Key points
- Brain tumors are a large group of diseases; meningioma is the most common primary tumor (mostly benign), and glioblastoma is the most common primary malignant brain tumor [1].
- The World Health Organization classification (WHO CNS5, 2021) bases the diagnosis on a combination of microscopic appearance and molecular markers such as IDH mutation and 1p/19q codeletion [2].
- The main diagnostic test is brain MRI with and without contrast (gadolinium), and the definitive diagnosis is made by tissue sampling and molecular testing [3].
- Standard treatment for glioblastoma is surgery with maximal safe resection, followed by radiation therapy with temozolomide (the Stupp protocol) [3, 5]; adding tumor treating fields (TTFields) improved survival in the EF-14 trial [7].
- In IDH-mutant gliomas, treatment after surgery, depending on the tumor type and grade, is close monitoring or radiation therapy followed by chemotherapy (temozolomide or PCV) [3, 12, 13, 21]; the newer oral drug vorasidenib is also an approved option for grade 2 IDH-mutant gliomas after surgery, when radiation therapy and chemotherapy can be postponed [9, 11, 22].
- In limited brain metastases, stereotactic radiosurgery alone causes less cognitive decline than when whole-brain radiation therapy is added [16, 17].
What is a brain tumor?
A brain tumor is an abnormal growth of cells in the brain or in the membranes around it. There are two main groups: primary tumors, which arise from the brain tissue itself, the membranes covering the brain (meninges) or the nerves; and brain metastases, which are cancers of other organs (such as the lung, breast or melanoma) that have spread to the brain [1, 16].
Not all brain tumors are malignant. According to the Central Brain Tumor Registry of the United States (CBTRUS), meningioma is the most common primary tumor of the central nervous system and is usually non-malignant, and glioblastoma accounts for more than half of primary malignant tumors; gliomas as a whole make up 22.2% of tumors [1].
The new WHO classification (CNS5)
The fifth edition of the World Health Organization classification of central nervous system tumors (WHO CNS5), published in 2021, greatly expanded the role of molecular diagnostics, while still relying on histology and immunohistochemistry. It emphasizes an integrated diagnosis (combining histological and molecular findings) and layered reporting, and it introduced some new tumor types based on technologies such as DNA methylation profiling [2].
- Grading is now done with Arabic numerals (1 to 4) and within each tumor type, rather than across different types [2].
- Adult-type diffuse gliomas have three main types: astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and glioblastoma, IDH-wildtype [2].
- The term “glioblastoma” is now used only for IDH-wildtype tumors [2, 4].
Signs and symptoms
The symptoms of a brain tumor depend on its location, size and growth rate. Tumors that cause symptoms within a few weeks are usually fast-growing, while tumors that caused symptoms for years before diagnosis are usually slow-growing [3]. In many patients, the symptoms in the year before diagnosis are non-specific, such as fatigue or headache [3]. Symptoms that point to a lesion in the brain [3]:
- Seizures, especially a first seizure in adulthood
- Speech problems (aphasia): difficulty finding words or understanding speech
- Weakness on one side of the body (hemiparesis)
- Sensory disturbances, such as numbness or tingling on one side
Many meningiomas cause no symptoms and are discovered incidentally on imaging done for another reason [14].
Warning signs
If you have a seizure for the first time, or suddenly develop weakness on one side of the body, speech problems, vision problems, or a severe headache that is different from your usual headaches and comes with vomiting or drowsiness, go to the emergency department right away. Most headaches have nothing to do with a brain tumor, but a medical evaluation is essential.
Diagnosis: from MRI to molecular pathology
Diagnostic pathway for a brain tumor
- 1
Neurological examination and history
Assessment of the symptoms, how quickly they are progressing, and family history or rare risk factors such as previous radiation to the head [3].
- 2
- 3
Surgery or biopsy
Treatment decisions are based on the tissue diagnosis. Wherever possible, maximal safe resection is recommended; otherwise, a stereotactic biopsy is performed [3].
- 4
- 5
Multidisciplinary team meeting
The neurosurgeon, oncologist, radiation oncologist, neuroradiologist and pathologist decide on the treatment plan together [3].
Treatment by tumor type
Glioblastoma
Glioblastoma is the most common primary malignant brain tumor in adults and grows quickly [1, 4]. Its treatment has several stages and is decided by a multidisciplinary team [3]:
- Surgery to remove as much of the tumor as can be removed safely [3].
- Radiation therapy with temozolomide tablets (the Stupp protocol): about 6 weeks of radiation therapy with daily temozolomide, followed by 6 cycles of temozolomide [3, 5]. The greatest benefit is seen in tumors with the feature called “MGMT methylation” [6].
- TTFields device: a portable device that, through four pads placed on the shaved scalp, delivers a weak alternating electric field to the tumor for at least 18 hours a day and disrupts cell division; it may be offered alongside temozolomide. Its most common side effect is skin irritation under the pads [7].
- Older adults: a shorter course of radiation therapy (about 3 weeks) with temozolomide; for those who cannot tolerate the combined treatment, short-course radiation therapy or temozolomide alone, depending on the tumor’s MGMT status [3, 8].
- Recurrence: treatment depends on the patient’s general condition and on the location and timing of the recurrence; repeat surgery may be possible in some patients [26], and the oral drug lomustine is the most commonly used drug treatment at this stage [23, 24].
IDH-mutant gliomas and low-grade gliomas
IDH-mutant gliomas (astrocytoma and oligodendroglioma) occur mostly in younger adults, grow more slowly than glioblastoma and have a better prognosis, but over time they can lead to neurological disability and premature death [9, 12]. After surgery, depending on the tumor type and grade, close monitoring or additional treatment is recommended [3, 21].
Radiation therapy and chemotherapy (temozolomide or PCV) are proven treatments for IDH-mutant gliomas and improve long-term survival [12, 13, 21]. Vorasidenib is a newer option for grade 2 IDH-mutant gliomas after surgery, in patients who do not need radiation therapy or chemotherapy right away and in whom these treatments can be postponed [11, 22]. This drug requires regular monitoring of liver enzymes [9]. Talk with your doctor about the best timing and order of treatments.
Meningioma
Meningioma arises from the membranes covering the brain and is the most common intracranial tumor [1, 14]. Most meningiomas are slow-growing and non-malignant, and they are more common in women [1].
- Monitoring with imaging: a substantial proportion of meningiomas, especially in people without symptoms or in older adults, can be managed with a “watch and periodic imaging” strategy [14].
- Surgery: complete removal of the tumor together with the involved dura is often curative and allows a definitive diagnosis and grading [14].
- Radiosurgery or radiation therapy: for inoperable or recurrent tumors, depending on their size and proximity to sensitive structures [14].
- Drug treatment: all systemic treatments are still experimental, and no standard systemic therapy has been established [14].
Brain metastases
Brain metastasis occurs when a cancer of another organ spreads to the brain. Treatment depends on the number and size of the lesions, the symptoms, the type of primary cancer and the systemic treatment options, and is decided by a multidisciplinary team [15, 16].
- Stereotactic radiosurgery: radiosurgery delivers a focused, precise, high dose of radiation to the lesion in one or a few sessions. In patients with a limited number of metastases, radiosurgery alone causes less cognitive decline than when whole-brain radiation therapy is added [16, 17].
- Surgery: for a large tumor causing mass effect [16].
- Whole-brain radiation therapy: if it is needed, the drug memantine and sparing of the hippocampus (a brain region involved in memory) are used where possible to reduce cognitive decline [16, 39].
- Targeted drugs: some newer drugs, such as osimertinib in EGFR-mutant lung cancer and trastuzumab deruxtecan or tucatinib in HER2-positive breast cancer, penetrate the brain and can shrink or control brain lesions [19, 20, 25]. However, symptomatic metastases should receive local treatment regardless of drug therapy [16].
What should I do after diagnosis?
Frequently asked questions
Is my headache a sign of a brain tumor?
Most headaches have a benign cause. Headache caused by a brain tumor usually comes with other symptoms such as seizures, weakness on one side of the body, speech problems or changes in sensation [3]. If you have a new or worsening headache, or one that comes with these symptoms, see a doctor.
My meningioma is small and causes no symptoms; do I need surgery?
Not necessarily. Many meningiomas that cause no symptoms can be monitored with periodic MRI and treated only if they grow or start to cause symptoms [14].
How is glioblastoma treated?
What is an IDH mutation, and why does it matter?
An IDH mutation is a genetic change in the tumor cells. Gliomas with this mutation usually grow more slowly and have a better prognosis [2, 9]. Their proven treatments after surgery are radiation therapy and chemotherapy (temozolomide or PCV) [21]; the newer targeted drug vorasidenib has also been approved for some grade 2 gliomas with this mutation [11, 22].
Does whole-brain radiation therapy cause memory problems?
Whole-brain radiation therapy can reduce cognitive function; that is why focused radiosurgery is preferred in patients with a limited number of metastases [16, 17]. If whole-brain radiation therapy is needed, the drug memantine and sparing of the hippocampus are recommended to reduce this side effect [16].
Are brain tumors hereditary?
Most brain tumors are not hereditary. Only in rare cases are inherited syndromes such as Li-Fraumeni or Lynch syndrome linked to glioma, and genetic counseling is recommended for these families [3].
Evidence and recent advances (for physicians)
For physicians
WHO CNS5 molecular criteria
- An IDH-wildtype diffuse astrocytic glioma in an adult is diagnosed as glioblastoma if there is microvascular proliferation or necrosis, or a TERT promoter mutation, EGFR gene amplification or a +7/−10 chromosomal alteration, even if its microscopic appearance is low grade [2].
- In IDH-mutant astrocytoma, homozygous CDKN2A/B deletion raises the grade to 4 even without necrosis or microvascular proliferation [2].
- In meningioma, a TERT promoter mutation and/or homozygous CDKN2A/B deletion places the tumor in grade 3 (malignant) [2].
| Tumor type | Defining molecular feature | CNS WHO grade | General treatment approach |
|---|---|---|---|
| Glioblastoma, IDH-wildtype | No IDH mutation; necrosis/microvascular proliferation or TERT, EGFR or +7/−10 | 4 | Surgery with maximal safe resection, then radiotherapy + temozolomide and maintenance temozolomide [3, 5] |
| Astrocytoma, IDH-mutant | IDH1/2 mutation without 1p/19q codeletion; CDKN2A/B deletion means grade 4 | 2, 3 or 4 | Grade 2: observation, or radiotherapy followed by temozolomide or PCV; grade 3: radiotherapy followed by 12 cycles of temozolomide [3, 13, 21]; newer option: vorasidenib for grade 2 after surgery, when radiotherapy and chemotherapy can be deferred [9, 22] |
| Oligodendroglioma, IDH-mutant and 1p/19q-codeleted | IDH mutation + 1p/19q codeletion | 2 or 3 | Grade 2 after complete resection: observation without treatment is reasonable; if treatment is needed (grades 2 and 3): radiotherapy followed by PCV; temozolomide is a reasonable alternative if PCV is not tolerated, without high-level supporting evidence [3, 21]; newer option: vorasidenib for grade 2 after surgery, when radiotherapy and chemotherapy can be deferred [9, 22] |
PCV: procarbazine, lomustine (CCNU) and vincristine. Treatment is chosen by a multidisciplinary neuro-oncology team.
Newly diagnosed glioblastoma
In the EORTC-NCIC trial of 573 patients, adding concurrent and maintenance temozolomide to radiotherapy (the Stupp protocol) increased median survival from 12.1 to 14.6 months (HR 0.63) and 2-year survival from 10.4% to 26.5% [5]. At 5-year follow-up, 5-year survival was 9.8% vs 1.9%, and MGMT methylation status identified the patients who benefit most [6]. In the EF-14 trial of 695 patients, adding TTFields to maintenance temozolomide increased median overall survival from 16.0 to 20.9 months (HR 0.63) [7].
The EANO guideline notes the PFS and OS superiority of TTFields across all subgroups without a meaningful difference in quality of life, but points to questions about the mechanism of action, the open-label design without a sham control group and the interpretation of the data, and considers its feasibility and cost-effectiveness as a standard of care “highly controversial” [3]. In recurrent glioblastoma, TTFields was not superior to physician’s choice of therapy [3]. The ASCO-SNO guideline also recommends that TTFields be considered for patients with newly diagnosed glioblastoma [21].
Glioblastoma in older adults
In the CCTG CE.6/EORTC 26062 trial of 562 patients aged 65 years or older, adding temozolomide to short-course radiotherapy (40 Gy in 15 fractions) increased median survival from 7.6 to 9.3 months (HR 0.67); the greatest benefit was in MGMT-methylated tumors (13.5 vs 7.7 months) [8]. In the Nordic trial (age 60 years or older), temozolomide alone increased median survival compared with standard 6-week radiotherapy from 6.0 to 8.3 months (HR 0.70), whereas short-course radiotherapy (34 Gy in 3.4 Gy fractions) was not significantly superior (7.5 months; HR 0.85); in patients older than 70 years, both temozolomide (HR 0.35) and short-course radiotherapy (HR 0.59) were superior to standard radiotherapy, and in the temozolomide group, MGMT-methylated tumors had longer survival (9.7 vs 6.8 months) [41]. In the NOA-08 trial (older than 65 years, anaplastic astrocytoma or glioblastoma), temozolomide alone was non-inferior to radiotherapy alone (median survival 8.6 vs 9.6 months; HR 1.09); in MGMT-methylated tumors, event-free survival was longer with temozolomide (8.4 vs 4.6 months), and the opposite was seen in unmethylated tumors [40]. According to the EANO guideline, in older patients who are not candidates for combined treatment, MGMT-unmethylated tumors are treated with short-course radiotherapy alone and methylated tumors with temozolomide alone [3].
Recurrent glioblastoma
Lomustine is the most commonly used systemic therapy at this stage and the comparator arm of recent trials [23, 24]. In the EORTC 26101 trial of 437 patients, adding bevacizumab to lomustine increased progression-free survival from 1.5 to 4.2 months but did not improve overall survival (9.1 vs 8.6 months; HR 0.95) [23]. Regorafenib, which looked promising in a phase 2 trial, did not improve overall survival compared with lomustine in the larger GBM AGILE trial and was more toxic [24].
IDH-mutant gliomas: radiotherapy and chemotherapy
In the RTOG 9802 trial, adding 6 cycles of PCV chemotherapy after radiotherapy in high-risk grade 2 gliomas increased median overall survival from 7.8 to 13.3 years (HR 0.59) [12]. In the final analysis of the CATNON trial in anaplastic gliomas without 1p/19q codeletion (median follow-up 10.9 years), 12 cycles of adjuvant temozolomide after radiotherapy improved survival (HR 0.65), but temozolomide concurrent with radiotherapy gave no significant benefit; in IDH-mutant tumors, median overall survival was 12.5 years with adjuvant temozolomide vs 6.0 years without it (HR 0.54), and no benefit was seen in IDH-wildtype tumors [13].
IDH-mutant gliomas: vorasidenib and the INDIGO trial
Vorasidenib is an oral, brain-penetrant inhibitor of the mutant IDH1 and IDH2 enzymes. In the double-blind phase 3 INDIGO trial, 331 patients with grade 2 IDH-mutant glioma who had received no treatment other than surgery were given vorasidenib 40 mg once daily or placebo. Median progression-free survival was 27.7 vs 11.1 months (HR 0.39), and the time to next intervention (surgery, radiotherapy or chemotherapy) was also significantly delayed (HR 0.26) [9]. With longer follow-up, the tumor volume growth rate was −1.3% with vorasidenib vs 14.4% with placebo, seizures were less frequent, and no negative effect on quality of life or cognitive function was seen [10]. On August 6, 2024, the US Food and Drug Administration (FDA) approved vorasidenib for patients aged 12 years and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation after surgery [11]. The 2025 rapid update of the ASCO-SNO guideline gives a conditional recommendation for vorasidenib in grade 2 IDH-mutant oligodendroglioma and astrocytoma after one or more surgeries, when radiotherapy and chemotherapy can be deferred [22].
Brain metastases: radiosurgery and whole-brain radiotherapy
In the N0574 trial of 213 patients with 1 to 3 brain metastases, cognitive deterioration at 3 months occurred in 63.5% with radiosurgery alone and in 91.7% with the addition of whole-brain radiotherapy (WBRT); quality of life was better with radiosurgery alone and overall survival did not differ (HR 1.02), although intracranial tumor control was lower with radiosurgery alone [17]. The Japanese prospective study JLGK0901 (1194 patients) showed that overall survival after radiosurgery in patients with 5 to 10 metastases was non-inferior to that in patients with 2 to 4 metastases (median 10.8 months in both groups) [18]. In the RTOG 0614 trial, memantine with whole-brain radiotherapy delayed the time to cognitive decline (HR 0.78) [38]; in NRG CC001, with 518 patients, hippocampal avoidance plus memantine reduced the risk of cognitive failure (HR 0.74) with no difference in overall survival or intracranial progression-free survival [39].
Brain metastases: targeted therapy with intracranial activity
In the subgroup of patients with brain metastases in the FLAURA trial (EGFR-mutant lung cancer), the intracranial objective response rate in patients with measurable lesions was 91% with osimertinib vs 68% with older EGFR inhibitors [19]. In HER2-positive breast cancer with brain metastases, trastuzumab deruxtecan in the single-arm DESTINY-Breast12 study (263 patients with stable or active brain metastases previously treated with anti-HER2 therapy) achieved a 12-month progression-free survival of 61.6% and a 12-month CNS progression-free survival of 58.9% [25]. Another option is adding tucatinib to trastuzumab and capecitabine, which in the randomized HER2CLIMB trial reduced the risk of intracranial progression or death by 68% (HR 0.32) and increased median overall survival from 12.0 to 18.1 months [20].
| Clinical situation | Preferred option | Evidence |
|---|---|---|
| Symptomatic metastases | Local treatment, regardless of systemic therapy | ASCO-SNO-ASTRO guideline [16] |
| 1 to 4 unresected, asymptomatic metastases, no systemic option | Radiosurgery alone (except in small cell lung cancer) | ASCO-SNO-ASTRO guideline [16]; N0574 [17] |
| 5 to 10 small metastases | Radiosurgery is an option to consider | JLGK0901: non-inferior survival compared with 2 to 4 metastases [18] |
| 1 to 2 resected metastases | Radiosurgery to the surgical cavity | ASCO-SNO-ASTRO guideline [16] |
| Large tumor with mass effect | Surgery | ASCO-SNO-ASTRO guideline [16] |
| Whole-brain radiotherapy is needed | Memantine + hippocampal avoidance (no hippocampal lesion, life expectancy ≥4 months) | ASCO-SNO-ASTRO guideline [16] |
| KPS ≤50, or KPS <70 without a systemic option | Radiotherapy offers no benefit; supportive care | ASCO-SNO-ASTRO guideline [16] |
The final decision is made by a multidisciplinary team, taking into account the type of primary cancer and the targeted therapies that exist for it.
Treatment regimens and dosing (for physicians)
Treatment regimens and doses: index15 regimens
Per the temozolomide FDA label [27], these points apply to all temozolomide-containing regimens (the regimens below and the CATNON regimen); the dose-modification rules refer to the schedule concurrent with radiotherapy and to the 5-day maintenance schedule:
- Blood counts: before each dose, an absolute neutrophil count of at least 1.5 × 10⁹/L and platelets of at least 100 × 10⁹/L are required. During the concurrent phase, weekly blood counts; during the maintenance phase, a blood count on day 22 of each cycle.
- Pneumocystis pneumonia (PCP) prophylaxis: throughout the concurrent phase, continued in patients with lymphopenia until recovery to grade 1 or lower.
- Dose modification during the concurrent phase: neutrophils 0.5 to 1.5 or platelets 10 to 100 (× 10⁹/L) or grade 2 non-hematologic toxicity → withhold; neutrophils below 0.5, platelets below 10 or grade 3 to 4 non-hematologic toxicity → discontinue permanently.
- Dose modification during the maintenance phase: escalate to 200 mg/m² only if no withholding or discontinuation was required in cycle 1 (if the dose was not escalated at the start of cycle 2, do not escalate it later); after withholding, give the next cycle at a dose 50 mg/m² lower; if 100 mg/m² is not tolerated, discontinue permanently.
- Liver: liver tests at baseline, midway through the first cycle, before each cycle and 2 to 4 weeks after the last dose (risk of severe hepatotoxicity).
- Administration: to reduce nausea, take the drug on an empty stomach or at bedtime, with an antiemetic; capsules must not be opened or chewed.
For physicians
Newly diagnosed glioblastoma: after surgery
Stupp protocol: radiotherapy + concurrent and maintenance temozolomide (EORTC-NCIC)
Newly diagnosed glioblastoma after maximal safe resection or biopsy; patients younger than 70 years with good performance status
Newly diagnosed glioblastoma after maximal safe resection or biopsy; patients younger than 70 years with good performance status [3, 5]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Concurrent phase (6 weeks) | |||
| Focal radiotherapy | 60 Gy in 30 fractions (2 Gy per day) | External beam radiotherapy | 5 days a week for 6 weeks |
| Temozolomide | 75 mg/m² once daily | Oral | Daily from the first to the last day of radiotherapy (42 to 49 days) |
| Maintenance: 6 cycles, starting 4 weeks after the end of radiotherapy | |||
| Temozolomide (cycle 1) | 150 mg/m² once daily | Oral | Days 1 to 5 |
| Temozolomide (cycles 2 to 6) | 200 mg/m² once daily if tolerated | Oral | Days 1 to 5 |
The greatest benefit was seen in tumors with MGMT promoter methylation [5, 6]. Temozolomide monitoring and dose modification as in the “Common safety considerations” above [27]. Dose source: [5, 27].
Evidence: EORTC 26981/22981–NCIC CE.3 (2009), EORTC 26981-22981 / NCIC CE.3 (Stupp) (2005)
Short-course radiotherapy + temozolomide in older adults (CCTG CE.6/EORTC 26062)
Newly diagnosed glioblastoma in patients aged 65 years or older who are not candidates for 60 Gy in 30 fractions with temozolomide; ECOG 0 to 2; greatest benefit in MGMT-methylated tumors
Newly diagnosed glioblastoma in patients aged 65 years or older who are not candidates for 60 Gy in 30 fractions with temozolomide; ECOG 0 to 2; greatest benefit in MGMT-methylated tumors [8, 35]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Concurrent phase (3 weeks) | |||
| Radiotherapy | 40 Gy in 15 fractions | External beam radiotherapy | About 3 weeks |
| Temozolomide | 75 mg/m² once daily | Oral | Daily from the first to the last day of radiotherapy (up to 28 days) |
| Adjuvant: up to 12 cycles | |||
| Temozolomide | 150 mg/m²; from cycle 2, up to 200 mg/m² if tolerated | Oral | First 5 days of each cycle |
The trial required granulocytes of at least 1500/mm³ and platelets of at least 100,000/mm³, creatinine and bilirubin no more than 1.5 times the upper limit of normal, and ALT/AST less than 2.5 times the upper limit of normal [35]. Temozolomide monitoring as in the “Common safety considerations” [27]. Dose source: protocol NCT00482677 [35].
Evidence: NCIC CE.6 / EORTC 26062-22061 / TROG 08.02 (Perry) (2017)
Temozolomide alone in older adults with MGMT-methylated tumors (Nordic and NOA-08)
Newly diagnosed glioblastoma in older patients who are not candidates for combined treatment, with an MGMT promoter-methylated tumor; Nordic: age 60 years or older; NOA-08: older than 65 years, KPS 60 or higher, anaplastic astrocytoma or glioblastoma
Newly diagnosed glioblastoma in older patients who are not candidates for combined treatment, with an MGMT promoter-methylated tumor [3]; Nordic: age 60 years or older [41]; NOA-08: older than 65 years, KPS 60 or higher, anaplastic astrocytoma or glioblastoma [40]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Nordic schedule | |||
| Temozolomide | 200 mg/m² | Oral | Days 1 to 5 every 28 days |
| Or the NOA-08 dose-dense schedule | |||
| Temozolomide | 100 mg/m² | Oral | Days 1 to 7; one week on, one week off |
In Nordic, the most common grade 3 to 4 adverse events in the temozolomide group were neutropenia and thrombocytopenia [41]; in NOA-08, the most common grade 3 to 4 adverse events (number of patients, temozolomide group vs radiotherapy group) were lymphopenia 46 vs 1, infection 35 vs 23, elevated liver enzymes 30 vs 16, thromboembolic events 24 vs 8, neutropenia 16 vs 2 and thrombocytopenia 14 vs 4 [40]. Monitoring as in the temozolomide “Common safety considerations” [27]. For MGMT-unmethylated tumors, the EANO guideline recommends short-course radiotherapy alone (next regimen) [3]. Dose source: trial abstracts [40, 41].
Short-course radiotherapy alone in older adults (Nordic)
Newly diagnosed glioblastoma in older patients who are not candidates for combined treatment, with an MGMT-unmethylated tumor; Nordic: age 60 years or older
Newly diagnosed glioblastoma in older patients who are not candidates for combined treatment, with an MGMT-unmethylated tumor [3]; Nordic: age 60 years or older [41]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Short-course (hypofractionated) radiotherapy | 34 Gy in 3.4 Gy fractions | External beam radiotherapy | Over 2 weeks |
TTFields + maintenance temozolomide (EF-14)
Newly diagnosed glioblastoma after completion of chemoradiotherapy with temozolomide, without disease progressionEach drug’s schedule in the table
Newly diagnosed glioblastoma after completion of chemoradiotherapy with temozolomide, without disease progression
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| TTFields (200 kHz alternating electric field) | Via 4 transducer arrays on the shaved scalp, connected to a portable device | On the scalp | At least 18 hours a day, continuously |
| Temozolomide | 150 to 200 mg/m² once daily | Oral | Days 1 to 5, every 28 days |
Mild to moderate skin irritation under the arrays occurred in 52% of patients; systemic adverse events occurred in 48% vs 44% [7]. Temozolomide monitoring as in the “Common safety considerations” [27].
Evidence: EF-14 (2017)
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Per the lomustine FDA label [28], these points apply to all lomustine-containing regimens (the two regimens below and PCV):
- Prescribe and dispense only one dose per cycle (taking more than the recommended dose can be fatal).
- Delayed myelosuppression (4 to 6 weeks after the dose), which is also cumulative: weekly blood counts for at least 6 weeks after each dose; delay the next dose until platelets recover to 100,000/mm³ or more and white blood cells to 4000/mm³ or more.
- Dose reduction based on the nadir of the previous cycle: white blood cells 2000 to 2999 or platelets 25,000 to 74,999 → reduce by 30%; white blood cells below 2000 or platelets below 25,000 → reduce by 50%.
- Lungs: pulmonary function tests before treatment and frequently during it (risk of pulmonary fibrosis; discontinue permanently if fibrosis develops).
- Round the dose to the nearest 10 mg.
For physicians
Recurrent or progressive glioblastoma
Lomustine (recurrent glioblastoma)
Recurrent or progressive glioblastoma after chemoradiotherapy; the most commonly used systemic therapy and the comparator arm of recent trialsCycle length: Every 6 weeks
Recurrent or progressive glioblastoma after chemoradiotherapy; the most commonly used systemic therapy and the comparator arm of recent trials
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Lomustine | FDA label: 130 mg/m² (100 mg/m² with compromised bone marrow reserve); in EORTC 26101: 110 mg/m² (maximum 200 mg) | Oral | A single dose on day 1; do not repeat for at least 6 weeks |
Lomustine + bevacizumab (EORTC 26101)
First progression of glioblastoma at least 3 months after chemoradiotherapy; no prior bevacizumab or nitrosoureaEach drug’s schedule in the table
First progression of glioblastoma at least 3 months after chemoradiotherapy; no prior bevacizumab or nitrosourea [36]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Lomustine | 90 mg/m² (maximum 160 mg); in the absence of hematologic toxicity above grade 1 in the first cycle, 110 mg/m² (maximum 200 mg) from the second cycle | Oral | Day 1 every 6 weeks |
| Bevacizumab | 10 mg/kg | IV | Every 2 weeks |
Improved progression-free survival but not overall survival [23]. The FDA-labeled bevacizumab dose in recurrent glioblastoma is 10 mg/kg every 2 weeks; do not give it for at least 28 days before and after major surgery; monitor blood pressure and urine protein; discontinue for grade 3 to 4 hemorrhage, gastrointestinal perforation, severe arterial thromboembolism or posterior reversible encephalopathy syndrome (PRES) [29]. Lomustine points as in the “Common safety considerations” [28]. Dose source: protocol NCT01290939 [36].
Evidence: EORTC 26101 (2017)
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
IDH-mutant gliomas (astrocytoma and oligodendroglioma)
Radiotherapy followed by PCV (RTOG 9802)
High-risk grade 2 glioma (younger than 40 years with subtotal resection or biopsy, or 40 years or older); per the guidelines, the preferred regimen for grade 2 and 3 oligodendroglioma when treatment is neededCycle length: PCV every 8 weeks
High-risk grade 2 glioma (younger than 40 years with subtotal resection or biopsy, or 40 years or older); per the guidelines, the preferred regimen for grade 2 and 3 oligodendroglioma when treatment is needed [3, 12, 21]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Radiotherapy | |||
| Radiotherapy | 54 Gy in 30 fractions of 1.8 Gy | External beam radiotherapy | Over 6 weeks |
| Then 6 cycles of PCV | |||
| Lomustine (CCNU) | 110 mg/m² | Oral | Day 1 |
| Procarbazine | 60 mg/m² per day | Oral | Days 8 to 21 |
| Vincristine | 1.4 mg/m² (maximum 2 mg) | IV | Days 8 and 29 |
Toxicity is mainly hematologic: grade 3 neutropenia in 44 and grade 4 in 11 of the 125 patients in the PCV group [12]. Lomustine warnings (delayed myelosuppression, dispensing only one dose per cycle, pulmonary function testing) as in the lomustine “Common safety considerations” in the recurrent glioblastoma regimens [28]. Temozolomide is a reasonable alternative for patients who do not tolerate PCV [21]. Dose source: full text of the article [12].
Evidence: RTOG 9802 (2016)
Radiotherapy followed by 12 cycles of adjuvant temozolomide (CATNON)
IDH-mutant astrocytoma (anaplastic glioma without 1p/19q codeletion), grade 3, and grade 2 when adjuvant chemotherapy is given; WHO PS 0 to 2Cycle length: Every 28 days
IDH-mutant astrocytoma (anaplastic glioma without 1p/19q codeletion), grade 3, and grade 2 when adjuvant chemotherapy is given; WHO PS 0 to 2 [13, 21]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Radiotherapy | |||
| Radiotherapy | 59.4 Gy in 33 fractions | External beam radiotherapy | Daily |
| Adjuvant: starting 4 weeks after the end of radiotherapy | |||
| Temozolomide (cycle 1) | 150 mg/m² once daily | Oral | Days 1 to 5 |
| Temozolomide (cycles 2 to 12) | 200 mg/m² if there was no or minimal toxicity in cycle 1 | Oral | Days 1 to 5 |
Temozolomide concurrent with radiotherapy (75 mg/m² daily) gave no significant benefit; the benefit came from adjuvant temozolomide [13]. Blood count monitoring, dose reduction and liver tests for temozolomide as in the temozolomide “Common safety considerations” in the glioblastoma regimens [27]. Dose source: [27, 37].
Evidence: CATNON (EORTC 26053 (2026), CATNON (EORTC 26053-22054) (2021)
Vorasidenib (INDIGO)
Grade 2 astrocytoma or oligodendroglioma with an IDH1 or IDH2 mutation, after surgery (biopsy, subtotal or gross total resection), age 12 years or older; in patients in whom radiotherapy and chemotherapy can be deferred
Grade 2 astrocytoma or oligodendroglioma with an IDH1 or IDH2 mutation, after surgery (biopsy, subtotal or gross total resection), age 12 years or older; in patients in whom radiotherapy and chemotherapy can be deferred [22, 30]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Vorasidenib | 40 mg once daily (children aged 12 years and older weighing less than 40 kg: 20 mg) | Oral | Continuously, with or without food |
Hepatotoxicity: liver tests before starting, every 2 weeks for the first 2 months, then monthly for up to 2 years; depending on severity, withhold, reduce the dose or discontinue permanently. Dose reductions (adults and patients weighing 40 kg or more): 20 mg, then 10 mg daily; discontinue permanently if 10 mg is not tolerated. Avoid concomitant strong and moderate CYP1A2 inhibitors, moderate CYP1A2 inducers and smoking; non-hormonal contraception is required. Swallow tablets whole; take a missed dose only if no more than 6 hours have passed [30]. Grade 3 or higher ALT elevation occurred in 9.6% of patients [9].
Evidence: INDIGO (2025), INDIGO (2023)
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Brain metastases: local treatment
Stereotactic radiosurgery (N0574 and JLGK0901)
1 to 3 metastases smaller than 3 cm (N0574); in the JLGK0901 study, up to 10 metastases with the largest lesion smaller than 10 mL and a total volume of no more than 15 mL, KPS 70 or higher
1 to 3 metastases smaller than 3 cm (N0574); in the JLGK0901 study, up to 10 metastases with the largest lesion smaller than 10 mL and a total volume of no more than 15 mL, KPS 70 or higher [17, 18]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| SRS alone (N0574) | |||
| Single-fraction radiosurgery | 24 Gy for lesions smaller than 2 cm; 20 Gy for 2 to 2.9 cm | Radiosurgery | One session |
| JLGK0901 (Gamma Knife) | |||
| Single-fraction radiosurgery | 22 Gy at the margin for lesions smaller than 4 mL; 20 Gy for 4 to 10 mL | Radiosurgery | One session |
| If WBRT is added (N0574) | |||
| Radiosurgery + whole-brain radiotherapy | SRS 22 or 18 Gy (depending on size) + WBRT 30 Gy in 12 fractions | Radiotherapy | WBRT within 14 days after SRS, 5 days a week |
Grade 3 to 4 adverse events of radiosurgery in JLGK0901 occurred in 2 to 3% [18]. If whole-brain radiotherapy becomes necessary, memantine and hippocampal avoidance are recommended (next regimen) [16].
Evidence: N0574 (Alliance) (2016), JLGK0901 (2014)
Memantine with whole-brain radiotherapy (RTOG 0614 and NRG CC001)
Brain metastases when whole-brain radiotherapy is needed; KPS 70 or higher (in RTOG 0614 also MMSE above 18); hippocampal avoidance when there are no metastases within 5 mm of the hippocampus and no hydrocephalus, leptomeningeal metastases or prior WBRT; per the guideline: no hippocampal lesion and a life expectancy of 4 months or more
Brain metastases when whole-brain radiotherapy is needed; KPS 70 or higher (in RTOG 0614 also MMSE above 18) [38, 39]; hippocampal avoidance when there are no metastases within 5 mm of the hippocampus and no hydrocephalus, leptomeningeal metastases or prior WBRT [39]; per the guideline: no hippocampal lesion and a life expectancy of 4 months or more [16]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Memantine: start no later than the third day of radiotherapy | |||
| Memantine | 5 mg in the morning | Oral | Week 1 |
| Memantine | 5 mg twice daily | Oral | Week 2 |
| Memantine | 10 mg in the morning and 5 mg in the evening | Oral | Week 3 |
| Memantine | 10 mg twice daily (20 mg per day) | Oral | Weeks 4 to 24 |
| Whole-brain radiotherapy | |||
| Whole-brain radiotherapy with hippocampal avoidance (NRG CC001) | 30 Gy in 10 fractions | Intensity-modulated radiotherapy (IMRT) | |
| Whole-brain radiotherapy (RTOG 0614) | 37.5 Gy in 15 fractions of 2.5 Gy | External beam radiotherapy | |
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Brain metastases: systemic therapy with intracranial activity
Osimertinib (EGFR-mutant lung cancer)
Metastatic non-small cell lung cancer with an exon 19 deletion or L858R mutation, first line; brain metastases not requiring corticosteroids, with stable neurological statusCycle length: Continuous
Metastatic non-small cell lung cancer with an exon 19 deletion or L858R mutation, first line; brain metastases not requiring corticosteroids, with stable neurological status [31]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Osimertinib | 80 mg once daily | Oral | Continuously, with or without food |
Permanently discontinue for interstitial lung disease; in patients with a history of or predisposition to QTc prolongation, or taking QTc-prolonging drugs, monitor the ECG and electrolytes; assess LVEF in patients with cardiac risk factors; refer patients with symptoms of keratitis to an ophthalmologist [31]. In FLAURA, the comparator was gefitinib 250 mg or erlotinib 150 mg daily [31].
Trastuzumab deruxtecan (DESTINY-Breast12)
Advanced HER2-positive breast cancer that has progressed after at least one anti-HER2 regimen, no more than 2 prior lines in the metastatic setting, no prior tucatinib, ECOG 0 to 1; stable or active brain metastases (untreated ≤2 cm or progressing after local treatment) without an immediate need for local treatmentCycle length: Every 3 weeks
Advanced HER2-positive breast cancer that has progressed after at least one anti-HER2 regimen, no more than 2 prior lines in the metastatic setting, no prior tucatinib, ECOG 0 to 1; stable or active brain metastases (untreated ≤2 cm or progressing after local treatment) without an immediate need for local treatment [25]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Trastuzumab deruxtecan | 5.4 mg/kg (first infusion over 90 minutes, then 30 minutes if tolerated) | IV | Day 1 |
In the trial, dexamethasone up to 3 mg per day was allowed, and intervals of at least 7 days from radiosurgery and at least 21 days from WBRT were required [25]. Do not substitute for trastuzumab or trastuzumab emtansine; premedicate for nausea and vomiting; permanently discontinue for grade 2 or higher ILD; blood counts before each dose and LVEF before starting and periodically [33]. ILD/pneumonitis occurred in 16% of patients with brain metastases [25].
Evidence: DESTINY-Breast12 (2024)
Tucatinib + trastuzumab + capecitabine (HER2CLIMB)
Metastatic HER2-positive breast cancer previously treated with trastuzumab, pertuzumab and trastuzumab emtansine; brain metastases (even untreated or progressing) with stable neurological status and no immediate need for radiotherapy or surgery; no leptomeningeal involvementEach drug’s schedule in the table
Metastatic HER2-positive breast cancer previously treated with trastuzumab, pertuzumab and trastuzumab emtansine; brain metastases (even untreated or progressing) with stable neurological status and no immediate need for radiotherapy or surgery; no leptomeningeal involvement [32]
Before prescribing: Common safety considerations Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Tucatinib | 300 mg twice daily | Oral | Continuously, about 12 hours apart |
| Trastuzumab | Loading dose 8 mg/kg on day 1 of cycle 1 (if needed), then 6 mg/kg; or 600 mg SC | IV or SC | Day 1, every 21 days |
| Capecitabine | 1000 mg/m² twice daily | Oral | Days 1 to 14, every 21 days |
Tucatinib: severe diarrhea may occur (antidiarrheal treatment); ALT, AST and bilirubin before starting and every 3 weeks; 200 mg twice daily in severe hepatic impairment [32]. Capecitabine: before starting, test for DPYD gene variants (DPD deficiency carries a risk of severe and fatal toxicity) unless treatment is urgently needed; reduce the dose by 25% for creatinine clearance 30 to 50 mL/min, and no dose has been established below 30; take within 30 minutes after a meal [34]. Dose source: tucatinib label [32].
Evidence: HER2CLIMB (2020)
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Scientific evidence
Key studies
10 itemsShort-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma
Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial
Concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): final and exploratory analyses of a randomised, open-label, phase 3 trial
Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial
Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study
Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial
Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma
Lomustine and Bevacizumab in Progressive Glioblastoma
Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma
Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma
Clinical guidelines
6 itemsTherapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline
Glioblastoma in adults: A Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions
EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood
Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline
EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours
EANO guideline on the diagnosis and management of meningiomas
References
41 referencesShow all references, 23 with a study cardClose the reference list
Numbers in the text, such as [1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.
- 1
- 2
- 3
- 4Glioblastoma in adults: A Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions
- 5
- 6
- 7
- 8
- 9
- 10Vorasidenib in IDH1-mutant or IDH2-mutant low-grade glioma (INDIGO): secondary and exploratory endpoints from a randomised, double-blind, placebo-controlled, phase 3 trial
- 11
- 12
- 13
- 14
- 15EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours
- 16
- 17
- 18
- 19CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer
- 20Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial
- 21
- 22
- 23
- 24
- 25
- 26EANS-EANO guidelines on the extent of resection in gliomas
- 27
- 28
- 29AVASTIN (bevacizumab) injection, for intravenous use: Prescribing Information
- 30
- 31
- 32
- 33ENHERTU (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use: Prescribing Information
- 34XELODA (capecitabine) tablets, for oral use — Prescribing Information
- 35
- 36
- 37Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study
- 38
- 39
- 40
- 41
This page is based on reputable scientific sources and was last updated on 21 October 2026. The content of this website is for educational and informational purposes only and does not replace consultation, diagnosis or treatment by a specialist physician. Consult your treating physician about any treatment decision.