CNS radiobiology

1. Radiobiology and Dose Time
Fractionation for radiation of CNS
tumors
G . Lakshmi Deepthi

2. Radiobiology :
is the study of effect of radiation on living
systems.
CNS = Brain + Spinal cord
• Microscopic response of both tissue is same
• But the effects are different as the function and volume
are different

3. TARGET CELL
 No single target cell
 No single defined pathway of radiation induced
damage
Primary management of any brain tumor is by
surgery followed by radiation

4. Potential Target :
 Endothelial cells
 Oligodendrocytes

5. Vascular hypothesis :
Endothelial cell loss
Increased vascular permeability
Ischemia of the cell
Necrosis
• Time and dose dependent

6. Glial Hypothesis :
O-2A progenitor cells
Oligodendrocytes
Myelination
For :White matter selectivity of CNS
injury
Against : late onset of necrosis
No necrosis in demyelinating disease

7. • Time and dose dependent damage
• Recovery of O-2A progenitor cells time and dose dependent

8. CNS is highly integral in nature
 Relies on cell – cell interactions , hence response on
other cells important
Other cell types :
• Astrocytes
• Microglia
• Neurons
• Neural stem cells

9. Astrocytes :
 Modulating phenotype
 Most prevalent cell

10. Regulates biology of target cells in CNS
Survival Factors :
IGF1
CNTF
PDGF
terminally differentiated,
Myelinating oligodendrocytes
Growth Factors :
PDGF
FGF-2
CNTF
regulation of
proliferating , differentiating
And migrating activity of O-
2A progenitor cells

11.  Produces VEGF and angiotensinogen – regulates CNS
vascular permeability.
 Protects endothelial cells , oligodendrocytes, neurons
from oxidative injury
Post Radiotherapy :
• Increase in no of astrocytes -10-20%
• Gfap increased

12. Microglia :
• Post radiation- increase in number of microglia observed
• radiation-induced lesions through the production of
hydrolytic enzymes or oxygen radicals that could aggravate
primary lesions.

13. Neurons :
 Old hypothesis : not affected by radiation
 Now with increased survival – neurobehavioral sequelae
were observed ,
 Neurons are affected – apoptotic cell death occurs in the
interphase , as neurons do not divide –hence direct killing
of cells
 Doses in the order of 100000 rad are necessary to destroy
cell metabolism in non proliferating cell systems
Terminally
differentiated

14. Rodent Brain
 cytoskeleton-associated protein (Arc)
 N - methyl-D-aspartic acid (NMDA) receptor subunits
 glutaminergic transmission
 hippocampal long-term potentiation
• Necessary for synaptic plasticity and cognition
• Thus, subtle cellular and/or molecular changes in the
neurons themselves or subtle changes in the
association/communication between neurons and
astrocytes must play an as yet unidentified role in late
radiation-induced cognitive impairment.

15. Neural Stem cells:
Anterior Posterior
SUBEPENDYMA (SE)
NEURONS
ASTROCYTES
OLIGODENDROCYTES
Olfactory lobe
Striatum
Corpus callosum
neocortex

16. • Dose dependent loss of cellularity within SE
• High doses – loss of glial precursor
• Low doses – SE cells can repair—gradual restoration of
neuroglia
• Repopulation of SE studied using cell specific antibodies
• This repopulation was impaired in a dose dependent
manner up to 180 days after treatment .
Radiation

17. Blood Brain Barrier
 Brain tumors – BBB permeability 20% more than in
normal brain tissue
 malignant tumors produce angiostimulating factors,
which cause vascular proliferation with increased
permeability in and around the tumor .
 Radiation further disrupts this BBB
1. imbalance in the levels of the matrix
metalloproteinase-2 and the metalloproteinase-2 tissue
inhibitor
2. degradation of collagen type IV,
3. changes in the mRNA and protein expression of VEGF,
Ang-1,and Ang-2

19.  Increased paracellular permeability seen after 8 days of
radiation
 Studies suggests that, in order to increase the permeability of
the BBB by irradiation, a total dose of 20 to 30 Gy
 Irradiation will cause cell kill and may enhance the effect of
chemo therapy.
 Radiation-induced BBB disruption may be considered for the
treatment of primary brain tumors, e.g., gliomas, prophylactic
cranial irradiation in small cell lung cancer (SCLC) and
cerebral metastases.

20. CNS injury response :
 CNS lesions induced after radiation are not unique and
similar to those that occur after other types of injury.

21.  Direct cell death—seen in tumor,
cant be modulated
 Recovery process
protective cytokines :
1. RNAse
2. TNF-mediate antioxidant defenses and induces the
anti-apoptosis proteins Bcl2 and Bcl2l1
3. FGF-2-neuronotrophic--reduces generation of ROS
and protects neurons against mitochondrial
dysfunction. regulation of the proliferation and
differentiation of the O-2A progenitor cell
 Reactive process– oxidative stress

22. CNS – Oxidative stress:
 High rate of oxidative metabolism -2-5% of consumed
oxygen converted to superoxide & ROS
 Limited capacity for anaerobic glycolysis under hypoxic
conditions leading to increased mitochondrial production of
ROS
 Low levels of antioxidant defenses in oligodendrocytes ,
neurons, endothelial cells.
CNS environment is more conductive to this oxidative stress
due to high content of peroxidizable fatty acids with myelin
membrane—target for ROS.

23. DNA

24. Nature of CNS: sensitive or resistant?
 Cell survival after a single hit of radiation defines its
radio sensitivity.
Bergonie and Tribondeau Law :
The radio sensitivity of a tissue depends on:
 The excess amount of less-differentiated cells in the
tissue
 The excess amount of active mitotic cells
 The duration of active proliferation of the cells
 Cells like neurons which do not divide are the most
radioresistant.

27. CNS TUMORS
Late responding
target embedded
within late
responding
tissue
Late responding
target
surrounded by
late responding
tissue
early responding
target embedded
within late
responding
tissue
early responding
target
surrounded by
late responding
tissue
AVM Meningioma Low grade
Glioma
Metastasis
GBM
Larson et al.
1992

28. TIME :
 Overall duration deliver a prescribed dose
 With increase in treatment time , the dose has to be
increased to counteract the tumor repopulation.
 Conventional : 5-6 wks
 Short duration : poor KPS
palliatve treatment
small tumors

29. Tumor doubling time
 Medulloblastoma – Ts -7-10hrs
Tp – 25-82 hrs
Actual doubling time – 24days
 Glioblastoma :
pre treatment doubling time – 49 days
treatment doubling time -2-17days
protracted radiation schedules can be compromised from
tumour repopulation in tumours such as GBM with rapid
doubling time

30. DOSE :
 Amount of radiation energy absorbed from a beam of
radiation
 Radical dose : to achieve tumor lethal dose
 Factors :Radio sensitivity
Size of treatment volume
Dose limiting structures

32. Volume
 Sheline,1975 – same median survival
 Fossati et al,1979 – improved median survival
 Payne et al,1982– same benefit
Before 1970 After 1970
Decreased
toxicity

33. GBM
BTSG 6601 6901 7201
50Gy (CF)
55Gy(CF)
60Gy (CF)
No RT 18 weeks
28 weeks
35 weeks
42 weeks

34. Dose limiting structures :
 Leibel and Sheline –brain necrosis
dose incidence
<57.6Gy 0%
57.6-64.8Gy 3.3%
64.81-75.6Gy 17.8%

35. Fractionation :
1930’s – conventional preferred
Linear Quadratic
Model
BED = nd (1+d/αβ)
Hyperfractionation
<1.8Gy/#
Hypofractionation
>2.5Gy /#
Accelerated
Fractionation

36. Conventional Fractionation :
 1.8-2Gy/#
Advantage :
• Repair of normal tissue
• Re-assortment of the cells to radiosensitive G2 and M phase
• Repopulation of surviving tumor stem cells during
fractionated radiotherapy
• Reoxygenation of hypoxic tumor cells

37. Importance of Oxygen :
Neoplastic cells- faulty
angiogenesis
Hypoxia of tumor cells
Migration of tumor
cells closer to normal
blood vessels
(+)

38.  Fractional doses smaller than conventional, given 2-3
times daily, to achieve an increase in the total dose given
in the same overall time as CF.
Rationale :
 greater sparing for late responding tissues.
 Oxygen enhancement ratio (OER) seems to be lower at
low doses per fraction, tumor radio resistance due to
hypoxic cells should be less important with HF
Hyper fractionation :

39.  Doubling the no of #/day over same treatment time –
better tumor control with less side effects
 12% increase in BED to tumor
 5% decrease in toxicity to normal brain
Trials :
 BTCG 77-02 – 66Gy – 1.2Gy/# twice a day
 RTOG 8302 – HF (up to 81.6Gy) or AHF(54.4Gy)
 RTOG 9006 -72Gy-1.2Gy/#, twice a day
• No statistical significant difference in terms of
survival in Malignant Glioma
• Increased toxicity seen in hyper fractionation arm

40. Accelerated Fractionation :
 Decreasing treatment time
 Reduce tumor repopulation
 Better cell cycle redistribution
 No increase in survival or toxicity
 Benefit patients with fast growing tumor
pot doubling time < 4days
• RTOG 9411 -64Gy & 70.4Gy -1.6Gy/#, twice a day
• On comparison with retrospective data ,no difference in
median survival time

41. GLIOMA – Accelerated Fractionation
• None of the studies reported a significant
improvement in survival by altered fractionation
• Doses of 60–70 Gy do not appear to improve
survival compared to 50–60 Gy

42. Brainstem Glioma- Hyperfractionation
• Packer et al. -72 Gy >64.8 Gy. However, the updated results
showed a fairly lower 2-year survival rate (14% vs.
previous 22%).
• Obtaining 2-year survival of 6-23% without statistically
significant difference between arms

43. Brain Metastasis :
 Accelerated fractionation or hyperfractionation ---
convenient alternative to more conventional
fractionation schedules for palliation.
Authors
(n)
Dose
/#
#/d
ay
Total
Dose
Time Tumor response Side
effects
Franchin et
al
1.6
2
3
1
48Gy
40Gy
MST – 21wks
16wks
Murray et
al (429)
HF vs. AhF
1.6
3
2
1
54.4Gy
30Gy
3.5
2
1 yr OS 19% in HF
vs. 16% in AhF.
OS same
Similar
• Biti et al : accelerated fractionation -30Gy/3# per day /5days
good palliation >85% of cases

44. High radio-resistance of malignant
gliomas ?
 The presence of a significant fraction of hypoxic tumor
cell
 The high proportion of the clonogenic malignant cells
and their rapid turnover rate
 A supposed high repair capacity from sub lethal or
potentially lethal damage ,
Hypoxic cells are more radio resistant than
well oxygenated cells and the presence of such oxygen
deprived cells may represent one major reason for failure
to control tumors with RT
 Potential doubling times ranging from 2 to 17 days in
glioblastoma.

45. Hypo fractionation—tumor Doubling
Time :

46. Hypo fractionation:
 >2.5 Gy per fraction and above
 High dose is delivered in 2-3# / wk
 Rationale
◦ Treatment completed in a shorter period of time..
◦ Higher dose /# gives better control for larger tumors.
◦ Higher dose /# also useful for hypoxic fraction of
large tumor.
 Disadvantage :
◦ Higher potential for late normal tissue complications.

47. Author Dose outcome
Thomas et al(n=38) 30Gy/6#/2wks MS=6months,1yr survival -23%
No significant toxicity
McAleese et al(n=92) 30Gy/6#/2wks MS=5 months
1 year survival=12%
No significant toxicity
Chang et al(n=59) 40Gy/16# f/b 10Gy/4# MS=7 months
(poor prognosis sub-group) No
significant toxicity
Lutterbach et al Retrospective
(n=550)
42Gy/16# MS=7.3 months,2 year survival-26%
No significant toxicity
Kleinberg et al Retrospective(
n=219 )
30 Gy/10#—Phase 1
21 Gy /7#—Phase 2
MS=13, 8, 5 months in RPA IV, V,
and VI, respectively
No significant toxicity
Roa et al - RCT
(n=100 )
40 Gy/15# vs. 60
Gy/30#
MS of 5.6 months with HFRT vs. 5.1
months with conventional RT
No significant toxicity
Hulshof et al RCT
n=155
40 Gy/5 #—3# per week
28 Gy/4 #—2 to 3# per
week
MS of 5.6 months –40Gy
6.6 months -28 Gy arms,
No significant toxicity
All studies have showed equivalent
survival with no significant toxicity

48. • the median overall survival:
6.8 months --25 Gy in 5 fractions
6.2 months --40 Gy in 15 fractions,
which is not statistically different.
• A short-course RT regimen of 25 Gy in 5 fractions is an
acceptable treatment option for patients over 65 years old,
mainly for those with poor performance

49. SRS (Stereotactic radiosurgery ):
 delivery of a single high dose of irradiation to a small
and critically located intracranial volume through the
intact skull
Rationale :
 Limit repopulation
 No reoxygenation or reassortment
Mechanism :
DNA damage  cell death
endothelial cell apoptosis  cell death

51. Death of endothelial cells
Increased vascular permeability
Plasma extravasation, stasis of blood in cells
Increased interstitial fluid pressure
Vascular collapse
Death of parenchymal cells

52. High grade gliomas :
hypofractionation = conventional
 40Gy/15# + TMZ = 60Gy/30# + TMZ
similar survival
 SRS has shown equivalent benefit in small recurrences
 It was not done upfront in these tumors in view of the
large size and the infiltrative nature
Vestibular schwanoma:
- Slowly proliferative ,hence not responsive to
conventional
- SRS = Fractionated Stereotactic radiotherapy
- Dose -12-13Gy
- Local control -95-97% . PFS > 90%

53.  Pituitary Adenoma : 45-50.4Gy --- 1.8Gy/# preferred
 risk of structural damage due to such treatment is <1%
 SRS -higher tumour cell kill however leads to
unacceptable normal tissue toxicity if it affects critical
regions such as optic chiasm,cranial nerves.
 SRS is suitable only for small lesions located away from
critical structures, and the optic apparatus should not
exceed single doses above 10Gy

54.  Meningioma :
Disease of the elderly
Hypo fractionation decreases burden on the patient
REGIMEN DOSE LOCAL CONTROL
Conventional 50.4Gy/28#/5.3wks 94%
Hypofractionation 25Gy/5#/1wk 94%
SRS 12.5Gy 91%
No significant difference in the radiographic and clinical response

55. Paraganglioma :
 45-50Gy/25-28# preferred
 Hypofractionation and SRS provides equal tumor
control with less necrosis and less secondary tumors
Craniopharyngioma :
 50-54Gy (1.8Gy/#)
 Least complications(visual loss1-1.5%)
 SRS can be used in small or recurrent tumors if tumor
size <3cm and about 3-5mm away from optic apparatus

56. SRS Dose constraints :
 Necrosis –occurs 1-2yrs after treatment
2cm -- 24Gy
2-3cm – 18Gy
3-4cm – 15Gy
If volume of brain >12Gy is in the region of either
temporal and occipital lobe ,there are high chances of
necrosis.

57.  Brainstem – dose >15Gy – cranial nerve complication
 Optic nerve/chiasm : Dmax-10Gy
Dose RION risk
<10Gy 0-2%
>12Gy high
>15Gy 78%
 Spinal Cord
10Gy- 10% of cord volume
Dmax-spinal cord- 14Gy
cauda equina – 16Gy

58. Brachytherapy :
 greater than 80% of glioma recurrences are within 2 cm
of the site of origin,
 Placement of radioactive isotopes of iodine-125 in tumor
volume
 Dose rate :range of 1 cGy/min or less.
 The desired dose is therefore delivered over a few days
or a few months, depending on the activity of the
radioactive sources used. This is called ‘low-dose rate
irradiation’.

59. Radiobiology :
 Continuous low dose rate –
re-assortment of tumor cells
to G2 and M phases
 The continuous low dose rate caused less biologic effect
(sub lethal damage) which can be repaired efficiently in
normal tissue leading to less damage

60. Complications :
Acute :hemorrhage , poor wound healing
Early delayed: raised ICT
Late delayed :volume loss secondary to atrophy
frank radiation-induced necrosis
delayed occlusion of both large and small
arteries resulting in progressive neurologic decline and
large arterial infarcts
failed to show a significant survival advantage

61. Problems in brain radiotherapy :
Late toxicity
High local
recurrence
No role of
altered
fractionation
Hypoxia

62. Increasing Therapeutic Ratio :
DNA Damage :
Chemotherapy
Halogenated pyrimidine's
Hypoxia :
Hypoxic Cell Sensitizers
Hyperbaric Oxygen
Repair :
High LET

63. Chemotherapy -Radio sensitizers :
Temozolamide :
• alkylating agent
• microscopic disease outside the radiation field (spatial
cooperation)
• increases the radiation effects (radiosensitisation)
• the modalities have different toxicity profiles (toxicity
independence)
• selectively active on glioma cells with low amounts of AGT
(protection of normal tissues).

64.  methylation at the N7 position of guanine
O3 position of adenine
O6 position of guanine

65. EORTC.2009
RT alone RT + TMZ
Median survival 12.1months 14.6months
2yr survival 6% 26%
5yr survival 1.9% 9.8%
Stupp et al. 2005

66. Halogenated Pyrimidine's :
 5-bromodeoxyuridine (BUdR) and 5iododeoxyuridine
(IUdR)
 preferential incorporation into actively dividing
neoplastic cells rather than the slower replicating glial
and vascular cells of the normal brain.
 Mechanism :these incorporated halogenated
deoxyuridines react with radiation-induced hydrated
electrons to form highly reactive uracilyl radicals and
halide ions which enhance radiation-induced single- and
double- strand DNA breaks.

67. • Sensitizer enhancement ratios of 1.5-3.0 have been
observed.
• Studies :anaplastic astrocytoma and GBM --have
shown no significant benefit
• The San Francisco group :Anaplastic astrocytoma
increase in the median survival –
82(historic controls) to 252wks (BUdR)

68. Hypoxic Cell Radio sensitizers:
 Hypoxic tumor cells have been estimated to be 2-3 times
more resistant to radiation than well oxygenated cells
• Misonidazole,
• Metronidazole
• Benznidazole
• Etanidazole,
• Pimonidazole
• Nimorazole,
• Ornidazole
• Rsu1069

69. Randomized Control Trials :
combined with radiotherapy or chemotherapy failed to show
any survival benefit

70. Hyperbaric oxygen :
 normal brain tissue, oxygen is observed at approximately 25–
50 mmHg
 Brain tumours- oxygen transport is seriously hindered leading
to local hypoxic regions.
 Application of HBO increases oxygen transport via blood
plasma, independently from transport via haemoglobin
 the oxygen level can rise by as much as 100–115 % upon HBO
exposure

71.  Chang et al – Glioblastoma
36Gy/12#/3wks
60Gy/30#/6wks
 Problems : radiation necrosis and seizure
 Optimal time : 15 mins before RT
that the higher oxygen pressure in the tumour
lasted only for a short time after oxygenation
 High cost and difficulty of widespread approach -
impractical
Median survial >18months survival
RT alone 31wks 10%
HBO fb RT 38 wks 28%

72. High LET radiation :

73. Protons :
 The RBE of protons is only marginally better than that
of cobalt-60 gamma rays with a similar oxygen
enhancement ratio.
Bragg peak

74. • Protons has exactly the same biologic effects as X-rays...RBE is 1.1
• only diff lies in the physical properties of the beam and not in the
biologic effects in tissue.
Chordoma And Chondrosarcoma : (Dose – 70-76Gy RBE)
• Five year PFS 100% for chondrosarcoma and 77% for chordoma
• 5-year OS was 100% for chondrosarcoma and 81% for chordoma
Habrand et al.

75. Ependymo
ma
Medullob
lastoma
Cranioph
aryngiom
a
Low
grade
glioma
• Macdonald et al
• Amsbaugh et
al-51.1Gy
• Preserve hearing
• Neuroendocrine
• Neurocognitive
• Similar tumor control
Merchant et al.
Boehling et al.
Luu et al.
Laffond et al
Better spares
• Cochlea
• Hypothalamus
• Brain /temporal lobe
• Better neurocognition
Zhang et al
Perez et al
Clair et al
Moeller et al
• Less dose to structures beyond vertebral body
• Less risk of premature ovarian failure
Fuss et al.
• Better Optic
nerve sparing

76. Boron Neutron Capture
Therapy(BNCT) :
 Boron containing chemicals will be preferentially be
taken up by tumor cells as opposed to normal cells
 This energy is deposited at a short distance
 Supports vascular theory of brain damage

77. Radiobiology:
 low LET gamma rays, resulting primarily from the
capture of thermal neutrons by normal tissue hydrogen
atoms
 high LET protons, produced by the scattering of fast
neutrons and from the capture of thermal neutrons by
nitrogen atoms
 high LET, heavier charged alpha particles and lithium-7
ions, released as products of the thermal neutron capture
and fission reactions

78. CNS TUMORS
Late responding
target embedded
within late
responding
tissue
Late responding
target
surrounded by
late responding
tissue
early responding
target embedded
within late
responding
tissue
early responding
target
surrounded by
late responding
tissue
AVM Meningioma Low grade
Glioma
Metastasis
GBM
SRS Hypofractionated or
conventional conventional
Hypo# or
Conventional
or SRS

79. NORMAL TISSUE TOXICITY :
Tolerance depends on
 volume,
 total dose,
 dose per fraction,
 duration of irradiation.

81. Spinal cord :
Early-delayed Myelopathy
 Transient demyelination due to damage of schwann cells
 Lhermitte’s sign
Late delayed :
 Spinal cord necrosis
 Spinal myelopathy-6months – 10yrs
 Spinal haemorrhage – 6-30yrs , radiation induce
telangiectasias are the likely cause of hemorrhage.
DOSE RISK OF MYELOPATHY
50Gy <1%
60Gy 6%
69Gy 50%

82. Normal Structures
SERIES
 Spinal cord
 Brainstem
 Brain
 Optic pathway

83. Emami et al.1991
ORGAN TD 5/5
1/3
TD5/5
2/3
TD5/5
3/3
TD 50/5
1/3
TD50/5
2/3
TD50/5
3/3
Endpoint
Brain 60Gy 50Gy 45Gy 75Gy 65Gy 60Gy necrosis
brainstem 60Gy 53Gy 50Gy - - 65Gy necrosis
Optic
nerve
- - 50Gy - - 65Gy blindness
Optic
chiasma
- - 50Gy - - 65Gy blindness
lens - - 10Gy - - 18Gy cataract
retina - - 45Gy - - 65Gy blindness
Spinal
cord
5cm
50Gy
10cm
50Gy
20cm
47Gy
5cm
70Gy
10cm
70Gy
20cm
65Gy
Myelitis
necrosis
Cauda
equina
- - 60Gy - - 75Gy Nerve
damage

84. QUANTEC :

85. Hippocampus :
 Dmean <9Gy
 Dmax <16Gy

86.  relatively modest doses of radiation cause apoptosis and
a sharp and prolonged decline in neurogenesis in the
subgranular zone
 compartmental cell loss is associated with the extinction
of short-term memory,
 neurogenesis is also inhibited by inflammation in the
area surrounding the NSCs
 that sparing the hippocampus could yield clinically
significant neurocognitive benefit
avoiding the hippocampus, focusing on the dentate gyrus
and cornu ammonus, rather than comprehensively
avoiding the entire limbic circuit

87. Acute radiation Syndrome :
 Cerebrovascular syndrome with doses>100Gy
 Death occurs in 24-48hrs before damage of other
systems can be expressed
 Cause : exact unknown
damage to microvasculature
increase in fluid content of the brain due to leakage of
small vessels
build up of pressure

88. Conclusion :
 Understanding the radiobiological effects of radiation on
normal and neoplastic tissue is the key to its proper use
 So far , altered fractionation schedules have failed to show
any significant survival benefit in brain tumors
 The dose and fractionation being prescribed to any tumor
should be done with respect to its nature ,radio sensitivity and
tolerance of nearby structures.
 Ultimately the genetic and molecular basis of radiation
resistance must be investigated further for better outcome
with radiation

89. Thank You...