Radiation Therapy or Temozolomide in Treating Patients With Gliomas

• Overall survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
• Quality of life as measured by QLQ-C30 v3.0 and EORTC BN-20 [ Time Frame: every 3 months until progression, and then every 6 months until death ] [ Designated as safety issue: No ]
• Mini-Mental State Examination [ Time Frame: every 3 months until progression, and then every 6 months until death ] [ Designated as safety issue: No ]
• Adverse events as measured by CTCAE v3.0 [ Time Frame: As indicated in the protocol ] [ Designated as safety issue: Yes ]

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether radiation therapy is more effective than temozolomide in treating gliomas.

PURPOSE: This randomized phase III trial is studying radiation therapy to see how well it works compared to temozolomide in treating patients with gliomas.

OBJECTIVES:

Primary

• Compare the progression-free survival of patients with low-grade gliomas treated with radiotherapy vs temozolomide.

Secondary

• Compare the overall survival of patients treated with these regimens.
• Determine whether the incidence of late toxicity can be decreased in patients who are randomized to receive temozolomide.
• Compare the toxic effects of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, controlled, multicenter study. Patients are stratified according to participating center, chromosome 1p status (deleted vs normal vs undeterminable), contrast enhancement on MRI (yes vs no), age (< 40 years vs ≥ 40 years), and WHO performance status (0 or 1 vs 2). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo radiotherapy once daily, 5 days a week, for a total of 28 fractions (i.e., 5½ weeks).
• Arm II: Patients receive oral temozolomide once daily on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and then every 3 months until disease progression.

After completion of study treatment, patients are followed every 6 months for survival.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A minimum of 699 patients (a total of 466 randomized [233 per treatment arm]) will be accrued for this study within 5 years.

• Drug: temozolomide
  Temozolomide 75 mg/m2 daily x 21 days, q 28 days until progression or for max. 12 cycles
• Radiation: radiation therapy
  50.4 Gy, standard fractionation (28 x 1.8 Gy), conformal techniques

• radiotherapy
  Radiotherapy (control arm), 50.4 Gy, standard fractionation (28 x 1.8 Gy), conformal techniques
  Intervention: Radiation: radiation therapy
• Experimental: Temozolomide
  Temozolomide 75 mg/m2 daily x 21 days, q 28 days until progression or for max. 12 cycles (experimental arm)
  Intervention: Drug: temozolomide

DISEASE CHARACTERISTICS:

• Histologically confirmed low-grade glioma, including any of the following types:

  • Astrocytoma (gemistocytic, fibrillary, or protoplasmatic)
  • Oligoastrocytoma
  • Oligodendroglioma
• WHO grade II disease
• Supratentorial tumor location only
• RTOG neurological function 0-3
• Not a candidate for surgical treatment alone

• Requires treatment, as determined by ≥ 1 of the following criteria:

  • Age ≥ 40 years
  • Radiologically-proven progressive lesion
  • New or worsening neurological symptoms other than seizures only (e.g., focal deficits, signs of increased intracranial pressure, or mental deficits)

  • Intractable seizures, defined by both of the following criteria:

    • Experiences persistent seizures that interfere with everyday life activities except driving a car
    • Failed 3 anti-epileptic drug regimens, including ≥ 1 combination regimen
• Tumor material (paraffin-embedded) or histopathologic slides available

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• WHO 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• No chronic hepatitis B or C infection
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST or ALT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN

Renal

• Creatinine ≤ 1.5 times ULN

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 6 months after completion of study treatment
• No known HIV positivity
• No other serious medical condition
• No other prior or concurrent malignancy except surgically cured carcinoma in situ of the cervix or nonmelanoma skin cancer
• No psychological, familial, sociological, or geographical condition that would preclude study participation
• No medical condition that would preclude receiving oral medication (e.g., frequent vomiting or partial bowel obstruction)

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent growth factors for elevating absolute neutrophil counts for the purpose of temozolomide administration
• No concurrent epoetin alfa
• No concurrent immunotherapy or biologic therapy

Chemotherapy

• No prior chemotherapy
• No other concurrent chemotherapy, including adjuvant chemotherapy for patients randomized to undergo radiotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy to the brain
• No concurrent integrated boost with intensity-modulated radiotherapy

Surgery

• Recovered from prior surgery
• No concurrent surgical tumor debulking

Other

• No prior randomization to this study
• No other concurrent investigational drugs

• No concurrent regular use of agents known to be radiosensitizers or radioprotectors (e.g., cyclooxygenase-2 inhibitors, thalidomide, or amifostine) during study radiotherapy

  • Occasional use of nonsteroidal anti-inflammatory drugs for pain allowed

• NCIC Clinical Trials Group
• British Medical Research Council
• Trans-Tasman Radiation Oncology Group (TROG)