Glioblastoma

Glioblastomas are the most common malignant brain tumors in adults. They arise from the brain’s glial cells, grow along fiber tracts, and thereby spread locally, regionally and supraregionally. Glioblastomas generally do not metastasize (form secondary tumors) outside the nervous system.

According to the World Health Organization (WHO) classification, a glioblastoma is classified as WHO Grade 4 and thus belongs to the highest category of malignancy among brain tumors. The classification is based on histological features such as

• a high rate of cell division
• the presence of necrosis (tissue death)
• increased formation of new blood vessels (vascular proliferation)

In addition, molecular genetic analyses are now performed. These can identify specific alterations, such as methylation of the MGMT promoter. This information has prognostic significance and can influence the decision to pursue certain treatment approaches.

Rare variants of glioblastoma include gliosarcoma, giant-cell glioblastoma, and epithelioid glioblastoma.

Glioblastoma typically occurs in older adults (50–85 years) with an average age of 64 years *. Although glioblastomas can occur in children, they account for only 2.9% of all brain tumors in the 0–19 age group *. 

Overall, these are rare tumors with approx. 3–4 new diagnoses per 100,000 inhabitants per year *. Men are affected 1.5 times more frequently than women.

The symptoms basically depend on the location of the tumor in the brain. The same applies to all brain tumors:

• Epileptic seizures: epileptic activity or hyperexcitability of healthy tissue at the edge of the tumor
• Failures or functional disorders: Impairment of speech, motor function, sensation, vision, calculation, thinking, memory, balance, orientation, mood, behavior, alertness, drive, social behavior, etc. due to pressure of the tumor on neighboring brain structures or ingrowth into the surrounding tissue
• Headaches, nausea, vomiting: an advanced tumor leads to an increase in pressure in the skull
• Nonspecific symptoms: If the tumor grows in functionally silent (non-eloquent) parts of the brain, it may go unnoticed for some time until non-specific symptoms such as changes in personality, fatigue, forgetfulness, disorientation and confusion occur. The symptoms usually last for several weeks to a few months at the time of diagnosis.

The standard therapy for glioblastomas consists of a combination of microsurgical resection, radiotherapy and chemotherapy. 

Surgical resection is a key component of the treatment plan *, *, *, *, *, *, *. The more tumor mass that can be removed, the more favourable the further course of the disease *, *, *, *, *, *, *, *, *. Therefore, a complete tumor resection, which is confirmed by an MRI image, is the goal of the operation. 

Removing the tumor also reduces pressure on the surrounding brain tissue and can thereby alleviate tumor-related symptoms. The removed tumor tissue is then examined histologically and through molecular biology.

Because glioblastomas diffusely infiltrate the brain tissue and grow along the fiber tracts of the white matter, tumor cells that are not visible on imaging remain even after complete removal of the tumor visible on MRI. For this reason, the surgery is followed by radiation therapy and chemotherapy to combat these remaining tumor cells.

According to current studies, it is assumed that at least 80% of the tumor must be removed for the patient to have a survival advantage from the operation.

A clear survival advantage can only be achieved by complete removal of the tumor as verified by MRI *, *.

Therefore, the primary goal of surgery should be the complete removal of the brain tumor, ideally including the infiltration zone visible in the MRI image, and this without causing permanent neurological damage.

Due to the rapid growth of glioblastomas, surgery should be performed promptly. The more time passes, the more tumor cells migrate into the surrounding area. The tumor expands and becomes larger, the surgical risk increases and the possible radicality of the resection decreases. The operation should therefore ideally be performed within 1–2 weeks of diagnosis.

Surgical safety is guaranteed by various innovative techniques. Thanks to precise surgical procedures and extensive intraoperative monitoring, the complication rate of tumor resections is now very low *, *, *, *, *, *, *, *.

Since it is often difficult to distinguish between tumor tissue and healthy brain tissue at the tumor margin, residual tumor tissue may remain despite the use of state-of-the-art surgical techniques.

A follow-up MRI within 24–48 hours shows whether any removable residual tumor is present. In such cases, a second surgery can be performed as early as the following day. At Inselspital, this applies to about 5–10% of patients. Our experience shows that the residual tumor can usually be completely removed during this procedure and that the second surgery is well tolerated. *

Following the histological examination of the excised tissue, the next steps are discussed at our weekly interdisciplinary tumor board. This involves collaboration among specialists in neurosurgery, radiation oncology, oncology, neuropathology, neuroradiology, and neurology. The team is supplemented by internationally renowned neuro-oncology experts who regularly join the conference via videoconference.

Neurological rehabilitation may be beneficial in cases of neurological deficits, but it should not delay further tumor treatment. Patients without neurological deficits generally do not require inpatient rehabilitation.

Older patients (over 70 years of age) represent a special case in treatment. In order to avoid putting too much strain on older patients, they are treated according to a shortened schedule. The radiotherapy is then usually carried out in 15 sessions up to a total dose of 40 Gy *.

Alternatively, for patients in poorer general condition, either radiation therapy alone or chemotherapy alone may be administered – depending on the tumor's molecular markers *.

Temozolomide (Temodal®) is the primary chemotherapeutic agent used in the treatment of glioblastoma *, *. It is administered daily during radiation therapy and then continued as maintenance therapy. If well tolerated, treatment typically consists of six cycles. This is followed by regular follow-up MRI scans.

Temozolomide is generally well tolerated. Nausea and fatigue are common. A rare but serious side effect is suppression of blood cell production in the bone marrow.

For patients with clear MGMT promoter methylation and good overall health, we additionally use lomustine and treat according to the lomustine/temozolomide regimen.

This approach is based, among other things, on the results of the NOA-09 study. In this randomized Phase III study, the combination of lomustine and temozolomide demonstrated longer overall survival than temozolomide alone in patients with MGMT-methylated glioblastoma. However, due to the relatively small study population, the results should be interpreted with caution. *, *, *, *

Immunotherapy is an important area of research in the treatment of glioblastoma. The goal is to specifically activate or support the body’s own immune system so that it can better recognize and fight tumor cells.

Glioblastoma is considered an immunologically “cold” tumor: the tumor microenvironment contains only a few lymphocytes, but numerous myeloid cells that have an immunosuppressive effect. This hinders an effective immune response and explains why immunotherapies to date have not yet achieved a breakthrough. Various approaches are therefore being intensively researched:

In recent years, methadone has repeatedly been discussed as a potential treatment for glioblastoma. Despite reports in online forums and the media, there is as of yet no scientifically substantiated evidence of methadone’s effectiveness in treating glioblastoma. Methadone is therefore not part of the established standard of care.

Laboratory and animal studies show that the approved antidepressant Vortioxetine can inhibit glioblastoma cells. It is currently unclear whether this effect will also be confirmed in patients. Further studies are planned to investigate its therapeutic potential. *

Current research is exploring personalized treatment strategies that specifically target molecular alterations in glioblastoma. A recently published study showed a significant survival benefit in patients with an activated mTOR signaling pathway who were treated with temsirolimus. Further studies on this topic are in the works. *

In the event of recurrence, surgical resection of the recurrent tumor should always be considered. However, a higher complication rate is to be expected with recurrence operations. In this case, survival time can only be favorably influenced if the functions that ensure a good quality of life for the patient are maintained.

In addition to surgery, further radiotherapy and/or chemotherapy can often be carried out. In patients with MGMT promoter hypermethylation and a relapse during the treatment break, the DIRECTOR study was able to prove that these patients benefit again from treatment with Temodal *.

A standardized second-line chemotherapy does not yet exist. We decide on this as part of our interdisciplinary tumor board at the Inselspital. Important factors in the decision are the different molecular characteristics of the tumor and a detailed genetic analysis of the tumor's driving mutations. In discussions with renowned experts, who are connected to the tumor board via conference call, it may then be possible to identify and use drugs that have been successful in other tumor types with the same mutations.

The prognosis for glioblastoma is influenced by numerous factors. The available findings are based primarily on average values from large patient cohorts and therefore do not allow for a reliable prediction of the individual course of the disease. The factors that can influence the prognosis are explained below.

Long-term survivors are defined as patients who live for more than five years after diagnosis. With current standard treatment, approximately 10% of those affected achieve this *. However, the likelihood depends on various factors. For example, the rate is 17% among patients under 50 years of age, compared to 6.4% among those over 50. A younger age, good overall health, MGMT promoter methylation, and complete tumor resection are associated with longer survival *, *, *. 

Although many long-term survivors exhibit cognitive deficits, a good quality of life can still be achieved in most cases  *, *. It is important to note that recurrences also occur in long-term survivors; therefore, one cannot speak of a cure *.