Management of Low Grade Gliomas (LGG)

Current & Future Trends

Dr. Gaurav Kumar

Narayana Superspeciality Hospital
Gliomas are divided into low grade and high grade based on:
nuclear abnormalities, mitoses, endothelial proliferation, and
necrosis.

Currently Most widely used: WHO grading system

WHO Grade I lesions have low proliferative potential.

WHO Grade II neoplasms are infiltrative, recur, and tend to
progress to higher grades of malignancy despite low level
proliferative activity
WHO Grade III & IV: High grade Gliomas with marked
nuclear atypia & high mitotic counts.
Grade I: Pilocytic Astrocytoma, typically have
very slow growth rate, rare mitosis &rarely transforms and
possibile to be cured by surgery alone.

Grade II: Diffusely infiltrative low-grade astrocytomas include

the fibrillary, protoplasmic, and gemistocytic types.

This group poses the challenge:

They can recur/Progress
They can transform to high grade
They occur in relatively younger population

So, there lies the true need of

Multimodal treatment
Most oligoastrocytomas and 50% to 75% of oligodendrogliomas
recur as AAs or GBM.

Tumor Aggressiveness can be assessed with Ki-67 labeling.

Multiple studies has revealed correlation between

high Ki-67/MIB 1 labeling index with increasing grade of
malignancy.
Genetic Makeup :

1p and 19q codeletion : Associated with better prognosis

and are common in oligodendrogliomas.

TP53 mutations: Common in diffuse astrocytomas and

are
mutually exclusive from 1p/19q co-deletions.

IDH1 mutations found both in tumors with TP53

mutations and in tumors with1p/19q co-deletions.
Case Summary:
Clinical:
42 yrs old right handed male
P/W: 04 months history of on-off headache
01 month history of focal seizures
No comorbidities

MRI Findings:
Hypo-intense on T1,
Hyper-intense on T2/FLAIR ,
Non-enhancing,
Well-circumscribed, solid SOL,
Size- 5.5x6 cm,
Not crossing midline.

Surgery:
Maximum Safe Resection
Images:

A: T1 Non Contrast
B: T2
C:T1 Contrast
HP:
Mixed Oligoastrocytoma; WHO Grade II

IHC:
1p&19q Codeleted

Postop MRI:
Small residual disease with moderate perilesional edema & P/O
Changes.

Clinically patient is asymptomatic, no neurological deficit.

Now what?
Questions needed to be addressed:

1] Immediate Postop RT vs RT at Disease Progression?

2] Dose of RT?

3] RT Alone or RT + Chemotherapy?

4] If Chemotherapy added to RT- Which Chemotherapy?

5] RT alone vs Chemotherapy alone at Disease progression?

6] Disease Progression after PORT?

 1] Immediate vs delayed PORT

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)
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.

RTOG 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%
So, on the basis of above 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 !!!!

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.
 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.

3] RT Alone or RT + Chemotherapy?

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
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
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
 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
4] If Chemotherapy added to RT- Which Chemotherapy?

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
5] RT alone vs Chemotherapy alone at Disease progression?

Head to Head trial lacking

HOANG-XUANK., CAPELLEL. et al. : Temozolomide as initial

treatment for adults with low-grade oligo-dendrogliomas or
oligoastrocytomas and correla-tion with chromosome 1p
deletions. J. Clin.Oncol., 2004, 22(15) : 3133-8.

BRADA M., VIVIERS L. et al. Phase II study of primary

temozolomide chemotherapy in patients with WHO grade II
gliomas. Ann. Oncol., 2003, 14(12) : 1715-21
Ann Oncol. 2003 Dec;14(12):1722-6.
Temozolomide chemotherapy for progressive low-grade
glioma: clinical benefits and radiological response.
Pace A et. al.

High response rate of 47% (95% CI 31% to 61%) confirms that

TMZ chemotherapy is a valid option in the treatment of
progressive LGG specially in children below 5 years age.

For Adults: Replacing RT with chemotherapy at progression need

more robust & head to head comparable data.
6] Disease Progression after PORT?

Options Include

Resurgery (If resectable)

Chemotherapy (Unresectable disease)

Reirradiation with SRS/FSRT (Small recurrences)

Newer agents under trial (Blocking mTOR with an investigational

agent ridaforolimus ).
Take Home Massage:

1] Immediate PORT High Risk Low Grade Glioma (Astrocytoma

histology, Residual >1 cm, Preop tumour > 4/6 cm, Age >40 years).

2] Dose of PORT – 54 Gy/30# (No role of dose escalation)

3] Adjuvant PCV/ Temozolomide –Still not standard of care but can be

considered in patients with High Risk Disease with 1p & 19q codeleted
& IDH1/2 mutated (Subject to individual risk benefit assessment).

4] Radiotherapy still standard of care (above chemotherapy) in adult

patients with progressive disease (Patient kept under observation
after surgery)

5] Chemotherapy with Temozolomide is equally effective and less toxic

as compared to PCV and can be incorporated as adjuvant, salvage
therapy.
Thank You