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Central nervous system gliomas – 2017

UPDATED JULY 2017

1. GENERAL INFORMATION

1.1 What is the disease and how is it treated?

What are central nervous system gliomas?
Gliomas are malignant tumours stemming from glial cells, a particular kind of cells that surround nerve cells, protecting and nourishing them. Gliomas may be classified into three categories on the basis of the cell type from which they stem: astrocytomas, ependymomas, and oligodendrogliomas.

How do these gliomas manifest themselves?
Symptoms vary depending on the type, size, location, and malignancy of the tumour.
Astrocytomas: the most common early symptoms are headaches, seizures, memory loss, and changes in behaviour.
Ependymomas: in babies, one of the first symptoms may be an increase in head size. Irritability, sleeplessness, and vomiting may follow. In older children and adults, nausea, vomiting, and headache are the most common symptoms.
Oligodendrogliomas: since these tumours generally grow slowly, they are often diagnosed after years from the disease’s actual onset. The most common symptoms are seizures, headaches, and personality changes.

What are the causes of the disease?
Radiation exposure has been considered an increased risk factor for brain tumours. However, epidemiological studies have failed to unequivocally prove it.
A possible genetic origin is not excluded, since recurrence among relatives seems to be higher and some genetic signatures have been identified.

Is it a frequent disease?
As a whole, gliomas are rare: about 5 cases per 100,000 persons per year. The frequency depends on the type of tumour.
Astrocytomas: their frequency (5 cases per 100,000 persons per year – RARECAREnet) is higher in males than in females, and increases with age.
Ependymomas: they are the least common (0.2 cases per 100,000 persons per year), but the most frequent in children.
Oligodendrogliomas: is very uncommon with an incidence rate of 0.4 per 100,000 people per year

How is it diagnosed?
The best way to diagnose gliomas is with brain imaging. A magnetic resonance imaging (MRI) scan with the use of a contrast medium is the standard exam.

How is it treated?
Surgical resection is the first treatment option. Chemotherapy has been selected as an initial treatment for patients with unresectable tumours or large residual tumours after surgery. Today an association between radiotherapy followed by chemotherapy seems to promise an improvement in overall survival.

2. WHAT IS IT, HOW DOES IT OCCUR, HOW IS IT DIAGNOSED?

2.1 What are central nervous system gliomas?

Glia is the supportive (“gluey”) tissue of the brain, which helps to keep the neurons in place and functioning well. Glia comprises three types of cells that can produce tumours: astrocytes (producing astrocytomas), oligodendrocytes (oligodendrogliomas), and ependymal cells (ependymomas).
Tumours made of a mixture of these cells are called mixed gliomas.

2.1.1 Disease stats

Frequency
As a whole, gliomas are rare: they count about 5 cases per 100,000 persons per year. But each type of tumour has a characteristic incidence.
Glioma:  every year, about 5 persons out of 100,000 are diagnosed with an astrocytoma (RARECAREnet); its incidence is higher in males than in females (5.4 vs. 3.6, respectively), and increases with age, from 0.9 in children to 12.1 in the elderly (aged 65+ years).
Ependymoma: it is the least common glioma (0.2/100,000 – RARECAREnet), but it is the more frequently diagnosed glioma in children. Its incidence is significantly higher in males than in females (about +15%).

Geographical distribution
Glioma: the highest rates are found in the North of Europe, UK, and Ireland (5.7/100,000) and the lowest in the South and East of Europe (3.9 and 3.7, respectively).
Ependymoma: the highest rates are in the North of Europe (0.33), the lowest in Eastern Europe (0.16).

Prevalence
At the beginning of 2008, in Europe more than 154,000 persons with rare CNS gliomas were estimated to be alive (prevalent cases): over 100,000 had been diagnosed with an astrocytoma (31% of them had survived 5 years or less after diagnosis, about 50% had survived 15 years or more after diagnosis), 19,000 with an ependymoma (21% of them had survived 5 years or less after diagnosis, 45% had survived more than 10 years after diagnosis), and about 30,000 with an oligodendroglioma.

Survival
Astrocytoma. Prognosis is generally poor: in Europe, less than half of the persons diagnosed with an astrocytoma between 2000 and 2007 survived 1 year after the diagnosis (1-year survival: 41%); this percentage decreased to 18% and 15% for 3- and 5-year survival, respectively. Five-year survival is significantly higher in children (<15 years) and young adults (15-24 years): 58% and 55%, respectively. For glioblastoma multiforme, the more lethal type of astrocytoma, 5-year survival is 2.7%.  Prognosis is also poor for anaplastic glioma (another subset of astrocytic tumours): 15.8% at 5 years.
Ependymoma. Prognosis of ependymoma is generally good. Based on diagnoses made in Europe between 2000 and 2007, 1-, 3-, and 5-year survival was 87%, 77%, and 73%, respectively.
Oligodendroglioma. Intermediate survival figures are for oligodendroglioma, 1-, 3-, and 5-year survival figures were 80%, 62%, 52%, respectively .

2.2 Risk factors

Gliomas are strictly related to alterations in cellular DNA, but only 5% of gliomas have a genetic origin. The rest comes from exposure to risky environments.
Therapeutic ionising radiation was once considered an increased risk factor of developing brain tumours. However, more recent epidemiological studies found a significant increased risk only for people exposed to computed tomography scans in childhood and adolescence, with a dose-response relationship and greater risk after exposure at younger ages.
Gliomas are more frequent among professionals dealing with electrical or electronics devices, or workers exposed to organic chemicals in petroleum refining and chemical manufacturing.
The potential association between mobile phone use and brain tumours remains controversial. Long-term exposure (>10 years) and heavy use (>897 hours lifelong cumulative duration) seem to increase the risk. The potential risks seem to be higher when the long-term heavy use happens during childhood and adolescence.
The growth of non-cancerous tumours in the nervous system, a hereditary disorder called neurofibromatosis type 2, seems to be associated with an increased incidence of ependymomas. However, the causes of childhood ependymoma are unknown. Maternal consumption of vitamin supplements during pregnancy seems to counteract the development of brain tumour during childhood.

2.3 What are the symptoms?

The symptoms of glioma vary by tumour type as well as size, location, and rate of growth.
The most common symptoms are headache, nausea, or vomiting. Patients can also experience seizures, memory loss, physical weakness, loss of muscle control, visual symptoms, language problems, cognitive decline, and personality changes.
As the tumour continues to grow and destroys brain cells, compresses parts of the brain, and causes swelling in the brain and pressure in the skull, symptoms may worsen or change.

2.4 Diagnosis

Often, the diagnosis of a brain tumour is made several months after the appearance of initial symptoms, especially in patients with intermittent headaches or “unclear” cognitive or motor deficit.
Brain imaging has a central role in brain tumour diagnosis. Magnetic resonance imaging (MRI), has been recognized as a standard procedure for diagnosis and follow-up in patients with brain tumours. The extension of neoplastic tissue can be viewed through magnetic resonance spectroscopy (MRS). Recently the combination of clinical, genetic, and imaging data has improved prognosis, connecting shape and localization with molecular mechanisms.  It is an important advancement in the identification of potential therapeutic targets.
Surgical exploration and biopsy with subsequent histological analysis of the tissue are essential for the selection of appropriate treatment. The research of molecular markers in the biopsy sample can help assess the type of tumour.

2.4.1 Do these tests involve any risks for patients?

Generally, these exams are well tolerated. Biopsy may require the use of a local or general anaesthetic. Usually, and in order to obtain clearer images, a dye (or contrast medium) is injected just before performing an MRI scan. Anaesthetics and contrast media could give rise to side effects.

3. HOW ARE GLIOMAS TREATED?

3.1 Astrocytoma

Surgery is the first choice treatment for these tumours.
Radiotherapy is usually employed after surgery, in adults and older children, in case the tumour cannot be completely removed, to keep under control the remaining part (residual tumour). In the presence of inoperable astrocytomas, radiotherapy can substitute for surgery.
Chemotherapy may be recommended in some cases immediately after radiotherapy or when, and if, the tumour recurs. It may also be used to delay radiation in young children.

3.2 Ependymoma

Surgery is the standard treatment for ependymomas. Resection normally is not complete because these tumours usually grow in highly specialized areas of the central nervous system.
Radiotherapy is usually recommended for older children and adults after surgery, in some cases even if the tumour was completely removed.
Chemotherapy may be used to treat tumours that have grown back after radiation therapy, or to delay radiation in infants and very young children.

3.3 Oligodendroglioma

Surgery is the standard treatment for oligodendroglioma, if the tumour is accessible; it may be followed by radiotherapy, especially if part of the tumour has not been removed.
If the tumour is not accessible, a biopsy is necessary in order to confirm the diagnosis and determine the tumour grade.
Some oligidendrogliomas may be treated with a combination of radiotherapy and chemotherapy.
Recurrent low-grade oligodendrogliomas can be treated with surgery, radiation therapy (if not given initially), and chemotherapy.

3.4 Treatments of symptoms

Seizures: antiepileptic prophylaxis treatment is required in patients with brain tumours with a history of seizures. However, approximately 20% of patients treated with anti-epileptic drugs experience serious adverse events, due to the interaction of antiepileptic drugs with chemotherapy.
Thrombosis: brain cancer exposes patients to a high risk (about 30%) of thromboembolic events. The risk is even higher in the post-operative period, in the presence of glioblastoma histology, in patients older than 60 years or in patients undergoing chemotherapy or receiving steroids. Since the usual antithrombotic prophylaxis with low-molecular-weight heparin is not indicated, attention must be given to early adverse signals.
Intracranial pressure and vasogenic oedema can be associated with brain tumours. Steroid therapy could be beneficial to maintain optimum neurologic function, but it can carry side effects, including serious ones.

4. STAGING AND GRADES OF GLIOMA

The stage of a tumour indicates its extension and its spread beyond its site of origin (metastases). It is important in order to choose the most appropriate treatment. Since malignant gliomas do not metastasize and tend to present as a localized brain lesion, no formal staging outside the brain is required unless suspicious symptoms are present.
The grade (indicated by a Roman number, from I to IV) of a tumour refers to the speed at which the tumour may progress and is related to the appearance of cancer cells under the microscope. A low-grade cancer is made of cells looking very much like normal cells, growing slowly and less likely to spread. Highly abnormal cells, which tend to grow quickly and spread, are typical of high-grade tumours. Low-grade tumours usually grow slowly, but may transform into high-grade tumours with time.
Grade I tumours grow slowly and can sometimes be totally removed by surgery, while grade IV tumours are fast-growing, aggressive, and difficult to treat.
The World Health Organization (WHO) classifies gliomas as follows:

Malignant astrocytomas:

  • Grade I gliomas are called pilocytic astrocytomas and are usually seen in children.
  • Grade II tumours are called diffuse astrocytomas and are low grade.
  • Grade III gliomas are called anaplastic astrocytoma. They are considered high grade.
  • Grade IV glioblastoma is considered high grade.

Oligodendroglial tumours:

  • Grade II or low grade oligodendroglioma
  • Grade III or anaplastic oligodendroglioma

Ependymal tumours are classified as ependymoma and anaplastic ependymoma, with the latter being more aggressive.

5. PROGNOSIS

5.1 General information

Prognosis indicates the likelihood that a treatment will be successful. It is a statistical measure obtained from different studies that observe the progress of the disease in a high number of patients. Generally, it is referred to as the percentage of survival at 5 or 10 years since the start of treatment: this indicates the percentage of patients that are still alive after 5 or 10 years since the beginning of therapy, as demonstrated in large studies.
It is important to remember that these statistics merely provide an indication: no doctor is able to predict exactly what the outcome of treatment in an individual patient will be, nor how long the patient will live, as prognosis depends on several factors related to the individual patient.

5.2 Prognosis for gliomas

Prognosis for gliomas is frequently defined by the malignant grade or the genetic features of the tumour.
Astrocytomas: prognosis is generally poor. In Europe, the survival rate is 41% for the first year but then drops to 18% and 15%, respectively, for 3- and 5-year survival. Age negatively affects the survival rate.
In particular, only 2.7% of patients affected by glioblastoma multiforme (the most malignant of all astrocytic tumours) survive 5 years after diagnosis. Despite recent advancements in therapeutic management, the median survival period for patients with glioblastoma multiforme remains less than 18 months.
Prognosis is poor even for anaplastic gliomas (highly aggressive tumours involving astrocytes or oligodendroglia, or both) because they frequently evolve from a less malignant precursor lesion and may further transform into glioblastomas: 15.8% at 5 years.
Ependymomas: prognosis is generally good. Five-year survival is 89%, 94%, and 90% in children (<15), young adults (15-24), and adults (25-64), respectively. For older patients (65+ years), survival decreases to 67%.

6. WHAT TO DO AFTER TREATMENT

6.1 Late sequelae

Memory loss, apathy, concentration difficulties and personality changes are extremely common in long-term survivors of brain tumours. Several factors, some of which related to treatment, may influence the severity of these symptoms.
Surgery, for example, may contribute to cognitive deficits. Radiotherapy may induce neurocognitive and neurobehavioural alterations or increase the risk of radionecrosis, while a variety of neurological complications (i.e., acute and chronic encephalopathy, insomnia, confusional state) have been associated with chemotherapy.
A therapy based on acetylcholinesterase inhibition has been successfully tested to palliate neurocognitive symptoms.
Necrosis induced by radiotherapy can be treated with surgery, bevacizumab, or hyperbaric oxygen.
For the treatment of seizures, which may have a great impact on the quality of life even in patients with well-controlled tumours, newer anti-epileptic drugs with fewer side effects are now available.

6.2 Follow-up

Follow-up should be tailored to the individual patient, on the basis of previous treatment and tumour grade.
Clinical evaluation, including a careful neurological examination and MRI scans after completion of a radiotherapy and chemotherapy programme, should be performed every 3 months.
Venous thrombotic events occur frequently and patients must be monitored. Furthermore, painkillers, corticosteroids, and antiseizure medications are usually administered to palliate late effects and laboratory tests are recommended to assess drug toxicity.

7. WHAT TO ASK DOCTORS

General questions

• May I phone you? What is the best time? If you are not available, may I ask for other specialists? Whom specifically?
• What leaflets, books, or websites could I read to learn more about central nervous system gliomas?
• Is there a patient association I could contact?
• Do you have special advice regarding nutrition?
• Does glioma run in families? Are my children at risk of getting it?

Diagnosis and exams

• What tests are you going to do?
• What are you looking for?
• What should I do in preparation for a CT or MRI scan?
• How long will the exam take?
• Is it painful?
• Will I be asleep?
• Should someone be with me?
• Are CT or MRI dangerous because of radiation exposure?
• Is biopsy painful? Is it performed under general or local anaesthesia?
• How long will it take to confirm diagnosis?

Treatment

• Do I need a highly specialized centre?
• What type of treatment do I need?
• Is there any choice of treatments?
• What are the risks and benefits of the treatments?
• What are the side effects?
• How can I help to reduce the side effects?
• What signs should I recognize so that I can tell the doctor and ask if the approach needs to be changed?
• Is surgery performed under general or local anaesthesia? Will it be painful? What should I do before and after surgery?
• What are the possible side effects of therapy?
• During treatment should I take special precautions or change my habits?
• Is there any behaviour I could adopt to improve my prognosis?
• What late effects could treatment have?
• What supportive therapy is suggested during the treatment?
• How will my treatment affect me?
• Will I ever get back to normal, or will I have any long-term effects?
• Will I need a special diet? Is there anything I shouldn’t eat?
• Will I be able to go back to work?
• Could the cancer recur