Professional Documents
Culture Documents
Lowgradegliomas
Lowgradegliomas
Lowgradegliomas
DR ARNAB BOSE
Dept. of Radiotherapy
NRS Medical Colleg,Kolkata
1
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
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.
3
WHO Grade I lesions have low proliferative potential, with
the possibility of cure following surgery alone.
4
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
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%).
6
The Diffusely infiltrative low-grade astrocytomas (WHO grade II)
are the most common and include the fibrillary, protoplasmic, and
gemistocytic types.
7
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.
8
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.
9
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.
10
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.
11
Tumor Proliferation can be assessed with Ki-67 labeling.
12
Biologic Characteristics :
13
Low-grade gliomas are generally a disease of patients in their
20s, 30s, or 40s.
15
Pilocytic astrocytoma (Grade I) : enhancing nodule,
highly vascular, 50% associated with cysts.
16
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.
18
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
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
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
A number of retrospective studies have suggested a benefit for
greater extent of resection.
23
Investigators from the University of California San Francisco
(UCSF) measured tumor volumes based on FLAIR imaging in 216
low-grade glioma patients.
26
External Beam Radiation
27
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.
28
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.
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
In patients with all three unfavorable prognostic factors,
the 2- and 5-year rates of PFS were 60% and 13%, respectively.
30
Radiation, however, has several other beneficial effects besides
the potential delay in tumor recurrence.
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
Dose of Radiation
33
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.
Best survival in patients <40 year, tumor <5 cm, oligo histology and
GTR.
35
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.
36
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.
37
Data from phase III studies on chemotherapy in low-grade
gliomas are scarce.
39
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
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
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.
43
Oligodendroglioma, Oligoastrocytoma, Astrocytoma (adults) :
44
Or,
45
Oligodendroglioma, Oligoastrocytoma, Astrocytoma (children) :
46
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
thank you
48