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Initial treatment and prognosis of IDH-wildtype glioblastoma in adults

Initial treatment and prognosis of IDH-wildtype glioblastoma in adults
Literature review current through: Jan 2024.
This topic last updated: May 24, 2023.

INTRODUCTION — Glioblastoma is the most common malignant primary brain tumor in adults, with a median age of onset of approximately 55 to 60 years. As of the 2021 revision of the World Health Organization (WHO) Classification of Central Nervous System (CNS) Tumors, tumors previously called glioblastoma are now divided into two separate diagnoses based primarily on isocitrate dehydrogenase (IDH) mutation status (algorithm 1) [1]:

Glioblastoma, IDH-wildtype, CNS WHO grade 4

Astrocytoma, IDH-mutant, CNS WHO grade 4

For the purposes of this topic, glioblastoma refers to IDH-wildtype glioblastoma unless specifically stated otherwise. IDH-mutant grade 4 astrocytomas are discussed along with other IDH-mutant astrocytomas. (See "Treatment and prognosis of IDH-mutant astrocytomas in adults".)

Most patients with glioblastoma are managed with a combined-modality approach, incorporating adjuvant postoperative radiation therapy and adjuvant chemotherapy following initial surgery. Even with maximal therapy, glioblastoma has a high rate of recurrence and poor overall survival, ranging from 1.5 to 2 years.

Selection and administration of initial systemic therapy, monitoring, and prognosis are reviewed here. Other topics that are covered separately include:

(see "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors")

(see "Overview of the clinical features and diagnosis of brain tumors in adults")

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

(see "Radiation therapy for high-grade gliomas")

(see "Management of glioblastoma in older adults")

(see "Management of recurrent high-grade gliomas")

(see "Treatment and prognosis of IDH-mutant astrocytomas in adults")

SURGICAL RESECTION — A histologic diagnosis is required for optimal treatment of patients with brain tumors. This can be accomplished either at the time of surgical resection or with a stereotactic biopsy. Biopsy alone is used in situations where the lesion is not amenable to resection, a meaningful amount of tumor tissue cannot be removed, or the patient's overall clinical condition will not permit surgery.

For patients with glioblastoma, maximal surgical resection consistent with preservation of neurologic function is preferred. Although gross total resection is preferred whenever possible, subtotal resection or biopsy alone may be required depending upon the location and extent of the tumor. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas".)

ADJUVANT RADIATION THERAPY — Adjuvant radiation therapy is a standard component of therapy for glioblastoma and has been shown to improve local control and survival after resection. Treatment field, dose, and delivery methods of radiation therapy for glioblastoma are reviewed separately. (See "Radiation therapy for high-grade gliomas".)

SELECTION OF SYSTEMIC THERAPY — Selection of appropriate systemic therapy for patients with glioblastoma and other infiltrative gliomas depends on adequate molecular characterization (table 1). For glioblastoma, tumor specimens should be tested for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and for isocitrate dehydrogenase (IDH) type 1 or type 2 mutations (particularly in patients <55 years of age). Methods of testing and the proportion of tumors with these alterations are reviewed separately. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'Key molecular diagnostic tests' and "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas", section on 'Pathology' and 'MGMT methylation status' below.)

While the presence of an IDH1/2 mutation does not yet have treatment implications for upfront therapy in routine clinical practice, it does confer significantly improved prognosis and may impact clinical trial eligibility. In addition, most IDH1/2-mutant grade 4 astrocytomas also show methylation of the MGMT promoter, which is relevant to treatment selection as well as prognosis. Methylation of the MGMT promoter in glioblastoma leads to gene silencing and loss of expression of the MGMT DNA repair protein, which is predictive of benefit from alkylating agent chemotherapy and prognostic of improved survival. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas", section on 'Pathology' and 'MGMT methylation status' below.)

MGMT-methylated tumors, age ≤70 years — For patients with newly diagnosed MGMT-methylated glioblastoma who are 70 years of age or younger, we recommend use of concurrent temozolomide in combination with radiation therapy followed by monthly adjuvant temozolomide. A dual regimen of temozolomide and lomustine in combination with radiation therapy is an alternative option in younger, fit patients with MGMT-methylated tumors, although data supporting improved efficacy are inconclusive and toxicity may be higher.

The efficacy of concurrent and adjuvant treatment with temozolomide in adults with glioblastoma was first shown by a European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada (EORTC/NCIC) open-label trial in which 573 patients age 18 to 70 years were randomly assigned to receive involved-field radiation therapy alone or radiation plus concurrent daily temozolomide followed by up to six monthly cycles of adjuvant temozolomide [2]. With a median follow-up of over five years, the addition of temozolomide to radiation improved median overall survival compared with radiation alone (14.6 versus 12.1 months, hazard ratio [HR] 0.63, 95% CI 0.53-0.75) [2]. With long-term follow-up, survival continued to be superior in the temozolomide arm at two years (27 versus 11 percent) and five years (10 versus 2 percent) [3]. Grade 3 or 4 hematologic toxicity was more common in the temozolomide arm, primarily thrombocytopenia (12 percent) and lymphopenia (7 percent), but health-related quality of life was maintained [2,4]. Benefits from adjuvant temozolomide were observed in all patient subsets, including those over 60 years and those with other poor prognostic factors [2,3]. Similar results were seen in a second, smaller phase II trial in patients with glioblastoma [5].

In an analysis of a subset of 206 patients in the EORTC/NCIC trial for whom MGMT methylation status was determined retrospectively, methylation of the MGMT promoter was a major prognostic factor for improved survival and was predictive of benefit from chemotherapy [6]. For those with MGMT methylation (45 percent of cases), the addition of temozolomide was associated with a doubling of two-year overall survival compared with radiation alone (46 versus 23 percent; median overall survival 21.7 versus 15.3 months, HR 0.45, 95% CI 0.32-0.61) [6]. For those without MGMT methylation, there was a smaller difference in survival that was not statistically significant (two-year survival 14 versus <2 percent; median overall survival 12.7 versus 11.8 months, HR 0.69, 95% CI 0.47-1.02).

Subsequent trials in patients with MGMT-methylated glioblastoma have attempted to improve upon the standard of radiation plus temozolomide. One such trial (CeTeG/NOA-09) screened >650 patients to enroll 141 patients age 18 to 70 years with MGMT-methylated glioblastoma and randomly assign them to a combined lomustine/temozolomide regimen during and after radiation therapy (up to six 42-day cycles of lomustine 100 mg/m2 on day 1 plus temozolomide 100 mg/m2 on days 2 to 6) or standard therapy (daily temozolomide with radiation therapy followed by up to six cycles of adjuvant monthly temozolomide) [7]. Randomization was stratified by center. Twelve randomized patients (six in each arm) dropped out prior to receiving therapy, leaving 129 patients in a modified intent-to-treat (mITT) analysis. The sex distribution was statistically different between treatment groups, and multiple other baseline prognostic factors were numerically different between groups. In the mITT population, median overall survival was similar for lomustine/temozolomide versus standard temozolomide (37.9 versus 31.4 months, HR 0.90, 95% CI 0.58-1.41). An adjusted mITT analysis on these 129 patients using inverse probability weights found a nonsignificant trend towards improved survival in the lomustine/temozolomide arm (HR 0.74, 95% CI 0.47-1.17) and no difference in progression-free survival (HR 0.99, 95% CI 0.68-1.46). Prespecified analyses, which included matching by center and recursive partitioning analysis (RPA) class, excluded 32 randomized patients; in this matched analysis (n = 109), overall survival was improved in the combination arm (48.1 versus 31.4 months, HR 0.60, 95% CI 0.35-1.03) and progression-free survival was similar (16.7 months in both groups). Grade 3 or 4 hematologic toxicity was more common with combination therapy (36 versus 29 percent); nausea was also more common with combination therapy (30 versus 19 percent). The rate of completion of all six cycles of chemotherapy was 39 percent for lomustine/temozolomide and 60 percent for standard temozolomide.

These results are provocative and support the conclusion that lomustine/temozolomide combination therapy might improve survival compared with standard temozolomide in selected younger, fit patients with MGMT-methylated glioblastoma. However, confidence in the superior efficacy of combination therapy is reduced by limitations of the trial, including small size and exclusion of a significant number of randomized patients in the prespecified analyses. In addition, combination therapy is associated with higher risks of nausea and hematologic toxicity, which may lead some patients and clinicians to reasonably choose standard temozolomide pending further studies.

MGMT-unmethylated tumors, age ≤70 years — Patients with MGMT-unmethylated tumors have a poor prognosis and response to standard therapies and are encouraged to participate in clinical trials. Outside of a clinical trial, we suggest use of temozolomide along with radiation in most patients with MGMT-unmethylated glioblastoma, based on results of the EORTC/NCIC trial, in which MGMT status was not known prospectively [2,3].

Patients with MGMT-unmethylated tumors have worse overall survival and derive less benefit from temozolomide compared with patients with MGMT-methylated tumors, however. As discussed above, an analysis of 206 patients in the EORTC/NCIC trial for whom MGMT status was determined retrospectively found that among patients with MGMT-unmethylated tumors (n = 114), the addition of temozolomide to radiation therapy was associated with a small difference in survival that was not statistically significant (two-year survival 15 versus 2 percent; median overall survival 12.7 versus 11.8 months, HR 0.69, 95% CI 0.47-1.02) [6].

Alternatives to temozolomide are being actively investigated in patients with MGMT-unmethylated tumors. As an example, a randomized, unblinded phase II study of 182 patients with newly diagnosed MGMT-unmethylated glioblastoma compared bevacizumab during radiation followed by bevacizumab plus irinotecan with radiation plus concurrent and adjuvant temozolomide [8]. Similar to the trials reviewed below in unselected glioblastoma, the bevacizumab regimen was associated with improved six-month progression-free survival (79 versus 43 percent) but no difference in median overall survival (16.6 versus 17.5 months) or quality-of-life outcomes. Two-thirds of the patients in the temozolomide group received bevacizumab at progression. A separate trial comparing radiation plus nivolumab with radiation plus concurrent and adjuvant temozolomide found that survival was worse in the nivolumab arm (median overall survival 13.4 versus 14.9 months, HR 1.31, 95% CI 1.09-1.58) [9].

MGMT status unknown — Assays to determine MGMT methylation status are not successful in a sizable minority of patients due to insufficient tissue, particularly those who undergo stereotactic biopsy. When MGMT status is not known at the time of postoperative decision-making and the patient is otherwise a candidate for standard therapy (ie, age ≤70 years, good functional status), we recommend use of temozolomide in combination with radiation therapy. The rationale is based on the clinically meaningful improvement in survival expected from temozolomide for the 30 to 40 percent of patients predicted to have an MGMT-methylated tumor, the lack of better alternatives for MGMT-unmethylated tumors, and the relative safety and tolerability of temozolomide. (See 'MGMT-methylated tumors, age ≤70 years' above.)

Older adults and those with poor functional status — Combined-modality therapy is the standard of care for younger patients with glioblastoma, but with advancing age or low functional status the benefits become more closely balanced with risks of toxicity and side effects. An approach to initial treatment decisions in adults >70 years of age and those with low functional status (algorithm 2) is reviewed separately. (See "Management of glioblastoma in older adults".)

Limited role of bevacizumab — Bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor (VEGF), is not recommended for routine use in patients with newly diagnosed glioblastoma [10]. Although bevacizumab has potent antiedema effects, which can improve clinical function and reduce glucocorticoid requirements in selected patients, it does not improve overall survival when used as part of initial therapy and increases the risk of toxicity [11].

We do consider early bevacizumab as a supportive medication in selected patients with bulky, nonresectable tumors in an attempt to control refractory edema and mass effect that may arise during or shortly after completion of radiation therapy. (See "Management of recurrent high-grade gliomas", section on 'Bevacizumab'.)

While the use of bevacizumab in the up-front setting appeared promising in phase II studies [12-14], this benefit was not confirmed in two large randomized trials [15,16]. In the AVAglio study, 921 patients were randomly assigned to receive bevacizumab or placebo in conjunction with radiation and temozolomide [15]. After completion of radiation, patients were treated with six cycles of monthly temozolomide plus bevacizumab or placebo every two weeks, followed by maintenance bevacizumab or placebo every three weeks until progression. The following results were observed:

Median progression-free survival was improved in patients treated with bevacizumab compared with placebo (10.6 versus 6.2 months, HR 0.64, 95% CI 0.55-0.74). Similarly, baseline health-related quality of life and performance status were maintained longer in the bevacizumab group [17].

Median overall survival was not significantly different (HR 0.88, 95% CI 0.76-1.02).

There was an increase in the rate of serious adverse events in patients treated with bevacizumab compared with placebo (67 versus 51 percent).

In the Radiation Therapy Oncology Group (RTOG) 0825 study, 637 patients were randomly assigned to receive bevacizumab or placebo starting at week 4 of standard chemoradiation with temozolomide, followed by 6 to 12 cycles of maintenance temozolomide plus bevacizumab or placebo [16]. The following results were observed:

Median progression-free survival was improved in patients treated with bevacizumab compared with placebo (10.7 versus 7.3 months, p = 0.007), but the result did not meet the predefined significance threshold of p <0.004.

Median overall survival did not differ in patients treated with bevacizumab compared with placebo (15.7 versus 16.1 months, p = 0.21).

MGMT promoter methylation was associated with improved progression-free survival (14 versus 8 months) and overall survival (23 versus 14 months), regardless of study treatment.

There was an increased rate of serious adverse events in patients treated with bevacizumab, primarily neutropenia, hypertension, and thromboembolism.

The bevacizumab group experienced an increased symptom burden, worse quality of life, and more frequent decline in neurocognitive function compared with the placebo group [18].

Investigational therapies and clinical trials — A variety of therapies are being explored in clinical trials for patients with newly diagnosed glioblastoma, typically in combination with radiation and temozolomide chemotherapy. Most studies are testing either molecularly targeted agents or biologic approaches such as immunotherapy, vaccine-based therapies, or local gene therapy. A searchable database of clinical trials is available through the United States National Library of Medicine.

Further information on tumor genotyping and emerging therapies for glioblastoma can be found separately. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas", section on 'Role of tumor genome sequencing' and "Management of recurrent high-grade gliomas", section on 'Genotype-directed therapies'.)

ADMINISTRATION OF SYSTEMIC THERAPY

Temozolomide

Dose and schedule — Temozolomide is an oral alkylating agent that is dosed based on body surface area (BSA). During radiation, temozolomide is given daily (seven days per week) at a dose of 75 mg/m2. Temozolomide is taken on an empty stomach, at least two hours after the last meal.

Some clinicians advise patients to time weekday doses of temozolomide one hour before radiation therapy, in theory to maximize synergy with radiation. Other clinicians have patients take their dose at the same time each day, either first thing in the morning before eating breakfast or at bedtime, two or more hours after dinner.

During the concomitant phase, weekly complete blood counts (CBCs) are required for monitoring. Temozolomide should be held if platelets fall below 100,000/microL or absolute neutrophil count (ANC) falls below 1500/microL, as counts can fall precipitously (table 2). More frequent monitoring may be necessary thereafter until nadirs are determined.

The first postradiation cycle of temozolomide typically begins four weeks after completion of radiation therapy and is given at a dose of 150 mg/m2 daily for 5 days out of a 28-day cycle (figure 1 and table 3A-B). Subsequent cycles (2 through 6) are dosed at 200 mg/m2 if blood counts are acceptable. A CBC should be obtained on days 22 and 29 of each 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 of hematologic toxicity. (See 'Side effects and monitoring' below.)

Other schedules of temozolomide have not been shown to be more effective than the standard postradiation schedule of 5 days every 28 days in the adjuvant setting [19-21].

Antiemetics — Temozolomide is moderately emetogenic, and premedication with an oral serotonin 5-hydroxytryptamine (5-HT3) antagonist such as ondansetron 8 mg orally should be given 30 minutes before each dose. 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 prophylaxis — Antimicrobial prophylaxis for pneumocystis pneumonia is recommended in the temozolomide labeling information for all patients during the concomitant radiation phase of treatment. This guidance is based on the risk of selective lymphopenia and impaired T cell-mediated immunity with daily temozolomide as well as the occurrence of two cases of pneumocystis pneumonia in an initial phase II trial in patients with newly diagnosed glioblastoma [22].

However, clinical experience in the years since the approval of temozolomide for glioblastoma suggests that pneumocystis pneumonia is uncommon and usually occurs in patients with additional risk factors for opportunistic infection, such as use of glucocorticoids or lymphopenia. In a population-based retrospective cohort study that included more than 5000 Canadian patients with gliomas treated with temozolomide chemoradiotherapy, 38 patients (0.74 percent) were diagnosed with pneumocystis pneumonia within one year of treatment, at an average of approximately three months from the start of radiation [23]. The number of case fatalities was low (<6 patients). A separate study on a subset of the same cohort for which data on pneumocystis prophylaxis use (mostly trimethoprim-sulfamethoxazole) were available found that the absolute risk reduction associated with prophylaxis was low (estimated number needed to treat to prevent one infection: 288), while the risk of grade 3/4 neutropenia was elevated (number needed to harm: 34) [24]. Overall survival and hospitalization rates were similar between groups.

Based on these data, and considering other risks of trimethoprim-sulfamethoxazole (eg, thrombocytopenia, hypersensitivity, acute kidney injury), we have adopted a more selective approach to prophylaxis, prescribing it only in patients with additional risk factors for opportunistic infection (eg, glucocorticoid use, lymphopenia). This selective strategy has not been studied prospectively, however, and it remains reasonable to abide by the labeling information in all patients [25]. When used, prophylaxis is typically continued until lymphocytes have recovered to >800/microL (table 4) [26,27]. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Regimens'.)

Side effects and monitoring

Hematologic toxicities — Patients receiving temozolomide chemotherapy are at risk for hematologic toxicity and should be monitored with weekly CBCs during radiation therapy (table 2). The incidence of hematologic toxicity due to temozolomide is approximately two to three times higher in females than in males for reasons that are not yet clear [28-31].

During monthly cycles of adjuvant temozolomide, a CBC should be obtained on days 22 and 29 of each cycle to monitor for toxicity and help guide dose adjustments, if necessary (figure 1 and table 3A-B). Subsequent cycles should not be given until platelets have recovered to >100,000/microL and the ANC is >1500/microL.

Moderate to severe thrombocytopenia is the most common hematologic adverse effect, occurring in approximately 10 to 20 percent of patients [28]. During the concurrent phase of therapy, daily temozolomide should be held if the platelet count falls below 100,000/microL.

Radiation therapy is not known to increase bleeding risk and can be continued safely during periods of mild to moderate thrombocytopenia. In patients with severe thrombocytopenia (eg, counts less than 10,000 to 20,000/microL), some practitioners elect to hold radiation until hematologic stability has been achieved.

Moderate to severe lymphopenia and neutropenia occur in at least 15 percent of patients, and up to 75 percent of patients have CD4+ T cell counts less than 300 cells per mm3 at the completion of six weeks of daily temozolomide with concurrent radiotherapy [29]. In one retrospective study that included 183 patients receiving concurrent radiation and daily temozolomide, the rate of acute severe lymphopenia (ASL; defined as total lymphocyte count <500/microL) was 29 percent within three months of starting radiation [32]. Risk factors for ASL include female sex, lower baseline lymphocyte count, and large radiation volume [30,32].

With appropriate dose delays and dose reductions, most patients are able to complete the intended number of cycles of adjuvant temozolomide. Secondary prophylaxis with growth factor support is not routinely used or required. Patients who develop severe grade 3/4 thrombocytopenia during concurrent radiation therapy may be an exception, and some of these patients have prolonged thrombocytopenia and platelet transfusion requirements.

Use of a thrombopoietin receptor agonist is a potential strategy to improve future exposure to temozolomide after dose-limiting thrombocytopenia, although further data are needed. A small feasibility study found that weekly subcutaneous romiplostim was safe as secondary prophylaxis in patients with temozolomide-induced thrombocytopenia [33]. Among 16 patients who developed grade 3/4 thrombocytopenia during radiation and received continuous weekly romiplostim beginning one week after completion of radiation therapy, nine patients were able to complete six cycles of adjuvant temozolomide, three patients never started adjuvant temozolomide due to failure of romiplostim, and the remaining patients came off study for progression or unrelated adverse events. Even with romiplostim, the majority of patients had recurrent grade 3/4 thrombocytopenia and required dose reductions and delays. There were no major bleeding events. A randomized trial is planned to assess whether romiplostim improves patient-important outcomes including transfusion requirements, bleeding complications, and survival. (See "Clinical applications of thrombopoietic growth factors".)

Rare cases of temozolomide-associated aplastic anemia, myelodysplasia, plasmablastic lymphoma, and treatment-related acute myeloid leukemia (t-AML) have been described [34-37]. Aplastic anemia typically manifests as early and profound myelosuppression during the course of daily temozolomide with concurrent radiation [36-44]. The estimated incidence is <1 percent among patients receiving temozolomide for central nervous system (CNS) malignancies [37]. Approximately two-thirds of patients achieve hematologic recovery; among those who do not, many succumb to complications of pancytopenia.

Cases of secondary t-AML and other hematologic malignancies in association with temozolomide exposure have mostly been in patients with previous exposure to other alkylating agents [45-52]. In three cases with no other leukemogenic drug exposures, the total duration of temozolomide exposure ranged from 22 to 28 months and the latency ranged from 3 to 36 months [34]. Deletion of chromosomes 5 and 7 was the most common cytogenic abnormality. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

Nonhematologic toxicities — The most common nonhematologic side effects of temozolomide are nausea, anorexia, and fatigue. Fatal and severe hepatotoxicity has been reported in patients receiving temozolomide [34,53-55]. The manufacturer's product labeling recommends that liver biochemical tests be performed at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide [56]. Patients with mild to moderate hepatic dysfunction have similar pharmacokinetics compared with those with normal function, although patients with severe hepatic dysfunction have not been studied [57].

In addition to severe hepatotoxicity, other rare but life-threatening idiosyncratic reactions reported in association with temozolomide include hypersensitivity pneumonitis, allergic skin reactions, and opportunistic infections [34].

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 [58]. Patients of childbearing potential should be counseled on effective contraception as well as options for fertility preservation before beginning therapy, if possible. (See "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults", section on 'Reproductive health'.)

Treatment duration — Our practice is generally to treat with up to six cycles of postradiation temozolomide, based on the design of the original study that led to the acceptance of temozolomide as the standard of care [2]. Patients with stable disease after six cycles enter surveillance, with magnetic resonance imaging (MRI) every two to three months. Continuing temozolomide longer than six cycles in stable patients has not been shown to prolong survival but does expose patients to ongoing side effects and risks of chemotherapy.

Supporting evidence for this approach includes results of a phase II randomized trial, in which 159 patients with glioblastoma who had not progressed after six cycles of adjuvant temozolomide were randomly assigned to stop temozolomide (control) or continue temozolomide for up to 12 total cycles [59]. With a median follow-up of 33 months, progression-free survival was similar between groups, and overall survival was nonsignificantly worse in the extended temozolomide group (hazard ratio [HR] 1.3, 95% CI 0.90-1.88). The incidence of lymphopenia, thrombocytopenia, and nausea was higher in the extended temozolomide group. In secondary analyses, neither MGMT methylation status nor measurable disease were predictive of benefit from additional temozolomide cycles, with the limitation that the study had limited power to exclude clinically important differences.

Observational studies have come to similar conclusions [60,61]. In a retrospective study of 624 patients enrolled in one of four randomized trials who were free of progression after six cycles of adjuvant temozolomide, receipt of more than six cycles of temozolomide was associated with improved progression-free survival, especially in patients with MGMT-methylated tumors (HR 0.65, 95% CI 0.50-0.85), but no difference in overall survival (HR 0.92, 95% CI 0.71-1.19), even in the MGMT-methylated subgroup (HR 0.89, 95% CI 0.63-1.26) [61].

Temozolomide and lomustine — In the CeTeG/NOA-09 trial, combined temozolomide and lomustine was administered in six-week cycles starting during the first week of radiation therapy [7]. The first cycle was dosed as follows:

Lomustine (CCNU) 100 mg/m2 orally on day 1

Temozolomide 100 mg/m2 on days 2 to 6

Weekly CBCs should be performed during radiation therapy to monitor for hematologic toxicity, similar to the procedure in patients treated with daily temozolomide. In subsequent cycles, CBCs should be performed weekly starting at day 21. Basic metabolic panel and liver biochemical tests should be performed at the beginning and halfway through each cycle.

The risk of grade ≥3 hematologic toxicity in the CeTeG/NOA-09 trial was nonsignificantly higher with temozolomide plus lomustine compared with temozolomide alone (36 versus 29 percent) [62]. Toxicity mostly occurred during concurrent chemoradiotherapy; in patients who went on to receive one or more adjuvant cycles of chemotherapy, the risk of repeat hematologic toxicity was 42 percent. Risk factors for hematologic toxicity were female sex (odds ratio 2.5) and older age.

In the trial protocol, dosing of subsequent cycles was determined by the timing and depth of white blood cell (WBC) and platelet nadirs in relation to day 25. If a grade ≥3 nadir (WBC <1500/microL or platelets <50,000/microL) occurred after day 25, the next cycle of lomustine was dosed at 75 percent of the initial dose. One further dose reduction was permitted (to 50 percent of cycle 1 dose) for a grade ≥3 nadir in a subsequent cycle. Lomustine was permanently discontinued for a grade ≥3 toxicity after two dose reductions.

Temozolomide was adjusted according to nadirs during the first 25 days of the preceding cycle as follows:

WBC <1000/microL or platelets <25,000/microL – decrease to 50 mg/m2 (daily on days 2 to 6) on next cycle. Discontinue permanently if WBC <1500/microL or platelets <50,000/microL at the lowest dose level of 50 mg/m2.

WBC 1000 to 1500/microL or platelets 25,000 to 50,000/microL – decrease to 75 mg/m2 (daily on days 2 to 6) on next cycle.

Dose escalation of temozolomide to 120 mg/m2 was permitted if none of the above nadirs occurred during the first 25 days of the first cycle and counts had recovered by the end of radiation (WBC >2500/microL and platelets >100,000/microL). Two further dose increases were permitted in subsequent cycles meeting these criteria, to 150 mg/m2 and 200 mg/m2, respectively.

Temozolomide side effects are reviewed above (see 'Side effects and monitoring' above). Lomustine is a nitrosourea alkylating agent with overlapping hematologic toxicities and risk of severe myelosuppression. Like temozolomide, it is moderately emetogenic and should be given with adequate antinausea premedication. Other potential nonhematologic side effects include stomatitis, alopecia, progressive azotemia and nephrotoxicity, and hepatotoxicity. Pulmonary infiltrates and/or fibrosis can occur, usually at cumulative doses >1000 mg/m2, and serial monitoring of pulmonary function tests is advised. (See "Nitrosourea-induced pulmonary injury".)

ALTERNATING ELECTRIC FIELDS — A portable medical device applied to the scalp that generates TTFields first became available in 2011 for treatment of recurrent glioblastoma [63], and results of a subsequent open-label randomized trial suggest that the device improves both progression-free and overall survival when used along with monthly temozolomide in patients with newly diagnosed glioblastoma in the postradiation setting [64,65]. Use of the device is encouraged in interested patients, although the requirement to carry a device and maintain a shaved scalp for the duration of treatment presents a potential burden that is not acceptable to all patients.

Data supporting the role of TTFields in the up-front setting consist of an unblinded, multicenter international trial in which 695 patients with newly diagnosed glioblastoma were randomly assigned in a 2:1 fashion to monthly temozolomide plus TTFields or monthly temozolomide alone upon completion of standard radiation and concurrent daily temozolomide [64,65]. Eligible patients must have completed concurrent radiation and daily temozolomide without progression and were enrolled within seven weeks of completing radiation. The primary endpoint was progression-free survival. The trial was stopped early for benefit, at the time of a planned interim analysis of the first 315 patients with ≥18 months of follow-up; at this time trial enrollment had already reached the intended 695 patients [64].

Baseline patient characteristics were similar between the device arm (n = 466) and the control arm (n = 229) [65]. The median age was 56 years, the median Karnofsky Performance Status (KPS) was 90, and 54 percent of patients underwent gross total resection. MGMT promoter methylation status was available in 82 percent of patients and was methylated in 41 percent. MRI was reviewed centrally by two blinded radiologists according to Macdonald criteria. The median time from diagnosis to randomization was 3.8 months in both groups.

After a median follow-up of 40 months in surviving patients, those assigned to the TTFields device had improved progression-free survival compared with those assigned to temozolomide alone (6.7 versus 4.0 months, HR 0.63, 95% CI 0.52-0.76). Overall survival from the time of randomization was also improved (20.9 versus 16.0 months, HR 0.63, 95% CI 0.53-0.76). The most common device-related adverse effect was skin irritation (54 percent all grades, 2 percent severe), and the rate of systemic adverse effects did not differ between groups [65]. Secondary analysis of quality-of-life outcomes found no difference between the groups at 9 and 12 months [66,67].

A limitation of the trial was the lack of a sham device in the control arm, raising the possibility that differences in supportive care or health-promoting behaviors could have contributed to improved outcomes in the device arm. However, such an effect seems unlikely to fully explain the five-month difference in overall survival observed in the trial.

Experimentally, the biologic activity of the therapy is reported to derive from an antimitotic effect imposed by the alternating electric fields, which exert forces on charged tubulin subunits and thereby interfere with formation of the mitotic spindle [68,69].

Clinicians must be trained and certified to prescribe the device. The device is applied to a shaved scalp, with four transducer arrays connected to a portable battery or power supply-operated device. The device is intended to be worn continuously or at least 18 hours per day, and a shaved scalp must be maintained for the duration of therapy. Depending upon the functional status of the patient and the level of caregiver support, wearing and maintaining the device may represent a significant burden.

FOLLOW-UP AND MONITORING

Assessment of response and progression — Patient management decisions require an assessment of both initial response to treatment and subsequent evidence of progressive disease. Brain MRI with contrast is typically obtained within one month after completion of radiation therapy and then every two months during adjuvant temozolomide to assess disease status.

Early progression versus pseudoprogression — Pseudoprogression is a subacute treatment-related effect with MRI features mimicking tumor progression, usually occurring within three months of completion of chemoradiation in patients with glioblastoma (image 1). Distinguishing treatment-induced imaging changes from progressive disease has important implications to avoid premature and inappropriate discontinuation of a treatment regimen. Pseudoprogression is more common in patients with MGMT-methylated glioblastoma. Diagnosis and management of pseudoprogression are reviewed separately. (See "Management of recurrent high-grade gliomas", section on 'Early progression versus pseudoprogression'.)

Surveillance after treatment — There are no formal clinical trials that define the optimal frequency for follow-up after treatment. Guidelines from the National Comprehensive Cancer Network (NCCN) recommend that a repeat MRI should be obtained in patients with glioblastoma approximately four weeks after completion of radiation therapy, then every two to four months for two to three years, and less frequently thereafter [70].

PROGNOSIS — The most important prognostic factors affecting outcome in patients with glioblastoma are age, Karnofsky Performance Status (KPS) (table 5), MGMT status, and several additional molecular genetic alterations. As discussed above, the extent of initial surgical resection also appears to influence prognosis. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas", section on 'Extent of resection'.)

Population-based estimates — The median overall survival of patients with glioblastoma in population-based studies is approximately 10 to 12 months [71-73]. For glioblastoma diagnosed between 2002 through 2010 in the United States and Taiwan, for example, one-year survival rates ranged from 38 to 50 percent and five-year survival ranged from 5 to 10 percent [74]. In a separate population-based study that examined changes in glioblastoma survival over a 20-year period, median overall survival for glioblastoma improved from 4.9 months in the period of 1980 through 1994 to 11.5 months in the period of 2005 through 2009 [75].

Patient-level prognostic tools — A nomogram derived from a clinical trial population and validated on a separate trial cohort is available online [76]. Nearly all patients included in the derivation and validation cohorts underwent at least subtotal resection and received standard radiation with concurrent temozolomide followed by monthly temozolomide; information on IDH mutation status was not available, but the majority can be assumed to have had IDH-wildtype tumors. The nomogram estimates are therefore likely most applicable to patients with IDH-wildtype glioblastoma. It has been validated in at least one cohort of nonclinical trial participants [77].

The nomogram incorporates patient age at diagnosis, sex, KPS, extent of resection, and MGMT status to estimate 6-, 12-, and 24-month survival probability [76]. As an example, the nomogram estimates that a 50-year-old male with a KPS of 90 who undergoes gross total resection of an MGMT-methylated tumor has 12- and 24-month survival probabilities of 80 and 52 percent, respectively. Survival probabilities for the same patient with an MGMT-unmethylated tumor are 27 and 10 percent, respectively.

A previously validated prognostic tool is the recursive partitioning analysis (RPA) classification of glioblastoma, which was developed in the pre-temozolomide era and validated on patients who received primarily radiation alone [78]. The classification estimates median survival in three subgroups:

RPA class III (age <50, KPS ≥90) – 17.1 months (12-month survival 70 percent)

RPA class IV (age <50, KPS <90; or age ≥50, KPS ≥70, resection, and working) – 11.2 months (12-month survival 46 percent)

RPA class V (all others) – 7.5 months (12-month survival 28 percent)

A similar analysis in older adults age ≥70 years identified four prognostic subgroups based on age, extent of surgery (biopsy versus resection), and KPS; median survival ranged from 2.3 months in subgroup IV (biopsy only, KPS <70) to 9.3 months in subgroup I (surgical resection, age <75.5) [79]. (See "Management of glioblastoma in older adults", section on 'Prognostic factors'.)

MGMT methylation status — MGMT is an enzyme that is responsible for DNA repair following alkylating-agent chemotherapy. In the course of tumor development, the MGMT gene may be silenced by methylation of its promoter, thereby preventing repair of DNA damage and increasing the potential effectiveness of alkylating agent chemotherapy.

Multiple clinical studies have confirmed that MGMT promoter methylation is prognostic of improved survival, independent of established clinical factors. In a meta-analysis of 11 studies examining the prognostic value of MGMT promoter status, a methylated MGMT promoter was associated with an improvement in both progression-free survival (hazard ratio [HR] 0.56, 95% CI 0.32-0.80) and overall survival (HR 0.50, 95% CI 0.35-0.66) [80].

MGMT promoter methylation may also be predictive of chemotherapy responsiveness in patients with glioblastoma, although this has not been confirmed in a prospective manner [6,81]. In a large randomized trial comparing radiation alone with radiation plus concomitant and adjuvant temozolomide, the two-year overall survival for patients treated with combined radiation and chemotherapy was 49 percent for those with MGMT-methylated tumors and 15 percent for those with unmethylated tumors; moreover, those with a methylated MGMT promoter derived a greater degree of benefit from the addition of temozolomide to radiation than those with an unmethylated promoter. (See 'Temozolomide' above.)

This prognostic and predictive role of MGMT promoter methylation has also been observed in studies of older adults with glioblastoma and can be used to guide treatment [82-84]. (See "Management of glioblastoma in older adults", section on 'Selection of therapy'.)

The presence of methylation of the MGMT promoter may also influence the patterns of clinical relapse. This was illustrated by a study of 95 patients treated with radiation therapy and temozolomide [85]. At a median follow-up of 19 months, patients with methylated MGMT had a longer time to initial relapse and were more likely to relapse outside the radiation treatment field (8 of 17 versus 9 of 60 with an unmethylated primary tumor).

Of note, a number of assays are in clinical use to measure MGMT promoter methylation, and there is no consensus on the optimal method [86-88]. Reliability, availability, and cost vary among methods, and there is a need for better quality control and validation. The proportion of patients with glioblastoma classified as having a methylated MGMT promoter is considered in the range of 40 to 50 percent, although a broader range (30 to 60 percent) may be seen depending on the assay used and study cohort [89-91].

Other molecular factors — Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been described in 55 to 80 percent of primary glioblastomas and are associated with worse survival, independent of other clinical and molecular factors [92-94]. As of the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors, the presence of a TERT promoter mutation in an IDH-wildtype astrocytoma establishes a diagnosis of glioblastoma, even in the absence of high-grade histologic features [1]. The same is true for two other molecular features: epidermal growth factor receptor (EGFR) amplification and concurrent gain of chromosome 7/loss of chromosome 10. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'EGFR, TERT, +7/-10 genotype'.)

Additional molecular alterations in high-grade gliomas are reviewed separately. (See "Molecular pathogenesis of diffuse gliomas".)

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 5th to 6th 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 10th to 12th 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: Glioblastoma (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

Note on terminology – As of 2021, tumors previously called glioblastoma are now divided into two separate diagnoses based primarily on isocitrate dehydrogenase (IDH) mutation status (algorithm 1): glioblastoma, IDH-wildtype, grade 4; and astrocytoma, IDH-mutant, grade 4. For the purposes of this topic, glioblastoma refers to IDH-wildtype glioblastoma unless stated otherwise. Treatment of IDH-mutant astrocytomas is reviewed separately. (See 'Introduction' above and "Treatment and prognosis of IDH-mutant astrocytomas in adults".)

Surgical resection – Maximal surgical resection consistent with preservation of neurologic function is the initial step in management. Surgical management of high-grade gliomas is reviewed separately. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas".)

Importance of molecular testing – Selection of appropriate postoperative therapy for patients with glioblastoma and other infiltrative gliomas depends on adequate molecular characterization (table 1). Tumor specimens should be tested for IDH mutations and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. (See 'Selection of systemic therapy' above.)

Selection of systemic therapy – Radiation and temozolomide are the backbone of initial therapy for newly diagnosed glioblastoma in patients with an adequate functional status. The quality of supporting evidence and alternative treatment options vary based on patient age and MGMT methylation status:

MGMT-methylated glioblastoma, ≤70 years – We recommend postoperative radiation therapy with concurrent and adjuvant temozolomide (Grade 1A). A dual regimen of temozolomide and lomustine in combination with radiation therapy is an alternative option in younger, fit patients, although data supporting improved efficacy are inconclusive and toxicity may be higher. (See 'MGMT-methylated tumors, age ≤70 years' above.)

MGMT-unmethylated glioblastoma, ≤70 years – We suggest postoperative radiation therapy with concurrent and adjuvant temozolomide (Grade 2B). Patients with MGMT-unmethylated tumors have worse overall survival and derive less benefit from temozolomide compared with patients with MGMT-methylated tumors, but better alternatives are lacking. Participation in clinical trials is encouraged. (See 'MGMT-unmethylated tumors, age ≤70 years' above.)

Unknown MGMT methylation status, ≤70 years – Radiation plus temozolomide remains the standard of care based on the clinically meaningful improvement in survival expected from temozolomide for the 30 to 40 percent of patients predicted to have an MGMT-methylated tumor, the lack of better alternatives for MGMT-unmethylated tumors, and the relative safety and tolerability of temozolomide. (See 'MGMT status unknown' above.)

Age >70 years or low functional status – Treatment recommendations for older adults (algorithm 2) and those with poor functional status are presented separately. (See "Management of glioblastoma in older adults", section on 'Summary and recommendations'.)

Administration of systemic therapyTemozolomide is taken on an empty stomach, at least two hours after the last meal, with antiemetic pretreatment. Patients require regular monitoring of complete blood counts and liver function tests. (See 'Administration of systemic therapy' above.)

For patients with additional risk factors for opportunistic infection (eg, use of glucocorticoids, lymphopenia), we suggest antimicrobial prophylaxis for pneumocystis pneumonia during radiation with concurrent temozolomide (Grade 2C). In other patients, the risks of prophylaxis may outweigh the benefits, given the low risk of pneumocystis. (See 'Pneumocystis prophylaxis' above.)

Duration of systemic therapy – For patients treated with standard concurrent and adjuvant temozolomide, we suggest treating with six cycles of adjuvant monthly temozolomide rather than a more prolonged course (Grade 2B). (See 'Treatment duration' above.)

Adjunctive device therapy – In addition to radiation and temozolomide, we discuss the option of low-intensity alternating electric field therapy (TTFields), which improved survival in a large randomized trial. Use of the device is encouraged in interested patients, although the requirement to carry a device and maintain a shaved scalp for the duration of treatment presents a potential burden that is not acceptable to all patients. (See 'Alternating electric fields' above.)

Prognosis – The median overall survival of patients with glioblastoma is approximately 10 to 12 months in population-based studies and approximately 15 to 18 months in clinical trials of standard therapy. The most prognostic factors are age, performance status, and MGMT promoter methylation status. (See 'Prognosis' above.)

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Topic 5207 Version 82.0

References

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