This seminar is presented in weekly journal club and seminar conducted in Apollo Hospital,Kolkata Department of Radiation Oncology

1. FUTURE DIRECTION IN THE MANAGEMENT OF
HIGH RISK LOW GRADE GLIOMA
JOURNAL CLUB
Dr. Joydeep Basu
Registrar
Apollo Gleneagles
Cancer Hospital

2. WHO CLASSIFICATION OF GLIOMA
 Grade I – Pilocytic Astrocytoma
 Grade II – Diffuse Fibrillary Astrocytoma,
Oligoastrocytoma , Oligodendroglioma
 Grade III – Anaplastic Astrocytoma
 Grade IV – Glioblastoma Multiformes

3. MANAGEMENT OF LOW GRADE GLIOMA
Maximal Safe Resection of the Tumour
Post operative Radiotherapy
CONTROVERSIES
a. Timing of Radiotherapy
b. Dose of Radiotherapy
c. Role and timing of Chemotherapy

5. TIMING OF RADIOTHERAPY
EORTC 22845
 314 patients with LGG were randomized to observation or post-
operative radiotherapy
 Patients who were observed, received radiation on progression.
 Dose – 54Gy/30Fr/6 weeks
 Median PFS was 5.3 years in early RT arm vs 3.4 years in
observation arm (p <0.0001).
 Seizure control was superior in early RT arm
 Median survival (7.4 vs 7.2 years) & future malignant
transformation rate in both arms are similar

7. DOSE OF RADIOTHERAPY
EORTC 22844
 379 Patients were randomized to receive 45Gy in 5 weeks or
59.4Gy in 6.6 weeks.
 Median follow up of 7.4 years
 Overall Survival (56% vs 59%) & Progression free survival
(47% vs 50%) were similar in both groups.

8. DOSE OF RADIOTHERAPY CONTD.
Joint NCCTG, RTOG & ECOG study
 203 patients were randomized to 50.4Gy in 28 Fr. or 64.8Gy in
36 Fr.
 No difference in PFS & OS between both arms
 Grade 3 &5 neurotoxicity occurred in 5% of patients in high
dose arm & 2.5% of patients in low dose arm.
 Low dose radiotherapy is the standard of care for patients
with Low Grade Glioma.

10. TRIAL DETAILS
 RTOG 0424 is a single arm Phase II trial.
 Survival data are compared with historical data.
 43% (40.5 months to 57.9 months) increase in median survival
time & 20% (54% to 65%) increase in 3 year overall survival are
required for statistical significance.

11. TRIAL DETAILS CONTD.
 Study was started in Jan. 2005
 Amended in Feb. 2006 for post hoc determination of QOL,
neurological functional status evaluation & Methylguanine DNA
methyltransferase promoter methylation status.
 Study was closed in Aug. 2009.
 Total 136 patients entered the study of which 7 were excluded from
the final analysis.
 So 129 HIGH RISK patients were available for the final analysis.

12. DEFINITION OF HIGH RISK LGG PATIENTS
Risk Factors
a) Age > 40 years
b) Largest pre-operative tumour diameter of >= 6 cm .
c) Tumour crossing corpus callosum.
d) Astrocytoma histology
e) Pre-operative neurological function deficit.
Patients with >= 3 risk factors are considered high risk patients.

13. ELIGIBILITY CRITERIA
 Supratentorial WHO Grade II astrocytoma, oligoastrocytoma,
oligodendroglioma confirmed by central pathology review with
at least 3 risk factors.
 Cancer free for at least 5 years
 Must be enrolled < 12 weeks from surgery
 Pre-treatment ECOG performance status of 0 to 2
 Pre & post operative brain MRI with & without contrast were
required within 4 weeks of surgery.

14. BASELINE INVESTIGATIONS
 Physical examinations
 MRI Brain (with/without contrast)
 Full blood counts
 Biochemistry assays

15. TREATMENT
 Maximal safe Resection
 Radiation therapy by 3-D conformal radiation (3-D CRT) to a
dose of 54Gy/30 Fraction/6 weeks
 Radiation volume – Post-operative T2 weighted MRI images of
residual tumour and/or surgical cavity plus a 2 cm margin is
used.

16. TREATMENT CONTD.
 Concurrent oral Temozolamide (Dose - 75 mg/m2/day) was
given during radiation
 Adjuvant oral Temozolamide (Dose – 150-200 mg/m2/day), Day
1-5, repeated every 28 days for upto 12 cycles.
 Prophylaxis was given for P. carinii infection.
 Dose modification done on basis of low blood count.
 Drug stopped on progression or unacceptable toxicity.

17. FOLLOW UP
 Evaluated monthly post radiation during adjuvant TMZ therapy.
 After 4 month post – TMZ adjuvant therapy.
 Every 6 months thereafter.
 MRI brain was done 4 weeks post radiation & then every 3
months.

19.  123 of 129 patients (95.3 %) received radiation
according to protocol.
 Target volume received 90% - 110% of the prescribed
total dose of radiation.
 98 of 129 patients (80%) received chemotherapy
according to protocol.
 Median follow up for all patients and all surviving
patients were 4.1 years & 5.0 years respectively.

20. RESULTS
 3 year OVERALL SURVIVAL is 73.1% which is significantly
higher than the historical data (p < 0.001).
 Median PROGRESSION FREE SURVIVAL was 4.5 years.
 3 year PROGRESSION FREE SURVIVAL was 59.2%.
 Median survival time has not been reached.
 Analysis of relation between OS & PFS with risk factors showed
that only histology is significantly associated with OS & PFS.

23. CRITICISM OF THE STUDY
 Data are compared with historical data. Surgery, imaging,
radiation planning & treatment delivery have changed a lot over
time.
 There was lack of central pathological review in historical
studies.
 There is difference in timing of treatment intervention in Low
Grade Glioma patients in US & Europe. In Europe treatment is
delayed till tumour or symptom progression. It is not so in USA.
This leads to Lead Time Bias.

24. MOLECULAR SUBGROUP ANALYSIS
 Patients with MGMT methylation has increased response to
Temozolamide.
 1p19q codeletion, IDH mutation are associated with increased
response to Temozolamide.
 Study was amended in Feb. 2006 and tissue samples are
collected for post hoc determination of MGMT methylation
status.
 Molecular analysis of 1p19q codeletion, IDH mutation, PTEN
promoter methylation is underway and will be reported
separately.

28.  In order to fit the trial data to EORTC SURVIVAL CALCULATOR
a) tumor size had to be reclassified as <5 cm versus 5cm
(rather than <6 cm vs 6 cm)
b) 5 histopathological categories had to be reassigned to
2 categories (ie astrocytoma vs oligodendroglioma
and oligoastrocytoma [O/OA]).
 According to the survival calculator there are 12 low risk cases.
Remaining 117 patients are intermediate & high risk patients.
 Comparison with EORTC & RTOG/NCCTG trials show similar
survival in high risk group, & somewhat improvement in survival
in intermediate risk group.

32. CONCLUSION
 Initial results show that addition of chemotherapy to radiation
therapy for LGG patients has survival benefit.
 Further molecular analysis is required for determining the
subgroup of patients who will benefit from addition of
chemotherapy the most.
 Future efforts should also include neurocognitive assessment,
QOL, and development of surrogates for OS to allow for earlier
evaluation of results in this group of patients with prolonged
OS.