Brain-stem glioma trial:

Concomitant and adjuvant Temozolomide with radical radiotherapy in children with brain stem gliomas – a prospective study

Principal Investigator: Rakesh JALALI
Co Investigators: Purna KURKURE, Rajiv SARIN, Soumen KHATUA, Nikhil MERCHANT and Tejpal GUPTA

Background and rationale

Brain stem gliomas are perhaps the most challenging paediatric tumours and one of the most dreaded central nervous system neoplasms to treat. These tumours comprise of 15-20% of paediatric brain tumours (Smith). They are universally associated with dismal outlook.

Standard management of these tumours is with local radiotherapy to doses of 54-60 Gy but is largely palliative. While many of these patients may show improvement in neurological function following radiotherapy, a vast majority of them eventually progress leading to median overall survival time of less than a year (Freeman). The 2 year survival unfortunately is less than 10%.

One of the most exciting agents which have generated a considerable amount of interest recently in CNS tumours is Temozolomide (TMZ). TMZ has also been tried in paediatric population with acceptable tolerance.Patients treated with radical intent with TMZ given upfront along with radiotherapy appear to be a reasonable strategy to be tested in a research protocol.

Objective:

To assess the efficacy of TMZ given concomitantly and as an adjuvant to radical radiotherapy in patients with diffuse intrinsic pontine or high grade brain stem gliomas

Study design:

Twenty children presenting with clinical and radiological features characteristic of a brain stem glioma accrued and is under followup.

Endpoint:

• 1) Progression free survival
• 2) Overall survival
• 3) Toxicity of treatment

Eligibility criteria

• 1. Patients aged: 3-21 years
• 2. Presence of at least two of the following: pyramidal tract involvement, cerebellar signs and symptoms and/or cranial nerve deficits attributable to tumour
• 3. Cranial CT/MRI at diagnosis either demonstrating diffuse involvement of the brain stem i.e. at least 50% involvement of a brain stem segment or involvement of more than two of these segments with or without enhancement on injection of intravenous contrast material (ultravist for CT/ gadolinium for MRI).
• 4. Patients with a large exophytic component that exceeded 50% of the total tumour volume would not be generally eligible. However, they would be considered for inclusion if the histology of these tumours after a surgical intervention (biopsy, partial/radical excision) is that of a high grade astrocytoma (WHO grade III- anaplastic astrocytoma or WHO grade IV astrocytoma-glioblastoma multiforme).
• 5. Patients with Lansky scale or Karnofsky Performance status (KPS) of at least of 50% or above (lansky).
• 6. Patients suitable for radical radiotherapy
• 7. Informed consent from the patient’s parents or legal guardians as the case may be.
• 8. Adequate haematological parameters, namely Haemoglobin > 11 grams, total leukocyte count of at least 4000 per mm3 with absolute neutrophil count (ANC) > 1500 per mm3 and platelets > 100,000 per mm3
• 9. Normal hepatic and renal functions, i.e. aspartate aminotransferase or alanine aminotransferase less than 2.5 times the upper limit of normal and serum creatinine < or equal to 1.5 mg%.

Ineligibility criteria

• 1. Prior radiotherapy or chemotherapy
• 2. No severe underlying disease (HIV and chronic hepatitis B or C infection).
• 3. Any medical condition that could interfere with oral administration of TMZ.
• 4. Patients who cannot be followed regularly.
• 5. Patients not suitable or likely to complete the full course of radiotherapy.

Present status:

Accrual of 20 patients completed and is on followup.Interim analysis has been done.