Version May 2024
INTRODUCTION — Oligodendroglial tumors constitute approximately 5 to 10 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, they are almost always life limiting.
Historically, management decisions in patients with oligodendroglial tumors have been based primarily on tumor grade (2 versus 3) and informed by results from studies in patients with both astrocytic and oligodendroglial tumors, carried out prior to the recognition of the molecular and prognostic differences between oligodendroglial and other glial tumors. In some of those studies, enrolled patients were later assessed for 1p/19q status, allowing for treatment recommendations according to the present World Health Organization (WHO) classification [1].
According to the WHO classification for central nervous system tumors, the diagnosis of an oligodendroglioma requires the presence of both an isocitrate dehydrogenase (IDH) mutation and combined 1p/19q loss (algorithm 1) [2]. Tumors continue to be categorized as either grade 2 (low-grade) or grade 3 (anaplastic) oligodendroglioma based on histopathologic features. However, in the era of molecular glioma diagnosis, the biologic and prognostic differences between grade 2 and grade 3 oligodendroglioma treated with radiotherapy and chemotherapy have become marginal. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors".)
The treatment and prognosis of grade 2 and 3 IDH-mutant, 1p/19q-codeleted oligodendrogliomas will be reviewed here. The clinical manifestations, pathology, and molecular diagnosis of oligodendroglial tumors and the management of IDH-mutant diffuse astrocytomas are discussed separately. (See "Clinical features, diagnosis, and pathology of IDH-mutant, 1p/19q-codeleted oligodendrogliomas" and "Treatment and prognosis of IDH-mutant astrocytomas in adults".)
SURGICAL RESECTION — Surgery provides tissue to establish the diagnosis and is used to relieve symptoms due to mass effect in patients with suspected diffuse gliomas. As with other gliomas, maximal resection is the preferred approach for oligodendrogliomas, but depending upon the location and extent of the tumor, only a partial resection or even just a biopsy may be safely feasible.
Microsurgical techniques and pre- and intraoperative planning tools are used to remove as much tumor tissue as safely feasible while maintaining a low risk of new neurologic deficits. When these two goals are at odds, the priority is to prevent new permanent neurologic deficits [3]. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas", section on 'Preoperative imaging' and "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas", section on 'Intraoperative techniques'.)
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 (grade 2 and 3) comes from secondary analyses of two large trials, which demonstrated a positive association between a more extensive resection and prolonged survival [4,5]. There is growing consensus that the amount of residual tumor following surgery is correlated with outcome in low-grade glioma patients. This has also been demonstrated in observational studies of molecularly defined oligodendroglioma [6-8].
The timing and extent of surgery for diffuse gliomas is discussed in more detail separately. (See "Treatment and prognosis of IDH-mutant astrocytomas in adults", section on 'Surgical management'.)
SELECTION OF POSTOPERATIVE THERAPY — Surgery is not curative in patients with oligodendrogliomas, and additional therapy (eg, radiation therapy [RT] and chemotherapy) is ultimately required in all patients. Standard of care has evolved over time as long-term follow-up of randomized trials initiated in the 1990s has shown that combined-modality therapy is superior to RT alone in both grade 2 and grade 3 oligodendrogliomas, and with subsequent development of isocitrate dehydrogenase (IDH)-specific targeted therapies. The optimal timing of additional therapy remains uncertain in some cases, especially for patients with particularly low-risk disease.
Grade 2 tumor, emerging approach — Patients with a newly-diagnosed grade 2 oligodendroglioma will soon have three options for postoperative management, outside of clinical trials: watchful waiting, RT plus chemotherapy, and IDH-targeted therapy. Use of an IDH inhibitor in this setting is based on results of the INDIGO trial of vorasidenib (an investigational IDH1/2 inhibitor not yet approved by the US Food and Drug Administration [FDA]), presented at the 2023 American Society for Clinical Oncology (ASCO) meeting and discussed below.
The approach to these patients is evolving as data on IDH-targeted therapies become available and as definitions of risk are revised. Treatment guidelines have traditionally defined risk based on age, extent of resection, and tumor grade to select patients for immediate postoperative RT and chemotherapy, but data to justify treatment decisions based on these factors alone in the era of integrated molecular glioma diagnoses are in fact absent. In particular, the evidence for age and grade as risk factors is weak and often too strictly interpreted. An alternative understanding of risk continues to recognize certain high-risk features favoring early treatment with RT and chemotherapy (eg, uncontrolled disease-related symptoms, contrast enhancement on brain magnetic resonance imaging [MRI]) and broadens the pool of patients who may be candidates for watchful waiting or IDH-targeted therapies before committing to RT and chemotherapy.
●Patients with gross total resection of a grade 2 tumor – Watchful waiting has traditionally been favored for most of these patients, who are at low risk for early progression and may not require further therapy for many years. IDH-targeted therapy may be an option to prolong progression-free survival, although patients without measurable disease were not included in the INDIGO trial, and safety data for very long-term treatment with vorasidenib are only available for a limited number of patients treated on phase 1 trials.
●Patients with residual disease after surgery (eg, ≥1 cm in two dimensions), meeting INDIGO criteria – For most such patients, IDH-targeted therapy with vorasidenib may have a major role, based on the progression-free survival advantage over placebo shown in the INDIGO trial and the benefits of delaying toxicities of RT and chemotherapy. Both watchful waiting and immediate RT plus chemotherapy will remain reasonable alternatives in patients who do not have access to IDH-targeted therapies, depending on an individualized assessment of risks and benefits.
The multicenter phase 3 INDIGO trial enrolled 331 patients 12 years of age or older with residual or recurrent grade 2 IDH-mutant glioma who had undergone no prior therapy other than surgery, had measurable nonenhancing disease (≥1 cm in two dimensions), high performance status (Karnofsky Performance Status ≥80), were not on glucocorticoids, and were considered appropriate for a watch-and-wait approach [9]. Patients were randomly assigned to receive either oral vorasidenib (40 mg once daily) or placebo. Median age of participants was approximately 40 years (range, 16 to 71 years), and more than 80 percent of patients had residual disease >2 cm in diameter. Thus, most patients met historical criteria for "high-risk" for low-grade glioma (eg, as per National Comprehensive Cancer Network [NCCN] guidelines [10]). Histologic subtype was oligodendroglioma in 52 percent of patients and astrocytoma in 48 percent.
With a median follow-up of 14.2 months, patients in the vorasidenib group had significantly-improved progression-free survival compared with the placebo group (27.7 versus 11.1 months, hazard ratio [HR] 0.39, 95% CI 0.27-0.56) [9]. The likelihood of not receiving a next treatment intervention was higher in the vorasidenib group at 18 months (85.6 versus 47.4 percent) and at 24 months (83.4 versus 27.0 percent). Data on seizure control, quality of life, and overall survival are not yet available. Vorasidenib was well tolerated overall, with a low incidence of serious adverse events (<2 percent in both groups). The most common grade 3 or higher adverse event related to vorasidenib was elevated alanine aminotransferase (9.6 percent). Rates of treatment discontinuation due to treatment were <4 percent in both groups. Vorasidenib is not available for clinical use and is under review by the FDA.
Several other IDH inhibitors are FDA-approved for other cancers and are under investigation for IDH-mutant gliomas, including ivosidenib, olutasidenib, and safusidenib (mutant-IDH1 inhibitors) and enasidenib (mutant-IDH2 inhibitor). More data from well-designed trials are needed to understand their role in IDH-mutant glioma. (See 'Investigational IDH-targeted approaches' below.)
●Patients with uncontrolled symptoms or contrast enhancement – Immediate postoperative therapy with RT and chemotherapy is advised for most patients with uncontrolled disease-related symptoms or contrast enhancement on brain MRI. Such patients were excluded from the INDIGO trial, and data from other IDH inhibitors indicate that response rates are much lower for enhancing tumors compared with nonenhancing tumors. (See 'Investigational IDH-targeted approaches' below.)
Grade 2 tumor, existing approach — Until vorasidenib becomes available for clinical use, the approach reviewed below continues to be applicable for most patients. This approach (algorithm 2) is generally consistent with consensus-based guidelines published by the NCCN, the American Society of Clinical Oncology and Society for Neuro-Oncology, and the European Association of Neuro-Oncology [3,10-12].
Gross total resection, grade 2 tumor
●Rationale for observation – A "wait and see" approach following initial surgery is suggested for most patients who have undergone complete or near-complete resection of an IDH-mutant, 1p/19q-codeleted grade 2 oligodendroglioma (algorithm 2). These tumors have a lower annual growth rate compared with astrocytic low-grade gliomas, and some patients may not require further therapy for many years [13]. Surgery is not curative, and it is expected that these patients will eventually require additional therapy at the time of tumor progression. Delaying RT in this setting does not have an adverse impact on overall survival [14,15], and it postpones the potential toxicities of therapy. Patients who are uncomfortable with the uncertainties surrounding observation may reasonably choose immediate postoperative therapy, even though this approach is associated with more toxicity in the short term. (See 'Subtotal resection, grade 2 tumor' below.)
Of note, often older age (eg, >40 years) and the presence of neurologic deficits are taken as arguments for immediate further treatment, but these are prognostic and have never been tested in prospective trials to identify which patients may benefit from early treatment, particularly for a genetically uniform group of tumors. However, because age >40 years was one of the risk-defining inclusion criteria for Radiation Therapy Oncology Group (RTOG) 9802 of RT with or without procarbazine, lomustine, and vincristine (PCV) for high-risk low-grade glioma [16], this criterion is used by some experts, including the NCCN consensus guidelines, to select patients for immediate postsurgical treatment [10].
The natural history of untreated completely resected grade 2 oligodendrogliomas is largely informed by older studies that enrolled a mix of oligodendroglial and astrocytic tumors with unknown IDH status. In a prospective series of 111 patients <40 years of age with low-grade gliomas who were felt to have a gross tumor resection based upon surgical assessment, overall survival rates at two and five years were 99 and 93 percent, respectively [17]. Among patients with histologically pure oligodendroglioma, <1 cm residual disease, and a preoperative tumor size <4 cm, two- and five-year progression-free survival rates were 100 and 70 percent, respectively. Similar rates have been reported in small retrospective series of patients with molecularly confirmed IDH-mutant, 1p/19q-codeleted grade 2 oligodendrogliomas who are observed after gross total resection [18].
●Surveillance interval – Active surveillance typically involves MRI with contrast every three to four months [19]. Some clinicians lengthen the follow-up interval to six to nine months after one to two years of stable imaging, given the long progression-free survival in many of these patients.
Oligodendrogliomas tend to recur locally at the margins of the resection cavity, and interpretation of small changes over time can be challenging. New MRIs should always be compared with the oldest available postoperative imaging as the most relevant baseline. It can sometimes take several years for the clinician to become confident that minor changes or increases in nonenhancing T2/fluid-attenuated inversion recovery (FLAIR) signal are definitively progressive and indicative of tumor recurrence. Not every minor change is an immediate reason for further treatment; especially in slow-growing lesions, it can be cumbersome to identify the right moment for further treatment.
●Management at the time of progression – Management of recurrent or progressive tumor in patients who have been observed following initial resection is individualized. Decisions take into account the rate of change from one MRI interval to the next, the overall volume of tumor, its location in the brain and resectability, patient preferences with regard to more surgery, presence of contrast enhancement, and histopathologic grade of the progressive tumor, when available.
Some of the more common scenarios include the following:
•For patients with recurrent tumors in whom a re-resection appears safe and likely to be extensive or gross total, we typically propose re-resection. If the re-resection leaves no or little residual tumor behind and pathology confirms a grade 2 tumor, a watch-and-wait strategy can again be considered.
•For patients with a relatively low volume of recurrent, nonenhancing tumor or those who are not eligible for or do not wish to undergo further surgery, we typically proceed with RT plus chemotherapy, per standard of care for grade 2 oligodendrogliomas. (See 'Subtotal resection, grade 2 tumor' below.)
•For patients with a large or rapidly progressive recurrence, re-resection is often indicated for debulking as well as to confirm the diagnosis and grade. This may be most relevant for patients who have had a prolonged disease-free interval and those whose tumors were diagnosed in an era prior to full molecular characterization. The need for tissue confirmation of grade may be less important in the molecular era for fully categorized tumors, however, as both the therapeutic and prognostic implications of grade 2 versus grade 3 oligodendroglioma have become less important. (See 'Prognosis' below.)
Postoperative management decisions depend on the extent of resection achieved and the pathology of the recurrent tumor, as described below for newly diagnosed patients. (See 'Subtotal resection, grade 2 tumor' below and 'Grade 3 tumor, any resection' below.)
Subtotal resection, grade 2 tumor — Immediate postoperative therapy is appropriate for most patients with a newly diagnosed grade 2 oligodendroglioma who have significant residual or symptomatic tumor (apart from well-controlled seizures) after maximal safe resection. However, a period of observation may be justified in some of these patients who wish to postpone therapy, such as younger adults (eg, <40 to 50 years) or patients with modest amounts of residual tumor, provided that they do not have symptoms from the tumor aside from well-controlled epilepsy [3,10]. Further treatment can then be started upon documented tumor growth.
When the decision is made to pursue further therapy, it should consist of both radiation and chemotherapy in most patients, based on long-term follow-up data from the RTOG 9802 trial [16,20], as well as similar data in grade 3 (anaplastic) oligodendrogliomas reviewed below (see 'Rationale for RT plus chemotherapy' below). The specific chemotherapy regimen selected (ie, PCV versus temozolomide) should be individualized.
Potential exceptions include patients with very large or multifocal tumors, in whom a chemotherapy-alone approach may be preferred initially to avoid or postpone what would otherwise be a very large radiation field [21]. (See 'Diffuse tumors with large RT field' below.)
●RTOG 9802 trial – Supporting evidence for the combination of RT plus chemotherapy in low-grade oligodendrogliomas comes from the RTOG 9802 trial, in which 251 patients with a supratentorial low-grade glioma were randomly assigned to postoperative RT (54 Gy in 30 fractions) with or without six cycles of adjuvant PCV chemotherapy [22]. Eligible patients were either age 18 to 39 years with subtotal resection or biopsy, or age ≥40 years with any extent of resection. The patient population included those with diffuse astrocytoma, oligodendroglioma, and mixed astrocytoma/oligodendroglioma in 26, 42, and 32 percent of cases, respectively. Randomization was stratified by age, presence of enhancement, and histology (astrocytic versus oligodendroglial predominant).
With a median follow-up time of 11.9 years, median overall survival was superior in the post-RT PCV group (13.3 versus 7.8 years, HR 0.59, p = 0.03) [16]. The incidence of grade 3 and 4 hematologic toxicity was 8 and 3 percent, respectively, in the RT-alone arm compared with 51 and 15 percent in the RT-plus-PCV arm; there were no treatment-related deaths and no cases of secondary leukemia [22].
The survival benefit conferred by PCV was present in all histologic subtypes, but the magnitude of the effect was greatest in patients with histologic oligodendroglioma (n = 101, HR 0.43, 95% CI 0.23-0.82) [16]. Post hoc molecular analysis of the RTOG 9802 trial in 42 percent of enrolled cases demonstrated the marked survival advantage in molecularly confirmed IDH-mutant, 1p/19q-codeleted oligodendrogliomas (HR 0.21, p = 0.029) [23].
It is unclear whether temozolomide is equally effective as PCV, and there are no trials that have compared these two regimens head-to-head in patients with oligodendroglioma. Both regimens have activity in oligodendroglioma and other types of diffuse gliomas, but only PCV has been investigated in randomized trials in patients with oligodendroglial tumors. On the other hand, temozolomide has advantages over PCV in terms of its ease of administration, better patient tolerance, and more consistent availability in some regions, and its efficacy in combination with RT is supported by indirect evidence in other types of gliomas. (See 'Choice of PCV versus temozolomide' below.)
Grade 3 tumor, any resection — Immediate postoperative RT plus adjuvant chemotherapy is indicated in most patients with newly diagnosed grade 3 (anaplastic) oligodendroglioma, regardless of the degree of resection or other risk factors (algorithm 2). The specific chemotherapy regimen selected (ie, PCV versus temozolomide) should be individualized. (See 'Choice of PCV versus temozolomide' below.)
Younger patients who undergo gross total resection of a grade 3 tumor with no evidence of homozygous CDNK2A/B deletion are one potential exception to immediate therapy, in light of the uncertainty of the prognostic value and reproducibility of grade 2 versus 3 in fully molecularly characterized oligodendrogliomas and their otherwise favorable prognosis [3,24-26]. In such patients, an argument can be made for a watch-and-wait strategy, as in resected grade 2 oligodendrogliomas (see 'Grade 2 tumor, emerging approach' above and 'Grade 2 tumor, existing approach' above). However, this approach has not been studied prospectively.
Rationale for RT plus chemotherapy — Two cooperative group randomized phase III trials with prolonged follow-up and molecular analysis provide strong, complementary evidence that a combination of both RT and PCV following surgery is associated with improved survival on long-term follow-up compared with RT alone in patients with grade 3 oligodendroglial tumors [27-29].
●EORTC 269521 – In the European Organisation for Research and Treatment of Cancer (EORTC) 26951 trial, 368 patients with anaplastic oligodendroglioma or anaplastic oligoastrocytoma were randomly assigned to immediate RT only or RT followed by six cycles of PCV [5,27,29,30]. The total dose of RT on each treatment arm was 59.4 Gy. 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.
With a median follow-up of 19 years in the entire trial population, patients randomly assigned to RT plus PCV had improved overall survival compared with those assigned to RT alone (median 3.5 versus 2.6 years, HR 0.78, 95% CI 0.63-0.98); the benefit from initial combined PCV and RT was seen primarily in patients whose tumors contained the 1p/19q codeletion [29]. 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, progression-free survival was significantly increased when patients were treated with RT plus PCV compared with RT alone (median 13.1 versus 4.2 years, HR 0.49, 95% CI 0.29-0.83), and there was a trend toward increase in overall survival (median 14.2 versus 9.3 years, HR 0.60, 95% CI 0.35-1.03). Thirty-seven percent of patients with a 1p/19q-codeleted tumor in the RT plus PCV arm were projected to be alive at 20 years compared with 14 percent in the RT alone group.
In a subset analysis that included data from 115 patients whose tumors were available for methylation profiling, O6-methylguanine-DNA methyltransferase (MGMT) methylation and a CpG island hypermethylated phenotype (CIMP) were also predictive of a benefit from PCV [31]. 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).
●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 [28]. The cumulative dose of RT on both treatment arms was 59.4 Gy. With long-term follow-up of over 17 years, among 125 patients whose tumor contained the 1p/19q codeletion, overall survival was prolonged by intensified PCV followed by RT compared with only RT initially (median 13.2 versus 7.3 years, HR 0.61, 95% CI 0.40-0.94) [29]. Thirty-seven percent of patients in the PCV plus RT arm were projected to be alive at 20 years compared with 15 percent in the RT alone group.
Choice of PCV versus temozolomide — Both PCV and temozolomide are reasonable options for adjunctive therapy along with RT in patients with oligodendrogliomas, and there is no consensus among experts about which regimen is preferred.
Use of PCV is supported by results of the RTOG 9802 trial in patients with grade 2 oligodendrogliomas and the two randomized trials in patients with anaplastic oligodendroglial tumors (EORTC 26951 and RTOG 9402). In all three trials, the addition of PCV to RT was associated with improved progression-free and overall survival compared with RT alone in those with 1p/19q-codeleted tumors (see 'Subtotal resection, grade 2 tumor' above and 'Rationale for RT plus chemotherapy' above). A small subset analysis of a German anaplastic glioma study and a large retrospective survey of 1000 patients with anaplastic oligodendroglial tumors have suggested better survival in 1p/19q-codeleted oligodendroglioma after PCV chemotherapy compared with temozolomide, but confidence in these data is limited and neither study was designed prospectively to compare the two regimens when given along with RT [32,33].
On the other hand, adjuvant temozolomide is easier to administer, has better patient tolerance, and has been shown to improve survival in other types of malignant gliomas (see "Treatment and prognosis of IDH-mutant astrocytomas in adults", section on 'Grade 3 tumor, any resection'). Therefore, patients who prioritize convenience and avoidance of short-term toxicity may reasonably choose temozolomide over PCV.
It is unclear if the addition of temozolomide during RT will help to improve outcome compared with sequential RT and temozolomide, or if it may contribute to delayed treatment-related toxicities. A randomized trial in 1p/19q-codeleted tumors comparing RT plus PCV with RT plus concurrent and adjuvant temozolomide ("CODEL") is ongoing. (See 'Ongoing randomized trials' below.)
Order of therapy — The optimal order of RT and chemotherapy when given as a combined approach for 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 NCCN recommend that standard PCV be administered after RT (as per EORTC 26951), in particular since the intensive PCV regimen given prior to RT was not tolerated as well [10]. Similarly, temozolomide is typically sequenced after RT rather than before.
Diffuse tumors with large RT field — Although RT plus chemotherapy has generally replaced single-modality therapy as the standard of care for grade 2 and grade 3 diffuse gliomas, there are selected clinical scenarios in which initial treatment with chemotherapy alone can be justified. In patients with oligodendrogliomas, the most common of these is probably the case of a diffuse, multilobar or bihemispheric oligodendroglioma, for which the necessary radiation field would be very large or essentially whole brain radiation. In such cases, concerns about the potential for delayed neurocognitive toxicity take on greater weight than in the case of focal brain radiation, and chemotherapy alone can be a reasonable initial treatment strategy. (See "Delayed complications of cranial irradiation", section on 'Whole brain radiation'.)
This approach has not been well studied prospectively in oligodendroglial tumors, although some data exist in both grade 2 and grade 3 gliomas with subsequent molecular analyses that may help inform individualized treatment decisions. In general, and although the data are not directly comparable, these studies all report inferior overall survival compared with what has been observed with combined-modality therapy in the studies reviewed above. (See 'Subtotal resection, grade 2 tumor' above and 'Rationale for RT plus chemotherapy' above.)
The most robust outcomes data for single-modality temozolomide in grade 2 oligodendrogliomas come from the EORTC 22033-26033 trial, in which 477 patients with high-risk low-grade glioma (defined as age >40 years, progressive disease, tumor >5 cm, tumor crossing midline, or neurologic symptoms) were randomized to receive either 12 cycles of postoperative dose-intense temozolomide (75 mg/m2 daily for 21 days out of 28) or radiotherapy (50.4 Gy) [34]. Randomization was stratified by 1p status. In the subgroup of patients with IDH-mutant, 1p/19q-codeleted oligodendrogliomas, progression-free survival was similar for temozolomide and RT (55 and 62 months, respectively) with a median follow-up of four years. Mature survival data are not yet available.
In grade 3 tumors, data from a truncated randomized trial in which chemotherapy alone was one of three treatment arms in patients with newly diagnosed anaplastic oligodendrogliomas (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, and 3 of the 12 tumors in patients in the temozolomide-only arm were IDH wildtype [35]. With a median clinical follow-up of 6.6 years, 10 out of 12 patients (83 percent) treated with temozolomide alone had progressed, compared with 37.5 percent of RT-treated patients (HR 3.12, 95% CI 1.26-7.69). Adjusted overall survival was nonsignificantly worse in the temozolomide-alone arm (HR 2.78, 95% CI 0.58-13.2). There were no differences in neurocognitive decline at three months.
Single-modality chemotherapy versus RT was also evaluated in the initial stage of a phase III trial (NOA-4) in patients with grade 3 gliomas (anaplastic astrocytoma, anaplastic oligoastrocytoma, and anaplastic oligodendroglioma) [36]. Longer-term follow-up results presented in a small subset of patients suggested longer progression-free survival with PCV compared with temozolomide in patients with 1p/19q-codeleted tumors (9.4 versus 4.5 months), but no difference between initial chemotherapy versus initial radiotherapy [32].
Ongoing randomized trials — Management of diffuse gliomas remains an active area of research, with trials evolving as molecular diagnostics have altered tumor classification.
The largest ongoing trial in oligodendroglial tumors is a phase III Alliance for Clinical Trials in Oncology/EORTC intergroup trial ("CODEL"), in which patients with 1p/19q-codeleted 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 France, an ongoing trial (POLCA) compares PCV chemotherapy with radiotherapy followed by PCV chemotherapy, with cognition as the primary endpoint.
ADMINISTRATION OF THERAPY
Involved field radiation therapy — The goal of radiation therapy (RT) in patients with diffuse gliomas is to improve local control without inducing neurotoxicity [3]. The timing, dosing, and schedule are determined by the disease subtype and prognostic factors, as discussed above. (See 'Selection of postoperative therapy' above.)
Dose and schedule — Once the decision is made to treat with RT, the dose and schedule depend on the grade of the tumor. When RT is administered postoperatively, it should generally start within three to five weeks after surgery.
●Grade 2 oligodendroglioma – A dose of 45 to 54 Gy in 1.8 Gy fractions is typically used to treat grade 2 oligodendrogliomas and other low-grade gliomas [10]. The clinical target volume includes a 1 cm margin around the gross tumor volume as determined by MRI. This dose range provides a reasonable balance between efficacy and toxicity, and higher doses have not been shown to improve outcomes in historical trials [37-39].
●Grade 3 oligodendroglioma – A dose of 59.4 to 60 Gy in 1.8 to 2 Gy fractions is typically used to treat grade 3 oligodendrogliomas and other high-grade gliomas [10]. (See "Radiation therapy for high-grade gliomas", section on 'Adjuvant RT'.)
Alternative RT approaches that have been evaluated in infiltrative gliomas include hyperfractionated RT [40], proton RT [41,42], and fractionated stereotactic radiotherapy [43]. However, no advantage has been demonstrated for these strategies compared with conventional RT.
Side effects — Although RT is relatively well tolerated, a range of short- and long-term toxicities can occur:
●Common acute toxicities include hair loss, fatigue, and loss of appetite. In some cases, increased cerebral edema during RT may cause headaches and aggravation of existing or prior neurologic symptoms such as seizures or weakness.
●Certain potential late effects are specific to the location of treatment, for example, hearing loss when radiation fields include the cochlea, or hypopituitarism when fields include the hypothalamus and/or pituitary gland. (See "Delayed complications of cranial irradiation", section on 'Ototoxicity' and "Delayed complications of cranial irradiation", section on 'Endocrinopathies'.)
●Progressive delayed neurocognitive impairment is a potential consequence of both the disease and its treatment. However, it is not always clear whether any observed impairment is an effect of the RT or whether the tumor itself and antiseizure medication treatment are contributory. (See "Delayed complications of cranial irradiation", section on 'Partial brain radiation'.)
●There is a low risk of secondary tumor formation such as meningioma or, less commonly, de novo malignant glioma. (See "Risk factors for brain tumors", section on 'Ionizing radiation' and "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Ionizing radiation'.)
Procarbazine, lomustine, vincristine (PCV) — The PCV regimen is administered in six- to eight-week cycles for a total of six cycles. An eight-week cycle length is preferred for grade 2 tumors, based on the regimen used in the RTOG 9802 trial [22], and a six-week cycle length is preferred for grade 3 tumors, based on the EORTC 26951 regimen [27]. Each cycle is dosed as follows [3]:
●Lomustine 110 mg/m2 orally, day 1; often, a cap of 200 mg is used
●Procarbazine 60 mg/m2 orally, days 8 to 21
●Vincristine 1.4 mg/m2 intravenously (maximum 2 mg per dose), days 8 and 29
The value of vincristine in this combination regimen has been questioned, since it does not penetrate an intact blood-brain barrier. However, studies comparing PCV with a two-drug regimen (lomustine and procarbazine) are lacking.
Baseline and pretreatment laboratory studies on day 1 of each cycle should include complete blood count (CBC) with differential, serum creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin [44]. Weekly CBCs are typically performed starting at week 4.
Lomustine and procarbazine are moderately emetic, and patients should receive premedication with an orally administered 5-hydroxytryptamine (5-HT3) antagonist (eg, ondansetron 8 mg) before each dose. Vincristine has minimal risk of nausea and vomiting and does not require antiemetic prophylaxis. Constipation related to vincristine and/or antiemetics is common, and many patients require a daily bowel regimen (eg, docusate sodium and senna) to maintain normal bowel function. (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Oral chemotherapy'.)
For procarbazine, the US Food and Drug Administration (FDA) label includes a warning about potential drug-drug and drug-food interactions based on weak inhibition of monoamine oxidase (MAO) in the gastrointestinal system. Tyramine-rich foods (eg, aged cheese, smoked meats) should be avoided, and concurrent use of an MAO inhibitor is contraindicated due to risk of hypertensive crisis. Despite the label warning, evidence of clinically significant effect on MAO inhibition is lacking, however [45]. Alcohol must be avoided due to potential for a disulfiram-like reaction.
Both lomustine and procarbazine contribute to hematologic toxicity. Lomustine is the most myelosuppressive, with a white blood cell (WBC) and platelet nadir between days 28 and 35. The most common grade 3/4 toxicities are lymphopenia (30 to 40 percent), thrombocytopenia (25 to 30 percent), and neutropenia (10 percent) [46]. Thrombocytopenia is usually more severe than leukopenia. Both lomustine and procarbazine are typically dose reduced for hematologic toxicity based on depth of nadir and duration of recovery [44].
Increased liver biochemical tests occur in over half of patients [46]. Cycles should generally be delayed until ALT/AST have recovered to <2 times the upper limit of normal. Dose adjustments may be required for all three drugs depending on timing and severity of liver toxicity. Lomustine and procarbazine are associated with a small risk of progressive azotemia, and both occasionally require dose adjustments for renal dysfunction. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents" and "Nephrotoxicity of chemotherapy and other cytotoxic agents", section on 'Nitrosureas'.)
Approximately 25 to 50 percent of patients develop a cutaneous maculopapular rash related to procarbazine hypersensitivity. Procarbazine should be stopped if rash develops, and the risk of a more severe hypersensitivity reaction with reexposure appears to be high [47]. Procarbazine-induced encephalopathy can also occur, albeit rarely. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Procarbazine'.)
Neurotoxicity due to vincristine occurs in over half of patients, typically manifest by a length-dependent sensory peripheral neuropathy and constipation (due to autonomic neuropathy). Given the unclear added benefit of vincristine to the schedule, vincristine is often discontinued at the earliest sign of neurotoxicity. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Vincristine'.)
Rare but serious pulmonary toxicity (infiltrates, fibrosis) can occur due to lomustine (<1 percent). (See "Nitrosourea-induced pulmonary injury".)
Temozolomide — The administration of concurrent and/or adjuvant temozolomide in patients with diffuse gliomas, including discussion of side effects and monitoring, is reviewed separately. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Temozolomide' and "Treatment and prognosis of IDH-mutant astrocytomas in adults", section on 'Temozolomide'.)
MONITORING AND SUPPORTIVE CARE
Response assessment and surveillance — Patient management decisions require an assessment of both initial response to treatment as well as subsequent evidence of progressive disease. Response assessment for diffuse gliomas considers both enhancing and nonenhancing disease volume on MRI as well as clinical status.
The schedule for follow-up imaging is based on the expected natural history and overall prognosis, as informed by molecular subtype, clinical status, grade, treatment history, and goals of care [19]:
●Observation after surgery – Surveillance recommendations for untreated tumors are reviewed above. (See 'Gross total resection, grade 2 tumor' above.)
●During RT plus chemotherapy – Brain MRI has traditionally been obtained two to six weeks after completion of radiation therapy (RT) before starting adjunctive chemotherapy. However, with a median progression-free survival of greater than 10 years in clinical trials of grade 2 and 3 oligodendrogliomas, early post-RT progression is unlikely, and postponing the first MRI scan until four months after the end of RT in these patients limits the risks of picking up pseudoprogression. During adjunctive chemotherapy, brain MRIs are typically obtained every two to three chemotherapy cycles for patients receiving PCV and every two to four cycles for those receiving monthly temozolomide.
●Posttreatment – After completion of initial RT plus chemotherapy, MRIs should be obtained every six to nine months indefinitely for both grade 2 and 3 tumors. Patients treated with RT alone or chemotherapy alone should be imaged as often as every three to four months but at least every six months until progression. Earlier MRIs should be obtained as clinically indicated in the event of a clinical change such as development of seizures or neurologic deterioration.
After first progression, follow-up MRIs are performed even more frequently, given the heightened risk of further tumor growth.
Tumor-associated epilepsy — Seizures associated with supratentorial oligodendrogliomas can be a source of major morbidity [48]. In patients with refractory seizures due to low-grade gliomas, consideration should be given to surgical resection of the tumor. Complete or near-complete surgical resection is associated with improved seizure frequency in the majority of patients [49]. Some clinicians advocate seizure-type surgery with intraoperative recording to localize the seizure focus in these instances, although it is difficult to definitively demonstrate that this approach is superior to a standard tumor resection [50,51]. RT and chemotherapy are also associated with improved seizure control in many patients, even in the absence of a radiographic response [52]. (See "Seizures in patients with primary and metastatic brain tumors" and "Surgical treatment of epilepsy in adults".)
Reproductive health — Oligodendrogliomas and other IDH-mutant diffuse gliomas commonly impact patients in their childbearing years. The possibility of infertility due to chemotherapy should be addressed as early as possible before chemotherapy is planned [53].
Before starting chemotherapy, males who are interested in future paternity should be referred for sperm banking, and females should be referred to reproductive specialists for discussion of fertility preservation options such as embryo and oocyte cryopreservation [54]. Cryopreservation should ideally be done before starting chemotherapy to avoid potential genetic damage to gametes. Reproductive counseling prior to gonadotoxic therapy is reviewed in detail separately. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
Among specific drugs, procarbazine is considered to have a high risk of infertility. As an alkylating agent, temozolomide also has the potential to impact reproductive function. Changes in semen parameters after exposure to temozolomide have been demonstrated in males with gliomas [55]; however, the clinical importance of these changes and rates of infertility after temozolomide are not well studied in males or females. Fetal harm and adverse developmental outcomes associated with temozolomide exposure have been reported in both pregnant patients and pregnant partners of male patients, as well as in animal studies [56]. (See "Effects of cytotoxic agents on gonadal function in adult men".)
Cognitive function — Patients with primary brain tumors are at increased risk for neurocognitive dysfunction due to the tumor itself, surgery, comorbid conditions such as epilepsy, medication side effects, and early and delayed effects of chemotherapy and RT. Baseline neurocognitive testing can be useful to document objective findings, validate concerns, and provide patients with an integrated assessment of both weaknesses and strengths. Cognitive rehabilitation may be of benefit in patients with deficits [57].
Risks, evaluation, and management of neurocognitive dysfunction after brain radiation are reviewed separately. (See "Delayed complications of cranial irradiation", section on 'Neurocognitive effects'.)
RECURRENT DISEASE — First-line therapy informs the choice of treatment for recurrent disease [3]. Both procarbazine, lomustine, and vincristine (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 with treatment at first diagnosis or at first recurrence after radiation therapy (RT).
Repeat surgery and reirradiation 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'.)
Temozolomide — Most trials of second-line chemotherapy have evaluated the activity of temozolomide in patients with histologically classified oligodendroglioma and mixed tumors. Some had received prior PCV, either given as an adjuvant or at first recurrence [58,59]. In some of these studies, later analyses reported on the subsets of patients with 1p/19q-codeleted glioma.
The activity of temozolomide after failure with PCV was illustrated by a retrospective series of 48 patients with anaplastic oligodendrogliomas and oligoastrocytomas [59]. In this series, 21 patients (44 percent) had an objective response, including eight with a complete remission. The median progression-free survival 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 [60].
Bevacizumab — Bevacizumab is an antivascular endothelial growth factor (VEGF) monoclonal antibody that has some activity in patients with recurrent glioblastoma, primarily related to vascular normalization and potent antiedema effects. (See "Management of recurrent high-grade gliomas", section on 'Bevacizumab'.)
Evidence in recurrent oligodendroglial tumors is sparse and inconsistent, and at present the role of bevacizumab seems limited to that of an alternative to glucocorticoids for management of symptomatic edema.
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) [61]. 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 [62]. No clear correlation was found between the genotype and outcome.
The TAVAREC study in 1p/19q-intact grade 2 and 3 recurrent gliomas failed to observe any benefit from adding bevacizumab to temozolomide, regardless of IDH status [63]. (See "Treatment and prognosis of IDH-mutant astrocytomas in adults", section on 'Chemotherapy'.)
Other cytotoxic 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 histologically defined oligodendroglial tumors include paclitaxel, irinotecan, carboplatin, and the combination of etoposide plus cisplatin [64-74]. Response rates with these agents have generally been low (less than 15 percent), and almost all patients progress in less than 12 months.
Investigational IDH-targeted approaches — In addition to vorasidenib (see 'Grade 2 tumor, emerging approach' above), other small molecule inhibitors of mutant IDH1 and IDH2 are in clinical trials for IDH-mutant gliomas. Vaccine strategies are also being explored.
Ivosidenib, a mutant-IDH1 inhibitor approved in the United States for advanced acute myeloid leukemia, was well tolerated with no dose-limiting toxicities in a phase I trial in 66 patients with advanced IDH1-mutant astrocytoma, oligodendroglioma, or glioblastoma [75]. Among 35 patients with progressive nonenhancing gliomas, a partial response or stable disease was observed in 3 and 86 percent of patients, respectively, with a median progression-free survival of 13.5 months. There were no objective responses in enhancing tumors, although a decrease in volumetric growth rate was observed in some patients. Olutasidenib, another mutant-IDH1 inhibitor, has also shown some activity in phase I/II testing in adults with recurrent/refractory IDH-mutant gliomas, warranting further studies [76]. Safusedinib was tested in a phase I trial with some responses observed mainly in nonenhancing tumors, and a phase II trial is ongoing [77].
PROGNOSIS — Despite the prolonged clinical course seen with oligodendroglial tumors, almost all are life limiting due to eventual acceleration of tumor growth and resistance to existing therapies.
In historical population-based or multicenter studies, the median overall survival for patients with low-grade oligodendroglioma ranges from 10 to 15 years, and the median survival for patients with anaplastic oligodendroglioma ranges from five to nine years [33,78,79]. These estimates are based on histopathologic diagnoses made prior to the 2016 World Health Organization (WHO) introduction of the integrated histopathologic and molecular diagnosis of oligodendroglioma, however, and include a wider range of tumors, many of which may have a less favorable prognosis.
Historical studies may therefore understate the prognosis of fully characterized, IDH-mutant, 1p/19q-codeleted oligodendrogliomas. Based on long-term follow-up data from multicenter randomized trials of radiation with or without chemotherapy, the median survival of patients with 1p/19q-codeleted oligodendrogliomas treated with radiation plus procarbazine, lomustine, and vincristine (PCV) may be closer to 20 and 14 years for grade 2 and 3 tumors, respectively [16,27-29].
Clinical factors that impact prognosis in patients with oligodendroglial tumors overlap with those identified in other gliomas. Some of the more commonly identified clinical features that predict worse overall survival include older age, male sex, poor functional status and/or baseline neurologic deficits, nonepilepsy presentation, tumor location other than the frontal and parietal lobes, and large tumor size (ie, >4 to 5 cm) [80-82]. Whether these prognostic factors retain significance for molecularly characterized oligodendrogliomas is uncertain, and further studies are needed in the post-IDH era.
WHO grade 3 oligodendroglial tumors have historically been associated with worse prognosis compared with grade 2 tumors, with an average difference in overall survival of approximately five years. The prognostic value of WHO grade may be lower in the more narrowly defined molecular subset of IDH-mutant, 1p/19q-codeleted oligodendrogliomas; however, more long-term follow-up studies are needed [83,84].
The presence of homozygous CDNK2A/B deletion in oligodendrogliomas is a negative prognostic marker [24]. Such deletions are almost invariably found in grade 3 tumors.
Limited data suggest that among IDH-mutant, 1p/19q-codeleted anaplastic oligodendrogliomas, microvascular proliferation, necrosis, number of mitoses, and Ki-67 labeling index do retain prognostic significance as risk factors for shorter overall survival [85]. (See "Clinical features, diagnosis, and pathology of IDH-mutant, 1p/19q-codeleted oligodendrogliomas", section on 'Pathology'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)
SUMMARY AND RECOMMENDATIONS
●Classification – Oligodendrogliomas are diffuse gliomas defined molecularly by the presence of both an isocitrate dehydrogenase (IDH) mutation and chromosome 1p/19q codeletion. A World Health Organization (WHO) grade of 2 or 3 is assigned based on histologic features (algorithm 1). (See 'Introduction' above.)
●Surgical resection – Surgery is the initial step in management of all suspected diffuse gliomas. Maximal safe resection is the goal. Gross total resection is associated with improved outcomes in patients with oligodendroglioma but is not always possible based on the location or extent of the tumor. (See 'Surgical resection' above.)
●Timing of additional therapy – Surgery is not curative, and radiation therapy (RT) and chemotherapy are ultimately required in all patients. Treatment timing varies according to tumor grade, clinical status, and extent of resection (algorithm 2).
•For most patients who undergo complete or near-complete resection of a grade 2 oligodendroglioma, we suggest initial observation after surgery (Grade 2C). Patients who are uncomfortable with the uncertainties surrounding observation may reasonably choose immediate postoperative therapy, even though this approach is associated with more toxicity in the short term. (See 'Gross total resection, grade 2 tumor' above.)
•Immediate postoperative therapy is appropriate in most patients with significant residual or symptomatic grade 2 oligodendroglioma and in patients with grade 3 (anaplastic) oligodendroglioma. (See 'Subtotal resection, grade 2 tumor' above and 'Grade 3 tumor, any resection' above.)
•IDH-targeted therapy is an emerging option for some of these patients, pending regulatory review of the IDH1/2 inhibitor, vorasidenib. (See 'Grade 2 tumor, emerging approach' above.)
●Components of additional therapy – When patients with grade 2 or 3 oligodendroglioma are selected for additional therapy, we recommend RT plus chemotherapy rather than RT alone (Grade 1A). This recommendation is based on the survival benefit conferred by combination therapy in long-term follow-up of trials in both grade 2 and grade 3 oligodendroglial tumors. (See 'Subtotal resection, grade 2 tumor' above and 'Rationale for RT plus chemotherapy' above.)
●Choice of adjunctive chemotherapy – Both procarbazine, lomustine, and vincristine (PCV) and temozolomide are reasonable options for adjunctive chemotherapy along with RT in patients with oligodendroglioma, and the two regimens are being compared in an ongoing intergroup randomized trial ("CODEL"). Decisions should be individualized.
Some patients may reasonably choose PCV because it is the regimen demonstrated to improve survival in randomized trials that have included patients with oligodendroglioma, whereas others may reasonably choose temozolomide because it is easier to administer, has a better side effect profile, and has been shown to improve survival in other types of diffuse gliomas. (See 'Choice of PCV versus temozolomide' above and 'Ongoing randomized trials' above.)
●Limited role of chemotherapy without RT – A chemotherapy-alone approach is sometimes justified in patients who are poor candidates for RT. One example is patients with diffuse, multilobar or bihemispheric oligodendrogliomas, for which the necessary radiation field would be very large or essentially whole brain radiation. (See 'Diffuse tumors with large RT field' above.)
●Recurrent disease – Management of recurrent oligodendrogliomas is individualized based on prior therapies, location and resectability of recurrent disease, and the time elapsed since prior RT. (See 'Recurrent disease' above and "Management of recurrent high-grade gliomas".)
●Prognosis – Despite the prolonged clinical course seen with oligodendroglial tumors, almost all are life limiting due to tumor relapse, eventual acceleration of tumor growth, and resistance to existing therapies. For fully characterized IDH-mutant, 1p/19q-codeleted tumors, median survival in prospective trials is approximately 15 to 20 years. (See 'Prognosis' above.)
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