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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 oligodendrogliomas and oligoastrocytomas occurring at an earlier age than anaplastic oligodendrogliomas and anaplastic oligoastrocytomas. Despite the prolonged clinical course seen with oligodendroglial tumors, the outcome is almost always fatal.
The treatment of oligodendroglial tumors will be reviewed here. The clinical manifestations, pathology, and molecular prognostic factors of oligodendroglial tumors are discussed separately. (See "Clinical features, pathology, and prognostic factors for oligodendroglial tumors".)
ANAPLASTIC OLIGODENDROGLIAL TUMORS — 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 differences between oligodendroglial and other glial tumors. Surgery remains the initial treatment modality for most patients. Radiation therapy (RT) and chemotherapy are important components of the management for these patients as well as for those with large low-grade oligodendroglial tumors that are not completely resected.
Contemporary clinical trials are focusing on the role of molecular markers as prognostic and predictive markers in patients with anaplastic oligodendroglial tumors [1,2]. In general, the presence of 1p/19q codeletion, MGMT promoter methylation, or IDH1 mutations is associated with a significantly improved prognosis and longer overall survival. Codeletion of 1p/19q is also predictive of an improved response to treatment. (See "Clinical features, pathology, and prognostic factors for oligodendroglial tumors", section on 'Codeletion of 1p/19q'.)
Surgery — Surgery provides tissue to establish the diagnosis and is used to relieve symptoms due to mass effect in patients with oligodendroglial tumors. In addition, gross total resection of the tumor is recommended if possible as part of the initial treatment in an effort to improve the long-term prognosis. (See "Management of low-grade glioma", section on 'Surgery' and "Clinical manifestations and initial surgical approach to patients with malignant 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 .
Following surgery, further treatment (RT and/or chemotherapy) is recommended for patients with anaplastic tumors, as well as for selected patients with low-grade tumors with focal deficits or residual lesions with mass effect. (See 'Low-grade oligodendroglial tumors' below.)
Postoperative therapy — Both RT and chemotherapy are active treatment modalities for patients with oligodendroglial tumors. Historically, various treatment strategies have been evaluated following surgery including RT with deferred chemotherapy, chemotherapy with deferred RT, RT followed immediately by adjuvant chemotherapy, and neoadjuvant chemotherapy followed by RT.
Radiation therapy — Randomized trials that included high-grade gliomas of all types demonstrated that adjuvant RT with doses of 60 to 65 Gy in 30 to 35 fractions provides a significant survival benefit. The effectiveness of RT has not been assessed in randomized trials specifically looking at patients with oligodendroglial tumors. (See "Adjuvant radiation therapy for malignant gliomas".)
Although retrospective studies have given conflicting results about whether postoperative RT prolongs survival [4-9], RT has been considered an integral component of the treatment for patients with anaplastic lesions or a large residual tumor. The recognition that oligodendroglial tumors are sensitive to chemotherapy has led to trials that are reexamining the sequence in which RT and chemotherapy are administered. (See 'Postoperative therapy' above and 'Recurrent disease' below.)
Chemotherapy — Oligodendroglial tumors are markedly more sensitive to chemotherapy than nonoligodendroglial tumors.
This chemosensitivity was initially demonstrated with a PCV regimen (procarbazine, lomustine, and vincristine) in patients who had recurred or progressed after RT [10-15]. These observations led to the evaluation of PCV as part of a combined modality approach for the initial management of these patients, as well as to its use in the treatment of recurrent disease. Subsequent studies showed that temozolomide is also highly active [16,17].
There are no randomized trials in patients treated with chemotherapy only that directly compare PCV and temozolomide. Temozolomide is generally preferred over the PCV regimen, based upon its ease of administration and better patient tolerance, although PCV remains an option.
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 chemotherapy following surgery is associated with an improvement in survival on long-term follow-up in the subset of patients with codeletion of 1p/19q.
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 2012 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 codeletion. Samples from 316 of 368 patients (86 percent) were available for analysis for 1p/19q codeletion.
•Among the 80 patients whose tumor contained the 1p/19q codeletion, 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 codeletion, 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).
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 2012 .
●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 molecular characteristics of the tumor and were consistent with those seen in the EORTC 26951 trial.
•For patients whose tumors contained the 1p/19q codeletion, 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 codeletion, 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).
Chemotherapy and deferred RT — The sensitivity of oligodendroglial tumors to chemotherapy led to the evaluation of chemotherapy rather than RT as the initial treatment after surgery [23,24]. The goal of this approach is to minimize late neurotoxicity caused by RT.
This approach was evaluated in a phase III trial (NOA-4) that included patients with anaplastic astrocytomas, anaplastic oligoastrocytomas, and oligodendrogliomas. There was no significant difference in time to treatment failure either in patients with oligodendroglial tumors or those with malignant astrocytomas. (See "Adjuvant chemotherapy for glioblastoma and anaplastic astrocytoma", section on 'Adjuvant RT or chemotherapy alone'.)
Summary — The results from the EORTC 26951 and RTOG 9402 trials have established that a combination of chemotherapy and RT following surgery results in a clinically meaningful prolongation in overall survival compared with RT alone for patients with a grade III oligodendroglial tumor and codeletion of 1p/19q.
The optimal chemotherapy regimen (PCV or temozolomide) remains uncertain, as does the relative timing of RT and chemotherapy. A PCV (procarbazine, lomustine, vincristine) regimen has been validated in these phase III trials, but temozolomide is easier to administer and is better tolerated.
For patients with an oligodendroglial tumor but without a codeletion of 1p/19q, the prognosis is significantly worse, and the benefits of adding chemotherapy to postoperative adjuvant RT remain uncertain.
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.
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 malignant 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 codeletion 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. Response rates with these agents have generally been low (less than 15 percent), and almost all patients' progress in less than 12 months. (See "Experimental treatment approaches for malignant gliomas".)
LOW-GRADE OLIGODENDROGLIAL TUMORS — The management of patients with low-grade oligodendroglial tumors is dependent upon the size of the tumor and the extent of symptomatology.
Surgery — The optimal management of patients with small, minimally symptomatic low-grade glial tumors remains controversial. Many of these patients will remain stable for a protracted period without treatment, and some physicians recommend deferring treatment until there is clinical or imaging evidence of progression. This may result in a deferred tissue diagnosis, and many of these patients will ultimately be found to have oligodendroglial tumors. The advantages and disadvantages of deferring treatment for patients with presumed low-grade glioma are discussed elsewhere. (See "Management of low-grade glioma", section on 'Surgery'.)
Surgery is generally indicated for symptomatic patients, for lesions with clear mass effect or showing clear growth. Patients whose only symptoms consist of seizures that can be medically controlled may not require surgery. Most observational studies suggest outcome may be better in patients undergoing early extensive surgery, but it is unclear to what extent that may be due to patient selection.
Postoperative therapy — For patients with do undergo immediate surgical resection, the decision whether or not to include additional treatment (RT or chemotherapy) depends upon the presence of focal deficits, a residual lesion with mass effect, and whether or not foci containing anaplastic tumor are identified. (See 'Radiation therapy' above and 'Chemotherapy' above and "Management of low-grade glioma", section on 'Timing of RT' and "Management of low-grade glioma", section on 'Adjuvant chemotherapy'.)
A "wait and see" approach following initial surgery may be followed in young patients with a favorable prognosis whose symptoms are limited to seizures and who have undergone an extensive resection for a low-grade tumor, especially if molecular studies show the presence of a 1p/19q codeletion. These tumors have a lower annual growth rate compared to low grade tumors without 1p/19q codeletion . (See "Clinical features, pathology, and prognostic factors for oligodendroglial tumors", section on 'Genetic abnormalities'.)
Chemotherapy in patients with low-grade oligodendroglial tumors may be associated with a prolonged response, which may develop in a delayed fashion, sometimes even after the end of treatment [14,31,32]. In a series of 21 patients with low-grade gliomas, including 15 oligodendrogliomas and 4 with oligoastrocytomas, patients were treated with PCV chemotherapy for a maximum of six cycles . All patients had progressive disease that was measurable on MRI. Patients were then followed without additional therapy until there was evidence of progression. Overall, 20 of 21 patients had an ongoing decrease in mean tumor diameter after completion of chemotherapy, with a median duration of over three years.
These data suggest that an extended course of treatment with temozolomide as has been suggested may not be necessary for prolonged disease control. However, in contrast to patients with oligodendroglioma and 1p/19q loss, the duration of benefit from chemotherapy with temozolomide is thought to be more limited in patients with low-grade astrocytoma .
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.
●For patients with low-grade oligodendroglial tumors, a repeat MRI should be obtained every three to six months for five years, and then at least annually 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 [35,36]. (See "Assessment of disease status and surveillance after treatment in patients with brain tumors".)
SUMMARY AND RECOMMENDATIONS — Oligodendrogliomas (ODs) and oligoastrocytomas (OAs) have important differences from other glial tumors, with significant ramifications for patient management. Many of these tumors contain a characteristic codeletion 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. Tissue should be tested whenever possible to determine whether codeletion of chromosomes 1p and 19q is present. Testing for IDH mutations should be considered, although this will not alter patient management. (See 'Chemotherapy' above and "Clinical features, pathology, and prognostic factors for oligodendroglial tumors", section on 'Genetic abnormalities'.)
Anaplastic oligodendrogliomas and oligoastrocytomas
●For patients with a newly-diagnosed anaplastic oligodendroglioma or oligoastrocytoma, we recommend maximal surgical resection consistent with preservation of neurologic function (Grade 1C). 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 patients whose tumor contains the characteristic 1p/19q codeletion, we recommend adjuvant treatment that includes both radiation therapy (RT) and chemotherapy (Grade 1A). Whether chemotherapy should be given before or after RT remains uncertain. Although PCV (procarbazine, lomustine, vincristine) has been demonstrated to be effective in two phase III trials, temozolomide is easier to administer and has better patient tolerance. (See 'Postoperative therapy' above.)
●For patients whose tumor does not contain the 1p/19q codeletion, we suggest postoperative RT, with chemotherapy withheld until there is evidence of disease progression (Grade 2C). (See 'Postoperative therapy' above.)
Low-grade oligodendrogliomas and oligoastrocytomas
●For young patients with transient symptoms and a small tumor not creating a mass effect on adjacent structures, we suggest maximal surgical resection if safely possible (Grade 2C).
For young favorable prognosis patients (eg, under 50 years of age presenting without focal deficits or signs of increased intracranial pressure) who have undergone surgical resection, we suggest that further treatment with either RT or chemotherapy be deferred until there is evidence of recurrence or progression of symptoms (Grade 2C). (See 'Low-grade oligodendroglial tumors' above and "Management of low-grade glioma".)
Careful observation is an alternative to immediate surgery in these patients, with surgery reserved until there is clinical or imaging evidence of progressive disease. (See 'Low-grade oligodendroglial tumors' above.)
●For patients presenting with poor prognostic features (a large mass, extensive neurologic symptoms, an age above 40 to 50 years), we recommend immediate surgery to debulk the tumor and establish the diagnosis (Grade 1C). (See 'Surgery' above and "Clinical features, pathology, and prognostic factors for oligodendroglial tumors", section on 'Genetic abnormalities'.)
•Single modality treatment with either chemotherapy or RT alone is indicated in those patients whose tumors contain the chromosome 1p/19q deletions. Chemotherapy (temozolomide or PCV) can be considered for the initial postoperative treatment of residual or progressive disease in lieu of RT because of the prolonged natural history of the disease in these patients. RT is then reserved for progression after chemotherapy. Whether combining RT with adjuvant PCV will also prolong survival here is still unknown. (See 'Chemotherapy and deferred RT' above.)
•For patients whose tumors do not contain the 1p/19q codeletion, we suggest that RT be administered postoperatively (Grade 2C). Chemotherapy should be reserved for patients with progressive symptoms following RT. (See 'Radiation therapy' above.)
Posttreatment surveillance — 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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