GLIOBLASTOMA MULTIFORME

WHAT IS A BRAIN TUMOUR?

A brain tumour is a group of cells that grow uncontrollably due to failure of their cell growth-control mechanisms. There are basically two types of brain tumours:

• Primary brain tumours originate in the brain and do not spread. They can be benign (slow-growing) or malignant (rapid and aggressive growth, invading nearby tissues).
• Secondary or metastatic tumours develop elsewhere in the body and spread to the brain through the bloodstream.

Types of primary brain tumours	Types of metastatic (secondary) brain tumours

WHAT IS A GLIOBLASTOMA MULTIFORME?

Approximately 50% of primary brain tumours are gliomas, within which we find astrocytomas. Astrocytomas are graded according to their degree of malignancy (I-IV), the most malignant being the IV, also known glioblastoma multiforme (GBM). This tumour’s growth is so fast that it is near the growth rate of a human foetus. It often originates in the cerebral hemispheres but may also do so in the brainstem, cerebellum, or spinal cord. The extension of GBM to other parts of the organism (metastases) is, however, extremely rare. Symptoms can include headaches, due to increased pressure inside the head, as well as memory loss, seizures, changes in character, and coordination difficulties.

MRI image of GBM

More men than women are affected by this tumour, especially between 40 and 60 years of age, but it is rare in children and only 5 to 10% of brain tumours appear in this age group.

HOW IS GBM DIAGNOSED?

	CT scans, MRI, and PET (Positron Emission Tomography) are all neuroimaging tests. Data from them can give an idea of the type of tumour and benign or malignant nature, but a sample of the tumour (biopsy) is required to establish the exact nature of the tumour.
Brain biopsy for the diagnosis of a brain tumour

CT scans are performed by tomography, i.e. imaging by sections using X-rays.  It is especially useful for bones but images of tumours can be enhanced administrating iodinated contrast. Overall, however, the resolution it provides of soft tissue is markedly inferior to that of MRI.

	MRI does not use radiation but magnetic fields, and a contrast agent called gadolinium. It produces finely detailed images of brain structures, thus showing both tumours and soft tissue with a significantly higher resolution than CT scans, but the images of bone and calcified tissue are of a lower quality than those provided by CT scans.
MRI image of GBM

PET, on the other hand, measures cell activity. A radioactive isotope of glucose is first injected, and then the tumour is analysed, assessing whether the tumour is benign or malignant and if the tissue is alive or necrotic. It is very useful but is not 100% reliable, so sometimes there are false positives or false negatives.

MRI image of a thalamic tumour	PET image of the thalamic tumour: red and yellow should tumorous areas

WHAT SIDE EFFECTS MAY THE DIAGNOSTIC TESTS HAVE?

The contrast agent used in CT scans, iodine, can cause allergic reactions. In most cases they will be self-limiting reactions such as a rash, feeling of heat, or shortness of breath, but sometimes the reaction can be severe and occasionally even cause death. The contrast agent used in MRI, gadolinium, can also provoke side effects, such as headache or malaise. It is extremely rare for more severe side effects to appear. Since MRI uses magnetic fields, people with metal implants in their body must notify them. If wearing pacemakers, neuro-stimulators or some metal prosthesis, it is highly recommended to avoid performing MRI and a CT scan will be needed. In patients with claustrophobia or in children sedation may be necessary. And, although the image has a lower resolution, in our hospital we have an open MRI for claustrophobic people if it is preferred to sedation. Nowadays, through spectroscopy, MRI allows the composition of tumours to be analysed without performing a biopsy, and thus to more accurately shape their nature without the need of extracting a sample of the tumour.

Spectroscopic image of a brain tumour

HOW IS GBM TREATED?

The treatment for GBM involves a combination of surgery, radiotherapy and chemotherapy.

The objective of surgery is to confirm the diagnosis by extracting a sample of the tumour for the pathologist to analyse it and to remove as much tumour as possible without causing sequelae (paralysis, loss of speech…), for it has been show that patient survival is greater when a smaller amount of tumour remains, both for benign and malignant tumours. In addition, this stops the compression of the normal, healthy brain, and the patient’s symptoms disappear.

Radiotherapy and chemotherapy are then applied to destroy those tumour cells that could not be removed by surgery. However, the effectiveness of these therapies will in general be very limited if the tumour is not removed as completely as possible.

WHAT DOES THE SURGICAL TREATMENT OF GBM CONSIST OF?

As previously stated the purpose of surgery is to remove as much tumour as possible. Several factors will determine whether it will be possible or not to remove the tumour, including its location, degree of invasion of surrounding tissue, and its relation to the blood supply to the brain.

Recent technological advances allow greater accuracy in the surgical removal of tumours.

• The surgical microscope is used to provide a light source and to magnify the surgical field.
• The ultrasonic aspirator eases the removal of tumour tissue.
• The neuronavigator allows a more accurate 3D surgical orientation. An MRI is performed for this purpose the day before surgery and the imagines are transferred to a monitor in the operating room which will provide images during surgery showing the exact position in the brain of the tumour.

When the tumour is located near particularly delicate areas, special pre-operative tests may be necessary to delimitate as well as possible the lesion and the surrounding tissue which we wish to conserve. Sometimes, surgery is performed under local anaesthesia so that the patient can cooperate in preserving the role of sensitive areas (mainly speech and movement). It is important to remove as much tumour as possible, without causing sequelae. To ensure this is accomplished, all techniques of intra-operative monitoring are used, the tumour is marked with δ-aminolevulinic acid, and once the tumour is removed, photodynamic therapy is applied to kill those tumour cells which have invaded the edges of the cavity left after tumour removal. In selected cases, chemotherapy tablets (Gliadel) are left in the tumour cavity for a slow but locally continuous administration with higher effectiveness.

GBM in the insula with marked mass effect and displacement of the brain to the opposite side	GBM in the insula with marked mass effect and displacement of the brain to the opposite side

RADIOTHERAPY

For patients that have already undergone surgery or when surgery is not possible, the treatment to apply will be radiotherapy, with or without chemotherapy depending on the case. Given GBM’s aggressiveness, it is common to apply all available treatments in an attempt to stop the tumour’s growth.

The goal of radiotherapy is to destroy tumour cells without damaging normal brain cells around the tumour’s borderlines. It is given after assessing the amount of tumour remaining after surgery; the radiotherapist will then try to radiate the remaining tumour cells minimising the amount of radiation to neighbouring nervous tissue. Prior to application of radiotherapy, the radiotherapist will discuss with the patient the potential benefits and side effects of this treatment. Radiotherapy is usually given in one dose per day for 2 to 6 weeks, and though the amount of radiation depends on the type of tumour and its extension, in the case of GBM the dose is always the maximum (60Gy), which often leads to hair loss in the radiated area.

TYPES OF RADIOTHERAPY

In conventional radiotherapy an external beam of radiation is aimed and applied at an entire region of the brain containing the tumour. The radiation is split into many small doses administered over a long period of time, usually 5 to 7 weeks not including weekends. Its main disadvantage is that it radiates large areas of healthy brain tissue, which may suffer varying degrees of damage, while the tumour can receive a dose which is lower than the optimal dose that it should ideally receive. It is an old treatment against GBM.

Conventional radiotherapy

Conformal radiotherapy is a type of conventional radiotherapy in which the radiation beam has been modified so that it is shaped like the tumour.  Its aim is to apply the maximum amount of radiation to the tumour while reducing the amount of radiation that reaches other parts of the brain. This technique is more modern and causes less damage to normal brain than the older methods of conventional radiotherapy.

Stereotactic radiosurgery delivers a high dose of radiation to a small volume of tissue (up to 3 cm in diameter) in one single dose and one single application. There are different application systems, such as Gamma-knife, radiosurgery with linear accelerator, or radiosurgery with ciberknife and cyclotron, which allows radiotherapy to be applied to other areas of the human body as well as the brain.  It is useful to treat small tumour remains after surgery or small recurrences (when the tumour grows back after some time). In our centre we have extensive experience with radiotherapy with linear accelerator.

Radiosurgery with Gamma-knife

Stereotactic radiotherapy combines the accuracy of radiosurgery with the fractionation of other techniques. Radiation is applied precisely using stereotactic techniques but it is administered over several sessions. This allows the damage to tissues surrounding the tumour to be minimised, because normal tissue recovers better and quicker from the effects of radiation than tumorous tissue. This is why this technique is employed against tumours located near the optic nerves, brainstem or eyes, as well as large tumours and tumours in children.

In brachytherapy small radioactive seeds or a radioactive liquid are directly implanted into the tumour or its cavity for a short period of time, normally 5 to 7 days. This type of radiation is used to apply radiotherapy more than once since other types of radiation have already been applied, and is particularly useful to treat tumour recurrences when the patient has already received the maximum amount of radiation that can be given externally.

Brachytherapy in the treatment of GBM

	Intra-operative radiotherapy is the administration of radiotherapy during surgery. It requires complex apparatus (Mevatron), but it makes it possible to administer radiation to treat tumour recurrences when the patient has already received the maximum amount of radiation that can be given externally.
Intra-operative radiotherapy

CHEMOTHERAPY

Chemotherapy also helps control tumour growth. It can be administered before, during, or after radiotherapy. Usually it will be given after surgery but sometimes it can also be given before surgery to reduce the tumour’s size, making easier its surgical removal. The most common drugs include temozolomide, BCNU (carmustine) and CCNU (lomustine), but there are many others and the effectiveness of some new ones is also being investigated. Temozolomide is especially useful due to its limited impact on the bone marrow, due to the fact that it does not provoke hair loss and because is it taken orally. Angiogenesis inhibitors, such as bevacizumab, are very effective, but they prevent healing so the patient cannot undergo surgery until after, at least, one month of their administration. In addition, they mustn’t be administered until after one month of surgery to avoid the wounds opening, especially if the operation was a re-intervention and the patient has already received radiotherapy. Which, out of the chemotherapeutic agents, is the most suitable one will depend on the nature of the tumour and on how it responds to the agent. Ideally, a sample of the tumour should be extracted so that it can be analysed to find the best chemotherapeutic agent against it, for this prevents the administration of treatments that are both toxic and, in that case, ineffective.

Chemotherapy is usually given intravenously, though some chemotherapeutic agents can, too, be administered orally. BCNU can also be administered directly into the tumour cavity during surgery by implanting it in tablet form. Drugs that temporarily increase the permeability of the blood-brain barrier can also be used, allowing the therapeutic agents to reach the tumour more effectively.

SIDE EFFECTS OF THE TREATMENT

All treatments can have side effects because radiotherapy and chemotherapy attack neighbouring normal tissues as well as tumour cells.

Chemotherapy can cause nausea and may be associated with fatigue, weight loss, anaemia, depressed immune system (and thus increased risk of infection), and hair loss. Each drug has a particular set of side effects that the oncologist will discuss with the patient.

Radiotherapy is usually given daily on an outpatient basis. Patients are usually able to function at a normal level during the treatment, but malaise, nausea, fatigue and hair loss are common. In some cases it can cause neurological damage.

Currently there are drugs that can help relieve the side effects of the treatment which will be administered as needed.

WHAT DRUGS ARE GIVEN TO TREAT THE SYMPTOMS OF GBM?

The most commonly used drugs are corticosteroids, to reduce brain swelling, and antiepileptic drugs, to prevent seizures.
Corticosteroids are given to reduce brain swelling around the tumour, especially after surgery, but do not destroy the tumour cells. They are very useful to improve the patient’s general and neurological condition, and when only given for a few days do not cause any side effects other than oedema of the face, hands and feet, fluid retention, and increased appetite. If used for long periods of time, they can cause major changes such as moon face, muscle wasting in arms and legs, increased body fat, osteoporosis, skin striae, acne, and changes in character (Cushing’s syndrome). Other side effects include fragile skin and diabetes mellitus. These side effects usually disappear when corticosteroids are withdrawn, but their withdrawal must be carried out gradually, for if done suddenly it could cause unpleasant side effects.

Antiepileptic drugs are administered to prevent seizures. Commonly used antiepileptic drugs include phenobarbital, phenytoin, carbamazepine, sodium valproate, the leviracepam, topiramate or lamotrigine. Recent studies recommend the administration of leviracepam to prevent the occurrence of epileptic seizures in the period around the operation.

WHAT ARE THE RESULTS?

This tumour’s response is not particularly good and requires a very aggressive therapeutic approach, including all available treatments. Ideally, the lesions would be discovered when they are still small, thus allowing complete removal with clean edges and treatment with photodynamic therapy to destroy any tumour cells that could have potentially infiltrated neighbouring tissue beyond the resection margins.

It is common in patients who survive over a year to develop hydrocephalus and so require the implantation of a ventricular-peritoneal shunt.

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