Both radiation and temozolomide, a generic chemotherapy treatment in pill form, have meaningful single-modality anti-tumor activity against slow-growing, low-grade gliomas. The randomized phase 3 trial E3F05 by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) tested whether combined therapy using temozolomide alongside radiation therapy is more effective than radiation therapy alone in these patients. The trial followed 172 patients for more than 10 years, and its results have an immediate clinical impact by providing the first evidence from a randomized phase 3 trial that temozolomide improves long-term survival for these patients.
We found that the 10-year survival rate was 70% with the combined treatment with temozolomide chemotherapy and radiation, compared to 47% with radiation alone as the initial approach. This discovery is important because until now, we have not had compelling evidence that temozolomide improves overall survival in grade 2 gliomas."
David Schiff, MD, lead investigator, the Harrison Distinguished Professor of Neurology, Neurological Surgery and Medicine and co-director, UVA Neuro-Oncology Center, University of Virginia
Dr. Schiff presented the striking results as a late-breaking abstract at the Society of Neuro-Oncology's 2024 SNO Annual Meeting. The trial was funded by the US National Institutes of Health's National Cancer Institute through its National Clinical Trials Network (NCTN).
The E3F05 trial started in September 2009 and enrolled patients with low-grade gliomas who had not received prior radiation or chemotherapy treatment. Trial participants were randomized 1:1 to receive either radiation alone (50.4 Gy in 28 fractions) or radiation (50.4 Gy) with temozolomide followed by 12 four-week cycles of post-radiation temozolomide).
Accrual stopped five years later, in 2014, after another cooperative group trial, RTOG 9802 (also funded by the NCI) reported benefit from the addition of PCV chemotherapy to radiation in grade 2 gliomas. PCV is procarbazine (P), CCNU (C), which generically is known as lomustine, and vincristine (V). By the time accrual stopped, 172 patients had enrolled in E3F05. The median age of the 172 participants was 44 (range 19-78), and 54% were male.
"Because the RTOG 9802 trial was positive for a benefit from PCV chemotherapy, it was no longer ethical to have a radiation-alone arm in E3F05, which is why our trial was closed to accrual. Even though we could not enroll the entire group as planned, after following all patients on the trial, results reached statistical significance showing the benefit of combined-modality temozolomide versus radiation alone," said Dr. Schiff.
The results of this trial will have an immediate clinical impact.
"Since the results of RTOG 9802 came out in 2014, patients with grade 2 glioma are routinely receiving radiation plus chemotherapy. Some are getting PCV because that is what RTOG showed was beneficial. Others are getting radiation plus temozolomide because temozolomide is a lot easier for the oncologist to give and a lot less toxic for patients to take, and it doesn't involve an intravenous infusion of vincristine. But until now, there really was no supporting evidence in grade 2 gliomas that temozolomide was beneficial," said Dr. Schiff.
While grade 3 or higher toxicity was more common in E3F05 trial participants treated with temozolomide compared to radiation, toxicity was consistent with prior studies of temozolomide.
"There were no unexpected toxicities from the addition of temozolomide," said Dr. Schiff. "We saw more fatigue, gastrointestinal distress (nausea), and myelosuppression (thrombocytopenia, neutropenia, etc.) but very similar to what has been reported many, many times."
He added, "Importantly, the magnitude of survival benefit from the addition of temozolomide was similar in oligodendrogliomas and astrocytomas. This finding stands in contrast to some uncontrolled and retrospective studies suggesting that temozolomide may be significantly less effective against oligodendrogliomas than PCV."
There is more to come from E3F05. Pending correlative studies are investigating the quality of life and neurocognitive data collected from patients on both arms of the study, as well as additional molecular analyses.
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