2. Introduction
• Earlier some radiotherapists believed that fractionated
treatment was inferior & single dose was necessary to
cure cancer.
• While radiobiological experiments conducted in France
favored fractionated regimen for radiotherapy which
allows cancerocidal dose to be delivered without
exceeding normal tissue tolerance
3. 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
5. FOUR R’s OF RADIOBIOLOGY
• Delivery of tumorocidal dose in small dose
fractions in conventional multifraction regimen is
based on 4R’s of radiobiology namely
Repair of SLD
Repopulation
Redistribution
Reoxygenation
• Radio sensitivity is considered by some authors to
be 5th R of radiobiology.
6. Repair
• Most important rationale for fractionation
• Mammalian cells can repair radiation damage in b/w dose
fractions. This is a complex process involving repair of SLD by a
variety of repair enzymes & pathways.
• Since tumorocidal doses are very high as compared to NTT there
are two ways to deliver such high doses:
1. One option is to deliver much higher dose to tumor than to
normal tissue – basis of conformal radiotherapy
2. Other option is to fractionate the dose. So that there is sufficient
time b/w consecutive fractions for complete repair of all cell that
suffered SLD during 1st # before 2nd #& so on.
• So small dose /# spares late reactions preferentially & reasonable
schedule duration allows regeneration of early reacting tissues.
7. • Radiation damage to mammalian cells are divided into
three categories:
1. Lethal damage :irreversible, irreparable & leads to
cell death
2. Sub lethal damage : can be repaired in hours unless
additional sub lethal damage is added to it
3. Potentially lethal damage : can be manipulated by
repair when cells are allowed to remain in non-
dividing state.
8. • 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
• The data were obtained with cultured
mammalian cells maintained at room
temperature (24° C) between the dose
fractions to prevent the cells from moving
through the cell cycle during this interval.
9. 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.
• A given total dose delivered as
single # is found to be more
effective compared to same dose
delivered in more #s.
10. Repair of SLD depends on
• Dose rate
• Type of radiation
• Cell in different cell cycle phase
• Type of cell
12. 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
13. • Increase in survival during 1st 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.
• Hence dose fractionation enable normal
tissue to recover b/w #s reducing damage
to normal tissue
• Ability of normal tissue to repair radiation
damage better than tumor forms basis of
fractionation.
14. • 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 & G2 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 .
15. Repopulation
• In b/w dose fractions normal cells as well as tumor
cells repopulate.
• So longer a radiotherapy course lasts, more difficult it
becomes to control tumor & may be detrimental
• But 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
16.
17. Accelerated repopulation
• Treatment with any cytotoxic agent , including radiation,
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 .
18. • Accelerated repopulation is triggered by chemotherapy
as well as radiation therapy. When radiation treatment
starts after chemotherapy, the tumor is already at an
accelerated repopulation stage, using up about 0.61
Gy/day to kill repopulated cells from day 1 of radiation
treatment.
• This is a possible explanation that In head and neck
cancer, neoadjuvant chemotherapy failed to improve
the final outcome despite initial tumor regression
19. Reoygenation
• Cells at the center of tumor are
hypoxic & are resistant to low
LET radiation.
• Hypoxic cells get reoxygenated
which occurs during a
fractionated course of treatment,
making them more
radiosensitive to subsequent
doses of radiation.
20.
21. Mechanism of cell killing by oxygen
Non
restorable
form
Restorable
form
23. Time dose models
• With introduction of various fractionation
schemes in radiotherapy need for quantitative
comparisons of treatments was felt in order to
optimize treatment for particular tumor.
• Strandquist was 1st to device scientific
approach for correlating dose to overall t/t to
produce an equivalent biological isoeffect.
24. Cube root model
• By Strandqvist (1944)
• He demonstrated that isoeffect curves (i.e. dose vs. no.
of #s to produce equal biological effect) on log-log
graph for skin reactions (erythema & skin tolerance)
were straight lines with a slope of 0.33
• As these plots were for fixed no. of #s N hence T was
linear function of N & D was proportional to cube root
of N
• D αT 0.33
25.
26. • Cohen analyzed three diff. set of data of
skin damage with end points as weak or
strong erythema &skin tolerance.
• Cohen found an exponent of 0.33 for skin
erythema / skin tolerance & 0.22 for skin
cancers.
• According to Cohen’s results, relationship
b/w total dose & overall treatment time for
normal tissue tolerance & tumor can be
written as
• Dn= k1T0.33
• Dt= k2T0.22
Where K1& K2 are proportionality
constants. Dn, Dt &T are normal tissue
tolerance dose , tumor lethal dose & overall
treatment time respectively
• The exponents ,0.33& 0.22 of time factor
represents the repair capabilities of normal
27. Fowler
• Difference in exponents of time factor in Cohen’s formulations
indicate that repair capacity of normal tissue is larger than that of
tumor
• Fowler carried experimental studies on pig skin showing normal
tissue have two type of repair capabilities
1. Intracellular – having short repair half time of 0.5 to 3hrs & is
complete within few hrs of irradiation. multiplicity of completion
of recovery is equal to no. of #s. Hence no. of #s are more
important than overall t/t
2. Homeostatic recovery that takes longer time to complete
• This led Ellis to formulate NSD
28. NSD MODEL
• According to Ellis ‘s NSD formula time factor was a
composite of N (no. of #s) & T (overall treatment time)
• Exponents for intracellular & homeostatic recovery are 0.22
& 0.33-0.22=0.11 respectively
• Fractionation is twice as important as time according to
clinical observations of Ellis.
• Hence dose is related to time & no. of #s as Where NSD
(nominal standard Dose) is proportionality constant for
specific level of skin damage
• D = (NSD)X T 0.11 X N 0.24
29. Criticisms of NSD
• Do not take into account complex biological processes that take place
during or after irradiation
• Values of exponent of N in NSD eq. are not same for diff. tissue types.
• Validity of NSD w.r.t. different effects in same tissue is doubtful. For late
effects in skin the influence of no. of #s may be considerably larger than
for acute skin responses
• Another difficulty is with time factor T0.11. this suggests an increase in
dose by approx. 20% in 1st week,10% in 2nd week & 5% in 3rd week. but
for acute reactions in skin & mucosa accelerated repopulation starts only
after 2-3wks after start of fractionated treatment while for late reacting
tissue cell proliferation during the fractionated course(4-8 wks) is not
expected to increase tolerance dose as predicted by NSD formula
31. 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 ,
32. 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.
33. Overview of the fractionation schedules used in the three Danish
head and neck trials.
Only the well-differentiated and moderately differentiated tumors were
significantly influenced by overall treatment time.
35. Dose
• Dose is energy deposited by radiation per unit mass of
tissue
• Unit= Gy = 1joule/kg
• But different radiation have different effectiveness and
different organs have different sensitivity
• Hence, equivalent dose = dose X weighting factor
• Unit= sievert
36. 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 his working hypothesis are :-
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.
37. 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
41. Advantage 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.
• Radiation induced redistribution & sensitization of rapidly
proliferating cells.
• Reduction in hypoxic cells leads to –
Reoxygenation
Opening of compressed blood vessels
Reduction in no. of tumor cells with each dose #
42. Various fractionations
• Fractionated radiation exploits difference in 4R’s between
tumors and normal tissue thereby improving therapeutic
index
• Types
1. Conventional
2. Altered
Hyper fractionation
Accelerated fractionation
Split course
Hypofractionation
43. Conventional fractionation
• 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.
• Rationale for using conventional fractionation
Most tried & trusted method
Both tumorocidal & tolerance doses are well documented
44. Multiple fractions per day
• Hyperfractionation was based on premise that because
fractionation separates early and late effects, then
hyperfractionation with double the number of fractions
should even be better.
• To reduce OTT, two treatments each day separated by
6hrs to allow SLD repair.
45. CHART
(Continuous Hyperfractionated RT)
• With CHART treatments 6hrs apart delivered 3times a day,7days
a wk. with dose of 1.5Gy, total dose of 54Gy can be delivered in
36 over 12 consecutive days including weekends.
• Characteristics
1. Low dose
2. Short treatment time
3. No gap in treatment, 3#/day at 6hr interval
• Implications
1. Better local tumor control
2. Acute reactions are brisk but peak after treatment is completed
3. Dose small hence late effects acceptable
4. Promising clinical results achieved with considerable trauma to
pt.
47. • Dose escalated hyperfractionation has been tested in
two large multicentre randomized clinical trials on head
and neck squamous cell carcinoma
1. EORTC 22791
2. RTOG 9003
48. • As expected, local-regional control improved and acute effects
increased. Unexpectedly, severe late complications increased
significantly, such as severe fibrosis, radiation myelitis (spinal cord
dose at 42 Gy and 48 Gy), peripheral neuropathy, and severe
mucosa sequelae including necrosis.
49. • In the RTOG 9003 trial, local tumour control was
increased by 8% after hyperfractionation (68 fractions
of 1.2 Gy, two fractions per day, 6 hours apart, total
dose 81.6 Gy) compared with conventional
fractionation using 2 Gy fractions to 70 Gy in the same
overall time of 7 weeks. Overall survival was not
significantly improved but the prevalence of grade III
late effects was significantly increased after
hyperfractionation.
• Both these clinical trials thus confirm the
radiobiological expectation that local tumour control
can be increased by dose-escalated
hyperfractionation, thereby supporting a high average
α/β value for squamous cell carcinoma of the head and
neck
50. Hypofractionation
• High dose is delivered in 2-3 wk
• Rationale
Treatment completed in a shorter period of time.
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.
51. • There is renewed interest in hypofractionation—that is,
a smaller number of high dose fractions. There are
several circumstances where this may be exploited:
• (1) for prostate cancer for which the α/β ratio is closer
to that for late-responding tissues, which removes the
benefit of fractionation
• (2) for SRS and SBRT where technologic advances
allow a high tumor dose with less dose to a smaller
volume of normal tissue
• (3) for carbon ion beams, where the dose distribution is
improved and, in addition, the radiation has a relatively
high LET.
54. START A and B trial in breast cancer
• 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.
55. Hypofractionation in lung cancer rationale
• Conventional XRT limited to 70Gy
• Duration of therapy 6 to 7 weeks for conventional
therapy is difficult for patients to complete
• SBRT:
• Biologic Equivalent doses greater than 120Gy at
2Gy/fx
• Typically 5 or less treatments– high dose per
treatment
• Highly focused radiation concentrated on the
tumor with sub-millimeter accuracy
• Continuous tumor tracking – via respiratory gating
57. Treatment gaps and their management
Carcinoma of the larynx; Robertson et al 1998 IntJ RadiatOncolBiolPhys 40: 319-29
58. Options
1. Transfer to other machine if treatment
machine has failed
2. Treat on weekends
3. Treat twice a day
Less difficult
cases
More difficult
cases
Gap duration Short gap Long gap
Postion of gap Early in treatment Late in treatment
Tumor type Slow growing Fast growing
59.
60.
61. Management of unplanned gaps
• Important because of strength of evidence showing a negative effect
of gaps in radiotherapy schedules
• When gaps occur remaining treatment should be modified to adjust
for the interruption
• When radiotherapy is given as 5 daily fractions, then the number can
be increased either by giving two fractions per day (> 6 hrs apart) or
treating on Saturday and/or Sunday. This delivers the planned dose
within the planned treatment time.
• The remaining part of the treatment could be delivered with
hypofractionation, i.e. increased dose per fraction. Could increase
late effects.
• The dose lost due to proliferation during a gap can be estimated
using BED/EQD
62. Summary
The basis of conventional fractionation may be explained as follows
1. Dividing a dose into several fractions spares normal tissues because
of the repair of sublethal damage between dose fractions and
cellular repopulation. At the same time, fractionation increases tumor
damage because of reoxygenation and reassortment.
2. The extra dose required to counteract proliferation in a normal tissue
irradiated in a fractionated regimen is a sigmoidal function of time.
No extra dose is required until some weeks into a fractionated
schedule.
3. Prolonging overall time within the normal radiotherapy range has
little sparing effect on late reactions but a large sparing effect on
early reactions.
4. 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.
5. 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.
