Martin J. Van Den Bent, MD
Results from a phase III trial investigating the benefit of adjuvant temozolomide in combination with radiation therapy (RT) has the potential to be “practice changing” for a rare type of brain cancer, according to its lead author, Martin J. van den Bent, MD, at the 2016 ASCO Annual Meeting.
The trial found that patients with anaplastic glioma who did not have the codeletion of chromosome arms 1p and 19q demonstrated 5-year survival rates of 56% when temozolomide was added to RT compared with survival rates of 44% in patients who did not receive the adjuvant chemotherapeutic agent.
Further, the addition of adjuvant temozolomide also delayed disease progression by more than 2 years, said van den Bent, professor of Neuro-Oncology at Erasmus MC Cancer Center in Rotterdam, The Netherlands. The median time to disease progression was more than twice as long in the adjuvant temozolomide group (42.8 months vs 19 months).
Previous phase III studies conducted have shown that administering temozolomide during and after RT improves outcomes in glioblastoma in patients who are chemotherapy insensitive. In another trial, when chemotherapy was administered after RT in chemotherapy-sensitive patients with anaplastic glioma, it had no impact on outcome.
In these studies, the researchers noted worse outcomes in a particular subset—glioma patients without the 1p/19q co-deletion, which led to the question, ‘if we give temozolomide to treat patients with glioma without the co-deletion, would it improve their outcome?’
To find out, researchers registered and screened 1407 patients from 118 institutions in 12 countries across 3 continents. To be eligible for the trial, patients had to have a confirmed diagnosis of anaplastic glioma and the absence of 1p/19q. After confirming the diagnosis, 751 patients were randomized between December 2007 and September 2014.
“Patient samples had to be sent in before they were considered for inclusion,” said van den Bent, which added to the complexity and difficulty in identifying appropriate candidates. Anaplastic gliomas are rare, accounting for about 2% of primary brain cancers, with 1250 to 1500 new patients diagnosed in the United States yearly. The disease often strikes young adults, and the median age is 35 to 50 years at diagnosis.
In the trial, patients were randomly assigned to 4 different treatment groups: RT alone; RT with concurrent daily 75 mg/m2
temozolomide; RT followed with 12 cycles of 150-200 mg/m2
adjuvant temozolomide; and RT with both concurrent temozolomide and 12 cycles of adjuvant temozolomide. The primary endpoint was overall survival (OS). All patients received RT 59.4 Gy in 33 fractions.
An interim analysis conducted October 6, 2015, and based on 221 events (median follow-up: 27 months) showed a hazard ratio (HR) reduction for OS of 0.645 (95% CI 0.450-0.926; P
= .0014) in the two arms treated with adjuvant temozolomide.
The researchers noted that 06-methyl-guanine DNA methyltransferase (MGMT) status could be determined in 74% of patients, and in 42% of them, found to be methylated. MGMT methylation was prognostic for OS (HR 0.54, 95% CI 0.38, 0.77; P
= .001), but did not predict improved outcome with adjuvant temozolomide. For progression free survival (PFS), the risk-adjusted HR of adjuvant temozolomide was 0.586 (95% CI 0.472-0.727; P
“Those are highly statistically significant hazard ratios,” said van den Bent. “We know that temozolomide given after RT improves survival in this disease. But we need to follow up to further elucidate the role of concurrent temozolomide.”
The median OS has not been reached in arms 3 or 4 (adjuvant temozolomide). Van den Bent said that the results of the temozolomide treatment given only during RT are not yet available, and final data from this study are expected in 2020. The most common toxicities reported were hematologic (eg, low platelets and white blood cells), with severe toxicity in 5% to 10% of patients.
The trial also “demonstrates that even with a rare tumor type and using standard chemotherapy, we can select patients who will benefit from treatment and at the same time potentially spare patients the toxicity of a therapy that they are unlikely to benefit from,” said moderator Don S. Dizon, MD, chair, ASCO’s Cancer Communications Committee.
The researchers noted that they plan to assess additional genetic abnormalities known to affect prognosis in this cancer—ie, MGMT promotor methylation and isocitrate dehydrogenase (IDH) mutation.
Van den Bent M, Erridge S, Vogelbaum MA, et al. Phase III trial on concurrent and adjuvant temozolomide chemotherapy in NON-1p/19q deleted anaplastic glioma: the CATNON intergroup trial (EORTC 26053-22054). Presented at: 2016 ASCO Annual Meeting. J Clin Oncol. 34, 2016 (suppl; abstr LBA2000).
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