Oligodendrogliomas

NEW ORLEANS—Results of a randomized Phase III study initiated in 1994 showed that aggressive treatment with neoadjuvant chemotherapy followed by radiotherapy failed to prolong survival for patients with newly diagnosed pure and mixed oligodendrogliomas compared with the use of radiotherapy alone. Although the duration of progression-free survival was longer in patients who received neoadjuvant procarbazine, lomustine, and vincristine (PCV) and radiation (aggressively treated patients), overall survival was not different compared with patients who were treated with radiotherapy alone, said J. Gregory Cairncross, MD, of the Department of Clinical Neurosciences at the University of Calgary and Foothills Hospital in Alberta, Canada, in reporting the results here at the ASCO Annual Meeting. The study identified 1p and 19q allelic loss as an independent predictor for significant improvement in survival, he reported. Temozolomide Preferred At the time the study was initiated, the genetics of oligodendroglioma were just beginning to be elucidated, and temozolomide was under development, he said, noting that he no longer uses PCV chemotherapy and that temozolomide would now be the preferred agent. The study enrolled 299 patients randomized at 76 institutions across North America. Eight patients were ineligible. The analysis Dr. Cairncross presented was on eligible patients. Seventy-three percent of patients received chemotherapy as per protocol; 46% of patients completed four full-dose cycles of intensive PCV. Seventy-nine percent of patients received radiotherapy as per protocol. Three-year survival data were available for 84% of eligible cases. Seventy-nine percent assigned to the radiotherapy arm were treated with chemotherapy at disease progression. The treatment arms were balanced for demographics and disease characteristics. Two thirds of tumors were pure and one third were mixed oligodendrogliomas. Patients were stratified by age, performance status, and degree of anaplasia in the tumor and then randomized to the experimental arm (intensive PCV times for 4 cycles, followed by radiation therapy) versus radiation alone. Seventy-nine percent of patients in the radiotherapy arm eventually had disease progression and were treated with chemotherapy. The median overall survival times were similar–4.9 years in the experimental arm vs 4.7 years in the control arm. For progression-free survival, a statistically significant difference favored the experimental arm: 2.5 vs 1.9 years, respectively. Similarly for time to progression: three years in the experimental arm vs 2.2 years in the control arm.Figure: J. Gregory Cairncross, MD: “1p, 19q deletion was a significant predictor of improved survival in this tumor type, and probably defines a particular kind of high-grade glioma, one that might be tested separately in future trials.”Toxicity & Quality of Life Thirty-two percent of patients receiving PCV had a Grade 4 toxicity and 32% had a Grade 3 toxicity. The most common toxicities with this regimen were hematologic—peripheral neuropathy related to vincristine, and nausea and vomiting. Radiotherapy-related side effects were comparatively minor, Dr. Cairncross reported. Grade 1 and 2 skin reactions were common; there were rare Grade 3 and 4 central nervous system toxicities, such as seizures or transient neurological deterioration in the early phases of radiation. No data were available on quality of life at the time of the report at the ASCO meeting. A companion molecular analysis on 70% of patients showed that both arms were balanced with respect to 1p deletion, 19q deletion, and combined 1p and 19q deletions; 46% of tested cases had 1p and 19q loss. “1p, 19q deletion was a significant predictor of improved survival in this tumor type, and probably defines a particular kind of high-grade glioma, one that might be tested separately in future trials,” Dr. Cairncross stated. Referring to a study presented at the Plenary Session by Roger Stupp, MD (Abstract #2, OT, 7/10/04), Dr. Cairncross said, “With this moderately chemosensitive tumor, there was no impact on survival by aggressive initial treatment. Another paper at ASCO reports on a chemoresistant tumor where novel use of temozolomide [plus radiotherapy yielded a different result. I think it's fascinating to have these two studies juxtaposed at this meeting.” When asked how patients with no 1p, 19q allelic deletion should be treated, Dr. Cairncross said he relies on radiation therapy. He added that there is no evidence to support a role for chemotherapy as used in the study in that group of patients. “There might be another way in which to incorporate chemotherapy into their initial treatment that would be beneficial,” he suggested. Timing of Chemotherapy? The Discussant for Dr. Cairncross's study, Patrick Y. Wen, MD, Associate Professor of Neurology at Dana-Farber Cancer Institute, said, “The major point in this paper is that 79% of patients in the radiation therapy arm eventually got chemotherapy at progression. So this is not really a study comparing radiation therapy alone to radiation therapy with chemotherapy, but rather, a study of when to get chemotherapy.” Since outcomes were similar regardless of whether patients were treated with PCV upfront or at relapse, given the toxicity of intensive PCV, treatment should probably be at recurrence if this regimen is used, Dr. Wen said. Clinical Practice Has Evolved Since Study Started He emphasized that clinical practice has evolved since this study was first initiated. Temozolomide is becoming more widely used, and several studies support the role of this agent in anaplastic oligodendrogliomas and mixed gliomas. “And temozolomide, as we all know, is a much better tolerated regimen, so the issue of toxicity becomes less of a problem,” Dr. Wen said. Based on the work of Dr. Cairncross and his colleague, David Lewis, patients are being genotyped for 1p19q loss. This study also supports the association of deletion of 1p19q with improved survival. “Interestingly, survival in patients with 1p19q deletion was independent of initial treatment, which raises the issue of whether the deletion is associated with increased sensitivity to treatment, better prognosis, or perhaps a combination of both,” Dr. Wen continued. At this time, patients with anaplastic oligodendrogliomas and mixed gliomas should be treated with temozolomide and radiation therapy in some combination, he said. “The exact timing of temozolomide probably doesn't matter that much. Increasingly, people are deferring radiation therapy, and the significance of this is not clear. Deferring radiation therapy may reduce progression-free survival, but probably will not affect overall survival. Patients with intact 1p and 19q should be treated with radiation therapy and be considered early for experimental treatments.” Discussant Patrick Y. Wen, MD: “Interestingly, survival in patients with 1p19q deletion was independent of initial treatment, which raises the issue of whether the deletion is associated with increased sensitivity to treatment, better prognosis, or perhaps a combination of both.”

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