LONG TERM TOXICITIES AND QUALITY OF LIFE AFTER RADIATION TO CENTRAL NERVOUS SYSTEM

2. INTRODUCTION
 Radiobiological perspective
 Acute toxicity: within days to weeks after radiation
 Early delayed toxicity : within 1-6 months postirradiation
 Late toxicity : >6 months post irradiation
 Clinical Perspective : RTOG defined
 Acute toxicity : <90 days post radiation
 Late toxicity : >90 days post radiation
Front Oncol. 2012; 2: 73.

3. RISK FACTORS FOR LATE CNS TOXICITIES
 Volume of normal brain tissue irradiated
 The total irradiation dose
 The fractionation schedule
 The use of concurrent medications
 Host variables :
 Age
 Use of concurrent or sequential chemotherapy
 Genetic factors

4. MECHANISMS OF CNS TOXICITY
POST IRRADIATION
 Photons to heavy charged particles produce toxicity in CNS
 Ionizing particles have physical ability to generate free radicals
that cause direct or indirect DNA damage
 CNS is particularly susceptible to metabolic stress
 Most accepted mechanism : double stranded DNA damage
leading to mitotic catastrophe

5.  But, this mechanism is more relevant in cells undergoing active
cell division
 CNS : limited mitotic potential so there is growing evidence to
suggest other mechanisms of radiation induced damage, which
includes
 Oxidation of lipid bilayer
 Changes in microvascular permeability
 Cell-cell junctional complex rearrangements and
 Mitochondrial alterations inducing additional oxidative stress
MECHANISMS OF CNS TOXICITY
POST IRRADIATION

6. OXIDATIVE STRESS
 Contribute to both acute and chronic radiation injury
 They produce Reactive oxygen species (ROS) which have
unpaired electron in shells, which are highly reactive
RADIATION
Hydrolysis of H2O
Increased ROS
RADIATION
Injury and inflammation (injured
endothelial cells, epithelial and
inflammatory cells)
Generation of reactive nitrogen
species (superoxide and nitric oxide )

7. Brain is highly susceptible to oxidative stress because
1. High rate of aerobic glycolysis
(Continual supply of ROS within mitochondria)
2. Relative to other tissue, glial cells and neurons contain
low levels of antioxidant system such as SOD, catalase,
glutathione peroxidase etc
3. Myelin membranes contain high levels of perodizable
fatty acids, making them exceptionally vulnerable to ROS
OXIDATIVE STRESS

8. CHANGES IN MICROVASCULAR
PERMEABILITY
 VEGF is the first growth factors upregulated during the
pathogenesis associated with late delayed effects
 It is intimately involved in the development of vascular
pathologies and white matter necrosis

9. Brain radiation
Upregulation of VEGF
Gradual depletion of vascular endothelial cells
Diminishes the integrity of BBB
Vasogenic edema, inflammation and tissue
hypoxia
Induction of HIF-1 alpha and VEGF
Exacerbates disruption of BBB, worsening edema,
inflammation and tissue hypoxia
Further increase in VEGF
Induce endothelial proliferation (angiogenesis)

10. Dramatic increase in endothelial cells – k/a
“conditional renewal”
This angiogenic response persists for
approximately 20 weeks
Ultimately fails to restore BBB integrity
Decline in number of endothelial cells
Eventually leading to white matter necrosis

11. THE PARENCHYMAL HYPOTHESIS OF
RADIATION INDUCED BRAIN INJURY
OLIGODENDROCYTES
Radiation
Loss of oligodendrocyte type 2 astrocyte (O-2A)
reproductive capacity
Demyelination and white matter necrosis

12. ASTROCYTES
(50% of total brain cells)
Radiation
Astrocytes – proliferation, hypertropic nuclei/cell
bodies and increased expression of glial fibrillary
acidic protein (GFAP)
Increased COX-2 and ICAM - 1
Aid the infiltration of leucocytes into brain viz BBB
breakdown

13. MICROGLIA
(12 % of total brain cells)
Radiation
Microglia becomes activated, characterized by rounding of
cell body, retraction of cell process and proliferation and
increased production of ROS, cytokines and chemokines
Neuroinflammation

14. NEURONS
 Once considered radioresistant population as they no
longer could divide, neurons have now been shown to
respond negatively to radiation
CHANGES IN NEURONS DUE TO RADIATION
 Neuronal receptors expression of immediate early gene
activity regulated cytoskeleton associated protein (Arc)
 NMDA receptor subunits
 Glutaminergic transmission
 Hippocampal long term potentiation
Important for synaptic plasticity and cognition

15. CLINICAL MANIFESTATIONS
 Acute : 1-6 weeks
 Fatigue
 Headache
 Seizure and
 Coma
 Cause :
 Secondary to
edema and
 Disruption of BBB
Front Oncol. 2012
 Early delayed
 Reversible symptons
 Generalized weakness
 Somnolence : transient
demyelination
 Late
 Irreversible neurological
consequences
 Minor to sever cognitive defects
 focal diffuse necrosis of brain
parenchyma

16. CLINICAL MANIFESTATIONS

17. LATE TOXICITIES
 Radiation necrosis
 Neurocognitive Dysfunction
 Endocrinopathies
 Cerebrovascular effects
 Migraine like headache Syndrome
 Effects on the eyes and optic pathways
 Ototoxicity
 Secondary Tumor Formations

18. RADIATION NECROSIS
 Typically develops 1 to 3 years after radiation
 Dose that causes 5% of radiation necrosis using conventional 2
Gy/# is usually estimated to be 72 Gy
 Increased risk with high dose/# and the use of concurrent
chemotherapy
 Location :Adjacent to the original site of tumor
 Symtoms
 Depend on the location of lesion
 Can include focal neurological deficits or symptoms due to
raised ICP

19. DIAGNOSIS: RADIATION NECROSIS
 Very difficult with conventional imaging
 Imaging features are entirely overlapping with high grade
glioma
 However, PWI : decreased CBV : rad necrosis and increased
CBW : tumor
 DWI : restricted diffusion : active tumor
 MRS : lipid peak : necrosis
 PET : increased FDG/methionine : tumor
 Ultimate diagnosis : biopsy

20. FOCAL RADIATION INJURY

21. DIFFUSE RADIATION INJURY

22. DIFFUSE NECRITIZING
LEUCOENCEPHALOPATHY

23. TREATMENT: RADIATION NECROSIS
 Usually it is self limiting process
 If symptomatic, steroid, T. Dexa 8 mg tds and the tapering
 No respone to steroid : Bevacizumab
• Bevacizumab @ 7.5 mg/kg 3 weekly for 2 cycle
• MRI done, if favourable response further 2 cycles
• And then MRI every 3 monthly for 24 months
• Concluded : bevacizumab stopped the progression of radiation
necrosis

24.  Surgical resection if diagnostic uncertainity
 Advantage : decreases mass effect
 Decreases post op steroid requirements

25. NEUROCOGNITIVE IMPAIRMENT
 High dose radiation : demyelination and vasculopathies
 Low dose exposure : cognitive dysfunction without obvious
morphologic changes
 Exact pathogenesis of radiation induced cognitive dysfunction
is unknown
 Recent studies suggest that impaired neurogenesis within the
subgranular zone (SGZ) of the dentate gyrus of hippocampus
 WBRT as low as 2 Gy are sufficient to reduce the rate of
proliferation among neuronal progenitor cells within the sub-
granular zone (SGW)

26. NEUROCOGNITIVE IMPAIRMENT
 Radiation induced cognitive impairment including
dementia occurs in 50-60% of adult brain tumor patients,
living > 6 months post irradiation
 Cognitive impairment is marked by
 Decreased verbal memory
 Spatial memory
 Attention and
 Novel problem solving ability
Front Oncol. 2012; 2: 73.

27. Radiation induced cognitive impairment occasionally progress to
dementia where patient experience
 Progressive memory loss
 Ataxia and
 Urinary incontinence
 Radiation induced dementia is a rare occurrence with
fraction size < 3 Gy
 However patients surviving more then 2 years after
fractionated whole brain irradiation are at increasing risk of
dementia over time
NEUROCOGNITIVE IMPAIRMENT

28. All these late sequel can be seen in the absence of the radiographic
or clinical evidence of demyelination or white matter necrosis
NEUROCOGNITIVE IMPAIRMENT
Front Oncol. 2012; 2: 73.

29. IMAGING FOR RADIATION INDUCED COGNITIVE
IMPAIRMENT
 Radiation induced cognitive impairment occur in the absence
of radiographic e/o gross anatomical changes
 CT, T1/T2 and MRI are not likely to provide information
relevant to the occurrence and progression of Radiation
induced cognitive impairment.
 MRI and PET have been used to evaluate Neurocognitive
impairment
 MRS utilizes MR scanner to identify and quantify metabolites
that reflect altered cellular properties in specific region of
normal brain tissue

30. TESTS FOR NEUROCOGNITIVE ASSESSMENT

31. ENDOCRINOPATHIES
 Hypothalamic and pituitary endocrinopathies – 80% of
patients post XRT that includes these structures
 Dose <20 Gy : may cause endocrinopathies
 Abnormal serum hormonal levels long before clinical
symptoms
 Screening
 Baseline endocrine evaluation in a year of RT
completion and annual blood to screen for HPA
dysfunction

32. Most common abnormality
 GH deficiency 35%
 Gonadotropin deficiency 25%
 Hyperprolactinemia, 24%
 ACTH 19%
 Hypothyroidism 16%
.
ENDOCRINOPATHIES

33. PITUITARY INSUFFICIENCY
 Prevalence of pituitary failure
 6% @ 1 year
 35% @ 2 year
 56% @ 3 year and
 62 % @ 4 and 5 year
 GH deficiency occurred at mean of 2.6 year
 Failure of pituitary gonadotropin and hyperprolactinemia after 3.8
years
 ACTH insufficiency after 6 years and
 Finally TSH insufficiency after a mean of 11 years
J LAB CLIN MED 109 : 364 - 372

34.  Included
 32 pts with brain tumor, 6 to 65 years
 f/u – 2 to 13 years, post crainial RT
 Dose of radiation : 40 -70 Gy and 9 pts : 18 to 39.6 Gy to C-S axis
 Results
 Thyroid deficiency : 9 pts, 28%
 Oligomenorrhoea : 7/10 postpubertal, premenopausal ladies, 70%
 Low serum testosterone, 3/10, 30%
 Hyperprolactinemia : 50%
 No endocrine abnormality : 3/32, 9%
NEJM 1993

35. CEREBROVASCULAR EFFECTS
 Children are more susceptible
 Vulnerable sites : supraclinoid region of ICA and Circle of
Willis
 Risk factors :
 Conc. Chemotherapy
 Young age
 Radiation dose
 Neurofibromatosis I
 Radiation field including Circle of willis (>10 Gy)
 Prevention
 Use of antiplatelet therapy
 Management of other Cardiovascular risk factors

36. MIGRAINE LIKE HEADACHE SYNDROME
 Reversible syndrome
 Focal neurologic signs and/or seizure lasting days to weeks
 SMART (Stroke Like Migraine Attacks After Radiatin Therapy)

37. EFFECTS ON THE EYES AND OPTIC PATHWAYS
 Cataract
 Presents with painless visual impairment 2 to 8 years
following RT
 Retrospective studies, TBI done for BMT, 10 Gy/single #
- 60% developed cataract
12 Gy fractionated dose : 43% cataract
 Strongly correlated with chronic use of steroids in these
patients

38.  Xeropthalmia
 If lacrimal gland > 30 Gy
 Retinopathy :
 Usually presents with painless loss of vision
 Months to years post XRT
 Unusual, <45 Gy
 Optic Neuropathy
 Presents with painless mono-ocular or binocular visual
impairment
 Usually begin between 6 to 24 months post irradiation
 < 55 Gy with 2 Gy/# : unusual
 3-7% with 55-60 Gy
 7-20% with >60 Gy

41. PREVENTION OF RADIATION INDUCED BRAIN
INJURY
 Reducing Oxidative Stress
 Reducing Chronic inflammation
 Use of Neuronal stem cells
 Advanced Radiation Techniques
 Pharmacological agents

42. PREVENTION OF RADIATION INDUCED BRAIN
INJURY
 Oxidative stress :
 Reactive Oxygen Species scavengers
 Anti-inflammatory agents
 ROS scavengers are given little attention as they are likely to
protect brain tumors to the same extent as they protect
normal brain

43.  Anti-inflammatory agents
 Anti-inflammatory peroxisome proliferative activated agonists
(PPAR). Eg. Pioglitazone
 Preclinical study
 Pioglitazone was give 3 days prior to, during and for 4 to 54
weeks after radiation to brain
 Assessed cognitve function at 52 weeks : reduced the
radiation-induced cognitive impairment
PREVENTION OF RADIATION INDUCED BRAIN
INJURY
Br.J.Radiol. 2007

44.  Chronic inflammation
 Brain Renin angiotensin system (RAS) is involved in
modulation of BBB, stress, memory and cognition
 Both Angiotensin Converting Enzyme inhibitors (ramipril)
and Angiotensin receptor blocker have been proved
effective in treating experimental radiation neuropathy
(Moulder et al 2003)

45.  Neurogenesis
 Use of various stem cell therapies to restore neurogenic
niche and improve cognition
 Rational :
Radiation
Decreased
hippocampal
neurogenesis
Cognitive impairment
PREVENTION OF RADIATION INDUCED BRAIN
INJURY

46.  Direct injection of NSCs into rodent brains after WBI partially
restores neurogenesis and hippocampal dependant cognitive
function
 Then NSCs not only diffrentiate into neurons, but also
oligodendrocytes, astrocytes and endothelial cells
 Study in human : lacking
PREVENTION OF RADIATION INDUCED BRAIN
INJURY
PROC NATL ACAD SCI USA
2009

47. •Hippocampal avoidance volume : 3.3 cm3
•Helical Tomotherapy spared the hippocampus with median dose
of 5.5 Gy and maximum dose of 12.8 Gy
•Linac based IMRT spared hippocampus with median dose of 7.8
Gy and maximum dose of 15.2 Gy
•Conclusion Modern IMRT techniques allow for sparing of the
hippocampus with acceptable target coverage and homogeneity.

48. HIPPOCAMPAL SPARING IMRT

49. USE OF PHARMACOLOGICALAGENTS FOR
RADIATION INDUCED COGNITIVE
IMPAIRMENT
 For symptomatic treatment several drugs have been evaluated
 Psychostimulants (METHYLPHENIDATE)
 Reversible Choline esterase inhibitors (DONEPEZIL)
 NMDA receptor antagonist (MEMENTINE)

50. PSYCHOSTIMULANTS
 Mechanism of Action : Dopamine reuptake inhibitor
 Dose : 10 mg twice a day
 Result
 Significant improvement in cognitive functions
 Functional improvements :
 Improved gait
 Increased stamina
 1 case : increased bladder control
 AE were minimal
 No increase in seizure frequency and
 Majority of patients required lower dose of steroids

51. REVERSIBLE CHOLINE ESTERASE
INHIBITORS
 Donepezil
 Trial by wake forest community clinical oncology
programme research base
 200 brain tumor patients
 Surviving > 6 months
Placebo Donepezil 10mg/day for 6
months
Significant improvement in energy
level, mood and cognitive functions

52. NMDA RECEPTOR ANTAGONIST
•Mementine
•Blocks ischemia induced NMDA excitation
•Neuroprotective if radiation induced ischemia occur
after WBRT

53. TRIAL BY RTOG
Dose : 20 mg/d, within 3 days of initiating
radiotherapy for 24 weeks
Primary end point : memory deficits
No preliminary results
Trial closed after accrual of 554 patients

54. QUALITY OF LIFE (QOL) AFTER CNS
IRRADIATION
 Quality of life is a concept that encompasses the
multidimensional well being of a person and reflects an
individual’s overall satisfaction with life.
 Dimensions of QOL
1. Physical or functional status
2. Emotional well being
3. Social well being

55. INSTRUMENTS TO MEASURE QOL
 Karnofsky performance status (KPS)
 Mini Mental Status Examination (MMSE)
 Brain tumor specific QoL : commonly measured using the
Funtional Assessment of Cancer Therapy – Brain (FACT-
Br)
 EORTC-QLQ-C30
 EORTC-QLQ-B20

56.  Generally correlates
with overall QoL
 Appears to have
prognostic value
KARNOFSKY PERFORMANCE STATUS (KPS)

57.  However Using KPS to measure QOL is problematic because
1. it is only a measurement of functional ability and
2. its reliability and validity depend on observer
KARNOFSKY PERFORMANCE STATUS (KPS)

58.  To overcome these problems other evlauation scales used
 MMSE
 Hopkins Visual Learning Test (HVLT)
 The COWA test
 Trail Making Test (TMT)
 RANO criteria
 Brain tumor specific QoL : commonly measured using
the Funtional Assessment of Cancer Therapy – Brain
(FACT-Br)
 EORTC-QLQ-C30
 EORTC-QLQ-B20
QOLASSESSMENT INSTRUMENTS

59. MMSE
 Originally designed to assess the stroke patients, has also been
used to assess Neurocognitive Function (NCF) in patients with
brain tumor.
 It tests broad range of cognitive function including :
 Oreintation
 Recall
 Attention
 Calculation
 Language manipulation and
 praxis

61. LIMITATIONS OF MMSE
 MMSE (Mini mental Status Examination) : validated for
other cognitive disorders and is relatively insensitive for
assessing Radiation induced cognitive impairment.
Limitations of MMSE
a. Does not avoid memorized learning from repeat testing
b. Is biased against patients with lower educational
background
c. Relatively insensitive to the subtle changes in brain
caused by brain radiotherapy

62.  Quick, repeatable measure of verbal learning and memory
12 words are spoken aloud to patient from different
category
12 already spoken words and 12 distractor words are
added, requiring yes/no question
(25 minutes later)
HOPKINS VERBAL LEARNING TEST

63.  5-10 minutes test
 Measures verbal fluency
 It places high demand on executive control process
 Patients are given 1 minute to spontaneously name
as many words as possible, beginning with
predetermined letter or same category
THE CONTROLLED ORAL WORD ASSOCIATION
(COWA) TEST

64.  THE TRAIL MAKING TEST (TMT) :
 Test of executive function, visual attention and task
switching
 The time taken to complete each task reveals the extent
of cognitive impairment
 GROOVED PEGBOARD TEST (GP) :
 Motor speed and dexterity
 Meyers et al Proposed a panel involving the HVLT, COWA
and TMT as a brief and highly sensitive test of global NCF

65. RESPONSE ASSESSMENT IN NEUROONCOLOGY
CRITERIA (RANO)
 RANO Criteria working group recommended a battery of
cognitive tests that included at least the HVLT, TMT and
multilingual aphasia examination and COWA

66. BRAIN TUMOR SPECIFIC - QOL
 Is commonly measured using the functional assessment of
cancer therapy – Brain (FACT – Br) questionnaire
 FACT – Br covers four primary QoL domains :-
 Physical well being
 Social/family well being
 Emotional well being
 Functional well being

67. ALTERNATIVES MEASURE OF QOL BY EORTC
 EORTC – QLQ – C30
 30 item questionnaire
 Multi item scales incorporating :-
 Five functional scales: physical, cognitive, emotional and
social
 3 symptoms scales fatigue, pain, nausea and vomiting
 A global health and QoL scale

68.  Remaining single items : assess for additional symptoms
commonly reported by cancer patients
 Dyspnoea
 Appetite loss
 Sleep disturbance
 Constipation and diarrhoea
 Perceived financial impact of disease and treatment

69. EORTC – QLQ – B20
 20 item questionnaire that is specific to brain related
symptoms
 Requires 10 minutes to complete
 The EORTC-QLQ-C30 and FACT-Br are the most widely
used cancer specific questionnaires in clinical trials
 FACT-Br Vs EORTC-QLQ-C30 :
Social support and
relationship
More weight on social
activities and family life

70. CONCLUSION
 Late term toxicities are increasing as survival of brain tumor
patients post radiation is increasing
 Once neurons, considered radioresistant, they have been shown
to respond negatively to radiation
 With advances in RT techniques and use of pharmacological
geents, there is hope for prevention of neurocognitive
impairment
 FACT Br and EORTC QLQ C30 are most widely used QoL
instruments all over the world

71. Thank YOU