Low grade gliomas seminar

1. R2 Erion Junior de Andrade
Neurocirurgia
Hospital de Clínicas da UNICAMP
Low Grade Gliomas

2. 29-Mar-17 2
WHO 2016

3. 29-Mar-17 3
WHO 2016

4. • While the 2007 WHO classification of gliomas
was based on histological subtype:
• astrocytic,
• oligodendrocytic,
• oligoastrocytic
• WHO 2016 classification groups together
astrocytic and oligodendroglial tumours and
further defines specific entities based on IDH
mutation and 1p/19q codeletion status.
4
OVERVIEW

5. • It is now recognized that the majority of grade II
and III diffuse astrocytomas and essentially all
oligodendrogliomas harbor IDH mutations,
whereas the majority of glioblastomas are IDH-
wildtype.
5
OVERVIEW

6. 6
OVERVIEW

7. 7
OVERVIEW

8. OVERVIEW
LGGs have a better prognosis than their anaplastic counterparts;
the 10-year overall survival rate for patients with WHO grade II
astrocytomas is 35%.
Approximately 50% to 75% of WHO grade II gliomas transform
within 6 to 7 years of diagnosis.
8
OVERVIEW

9. OVERVIEW
• LGGs are primarily reported in the frontal lobes (44%),
followed by the temporal (28%) and parietal (14%) domains.
• Interestingly, LGGs originating in the cerebellar region are
associated with a better prognosis than those originating
supratentorially.
9
OVERVIEW

10. OVERVIEW
• The mean age at diagnosis is 39.4 years
• Factors associated with longer survival time are
– Younger age,
– Caucasian race,
– Tumor histology
– Extent of resection.
10
OVERVIEW

11. OVERVIEW
• The most common histologic subtype of LGG is
astrocytoma (69.3%), followed by oligodendroglioma
(21.1%) and mixed glioma (9.6%).
• Low-grade astrocytomas make up 10% to 20% of adult
primary brain tumors.
11
OVERVIEW

12. OVERVIEW
• Factors associated with an increased risk of
glioma
– Exposure to high dose radiation,
– Increasing age
– Hereditary disorders such as: Li-fraumeni syndrome
and NeuroFibromatosis type 1
12
OVERVIEW

13. Clinical Presentation
• 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)
13
Clinical Presentation

14. MANAGEMENT-CONTROVERSIES
• The treatment of low-grade gliomas remains one of the
most uncertain and controversial areas of modern
neurosurgery.
WHY CONTROVERSIES??
• The controversy largely stems from the lack of well-
designed clinical trials with adequate follow-up to
account for the relatively long progression-free survival
and overall survival of patients with LGG.
• No evidence of class I or II exists regarding the optimal
management of these patients
14
MANAGEMENT - CONTROVERSIES

15. WHAT CONTROVERSIES
1. Standard antiepileptic drug regimen for seizure control.
2. What neuroradiological features should guide management?
3. Which prognostic factors can help discriminate between favourable
and unfavourable patients with LGG?
4. Based on molecular characterization of tumours are there subgroups
of patients that benefit from more aggressive treatment modalities?
5. Should observation or surgery?
6. At what time should it be interveined? What surgery should be
performed?
7. What is the impact of extent of resection on PFS and OS in patients
with LGG?
8. What is the role of RT in the management of patients with LGG?
9. What is the role of chemotherapy in the management of LGG?
10. What protocol in follow up?
11. How should patients with recurrence be managed?
15
WHAT CONTROVERSIES?

16. Standard antiepileptic drug
regimen
• There is no standard antiepileptic drug regimen for
seizure control in patients with tumors; however,
levetiracetam is preferentially used because of its
favorable pharmacologic properties and relatively benign
side-effect profile.
Yuan Y, Yunhe M, Xiang W, et al. P450 enzyme-inducing and non enzymeinducing antiepileptic drugs for seizure
prophylaxis after glioma resection surgery: A meta-analysis. Seizure. 2014;23:616–621.
16
STANDART ANTIEPILEPTIC DRUG

17. Diagnostic Neuroimaging for LGG
• 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 .
29-Mar-17 17
DIAGNOSTIC NEUROIMAGING

18. Diagnostic Neuroimaging for LGG
• Calcifications can be detected in about 20% of
lesions and appear as distinct hyperintense foci
on T1-weighted images and hypointense foci on
T2-weighted images.
• Vasogenic edema and necrosis are not typical of
LGGs, owing to their slow growth rate.
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DIAGNOSTIC NEUROIMAGING

19. Diagnostic Neuroimaging for LGG
19
DIAGNOSTIC NEUROIMAGING

20. 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
20
DIAGNOSTIC NEUROIMAGING

21. Diagnostic Neuroimaging for LGG
• MRSpectroscopy
21
DIAGNOSTIC NEUROIMAGING

22. 29-Mar-17 22
Diffusion tensor imaging and tractography can often help to identify location of
fiber tracts in relation to tumors and to demonstrate whether these white
matter bundles are displaced or invaded by infiltrating tumor cells
DIAGNOSTIC NEUROIMAGING

23. Diagnostic Neuroimaging for LGG
23
Diffusion tensor imaging (DTI) and tractography can provide 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 preserving neurological function
DIAGNOSTIC NEUROIMAGING

24. • University of California at San Francisco (UCSF)
conducted a retrospective study of 256 patients and
proposed a scoring system to estimate patient overall
survival (OS) and progression-free survival (PFS).
• This scoring system assigns a 1-point value for the
following factors:
– Tumor location within eloquent cortices,
– Karnofsky performance scale score 80 or less,
– Age more than 50 years, and
– Maximal tumor diameter more than 4 cm.
24
PROGNOSTIC FACTOR, PATIENT
OUTCOME AND SURVIVAL

25. • Higher scores portend a worse prognosis:
• Patients with a UCSF score of 0 to 1 had a 97% 5-year
survival rate,
• Patients with a score of 3 to 4 had a 5-year survival rate
of 56%
25
PROGNOSTIC FACTOR, PATIENT
OUTCOME AND SURVIVAL

26. Prognostic factors for survival in adult patients with cerebral low-grade
glioma.
Pignatti F, van den Bent M, Curran D etal 2002
26
PROGNOSTIC FACTOR, PATIENT
OUTCOME AND SURVIVAL

27. • Radiation Therapy Oncology Group, and the
North Center Cancer Treatment Group
(RTOG/NCCTG) further defined prognostic factors
for WHO grade II gliomas.
• PFS and OS were negatively affected by the
following factors:
29-Mar-17 27
PROGNOSTIC FACTOR, PATIENT
OUTCOME AND SURVIVAL
Impaired baseline neurologic status,
Shorter time since first symptoms (<30 weeks),
Astrocytic histology, and
Maximal tumor diameter greater than 5 cm.

28. • Specific genetic markers helpful in dividing gliomas into subgroups with respect to
prognosis and response to chemotherapy:
• TP53 mutations: : Common in diffuse astrocytomas and are
mutually exclusive from 1p/19q co-deletions.
• 1p/19q co-deletion: 50-70% LG Oligodendroglial tumors
Loss of 1p or both 1p/19q may predict chemosensitivity and predicts prolonged survival in
LGO and LGOA
There are patients that are deleted that do less well than most and there are some intact
patients that do much better than most.
• IDH 1 mutations: 60-90% of LGG. Associated with improved survival.
May help diagnostically differentiate: gliosis vs tumor or (in comb w BRAF) pilocytic tumors
vs grade II astrocytoma
We still do not know confidently if IDH 1 mutations should be used to direct treatment or, if
so, how.
28
PROGNOSTIC FACTOR, PATIENT
OUTCOME AND SURVIVAL

29. 29
PROGNOSTIC FACTOR, PATIENT
OUTCOME AND SURVIVAL

30. • Symptom Management
• Observation
• Surgery
• Radiation Therapy
• Chemotherapy
• Intervention?
• How to?
• When to?
• Surgery: Radical Vs Partial
• Radiotherapy: Timing,
• Low Vs High Dose
• Role of Chemotherapy
30
TREATMENT

31. •Seizures: Medications such as levitiracetam, lacosamide,
topirimate, lamotrigine, and others such as phenytoin,
carbamazepine, etc
•Edema: Steroids, usually dexamethasone; however long
term use has potential for side effects (skin changes,
weight gain, muscle weakness, bone thinning, increased
risk of infection, etc)
•Obstructive Hydrocephalus: may require surgery and
perhaps placement of a “shunt” to bypass the blockage
and lower the pressure 31
SYMPTOMS MANAGEMENT

32. • Increased life span by surgery never proven.
• Increasingly patients are diagnosed neurologically
intact.
• Postpones surgical morbidity and mortality if any.
• Alternate treatment strategy are available
• Stereotactic biopsy and radiotherapy
• Technical reasons
– Distinction between tumor-brain difficult and early
radical surgery seldom serves purpose.
32
Watchful waiting – Why?

33. • Grading gliomas based on imaging characteristics alone
underestimated the degree of malignancy in 1/3 cases
• Tissue diagnosis should be attained whenever deemed safe and
possible
Scott JN, Brasher PM, SevickRu, Rewcastle NB, Forsyth PA. How often are
nonenhancingsupratentoralgliomas malignant? A popultion study. Neurology 2002:s9:947-9.
• Recent studies have showed that contrast enhancement may occur
in up to 40% of low grade gliomas.
• Scott CB, Scarantino C, Urtasun R, Movsas B, Jones CU, Simpson JR, eta. validation and predictive power
of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes ror malignant
glioma patients: A report using RTOG 90-06. Int J RadiatOncolBiol Phys 1998;40:51-5.
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Watchful waiting – Why NOT?

34. • The expectant management of patients with LGGs can bring on
other risks, such as,
– Malignant degeneration
– Subsequent tumorgrowth, and
– Irreversible neurological deficit.
• How ever despite these theoretical risks, several retrospective series
revealed that the timing of surgical intervention did not affect the
rates of malignant transformation, overall survival, or QOL.
• Reijneveld JC, Sitskoorn MM, Klein M, Nuyen J, Taphoorn Mj. Cognitive status and quality of life in
patients with suspected versus proven low grade gliomas, Neorology 2001;56:618-23
34
Watchful waiting – Why NOT?

35. • The role of immediate surgical resection versus
delayed resection is controversial and data are
limited to observational studies.
• Unless contraindicated, immediate surgical
resection is a first option to improve OS.
35
Surgery

36. • Although no randomized controlled trials (RCTs)
have evaluated the extent of surgery on
outcomes in LGG, numerous observational
studies suggest that greater extent of resection
(EOR) improves OS and seizure control.
• Maximizing tumour resection while keeping the
surgically induced deficit at an acceptable level is
recommended over simple debulking.
36
Surgery

37. • Surgery alone is NOT CURATIVE in patients with
LGG and additional therapy with RT and/or
chemotherapy will likely be required at some
point in their disease trajectory.
29-Mar-17 37
Surgery

38. 38
Surgery

39. RATIONALE FOR EARLY SURGERY
• Definitive diagnosis
• Possibility of gross total resection with potential for cure
• Control of seizures
• Neurological improvement
• Control of ICP
• Longer disease free interval
• Enhanced ability of immune cells to wipe out tumor
• Greater effect by post op RT
DISAGREEMENT WITH EARLY SURGERY
• Longer disease free interval is lead time bias
• Immunological activity against low grade glioma is controversial
• Post op radiotherapy does not kill all cells
39
Surgery – when?

40. Stereotactic Biopsy
• Operative strategies for patients with LGGs include open surgical
resection and stereotactic biopsy.
• The choice depends in part on the patient's clinical status, the
anatomic location of the tumor, and the surgeon's preference.
• Immediate stereotactic biopsy is increasingly uncommon, it
remains a reliable first step for cases in which the diagnosis is
uncertain.
• A recent Norwegian study had shown the significant difference of
survival in those centers with a preference for resection than those
selecting a biopsy and watchful waiting and with no significant
difference in health related quality of life.
Jakola AS, Myrmel KS, Kloster R, Torp SH, Lindal S, Unsgard G, Solheim O (2012)
Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful
waiting in low-grade gliomas. JAMA 308:1881–1888 40
Surgery

41. Microsurgical Resection
• In patients with accessible LGGs who have symptoms
of local mass effect, increased intracranial pressure,
and intractable seizures, the role of microsurgical
resection is well established.
• Resection serves several purposes in these
circumstances, including alleviation of mass effect,
cytoreduction, and diagnosis.
41
Surgery

42. EXTENT OF RESECTION
• Till date no class 1 evidence to support radical resection.
• There are lot of retrospective data to suggest benefit in survival
and in quality of life.
• Two prospective studies have shown benefit of extensive surgery in
overall survival on univariate analysis.
• On multivariate analysis these showed minimal benefits.
• Recent studies looking specifically at oligodendroglioma show that
extent of resection does improve PFS and overall survival but did
not influence time to malignant transformation.
Snyder LA, Wolf AB, Oppenlander ME, Bina R, Wilson JR, Ashby L, Brachman D, Coons
SW, Spetzler RF, Sanai N (2013) The impact of extent of resection on malignant
transformation of pure oligodendrogliomas. J Neurosurg. doi:10.3171/2013.10. JNS13368
42
Surgery

43. EXTENT OF RESECTION
• Hardesty and Sanai reviewed every major peer-reviewed clinical
publication on the role of EOR in glioma outcome between the
years 1990 to 2012.
• Eleven LGG articles were examined for quality of evidence,
expected EOR, and survival benefit.
• Three studies using volumetric analysis to determine EOR in LGG
pts (n=462, range 90-216) demonstrated a benefit to increasing
EOR in univariate and/or multivariate analysis.
• Five-year OS was improved in all studies
Hardesty DA, Sanai N. The value of glioma extent of
resection in the modern neurosurgical era. Front Neurol
2012 Oct 18;3:140
43
Surgery

44. 44

45. Contemporary neurosurgical methods
• Contemporary neurosurgical methods, including ultrasonography,
functional mapping, frameless navigational resection devices,
and intraoperative imaging techniques, enable the neurosurgeon
to achieve more extensive resections with less morbidity.
• Intraoperative ultrasonography provides real-time intraoperative
data and is helpful in detecting the tumor, delineating its margins,
and differentiating tumor from peritumoral edema, cyst, necrosis,
and adjacent normal brain tissue.
• Intraoperative MRI may also allow for greater extent of resection,
particularly when tumor-infiltrated tissue cannot be grossly
distinguished from normal.
Claus EB, Horlacher A, Hsu L, et al. Survival rates in patients with low-grade
glioma after intraoperative magnetic resonance image guidance. Cancer.
2005;103:1227–1233.
45
Surgery

46. Contemporary neurosurgical methods
• Stimulation mapping techniques are essential to minimize
morbidity and to achieve radical resections of tumors located in or
around cortical and subcortical, functionally eloquent sites.
• Intraoperative mapping techniques can effectively identify tissue
with motor, language, and sensory functionality.
Sanai N, Berger MS. Intraoperative stimulation techniques for functional pathway
preservation and glioma resection. Neurosurg Focus. 2010;28
• Awake language mapping is also essential owing to variability in
the localization of language pathways and should be considered
when a glioma is located in the dominant hemisphere near the
frontal operculum, temporal lobe, or angular gyrus.
46
Surgery

47. Functional Mapping and Cortical Stimulation
29-Mar-17 47
Surgery

48. 48
A 43-year-old man presenting with word finding difficulties. He underwent an awake
craniotomy for aggressive resection of the tumor involving Wernicke’s area with
language and motor cortex mapping. Note the multicompartmental endopial resection
of the tumor with preservation of the cortical veins overlying the tumor
Surgery

49. Defer Treatment Treat
Post op: When Should We Treat?
• After large or GTR
• Minimal disease
• No enhancement
• Seizures controlled
• Few or no Seizures
• Younger age
49
Post Op – When to treat?
Suspicion: ? Higher grade
Progressing LG
Enhancement
Mass effect
Symptomatic
> age 40
Surgery not indicated or
significant residual and Rx
necessary

50. Radiation Therapy
• Oligodendrogliomas, Astrocitomas and Mixed OA
all respond to RT
• RT may not always be best initial choice:
Chemotherapy may be the 1stchoice for some pts,
particularly with Oligodendroglioma or Mixed OA
whose tumors show 1p/19q deletions–deferring
treatment with RT
50
Radiation Therapy

51. Radiation Therapy
• Besides WBRT – other options?
• Proton beam thought to decrease risk to normal
brain however efficacy has not been compared to
standard external beam with margins. Risk is
under treating the margins
• SRS? Not usually indicated. Focused to small area,
but these tumors are infiltrative and “spread out”
51
Radiation Therapy

52. Why radiation therapy?
• Improves time to tumor progression
• Several studies show improved survival in patients with progressing or
aggressive tumors
• No systemic side effects
• Defined treatment time
Why not radiation therapy?
• No clear evidence of improved survival with immediate post op RT vs
delayed RT
• Delayed radiation induced neurotoxicity
• RT vs no RT
– Perform worse on cognitive tests
– Have lower Karnofskyscore
– Not accounted for by histology, location, extent of removal, progression
» Surm-aho et al, 2001
52
Rationale for RT

53. • In the Mayo Clinic study, Shaw et al compared the
outcome of 126 patients with supratentorial
astrocytoma or mixed oligo-astrocytoma treated with
surgery alone or surgery plus either low-dose (53 Gy) or
high-dose (53 Gy) RT.
• The 5-year OS was 32% with surgery alone, 47% with
low-dose RT, and 68% with high-dose RT, suggesting
that surgery without postoperative RT was inadequate
treatment and high-dose RT was better than lower dose.
Shaw EG, Daumas-Duport C, Scheithauer BW, et al: Radiation therapy in
the management of low-grade supratentorial astrocytomas. J Neurosurg
70:853-61, 1989
53
Rationale for RT

54. 54
Evidence
Phase III adult low grade glioma trials (EORTC 22844 and
22845): Risk Factors identified & Validated
Age>40 years
Size>6cm
Crossing Midline
Pure Astrocytoma histology
Neurological deficit before Surgery
Low Risk Patient: </= 2 factors (Median Survival- 7.7 years)
High Risk: 3 or more factors (Median Survival- 3.2 years)
Immediate or delayed PORT?
Age>40 years
Size>6cm
Crossing Midline
Pure Astrocytoma histology
Neurological deficit before Surgery

55. 55
EORTC 22845 (Karim et al, 2002 & Van den Bent et al, 2005)
Randomised phase III trial
RT Dose (54Gy/30#)
Immediate RT vs RT at Progression
Results: Improved median progression free survival
(5.3 yrs vs 3.4 yrs)
Better seizure control rates
No difference in Median survival (7.4yrs vs 7.2 yrs)
No difference in rate of malignant transformation.
Pitfall: No in-depth quality of life adjusted analysis.
Immediate or delayed PORT?

56. 29-Mar-17 56
RTOG (Radiation Therapy Oncology Group) 9802 (phase
II portion of protocol)
Risk Factors predictive of a poorer PFS
Astrocytoma histology
Residual tumor of >/=1 cm on Postop MR
Pre-operative tumor diameter of >/=4 cm
Patients with:
All three unfavourable factors- PFS at 5years 13%
None of the three factors- PFS at 5years 70%
Immediate or delayed PORT?
Astrocytoma histology
Residual tumor of >/=1 cm on Postop MR
Pre-operative tumor diameter of >/=4 cm

57. Delayed Radiation Encephalopathy
29-Mar-17 57
Immediate or delayed PORT?

58. So, on the basis of discussed data
Observation seems to be a reasonable strategy for the most
favorable subset i.e.
<1 cm residual tumor
Preoperative tumor diameter <4 cm
Oligodendroglioma histology
Younger patients
Following a gross total resection (GTR).
Mature result of this trial is pending !!!!
Radiation Therapy-Standard approach
58

59. Radiation Therapy-Standard approach
2] Dose of RT?
Evidence
EORTC 22844 (Karim et al. 1996) – phase III:
Postoperative RT 45 Gy vs. 59.4 Gy
5-year OS 58% with 45 Gy
59% with 59.4 Gy.
INT/NCCTG (Shaw et al. 2002) – phase III:
Postoperative RT 50.4 Gy vs. 64.8 Gy
5-year OS 73% with 50.4 Gy
68% with 64.8 Gy.
59

60. Based on these Phase III trials and Extrapolation of data of
in-field recurrences in high grade gliomas
It will be prudent to limit the Postoperative
RT Dose to 54 Gy.
60

61. Why Chemotherapy?
• Spares the normal tissue of the brain the delayed effect of RT
• Some low grade glioma are quite large meaning larger radiation ports
resulting in larger areas of normal brain exposed to RT
• Some low grade gliomas; particularly ones with 1p/19q deletions are
particularly sensitive
Why not Chemotherapy?
• Responses disappointing in some low grade gliomas; particularly those
without 1p or 1p/19q deletions
• Prolonged treatment
• Systemic (body) toxicity
• Quality of life over time
61
Chemotheraphy – Why or why not?

62. RT Alone or RT + Chemotherapy?
62
Evidence
INT/RTOG 9802 trial
(ASCO abstract 2008): phase III
Low-risk (<40 year + GTR) observed until symptoms
High-risk (>40 year or STR or biopsy) patients randomized to
RT alone vs. RT --> PCV ×6 cycles q8 weeks
5 year OS was 72 vs. 63% (p = 0.33)
5-year PFS was 63 vs. 46%
(p = 0.06) in favour of chemotherapy
RT alone or RT + CT?

63. 29-Mar-17 63
Largest reported retrospective analysis of 149 patients
Temozolomide at Progression (1p/19q LOH was present in
42%)
53% - Objective response (15% - Partial response and 38%
minor response)
37% - Stable disease
10% - progressive disease.
Kaloshi G, Benuaich-Amiel A, Diakite F, et al: Temozolomide for low grade gliomas: predictive
impact of 1p/19q loss on response and outcome. Neurology 2007; 68:1831-1836
RT alone or RT + CT?

64. 29-Mar-17 64
• Phase II Trial of Temozolomide in Patients With
Progressive Low-Grade Glioma
(Jennifer A. Quinn et al)
Objective response rate - 61% (24% CR and 37% PR)
Stable disease - 35%
IDH1 or IDH2 mutations predict longer survival and
response to temozolomide in low-grade gliomas.
(C. Houillier et al) Neurology October 26, 2010 vol. 75 no. 17 1560-1566
1p-19q codeletion, MGMT promoter methylation, and IDH mutation (p = 0.01)
were correlated with a higher rate of response to temozolomide
RT alone or RT + CT?

65. 65
 EORTC 22033-26033/CE5 phase III randomized trial for low
grade glioma: Phase III EORTC 22033-26033/NCIC CE5 intergroup
trial compares 50.4 Gy radiotherapy with up-front temozolomide
in previously untreated low-grade glioma (Open to accrual)
Conclusion:
• Low-grade gliomas respond to temozolomide
• Loss of chromosome 1p/19q predicts both a durable
chemosensitivity and a favorable outcome
RT alone or RT + CT?

66. If Chemotherapy added to RT- Which
Chemotherapy?
29-Mar-17 66
• Concerns about toxicity profile of PCV
• Nitrosoureas (In PCV) – Notorious for secondary malignancy
• Procarbazine - Infertility
• Availability of lesser toxic and effective substitute as
Temozolomide
• Oral administration- Convenient dosing of Temozolomide
Makes Temozolomide more preferable an option with respect
to PCV chemotherapy
Ok.. RT + CT, but which?

67. 29-Mar-17 67
Options Include
Reopertion (If resectable)
Chemotherapy (Unresectable disease)
Reirradiation with SRS/FSRT (Small
recurrences)
Newer agents under trial (Blocking mTOR with
an investigational agent ridaforolimus ).
Disease progression after PORT?

68. • Many/most low grade Oligodendrogliomas
respond to chemotherapy; sometimes
dramatically and for prolonged periods
• Clinical improvement, decreased even in
patients without obvious improvement on MRI
• Options?
• PCV (procarbazine, CCNU, vincristine)
• Temozolomide
68
Chemotherapy
PCV (procarbazine, lomustine (CCNU),
vincristine)
Temozolomide

69. • Length of treatment?
Clearer with PCV than TMZ
but PCV more toxic
• 1p/19q loss predicts response-in almost all pts
• Pts with 1p/19q intact LGO, LGOA, LGA less likely
to respond to chemotherapy; may be better
served by RT if/when they need treatment
69
Chemotherapy

70. Chemotherapy Risks/Toxicity
• Myelosuppression: acute, chronic, delayed
• Other organ toxicities
• Quality of life
• Toxicity of PCV significant and dose limiting
• Temozolomide
– significantly less toxic
– Length of treatment & response rate need to be
defined
70
Chemotherapy

71. • Classification = alkylating agent
• Rapid conversion at physiologic pH to MTIC
(CSF concentration is 30% of serum)
• MTIC cytotoxicity due to methylation of DNA
at the O6 position of guanine
• Antitumor activity is schedule dependent
• Cytotoxicity influenced by levels of MGMT
• Levels not infuenced by cytochrome p450
• Renal and hepatic clearance minor
71
Themozolamide

72. • DLT is myelosuppression, nadir 21-28 days,
recovery within 14 days of nadir
• Immunosuppression (lymphopenia)
• Nausea and vomiting
• Infertility and mutagenesis
72
Themozolamide - toxicity

73. Oligodendroglioma1p/19q deleted 6 cycles of Temozolomide
73
Themozolamide

74. • Glioma cells express receptors for several different
growth factors
• PDGF, VEGF, EGF
• Targeted therapies aim to inhibit these growth factor
receptors and their tyrosine kinasebased intracellular
signaling pathways
• Agents bind to cell surface receptors and either
compete w/ or block the normal substrates from
binding or bind directly to the growth factor
• In tumors dependent on such pathways for growth,
the use of these agents can potentially result in
tumor cell death
74
Target Therapy

75. 29-Mar-17 75

76. 76
Treatment Algorythm
Tratado de Neurocirurgia SBN, 2015

77. 77
Treatment Algorythm

78. 78
Treatment Algorythm

79. • Innovations within the diagnostic, therapeutic, and molecular
domains are intertwining and helping to understand and treat
LGGs more effectively.
• Prognostic factors derived from genetic analysis and clinical
characteristics allow us to stratify patients into proper treatment
groups to maximize therapeutic benefit.
• Maximizing the extent of resection can delay recurrence and
improve the time to transformation.
79
Conclusion

80. • However, this approach must be balanced with preservation of
neurologic function, which can be improved by using
intraoperative mapping.
• Chemotherapy combined with radiation therapy may prolong PFS
and OS.
• LGGs are not homogeneous and small genetic changes can
significantly affect outcomes.
• Future clinical trials that classify patients according to novel
prognostic factors will probably aid in creating patient-specific
treatment plans with better outcomes.
80
Conclusion

81. FINAL MESSAGE

82. • WHO Classification of Tumours of the Central Nervous System, Revised 4th Edition, Louis DN, Ohgaki H,
Wiestler OD, Cavenee WK (Eds), IARC, Lyon 2016.
• Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of
the Central Nervous System: a summary. Acta Neuropathol 2016; 131:803.
• Bailey P, Cushing H. A classification of the tumors of the glioma group on a histogenetic basis with a
correlated study of prognosis, JB Lippincott, Philadelphia 1926.
• KERNOHAN JW, MABON RF. A simplified classification of the gliomas. Proc Staff Meet Mayo Clin 1949;
24:71.
• RINGERTZ N. Grading of gliomas. Acta Pathol Microbiol Scand 1950; 27:51.
• Daumas-Duport C, Szikla G. [Definition of limits and 3D configuration of cerebral gliomas. Histological data,
therapeutic incidences (author's transl)]. Neurochirurgie 1981; 27:273.
• Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, et al. Comprehensive, Integrative Genomic
Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med 2015; 372:2481.
• Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma Groups Based on 1p/19q, IDH, and TERT
Promoter Mutations in Tumors. N Engl J Med 2015; 372:2499.
• Pouratian N, Schiff D. Management of low-grade glioma. Curr Neurol Neurosci Rep 2010; 10:224.
• Whittle IR. What is the place of conservative management for adult supratentorial low-grade glioma? Adv
Tech Stand Neurosurg 2010; 35:65.
REFERENCES

83. REFERENCES
• Sanai N, Chang S, Berger MS. Low-grade gliomas in adults. J Neurosurg 2011; 115:948.
• Aghi MK, Nahed BV, Sloan AE, et al. The role of surgery in the management of patients with diffuse low
grade glioma: A systematic review and evidence-based clinical practice guideline. J Neurooncol 2015;
125:503.
• Jakola AS, Myrmel KS, Kloster R, et al. Comparison of a strategy favoring early surgical resection vs a
strategy favoring watchful waiting in low-grade gliomas. JAMA 2012; 308:1881.
• Jakola AS, Skjulsvik AJ, Myrmel KS, et al. Surgical resection versus watchful waiting in low-grade gliomas.
Ann Oncol 2017; 28:1942.
• Recht LD, Lew R, Smith TW. Suspected low-grade glioma: is deferring treatment safe? Ann Neurol 1992;
31:431.
• Keles GE, Lamborn KR, Berger MS. Low-grade hemispheric gliomas in adults: a critical review of extent of
resection as a factor influencing outcome. J Neurosurg 2001; 95:735.
• Smith JS, Chang EF, Lamborn KR, et al. Role of extent of resection in the long-term outcome of low-grade
hemispheric gliomas. J Clin Oncol 2008; 26:1338.