Adjuvant chemotherapy with PCV (procarbazine [Matulane], lomustine [CeeNU], and vincristine) following standard radiation therapy delayed disease progression and increased survival in patients with a relatively rare type of brain tumor called anaplastic oligodendroglioma. A subgroup analysis found that the benefit of the addition of chemotherapy was largely driven by tumors with 1p/19q codeletion. Results of this randomized phase III EORTC 26951 trial, which took 17 years to complete, were reported at the Plenary Session during the 2012 ASCO Annual Meeting.1
Although a survival difference was not observed in 2006 when results were first reported, long-term follow-up showed median overall survival of 42 months in the PCV-plus-radiotherapy arm vs 31 months in the radiotherapy-alone arm, representing an improvement of 11 months in the entire intent-to-treat population. In patients with the 1p/19q codeletion, median overall survival has not yet been reached in the PCV-plus-radiotherapy arm and is 112 months in the radiotherapy-alone arm.
“Adjuvant PCV improves overall survival in anaplastic oligodendroglial tumors, and 1p/19q codeletion identifies patients with increased benefit after PCV. We saw no statistically significant benefit of PCV in ‘nondeleted’ tumors,” explained lead author Martin J. van den Bent, MD, Erasmus Medical College on Rotterdam, The Netherlands.
A second study reported at the Annual Meeting, RTOG 9402,2 confirms these findings, he said. “These studies make adjuvant PCV a new standard of care in 1p/19q codeleted tumors,” Dr. van den Bent told the audience.
Diffuse gliomas are the most common type of primary brain tumor in adults, and the histologic subtype of anaplastic oligodendroglial tumors accounts for about 5% to 10% of malignant brain tumors.
Prior to this study, optimal treatment was extensive resection followed by radiation therapy (2001). The trial was initiated in 1995, after PCV was found to have good activity in these tumors. During the accrual phase, the protocol was amended without a proven role for adjuvant chemotherapy, to explore the correlation between 1p/19q deletions and response, after these deletions were found to be associated with chemosensitivity.
From 1995 to 2002, 368 patients were randomly assigned to radiotherapy followed by six cycles of adjuvant PCV or to radiotherapy alone. Patients in the radiotherapy-alone arm could be treated with PCV at disease progression. Three-quarters of the patients in the radiotherapy-alone arm received PCV, so the study really compared early vs delayed chemotherapy after radiation, Dr. van den Bent explained. The treatment arms were well balanced for prognostic factors.
When results were reported in 2006, adjuvant PCV was shown to increase progression-free survival but not overall survival. The survival benefit did not emerge until about 5 years later. Median follow-up is now about 12 years, he said, noting that disease progressed in about 80% of patients enrolled in the trial, and about 25% are still alive.
A risk-adjusted analysis of survival showed that assignment to treatment remained an independent factor, reducing the risk of death by 24% in those treated with PCV plus radiotherapy. A total of 80 patients (25%) had 1p/19q deletions. In these patients with codeletions, progression-free survival increased from 50 months in the radiotherapy-alone arm to 157 months; for patients with the codeletions, median overall survival has not yet been reached in the PCV-containing arm but was 112 months in the radiotherapy arm. There was no significant advantage to adjuvant chemotherapy in non-codeleted patients.
PCV was used as chemotherapy when the trial was first initiated in 1995, but temozolomide may turn out to be a better option for treatment of non-codeleted anaplastic oligodendrogliomas, Dr. van den Bent suggested. This requires further study, he added. ■
Disclosure: Dr. van den Bent is a consultant for MSD.
1. Van Den Bent M, Hoang-Xuan K, Brandes AA, et al: Long-term follow-up results of EORTC 26951: A randomized phase III study on adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors (AOD). 2012 ASCO Annual Meeting. Abstract 2. Presented June 3, 2012.
2. Cairncross JG, Wang M, Shaw EG, et al: Chemotherapy plus radiotherapy versus RT alone for patients with anaplastic oligodendroglioma: Long-term results of the RTOG 9402 phase III study. 2012 ASCO Annual Meeting. Abstract 2008b. Presented June 3, 2012.
Commending the investigators for their undertaking, Mark Gilbert, MD, of The University of Texas MD Anderson Cancer Center in Houston, said, “Perseverance and analysis of long-term outcomes lead to practice-changing findings and important insights.”
He pointed out that two randomized trials...