Altered fractionation

1. Altered fractionation
DR KIRAN KUMAR BR

2. Radiation fractionation as cancer treatment. Fractionation refer
to a method of treating cancer with radiation therapy. When the
total dose of radiation is divided into several, smaller doses over
a period of several days, there are fewer toxic effects on healthy c
ells.

3. Historical Review
• Earlier some radiotherapists believed that fractionated trea
tment was inferior & single dose was necessary to cure ca
ncer.
• While radiobiological experiments conducted in France fa
vored fractionated regimen for radiotherapy which allows
cancerocidal dose to be delivered without exceeding norm
al tissue tolerance.
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5. Radiobiological rationale for Fractionation
• The five (historically four) R's of radiobiology are concepts th
at explain the rationale behind fractionation of radiotherapy.
• The 5 R's Of Fractionation:
- Repair
- Redistribution
- Reoxygenation
- Repopulation
- Radiosensitivity
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6. 5th R and LQ model – conventional RT
Linear-Quadratic Model
• assumes that there are two components to
cell killing by radiation
• one that is proportional to dose (Linear)
• one that is proportional to the square of th
e dose (Quadratic)
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8. Linear-Quadratic Model
• The ‘bendiness’ is determined by α/β
ratio
• SF = e-(αD+βD2)
• S is the fraction of cells surviving a do
se (D)
• α and β are constants.
• D is the dose in Gy
• If at a dose D, αD = βD2 then: D = α/β
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9. 5th R and LQ model – conventional RT
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The LQ model is simple and convenient
– better fit in the low dose–high survival region
– α (lethal/non-repairable) & β (sub-lethal/reparable)
– α/β ratio for early and late reactions in human normal
tissues consistent with results from experimental models

14. Repair
• Repair is the one of the primary reasons to fractionate radiothera
py. As discussed in DNA Damage and Repair
• There are three types of damage that ionising radiation can caus
e to cells:
-Lethal Damage :which is irreversible and irreparable and leads ir
revocably to cell death
-Potentially Lethal Damage(PLD):The component of radiation d
amage that can be modified by postirradiation environmental condi
tions
-Sublethal Damage(SLD):which under normal circumstances can
be repaired in hours unless additional sublethal damage is added
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23. Repair of Sublethal Damage
• Dose rate effect
• Type radiation
• Cell in different cell cycle phase
• Type cell
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24. Dose-rate effect
If a radiation dose is delivered in a series of equal fractions, separated by s
ufficient time for repair of sublethal damage to occur between doses, the eff
ective dose-survival curve becomes an exponential function
Of dose.
24 EFFECTIVE SURVIVAL CURVE FOR A MULTIFRACTION REGIMEN

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26. Cell in different cell cycle phase
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27. Type cell
• Cell survival is a function of cell type and radiation type
 Non- or slowly proliferating cells (nerve, muscle, secret
ory) are less susceptible to radiation damage.
 Highly-proliferating cells (epithelial, stem cells) are mo
re susceptible.
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28. Repair and Low Dose Rate treatment
• If the dose rate is sufficiently lo
w, repair may be able to take pl
ace during radiotherapy treatm
ent. This considerably reduces t
he cell death due to sublethal d
amage and is one reason low d
ose treatments show reduced ef
fectiveness at identical doses to
high dose rate treatment.
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29. Repair Half Life
• Intefraction interval and the repair half life is an important considerati
on when fractionating radiotherapy. Some tissues, notably the spinal c
ord, appear to have a slow repair mechanism with a half life of about
4 hours. It is important to separate dose by at least 6 hours and prefera
bly 8 hours if two fractions are given on the same day.
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30. Redistribution
• Cells move to more radiosensitive phase in the cell cycle betwe
en fractions.
• M and G2 most sensitive phases.
• Late S most resistant phase
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31. Redistribution
• Redistribution of proliferating cell popu
lations throughout the cell cycle increas
es cell kill in fractionated treatment rela
tive 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 fracti
onated course of RT if cells are caught i
n sensitive phase after each fraction
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32. Reoxygenation
• Cells at the center of tumor are hypoxic
& are resistant to low LET radiation.
• Hypoxic cells get reoxygenated occurs du
ring a fractionated course of treatment, m
aking them more radiosensitive to subseq
uent doses of radiation.
• Tumours may be acutely or chronically h
ypoxic. This oxygenation status may cha
nge during treatment.
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33. Reoxygenation
• In this particular tumor, the process of reoxygenation is
very rapid indeed.
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34. Conventional RT and Reoxygenation
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35. Repopulation
• Tends to increase cell survival.
• Occurs when fraction interval lengt
h greater than cell cycle doubling ti
me.
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36. Summery of Dose Rate Effect
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37. Radiosensitivity
• Radiosensitivity is a newer member of the R's
• It reminds us, that apart from repair pathways, redistribution of ce
lls, reoxygenation of malignant cells and repopulation there is an i
ntrinsic radiosensitivity or radioresistance in different cell types.
• Radio sensitivity expresses the response of the tumor to irradiatio
n.
• Malignant cells have greater reproductive capacity hence are mor
e radiosensitive.
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38. Factors affecting the radiosensitivity
• Physical
–LET (linear energy transfer):  RS
–Dose rate:  RS
• Chemical
–Increase RS: OXYGEN, cytotoxic drugs.
–Decrease RS: SULFHYDRL compounds (cys, cys
teamine…)
• Biological
–Cycle status:
•  RS: G2, M
•  RS: S38

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40. Radiation Response
• Response of all normal tissues to radn is n
ot same
• Depending on their response tissues are eit
her
• Early responding – constitute fast prolifera
ting cells such as skin, mucosa, intestinal e
pithelium, colon, testis etc.
• Late responding – have large no. of cells i
n the resting phase e.g. spinal cord, bladder
, lung, kidneys etc.
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41. Various Fractionation Schedule
Fractionated radiation exploits difference in 4R’s between tumors
and normal tissue thereby improving therapeutic index
• Types
Conventional
Altered
• Hyper fractionation
• Accelerated fractionation
• Split course
• Hypofractionation
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42. Conventional fractionation
• Division of dose into multiple spares normal tissue through repair
of SLD & repopulation of cells.
• Concurrently , fractionation increases tumor damage through reox
ygenation & redistribution of tumor cells.
• Hence a balance is achieved the response of tumor & early & late
reacting normal tissue.
• Most common fractionation for curative radiotherapy is 1.8 to 2.2
Gy
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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 eit
her 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
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50. Hyperfractionation
• the delivery of radiation in small-dose fractions( 2-3 times per day)
• aims to improve the therapeutic ratio, reducing the dose given in eac
h fraction, so as to reduce the late side effects while also permitting
an increased total dose to the tumor
• hyperfractionation provided the greatest benefit to patients with hea
d and neck cancer
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51. Hyperfractionation
• A hyper fractionated schedule of 80.5Gy/70(1.15Gy twice/da
y)/7wks compared with 70Gy/35/7wks in head & neck cance
r.
• Implications
• Increased local tumor control at 5yr from 40 to59%
• Reflected in improved survival
• No increase in side effects
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52. Accelerated Treatment
• Alternative to hyper fractionation
• Rationale – To reduce repopulation in rapidly proliferating tum
ors by reducing overall treatment time.
• Pure accelerated treatment – same total dose delivered in half th
e overall time by giving 2or more s/day. but it is not possible to
achieve as acute effects become limiting factor.
• Impure accelerated treatment – dose is reduced or rest period is
interposed in the middle of treatment.
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53. Types of accelerated fraction
• Comparison of head & neck cases accelerated regimen 72Gy
/45 (1.6Gy,3/day)/5wks with 70Gy/35/7wks
• Implications –
• 15% increase in loco regional control
• No survival adv.
• Increased acute effects
• Unexpected increase in late complications
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54. CHART
(Continuous Hyperfractionated RT)
With CHART treatments 6hrs apart delivered 3times a day,7daya a
wk. with dose of 1.5Gy, total dose of 54Gy can be delivered in 36 o
ver 12 consecutive days including weekends.
Characteristics
– Low dose
– Short treatment time
– No gap in treatment, 3/day at 6hr interval
Implications
– Better local tumor control
– Acute reactions are brisk but peak after treatment is completed
– Dose small hence late effects acceptable
– Promising clinical results achieved with considerable trauma to
pt.
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55. Split-Corse
• Total dose is delivered in two halves with a gap in b/w with inter
val of 4wks.
• Purpose of gap is
 to allow elderly pts. to recover from acute reactions of treatm
ent
 further morbidity who have poorly tolerated or disease progre
ssed despite treatment.
• Applied to elderly pts. in radical treatment of ca bladder & prost
ate & lung cancer.
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56. 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.
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