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Management of high grade Brain Tumors
1. MANAGEMENT OF HIGH GRADE
BRAIN TUMORS
Dr. Abhilash G
JR-2 Radiotherapy
SRMSIMS
2. INTRODUCTION
Sixty percent of all primary brain tumours are
glial tumours, and two-thirds of these are
clinically aggressive, high-grade tumours.
3.
4. The treatment of high-grade gliomas involves
the multimodality approach of surgery, RT,
and chemotherapy.
In general, for GBMs, all three modalities are
used at initial diagnosis. For other high-grade
gliomas, the sequencing of these modalities
remains controversial.
5. Standard treatment consists of maximal safe surgical
resection followed by radiotherapy with concurrent
temozolomide chemotherapy and subsequent
adjuvant temozolomide chemotherapy.
GLIOBLASTOMA
MULTIFORMAE
(GBM)
6. INDICATIONS FOR SURGERY
Biopsy for diagnosis
Resection with definitive intent
Palliative debulking for management of mass
Shunting to relieve symptoms caused by
increased intracranial pressure or
hydrocephalus
Resection of recurrent disease in selected
patients
9. INDICATIONS FOR RADIOTHERAPY
Definitive treatment (with concurrent and
adjuvant chemotherapy) after resection or
biopsy.
Palliative treatment to primary or metastatic
foci.
RT usually started within 5 weeks of
definitive resection.
10. RADIOTHERAPY TECHNIQUES
EBRT using Conventional RT, 3D-CRT or
IMRT (WBRT or Partial Brain Irradiation)
Stereotactic radiosurgery (SRS)
Fractionated Stereotactic RT (FSRT)
Craniospinal Irradiation (CSI)
Interstitial brachytherapy may have a role in
selected patients.
13. SIMULATION
Computed tomography (CT)-based treatment planning with magnetic
resonance (MR) fusion is used for defining gross tumor volume (GTV)
and partial tumour volume (PTV)
14. CONVENTIONAL PLANNING
Planning fast , saves time
Only Conventional
Simulator needed
Even treatment is
delivered in lesser time
Disadvantages
Irradiation of large volumes of brain
Higher toxicity and side effects
Lack of 3D visualization of tumour
2D planning of 3D tumour
Advantages
17. 3-D PLANNING
Advantages
Ideal for all
Conformal
Max. sparing of normal
tissue
Lower toxicity
Disadvantages
Time consuming
Cost
Technical support
18. FIELD ARRANGEMENTS
Treatment should be delivered with multiple fields in an
attempt to achieve homogeneity throughout the volume and
to spare dose to uninvolved brain.
In general, parallel opposed portals are not used; however,
in cases where tumour is infiltrating across midline through
corpus callosum, this may be a very reasonable field
arrangement.
On-board imaging techniques with kV images or cone-beam
CT can be used for daily treatment verification and setup
adjustment.
19. NORMAL TISSUE TOLERANCE
Organs at risk (OAR) in RT of gliomas
include eyes, optic nerves, optic chiasm,
brainstem, cochlea, spinal cord, and perhaps
the pituitary/hypothalamus.
20. STEREOTACTIC RADIOSURGERY (SRS)
In LINAC radiosurgery circular or oval
collimators ranging from 4 to 40 mm are
used to collimate the treatment beam into a
circular pencil beam
Treatment is delivered using multiple
noncoplanar arcs that intersect at a single
point to treat an approximately spherical
target of <4 cm in diameter.
Newer miniaturized multileaf collimators
allow beam shaping
21. Radiation Therapy Oncology Group (RTOG)
study 90-05
Maximum tolerated dose of single faction
SRS
≤20 mm - 24 Gy
21 to 30 mm - 18 Gy
31 to 40 mm - 15Gy
22. FRACTIONATED STEREOTACTIC RADIOTHERAPY
For lesions larger than 4 cm and/or located in
critical regions, the delivery of a single large-
fraction treatment as in SRS is not desirable
because of a high risk of CNS toxicity.
Reported accuracy of 1 to 3 mm.
23. HEAVY CHARGED PARTICLES
A small number of European and Japanese centers
are treating CNS tumors with carbon ions, which
putatively have higher LET and presumed superior
RBE, but no substantial clinical data are available
to back these claims.
Neutron-beam irradiation, with or without co
administration of boronated agents to increase the
cross-sectional area of interaction, continues to be
used in some U.S. centers.
24. BRACHYTHERAPY AND RADIOCOLLOID SOLUTIONS
Selection criteria for brachytherapy include
- Tumour confined to one hemisphere,
- No transcallosal or subependymal spread,
- Small size (<5 to 6 cm)
- Well circumscribed on CT or MRI
- Accessible location for the implant.
25. A balloon-based system, GliaSite placed into
the cavity at the time of surgery has been
employed in the treatment of recurrent
malignant gliomas whose largest spatial
dimension is <4 cm and are roughly
spherical.
After treatment planning the balloon is filled
with a liquid that contains organically bound
iodine-125 (125I), and treatment is completed
within 3 to 7 days.
26. DIRECT DELIVERY OF AGENTS
CED involves the use of intracerebrally
implanted catheters to deliver a drug into the
brain parenchyma or tumor at a slow but
continuous rate of flow.
Examples of agents used in CED studies
include viruses, paclitaxel, topotecan, and a
variety of engineered, targeted protein toxins
27. BCNU impregnated in a polymer and made
into a wafer has been used for local delivery,
placed on the walls of the resection cavity at
the time of surgery. The wafer slowly
undergoes biodegradation, releasing the
active drug.
This local delivery system has the
advantages of minimal systemic toxicity, no
limitation posed by the BBB, and delivery of
very high local concentrations of
28. RADIOTHEAPY DOSE SUMMARY
Standard therapy is a total dose of 60Gy in 30-
33 #
A benefit for dose > 60Gy has not been
demonstrated.
Dose intensification using 3D CRT or IMRT has
not shown to improve clinical outcome.
RTOG 83-02 – Hyperfractionated regimens
showed no difference in medial survival.
RTOG 0023 – FSRT Dose escalation showed no
survival advantage.
29. CHEMOTHERAPY
Indications for chemotherapy
- Concomitant treatment with RT
- Adjuvant treatment after RT
- Mainstay treatment for salvage palliative
therapy
Temozolomide, an oral alkylator that crosses
the BBB, is the chemotherapy of choice in
glioma, and it significantly improves treatment
outcome in patients with GBM.
30. FDA approved carmustine and lomustine for the
treatment of brain tumors in the 1970s.
The only chemotherapeutic agent that has
demonstrated efficacy in a randomized, controlled
clinical trials is temozolomide, an oral
imidazotetrazine derivative of dacarbazine that is
metabolized in vivo to an active agent.
Approval for the treatment of recurrent anaplastic
astrocytoma was obtained from the FDA in 1999
31.
32.
33.
34. Methylation of MGMT promoter
improves survival following
adjuvant radiotherapy plus
temozolomide
MGMT methylation occurs in
approximately 1/3 of patients[1]
Median survival[2]
Methylation: 22 mo
No methylation: 15 mo
2-year survival[2]
Methylation: 46%
No methylation: 25%
1. Rosell R, et al. Future Oncol. 2008;4:219-228. 2. Hegi M, et al. N Engl J Med. 2005;352:997-1003.
Unmethylated
Analysis of 206 GBM patients in a
Phase III Study[2]
ProbabilityofOS(%)
100
80
60
40
20
0
6 12 18 24 30 36 42
Methylated
114 100 59 16 7 4 1
92 84 64 46 24 7 1
0
No. at Risk Months
Methylated
MGMT promoter
Unmethylated
MGMT promoter
P < .00110
50
30
70
90
MGMT Methylation and OS in GBM
36. BIOMAb EGFR as a therapy option for
GBM
STUDY TITLE
An Open Label, Prospective, Multicentric Study to
Evaluate the Safety and Efficacy of BIOMAb EGFR
(Nimotuzumab) as Induction and Maintenance
Therapy in Combination with Radiotherapy Plus
Temozolomide (Concomitant & Adjuvant) in Indian
Patients with Glioblastoma Multiforme
37. Concomitant Stage
Induction : Nimotuzumab 200mg weekly X 6 Weeks
+ RT once daily at 1.8-2Gy per fraction 5d/wk for a total of 54 - 60 Gy
+ TMZ 75mg/m2 daily X 6 weeks
After the Induction: Nimotuzumab 200mg administration once every 3 weeks to continue
Adjuvant Stage
Administration of TMZ begins 4 weeks after end of radiation therapy.
Maintenance BIOMAb-EGFR® (Nimotuzumab) 200mg once every 3weeks + adjuvant TMZ
150mg/m2 for Cycle 1 and 200mg/m2 for Cycle 2 to 6 (d1-d5 of 28-Day Cycle)
Maintenance Stage
Maintenance BIOMAb EGFR® (Nimotuzumab) 200mg once every 3 weeks till disease
progression or end of the study (2 years)
Follow-up Stage
No study drug will be given in follow-up stage. Tumor response will be evaluated every
three months using MRI till disease progression or the completion of five years from
enrollment, whichever is earlier
Study treatment plan
38. BIOMAb Study vs. Stupp’s Study
Parameter BIOMAb Study Stupp’s study
Overall Survival
(median)
14.1 Mo 14.6 Mo
Progression Free Survival
(median)
9.3 Mo 6.9 Mo
RPA Class III
Overall Survival Not Reached
(>24mo)
17 Mo
Progression Free Survival 20.8 Mo Not Reported
39. CONCLUSION
At median follow-up period of 27.1 months, Nimotuzumab in
combination with TMZ and radiotherapy reported:
mOS of 14.1 months
- mOS observed in RPA class III and Class V were better than median OS
observed in Stupp et al., (2009) study showing a possible median survival
benefit in these two RPA sub-classes III and V by the addition of
Nimotuzumab
mPFS of 9.3 months, whereas it was 6.2 months in the Stupp et al.,
(2009) study on TMZ with radiotherapy
Nimotuzumab in combination with standard of care was well
tolerated with a good safety profile
Addition of BIOMAb EGFR (Nimotuzumab) to the temozolomide based
chemoradiotherapy has an apparent progression free survival benefit and a
possible overall survival benefit in RPA class III and V without major safety
concerns
40. BEVACIZUMAB
- Based on an impressive radiographic
response rate in two nonrandomized, phase
II clinical trials, single-agent bevacizumab
was approved by the FDA in 2009 for the
treatment of recurrent glioblastoma
41.
42. RESULTS
The results of the phase III AVAglio trial were presented at the 49th
ASCO in the Central Nervous System Tumours Session by Professor
Wolfgang Wick, M.D., Professor of Neurology, Chairman of the Division
of Neuro-oncology at the Neurology Centre.
People who received Avastin plus radiotherapy and temozolomide
chemotherapy did not have a statistically significant improvement in OS
(the other co-primary endpoint), compared to those who received
radiotherapy and temozolomide chemotherapy plus placebo (HR=0.88;
[95% CI 0.76, 1.02], p=0.0987). Median survival was similar in both arms
(16.8 months versus 16.7 months, respectively) but significant
improvement in PFS (mPFS 10.6 months vs 6.2 months). Study
experienced 39% reduction in the risk of disease worsening or death.
Currently, AVASTIN is approved in 60 countries worldwide for treatment
of progressive GBM following prior therapy. No new safety findings were
observed in the AVAglio study and adverse events were consistent with
those seen in previous trials.
43.
44. Anti EGFR vIII vaccine in recurrent GBM
Ongoing clinical ‘vaccine’ trials against EGFR vIII (CDX-110 Indian centres participating)
45. CLINICAL PROGNOSTIC FACTORS
Age at diagnosis (>50 yrs poor prognosis)
KPS
Extent of resection
Duration of symptoms
Neurological status
46. FOLLOW UP
At least 25% of patients with high-grade gliomas
treated with RT and temozolomide will develop
pseudoprogression on the initial post treatment
images.
47. THE CURRENT STANDARD OF CARE FOR PATIENTS
WITH ANAPLASTIC GLIOMAS IS MAXIMAL SURGICAL
RESECTION FOLLOWED BY POSTOPERATIVE
RADIOTHERAPY. THE RADIOTHERAPY TARGET
VOLUME AND DOSE ARE THE SAME AS FOR GBM.
ANAPLASTIC
GLIOMA
48. INTRODUCTION
WHO grade III gliomas:
Anaplastic Astrocytoma
Anaplastic Oligoastrocytoma
Anaplastic Oligodendroglioma
25% of high-grade gliomas in adults
Young to middle adulthood
Without necrosis or neovascularisation
49. MOLECULAR GENETICS
Allelic loss of 1p and 19q is believed to be an
early genetic alteration in the transformation
and progression of oligodendrogliomas.
Deletions in 1p and 19p have been
associated with longer PFS and
chemosensitivity and radiosensitivity.
The prognosis for patients with anaplastic
glioma is heavily influenced by a number of
molecular genetic factors.
50. RTOG 94-02 – PCV f/b RT Vs RT alone
- RTOG reported survival benefit from the
addition of PCV chemotherapy in the 1p19q
codeleted subset with longer median survival
time (8.7 vs 2.7 years)
EORTC 26951 – RT f/b PCV Vs RT alone
- Patients with codeletions of 1p and 19q had
significantly longer OS irrespective of treatment,
and similar to the RTOG trial
1p19q codeletion is both a prognostic and
predictive marker.
51. MGMT PROMOTER METHYLATION
MGMT promoter methylation has
demonstrated prognostic significance for
anaplastic oligodendroglial tumours.
MGMT promoter methylation has not shown
similar predictive significance for outcome to
PCV chemotherapy in anaplastic
oligodendroglial tumours.
52. IDH 1 MUTATION
IDH1 mutations have been observed in 55% to
80% of grade II and III gliomas.
IDH1 mutations are frequently present in
secondary grade IV gliomas that develop from
lower-grade tumours.
EORTC 26951 observed IDH1 mutations in 46% of
patients and demonstrated prognostic significance,
independent of 1p/19q codeletion, in both arms of
the trial for both PFS and OS.
German Phase III trial - IDH1 mutations to be a
stronger prognostic factor than 1p19q codeletion or
MGMT promoter hypermethylation.
53. CHEMOTHERAPY
Significant toxicity and only marginal survival
benefit.
Use of chemotherapy - not universally
adopted
Phase 3 studies are currently enrolling
patients to more clearly define the role of
chemotherapy for patients with anaplastic
astrocytoma, or non-codeleted anaplastic
gliomas.
For codeleted subset of anaplastic gliomas,
chemotherapy is now considered “standard
56. INTRODUCTION
Brainstem gliomas account for 15% of all
paediatric brain tumours but are rare in
adults.
DIPG – High grade astrocytomas or GBM
Focal, Dorsally exophytic or cervicomedullary
– Low grade
DIPG - Most challenging
Rapidly developing neurologic findings of multiple cranial nerve palsies
(most commonly VI and VII), hemiparesis, and ataxia, in combination
with MRI finding of diffuse enlargement and poorly marginated T2 signal
involving >50% of the pons. Most diffuse intrinsic pontine gliomas are
nonenhancing
57. TREATMENT
Corticosteroids may be necessary to manage
neurologic symptoms until treatment is
instituted.
Surgery is the treatment of choice for
operable lesions.
Involved field radiotherapy is the primary
treatment for infiltrating pontine gliomas
55.8 to 60 Gy using daily fractions of 1.8 to
2.0 Gy per day.
Chemotherapy has no established role
60. INTRODUCTION
The majority arise in the 20- to 40-year age group.
More frequently located laterally than those in childhood
(50% vs. 10%), and are more frequently desmoplastic.
Homer Wright rosettes (clustered cells surrounding a central
eosinophilic core) are characteristic.
CSF dissemination may manifest as positive cytology.
Systemic spread is seen in approximately 5% of patients,
mostly to bone and bone marrow.
61. TREATMENT
Complete resection if feasible.
Postoperative radiotherapy should begin within 28 to 30 days following
surgical resection.
Radiotherapy is delivered to the entire craniospinal axis. This is followed
by a boost to the entire posterior fossa using parallel-opposed portals or,
more commonly, posterior oblique fields or other multifield techniques to
spare the cochlea.
Adults treated for medulloblastoma with a mean dose to the whole brain
of 35 Gy have been shown to have long-term cognitive deficits.
The total dose to the posterior fossa should be 54 to 55.8 Gy.
62. Immobilization & positioning of a large target
area
Large & irregular shape of the clinical target
volume (CTV)
Multiplicity of fields
Inhomogeneity at the junctions between the
brain and spinal fields
Large number of critical normal structures
having direct bearing on the late effects in
these pediatric long term survivors.
CHALLENGES IN PLANNING
CSI
63. POSITIONING
PRONE:
It provides direct visualization of the field
junctions on the patient.
Good alignment of the spine.
SUPINE
Comfortable.
Useful in anesthesia(in < 7yr age gp)
64. IMMOBILIZATION
Prone position of patient
Arms by the side on a CSI board CSI
board(shoulders in low position if possible)
Lucite base plate with a sliding semicircular
Lucite structure for head-rest & chin-rest.
Slots from A to E to
allow various degrees
of extension of neck
Alignment of the thoracic & lumbar spine parallel
to the couch (to confirm under fluoroscopy)
65.
66. RADIOTHERAPY PLANNING
Phase I
Two lateral cranial fields
1 or 2 spinal fields
Phase II: Posterior fossa boost
Two lateral cranial fields
Conformal technique in low risk
cases.
67.
68. CRITICAL ISSUES IN CSI
FIELDS
• Concern 1
Divergence of the upper border of the spinal
field in case of single spinal field(and
interdivergence of spinal fields in case of 2
spinal fields)
• Concern 2
Divergence of both cranial fields
69. Spinal field simulated first (get to know
the divergence of the spinal field)
SSD technique
2 spinal fields if the length is > 36 cm
Upper border at low neck
Lower border at termination of thecal sac
or S2 whichever is lower
In case of 2 spinal fields , junction at
L2/L3
71. FIXED OR CALCULATED GAP
SPINAL FIELDS
Use of fixed gap ranging from < 5 mm to
10mm between fields OR
Customized gap for each patient depending
on the field length & depth of prescription,
may be more appropriate
Spinal fields are simulated after gap
calculation.
Width - vertebral body + 1 cm to include the
intervertebral foramina, usually 5 to 7 cm.
76. SIMULATION-CRANIAL FIELD
Whole brain field is simulated & lower border is
matched with the superior border of spinal field.
AP width & superior border include the entire skull with
2 cm clearance.
Techniques for matching craniospinal fields.
Collimator/couch rotation
Half beam block
Asymmetric jaws
Penumbra generators
Wedge
Tissue compensator
84. SHIELDING
More important is what not to shield !
DO NOT SHIELD
Frontal (cribriform plate)
Temporal region
85.
86.
87. MOVING JUNCTION IN CSI
5mm overlap at 4mv photons 30 to 40%
overdose(14Gy for 36Gy prescribed dose) which
may exceed cord tolerance
(Hopulka, 1993, IJROBP).
Systematic error during radiotherapy delivery
could further lead to an overlap or gap.
Feathering after every 5 to 7 fraction smoothens
out any overdose or underdose over a longer
segment of cord.
91. POSTERIOR FOSSA BOOST
Borders
Anterior: Posterior clinoid process.
Posterior: Internal occipital protuberance.
Inferior: C2-C3 interspace.
Superior: Midpoint of foramen magnum &
vertex or 1 cm above the tentorium (as seen
on MRI).
Field arrangement
Two lateral opposing fields.
3DCRT boost to the preop tumor bed with
appropriate margins
94. SUPINE CSI PLANNING -
CONVENTIONAL
Positioning:
Supine with arms by the side of body.
Check spinal column alignment on
fluoroscopy.
Neck in near neutral position but slightly
extended.
Immobilization:
Thermoplastic mold for immobilization of
face & neck.
Close fit at the nasion.
Any constraint for the jaw is removed to
95. Step 1: Two lead markers by the side of the neck at the same laser level
97. Step A : Gantry taken through table and the upper border of spinal field matched
with the markers.
Step B: Two additional markers placed in the line of upper border
98. Step C: Collimation of the cranial field adjusted according to
the line joining the two markers on one side of the
neck(which is the divergence of the spinal field)
100. STEPS IN CT SIMULATION
Patient positioned using all ancillary devices and the spinal
columns aligned with the sagittal external laser.
Topogram taken to confirm spinal alignment
Three-point reference marks drawn on the mask in a
transverse plane at the center of the head with the aid of
the external lasers.
Two or three reference marks were placed on the posterior
skin surface along the spinal column(if prone)
Spiral CT images of 3-5 mm thickness are acquired.
A total of 130–170 images are reconstructed depending on
the patient’s height.
101. OPTIONS AFTER CT CUTS HAVE BEEN TAKEN
Virtual simulation
3 D CRT planning
IMRT techniques
Dynamic IMRT
Tomotherapy
Volumetric Modulated arc therapy/
rotational therapies
105. SUMMARY
Multiple options and techniques available for
treating brain tumors.
Need to use the optimum technique
Decision to be based on need of patient and
available technique
CSI demands intensive planning and
meticulous delivery
107. INTRODUCTION
Meningiomas account for approximately 30% of
primary intracranial neoplasms and are the most
common benign intracranial tumour in adults.
The peak age of incidence is in the sixth and
seventh decades. They are more common in
women.
Malignant varieties with invasive growth and
aggressive behaviour occasionally occur.
108. 2007 WHO GRADING CRITERIA
Benign (78-80%) – Grade I
Atypical (20%) – Grade II
Anaplastic /Malignant (3-5%) – Grade III
109.
110. Meningiomas are known to be induced by ionizing radiation,
with an average interval to diagnosis of 19 to 35 years,
depending on the dose of radiation.
They may be multiple in patients with NF2 and in non-NF2
families with a hereditary predisposition to meningioma.
The most common cytogenetic alteration in meningiomas
involves a deletion of chromosome 22.
Allelic losses of chromosomal arms 6q, 9p, 10q, and 14q
are seen in both atypical and anaplastic meningiomas.
113. GRADE III MENINGIOMAS
For atypical or malignant meningiomas, the
recurrence rate after surgery alone is high (41% to
100% at 5 years), even after complete surgical
resection, and postoperative irradiation after
maximal resection is recommended for all patients.
Systemic therapy has no defined role. Combined
chemotherapy with vincristine, Adriamycin, and
cyclophosphamide has shown some efficacy in
patients with malignant meningiomas.
114. UNRESECTABLE OR RECURRENT MENINGIOMA
In patients in whom aggressive surgery is not an
option, radiotherapy may relieve symptoms and
decrease the rate of tumour progression.
Various chemotherapy regimes combined
doxorubicin and dacarbazine or ifosfamide and
mesna.
Long-term, low-dose daily hydroxyurea may have
some activity
115. HORMONAL MANIPULATION
Hormonal manipulation, including tamoxifen
and the antiprogesterone drug RU486,
showed some activity in a SWOG phase II
evaluation of tamoxifen in unresectable or
refractory meningiomas.
However, a subsequent SWOG phase III
study of mifepristone for unresectable
meningioma was negative.
117. INTRODUCTION
Ependymoma accounts for only 1.8% of all adult
brain tumors.
Rosette formation is a hallmark of ependymoma on
pathologic specimens.
75% of ependymomas in the adult population arise
in the spinal canal and present with sensory
deficits.
Occasionally disseminate through the CSF.
118. TREATMENT
Maximal surgical resection, including second
surgery if necessary, is the initial treatment for
ependymoma.
54 to 59.4 Gy are typically prescribed.
Patients with neuraxis spread (positive MRI or
positive CSF cytology) should receive craniospinal
irradiation (40 to 45 Gy), with boosts to the areas of
gross disease and to the primary tumor to total
doses of 50 to 54 Gy.
