Brain Tumor Treatment by Grade and Type

Most cancers are staged by how far they have traveled. Brain tumors are not, and the reason in NCI's summary is blunt.

Metastatic spread rarely applies to central nervous system tumors. NCI's stated reason is stark. Most people with these tumors do not live long enough to develop metastatic disease. So the T, N and M framework used elsewhere has little to describe.

What replaces it is grade, tumor type, and where in the brain the tumor sits.

NCI describes the grading scale as a malignancy scale based on the histological features of the tumor:

• Grade I. Low proliferative potential. Often discrete. Cure is possible with surgical resection alone.
• Grade II. Generally infiltrating, with low mitotic activity. It recurs more often than grade I after local therapy. Some types progress to higher grades.
• Grade III. Clear signs of malignancy under the microscope. Odd-looking nuclei. More cells dividing. Anaplastic and infiltrative. Usually treated with aggressive adjuvant therapy.
• Grade IV. Mitotically active, prone to necrosis, with rapid progression before and after surgery, and fatal outcomes. Also treated aggressively.

One caveat is visible in the source itself. The grade table in NCI's summary is reprinted from the 2007 WHO classification, which graded tumors by appearance alone. WHO's 2021 classification of central nervous system tumors does it differently: diagnosis and grade are set by the microscope and the molecular findings together, and entities are named accordingly — for example IDH-mutant astrocytoma, oligodendroglioma with IDH mutation and 1p/19q codeletion, or glioblastoma, IDH-wildtype. Your pathology report is likely to use that newer language. The molecular section of NCI's summary is closer to it than the grade table is, so when an older grade number and a newer molecular report seem to disagree, the molecular diagnosis is the one to ask about.

Four results carry most of the weight.

IDH1 and IDH2. Most grade II and III diffuse gliomas carry a variant at the R132 position of IDH1. A few carry it in the matching codon of IDH2. So do 5% to 10% of glioblastomas. NCI calls an IDH variant a strong prognostic factor. Survival is significantly longer, whatever the grade or the histological subtype. About 90% of these produce an R132H substitution. A specific antibody detects it, so a rapid stain can settle the question.

1p/19q codeletion. NCI says this predicts response to chemotherapy. One analysis covered 318 people with low-grade glioma. Those with IDH variants plus 1p/19q codeletion had the best prognosis. Those with wild-type IDH had the worst, whatever they were given.

MGMT promoter methylation. In that same analysis, the MGMT promoter was methylated in all 45 tumors with IDH variants and 1p/19q codeletion, in 86% of those with IDH variants but no codeletion, and in 56% of the IDH wild-type cases.

BRAF. This one belongs to pilocytic astrocytomas. A duplication at 7q34 makes a KIAA1549::BRAF fusion, found in about 70%. A BRAF V600E variant accounts for another 5% to 9%. In all, RAF alterations occur in roughly 80% of these tumors.

NCI states it directly. The standard for newly diagnosed glioblastoma is surgery, followed by radiation therapy with daily temozolomide, followed by six cycles of temozolomide.

The trial behind that assigned 573 people to radiation alone, or radiation with temozolomide. Radiation ran daily over several weeks to the tumor and a margin around it. Temozolomide capsules were taken by mouth every day throughout the radiation, then after a break in repeating cycles of a few days each, at a higher daily amount than during radiation.

Those are the shapes of the schedules, not instructions. Radiation dose, field and margin are planned individually against where the tumor sits and what healthy structures are nearby, and temozolomide is dosed from your body size, your blood counts and how you tolerate the first cycle. If you are taking temozolomide capsules at home, follow the schedule and strength written on your own prescription, and speak to your team before missing or changing a dose.

Overall survival was significantly better with the combination. The hazard ratio for death was 0.6, and 3-year overall survival was 16.0% against 4.4%.

The 60 Gy figure has its own trial behind it. It was compared with 45 Gy in 25 fractions over 4 weeks. Median survival was 12 months against 9. NCI calls 60 Gy the accepted standard dose for malignant gliomas.

This part matters as much as the part that worked.

• Bevacizumab added to standard therapy. Two large randomized trials tested it, RTOG 0825 and AVAglio. Neither improved overall survival. Median survival was around 16 to 17 months in every arm. Median progression-free survival was longer with bevacizumab in both, though in RTOG 0825 that result did not reach the trial's own significance threshold. In AVAglio, people on bevacizumab stayed functionally independent longer. They also started steroids later, at 12.3 months against 3.7. The two trials disagreed on quality of life and thinking.
• Dose-dense temozolomide. RTOG 0525 randomly assigned 833 people to the standard 5-day schedule or a 21-day schedule. Median overall survival was 16.6 months against 14.9, with no statistically significant difference.
• Carmustine wafers at surgery. In 240 people, median survival was 13.8 months with wafers against 11.6 with placebo wafers.

For high-risk, low-grade glioma, NCI reports that adding procarbazine, lomustine and vincristine to radiation after surgery extends survival. The same holds for anaplastic oligodendroglial tumors.

Radiation and temozolomide have also been compared head to head. EORTC 22033-26033 enrolled 707 people with grade II glioma. Each had at least one high-risk feature. Age over 40. Progressive disease. Tumor larger than 5 cm. Tumor crossing the midline. Or neurological symptoms. At a median 48 months, progression-free survival was 39 months with temozolomide and 46 months with radiation. The difference was not significant.

Seizures are the presenting symptom in roughly 20% of people with tumors above the tentorium. In slow-growing tumors they can come months or years before the diagnosis. Among all people with brain tumors, 70% of those with primary parenchymal tumors develop seizures at some point. So do 40% of those with metastatic brain tumors.

NCI names dexamethasone, mannitol and furosemide as the treatments for the swelling around a tumor. It states that anticonvulsants are mandatory for patients who have had seizures.

• Call 911 or go to an emergency department if a seizure lasts longer than five minutes, or a second seizure begins before recovery from the first, or there have been three or more seizures in 24 hours. Do the same for sudden weakness down one side, or sudden trouble speaking.
• Ring your brain tumor team at once, day or night, if your temperature hits 100.4°F (38°C) or higher while you are on temozolomide, with or without chills. Temozolomide lowers the blood counts that fight infection, and a fever then is a medical emergency, not something to hold until the next clinic day (CDC). If you cannot reach the team quickly, head to an emergency department and tell them you are on chemotherapy.
• Call 911 or go to an emergency department if you have a seizure for the first time.
• Call your care team the same day if you have a headache that is worst on waking and comes with vomiting, or new drowsiness or confusion.
• Call your care team within a day or two if you have missed doses of an anti-seizure drug, or dexamethasone is causing new problems such as high blood sugar, sleeplessness or mood change.

Start with brain tumors, then brain tumor grades and diagnosis and radiation therapy.

• NCI PDQ — Adult Central Nervous System Tumors Treatment (Health Professional Version)
• NHS — Epilepsy
• NCI — Infection and Neutropenia during Cancer Treatment
• CDC — Watch Out for Fever