Management of Low Grade Gliomas (LGG)Current & Future Trends

Dr. Gaurav KumarNarayana 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

levelproliferative 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/ProgressThey can transform to high gradeThey 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 aremutually 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 seizuresNo 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 yearsSize>6cm

Crossing MidlinePure 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 trialRT 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 ratesNo 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 tumorPreoperative tumor diameter <4 cmOligodendroglioma histologyYounger 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 disease10% - 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