FUTURE DIRECTION IN THE MANAGEMENT OF HIGH RISK LOW GRADE GLIOMA

JOURNAL CLUB

Dr. Joydeep BasuRegistrar

Apollo Gleneagles Cancer Hospital

WHO CLASSIFICATION OF GLIOMA

Grade I – Pilocytic Astrocytoma

Grade II – Diffuse Fibrillary Astrocytoma, Oligoastrocytoma , Oligodendroglioma

Grade III – Anaplastic Astrocytoma

Grade IV – Glioblastoma Multiformes

MANAGEMENT OF LOW GRADE GLIOMA

Maximal Safe Resection of the Tumour

Post operative Radiotherapy

CONTROVERSIESa. Timing of Radiotherapyb. Dose of Radiotherapyc. Role and timing of Chemotherapy

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

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.

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.

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.

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.

DEFINITION OF HIGH RISK LGG PATIENTS

Risk Factors

a) Age > 40 yearsb) Largest pre-operative tumour diameter of >= 6 cm .c) Tumour crossing corpus callosum.d) Astrocytoma histologye) Pre-operative neurological function deficit.

Patients with >= 3 risk factors are considered high risk patients.

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.

BASELINE INVESTIGATIONS

Physical examinations

MRI Brain (with/without contrast)

Full blood counts

Biochemistry assays

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.

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.

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.

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.

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.

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.

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.

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.

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.