Low-grade gliomas are slow-growing brain tumors that originate from glial cells. They account for about 20% of gliomas and 10% of primary brain tumors in adults. Key points in the management of low-grade gliomas include maximal safe surgical resection followed by radiation therapy to improve progression-free survival. Important molecular markers include IDH1/2 mutations, 1p/19q codeletion, and BRAF alterations. Close monitoring with MRI is important to detect progression or possible radiation necrosis. The goals of treatment are to prolong survival while maintaining quality of life with minimal side effects.
2. Introduction
WHO Classification
Epidemiology & Risk Factors
Molecular Markers
Clinical Presentation
Diagnostic workup
Surgery
Radiotherapy
Chemotherapy
Follow up
3. GLIOMAS
• A glioma is a primary brain tumor that originates from the supportive cells of the
brain, called glial cells.
• Three types of glial cells are there, from which gliomas arise.
• Astrocytes: Astrocytoma
• Oligodendrocytes: Oligodendroglioma
• Ependymal cells: Ependymoma
4. WHO Grading System (evolves)
Low-grade
o WHO Grade I i.e., Juvenile Pilocytic Astrocytoma
o WHO Grade II i.e., Diffuse Astrocytoma
High-grade
o WHO Grade III i.e., Anaplastic Astrocytoma
o WHO Grade IV i.e., Glioblastoma Multiforme
5. For grading points which are to be considered :
Nuclear atypia
Number of mitoses
Necrosis
Endothelial proliferation
7. WHO GRADING
Tumour grade as a prognostic factor was based on histological features.
It is one component of a set of criteria used to predict response to therapy and outcome.
Molecular parameters provide powerful prognostic information in addition to that provided
by histological grade.
Other criteria include:
- Clinical findings (e.g. patient age, performance status, and tumour location)
- Radiological features (e.g. contrast enhancement)
- Extent of surgical resection
- Proliferation index values
- Genetic alterations
8. • Low-grade gliomas are generally slower-growing tumors that are divided into
pilocytic and nonpilocyitc subtypes.
• They account for 20% of gliomas and 10% of primary intracranial tumors in
adults.
• Median survival between 4.7 to 9.8 years
• Goal – Prolong OS while maintaining good quality of life.
LOW GRADE GLIOMA
15. 1p/19q CODELETION:
Loss of the short arm of chromosome 1 (1p), along with the long arm of
chromosome 19 (19q); "genetic signature" of oligodendrogliomas.
80% to 90% in oligodendrogliomas (WHO grade II)
Partial loss of chromosome 1p in oligodendrogliomas has an opposite prognostic
significance when compared with tumors that have a complete 1p/19q loss
Almost all oligodendrogliomas with a 1p/19q codeletion are also positive for
IDH1 or IDH2 mutations.
The CIC gene (encoding for protein capicua homolog) is a tumor suppressor gene
present in Chr 19.
Loss of CIC gene loss of transcription repressor function.
16. • The first allele is lost (1st Hit) due to an imbalanced reciprocal translocation between chromosomes 1 and 19
• The second allele is disrupted (2nd Hit) by a somatic mutation capable of inhibiting protein function
• Co-deletions (ie, 9p or 10q loss) may lead to poor outcome independent of the 1p/19q status
17. IDH mutations disrupts chromosomal topology and allows aberrant
chromosomal regulatory interactions that induce oncogene expression
(such as PDGFRA).
Astrocytomas that show IDH 1/2 mutation have a favourable course from
wildtype tumors that have a less favorable course and exhibit more
aggressive clinical behaviour.
IDH-
Mutation
18. In IDH wildtype tumours, a genotype of 7q gain and 10q loss is associated
with worst outcome.
IDH1- mutant grade 4 astrocytomas show higher sensitivity to radiotherapy
and concurrent chemotherapy in than in those with IDH1-wildtype
Glioblastoma.
R132H mutant IDH1 IHC has become an invaluable diagnostic adjunct in the
distinction of diffuse glioma from reactive gliosis.
R132H
IDH1
19. Ki-67
Prognostic marker among grade II & III diffuse gliomas.
Results expressed as percentage of positive staining cells.
Ki-67 is a nuclear antigen expressed in cells actively engaged in the cell cycle but
not expressed in the resting phase G0.
Among grade II and III diffuse gliomas, the Ki-67 index provides prognostic value,
as there is strong inverse relationship to survival on multivariat analysis.
Helpful in determining grade in histologically borderline cases.
20. TP53
Diagnostic marker among gliomas.
TP53 mutation is a marker of astrocytoma lineage in the setting of IDH mutation
and occurs in infiltrative astrocytomas,grade II;anaplastic astrocytomas,grade
III; and GBM,WHO grade IV.
Extremely rare in Oligodendrogliomas with IDH mutation and 1p/19q
codeletion.
21. BRAF / KIAA1549 FUSION :
Part of the mitogen-activated protein kinase (MAPK) pathway
Serine/threonine kinase, modulates cell proliferation and survival
Ingliomas: BRAFactivation is by gene duplicationor point
mutation
Fusion between the KIAA1549 and BRAF genes
Identified in 60% to 80% of pilocytic astrocytomas
RAF inhibitors (vemurafenib and dabrafenib)
Interphase FISH: currently the best method for testing for this fusion
IHC : anti-BRAF V600E (VE1) antibody
22. Risk Factors
Factors associated with an increased risk of glioma
Exposure to high dose radiation,
Increasing age
Hereditary disorders such as: Li-fraumeni syndrome &
NeuroFibromatosis type 1.
Mobile phones …..????
23. • Epilepsy (65%-95%)
• Headache(40%)
• Normal neurological examination
• Focal neurological deficits
• Papilloedema
• Neuro-endocrine disturbance
Symptoms from tumor mass effect are comparatively less common,
probably owing to a slow growth rate (on average, 4.1 mm/yr)
Clinical Presentation
24.
25. • Magnetic resonance imaging (MRI) of LGGs demonstrates lesions that are:
isointense/hypointense on T1-weighted images
homogeneously hyperintense on T2-weighted images
do not enhance with contrast administration .
Diagnostic Neuroimaging for LGG
26. Diagnostic Neuroimaging for LGG
Calcifications can be detected in about 20%
of lesions.
Vasogenic edema and necrosis are not
typical of LGGs, owing to their slow growth
rate.
28. Diagnostic Neuroimaging for LGG
• MRSpectroscopy, have been used to differentiate glioma
grades and even to detect key LGG metabolic mutations, such
as those of the isocitrate dehydrogenase 1 (IDH1) gene
30. Diagnostic Neuroimaging for LGG
Diffusion tensor imaging and tractography can often help to identify locationof fiber tracts in
relation to tumors and to demonstrate whether these white matter bundles are displaced or
invaded by infiltrating tumorcells
31. Diffusion tensor imaging (DTI) and tractography
Diffusion tensor imaging (DTI)and tractography canprovide an elegant visualization of the white matter
tracts and their relationship with infiltrating tumors.
In this example, the right corticospinal tract (motor fibers from the foot area) is displaced medially rather
than being invaded by the tumor. The DTI and tractography can often help to maximize surgical resection
while preservingneurologicalfunction
32. Treatment goals:
Prolong progression-free survival & overall survival
Improve, maintain, slow the decline in neurological function
Minimize treatment-related effects
Treatment Options:
Observation
Surgery
Radiation
Chemotherapy
33.
34.
35.
36. Surgery
Pros:
• Benefits of surgery on seizures / raised ICT are fairly dramatic
• Early Surgery delays reappearance of symptoms and tumor growth
• Imaging can be misleading in upto 40% cases ,surgery provides histological
confirmation
• Survival advantage to gross resection in retrospective literature
Cons:
• Possibility of complications in a minimally symptomatic person
37. With advancement in technology ,morbidity of surgery has decreased hence surgery
is the mainstay of treatment
Observation with MRI monitoring :can be reserved for very few patients with ≤ 1cm
tumor and minimal symptoms
Extent of resection :No prospective randomized trials to assess the impact of
maximal tumor resection so maximal safe resection preferred
40. Adjuvantradiotherapy
PROS
Improves outcome in unresectable & partially resectable tumors
Increased Progression Free Survival
RT does not decrease seizure
CONS
No improvement in overall survival
Increased morbidity especially in young pt :neurocognitive decline , dementia ,
behavioural changes, vasculopathy, development of 2nd malignancy.
41. • phase III trial :311 pts (WHO 1–2, 51% astro., 14% oligo., 13% mixed oligo-astro)
• treated with surgery (42% GTR, 19% STR,35% biopsy)
• randomized to observation f/b RT at progression vs. post-op RT to 54 Gy.
• RT improved median PFS (5.3 year vs. 3.4 year hazard ratio 0.59, p<0.0001) but not OS
median survival 7.4 years RT arm vs. 7.2 in observation arm p=0.872).
• 65% pts in observation arm received salvage RT.
• Better seizure control rates at 1 year with early RT
• No difference in rate of malignant transformation (66–72%).
• QOL not studied whether time to progression reflects clinical deterioration not known
• CONCLUSION:
Early radiotherapy improves symptoms control & PFS but no improvement in OS
Delayed radiotherapy does not jeopardize survival
EORTC 22845 (Karim et al. 2002; van den Bent et al. 2005)
42. Indications for observation
So, on the basis of above data
Observation after surgery can be a reasonable strategy for the most favorable subset i.e.
Age ≤ 40 years
Preoperative tumor diameter <4 cm
Oligodendroglioma histology
gross total resection (GTR).
<1 cm residual tumor
43. Timing of RT : Early vs. delayed
Immediate,
If significant mass or symptoms
For incompletely resected unresectable or only biopsy tumors
Presence of ≥3 “high-risk” features on the basis of Pignatti score
Delayed,
If minimal mass or symptoms
After gross total resection
≤ 2 high-risk” features on the basis of Pignatti score
44. Consequently, low-dose radiotherapy, 45 -54 Gy in 1.8 Gy-2Gy per fractions, has
become an accepted practice
RT improved median PFS (5.3
year vs. 3.4 year)(p<.001) but
not overall survival.
45. Simulation
Position: supine
Immobilization : individualized headrest &
Thermoplastic mask
RTP scans using i.v contrast are taken with 1–3
mm slices from the vault to the base of the skull.
CECT-RTP data fused with MRI data
target volumes are defined using CT-MR fusion
data set
46. Target volumes
Low-grade gliomas.
Single phase treatment
EBRT dose: 1.8 Gy/fx to 50.4–54 Gy.
GTV =T2/FLAIR IMAGES
CTV = GTV + 1–1.5 cm margin.
PTV = CTV + 0.5 - 1 cm.
49. Acute Toxicity
within 6 weeks
Subacute Toxicity
6wks
to 6 months
Late Sequelae
6 months to many years
following treatment
RADIATION
TOXICITY
50. ACUTE TOXICITY
These symptoms are believed to be the consequence of a transient peritumoral
edema and usually respond to a short term increase or the institution of
corticosteroids.
Transient worsening of pretreatment deficits fatigue, headache, and
drowsiness
Mild dermatitis
Alopecia within the irradiated areas is common and may be permanent with higher
total doses.
Nausea and vomiting
Otitis externa and serous otitis media
Mucositis and esophagitis due to exit dose(in CSI).
Hematologic toxicity in CSI
51. Attributed to changes in capillary permeability, as well as to
transient demyelination due to damage to oligodendroglial cells.
Headache, somnolence, fatigability, and deterioration of
pre-existing deficits, usually respond to steroids.
The phenomenon of pseudoprogression temporally fits within
the subacute toxicity time frame.
SUB-ACUTE TOXICITY
52. LATE SEQUELAE
Usually irreversible and progressive
Due to white matter damage from vascular injury, demyelination, and
necrosis.
The most serious is radiation necrosis with peak incidence at 3
years.
Radiation necrosis can mimic recurrent tumor clinically by the
reappearance and worsening of initial symptoms and neurologic
deficits
Radiographically it shows development of a progressive,
irreversible, enhancing mass with associated edema on imaging.
53. PET, MR spectroscopy, and nuclear and dynamic CT scanning
procedures may aid in the differentiation of radiation necrosis
from recurrent tumor.
The best treatment for symptomatic necrosis is control of
symptoms with steroids, followed by surgical debulking, although
even after resection necrosis may progress.
Other options are bevacizumab,anticoagulants,hyperbaric
oxygen
Methotrexate can also cause necrosis
54. OTHER LATE SEQUELES
Hearing loss and vestibular damage
Loss of visual acuity
Hormonal deficiency
Neuropsychologic changes and neurocognitive impairment
Decline memory
55. • prognostic factor analysis done on Phase III adult LGG trials (EORTC 22844 and 22845):
• Risk Factors identified from EORTC 22844 & Validated in EORTC 22845
• Patients with pilocytic astrocytoma were excluded
• Multivariate analysis showed that unfavorable prognostic factors for survival were
age ≥ 40 years,
astrocytoma histology subtype
largest diameter of the tumor > or = 6 cm
tumor crossing the midline
presence of neurologic deficit before surgery
• Low Risk Patient: </= 2 factors (Median Survival- 7.7
years) High Risk: 3 or more factors (Median Survival
3.2 years)
• Low risk patients are typically observed postoperatively and given RT at disease progression or
56. Chemotherapy for Low Grade Gliomas
• Previously no role for chemotherapy in adult patients with low-
grade gliomas
57. Phase III Study Of Radiation With Or Without
PCV Chemotherapy In Unfavorable Low-
grade Glioma Initial results 2006
From 1998 to 2002,
251 patients
median follow up 6 years
RESULTS
5-year OS rates for RT versus RT/PCV were 7.5 years
versus not reached respectively (hazard ratio [HR] =
0.72, p = 0.33)
trend toward improved 5 year PFS 63 vs. 46%(p =
0.06)
acute grade 3/4 toxicity occurred in 67% in RT plus
PCV, vs. 9% in RT alone.
Conclusion: PCV do not provide a survival advantage over RT alone
INT/RTOG 9802 trial
59. PFS
• Median PFS = 4.4 yrs Vs not reached
• 5 year PFS = 46 % Vs 63%
60. median follow-up time is 11.9 years.
RT followed by PCV yielded significantly longer median survival (MST) compared to RT alone
(13.3 vs. 7.8 years, p = 0.03; HR = 0.59)
improvement in PFS (10.4 vs. 4.0 years, p = 0.002; HR = 0.50).
Treatment arm was identified as a prognostic variable in favour of RT + PCV for both OS (p =
0.003; HR = 0.59) and PFS (p < 0.001; HR = 0.49).
Molecular markers were not pre-specified; post-hoc analysis of these is ongoing.
Conclusion: PCV provided significant survival advantage over
RT alone
International Journal of Radiation Oncology • Biology • Physics , Volume 90 , Issue 1 , S37 - S38
61. RTOG 0424
• 129 WHO Grade 2 patients.
• High risk .
• Treated with RT / Concurrent and adjuvant TMZ
• Compared with historical controls received only RT.
62. • Eligibility
• WHO grade II astrocytoma, oligodendroglioma(O), or oligoastrocytoma (OA)
• With at least 3 of the following factors:
1. Age 40 years
2. Preoperative tumor diameter of 6 cm,
3. Bihemispherical tumor,
4. Astrocytoma histology,
5. Preoperative neurological function – moderate to severe impairment
63. • The 3-year OS rate is 73.1% , Significantly higher than the historical control
OS rate of 54%.
• 3-year PFS was 59.2% and median PFS - 4.5 years
• COX analysis showed :
Only histology was significantly associated with OS and PFS .
The other factors were not significantly associated with either OS or PFS.
64. Role of temozolomide
• More preferable option compared to PCV chemotherapy
• Oral administration
• Better toxicity profile
• Retrospective series and small phase II studies showed objective response
in disease progression 1-3
• First-line treatment with TMZ compared to RT did not improve PFS in high-risk LGG
patients (EORTC 22033)
• Further phase III trials needed
1.Hoang-Xuan K, Capelle L, Kujas M, et al. Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or
oligoastrocytomas and correlation with chromosome 1p deletions. J Clin Oncol 2004;22:3133–3138
2.BradaM, Viviers L,AbsonC,et al. PhaseII study of primary temozolomide chemotherapy in patients with WHOgrade II gliomas.Ann
Oncol 2003;14:1715–1721.
3.Quinn JA,Reardon DA,Friedman AH,et al. PhaseII trial of temozolomide in patients with progressive low-grade glioma. JClin Oncol
2003;21:646–651.
65. Conclusion for chemotherapy in high risk LGG*
• RTOG 9802 (1998-2002) shows significant survival advantage with PCV
chemotherapy
• However, in the intervening decade novel molecular markers as well as
newer chemotherapy agents such as temozolomide have been
developed.
• So optimal parameter for selecting patients for adjuvant PCV has yet to be
decided
• And It is still unclear if temozolomide can replace PCV
• Hence further trials needed
*Van den Bent MJ. Practice changing mature results of RTOG study 9802: another positive PCV trial makes adjuvant
chemotherapy part of standard of care in low-grade glioma. Neuro-Oncology. 2014;16(12):1570-1574.
*Radiation Therapy Oncology Group 9802: Controversy or Consensus in the Treatment of Newly Diagnosed Low-Grade
Glioma? Seminars in Radiation Oncology Volume 25, Issue3, July2015, Pages197–202
66.
67. SUMMARY
Grade I Gliomas
Complete resection: offers excellent survival, :majority (>90%) cured of the
tumor; no adjuvant therapy is necessary.
Incomplete resection: associated with long-term survival rates of 70% to 80% at
10 years hence usual recommendation is for close follow-up,
PORT: indicated in very few cases depending on the location of the tumor, the
extent of residual disease, the feasibility of repeated surgical excision, and
availability for follow-up
68. Grade II Gliomas
• Maximal surgicalresection
• Postoperative radiotherapy improves progression-free survival and seizure
control were superior. Thetypical radiotherapy dose is 45 to54 Gy
69. Take home message
Surgery is the mainstay of treatment
Complete resection is achieved in approx 80% of cerebral,
cerebellar, and spinal-cord tumors and 40% of diencephalic
tumors
RT in LGG
Tumor progression
Compromise neurologic function
Unresectable / residual
70. Take home message
Radiotherapy dose 50.4 Gy-54 Gy in 1.8 Gy-2Gy per
fractions IN LGG.
Chemotherapy has no proven benefits in LGG.