Long-term follow-up results of EORTC 26951: A randomized phase III study on adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors (AOD)
Reporter: J Taylor Whaley
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 3 de junio del 2012
Presenter: Martin J. Van Den Bent, MD, PhD Presenter's Affiliation: Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, Netherlands
Each year, more than 15,000 new cases of diffuse gliomas are diagnosed in the United States. Gliomas represent the most frequent primary CNS tumor in adults and survival is closely linked to the grade of the tumor.
For Grade III gliomas, which compose 5-10% of all gliomas, overall survival has been previously documented to lie between 3-7 years.
Anaplastic oligodendrogliomas are a small subset of gliomas that appear to be more responsive to chemotherapy than high-grade astrocytomas. To evaluate the value of adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in newly diagnosed patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas, the EORTC undertook a multicenter randomized controlled trial.
Between 1995 and 2002 the EORTC Brain Tumor Group conducted a prospective phase III study on adjuvant procarbazine, CCNU and vincristine chemotherapy (PCV) in anaplastic oligodendrogliomas.
The 5 year results have been previously presented at ASCO and the subsequent publication in the Journal of Clinical Oncology in 2006. At that time and with a median follow-up time of 60 months, adjuvant PCV chemotherapy appeared to improve progression free survival but failed to prolong overall survival in anaplastic oligodendroglioma.
Following the initiation of the EORTC trial, new discoveries obscured the results of the study. The detection of combined loss of 1p/19q was identified as a favorable subgroup of oligodendroglial tumors with improved responses to treatment. Although the study was amended to evaluate co-deletions in 1p19q, the 5-year follow up for the EORTC trial failed to identify a genetic subgroup that benefited with respect to overall survival from adjuvant PCV chemotherapy.
In the initial publication in 2006, median overall survival for radiation followed by adjuvant PCV chemotherapy was 3.4 years vs RT 2.6 years. Although a trend was present, this did not reach statistical significance. Progression free survival was significantly improved from 1.1 years to 1.9 years.
Additionally, analysis for the presence of 1p/19q deletions revealed that patients with co-deletions of 1p/19q had 5-year overall survival of 74% vs. those with wild-type 1p/19q with 5-year survival of ~30%.
These findings were supported by the RTOG 9402 trial which evaluated the role of PCV prior to radiation therapy. Although PCV appeared to improve progression free survival, there was no benefit for overall survival for the entire cohort.
The authors now present long-term follow-up.
Materials and Methods
This is a phase III, multi-center, randomized study of radiation alone vs. radiation with adjuvant PCV chemotherapy for patients with newly diagnosed locally advanced anaplastic oligodendrogliomas.
Entry criteria for the trial were as follows:
Pathologically proven anaplastic oligodendroglioma or anaplastic mixed oligoastrocytoma with at least 25% oligodendroglial elements
Age 16-70 years old
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2
Patients had not undergone prior chemotherapy or radiation to the skull
Adequate hematologic, renal, and hepatic function
Patients were randomized to either:
Radiation to a dose of 45 Gy to be delivered in 25 daily fractions of 1.8 Gy followed by a boost of 14.4 Gy (cumulative dose of 59.4 Gy).
Radiation as above followed by PCV chemotherapy (six cycles). Chemotherapy was require to start within 4 weeks after the end of RT. Each cycle consisted of lomustine 110 mg/m2 orally on day1, procarbazine 60 mg/m2 orally on days 8 to 21, and vincristine 1.4 mg/m2 intravenous on days 8 and 29. Cycles were to be repeated every 6 weeks
The control arm received radiation alone with the recommendation to administer chemotherapy at the time of progression. The protocol emphasized crossover with progression.
Primary endpoints were overall survival and progression-free survival.
1p/19q status, IDH status and MGMT promoter methylation were determined in 300, 167, and 186 pts respectively.
The results currently presented are with an additional 7 years of follow up, now a cumulative 12 years (140 months) of follow up.
Between 1996 and 2002, 368 pts were randomized. Median age was 49 years old at diagnosis. At the time of the most recent analysis, 281 pts (76.4%) had died.
Median PFS after radiation followed by PCV was significantly longer compared to RT alone (24.3 months versus 13.21 months).
More patients in the radiation arm received chemotherapy at progression (75% vs 53%).
With 12 years follow up, median overall survival was also significantly prolonged in the adjuvant PCV arm (42.3 months vs 30.6 months for the RT arm).
For patients with the 1p/19q co-deletion (n = 76), treatment with adjuvant PCV resulted in improved overall survival compared to radiation alone arm (median OS not reached vs 113 months).
In the 224 patients without 1p/19q co-deletion the difference in overall survival was non-significant (25 months vs 22 months).
There was a slight trend towards improved overall surivival in MGMT methylated and IDH mutated tumors versus unmethylated and IDH wild type tumors. Additionally, all 3 molecular markers were prognostically significant. Virtually all patients with 1p19q deletions have IDH mutated, and most patients with IDH have MGMT methylated.
Adjuvant PCV was discontinued in 38% of patients on the adjuvant PCV arm; additionally, 80% of patients on the radiation arm received chemo at progression.
With prolonged follow up, the addition of PCV to radiation increases progression free survival and overall survival in anaplastic oligodendrogliomas.
Patients with 1p/19q co-deletion appear to benefit the most from the addition of PCV, with a trend for improved OS in pts with MGMT methylation and IDH mutations as well. However, there was no proven benefit in the subgroup of 1p19q non-deleted patients.
With the new results, the authors concluded PCV with radiation should become the new standard of care for patients with anaplastic oligodendrogliomas and co-deletion of 1p19q.
The authors presented very long follow up on the phase III EORTC 26951 trial, which evaluated adjuvant PCV in patients with newly diagnosed anaplastic oligodendrogliomas. Their persistence and commitment should be commended.
Since the trial's initial design, the discovery of molecular markers, specifically the co-deletion of 1p19q, has dramatically altered the discussion of anaplastic oligodendrogliomas. The deletion is found in approximately 60-70% of tumors and results in a dramatically improved response when compared to the tumors without the co-deletion.
Two trials have now evaluated the use of PCV in anaplastic oligodendrogliomas. RTOG 9402 utilized sequential chemotherapy followed by radiation while the EORTC study employed adjuvant PCV. Up to this point, the results were strikingly similar with improvements in progression free survival though no change in overall survival. With mature data, it appears that patients may benefit from chemotherapy in addition to radiation for this disease when co-deletions of 1p19q are present.
Although the authors call for a new standard of care, several questions remain:
What is the optimal chemotherapeutic regimen?
How should chemotherapy be sequenced with regard to radiation? - sequentially, concurrently, or adjuvantly?
How would Temodar compare with PCV?
One finding that should not be forgotten is the significant toxicity associated with PCV. In the current trial, only 30% of patients were able to complete the 6 cycles of adjuvant chemotherapy as originally prescribed. Although these results are promising for this difficult diagnosis, many questions remain regarding the optimal treatment. Additional prospective studies evaluating the impact of Temodar as well as the optimal timing of chemotherapy with radiation are needed.
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