% (range of 0.4% to 2.5%) for each day that the overall treatment
time is prolonged.
• The corresponding figure for carcinoma of the cervix is about 0.5%
(range of 0.3% to 1.1%) per day.
• Such rapid proliferation is not seen in breast or prostate cancer.
 DOSE
•Dose is Amount of energy absorbed per unit mass of tissue
Absorbed Dose
• RAD- when 100 ergs of energy is deposited per gram of tissue
(100ergs/gram)
• SI unit is Gray:1 Gy =1joule/kg or 100 rads
Equivalent dose= absorbed dose x radiation weighing factor (Sievert)
Effective Dose= Equivalent dose ×tissue weighing factor (Sievert)
 TUMOR LETHAL DOSE

•Dose of radiation that produces

complete & permanent regression
of tumor in vivo in zone irradiated
•The expression of relationship
b/w lethal effect & dose was first
propounded by Holthusen
 CONSEQUENCES OF HOLTHUSEN’S
HYPTHESIS
•There is a dose point A below which there is no
appreciable lethal effect.
• As dose is increased lethal effect increases.
•At upper end of sigmoid curve there is a point TLD at
which 80-90% tumor resolves completely
•Above this point dose has to be increased considerably to
gain any appreciable rise in lethal effect.
 TISSUE TOLERANCE
•In RT the success of eradicating tumor depends on
radio sensitivity of tumor as well as tolerance of
surrounding normal tissue
•NTT limits the max. dose that can be delivered to
tumor eg in cervix & esophagus
•Usually <5% damage to normal tissue is acceptable
 NTT: FACTORS
•Site of tissue – axilla, perineum less tolerant
• Area or volume irradiated
• Vascularity & Supporting tissues (stroma and
parenchymal cells)
•Individual variation of tolerance.(intrinsic
radiosenstivity)
 THERAPEUTIC INDEX
•It is ratio of TLD/NTT
•This ratio determines whether a particular disease
can be treated or not
•TLD > NTT then radical dose of radiation cannot be
delivered.
•The more the curve B is to the right of curve A the
more is therapeutic ratio
•The optimum choice of radiation dose delivery
technique is one that maximizes the TCP &
simultaneously minimizes the NTCP
 THERAPEUTIC INDEX

The more the curve B is to the right of the curve A, the more is the therapeutic ratio
 HOW DOSE VARIES

•Intention to treat (Radical/palliative)

•Tumor sensitivity
•Treatment volume
•Site of tumor
 FRACTIONATION
•The method where total dose is divided in small
fraction and given over a period of time
•Fractionation helps to increase the therapeutic index
in radiotherapy
INTRODUCTION OF
FRACTIONATIONS
 REGAUD’S EXPERIMENT
•Tried to sterilize sheep by irradiation of their testis.
•Testis were regarded as model of a growing tumor & skin as dose limiting
normal tissue.
•He found that-
◦ Single dose – sterilization possible only with unacceptable skin damage
◦ Fractionated dose – sterilization achieved without excessive damage to skin
of scrotum.
•Later confirmed by different such experiment in Ram between 1920 and
1930 in Paris
 FOUR R’S OF
RADIOBIOLOGY
 REPAIR
•Most important rationale behind fractionation
•Lethal dose- irreversible and irreparable
•Sublethal dose – can be repaired unless additional
sublethal dose added
•Potentially lethal dose- can be manipulated to repair
when cells are allowed to remain in non-dividing state
•The figure shows data obtained in a split dose experiment
with cultured Chinese hamster cells.
•A single dose of 15.58 Gy leads to a SF of 0.005.
•If the dose is divided into two approximately equal
fractions separated by 30 min SF is already appreciably
higher than for a single dose.
• As the time interval is extended, SF increases until a
plateau is reached at about 2 hours, corresponding to a
surviving fraction of 0.02.
• The increase in survival in a split-dose experiment results
from the repair of sublethal radiation damage.
 REDISTRIBUTION
•Radiation kills cell in the dividing phase of cell cycle
• Main mode of injury : mitotic cell death
• Cells are most sensitive in mitotic phase
• Resistance is greatest in late S phase
• If cell cycle is considerable length then another phase of
resistance is obtained in early G1 phase followed by
sensitive phase at G2
•The figure shows the results of a parallel experiment in which cells
were exposed to split doses and maintained at their normal
growing temperature of 37° C.
• The pattern of repair seen in this case differs from that observed
for cells kept at room temperature.
• In the first few hours, prompt repair of SLD is again evident, but at
longer intervals between the two split doses, the surviving fraction
of cells decreases, reaching a minimum with about a 5-hour
separation.
• In Chinese hamster cells, most of the survivors from a first dose of
radiation are located in the S phase of the cell cycle.
• If about 6 hours are allowed to elapse before a second dose of
radiation is given, this cohort of cells progresses around the cell
cycle and is in G2/M, a sensitive period of the cell cycle at the time
of the second dose.
 REDISTRIBUTION
•If the increase in radiosensitivity in moving from late S to the G2/M period
exceeds the effect of repair of SLD, the surviving fraction falls.
•The pattern of repair shown in Figure 5.4 is therefore a combination of three
processes occurring simultaneously.
•First, there is the prompt repair of sub lethal radiation damage.
•Second, there is progression of cells through the cell cycle during the interval
between the split doses:reassortment.
• Third, there is an increase of surviving fraction resulting from cell division, or
repopulation, if the interval between the split doses is from 10 to 12 hours,
because this exceeds the length of the cell cycle of these rapidly growing cells.
 REPOPULATION
•In normal tissues, homeostatic response following radiation
injury, involve:
• reduction of cell cycle time: rapid doubling
• increase in growth fraction(e.g recruitment of resting cells)
• decrease in cell loss factor
•In tumors, rate of cell production exceeds rate of cell loss.
Repopulation may involve any of above three mechanisms.
• Repopulation may help to spare normal tissue damage but may
also reduce tumor control probability
 ACCELERATED REPOPULATION: CLINICAL
IMPLICATION
•Accelerated repopulation starts in head and neck
cancer in humans about 4 weeks after initiation of
fractionated radiotherapy.
•About 0.6 Gy per day is needed to compensate for this
repopulation.
 REOXYGENATION
•Cells at the center of tumor are hypoxic & are resistant to low LET radiation.
• A dose of x-rays kills a greater proportion of aerated cells than hypoxic cells
because aerated cells are more radiosensitive.
• Therefore, immediately after irradiation, most cells in the tumor are hypoxic.
•Hypoxic cells get reoxygenated during a fractionated course of treatment
•Possible mechanisms:
▶ Recirculation through temporarily closed vessels after acute hypoxia
▶ Release of chronic hypoxia due to tumor size shrinkage
 RADIATION RESPONSE
•Early responding: constitute fast proliferating cells such
as skin, mucosa, intestinal epithelium, colon, testis etc.
•Late responding: have large no. of cells in the resting
phase such as spinal cord, bladder, lung, kidneys etc.
 RADIATION RESPONSE: EARLY REACTING
TISSUE
•Early responding tissues are triggered to proliferate within
2-3wks after start of fractionated RT.
•Prolonging overall treatment time can reduce acute
reactions without sparing late damage
• Fraction size & overall t/t both determine response of
acutely responding tissues.
•Large fraction size may produce irreparable lethal damage
•Prolong OTT may repair SLD in early tissues
 RADIATION RESPONSE: LATE REACTING
TISSUE
•Late reacting tissues are more sensitive to changes in
fractionation pattern than early responding tissues.
• Fraction size is dominant factor in determining late effects.
•Overall t/t has little influence on late effects.
•If fewer and larger dose fractions are given, late reactions
are more severe, even though early reactions are matched
by an appropriate adjustment in total dose.
 SURVIVAL CURVES OF EARLY & LATE
RESPONDING CELLS
• Survival curves of early & late
responding cells have different
shapes.
• Curves for late responding tissue
are more curved because of
difference in repair capacity of late
& early responding tissues.
• For early effects, à/ ß ratio is large
• as a consequence, à (irreparable damage) dominates at
low doses, so that the dose- response curve has a marked
initial slope and does not bend until higher doses.
• The linear and quadratic components of cell killing are
not equal until about 10 Gy.
• For late effects, à/ ß ratio is small
•so ß (repairable damage ) has an influence at low doses.
• The dose-response curve bends at lower doses to appear
more curved
• the linear and quadratic components of cell killing are
equal by about 3 Gy.
 EXPLANATION FOR DIFFRENCE IN SHAPE
OF EARLY & LATE RESPONDING TISSUES
•The radio sensitivity of a population of cells varies with the
distribution of cells through the cycle .
• Two different cell populations may be radio resistant:
1. Population proliferating so fast that S phase occupies a major
portion of cycle .(early responding tissue)
2. Population proliferating so slowly that many cells are in early
G1 or not proliferating at all so that cells are in resting (G0)
phase (late responding tissue).
 VARIOUS FRACTIONATION SCHEDULES
•Fractionated radiations exploits difference in 4R’s
between tumors and normal tissue, thereby improving
therapeutic index
•Types:
-Conventional
- Altered (Hyper/Accelerated/Split/Hypo)
 CONVENTIONAL FRACTIONATION
•1.8-2Gy/#, 5 days a week for total f 5-6 weeks is considered
close to exploiting difference of tumor and normal tissue
and termed conventional fractionation
•Convenient, efficient and effective
•Most tried and trusted method
•Both tumorocidal and tolerance doses are well documented
ALTERED FRACTIONATION
 HYPERFRACTIONATION
•Same/higher total dose
•Smaller dose/fraction
•Multiple fractions/day
•Higher number of fractions
•Approximately same duration
 ACCELERATED FRACTIONATION
•Same/lower total dose
•Lower dose/fraction
•Multiple fractions/day
•Higher number of fractions
•Shorter overall duration
TRIALS OF PURE ACCELERATED
FRACTIONATION
 Early and late radiation-related morbidity
• Acute morbidity was significantly more frequent with
six than with five fractions, but was transient.
•Accelerated radiotherapy applied to squamous- cell
carcinoma of the head and neck yields better
locoregional control than does a conventional schedule
with identical dose
5 vs 6 FRACTIONS PER WEEK: IAEA TRIAL
 CHART
• Regimen conceived at Mount Vernon Hospital, London
•1.5Gy dose/# delivered 3 times a day, 6 hours apart, 7 days
a week
•Total dose of 54Gy/36# over 12 consecutive days including
weekendss
•Chosen to complete treatment before acute reactions start
appearing in 2 weeks
•Use in head, neck and MSCLC
 RESULTS OF CHART
• The results of the CHART protocol showed good local tumor control with
severe acute reactions.
• It was claimed that patients favored the protocol because treatment was
concluded quickly.
• The incidence of late effects in general did not increase and by some measures
actually decreased.
• The notable exception was damage to the spinal cord.
•Several myelopathies were recorded at total doses of 50 Gy, the probable cause
being that an interfraction interval of 6 hours is not sufficient for the full repair
of sublethal damage in this tissue.
ACCELERATED TREATMENT:
CONCOMITANT BOOST
 SPLIT-COURSE
• Total dose is delivered in two halves with a gap in between
with intervals of four weeks.
•Used for patients who have poor general condition and/or
advanced disease.
•Applied in radical treatment of ca bladder, prostate and lung
cancer.
•The disadvantage is that tumor cell repopulation results in
impaired tumor control due to gap and prolonged t/t.
 REASONS FOR INCREASED LATE TOXICITY
IN EORTC TRIAL
• This EORTC trial and several other trials testing accelerated treatment show
that attempting to keep the total dose as high as 66 to 72 Gy, but shortening
OTT by as much as 2 to 3 weeks from a conventional time of 6 or 7 weeks leads
to serious late complications.
• There are probably two reasons for this:
First, the late effects observed are “consequential” late damage, that is, late
damage developing out of the very severe acute effects. Second, there is
incomplete repair between dose fractions if several fractions per day are given.
•This is especially likely for protocols involving 3# per day, in which any
unrepaired damage in the first interval accumulates in the second interval in
each day and also because intervals between fractions of only 4 hours were
used in the early years of the EORTC trial.
(1) Standard fractionation
70 Gy/35 daily fractions/7 weeks
(2) Hyper fractionation
81.6 Gy/68 twice-daily fractions/7 weeks
(3) Accelerated fractionation with split
67.2Gy(1.6bid)/42 fractions/6 weeks with a 2-week rest
after 38.4 Gy
(4) Accelerated fractionation with concomitant boost
72 Gy/42 fractions/6 weeks.(1.8Gy/f with 1.5 Gy /f boost
on last 12 fractions)
LRC:
• Significant improvement in 2 yr LRC for the hyper
fractionation and concomitant boost arms .
DFS:
• Trend toward improved DFS (p = 0.067 and p = 0.054
respectively for the hyper fractionation and concomitant
boost arms
OS: Difference in overall survival was not significant.
TOXICITY:
• Altered fractionation regimens were associated with
higher incidence of grade 3 or worse acute mucosal toxicity,
but no significant difference in late toxicity
 RESULTS OF MARCH META-ANALYSIS
•There was a significant survival benefit in altered fractionation.(3.4%at
5 years).
•There was a benefit on locoregional control in favour of altered
fractionation versus conventional radiotherapy (6·4% at 5 years;
p<0·0001.
•The benefit was significantly higher in the youngest patients.
• Interpretation: Altered fractionated radiotherapy improves survival in
patients with head and neck squamous cell carcinoma. Comparison of
the different types of altered radiotherapy suggests that
hyperfractionation has the greatest benefit.
 LESSONS LEARNED FROM ALTERD
FRACTIONATION STUDIES RESULTS OF MARCH
META-ANALYSIS
•First, hyperfractionation appears to confer an unequivocal benefit in
the treatment of head and neck cancer, in terms of both local control
and survival, without a significant increase in late sequelae.
• By contrast, caution is needed in the application of accelerated
treatment because the EORTC trials showed an unexpected increase in
serious complications, both early and late.
• Particular caution is necessary if the spinal cord is in the treatment
field for twice-a-day treatments because repair of sublethal damage
has a slow component in this tissue.
 HYPOFRACTIONATION: HISTORY
•During the 1970s and the 1980s, the trend in radiotherapy,
particularly in the United States, has been to
HYPERFRACTIONATION to reduce the severity of late effects
as described in detail previously.
•However because of logistic reasons with
hyperfractionation a new fractionation regimen evolved
giving dose fractions much larger than 2 Gy for curative
radiotherapy
• Four lines of research point in this direction.
 FIRST EVIDENCE
•In the special case of prostate cancer, à/ß ratio is low, range of 2-3—
more similar to late-responding normal tissues than to tumors.
•This essentially removes the basic rationale for a multifraction regimen
of 35 or more fractions.
•The implication is that an EBRT regimen consisting of a smaller number
of larger dose fractions, or alternatively high dose rate (HDR)
brachytherapy delivered in a limited number of fractions, should result
in good local tumor control without increased normal tissue damage.
 SECOND EVIDENCE
•Second, the outcome of several large fractionation trials, mainly
involving head and neck tumors, and particularly the CHART trial, have
clearly demonstrated the advantage of “ acceleration,” that is,
shortening the overall treatment time to improve local control.
•On the other hand, the demonstration that the half-times of late
normal tissue repair are long severely limits the strategy of using
multiple treatments per day to attain acceleration
•The only alternative to achieve acceleration is a smaller number of
larger dose fractions.
 THIRD EVIDENCE
•The development of IMRT ,Tomotherapy, and proton beams
results in greater conformity.
• This means greatly improved dose distributions, with
smaller volumes of normal tissues receiving high doses.
• This suggest possibility of increasing the dose per fraction,
because need to spare late responding normal tissues by
fractionation is Reduced because of the lower dose to these
tissues.
 FOURTH EVIDENCE
•The development of carbon ion beams has led to trials
involving treatment with a small number of large dose
fractions. It is not clear at present whether the
apparent success of this strategy is caused by the
superior dose distribution due to Bragg Peak, or the
relatively high LET & RBE of the radiation.
 HYPOFRACTIONATION: INDICATION
•(a) for prostate cancer for which the à/ß ratio is closer to
that for late- responding tissues, which removes the benefit
of fractionation;
•(b) for IMRT and proton beams, where the dose distribution
is so improved that the volume of normal tissue exposed to
high doses is much reduced
• (c) for carbon ion beams, where the dose distribution is
improved and, in addition, the radiation has a relatively high
LET.
 CONCLUSION OF START TRIALS
•the combined trials present mounting evidence that
hypofractionation is a safe and effective approach to
breast cancer radiotherapy.
• Utilization of hypofractionation may offer considerable
savings to individual patients and the healthcare
system—without compromising clinical outcomes or
quality of life.
Thank You!