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INTRODUCTION — Oligodendroglial tumors constitute between 5 and 20 percent of all glial tumors. Oligodendroglial tumors typically arise in the fourth to sixth decades, with low-grade tumors occurring at an earlier age than anaplastic tumors. Despite the prolonged clinical course seen with oligodendroglial tumors, the outcome is almost always fatal.
Historically, the management of patients with anaplastic oligodendroglial tumors was based upon results from studies in patients with malignant gliomas, carried out prior to the recognition of the molecular and prognostic differences between oligodendroglial and other glial tumors. Compared with astrocytic tumors, oligodendroglial tumors are more likely to harbor certain favorable molecular markers, such as co-deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) and mutations in isocitrate dehydrogenase (IDH). Such mutations are relevant to treatment planning and prognosis.
The treatment of anaplastic oligodendroglial tumors will be reviewed here. The clinical manifestations, pathology, and molecular prognostic factors of oligodendroglial tumors and the management of low-grade oligodendrogliomas are discussed separately. (See "Clinical features, pathology, and prognostic factors for oligodendroglial tumors" and "Management of low-grade glioma".)
SURGERY — Surgery provides tissue to establish the diagnosis and is used to relieve symptoms due to mass effect in patients with suspected anaplastic oligodendroglial tumors. As with other high-grade gliomas, maximal resection is the preferred approach, but partial resection or biopsy may be required, depending upon the location and extent of the tumor. (See "Clinical manifestations and initial surgical approach to patients with high-grade gliomas", section on 'Extent of resection'.)
There are no randomized trials that have established the benefit of maximal surgical resection compared with a more limited resection, and such studies are unlikely to be conducted. Evidence supporting this approach specifically in oligodendroglial tumors comes from secondary analyses of two large trials, which demonstrated a positive association between a more extensive resection and prolonged survival [1,2]. However, in retrospective studies, small, superficial tumors with a relatively favorable prognosis are more likely to have been extensively resected, while large, deep-seated, or midline tumors with a poorer prognosis will not have been completely resected .
Limited data suggest that the presence of a mutation in isocitrate dehydrogenase 1 (IDH1) or IDH2 may be an additional factor relevant to the association between extent of resection and overall survival. In a retrospective series of high-grade astrocytic tumors, a positive association between gross total resection (of both enhancing and nonenhancing components) and overall survival was observed for IDH1-mutant tumors but not wild-type tumors . It is not yet clear whether this effect is also relevant for oligodendroglial tumors, or whether the association is confounded by factors relating to resectability.
General approach — Following surgery, evidence from multiple randomized trials strongly supports the use of both radiation therapy (RT) and chemotherapy rather than RT alone in patients with anaplastic gliomas. There is some uncertainty regarding the optimal chemotherapy in various patient subgroups, and treatment decisions should be individualized. The presence or absence of a 1p19q co-deletion may help to determine the optimal approach.
1p19q co-deleted tumors — For patients with 1p19q co-deleted tumors, both PCV (procarbazine, lomustine, and vincristine) and temozolomide are reasonable options, and there is no consensus among experts about which regimen is preferred.
Use of PCV is supported by two large randomized trials in patients with anaplastic oligodendroglial tumors, in which the addition of PCV to RT was associated with improved progression-free and overall survival compared with RT alone in those with 1p19q co-deleted tumors. (See 'EORTC 26951' below and 'RTOG 9402' below.)
On the other hand, temozolomide is easier to administer, has better patient tolerance, and has been shown to improve survival in other types of malignant gliomas. Therefore, reasonable patients who prioritize convenience and avoidance of short-term toxicity may reasonably choose temozolomide over PCV. (See 'Efficacy of RT plus chemotherapy' below and 'PCV versus temozolomide' below.)
Non-co-deleted tumors — Non-co-deleted anaplastic oligodendroglial tumors have historically included the histologic diagnoses of anaplastic oligodendroglioma and anaplastic oligoastrocytoma. As of the 2016 WHO classification system, most of these tumors are now properly categorized according to isocitrate dehydrogenase (IDH) mutation status as IDH-mutant anaplastic astrocytoma, or less commonly IDH-wildtype anaplastic astrocytoma .
In non-co-deleted anaplastic gliomas, we favor use of temozolomide rather than PCV in most patients, for the following reasons:
●Subgroup analysis of earlier randomized trials found that the benefit of PCV when used in combination with RT was attenuated or absent in patients with non-co-deleted anaplastic oligodendroglial tumors. (See 'EORTC 26951' below and 'RTOG 9402' below.)
●Temozolomide is generally easier to administer and is associated with a lower risk of side effects and toxicity compared with PCV.
Efficacy of RT plus chemotherapy — Two cooperative group randomized phase III trials with prolonged follow-up provide strong, complementary evidence that a combination of both RT and PCV following surgery is associated with an improvement in survival on long-term follow-up in the subset of patients with 1p19q co-deletion [6,7].
Both trials provide evidence that other molecular subgroups may benefit from adding PCV to radiotherapy, but firm conclusions are not possible due limitations inherent in post hoc analyses [6,8,9]. Proposed candidate markers are the presence of an IDH mutation and MGMT methylation. (See 'EORTC 26951' below and 'RTOG 9402' below.)
In addition, a third cooperative group trial ("CATNON"), restricted to patients with non-co-deleted anaplastic gliomas, provides evidence that a combination of RT and 12 cycles of adjuvant temozolomide improves survival compared with RT without 12 cycles of adjuvant temozolomide. (See 'CATNON' below.)
EORTC 26951 — In the EORTC 26951 trial, 368 patients were randomly assigned to immediate RT only or RT followed by six cycles of PCV . The total dose of RT on each treatment arm was 60 Gy. The results of this trial were originally published in 2006 with a median follow-up of five years . The results of the trial were updated in 2013 with a median follow-up of almost 12 years .
Patients were eligible to receive additional treatment after progression following their initial management. Among patients who initially were treated with RT plus PCV, 53 percent received subsequent chemotherapy, primarily with temozolomide. Among those who were given RT alone, 88 percent received subsequent chemotherapy, generally with PCV and/or temozolomide.
Results from EORTC 26951 include the following:
●At a median follow-up of 60 months , progression-free survival (PFS) was already significantly prolonged with adjuvant PCV compared to RT alone (23 versus 13 months), but the difference in overall survival at that time was not statistically significant (40 versus 31 months without adjuvant chemotherapy).
●With more prolonged follow-up, the survival curves with the two initial treatment regimens diverged , and the benefit from initial combined chemotherapy (PCV) and RT was seen primarily in patients whose tumors contained the 1p/19q co-deletion. Samples from 316 of 368 patients (86 percent) were available for analysis for 1p/19q co-deletion.
•Among the 80 patients whose tumor contained the 1p/19q co-deletion, PFS was significantly increased when patients were treated with RT plus PCV compared with RT alone (median 157 versus 50 months, HR 0.42, 95% CI 0.24-0.74), and there was a trend toward increase in overall survival (median not reached versus 112 months, HR 0.56, 95% CI 0.31-1.03).
•In the 236 patients whose tumor did not have the 1p/19q co-deletion, the prognosis was substantially worse and the impact of adding chemotherapy to RT was limited (PFS median 15 versus 9 months, HR 0.73, 95% CI 0.56-0.97, and overall survival median 25 versus 21 months, HR 0.83, 95% CI 0.62-1.10).
In a subset analysis that included data from 115 patients whose tumors were available for methylation profiling, MGMT methylation and a CpG island hypermethylated phenotype (CIMP) were also predictive of a benefit from PCV . For patients with MGMT methylated tumors, median overall survival was significantly longer in the RT plus PCV arm compared with RT alone (8.65 versus 1.98 years). A similar benefit from PCV was observed in patients with CIMP tumors (9.51 versus 3.27 years).
In the subset of 178 patients with known IDH1 mutation status, the presence of an IDH1 mutation was associated with significantly improved median overall survival (8.4 versus 1.4 years) . Firm conclusions could not be drawn regarding IDH1 mutation status (independent of 1p19q status) as a predictive marker of benefit from PCV in this dataset due to the small number of patients in each subgroup.
RTOG 9402 — In the RTOG 9402 trial, 291 patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas were eligible for analysis after random assignment to either four cycles of intensified PCV followed by RT or immediate RT without chemotherapy. The cumulative dose of RT on both treatment arms was 60 Gy. The results of RTOG 9402 were originally published in 2006  and were subsequently updated in 2013 .
●In the initial report of results from this trial , PFS was significantly increased with PCV followed by RT compared with RT alone (2.6 versus 1.7 years), but the difference in overall survival was not significant (4.9 versus 4.7 years).
●With 11.3 years follow-up , however, results were dependent upon the 1p19q status of the tumor and were consistent with those seen in the EORTC 26951 trial.
•For patients whose tumors contained the 1p/19q co-deletion, overall survival was significantly prolonged in patients treated with intensified PCV followed by RT compared with those given only RT initially (median 14.7 versus 7.3 years, HR 0.59, 95% CI 0.37-0.95).
•For patients whose tumors did not contain the 1p/19q co-deletion, prognosis was again substantially worse, and the impact of therapy not statistically significant (median survival 2.6 versus 2.7 years, HR 0.85, 95% CI 0.58-1.23).
A subsequent subset analysis examined the IDH mutation status in 210 of 291 tumors, of which 156 (74 percent) were IDH mutated . For patients with an IDH-mutant tumor, overall survival was significantly prolonged by the addition of PCV to RT for those with concomitant 1p19q co-deletion (14.7 versus 6.8 years, HR 0.49, 95% CI 0.28-0.85), as expected from earlier analyses; in addition, however, patients with IDH-mutant, non-co-deleted tumors also appeared to benefit from PCV plus RT versus RT alone (median survival 5.5 versus 3.3 years, HR 0.56, 95% CI 0.32-0.99). Patients with IDH wild-type tumors had a poor prognosis and did not appear to benefit from the addition of PCV (median survival 1.3 versus 1.8 years, p=0.67).
CATNON — The CATNON trial enrolled 748 patients with newly diagnosed anaplastic gliomas without 1p19q co-deletion and randomly assigned them to one of four treatment arms :
●RT with concurrent daily temozolomide
●RT followed by 12 cycles of adjuvant temozolomide
●RT with both concurrent and 12 cycles of adjuvant temozolomide
Results of an interim analysis of the trial were presented at the 2016 annual meeting of the American Society for Clinical Oncology . At the time of the analysis, 748 patients had been randomized and 221 events had occurred, with a median follow up of 27 months. Compared with no adjuvant temozolomide, groups who received 12 cycles of adjuvant temozolomide had a significant improvement in both progression free survival (HR 0.59, 95% CI 0.47-0.73) and overall survival (median 44.1 months versus not yet reached; HR 0.65, 95% CI 0.45-0.93). An analysis of the impact of concurrent temozolomide (during RT) has not yet been presented.
Based on these results, we now recommend 12 cycles of adjuvant temozolomide following RT in patients with non-1p19q-co-deleted tumors, rather than RT alone. It is not yet known whether the addition of low-dose daily temozolomide during RT provides benefit compared with post-RT temozolomide alone, but it does increase the risk of toxicity.
Order of therapy — The optimal order of RT and chemotherapy when given as a combined approach for anaplastic oligodendrogliomas is uncertain. In the EORTC 26951 study, PCV was administered after completion of RT; in the RTOG 9402 study, four cycles of intensified PCV were administered immediately before RT.
Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) recommend that PCV be administered after RT (as per EORTC 26951), since the intensive PCV regimen given prior to RT was not tolerated as well. Similarly, we typically administer temozolomide after RT rather than before.
PCV versus temozolomide — Oligodendroglial tumors are markedly more sensitive to chemotherapy than astrocytic tumors, but the optimal chemotherapy regimen (PCV or temozolomide) remains uncertain and could potentially vary based on molecular subgroup or other patient characteristics.
This chemosensitivity was initially demonstrated with a PCV regimen (procarbazine, lomustine, and vincristine) in patients who had recurred or progressed after RT [12-17]. These observations led to the evaluation of PCV as part of a combined modality approach for the initial management of these patients in the trials reviewed above, as well as to its use in the treatment of recurrent disease. Subsequent studies showed that temozolomide is also highly active [18,19].
There are no randomized trials in patients treated with chemotherapy alone that directly compare PCV and temozolomide. In the NOA4 trial in patients with anaplastic glioma, the efficacy of the two regimens was similar, but long-term follow up is not yet available and the study was not powered for comparison between PCV and temozolomide . Temozolomide is generally preferred over the PCV regimen by many neuro-oncologists, based upon its ease of administration and better patient tolerance, although PCV remains an option.
The administration of temozolomide with RT, including discussion of side effects and monitoring, is reviewed elsewhere. (See "Initial postoperative therapy for glioblastoma and anaplastic astrocytoma", section on 'Temozolomide'.)
Chemotherapy with deferred RT — The sensitivity of oligodendroglial tumors to chemotherapy and concerns about the potential for delayed neurotoxicity from RT have led to the use of chemotherapy rather than RT as the initial treatment in some patients with 1p19q co-deleted anaplastic oligodendroglial tumors [21,22]. This approach has not been well studied prospectively in comparison with RT plus chemotherapy.
Chemotherapy versus RT alone was evaluated in the initial stage of a phase III trial (NOA-4) that included patients with anaplastic astrocytomas, anaplastic oligoastrocytomas, and oligodendrogliomas . At the time of the first report, there was no significant difference in time to treatment failure either in patients with oligodendroglial tumors or those with malignant astrocytomas . Long term follow-up results presented in abstract form also do not support a difference in efficacy between primary temozolomide or PCV chemotherapy versus radiotherapy in any of the histological or molecular subgroups of anaplastic glioma . However, the similar overall survival after initial radiotherapy only or initial chemotherapy only implies that combined radiotherapy plus chemotherapy is likely to result in improved survival compared with initial chemotherapy alone. (See "Initial postoperative therapy for glioblastoma and anaplastic astrocytoma", section on 'Radiation or chemotherapy alone'.)
Preliminary data from a truncated randomized trial in which chemotherapy alone was one of three treatment arms in patients with newly diagnosed anaplastic glioma with 1p19q co-deletion (initial phase of "CODEL") found that patients treated with temozolomide alone fared worse than those treated with radiation with or without temozolomide, although the small number of patients (n=36) significantly limits confidence in this finding .
Ongoing radomized trials — There are two ongoing randomized trials designed to address many of the uncertainties described above:
●In a phase III Alliance for Clinical Trials in Oncology/EORTC intergroup trial ("CODEL"), patients with 1p19q co-deleted anaplastic or low-grade gliomas are randomly assigned to one of two treatment arms: RT followed by PCV; and RT with concurrent and adjuvant temozolomide (NCT00887146).
●In a phase III EORTC/North American intergroup trial ("CATNON"), patients with non-co-deleted anaplastic gliomas are randomly assigned to one of four treatment arms: RT; RT with concurrent temozolomide; RT followed by temozolomide; and RT with concurrent and adjuvant temozolomide (NCT00626990). Preliminary results of this trial are reviewed above . (See 'CATNON' above.)
RECURRENT DISEASE — Both PCV and temozolomide have activity in patients who have failed an initial chemotherapy regimen, although response rates are lower and the duration of disease control is generally shorter compared to treatment at first diagnosis or at first recurrence after RT.
Repeat surgery and re-irradiation are also utilized in selected patients. (See "Management of recurrent high-grade gliomas", section on 'Localized therapy' and "Management of recurrent high-grade gliomas", section on 'Reirradiation'.)
The activity of temozolomide after failure with PCV was illustrated by a retrospective series of 48 patients with anaplastic oligodendrogliomas and oligoastrocytomas . In this series, 21 patients (44 percent) had an objective response, including eight with a complete remission. The median PFS was 7 months and the median overall survival was 10 months. Treatment was well tolerated, and the primary toxicity was thrombocytopenia. In other series on similar patients, an objective response rate of 25 percent was noted.
PCV regimen — Experience with PCV after progression on temozolomide is more limited. Nonetheless, there is evidence that PCV is active in some patients who have progressed after previous treatment with temozolomide. In a retrospective study of 24 patients, second-line PCV induced an objective response in 17 percent of cases, 50 percent were progression-free at six months, and 21 percent were progression-free at 12 months .
Bevacizumab — Bevacizumab has some activity in patients with recurrent glioblastoma. (See "Management of recurrent high-grade gliomas", section on 'Bevacizumab'.)
Solid data are lacking, all results are from uncontrolled studies and are consistent with short duration effects consistent with a normalization of vasculature and anti-edema effect, despite high response rates. A retrospective analysis of 22 patients with recurrent, alkylator-refractory anaplastic oligodendroglioma  (all with co-deletion of 1p/19q and previously treated with surgery, RT, adjuvant chemotherapy, and one chemotherapy regimen for recurrent disease) noted a partial response observed in 15 cases (68 percent). Despite that, the median time to progression and median survival in this cohort were only 6.8 and 8.5 months, respectively. Another series of 25 patients with recurrent oligodendroglial tumors recurrent after RT and at least one chemotherapy regimen observed an objective response rate of 72 percent with the combination of bevacizumab plus irinotecan, with a median progression-free survival of only 140 days . No clear correlation was found between the genotype and outcome.
Other agents — The management of patients who have progressed on either temozolomide or PCV is experimental. Other agents that have shown some activity as second-line chemotherapy in patients with anaplastic oligodendroglial tumors include paclitaxel, irinotecan, carboplatin, and the combination of etoposide plus cisplatin [30-40]. Response rates with these agents have generally been low (less than 15 percent), and almost all patients' progress in less than 12 months.
SURVEILLANCE AFTER TREATMENT — There are no formal clinical trials that define the optimal frequency for follow-up after treatment.
Guidelines from the National Comprehensive Cancer Network (NCCN) recommend the following schedule for follow-up imaging :
●For patients with malignant gliomas including both anaplastic oligodendrogliomas and anaplastic oligoastrocytomas, a repeat MRI should be obtained two to six weeks after completion of radiation therapy, then every two to four months for two to three years, and less frequently thereafter.
Assessment of response and progression — Patient management decisions require an assessment of both initial response to treatment as well as subsequent evidence of progressive disease. Traditionally, this approach has used the Macdonald criteria which rely upon measurement of areas of contrast enhancement .
New criteria have been proposed by the Response Assessment in Neuro-Oncology (RANO) working group to address problems in assessing patients with pseudoprogression or in assessing progressive disease in patients with nonenhancing lesions [43,44]. (See "Assessment of disease status and surveillance after treatment in patients with primary brain tumors".)
SUMMARY AND RECOMMENDATIONS
●Oligodendroglial tumors (ie, oligodendroglioma and what has historically been called oligoastrocytoma) have important differences from other glial tumors, with significant ramifications for patient management. Many of these tumors contain a characteristic co-deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), which has been correlated with both a striking sensitivity to chemotherapy and a more prolonged natural history, independent of specific treatment. (See 'Introduction' above.)
●Tissue of grade II and III gliomas should be routinely tested to determine whether co-deletion of 1p19q and IDH mutations are present, as this information is necessary to accurately diagnose these tumors as of the 2016 WHO classification system. Testing for MGMT should also be considered. (See "Clinical features, pathology, and prognostic factors for oligodendroglial tumors", section on 'Genetic abnormalities'.)
●For patients with a newly-diagnosed anaplastic oligodendroglioma or oligoastrocytoma, we suggest maximal surgical resection consistent with preservation of neurologic function (Grade 2C). Although gross total resection is preferred whenever possible, subtotal resection or stereotactic biopsy may be required depending upon the location and extent of the tumor. (See 'Surgery' above.)
●For all patients with anaplastic gliomas, we recommend adjuvant treatment that includes both RT and chemotherapy (Grade 1A). The choice between PCV (procarbazine, lomustine, vincristine) and temozolomide chemotherapy should be individualized based on molecular characteristics of the tumor and patient preferences. (See 'General approach' above.)
•For patients whose tumor contains the characteristic 1p/19q co-deletion, both PCV and temozolomide are reasonable options, and the two regimens are being compared in an ongoing intergroup randomized trial ("CODEL"). PCV has been demonstrated to improve survival in this patient population in two phase III trials, whereas temozolomide is easier to administer, has better patient tolerance, and has been shown to improve survival in other types of anaplastic gliomas. (See 'Efficacy of RT plus chemotherapy' above.)
•For patients whose tumor does not contain the 1p/19q co-deletion, we recommend 12 cycles of adjuvant temozolomide rather than PCV (Grade 1B). It is not yet known whether the addition of low-dose daily temozolomide during RT provides benefit compared with post-RT temozolomide alone, but it does increase the risk of toxicity. (See 'CATNON' above.)
●Patients with oligodendroglial tumors should be followed after treatment with imaging. For those with anaplastic lesions, a repeat MRI should be obtained two to six weeks after completion of radiation therapy, then every two to four months for two to three years, and less frequently thereafter. For those with low-grade tumors, repeat MRI should be obtained every three to six months for five years, and then at least annually thereafter. (See 'Surveillance after treatment' above.)
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