different modalities of treatment in low grade gliomas

1. LOW GRADE GLIOMAS
DR ARNAB BOSE
Dept. of Radiotherapy
NRS Medical Colleg,Kolkata
1

2.  Low-grade gliomas are a pathologically and clinically diverse
group of uncommon central nervous system (CNS) tumors
that occur primarily in children and young adults.
2

3.  The concept of dividing astrocytomas into discrete grades
associated with a distinct clinical prognosis dates back to the
mid-1920s and early 1930s to the work of Bailey and Cushing,
who recognized a subset of astrocytomas that had a more
favorable outcome than glioblastoma.
 There have been many grading systems
(e.g., Kernohan, St. Anne-Mayo, and Ringertz systems) in the past,
and most of these grading systems share an assessment of nuclear
abnormalities, mitoses, endothelial proliferation, and necrosis,
but the most widely used and accepted grading system today is the
WHO system.
3

4.  WHO Grade I lesions have low proliferative potential, with
the possibility of cure following surgery alone.
 WHO Grade II neoplasms are infiltrative, often recur, and tend to
progress to higher grades of malignancy (e.g., grade II astrocytoma
transforms to grade III anaplastic astrocytoma) despite low level
proliferative activity.
 All grading schemes are limited by their need to separate gliomas
artificially into three or four groups, when in actuality they exist along a
biologic continuum.
4

5. Type WHO Grade
 Astrocytic Tumors
Subependymal giant cell astrocytomas I
Pilocytic astrocytomas I
Pleomorphic xanthoastrocytomas II
Diffuse astrocytoma II
 Oligodendroglial Tumors
Oligodendrogliomas II
 Oligoastrocytic Tumors
Oligoastrocytomas II
5

6.  Low-grade astrocytomas make up 5% to 15% of adult primary brain
tumors and 67% of low-grade gliomas,
the remainder of low-grade gliomas being mixed Oligoastrocytomas
(19%) and Oligodendrogliomas (13%).
 Astrocytic gliomas, arise from astrocytes, the supporting cells of the
brain and spinal cord. The cytoplasmic processes that extend from the
astrocytes contain a characteristic filamentous protein,
glial fibrillary acidic protein (GFAP), which provides an
immunohistochemical marker for these tumors.
6

7.  The Diffusely infiltrative low-grade astrocytomas (WHO grade II)
are the most common and include the fibrillary, protoplasmic, and
gemistocytic types.
 They represent 70% of low-grade cerebral astrocytomas.
 Diffuse astrocytomas are usually poorly circumscribed and are
capable of undergoing anaplastic transformation.
7

8.  Fibrillary astrocytomas, the most common subtype, and
Protoplasmic astrocytomas have been referred to as “ordinary”
astrocytomas and share a similar prognosis. Over time, at least 50% of
these tumors transform into more anaplastic lesions.
 Gemistocytic astrocytomas are composed of large, plump astrocytes
with abundant eosinophilic cytoplasm. Gemistocytes commonly
transform into highly anaplastic cells, and behave in an aggressive
fashion.
8

9.  The Pilocytic astrocytomas (WHO grade I), which comprise
nearly all of the remainder of the cerebral astrocytomas, tend
to be better circumscribed. They are composed of fusiform cells with
unusually long, wavy processes called Rosenthal fibers. Mitosis is rarely
seen. Pilocytic astrocytomas have a long natural history and rarely
transform. Although they occur more commonly in the cerebellum
of children (juvenile pilocytic astrocytoma), they also
occur in the cerebral hemispheres and near the optic tracts.
 Remaining are the uncommon low-grade glioma variants,
including the Pleomorphic Xanthoastrocytomas, Subependymal
Giant Cell Astrocytomas, and Dysembryoblastic Neuroepithelial tumor.
9

10.  A two-tiered system, low-grade and anaplastic, is used to grade
Oligodendrogliomas. In the WHO classification low-grade lesions are
labeled grade II and anaplastic lesions are labeled as grade III.
 Patients with grade II tumors have a median survival of 9.8 years
whereas those with grade III tumors have a median survival of 4.6
years.
 An important additional diagnostic assessment that should be
performed on all oligodendroglial tumors is for the presence of
deletions of chromosomes 1p and 19q. If these deletions are present,
tumors tend to behave more indolently and are more responsive to
therapy (especially chemotherapy).
10

11.  Many oligodendrogliomas are admixed with astrocytoma or
ependymoma components. The presence of up to 50% astroglial
component is accepted to make the diagnosis of mixed
Oligoastrocytoma in the WHO classification.
 The median survival for patients with low-grade mixed
oligoastrocytomas is 7 years.
 Most oligoastrocytomas and 50% to 75% of oligodendrogliomas
recur as AAs or GBM.
11

12.  Tumor Proliferation can be assessed with Ki-67 labeling.
 A large review on Ki-67 labeling revealed increasing values
of Ki-67/MIB-1 labeling index with increasing grade of malignancy.
 The MIB-1 labeling index differentiates diffuse astrocytomas
(WHO grade II) from anaplastic astrocytomas (WHO grade III) and
glioblastoma multiforme (GM) tumors.
12

13.  Biologic Characteristics :
Combined 1p and 19q deletions are associated with a superior
outcome and are most common in oligodendrogliomas.
TP53 mutations are more common in diffuse astrocytomas and are
mutually exclusive from 1p/19q co-deletions.
IDH1 mutations occur in the vast majority of low-grade gliomas and
are found both in tumors with TP53 mutations and in tumors with
1p/19q co-deletions.
13

14.  Low-grade gliomas are generally a disease of patients in their
20s, 30s, or 40s.
 The most common symptom is seizure, occurring in
two thirds of patients. Focal seizures are more common than
generalized ones.
 Headache and weakness occur in approximately one third of
patients.
 The remaining symptoms (vomiting, motor deficit, visual or
sensory loss, language disturbance, or personality change)
occur in 15% or fewer patients.
 Symptoms may be present for months or years before a diagnosis is
made.
14

15.  MRI : T1 - pre and post-gadolinium(contrast),
T2, and
FLAIR (fluid attenuation inversion recovery, removes
increased CSF signal on T2).
 Tumor enhancement with gadolinium correlates with breakdown of
the blood–brain barrier.
 Tumor: High grade – increased signal on T1 post-gadolinium
and T2 (T2 also shows edema).
Low grade – increased signal on T2 / FLAIR.
15

16.  Pilocytic astrocytoma (Grade I) : enhancing nodule,
highly vascular, 50% associated with cysts.
 Diffuse astrocytoma (Grade II) : non-enhancing,
hypo-intense on T1, hyper-intense on T2/FLAIR ,
well-circumscribed, solid.
 Oligodendroglioma : calcifications associated frequently
16

17.  A Prognostic Scoring system was developed using imaging, patient,
and tumor characteristics derived from the databases of two large
phase III adult low grade glioma trials (EORTC trials 22844 and
22845). The following negative risk factors were identified and
validated: age 40 years or older,
astrocytoma histology subtype(compared to oligo/mixed),
largest diameter of the tumor of 6 cm or more,
tumor crossing the midline, and
presence of neurologic deficit before surgery.
 The presence of 2 of these factors or fewer identified a low-risk
group (median survival, 7.7 years),
whereas 3 risk factors or more identified a high-risk group
(median survival, 3.2 years).
17

18. Observation
 The decision to Observe a patient with low-grade glioma has
been justified in the literature for several reasons. These
reasons include the relatively favorable natural history of the
disease, the lack of proven benefit for invasive interventions
such as surgical resection or radiation therapy, and the potential
morbidities of treatment.
 Patients who are observed should be monitored at regular intervals
(e.g., every 6 months) to detect radiologic progression before new
signs and symptoms occur.
18

19.  Despite the favorable survival rates observed in certain subsets of
patients with low-grade gliomas, the natural history of all pathologic
types of supratentorial low-grade gliomas, including the pilocytic
astrocytomas (WHO I), diffuse astrocytomas, oligoastrocytomas, and
oligodendrogliomas (WHO II), is significantly worse than that of an
age- and sex matched control population, for which the expected
survival rate is greater than 95%.
 Based on this observation, some have argued that all such patients
should undergo Maximal Safe Surgical Resection followed by
postoperative radiation therapy.
19

20. 20

21. Surgery vs. Observation
 Pros:
i)If symptoms are uncontrolled medically, then benefits of
surgery on seizures / raised ICT are fairly dramatic
ii)Imaging can be misleading in upto 40% cases
iii)Early Surgery delays reappearance of symptoms and tumor
growth
iv)Survival advantage to gross resection in retrospective
literature
 Cons:
i)Possibility of complications in a minimally
symptomatic person
21

22. Surgery
 The key surgical issues in the management of supratentorial
low- grade gliomas are : whether to perform a biopsy on a patient
whose clinical presentation and imaging studies suggest a low-grade
glioma, and what should be the extent of resection.
 Although one series in the literature suggests that the survival rate
of patients irradiated for presumed low-grade glioma is comparable to
that of patients irradiated for histologically verified low-grade
astrocytoma, the possibility of inappropriate management in up to
50% of cases diagnosed by imaging underscores the need for
histologic verification if a therapeutic intervention is planned.
22

23.  A number of retrospective studies have suggested a benefit for
greater extent of resection.
 A long-term follow-up (median, 13.6 years) study from
the Mayo Clinic reviewed 314 adult low-grade glioma patients and
found on multivariate analyses significantly improved OS and PFS
rates with gross total resection or nearly gross total resection. Almost
50% of patients after gross total resection or nearly gross total resection
were free of recurrence 10 years after diagnosis.
23

24.  Investigators from the University of California San Francisco
(UCSF) measured tumor volumes based on FLAIR imaging in 216
low-grade glioma patients.
Patients with at least 90% extent of resection had 5- and 8-year OS of
97% and 91%, respectively, whereas patients with less than 90% extent
of resection had 5- and 8-year OS of 76% and 60%, respectively.
After adjusting for age, Karnofsky performance status (KPS) score,
tumor location, and tumor subtype, OS and PFS outcomes were both
predicted by post-operative tumor volume.
Limitation of this study was the relatively short follow-up (4.4yrs).
24

25.  Prospective trials have also found a benefit for greater extent of
resection.
 The phase II portion of RTOG 9802 prospectively
observed 111 low-risk cases after neurosurgically defined gross total
resection. Review of the post-operative MRI emphasized the
importance of post-operative imaging to confirm the extent of
resection because a substantial minority of patients had residual
disease (32% with 1 to 2 cm of residual disease and 9% with more than
2 cm of residual tumor).
The crude incidence of tumor recurrence was 26% with a residual
tumor of less than 1 cm, 68% with a residual tumor of 1 to 2 cm, and
89% with a residual tumor of more than 2 cm.
25

26.  Although there are no randomized trials that directly assess the
impact of maximal tumor resection in low-grade gliomas, a review of
the literature suggests a benefit for Maximal Safe tumor Resection,
recognizing the importance of achieving this with as little morbidity as
possible.
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27. External Beam Radiation
 The key external beam irradiation (EBRT) issues in the
management of supratentorial low-grade gliomas are twofold.
The issues include
the timing of radiation with regard to when radiation is given
(post-operative vs. at the time of recurrence), and
the appropriate dose and treatment volume.
27

28.  EORTC 22845 (Karim et al. 2002; van den Bent et al. 2005) –
phase III: 311 patients (WHO 1–2, 51% astro., 14% oligo., 13%
mixed oligo-astro) treated with surgery (42% GTR, 19% STR,
35% biopsy) randomized to observation vs. post-op RT to 54 Gy.
RT improved median PFS (5.3 year vs. 3.4 year), 5-year PFS (55 vs.
35%), but not OS (68 vs. 66%). Sixty-five percent of patients in the
observation arm received salvage RT.
No difference in rate of malignant transformation (66–72%).
No survival benefit, but RT delays time to relapse by ~2 years.
28

29.  The RTOG phase II portion of protocol 9802 prospectively
observed 111 low-risk (age younger than 40 years and neuro-surgically
defined gross total resection) low-grade glioma patients.
In this “low-risk” population, the 5-year OS was 93%.
Astrocytoma histology,
residual tumor of 1 cm or more according to MR imaging, and
pre-operative tumor diameter of 4 cm or more
were found to be predictive of a poorer PFS.
29

30. In patients with all three unfavorable prognostic factors,
the 2- and 5-year rates of PFS were 60% and 13%, respectively.
In patients with none of the three unfavorable prognostic factors,
the 2- and 5-year rates of PFS were 100% and 70%, respectively.
These data suggest that observation is a reasonable strategy for the
most favorable subset (<1 cm residual tumor, preoperative tumor
diameter <4 cm, and oligodendroglioma histology) of younger patients
after a gross total resection (GTR).
30

31.  Radiation, however, has several other beneficial effects besides
the potential delay in tumor recurrence.
 In a small series of 25 patients with medically intractable epilepsy
resulting from an underlying cerebral low-grade glioma, achieved a
significant reduction (>50% decrease) in seizure frequency after
radiotherapy.
 In the EORTC phase III randomized trial 22845, there were no
differences in seizure control at baseline, but at 1 year there were
significantly fewer seizures in the irradiated group (25%) than in the
observation group (41%).
31

32.  It has been suggested that radiation therapy may either increase or
decrease the likelihood of malignant transformation or may delay
its onset.
 However, in the EORTC phase III randomized trial 22845,
there were no differences in the malignant transformation rate
(observation group-66% vs.72% in the irradiated group) between
the study arms at the time of progression.
 These data imply that irradiation neither increases nor decreases the
likelihood of malignant transformation, suggesting that dedifferentiation
is a biologic phenomenon observed in low-grade gliomas independent
of the treatment.
32

33. Dose of Radiation
 Regarding the potential benefit of higher doses of radiation
therapy compared with lower doses, two prospective randomized
clinical trials (EORTC 22844 and NCCTG 86-72-51) failed
to show improved outcome with higher radiation therapy doses.
 Taken together these trials support moderate doses in the
range of 45 to 54 Gy using localized fields.
33

34.  EORTC 22844 (Karim et al. 1996) – phase III: 343 patients
(WHO 1–2, astro., oligo. and mixed) treated with surgery (25% GTR,
30% STR, 40% biopsy) randomized to post-op RT 45 Gy vs. 59.4 Gy
radiation therapy using multiple localized treatment fields.
Initial analysis failed to demonstrate a difference in survival rates
between the two doses. The 5-year OS was 58% with 45 Gy and 59%
with 59.4 Gy.
Five-year OS oligo vs. astro = 75 vs. 55%,
<40 year vs. >40 year = 80 vs. 60%.
Age <40 year, oligo histology, low T-stage, GTR, and good neurologic
status are important prognostic factors.
34

35.  INT/NCCTG (Shaw et al. 2002) – phase III: 203 patients
(WHO 1–2, astro, oligo, mixed) treated with surgery (14% GTR,
35% STR, 51% Bx) randomized to post-op RT 50.4 Gy vs. 64.8 Gy.
also using multiple localized treatment fields.
Initial analysis also failed to demonstrate a difference in survival
rates between the two doses. The 5-year OS was 73% with
50.4 Gy and 68% with 64.8 Gy.
Best survival in patients <40 year, tumor <5 cm, oligo histology and
GTR.
Pattern of failure: 92% in field, 3% within 2 cm of RT field.
35

36.  Several series analyzing failure patterns in irradiated patients with
low-grade hemispheric gliomas suggest that when tumor progression
occurs, it almost always is at the site of the primary tumor within the
treatment volume, which implies that Partial Brain Irradiation is
appropriate.
 This was confirmed in NCCTG 86-72-51 (prospective dose
response trial) with 92% of failures occurring in the treatment field,
3% within 2 cm of the treatment field, and 5% more than 2 cm
beyond the treatment field.
 These data support the appropriateness of partial brain irradiation.
36

37.  Several phase II Chemotherapy studies have shown efficacy of
both Temozolomide and PCV (procarbazine,CCNU, vincristine)
chemotherapy in either newly diagnosed or progressing low-grade
gliomas.
 The studies on newly diagnosed tumors show that the response
assessment may be difficult, and that most cases have radiologically
stable disease as their best response to chemotherapy
(at times, even despite clinical improvement and improved
seizure control).
 As a result, the PFS appears to be a more informative endpoint than
the radiologic improvement rate.
37

38.  Data from phase III studies on chemotherapy in low-grade
gliomas are scarce.
 The most significant study is the INT/RTOG 9802 trial (ASCO
abstract 2008): phase III of low-grade gliomas.
Low-risk (<40 year + GTR) observed until symptoms.
251 high-risk (>40 year or STR or biopsy) patients randomized to
RT alone vs. RT --> PCV ×6 cycles q8 weeks.
RT 54 Gy to FLAIR + 2 cm margin. No boost.
Five-year OS was 72 vs. 63% (p = 0.33), 5-year PFS was 63 vs. 46%
(p = 0.06) in favour of addition of chemotherapy.
 This study noted an increase of PFS but not OS with radiotherapy
followed by PCV chemotherapy.
38

39.  Recently, Temozolomide has shown its effectiveness in the initial
treatment of low-grade glioma.
 In the largest reported retrospective analysis of 149 patients,
Kaloshi and colleagues reported a 15% partial response (PR) and 37%
stable disease with temozolomide as the initial therapy. The median
PFS was 2.8 years and the 3-year overall survival was 70%.*
*(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.)
39

40. Abstract of the study by Kaloshi et al
 OBJECTIVE:
To evaluate the predictive impact of chromosome 1p/19q deletions
on the response and outcome of progressive low-grade gliomas (LGG)
treated with up-front temozolomide (TMZ) chemotherapy.
 METHODS:
Adult patients with measurable, progressive LGG (WHO grade II)
treated with TMZ delivered at the conventional schedule
(200 mg/m(2)/day for 5 consecutive days, repeated every 28 days) were
retrospectively evaluated for response by central review of MRI-s.
Chromosome 1p and 19q deletions were detected by the loss of the
heterozygosity technique (LOH).
40

41.  RESULTS:
A total of 149 consecutive patients were included in this retrospective,
single center observational study. The median number of TMZ cycles
delivered was 14 (range 2 to 30). 77 patients (53%) experienced an
objective response (including 22 [15%] cases of partial response and 55
[38%] cases of minor response), 55 (37%) patients had stable disease, and
14 (10%) had a progressive disease. The median time to maximum tumor
response was 12 months (range 3 to 30 months). The median progression-
free survival (PFS) was 28 months (95% CI: 23.4 to 32.6).
Combined 1p/19q LOH was present in 42% of the cases and was
significantly associated with a higher rate (p = 0.02) and longer objective
response to chemotherapy (p = 0.017), and both longer PFS (p = 4.10(-5))
and overall survival (p = 0.04).
 CONCLUSION:
Low-grade gliomas respond to temozolomide and loss of chromosome
1p/19q predicts both a durable chemosensitivity and a favorable outcome.
41

42.  An EORTC trial attempts to address the role of temozolomide in
newly diagnosed low-grade glioma patients. This EORTC trial
randomizes patients with progressive disease, uncontrolled seizures
despite anticonvulsants, or neurologic symptoms to standard radiation
therapy or daily low-dose temozolomide. Patients are stratified based
on 1p status (intact vs. deleted), as well as age, tumor size,
and Karnofsky performance status (KPS) score with a primary
endpoint of PFS.
 An Intergroup phase III trial with similar eligibility criteria and
stratification factors is investigating the efficacy of combined
chemoradiation with temozolomide compared with radiotherapy
alone.
42

43. Recommended Treatment
 Juvenile Pilocytic Astrocytoma, Subependymal Giant Cell
Astrocytoma, Pleomorphic Xanthoastrocytoma,
Dysembryoblastic Neuroepithelial tumor :
i) Gross Total Resection  Observation
ii) Sub Total Resection  consider Observation
vs. Re-resection
vs. Radiotherapy
vs. Stereotactic Radiosurgery,
depending on the location of tumor, symptoms, age of patient
43

44.  Oligodendroglioma, Oligoastrocytoma, Astrocytoma (adults) :
i) Maximal safe resection (GTR or STR) 
Observation if - age <40 years,
oligodendroglioma,
GTR,
good function
Serial MRIs - if progresses  Radiotherapy 50–54 Gy
(standard dose for low-grade gliomas is 54 Gy)
44

45. Or,
ii) Immediate Post-operative Radiothrapy to 54 Gy.
No survival benefit, but RT delays time to relapse
by ~2 years (EORTC study)
Quality of life gained by delaying recurrence must be
weighted against QOL lost due to late toxicities of RT
45

46.  Oligodendroglioma, Oligoastrocytoma, Astrocytoma (children) :
i) Maximal safe resection (GTR or STR) 
Observation and serial MRIs.
Adjuvant Radiotherapy may improve DFS, but not
recommended for children <3 years.
ii) Consider Second Surgery for operable progression, and
Radiotherapy for inoperable progression
(doses 45–54 Gy)
46

47.  Dose : EBRT: 1.8 Gy/fx to 50.4–54 Gy.
 Volume of Treatment :
Pilocytic Astrocytomas
GTV: contrast-enhancing lesion and any associated cyst
PTV: GTV plus 1–1.5 cm
Infiltrating Low-Grade Gliomas
GTV: (FLAIR)/T2 abnormality and any contrast enhancement
PTV: GTV plus 1–1.5 cm
 Follow Up :
MRI 2–6 weeks after Radiotherapy, then every 6 month for 5 years,
then annually.
47

48. thank you
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