BY SUSAN KREIMER
Adjuvant temozolomide chemotherapy following radiotherapy significantly improved survival for patients with newly diagnosed 1p/19q non-co-deleted anaplastic glioma and should comprise the standard of care, the findings of a large international study published in the August 8 online edition of The Lancet suggested.
The absence or presence of the favorable molecular marker — 1p/19 co deletion molecular marker — has long been known to have an impact on survival in patients with anaplastic glioma, the study authors pointed out.
The results from the interim analysis from the CATNON trial — a phase 3, randomized, open-label intergroup study involving 745 patients — warranted immediate release, the researchers said.
With adjuvant temozolomide, the five-year overall survival rose from 44 percent to 56 percent, and median progression-free survival increased from 19 to 43 months. The survival curves for adjuvant compared with no adjuvant temozolomide widened further with expanding length of follow-up, which implies that overall survival could augment even more with time.
"It really paves the way for using temozolomide instead of a more toxic regimen," Martin J. van den Bent, MD, PhD, the study's principal investigator and head of the neuro-oncology unit at Erasmus MC Cancer Center in Rotterdam, the Netherlands, told Neurology Today.
The international collaboration is the first glioma study to base eligibility on a molecular marker. When it was launched in 2005, patients with anaplastic oligodendrogliomas, which were thought to be responsive to chemotherapy, had shown no survival benefit from treatment with procarbazine, lomustine, and vincristine chemotherapy administered after radiotherapy. In addition, prognosis was much worse in patients with 1p/19q non-co-deleted tumors than in those with 1p/19q co-deleted tumors.
"These so-called anaplastic gliomas are a mixed bag of different tumor types," Dr. van den Bent said, including the anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma or mixed glioma. "But there are two major types of anaplastic gliomas and that has to be defined at the molecular level."
Investigators are carefully examining whether it would be beneficial to combine giving temozolomide alongside radiation therapy. However, before reaching a conclusion, they want to be sure the co-treatment improves outcomes and avoids compounding side effects, Dr. van den Bent added.
Implications of all the available evidence suggest that the standard of care for 1p/19q non-co-deleted anaplastic glioma should be surgery followed by radiotherapy and 12 four-week cycles of temozolomide given on days one to five, the investigators wrote.
In the current study, researchers tested treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma. Further analysis is underway to evaluate the role of concurrent temozolomide treatment with radiotherapy and the effects of molecular signatures on outcome, Dr. van den Bent said, and additional data are likely to be released next year.
Between Decemer 2007 and September 2015, investigators screened 1,407 patients and randomly assigned 748 to four treatment groups (radiotherapy alone or with 12 cycles of adjuvant temozolomide or radiotherapy with concurrent temozolomide, with or without adjuvant temozolomide). They aimed to answer two questions: whether use of concurrent temozolomide improves overall survival irrespective of treatment with adjuvant temozolomide, and whether administration of adjuvant temozolomide improves overall survival irrespective of concurrent temozolomide.
Eligible patients had newly diagnosed anaplastic glioma without 1p/19q co-deletion, were at least 18 years old, and were taking stable or decreasing doses of corticosteroids. Prior surgery for low-grade glioma was allowed if an anaplastic tumor had been histologically confirmed at the time of progression. Treatment with other experimental agents was not permitted. Radiotherapy had to begin within seven weeks of surgery and within eight days of randomization.
Patients underwent weekly assessments during radiotherapy, every four weeks during adjuvant temozolomide treatment, and every three months after the completion of all treatment. Tumors were evaluated with magnetic resonance imaging at baseline, four weeks after the end of radiotherapy, and every three months thereafter until disease progression.
Treatment was generally well tolerated. Of the 549 patients who were randomized to receive temozolomide, 8 to 12 percent had grade 3-4 toxicity, with the most frequent event being thrombocytopenia (7-9 percent). Adverse events were mainly hematological and reversible. The median follow-up was 27 months (95% CI 25–30).
In the interim analysis, which addresses the second question, investigators reported a significant overall survival benefit with adjuvant temozolomide: The five-year overall survival was 55.9 percent, 95% CI 47.2–63.8 compared with 44.1 percent, 36.3–51.6 without adjuvant temozolomide.
Furthermore, in the treatment groups not given adjuvant temozolomide chemotherapy, 200 (54 percent) of 372 patients had disease progression, compared with 144 (39 percent) of 373 in those who did receive adjuvant chemotherapy.
The study still raises the issue of whether six cycles of temozolomide are sufficient, or whether 12 cycles may lead to better outcomes. In the report, Dr. van den Bent and his collaborators stated that they opted for 12 cycles of adjuvant temozolomide, whereas six cycles of adjuvant temozolomide are recommended for glioblastoma.
"We decided to use 12 cycles to ensure that patients assigned to receive adjuvant chemotherapy without preceding concurrent chemoradiotherapy would have sufficient exposure to temozolomide," they explained. "The role of concurrent temozolomide remains to be clarified. Concurrent radiotherapy and temozolomide improves outcomes in glioblastoma, but it remains unknown whether both concurrent and adjuvant temozolomide are needed for the improvement of outcomes in this disease."
The investigators speculated whether "the risk of late neurotoxic effects might be increased by concurrent administration of temozolomide and radiotherapy." These particular data "will be especially relevant in patients with favorable prognoses," they wrote.
At this point, a follow-up to the report in The Lancet would be immature, the investigators wrote, because 30 percent of patients have died and 46 percent incurred disease progression by the time of the interim analysis.
Look for expanded coverage of the study, including commentary from experts, in an upcoming issue of Neurology Today.