Results of international Phase III clinical trial for newly diagnosed brain tumors announced

In the randomized trial, RTOG 0525 Phase III Trial Comparing Conventional Adjuvant Temozolomide with Dose-Intensive Temozolomide in Patients with Newly Diagnosed Glioblastoma, no significant improvement in overall patient survival or disease progression was observed for patients who received the dose-intensive (dose-dense) TMZ plus radiotherapy as compared to patients who received standard-dose TMZ plus radiotherapy. The trial did however prove the feasibility of collecting and analyzing tumor tissue prospectively in a multi-center setting.. The international trial was led by RTOG principal investigator Mark R. Gilbert, MD (University of Texas M. D. Anderson Cancer Center, Houston) and conducted in concert with the European Organization for Research and Treatment of Cancer (EORTC) and the North Central Cancer Treatment Group (NCCTG).

Four presentations will report study results at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, June 3-7.

"Given the promising preliminary data of improved patient outcomes using an adjuvant dose-intensive schedule of temozolomide, the trial allowed us to robustly test whether this treatment strategy provides a significant benefit over standard-dose temozolomide treatment," says Gilbert. "While dose-dense temozolomide did not demonstrate improved efficacy for patients newly diagnosed with a glioblastoma, the study results confirmed the prognostic significance of MGMT gene methylation and demonstrated the feasibility of prospective tumor tissue collection, molecular stratification and collection of patient outcomes in a large transatlantic intergroup trial."

One hundred and eighty-five facilities in North America and 24 facilities in Europe enrolled 1173 study participants. Key study eligibility criteria required that tumor tissue, obtained at the time of biopsy or surgery and with patient consent, be sent for central pathology review to confirm the tumor as a glioblastoma and as adequate to perform MGMT gene methylation analysis and molecular risk classification (to assess whether a correlation exists between these biomarkers and study participant outcomes).

Upon pathology confirmation, eligible patients were enrolled in the trial and randomized into one of two adjuvant treatment arms: Arm 1 (standard arm: TMZ days 1-5 every 28 days for up to 12 cycles/months) or Arm 2 (experimental arm: TMZ days 1-21 every 28 days for up to 12 cycles/months).

Study participants were stratified to assess correlation of their outcome with three major criteria: (1) prognostic recursive partitioning (based upon age, performance status, extent of pretreatment surgery, neurologic function and mental status), (2) MGMT status (methylated, unmethylated, or indeterminate) and (3) radiation therapy treatment (US standard vs European).

Trial co-chair for neuropathology and correlative biology Kenneth D. Aldape, MD (M.D. Anderson Cancer Center, Houston), comments, "In this trial we've demonstrated the positive correlation between clinical outcomes and molecular classification of glioblastoma, which will enable improved future prognostic prediction, spur the development of specific therapies based on tumor biology, and ultimately lead to individualization of treatment." Aldape will present findings of the tumor tissue profiling at the 2011 ASCO Annual Meeting.

"This trial was a tremendous undertaking with the complexities of confirming the presence of the MGMT gene as an eligibility criteria -- the first time a molecular marker has been used in this manner -- and of conducting the trial internationally," says RTOG Group Chair Walter J. Curran, MD, FACR,(Winship Cancer Institute of Emory University, Atlanta). "The collaboration with EORTC and NCCTG significantly helped to expedite trial enrollment and consequentially to expediently report trial results."

The clinical trial also included longitudinal data collection to measure neurocognitive function, symptom burden and health-related quality of life, collectively called net clinical benefits. The important correlations of these measures with outcomes shown by the trial will also be reported at the ASCO meeting, along with seven presentations regarding other RTOG trials.

RTOG 0525 was supported by Award Number U10CA021661 from the National Cancer Institute.