Brain Tumour Trials

Introduction to brain cancer

Not all brain tumours are the same! Other than nerve cells, or neurones, the brain contains different cells from which tumours can grow. The name of the cell of origin of the tumour influences the name of the tumour itself. Studies into the treatment of brain tumours are often focused on tumours arising from one cell type. Examples of brain tumour types include:

Meningioma – Arise from meningeal cells. Meningeal cells form the membrane that is wrapped around the outside of the brain, inside the skull.

Glioma – The glial cells provide the architectural framework on which the main structure of the brain, consisting of neurones, is built and nourished. Glial cells include oligodendroglial cells, astroglial cells, microglial cells and ependymal cells.

Brain Metastasis - Tumours can spread, metastasise, from other sites in the body to the brain.

Strategies to improve the survival of people with brain tumours can be divided into three main areas. These are described below.

Maximum tumour removal

Meningiomas usually have a well defined edge that separates them from the normal brain. Provided that the tumour is in a part of the brain that is readily accessible to the Operating Surgeon, there is a very good chance that most if not all of the tumour can be removed.

Glioma grow within the substance of the brain and so are more difficult to remove. This is because it can be hard for the Operating Surgeon to tell where the tumour stops and the normal brain starts. This is particularly the case with gliomas that are more aggressive in their growth, such as glioblastoma multiforme (GBM). There is not a distinct boundary where tumour stops and normal brain starts. Aggressive tumours are described as being high grade; the grade of a tumour relates to attributes of the tumour cells when seen under a microscope.

So, we can see that better differentiating abnormal tumour cells in a glioma from normal brain cells would give the Operating Surgeon the chance to remove more tumour without damaging normal brain tissue. Removing as much tumour as possible is associated with better long term survival and better response to radiotherapy, if it is needed. Furthermore, in the UK, patients with GBMs can receive chemotherapy if more than 90% of the tumour has been resected.

5-aminolevulinic acid (5-ALA) is a drug that is used to help Surgeons to resect as much of a brain tumour as possible. Its is given to a patient before an operation, and by viewing the tumour with a special light during surgery, the tumour cells fluoresce, so can be more easily removed. Ongoing work is focused on whether patients survive longer is their tumour is resected in this way1.

Unfortunately, some brain tumours are located in parts of the brain that are inaccessible to Surgeons. This is because getting to the tumour would cause irreversible damage to other key areas of the brain.

Radiotherapy

Some patients with brain tumours will receive radiotherapy. This is usually after they have undergone surgery to remove all or most of the tumour. Where it is not possible to perform surgery for a brain tumour, perhaps because of the position of the tumour, a patient may be offered radiotherapy on its own.

Radiotherapy is conventionally given through the skull, external beam radiotherapy. It can also be delivered directly into the cavity of a tumour itself. When radiotherapy is given to the whole brain, there is a risk of damage to normal brain tissue. Different methods of giving radiotherapy are under investigation to try to get round this problem.

Small implants containing a radioactive source, iridium-192 or iodine-125, can be placed in the brain at the time of tumour resection, but this has not been shown to be of significant benefit.

A novel way to deliver radiotherapy directly to the site of a high-grade brain tumour is currently under investigation. The Gliasite® Radiation Therapy System delivers a radiotherapy solution via a balloon catheter placed into the tumour cavity at the time of surgery. The study will assess whether this is safe for patients and how well it controls tumour growth.

Lasers

Another way currently under investigation of delivering a burst of energy to a tumour in order to try to destroy it, is via lasers. Stereotactic guided laser-induced interstitial thermotherapy (SLITT) deliver energy in the form of laser light. It is given is given under local anaesthetic, and the laser light is delivered directly into the tumour via fiber optics. This technique is currently being trialled in the treatment of brain metastases and primary brain tumours.

Chemotherapy

Chemotherapy aims to interfere with the proliferation of tumour cells and so cause cell death. This has to be done with as little disruption as possible to normal cell proliferation.

Available chemotherapy strategies for high grade glioma include temozolomide and carmustine.

An important question is how best to deliver the chemotherapeutic agent to the brain tumour. Currently, carmustine-impregnated wafers can be placed in the tumour cavity at the time of surgery, or temozolomide can be given via a vein.

Carmustine is currently given to patients who have undergone maximal resection of a high grade brain tumour. It has been show to prolong survival in this group. Trials are looking at whether there is an additional benefit when temozolomide is given in addition to carmustine. Currently, patients often only receive one of other of these chemotherapy agents.

Ongoing work is also looking at the use of carmustine wafers in metastatic brain tumours

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A group of Researchers is also looking at an exciting new way of delivering chemotherapy directly into a high grade brain tumour. Researchers have shown in a lab model2 that drugs can be effectively delivered to brain tumours via a process called Intracerebral Clysis or Convection Enhanced Delivery. This involves a micro-infusion system directly into the brain, maximising delivery of the chemotherapy to the tumour, so minimising the side effects to the rest of the body! The current study is moving this technique from the lab into clinical practice to look at whether Toptecan can be given safely and effectively ito patients with high-grade gliomas. Topotecan is a drug currently used in tumours such as ovarian cancer, or small cell lung cancers, where it is given via peripheral veins.

Research into the treatment of many different cancers is focused on the use of monoclonal antibodies to specifically target proteins associated with tumour growth. A protein important for blood vessel growth in tumours, including brain tumours, is vascular endothelial growth factor. Cediranib inhibits a cell-based receptor that recognises this protein, therefore removing the signal that stimulates blood vessel growth. Tumours need to form new blood vessels in order to grow. Inhibiting blood vessel growth inhibits tumour growth. A trial is currently under way to see how effective Cediranib is when given with Lomustine in high grade brain tumours that have recurred after initial treatment.

Another way of manipulating the bodies own immune system in the fight against cancer is the use of cytokines. Cytokines are a group of proteins that regulate immune system activity. Interleukin-2 is one such cytokine and is currently used in the treatments of renal cell carcinoma that has metastasised. By giving a patient interleukin-2, T cells, one of the cells that make up the bodies own immune system, are stimulated to fight tumour cells. A group of Researchers is giving T Cells and Interleukin-2 to patients with recurrent high grade brain tumours.

References

1. Stummer W. Pichlmeier U. Meinel T. et al. ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncology. 7(5):392-401, 2006

2. Degen JW, Walbridge S, Vortmeyer O et al. Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model J Neurosurg 99:893-893, 2003

Author: Paul Brennan

Reviewers: Roger Thompson, Kenneth Baillie

Updated: August 04 2008.