Introduction Time dose & fractionation Therapeutic index Four R’s Of Radiobiology Radiation response Survival Curves Of Early & Late Responding Cells Various fractionation schedules Clinical trials of altered fractionation

2. CONTENT
PART A
• Introduction
• Time dose & fractionation
• Therapeutic index
• Four R’s Of Radiobiology
• Radiation response
• Survival Curves Of Early & Late
Responding Cells
• Various fractionation schedules
• Clinical trials of altered fractionation
PART B
• Physical Models For Time Dose &
Fractionation
• Strandqvist Plot
• Cohen’s Formula
• Fowler Concepts
• NSD Model
• TDF model
• Target Theory
• L Q model
• BED calculation of different
fractionation regimen

3. AIM OF RADIOTHERAPY
• To deliver precisely measured dose of radiation to a defined tumor
volume with minimal damage to surrounding normal tissue.
• Aims:
• To eradicate tumor,
• Improve quality of life &
• Prolongation of survival.

4. 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 ,

5. Time depends on
• 1. Intension to treat
For curative purposes overall t/t is 5-6wks
 Better tumor control with minimal morbidity
 Tumor response can be monitored.
 Radiation reactions can be monitored.
 If treatment time is more than 6wks then dose has to be increased
Short duration treatment time is justified for
 Treatment of small lesions: SRS/SRT
 To treat aged persons
 Palliative treatments
• 2. Site of tumor
 Rapidly proliferating tumor has poor LC with increase in time eg- head &
neck, NSCLC
 In slowly growing tumor eg. Breast and prostate overall treatment time not

6. 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.

7. Dose
• 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)

8. 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.
Probability of cell death
100%
A
TLD
%agelethaleffect
dose

9. 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

10. 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)

11. 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

12. Therapeutic index:
The more the curve B is to the right of curve A the more is therapeutic ratio

13. Dose varies with
70 GY

15. 3.Fractionation

16. History: Introduction Of Fractionation

17. 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

18. FOUR R’s OF RADIOBIOLOGY

20.  Figure 5.3 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
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.

21. • 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
REDISTRIBUTION

22. REDISTRIBUTION

23.  Figure 5.4 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.

24.  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.

25. 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

28. 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.

29. 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

30. SUMMARY

31. • Response of all normal tissues to radiation is not same
• Depending on their response tissues are either
• 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 e.g.
spinal cord, bladder, lung, kidneys etc.
RADIATION RESPONSE

32. • This diagram shows that time after the start of
fractionated regimen at which extra dose is
required to compensate for cellular proliferation is
quite different for late- versus early-responding
tissues.
• The other point made, of course, is that these are
data from rodents and that in the case of humans,
the time scales are likely to be very much longer
• In particular, the time at which extra dose is
required to compensate for proliferation in late-
responding tissues in humans is far beyond the
overall time of any normal radiotherapy
regimen.
• Prolonging overall time within the normal
radiotherapy range has little sparing effect on
late reactions, but a large sparing effect on
early-responding tissues.

33. 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

34. 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.

35. • 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.
Survival Curves Of Early & Late Responding Cells

36. • 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 that ß (repaieable 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.

38. 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).

39. • Population proliferating so fast that S phase occupies a major portion
of cycle .
• Redistribution occurs through all phases of cell cycle in such
population & is referred to as self sensitizing activity.
• New cells produced by fast proliferating population offset cells killed
by dose #s & thus offers resistance to effect of radiation in acutely
responding tissues & tumors.
• Thus proliferation occurring b/w dose #s help in repopulation of
normal tissue (i.e. spares normal tissue) at the risk of tumor
repopulation
EXPLANATION FOR DIFFRENCE IN SHAPE
OF EARLY RESPONDING TISSUES

40. • Population proliferating so slowly that many cells are in earlyG1 or
not proliferating at all so that cells are in resting (G0)phase.
• Hence late responding normal tissue are resistant due to presence of
many resting cells.
• Such resistance disappears at high dose/#
EXPLANATION FOR DIFFRENCE IN SHAPE
OF LATE RESPONDING TISSUES

51. TRIALS OF PURE ACCELERATED FRACTIONATION
*!Jackson et al. A randomised trial of accelerated versus conventional radiotherapy in head and neck cancer.Radiother Oncol 1997
*2Skladowski Ket al. 7-day-continuous accelerated irradiation (CAIR) of head and neck cancer—. Radiother Oncol 2000;55
*3Overgaard J,. The DAHANCA 6 and 7 trial: a study of 5 versus 6 fractions per week of conventional radiotherapy of (SCC) of the head and neck. Radiother Onco
*4Hliniak AZ.. Radiother Oncol 2000;56:S5.
*1
*2
*3
*4

52. Aim: to find whether shortening of treatment time by use of six instead of five radiotherapy
fractions per week improves the tumour response in squamous-cell carcinoma.
Lancet. 2003
1485 patients treated with primary radiotherapy alone,

53. Primary locoregional tumour control as
function of number of fractions per week
Overall 5-year locoregional control rates were
70% and 60% for the six-fraction and five-
fraction groups, respectively (p=0.0005).
primary tumour control (76 vs 64% for six and five
fractions, p=0.0001), but was non-significant for neck-
node control

54. Disease specific survival Overall survival
Disease-specific survival improved (73 vs 66%) for six and five fractions
but not overall survival

55. Early and late radiation-related morbidity
Acute morbidity was significantly more frequent with six than
with five fractions, but was transient.
CONCLUSION
Accelerated radiotherapy applied to squamous-
cell carcinoma of the head and neck yields better
locoregional control than does a conventional
schedule with identical dose and fractionation.

56. 2010
IAEA-ACC

59. 1997

60. RESULTS OF CHART
• The results of the CHART protocol showed good local tumor control
with severe acute reactions.
• It was claimed that patients favoured 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.

65. 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.

66. .
• Patients with stage III or IV SCC
(n=1076) were randomized to 4
treatment arms:
2000

67. (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)

68. RTOG 90-03 Results:
• 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

69. MARCH META-ANALYSIS
2006
2010
The Lancet, Volume 368, Issue 9538, Pages 843 - 854, 2 September 2006

70. 15 Randomized Trials of Varied Fractionation (1970-1998)
PATIENT CHARACTERISTICS
7073 patients
Tumours sites: mostly oropharynx and larynx
74% patients had stage III—IV disease
hyper fractionated
accelerated
accelerated with
total dose reduction
Overall survival was
the main endpoint
median follow up:6 yr

71. benefit Conventional vs Altered Hyper fractionation vs
Accelerated fractionation
Locoregional
control
Loco regional control
6.4 %times higher
benefit was higher with hyper
fractionated radiotherapy
( OS 8% at 5 years) than with
accelerated radiotherapy
(2% with accelerated
fractionation without total dose
reduction and 1·7% with total
dose reduction at 5 years, p=0·02)
Survival benefit absolute benefit of 3·4% at
5 years with altered
fractionated radiotherapy,

72. 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

73. LESSONS LEARNED FROM ALTERD
FRACTIONATION STUDIES
• 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.

75. 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.

76.  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
First evidence

77. 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.

78. 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.
3DCRT IMPT

79. 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.
Fourth evidence

81. 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.

82. Clinical implication
• Carcinoma breast
• Lung cancer

88. Role of Hypofractionation in breast carcinoma
Lancet Oncol 2008; 9: 331–41
START Trial A & B

89. TRIAL PROFILE
•START A
• Criteria: Early breast cancer (pT1-3,
pN0-1 M0); BCS or Mastectomy
50 Gy in 25 fractions over 5 weeks
41.6 Gy/3.2Gy per fraction in 13
fractions over 5 weeks, or
39 Gy/3Gy per fraction in 13 fractions
over 5 weeks
•START B
Criteria: Early breast cancer (pT1-3,
pN0-1 M0)
50 Gy/2 Gy per fraction, 25 fractions
over 5 wks,
40 Gy/2.67 Gy per fraction,15
fractions over 3 wks.

90. RESULTS OF START A & B
• START A • START B
• 10-year rates of local-regional
relapse:
50 Gy: 5.5%
40 Gy: 4.3% (p=0.21)
Results- 10-yr

91. DFS in Start a & b

92. 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.

93. 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

95. SBRT IN LUNG CANCER