Recognizing and treating gliomas using first-line therapies

Gliomas are brain tumors arising from the supporting cells of the brain. The majority arise from astrocytes and are known as astrocytomas. They will grow within the brain tissue itself and are considered intrinsic (e.g., intra-axial tumors).

Astrocytomas grow diffusely and spread far distances from their margins as seen on modern imaging. They frequently invade eloquent areas of the brain—areas involved in clearly identifiable functions such as speech, movement, sensation, and vision. For this reason, total resection is impossible without horrific neurological injury.

Astrocytoma growth can be compared to the growth of a weed. The tumor is akin to the part of the weed that is above the ground. However, as is true with many weeds, there is an elaborate root system that extends out into the surrounding brain tissue. These extensions radiate well beyond the tumor—even as far as the other side of the brain.

Astrocytomas are currently categorized by their histology into four grades (I–IV). At some point, they will likely be more effectively subtyped by various biomarkers.

All astrocytoma grades above grade I signify a fatal diagnosis. Grade I astrocytomas, commonly seen in children, can often be removed surgically with good long-term results. However, this is not always the case, and some will require aggressive adjunctive management such as chemotherapy and radiation. Some grade I astrocytomas still prove to be fatal.

Grade II astrocytomas often eventually degenerate into grade IV tumors. Some continue to spread into vital areas of the brain without this malignant degeneration. Median survival after diagnosis with grade II astrocytoma is around ten years.

Median survival for patients with grade III astrocytomas is currently three years, despite aggressive management.

The most common astrocytoma is grade IV astrocytoma, also known as glioblastoma multiforme (GBM). These tumors will almost always result in the patient’s death within one to two and a half years of diagnosis—no matter the management strategy. If GBM is not treated, death usually occurs within six to ten weeks of diagnosis.

Despite their inherent malignancy, gliomas seldom metastasize. This means that the tumors remain contained in the central nervous system. They result in death from the invasion of vital regions of the brain or from increased intracranial pressure.

Signs and symptoms

Patients with glioblastoma (Grade IV astrocytoma) often present with headaches, seizures, or progressive neurological deficits (depending on the location of the tumor). Patients may also present with progressive cognitive loss.

Although headaches are common in glioblastoma patients, they are often nonspecific. Nonetheless, it is common for definitive computed tomography (CT) or magnetic resonance imaging (MRI) to be indicated solely on a patient’s complaints of intensifying headaches.

Patients may experience symptoms of increased intracranial pressure (e.g., headaches, nausea, vomiting, and lethargy) or progressive neurological deficits (e.g., visual loss, aphasia, and hemiparesis). The neurological deficits will correlate with the region of the affected brain.

On T1-weighted post-contrast MRI images, a high-grade astrocytoma generally appears as an irregular and peripherally enhancing mass. The astrocytoma is often large, ugly, and causes significant mass effect and brain shift.

On T2-weighted MRI scans, high-grade astrocytomas often have a significant amount of surrounding high signal which signifies brain edema.

Further MRI sequences can sometimes distinguish these differentials, but a surgical biopsy is usually required for a definitive diagnosis. Most times, a surgical biopsy means an excisional biopsy that involves an aggressive removal of the visible tumor. The tumor is then sent to pathology for evaluation.

Obtain medical history and perform a neurological exam

On the initial evaluation of a patient with a newly discovered intrinsic brain mass, obtain a good medical history and look for evidence of cancer or infection.

Perform a neurological exam, particularly noting the degree of disability. You might perform a fundoscopic examination looking for papilledema (which signifies increased intracranial pressure).

Order additional imaging

Obtain CT of the chest, abdomen, and pelvis to rule out a primary tumor elsewhere in the body. Keep in mind that if there is more than one mass in the brain, the tumor is more likely metastatic (although multi-focal gliomas are not a rarity).

Because a definitive diagnosis cannot be made by imaging, do not lay out a prognosis of certain death to the patient. But, acknowledge that the mass could be malignant and could require surgery and additional treatments.

Surgical resection

Current management of grade III and IV gliomas includes surgical resection that is as aggressive as possible while trying to minimize associated neurological deficits. This is always something of a trade-off.

Grade III and IV astrocytomas cannot be totally removed (remember the extensive root system). Nonetheless, the greater the resection of the visible tumor, the better the survival (measured in months), according to our current understanding. So, surgeons will seek to remove as much tumor as possible—essentially chasing it into normal brain tissue.

More extensive resections are more likely to affect brain function (particularly when adjacent to eloquent regions). Push the surgery too far, and a patient can be neurologically devastated. However, do a minimal resection and the patient will succumb to their disease sooner, have severe postoperative swelling, and possibly die in the perioperative period. One way or the other, the patient will have definitive residual disease. Surgery alone is in no way curative for glioblastoma.

Radiation

After surgery, current recommendations involve a six-week course of focused and whole-brain external beam radiation to near-lethal doses. As a result, these patients cannot receive more radiation therapy in the future, even with tumor recurrence. Stereotactic radiation has been employed instead of whole-beam radiation, but current results are discouraging.

Chemotherapy

Patients with high-grade gliomas (grades III and IV) also undergo a course of chemotherapy. The current chemotherapy of choice is temozolomide which is a generally well-tolerated oral medication.

In relatively high-functioning patients, additional protocoled or experimental therapy at a research center is recommended with the hopes of developing further efficacious agents. However, there is no guarantee that the therapies will result in a better survival rate. Tumor genotyping can lead to improved survivals, sometimes up to two and a half years.

Additional considerations for grade III and IV gliomas

If feasible, a recurrent tumor is sometimes addressed via surgical re-resection. Sometimes, chemotherapeutic agents are directly implanted into the tumor at the time of surgery. Further rounds of standard chemotherapy or protocoled treatments are often initiated.

Stereotactic radiation has also been employed for treating tumor recurrence, although with the same discouraging results seen when treating the primary tumor. In low-functioning patients, aggressive management of tumor recurrence is not indicated.

Various biomarkers are associated with longer survivals, but nonetheless, the majority of patients with high-grade glioma can be expected to succumb to their disease within a few years, and often much sooner.

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