Treatment and prognosis of IDH-mutant astrocytomas in adults

INTRODUCTION — Diffuse astrocytomas represent the most common group of infiltrative primary brain tumors in adults. They exist on a spectrum of biologic aggressiveness, but all are incurable and the vast majority are life limiting.

Since discovery of the importance of isocitrate dehydrogenase (IDH) mutations in the pathogenesis and prognosis of diffuse gliomas, classification of astrocytomas has evolved, and treatment decisions are now considered separately for IDH-mutant astrocytomas and IDH-wildtype astrocytomas (eg, glioblastoma). Across all grades, the presence of an IDH mutation identifies a group of tumors with a more prolonged natural history and favorable prognosis than that of IDH-wildtype tumors. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors".)

Historically, management of patients with diffuse gliomas has been based on histologic subtype and tumor grade and informed by results from clinical trials in patients with both astrocytic and oligodendroglial tumors, carried out prior to the recognition of the molecular and prognostic differences among these tumors. In some cases, tumor specimens were later assessed for IDH and 1p/19q status and data reanalyzed according to the modern World Health Organization (WHO) classification. Going forward, trials are increasingly being aligned with integrated molecular tumor diagnoses rather than historical groupings of low-grade glioma and high-grade glioma.

This topic will review the initial management of IDH-mutant astrocytomas, grades 2, 3, and 4. Management of other diffuse gliomas is covered elsewhere:

●(See "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults".)

●(See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas".)

●(See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults".)

●(See "Management of glioblastoma in older adults".)

●(See "Focal brainstem glioma" and "Diffuse intrinsic pontine glioma".)

●(See "Optic pathway glioma".)

SURGICAL MANAGEMENT — Maximal safe resection is the preferred initial approach to patients with suspected diffuse gliomas of all grades, even for tumors discovered incidentally. Depending upon the location and extent of the tumor, only a partial resection or even just a biopsy may be safely feasible. Surgical management of suspected diffuse gliomas should take place at high-volume centers with oncologic neurosurgical expertise whenever possible.

●Surgical planning – Preoperative neurosurgical evaluation may include tools such as functional magnetic resonance imaging (MRI) and diffusion tensor imaging to help delineate the safety and feasibility of tumor resection. A variety of intraoperative techniques allow neurosurgeons to improve the extent of resection while minimizing damage to normal brain. (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'.)

●Timing of surgery – Surgery is typically performed at the time of initial presentation for patients with large or symptomatic astrocytomas as well as tumors with features concerning for high-grade histology (eg, enhancement, central necrosis, edema). For patients with small nonenhancing tumors and minimal symptoms, the role of immediate surgical intervention versus delayed resection has been debated [1,2]. However, the field has generally moved to favor maximal safe resection at the time of diagnosis for these patients as well, based upon observational data and reviews of the literature that have found a trend toward improved survival with this approach, even in patients with asymptomatic, incidentally discovered tumors [1,3-8]. In addition, because neuroimaging cannot establish grade or histology, early surgery permits a definitive histopathologic and molecular diagnosis, which informs treatment selection, urgency, and prognosis.

●Extent of resection – In patients with tumors that are amenable to resection, observational studies provide support for a more extensive resection rather than partial resection or biopsy [5,9-14]. In such studies, the completeness of initial resection of a diffuse glioma is an independent predictor of both progression-free survival and overall survival [10,12].

When molecularly defined subsets of diffuse gliomas are analyzed according to contemporary World Health Organization (WHO) criteria, the advantage of extensive resection exists across all molecular subtypes but appears to be most relevant for IDH-mutant astrocytomas. In these tumors, even limited residual disease on postoperative MRI (eg, ≤5 cm³) may be associated with a negative impact on overall survival when compared with complete resection [12].

SELECTION OF POSTOPERATIVE THERAPY — Surgery alone is not curative in patients with diffuse gliomas, even for grade 2 tumors, and additional therapy (eg, radiation and chemotherapy) is ultimately required in nearly all patients. While there is general agreement that most grade 3 and 4 IDH-mutant astrocytomas should be treated at the time of diagnosis with radiation and chemotherapy, the optimal timing of additional therapy for patients with grade 2 tumors is less certain, and the decision to proceed with immediate versus delayed postoperative therapy should be individualized. The approach is also evolving with the development of IDH-targeted therapies.

Our approach presented below and in the algorithm (algorithm 1) is generally consistent with consensus-based guidelines published by the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology and Society for Neuro-Oncology, and the European Association of Neuro-Oncology, except where noted [15-19].

Grade 2 tumor, emerging approach — Patients with a newly diagnosed IDH-mutant grade 2 astrocytoma 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 separately. (See "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults", section on 'Grade 2 tumor, emerging approach'.)

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 1) 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 [17,18,20,21].

Gross total resection

Observation versus immediate therapy

●Our approach – For most patients who undergo gross total resection of an IDH-mutant grade 2 astrocytoma, we suggest initial observation after surgery, rather than immediate postoperative radiation therapy (RT) and chemotherapy (algorithm 1). It is expected that these tumors will eventually recur and require additional therapy at the time of progression. As discussed below, supporting evidence indicates that delaying RT in this setting does not appear to detract from overall survival, while it does postpone the potential toxicities of therapy [22-24]. 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' below.)

Of note, a variety of factors have been used or proposed to define a high-risk subgroup after gross total resection that warrants immediate treatment. The most common of these are older age (>40 years, for example), large preoperative tumor volume (eg, ≥4 cm), and the presence of neurologic deficits. Use of these factors to support early therapy is complicated, however, because they are primarily prognostic indicators (rather than predictive), and they have not been tested in prospective trials to identify which patients may benefit from early treatment, particularly for a genetically uniform group of IDH-mutant tumors.

Practice regarding the importance of individual risk factors varies among experts, including the authors of this topic. Because age >40 years and/or incomplete resection were used as inclusion criteria for the Radiation Therapy Oncology Group (RTOG) 9802 low-grade glioma trial of RT with or without procarbazine, lomustine, and vincristine (PCV) [25], for example, these criteria are used by some experts as well as the NCCN consensus guidelines to select patients for immediate postsurgical treatment [15]. Data from retrospective series of IDH-mutant astrocytomas suggest that the age limit that carries a worse prognosis is probably higher than previously thought (50 to 60 years) [26,27].

●Supporting evidence – The outcomes of early versus delayed RT in low-grade glioma are illustrated by the European Organisation for Research and Treatment of Cancer (EORTC) 22845 trial, which randomly assigned 311 patients with low-grade gliomas to receive either immediate RT (54 Gy in six weeks) or no therapy until progression following initial biopsy or resection [22]. At a median follow-up of almost eight years, immediate postoperative RT prolonged progression-free survival compared with initial observation (5.4 versus 3.7 years) but did not affect overall survival (7.4 versus 7.2 years). Seizure control was better in the early RT group. The majority of patients in the no-therapy group (65 percent) received RT at progression. Among patients who underwent surgery at the time of recurrence, approximately two-thirds of tumors were high grade in each group. The IDH mutational status of the tumors of patients in this study is unknown.

The absence of a survival benefit for early RT compared with RT at the time of progression suggests that RT slows the progression of low-grade gliomas but does not prevent transformation into high-grade gliomas. These results are generally felt to justify postponing the potential toxicities of RT in patients who undergo complete resection of a newly diagnosed IDH-mutant astrocytoma, some of whom may not require further therapy for many years. (See 'Side effects' below.)

●Natural history after complete resection – The natural history of initial observation for completely resected diffuse astrocytomas is largely informed by older studies that enrolled a mix of astrocytic and oligodendroglial tumors with unknown IDH status. In a prospective series of 111 patients with low-grade glioma who were felt to have a gross tumor resection based upon surgical assessment, the overall survival rates at two and five years were 99 and 93 percent, respectively [28]. Approximately 50 percent of patients remained progression free at five years. Factors associated with earlier recurrence included large tumor size (≥4 cm), astrocytoma or oligoastrocytoma histology rather than oligodendroglioma, and residual disease ≥1 cm by MRI. In small retrospective series of patients with molecularly confirmed IDH-mutant grade 2 astrocytomas who are observed after initial surgery, five-year progression-free survival rates range from 30 to 40 percent overall, with higher rates after more extensive resections [12,29].

Surveillance interval — Active surveillance after surgery alone typically involves MRI with contrast every three to four months [30]. Some clinicians lengthen the follow-up interval to six months after one to two years of stable imaging, given the long progression-free survival in many of these patients.

IDH-mutant grade 2 astrocytomas may recur locally at the margins of the resection cavity, and interpretation of small changes over time can be challenging. 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.

In rare cases, tumor regrowth occurs more precipitously, with rapid change from one MRI to the next suggesting transformation to a higher-grade tumor. In addition to rapid interval growth, other clues of malignant degeneration include the development of new neurologic symptoms, enhancement, or peritumoral edema.

Management at the time of progression — Management of recurrent or progressive tumors in patients who have been observed following initial resection of an IDH-mutant grade 2 glioma 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, development of contrast enhancement, and histopathologic grade of the progressive tumor, when available.

Some of the more common scenarios include the following:

●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 IDH-mutant grade 2 astrocytomas. (See 'Rationale for RT plus chemotherapy' below.)

●For patients with a large or rapidly progressive recurrence, reresection is often indicated for debulking, which may also provide tumor grade and a molecular diagnosis if that was not yet available. Postoperative management typically includes RT and chemotherapy, as described below for newly diagnosed patients. (See 'Subtotal resection' below and 'Grade 3 tumor, any resection' below.)

Subtotal resection — Immediate postoperative therapy is appropriate for most patients with a newly diagnosed IDH-mutant grade 2 astrocytoma who have significant residual or symptomatic tumor (apart from well-controlled seizures) after maximal safe resection (algorithm 1).

Of note, the amount of tumor that constitutes significant residual disease is not strictly defined. Modest amounts of residual grade 2 tumor after surgery, even measuring >1 to 2 cm, may be reasonably observed in some cases, provided that the patient is asymptomatic from the tumor aside from well-controlled epilepsy [15,16]. As discussed above, such patients should be followed with serial neuroimaging, and determining when to initiate therapy in the face of small and incremental changes in residual tumor can be challenging. (See 'Surveillance interval' above.)

Rationale for RT plus chemotherapy — Once a patient has been selected for additional postoperative therapy, we recommend a combination of RT and chemotherapy (PCV or temozolomide) rather than RT alone [15,16]. Support for improved survival with this approach in patients with IDH-mutant grade 2 astrocytomas is based on long-term follow-up results of the RTOG 9802 trial (for PCV) and extrapolation from the CATNON trial in grade 3 tumors (for temozolomide) [31-33].

●RTOG 9802 trial – In the RTOG 9802 trial, 251 patients with a high-risk low-grade glioma were randomly assigned to postoperative RT (54 Gy in 30 fractions) with or without six cycles of adjuvant PCV chemotherapy [25,34]. High risk was defined as age 18 to 39 years with subtotal resection or biopsy, or age ≥40 years with any extent of resection. Tumor histology was diffuse astrocytoma, oligodendroglioma, and mixed oligoastrocytoma in 26, 42, and 32 percent of cases, respectively. With a median follow-up time of 11.9 years, the combination of RT plus PCV improved both progression-free and overall survival compared with RT alone (median overall survival 13.3 versus 7.8 years, hazard ratio [HR] 0.59, p = 0.003) [25]. 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, respectively, in the RT-plus-PCV arm; there were no treatment-related deaths and no cases of secondary leukemia [34]. Both treatment arms experienced significant improvement in Mini-Mental State Examination (MMSE) scores over time, and the addition of PCV to RT was not associated with MMSE decline [35].

The survival benefit conferred by PCV was present in all histologic subtypes [25] but was clearer by molecular subtypes. In a molecular analysis of 42 percent of the enrolled cases, the benefit of adjunctive PCV was observed for both oligodendroglioma (HR 0.21, p = 0.029) and IDH-mutant astrocytoma (HR 0.38, p = 0.013) [36]. Confidence in these analyses is limited by small numbers and incomplete data.

We generally do not offer chemotherapy alone as initial therapy for patients with IDH-mutant astrocytomas, as these tumors are not as chemosensitive as oligodendrogliomas. A potential exception is patients with extensive tumors, which would require a very large RT field, although progression-free survival is likely shorter with temozolomide than RT for patients with astrocytomas [37]. (See "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults", section on 'Diffuse tumors with large RT field'.)

Choice of PCV versus temozolomide — Both PCV and temozolomide are reasonable options for adjunctive therapy along with RT in patients with IDH-mutant grade 2 astrocytomas, and there are no trials that have compared these two regimens head-to-head.

We increasingly favor temozolomide because it is supported by data in grade 3 IDH-mutant astrocytomas, is easier to administer, is better tolerated, and has more consistent availability in some regions. On the other hand, use of PCV in patients with low-grade gliomas is supported by results of the RTOG 9802 trial reviewed above, which included both astrocytic and oligodendroglial tumors and showed a survival benefit of PCV plus RT over RT alone. (See 'Rationale for RT plus chemotherapy' above.)

Importantly, when temozolomide is chosen for grade 2 tumors, we generally treat with 12 cycles of post-RT temozolomide and omit daily (concurrent) temozolomide during RT, based on results of the CATNON trial in grade 3 tumors discussed below. (See 'Grade 3 tumor, any resection' below.)

The largest prospective experience with RT plus temozolomide in grade 2 gliomas is the single-arm RTOG 0424 study, in which 129 patients with low-grade glioma plus three or more risk factors (age ≥40 years, astrocytoma histology, bihemispheric tumor, preoperative tumor diameter >6 cm, preoperative neurologic function status >1) were treated with concurrent radiation (54 Gy in 30 fractions) with daily temozolomide followed by monthly temozolomide [38-40]. With a median follow-up time of nine years, five-year progression-free and overall survival were 47 and 61 percent, respectively. Median overall survival was 8.2 years and 10-year overall survival was 34 percent. These results are superior to those of historical controls treated with RT alone [41,42]; however, differences in eligibility criteria preclude a comparison with RT plus PCV. Grade 3 or 4 adverse effects occurred in 44 and 10 percent of patients, respectively; the majority of adverse effects were hematologic.

Grade 3 tumor, any resection — Immediate postoperative RT plus adjuvant chemotherapy is recommended in patients with newly diagnosed IDH-mutant grade 3 astrocytoma, regardless of the degree of resection or other risk factors (algorithm 1).

The evidence base for RT plus chemotherapy in patients with newly diagnosed IDH-mutant grade 3 astrocytoma consists of several key randomized trials showing that the addition of chemotherapy (either PCV or temozolomide) to RT improves survival over RT alone [32,33,43,44]. All trials enrolled patients prior to the 2016 World Health Organization (WHO) revised classification and therefore included a mix of grade 3 tumors with variable 1p/19q codeletion and IDH mutation status. Although temozolomide and PCV have not been compared head-to-head in this setting, temozolomide is more convenient and less toxic, and its use is supported by randomized data in IDH-mutant grade 3 astrocytomas.

●EORTC 26053 (CATNON) trial – Direct support for RT plus temozolomide in patients with IDH-mutant grade 3 astrocytoma is based on results of the EORTC 26053 CATNON trial [32,33]. In CATNON, 751 patients with newly diagnosed 1p/19q-non-codeleted anaplastic (grade 3) gliomas (both IDH-mutant and IDH-wildtype) were randomly assigned to one of four treatment arms: RT alone, RT with concurrent daily temozolomide, RT with concurrent daily temozolomide plus up to 12 cycles of monthly adjuvant temozolomide, and RT plus up to 12 cycles of monthly adjuvant temozolomide [32].

As of a second interim analysis with a median follow-up of 56 months, the use of adjuvant temozolomide improved median survival compared with no adjuvant temozolomide in the overall population (82 versus 47 months; HR 0.64, 95% CI 0.52-0.79) [33]. When analyzed according to IDH mutation status, however, the benefit of adjuvant temozolomide was observed only in IDH-mutant tumors (117 versus 78 months; HR 0.48, 95% CI 0.35-0.67) and not in IDH-wildtype tumors (21 versus 19 months; HR 1.0, 95% CI 0.75-1.33).

By contrast, concurrent temozolomide did not improve survival in the overall population (67 versus 60 months; HR 0.97, 99% CI 0.73-1.28), although a nonsignificant trend towards benefit in IDH-mutant tumors was present (117 versus 92 months; HR 0.80, 95% CI 0.58-1.10). Longer follow-up is needed to determine whether there is a clinically important benefit to concurrent temozolomide in patients with IDH-mutant tumors, but at present this is not observed in patients also receiving adjuvant temozolomide treatment.

Both pivotal trials of RT with or without PCV in newly diagnosed grade 3 oligodendroglioma/oligoastrocytoma (EORTC 26951 and RTOG 9402) included some patients with what would now be categorized as IDH-mutant grade 3 astrocytomas; in these trials, the benefit of PCV was most evident in histologic oligodendrogliomas, although there was a nonsignificant trend towards improved survival in the subgroup of IDH-mutant, non-codeleted tumors as well [43-45]. This observation, along with the greater convenience and tolerability of temozolomide [46,47], has led most clinicians to adopt temozolomide as the standard adjuvant chemotherapy in grade 3 astrocytomas, rather than PCV. The role of PCV in oligodendroglial tumors is discussed in detail separately. (See "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults", section on 'Rationale for RT plus chemotherapy'.)

In contrast to the CATNON trial of RT plus temozolomide as well as trials of RT plus PCV in oligodendroglial tumors, trials of chemotherapy alone (PCV or temozolomide) have not shown an improvement in survival compared with RT alone in newly diagnosed grade 2 or grade 3 diffuse gliomas [37,48]. Accordingly, the available data suggest that chemotherapy alone is inferior to RT plus chemotherapy in newly diagnosed patients.

Grade 4 tumor, any resection — Until the 2021 revision of the WHO classification [49], grade 4 IDH-mutant astrocytomas were referred to as glioblastomas (IDH-mutant), although a prognostic difference between IDH-mutant and IDH-wildtype glioblastomas has been recognized for some time. Compared with IDH-wildtype glioblastomas, IDH-mutant grade 4 astrocytomas occur in younger individuals and are more likely to show methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter [50].

Despite a more favorable prognosis compared with IDH-wildtype glioblastoma, IDH-mutant grade 4 astrocytomas, especially in the presence of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion, are nonetheless malignant tumors with aggressive clinical behavior and a median survival of less than five years. Outside of clinical trials, IDH-mutant grade 4 astrocytomas are treated with one of the following regimens (algorithm 1):

●RT followed by 12 cycles of adjuvant monthly temozolomide, based on results of the CATNON trial in patients with IDH-mutant grade 3 gliomas. (See 'Grade 3 tumor, any resection' above.)

●RT with daily (concurrent) temozolomide followed by six cycles of adjuvant monthly temozolomide, based on trial data in patients with glioblastoma completed prior to separation of the two entities by IDH status. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'MGMT-methylated tumors, age ≤70 years'.)

Both temozolomide regimens are considered appropriate and rational by expert groups in combination with RT, and there is no available evidence specifically in patients with IDH-mutant grade 4 astrocytomas [18]. Some clinicians favor concurrent plus six monthly cycles of temozolomide because trials supporting this regimen would have included IDH-mutant grade 4 tumors, albeit as a small percentage compared with IDH-wildtype tumors. Others favor 12 monthly cycles based on the CATNON trial results and the biologic similarity between grade 3 and 4 IDH-mutant astrocytomas. There is no evidence to support one regimen as "more aggressive" than another in terms of efficacy, and the risk of hematologic toxicity may be higher with concurrent therapy, particularly in females. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Hematologic toxicities'.)

ADMINISTRATION OF THERAPY

Involved field radiation therapy

Dose and schedule — Once the decision is made to treat with radiation therapy (RT), the dose and schedule depend on the grade of the tumor.

●Grade 2 tumors – A dose of 45 to 54 Gy in 1.8 Gy fractions is typically used to treat IDH-mutant grade 2 gliomas [15]. The clinical target volume most commonly is defined by a 1 cm expansion 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 [51-53].

●Grade 3 tumors – A dose of 54 to 59.4 Gy in 1.8 Gy fractions is typically used to treat IDH-mutant grade 3 gliomas [15]. (See "Radiation therapy for high-grade gliomas", section on 'Adjuvant RT'.)

●Grade 4 astrocytoma – A dose of 59.4 to 60 Gy in 1.8 to 2 Gy fractions is typically used to treat IDH-mutant grade 4 gliomas [15]. (See "Radiation therapy for high-grade gliomas", section on 'Adjuvant RT'.)

Other RT approaches that have been evaluated for incompletely resected lesions include hyperfractionated RT [54], proton RT [55,56], and fractionated stereotactic radiotherapy [57]. However, no clear 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 radiation 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. Latency for secondary tumor occurrence is generally a decade or longer from radiation exposure. (See "Risk factors for brain tumors", section on 'Ionizing radiation' and "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Ionizing radiation'.)

Temozolomide — The standard adjuvant regimen of temozolomide for IDH-mutant astrocytomas based on the CATNON trial consists of 12 monthly cycles, beginning approximately one month after completion of RT [32]. The first cycle of temozolomide is dosed at 150 mg/m² orally daily for 5 days out of a 28-day cycle. Subsequent cycles (2 through 12) are dosed at 200 mg/m² if blood counts are acceptable (figure 1 and table 1A-B). Dosing and monitoring of daily temozolomide during RT is reviewed separately. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Dose and schedule'.)

A complete blood count (CBC) should be obtained on days 22 and 29 of each monthly cycle, along with monthly basic metabolic panel and liver function tests, to monitor for toxicity and help guide dose adjustments, if necessary. Clinicians should reference temozolomide product labeling for dosing modifications for hematologic toxicity.

Temozolomide is moderately emetogenic, and premedication with an oral serotonin 5-hydroxytryptamine (5-HT3) antagonist such as ondansetron 8 mg orally is typically given 30 minutes before each dose on days 1 through 5 of each cycle. Some centers have experience giving ondansetron premedication only on days 1 and 2 of each cycle, rather than all 5 days, with good effect.

Both temozolomide and ondansetron are constipating, and patients should receive instructions for a maintenance bowel regimen. Some patients find that 4 mg of ondansetron is less constipating than 8 mg yet still adequate for prevention of nausea. Pneumocystis pneumonia prophylaxis is not necessary unless patients have additional risk factors for immunosuppression, such as daily glucocorticoid use.

Additional discussion of temozolomide administration, risks, and side effects is provided elsewhere. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Temozolomide'.)

Procarbazine, lomustine, vincristine (PCV) — Administration of PCV is reviewed separately. (See "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults", section on 'Procarbazine, lomustine, vincristine (PCV)'.)

MONITORING AND SUPPORTIVE CARE — 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 [30]:

●Observation after surgery – Surveillance recommendations for untreated tumors are reviewed above. (See 'Surveillance interval' 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 six to eight years in clinical trials of grade 2 and 3 IDH-mutant astrocytomas, 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 cycles.

●Post-treatment – After completion of initial RT plus chemotherapy, MRIs should be obtained at least every six months indefinitely for grade 2 and 3 tumors and every three to four months indefinitely for grade 4 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.

Similar to other diffuse gliomas, patients with IDH-mutant astrocytomas are at risk for seizures, neurocognitive dysfunction, and adverse effects of cancer therapies on reproductive health. These issues are reviewed separately. (See "Seizures in patients with primary and metastatic brain tumors" and "Delayed complications of cranial irradiation", section on 'Neurocognitive effects' and "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults", section on 'Reproductive health'.)

RECURRENT DISEASE — Most patients with diffuse and anaplastic astrocytomas will eventually recur, either at the same grade as the original tumor or eventually with transformation to a higher-grade, treatment-refractory tumor. In the event of recurrence, combinations of salvage surgery, radiation, and chemotherapy are considered, depending on prior treatments received.

Pseudoprogression after radiation therapy — Pseudoprogression refers to the phenomenon of progressive, radiation-induced enhancing lesions on MRI within a prior radiation field that spontaneously improve without treatment or, upon biopsy, are found to represent radiation necrosis rather than active tumor (image 1).

Pseudoprogression should always be considered on the differential diagnosis of tumor recurrence or progression when patients with a diffuse glioma develop new enhancement within a prior radiation field [58-63]. In a retrospective study of 106 patients who received radiation therapy (RT) for low-grade glioma, pseudoprogression occurred in 23 percent of patients at a median of 8.8 months after RT completion [63]. The cumulative incidence of pseudoprogression was 13 percent at one year, 22 percent at five years, and 28 percent at 10 years. The majority of cases were asymptomatic (83 percent). Mean lesion volume was 2.4 cm³. In a separate study, the median time to lesion resolution was six months (range 2 to 26) [58]. Some but not all studies have reported a predilection for periventricular and subependymal location.

The characteristics of pseudoprogression may vary based on the type of RT (eg, photon versus proton). In a study of 57 patients who received proton RT for low-grade glioma, pseudoprogression was seen in 25 percent of patients at a mean of 15 months after RT [64]. The pattern of enhancement tended to be multifocal, patchy, small (<1 cm), and at the distal ends of the proton beam, where the radiobiologic effect is speculated to be higher. By contrast, no cases of pseudoprogression were seen among 43 low-grade glioma patients treated with photons at the same institution. It is unclear if the risk of pseudoprogression is driven by radiation modality (protons versus photons), net biologic dose delivered, or other factors.

Distinguishing recurrent disease from radiation necrosis can be difficult using imaging procedures including MRI and positron emission tomography (PET), and biopsy may be required (although it carries a risk of sampling error). Most small enhancing lesions that arise after RT can be safely followed initially without a change in treatment or biopsy, especially if the location is subependymal. (See "Management of recurrent high-grade gliomas", section on 'Early progression versus pseudoprogression'.)

Radiation therapy — Following a complete course of RT (45 to 60 Gy), retreatment with conventional external beam RT is usually not feasible due to an increased risk of neurotoxicity and radiation-induced necrosis.

Occasionally, reirradiation can be safely delivered to the area of recurrence without undue risk of complications by limiting the volume of area of retreatment and minimizing the dose of radiation to normal structures. The possible role of radiation was illustrated by a series of 172 patients with recurrent gliomas, including 71 with grade 2 tumors and 101 with grade 3 or 4 lesions [65]. All had previously received a definitive course of RT, with a median dose of 60 Gy. At recurrence, all patients received an additional 36 Gy in 18 fractions, using stereotactic radiotherapy to improve conformal delivery. Treatment was well tolerated, and median survival following reirradiation among patients with low-grade gliomas was 22 months.

Chemotherapy — Temozolomide and nitrosoureas are the main salvage chemotherapy options in patients with recurrent diffuse astrocytomas [15,16]. Selection of therapy is individualized based on prior therapies received, comorbidities, and tumor type and grade (see "Management of recurrent high-grade gliomas", section on 'Systemic therapy'). With increasing use of first-line RT plus chemotherapy, more patients will be relapsing after prior chemotherapy, and most of the available studies do not reflect that situation.

Two historical studies, which included patients with both grade 2 astrocytomas and oligodendroglial tumors without information on IDH status, reported that the objective response rates to temozolomide for patients with astrocytomas were similar to those with oligodendroglial tumors, but response duration was shorter in patients without 1p/19q codeletion [66,67]. Over half of patients with astrocytomas in these two reports (25 out of 45) had a partial or complete response to temozolomide chemotherapy. In these two retrospective studies, progression-free survival was 73 and 39 percent at one year, suggesting at least several months of durable response in approximately one-half of patients.

Once tumors show high-grade transformation, response rates and duration of response are similar to those in relapsed anaplastic astrocytoma, with approximately two-thirds of patients alive and progression free at six months [68,69].

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF) that is approved for use in patients with recurrent glioblastoma, does not have a clear role in patients with recurrent lower-grade astrocytomas. In the TAVAREC trial, 155 patients with a first and contrast-enhancing recurrence of a grade 2 or 3 1p/19q-non-codeleted glioma after radiotherapy were randomly assigned to temozolomide with or without bevacizumab [70]. Patients who received temozolomide plus bevacizumab had similar response rates (52 versus 44 percent), progression-free survival, and overall survival at 12 months (55 versus 61 percent) compared with those who received temozolomide alone. Toxicity was higher in the combination arm, including one treatment-related death related to infection, intratumoral hemorrhage, and grade 4 thrombocytopenia. Prior chemotherapy did not have an effect on overall survival.

Investigational IDH-targeted approaches — Small molecule inhibitors of mutant IDH type 1 (IDH1) and type 2 (IDH2) are in clinical trials for IDH-mutant gliomas. Vaccine strategies are also being explored. These data are reviewed elsewhere. (See "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults", section on 'Investigational IDH-targeted approaches'.)

PROGNOSIS — IDH-mutant astrocytomas in adults are treatable but incurable tumors, and the vast majority are life limiting.

In the pre-IDH era, diffuse astrocytomas were a heterogeneous group of tumors with a broad and somewhat unpredictable range of biologic behavior and prognosis. The molecular categorization of these tumors according to IDH mutation status has greatly improved prognostic accuracy compared with histologic categorization alone. Further, when IDH status is taken into account, the prognostic difference between grade 2 and grade 3 tumors becomes much less pronounced.

For fully characterized IDH-mutant astrocytomas, median survival estimates range from approximately 2 to 12 years depending on the integrated diagnosis, including tumor grade [26,71-79]:

●IDH-mutant astrocytoma, grade 2 – 10 to 12 years

●IDH-mutant astrocytoma, grade 3 – 8 to 10 years

●IDH-mutant astrocytoma, grade 4 – 3 to 4 years

For most patients with IDH-mutant astrocytomas, there will be a period of relative radiographic and clinical stability after initial therapy that may be as long as 5 to 10 years for grade 2 or 3 tumors and as short as one to two years for grade 4 tumors, especially in the presence of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion. Tumor growth eventually accelerates in nearly all patients, with shorter intervals between subsequent recurrences, heralding poor outcome [80].

Clinical and molecular prognostic factors for IDH-mutant astrocytomas are evolving, and some traditional factors, such as patient age, require reexamination in pathologically homogeneous cohorts. Among histologically lower-grade IDH-mutant gliomas, homozygous deletion of CDKN2A/B is a negative prognostic marker, and as of the 2021 revision of the World Health Organization (WHO) classification, the presence of a CDKN2A/B deletion in an IDH-mutant astrocytoma established the tumor as grade 4, independent of histologic grade. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'Astrocytoma, IDH-mutant'.)

In the pre-IDH era, a meta-analysis of four large phase III studies of patients with centrally confirmed histologically low-grade gliomas (astrocytic and oligodendroglial) found that both progression-free survival and overall survival were negatively influenced by the presence of baseline neurologic deficits, a shorter time since first symptoms (<30 weeks), an astrocytic tumor type, and tumors larger than 5 cm in diameter [41]. Age was not an independent prognostic factor in the adjusted analysis, and subsequent studies in IDH-mutant astrocytomas suggest that if older age is a risk factor, the cutoff is likely higher than previously thought (eg, 50 to 60 years) [26,27]. Male sex is also a negative prognostic factor in IDH-mutant gliomas, for reasons that are not yet clear [81]. Further study is needed to determine whether other prognostic factors remain valid in tumors with uniform IDH mutation status, or whether other factors are more important.

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Astrocytoma (The Basics)")

●Beyond the Basics topic (see "Patient education: Low-grade glioma in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●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 IDH-mutant astrocytomas but is not always safely feasible based on the location or extent of the tumor. (See 'Surgical management' above.)

●Timing of additional therapy – Surgery is not curative in patients with IDH-mutant astrocytomas, and additional therapy (ie, radiation therapy [RT] and chemotherapy) is ultimately required in all patients. Treatment timing varies according to tumor grade, clinical status, and degree of resection (algorithm 1).

•Grade 2 tumor, gross total resection – For most patients who undergo gross total resection of an IDH-mutant grade 2 astrocytoma, we suggest observation after surgery, rather than immediate adjuvant therapy (Grade 2C). Delaying RT in this setting does not have an adverse impact on overall survival and postpones the potential toxicities of therapy. Patients who are uncomfortable with the uncertainties of observation may reasonably choose immediate postoperative therapy, even though this approach is associated with more side effects in the short term. (See 'Gross total resection' above.)

•All other IDH-mutant astrocytomas – Immediate postoperative therapy is appropriate in most other patients, including those with significant residual or symptomatic grade 2 tumors and all grade 3 and 4 tumors, regardless of the extent of resection. (See 'Subtotal resection' above and 'Grade 3 tumor, any resection' above and 'Grade 4 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

•Grade 2 or 3 tumor – When patients with grade 2 or 3 IDH-mutant astrocytomas are selected for postoperative therapy, we recommend RT plus chemotherapy rather than RT alone (Grade 1B). In randomized trials that included both of these tumor types, use of upfront combination therapy improved overall survival compared with RT alone. (See 'Subtotal resection' above and 'Grade 3 tumor, any resection' above.)

In most cases, we suggest adjuvant temozolomide rather than procarbazine, lomustine, and vincristine (PCV) as the chemotherapy regimen (Grade 2C). Although the two regimens have not been compared directly when given in combination with RT, supporting evidence for 12 cycles of adjuvant temozolomide is at least as good as that for six cycles of PCV for astrocytic tumors, and temozolomide is easier to administer and better tolerated. (See 'Choice of PCV versus temozolomide' above and 'Grade 3 tumor, any resection' above.)

•Grade 4 tumor – For patients with grade 4 IDH-mutant astrocytoma, acceptable regimens are RT plus concurrent and six cycles of monthly temozolomide, as per IDH-wildtype glioblastoma, or RT followed by 12 cycles of adjuvant temozolomide, per grade 3 IDH-mutant astrocytoma. (See 'Grade 4 tumor, any resection' above.)

●Recurrent disease – Surgery, radiation, and chemotherapy all can have a role in the management of patients who recur after initial therapy, and their application needs to be individualized based upon the site and extent of recurrence, along with the history of prior treatment. (See 'Recurrent disease' above.)

●Prognosis – IDH-mutant astrocytomas in adults are treatable but incurable tumors, and the vast majority are life limiting. Median overall survival is approximately 3 years for grade 4 tumors, 7 to 9 years for grade 3 tumors, and more than 10 years for grade 2 tumors. (See 'Prognosis' above.)