Pearls in Neuro-oncology is guest edited by Tracy Batchelor, MD, Director, Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, and Professor of Neurology, Harvard Medical School, Boston. The series is intended to provide the practicing oncologist with guidance in managing neuro-oncology issues that may present in their patients with cancer.
Anaplastic oligodendroglial tumors (oligodendrogliomas and mixed oligoastrocytomas) account for approximately 7% of all intracranial gliomas in adults and generally have a better prognosis than other types of high-grade gliomas. Several uncontrolled studies in the early 1990s suggested that these tumors were chemosensitive; therefore two large, prospective, randomized trials were initiated to investigate the role of adjuvant chemotherapy in addition to radiotherapy in newly diagnosed anaplastic oligodendroglial tumors.
Recently, the long-term results from these trials were reported.1,2 In addition to updating the progression-free and overall survival data since the initial publications,3,4 the follow-up reports retrospectively analyzed the prognostic and predictive impact of genetic markers frequently observed in oligodendroglial tumors. Both studies assessed for codeletion of chromosomes 1p and 19q, an alteration found in 60% to 90% of anaplastic oligodendrogliomas,5 and for isocitrate dehydrogenase (IDH) mutation, which occurs in 70% to 90% of anaplastic oligodendroglial tumors.6
Two Key Trials
In the European Organisation for Research and Treatment of Cancer phase III trial (EORTC 26951), patients were randomly assigned to receive either radiotherapy alone or radiotherapy followed by up to six cycles of PCV (procarbazine [Matulane], lomustine [CeeNu], vincristine).3 In the Radiation Therapy Oncology Group phase III trial (RTOG 9402) patients were randomized to receive either radiotherapy alone or up to four cycles of dose-intensified PCV prior to radiotherapy.4 In both studies, patients were treated with focal radiotherapy to a total dose of 59.4 Gy in 1.8-Gy fractions. Retrospectively, the status of chromosomes 1p and 19q were determined in 91% of patients in the RTOG study and 86% of patients in the EORTC study, and IDH status was evaluated in a subset of patients in both trials.
In the initial study results published in 2006, the addition of chemotherapy to radiotherapy improved progression-free survival but not overall survival in both trials.3,4 In addition, in both studies 1p/19q codeletion was a strong prognostic factor regardless of treatment assignment. However, in neither study was 1p/19q codeletion predictive for improved overall survival with the addition of chemotherapy, although the median overall survival had not been achieved in the codeleted subgroups, suggesting longer follow-up was needed.
Long-term Data
In the long-term follow-up results, the two trials differed in their findings with regard to overall survival in the overall study populations.1,2 In the RTOG trial, median overall survival was not different based on treatment group (4.6 years for PCV plus radiotherapy vs 4.7 years for radiotherapy alone, P = .1). However, in the EORTC study longer overall survival was observed for patients who received adjuvant PCV in the intent-to-treat analysis (42.3 vs 30.6 months in the radiotherapy arm, hazard ratio [HR] = 0.75; P = .018).
1p/19q Codeletion
Moreover, there was a significant impact of 1p/19q codeletion on overall survival in these trials. Regardless of treatment assignment, in both trials patients with 1p/19q codeletion survived longer than non-codeleted patients (eg, overall survival of 123 vs 23 months in the EORTC study), confirming the strong prognostic effect of 1p/19q codeletion.1,2 In subset analyses, both studies suggested 1p/19q codeletion predicts sensitivity to PCV.
In the RTOG study, patients with 1p/19q codeletion treated with radiotherapy plus PCV lived longer than those treated with radiotherapy alone (median overall survival = 14.7 vs 7.3 years, P = .03).2 Conversely, there was no difference in survival of non-codeleted patients between treatment assignments.
In the EORTC study, the median survival of 1p/19q codeleted patients who received PCV was not yet reached compared to 112 months for those treated with radiotherapy alone, which trended to significance (P = .059). In the non-codeleted subset, there was no difference in survival between treatment groups.1
These results are summarized in Table 1.
IDH Mutation
The prognostic impact of IDH mutation was also confirmed in both studies. (The vast majority of these mutations were in IDH1; only one case of IDH2 mutation was reported, in the EORTC trial.)
The EORTC trial retrospectively evaluated IDH status in 179 of 368 enrolled patients, and IDH mutation was an independent prognostic factor (median overall survival = 8.4 years for IDH-mutant vs 1.4 years for IDH wild-type patients).1 IDH mutation was also an important prognostic factor for overall survival in the RTOG study.2
Whether IDH mutation predicts sensitivity to chemotherapy, however, remains unresolved. In the EORTC study, IDH-mutant tumors seemed to derive more benefit from PCV, but the difference did not reach statistical significance.1 The RTOG investigators did not report on the predictive utility of IDH mutation.
Unresolved Questions
Taken together, these results suggest that the standard of care for 1p/19q codeleted anaplastic oligodendroglial tumors should include both radiotherapy and chemotherapy. However, many questions remain regarding the treatment of both 1p/19q codeleted and non-codeleted subsets.
One question is whether temozolomide, which is well tolerated and has activity in oligodendrogliomas,7,8 is equivalent to PCV. Limited data suggest that the relative efficacy may be similar: In the NOA-04 randomized phase III trial in anaplastic gliomas, there was no difference between the temozolomide and PCV arms in time to treatment failure, although the study was not powered for this comparison and the follow-up time was limited.9 In addition, a large retrospective study of anaplastic oligodendroglial tumors showed no statistically significant difference in progression-free or overall survival between PCV and temozolomide in 1p/19q codeleted patients who also received radiotherapy.10 However, prospective comparisons of PCV vs temozolomide are lacking.
Another question concerns the relative efficacy of concurrent chemoradiation vs sequential radiotherapy and chemotherapy with either PCV or temozolomide. Finally, the apparent chemosensitivity and prolonged natural history of 1p/19q codeleted tumors raises the question of whether chemotherapy can be used alone in these patients, with deferral of radiotherapy to mitigate the risk of cognitive dysfunction.
Some of these questions may be answered by the ongoing phase III intergroup RTOG/North Central Cancer Treatment Group (NCCTG) CODEL trial (NCT00887146) for 1p/19q codeleted anaplastic gliomas. The study arms include (1) radiotherapy followed by PCV, (2) concurrent radiotherapy plus temozolomide followed by temozolomide, and (3) temozolomide.
The optimal treatment for 1p/19q non-codeleted anaplastic oligodendroglial tumors also remains unresolved. No statistically significant overall survival benefit was observed in this subset treated with adjuvant PCV1,2 in either the EORTC or RTOG trials. Also, whether concurrent radiotherapy plus temozolomide is effective for these patients is unknown.
The ongoing phase III intergroup EORTC/RTOG CATNON trial (NCT00626990) for newly diagnosed anaplastic gliomas without 1p/19q codeletion will address these questions. Patients are randomly assigned to (1) radiotherapy, (2) concurrent radiotherpay plus temozolomide, (3) radiotherapy followed by temozolomide, or (4) concurrent radiotherapy plus temozolomide followed by temozolomide.
In Summary
The long-term, follow-up results of EORTC 26951 and RTOG 9402 for anaplastic oligodendroglial tumors provide strong evidence for the predictive value of 1p/19q codeletion and confirm the prognostic effect of both 1p/19q codeletion and IDH mutation. Patients with these types of tumors should have testing for chromosome 1p and 19q status as part of routine clinical practice.
However, many questions remain unanswered regarding the optimal treatment for both 1p/19q codeleted and non-codeleted patients. Evidence supports the use of both radiotherapy and PCV for newly diagnosed 1p/19q codeleted anaplastic oligodendroglial tumors. It remains to be determined whether temozolomide is equivalent to PCV, whether PCV or temozolomide can be used alone with deferral of radiotherapy until the time of progression, and whether concurrent radiotherapy plus temozolomide has a role among these options.
For non-codeleted tumors, adjuvant PCV does not confer a survival benefit. Although the poorer prognosis of these patients could justify a more aggressive treatment approach, the added toxicity, the impact on quality of life, and the uncertain efficacy of chemotherapy should be considered.
Ultimately, treatment of anaplastic oligodendroglial tumors should be individualized, taking into account molecular prognostic markers (1p/19q and IDH status), functional status, and comorbidities. Enrollment onto one of the ongoing randomized trials—either CODEL or CATNON—should be strongly considered.■
Dr. Chi is Assistant Professor of Neurology at Harvard Medical School and in the Division of Neuro-Oncology at Massachusetts General Hospital Cancer Center, Boston.
Disclosure: Dr. Chi reported no potential conflicts of interest.
References
1. van den Bent MJ, Brandes AA, Taphoorn MJ, et al: Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol 31:344-50, 2013.
2. Cairncross G, Wang M, Shaw E, et al: Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol 31:337-43, 2013.
3. van den Bent M, Carpentier A, Brandes A, et al: Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 24:2715-22, 2006.
4. Cairncross G, Berkey B, Shaw E, et al: Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 24:2707-14, 2006.
5. Reifenberger J, Reifenberger G, Liu L, et al: Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145:1175-1190, 1994.
6. Yan H, Parsons D, Jin G, et al: IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765-73, 2009.
7. Chinot OL, Honore S, Dufour H, et al: Safety and efficacy of temozolomide in patients with recurrent anaplastic oligodendrogliomas after standard radiotherapy and chemotherapy. J Clin Oncol 19:2449-55, 2001.
8. van den Bent MJ, Taphoorn MJ, Brandes AA, et al: Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. J Clin Oncol 21:2525-8, 2003.
9. Wick W, Hartmann C, Engel C, et al: NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27:5874-80, 2009.
10. Lassman AB, Iwamoto FM, Cloughesy TF, et al: International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro Oncol 13:649-59, 2011.
