Altered fractionation dose regimes for

radiotherapy

Moderator : Presented by:

Dr. Arun Singh Oinam Mamta Tyagi
M.Sc-II (Medical physics)
 INTRODUCTION
• AIM OF TREATMENT WITH RADIATION
To deliver precisely measured dose of radiation to a defined target
volume with minimal damage to surrounding normal tissue.
• OBJECTIVES
 Curative
 Tumor eradication
 Prolonged survival.
 Improve Quality Of Life
 Palliative
 Amelioration of symptoms
 FRACTIONATION
• Refers to the division of total dose into no. of separate
fractions over t/t .
• Size of dose # whether for cure or palliation depends
on tumor dose as well as normal tissue tolerance .
 HISTORICAL REVIEW OF FRACTIONATION
• Earlier some radiotherapists
believed that fractionated
treatment was inferior &
single dose was necessary to
cure cancer .
• While radiobiological
experiment conducted in
France (REGAURD’S RAM
EXPERIMENT ) favored
fractionated regimen for
radiotherapy .
 REGAURD’S RAM EXPERIMENT
• Regaurd tried to sterilize rams by irradiation of their testis.

• Testis were regarded as model of a growing tumor & skin as dose

limiting normal tissue.

• It was shown that sterilisation by testicular irradiation was not

possible with a single radiation fraction without extensive
damage to the scrotum.

• By fractionating radiotherapy over several weeks, sterilisation

was then possible without unacceptable skin damage.
RADIOBIOLOGICA RATIONALE FOR FRACTIONATION
• Delivery of tumorocidal dose in small dose fractions in
conventional multifraction regimen is based on 4R’s of
radiobiology namely
– Repair
– Repopulation
– Redistribution
– Reoxygenation
• Radio sensitivity (intrinsic property of a cell) is considered by
some authors to be 5thR 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
• Late-reacting normal tissue cells tend to exhibit a greater tendency for
repair of sub-lethel damage than do tumor cells.

• If the dose per fraction is below the crossover point , the resultant cell
survival curves gradually separate, with tumor cells suffering more
damage than normal cells .
 REDISTRIBUTION
• Cell-cycle progression effects.
• Cells that survive a first dose of radiation will tend to be in a resistant
phase of the cell cycle, and within a few hours, they may progress into a
more radiosensitive phase.

• It results in a therapeutic gain,

bcz sensitization by this
mechanism occurs only in
rapidly dividing cells and not
in late-responding normal
tissues.
 REOXYGENATION
• In a tumour the radioresistant hypoxic cells will selectively
survive after a dose fraction, but thereafter, when their oxygen
supply improves, their radiosensitivity will increase .

HF =no. of hypoxic cell/total

no. of cells of tumor bulk

Hand Book of Radiotherapy

(Gordon Steel)
 REPOPULATION
• There is considerably more repopulation of cancer cells than
cells of the late-responding normal tissues.
• 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.
 RADIOSENSTIVITY
• Radiosensitivity expresses the response of the tumor to
irradiation.
• Acc. to“Bergonie and Tribondeau (1906) Radiosenstivity LAWS”:
Radiosenstivity will be greater if the cell:
– Has high mitotic rate.
– Is undifferentiated.
– Has a long mitotic future.
• Malignant cells have greater reproductive capacity hence are
more radiosensitive.
 VARIOUS FRACTIONATION SCHEDULES
• Fractionated radiation exploits difference in 5R’s between
tumors and normal tissue thereby improving therapeutic index
• Types of fractionation
– Conventional
– Altered
• Hyper fractionation
• Hypofractionation
• Accelerated fractionation
 CONVENTIONAL FRACTIONATION
RATIONALE:
• Spares normal tissue through repair of SLD b/w fractions &
repopulation of cells.
• Increases tumor damage through reoxygenation & redistribution of
tumor cells

Schedule:

• Dose per week 9-10 Gy

ADVANTAGES
 Convenient: weekend breaks
 Efficient: 5 days a week treatment
 Effective: high doses delivered without exceeding normal tissue
tolerance.
 ALTERED FRACTIONATION
• Hyperfractionation
– Dose per fraction <1.8 Gy
• Hypofractionation
– Dose per fraction > 2 Gy
• Accelerated hyperfractionation
– Rate of accumulation exceeds 10 Gy per week
• Hybrid Schedules
– CHART
– Split course
– Concomitent boost
Fractionation Response : Early v/s Late
 α/β Ratio
• Dose where cell killing due to the linear and quadratic
components are equal.
• For low doses the low α/β tissues are relatively resistant
compared with high α/β tissues.
 REACTIONS α/β ratio (Gy)
EARLY
SKIN 9-12
JEJUNAM 6-10
COLON 10-11
TESTIS 12-13
CALLUS 9-10

LATE 1.7-4.9
SPINAL CORD 1.0-2.4
KIDNEY 2.0-6.3
LUNG 3.1-7
BLADDER

TUMORS
HEAD AND NECK 7-16
SKIN ~8.5
MELENOMA AND SARCOMA ~0.5
BREAST ~4
• α/β is a quantitative measure of the sensitivity to changes in fraction size.
• low ratios signify high fractionation sensitivity, and high ratios signify low
fractionation sensitivity.
• Low ratios imply relatively large changes in isoeffective dose when dose per
fraction is changed, and the converse for high values.
 Biologically Effective Dose (BED)
• BED is a measure of effect (E), in dose units, and for a given biological
tissue .
• BED values indicate how much damage a particular fractionation regime
will do .
• BED is given by
BED=D*RE
Where D is total dose
and RE is the Relative Effectiveness ,RE=(1+d/ (α/β))
• BED is the total dose which, if given in infinitely small fractions, is
equivalent to the actual fractionated regimen with fraction size d and
total dose D
 Hypofractionation
• Hypofractionation means the use of a reduced number of
fractions, or a larger dose per fraction.
• If the dose per fraction is increased above the reference value
of 2 Gy, then the total dose (for an isoeffect) must be reduced.

No. of fractions Dose/ fraction Overall time

: DECREASED : INCREASED : CHANGED
 Cont….
• EXPECTATION : lower therapeutic ratio between tumours and
late-responding normal tissues , compared with conventional
fractionation given in the same overall time.

• For tumours that have low α/β ratio, e.g. some melanomas,
liposarcomas and potentially early-stage prostate and breast
cancer , hypofractionation may be as good or even better than
conventional fractionation .
 Clinical Trial for Hypofractionation
Author Disease Conventional regimen Hypofractionation regimen
(Owen et al., invasive breast cancer with 50Gy in 25 # 39Gy in 13# 42.9Gy in 13#
2006) local tumour excision

RESULT:
Risk of tumor relapse
50 Gy grp 12.1%
39 Gy grp 14.8%
42.9 Gy grp 9.6%
• The α/β ratio of breast cancer was estimated to be 4.0Gy[95 per cent confidence interval( 1.0–7.8) ].

IMPLICATIONS

•Hypofractionation with a modest reduction of total dose had similar effectiveness to a conventional
fractionation schedule with respect to tumor control and late irradiation morbidity.
 BED Calculation
• For conventional fractionation
50Gy/25#/2Gyper #
 For tumor control
 BED = 50(1+2/4)
= 75
 For late effects
 BED=50(1+2/3)
=83.33
• For hypofractionation
 39Gy/13#/3 Gy per #
 For tumor control
BED=39(1+3/4) = 68.25
 For late effects
BED=39(1+3/3)=39
42.9 Gy/13#/3.3 Gy per #
 For tumor control
 BED=42.9(1+3.3/4) =78.29
 For late effects
 BED=42.9(1+3.3/3)=90.09
 HYPOFRACTIONATION IN PALLIATIVE RT

• Single-dose irradiation or hypofractionation with only few large

fractions are widely applied in palliative radiotherapy.
• Schedules use lower total doses than those applied in curative
radiotherapy.
• Patients have a limited life expectancy, late normal-tissue
damage is of only minor concern.
• Symptom control after palliative hypofractionated schedules is
comparable to that achieved with more highly fractionated
schedules.
• More convenient for the patient and help spare resources.
 HYPOFRACTIONATION FOR STEREOTACTIC RADIOTHERAPY

• For stereotactic radiotherapy of small tumors (e.g. in lung, where

very steep dose gradients can be achieved and hence only very
small volumes of surrounding normal tissue are at risk of radiation
damage) single doses or Hypofractionation with few large fractions
are also frequently applied in clinical practice.

ADVANTAGES:
– Treatment completed in a shorter period of time.
– Machine time well utilized for busy centers.
– Higher dose /# gives better control for larger tumors.

DISADVANTAGE:
– Higher potential for late normal tissue complications.
 Hyperfractionation

Total tumor dose: No. of fractions : Dose/fraction : Overall time:

INCREASED INCREASED DECREASED UNCHANGED

• Pure hyperfractionation – total dose & over all t/t same as

conventional regimen but delivering dose in twice as many fractions
i.e. treating twice daily.
• Impure hyperfractionation -Since dose/fraction decreases hence
total dose need to be increased.
• RATIONALE

 Use of small dose fractions allows higher total doses to be

administered within the tolerance of late-responding normal
tissues, and this translates into a higher biologically effective dose
to the tumor.
 The α/β ratio for tumor cells must be greater than that for the dose-
limiting normal tissue .
 Radiosensitization through redistribution and lesser dependence on
oxygen effect .
 With small fractional doses, the influence of tumor cell hypoxia is
reduced on two counts.
 Clinical Trials Of Hyperfractionation
• Dose-escalated hyperfractionation has been tested in two large
multicentre randomized clinical trials on head and neck
squamous cell carcinoma .

EORTC TRIAL 22851

Conventional regimen Hyperfractionation regimen

70Gy/35#/7wks 80.5Gy/70#(1.15Gy twice/day)/7wks
• RESULTS

• The larger total dose in the hyperfractionated treatment produced an

increase of about 19 per cent in long-term local tumour control .
• No increase in side effects .
 RTOG TRIAL
AUTHOR Conventional Regimen Hyperfractionation
KAREN K. FU et.al. 70 Gy/35#/7 wk 81.6 Gy/68# /1.2 Gy per #

RESULTS
• Local tumour control was increased by
8% after hyperfractionation compared
with conventional fractionation .
 BED Calculation
• For conventional fractionation • For hyperfractionation

70Gy/35#/2Gyper # 80.5Gy/70#(1.15Gy twice/day)/7wks

 BED(tumor control) =70(1+2/10)  BED(tumorcontrol=80.5(1+1.15/10)
= 84 = 89.76
 BED(late effects)=70(1+2/3)  BED(late effects)=80.5(1+1.15/3)
=116.64 =111.37
Effect of change in size of dose/fraction on
the total dose
 ACCELERATED FRACTIONATION
• Accelerated fractionation is defined as a shortening of the overall
treatment time or, more precisely, as an increase of the average dose/
week above the 10Gy given in conventional fractionation.

• Early normal-tissue reactions are expected to increase using accelerated

radiotherapy .

• In contrast, if recovery from sublethal radiation damage between fractions

is complete, late normal tissue damage is expected to remain constant for
accelerated fractionation schedules using 1.8-2Gy/fraction and total doses
comparable to conventional fractionation.
• RATIONALE

– The rationale for accelerated fractionation is that reduction in overall

treatment time decreases the opportunity for tumor cell regeneration
during treatment and therefore increases the probability of tumor
control for a given total dose.

– Because overall treatment time has little influence on the probability of

late normal tissue injury, a therapeutic gain should be realized,
provided the size of dose per fraction is not increased and the interval
between dose fractions is sufficient for complete repair to take place.

– When the overall duration of treatment is markedly reduced, it is

necessary to reduce total dose to prevent excessively severe acute
reactions.
 Accelerated fractionation

Pure fractionation Hybrid Accelerated fractionation

reduced overall treatment

reduced overall time , no
time,fraction size change , total
changes in fraction size or
dose and time distribution
total dose.
change
 Hybrid Accelerated fractionation

CHART SPLIT COURSE CONCOMITANT BOOST

drastic reduction in
total time, additional fractions
reduction in total added after 2-
Dose. time modestly 3wks, min gap 6 hr.
reduced, dose similar
range, break in
treatment
 CHART
• Abbreviation for “Continuous Hyperfractionated Accelerated Radiotherapy”.

• Strongly accelerated fractionation.

• Protocol applies 36 fractions over 12 consecutive days (starting on a Monday

and including the following weekend)

• 3 # per day with an interval of 6 hours between the fractions within each day.

• Dose /# is 1.5Gy to a total of 54Gy.

• Total dose is therefore reduced compared with conventional therapy, in order

to remain within the tolerance of acutely responding epithelial tissues.
 Clinical Trial For CHART
• Disches et.al. compared CHART with conventional regimen (66Gy/33#)for
treatment of squamous cell carcinoma of the head and neck .

• Loco-regional tumour control was identical in both treatment arms.

• Overall patient survival was identical in both treatment arm.
• Radiation mucositis was more severe with CHART; it occurred earlier but settled
sooner and was in nearly all cases healed by 8 weeks in both arms.
 SPLIT COURSE
• Split-course radiation therapy is an altered fractionation regimen originally
designed to diminish radiation morbidity by splitting the total dose into at
least two separate courses with an interruption of 10 to 14 days .

• Theoretical basis of the method consists of the differences in cell population

kinetics between normal and malignant tissues.

• The recovery of tumour cells during the rest interval is much slower than
that of normal proliferating cells; this gives time for normal tissues such as
the skin to recover.
ADVANTAGES:
• Can be followed for patients with poor general condition .

• To assess for response and tolerance of the initial half of treatment & to
exclude poorly tolerating patients from further morbidity .

DISADVANTAGE:
• Tumor cell repopulation resulting in impaired tumor control due to gap and
prolongation of treatment time .
 Concomitant boost
• A variation of accelerated hyperfractionation, giving a second daily dose of
radiation to a reduced "fieldwithinafield" during the course of conventional
fractionated radiotherapy.
• The small field includes only the primary lesion and the clinically palpable
lymph nodes adjacent to the primary site .
• Thus, the primary lesion and the lymph nodes receive as compared to the
rest of the large field , which is adequate for microscopic disease.
• CBT can be given in three forms:
– In the first variant (Arm I), the boost dose is delivered in the initial part of the
treatment.
– In the second variant (Arm II), it is given at the end of the treatment .
– in the third variant (Arm III), it is delivered throughout the treatment.
ADVANTAGES OF CBT

• As the area receiving accelerated fractionation RT is very small,

there is very little enhancement in acute reactions compared to
other accelerated fractionation regimens .
• The dose per fraction being the same, late reactions remain
unaffected.
• Shortens the total treatment duration from seven weeks to five
weeks.
 CLINICAL TRIAL OF CBT

AUTHOR DISEASE CONVENTIONAL CONCOMITENT BOOST

REGIMEN
S.Ghoshal Squamous Cell 66 Gy/33#/6.5 wks 67.5 Gy/40 #/ 5 wk
et. al. Carcinoma (phase 1: 45 Gy/25 #/5 wk
of the Head and Neck phase 2: 22.5 Gy/15#/3 wks as a
second daily fraction after a 6 h gap)
 RESULTS

• Patients treated with concomitant boost had a better 2-year disease-free survival
(71.7% vs 52.17%, ) and locoregional control rates (73.6% vs 54.5%,) than with
conventional fractionation.
 BED Calculation
• For conventional fractionation • For CBT

67.5 Gy/40 #/ 5 wk
66Gy/33#/2Gyper #
(phase 1: 45 Gy/25 #/5 wk
 BED (tumor control)= 66(1+2/10)
phase 2: 22.5 Gy/15#/3 wks as a
= 79.2
second daily fraction after a 6 h gap)
 BED(late effects)=66(1+2/3)
BED(tumorcontrol)
=110
=45(1+1.8/10)+22.5(1+1.5/10)
= 78.975
BED(late effects)
=45(1+1.8/3)+22.5(1+1.5/3)=105.75
 FRACTIONATION SENSISTIVITY OF DIFFERENT TUMORS

Tumor Definition Optimal fractionation Clinical level of evidence

fractionation schedule
sensitivity
Low / ratio of ca higher More, smaller-sized # with Level I evidence for improved
than that of late higher total dose, or fr. therapeutic ratio in head and
responding healthy given over a shorter time neck and lung ca
tissues course-> improves LC, same
late tox, more acute tox.
Moderate to high / ratio of ca similar or Fewer, larger-sized # might Level II evidence for
slightly higher than that achieve same LC and late therapeutic ratio equivalent to
of late responding toxicity as conventional conventional scheme in
healthy tissues fractionation BREAST CA

High / ratio of ca lower Fewer, larger-sized # Level III evidence for
than that of late improve LC with similar or therapeutic ratio equivalent to
responding healthy reduced late and acute tox conventional fr. In prostate ca
tissues effects
 Conclusion

• Hypofractionation can improve local tumor control, may be

beneficial in more radioresistant cancers .
• Acceleration can improve local tumor control and survival in
rapidly proliferating cancer.
• Hyperfractionation and acceleration require careful
scheduling to avoid increasing late complications.
Interfraction intervals >6h recommended.
• Hypofractionation, already useful in palliation, may find a
role in treating early stage cancers especially in stereotactic
and image-guided delivery.
 References
• Handbook of radiotherapy physics theory and practice

• Perez and Brady's ”Principles and Practice of Radiation Oncology”

• Basic clinical Radiobiology by Michael Joiner

• Treatment Planning in Radiation Oncology by F.M. Khan

• Treatment Planning in Radiation Oncology by Eric J. Hall

• Accelerated fractionation (AF) compared to conventional fractionation (CF)

improves loco-regional control in the radiotherapy of advanced head and neck
cancers: results of the EORTC 22851 randomized trial by Jean-Claude Horiota
et.al.

• Concomitant Boost Radiotherapy Compared with Conventional Radiotherapy in

Squamous Cell Carcinoma of the Head and Neck d a Phase III Trial from a Single
Institution in India by S. Ghoshal et.al.