Notes taken by Dennis Argall from a presentation by

Dr Helen Wheeler,
Medical Oncologist,
Royal North Shore Hospital (RNSH) and North Shore Private Hospital,
to the first meeting of the Sydney Neuro-Oncology Group (SNOG) Brain Tumour Support Group,
on 14 February 2001.

An Overview of Treatments of Brain Tumour
Please note that this is not Dr Wheeler's notes, but audience notes.
Note also that some subjects are covered in answers to questions as well as in opening presentation.

There are many different kinds of brain tumour, this presentation focuses on tumours from glial cells, the most common in adults. I am not an expert on children's tumours.

Here is a confession from doctors - we don't know the right way to treat gliomas. Thus you will hear, from different doctors, different views, be they in Sydney, Perth or the Mayo Clinic. While ever we are not conquering these tumours, people will have different approaches to their treatment.

As there is no established treatment, there are many continuing clinical trials, and Australia will probably become more involved in these - there are so many new drugs the drug companies will run out of patients to trial them on in the United States.

So what I present here is the "Wheeler impression"; but there is no right or wrong way to go...

• • • •

Every year 6-700 gliomas are diagnosed in Australia. They are not common, and there are not a lot of medical resources devoted to them. There is one focus of attention at RNSH in Sydney and one in Melbourne.

There is much speculation at present about the cause of these tumours. In very rare cases there appear to be inherited genetic defects. Epidemiological studies (studies of the incidence of disease in a population) suggest that there are likely to be environmental factors, as where husbands and wives, with no genetics in common, are affected.

There has been public concern about mobile phones. There is no conclusive evidence. However, I use a mobile phone.

What is cancer? Cancer is a genetically altered cell; the altered cells reproduce and travel. As these cells are, while altered, originally normal body cells of the host, it is difficult for the immune system to recognise and attack them. The immune system is geared to attack viruses, bacteria and foreign material, not altered cells from the person.

Research is going on to evaluate environmental cases of brain tumour. This requires detailed epidemiological research. There are, in a tumour, ten to twenty different genetic alterations. Maybe these occurred in the person at 6 months of age, at ten years, and so on. Epidemiological and environmental studies are exceptionally difficult to carry out properly; requiring say ten people sitting down and sifting through a mass of information.

The Human Genome Project will lead to rapid analysis of the genetic changes associated with cancer development. The nature and number of the genetic alterations suggests that more than one incident will be associated with cancer development, among them environmental toxins. There appear to be two distinct genetic abnormalities, young people having p53 abnormalities, older people with EGF receptor deformities. Yet even when tumour cells look the same, they behave differently, and respond differently to different therapies. Notably, children respond better than adults to chemotherapy. More information on the actual genetic changes in individual tumours will lead to the development of better treatments - drugs designed to target individual tumours more accurately.

• • • •

IMAGING can indicate the shape and extent of development of tumour. Although interpretation of scans is not always correct, it may need to be relied upon if a lesion is not biopsiable (that is, it is in a location where it is not possible, not safe to remove tissue surgically for pathology testing).

PRESENTATION

Patients present with a wide range of symptoms. Some will have severe symptoms, others will have very vague symptoms. Many GPs will not suspect a tumour problem, indeed most GPs will see no more than one glioma patient in a lifetime. CT scans don't always pick up tumours. As these tumours change very rapidly, often if a test is repeated, as when a patient, dissatisfied with one doctor goes to another, a new scan show an obvious problem.

GENERAL MANAGEMENT

It is essential to perform a tumour biopsy. However, in some cases, for example where the tumour is in the brain stem, this may be impossible. Whereas in others, a surgeon may be able to remove almost all tumour material. There is value in removing as much tumour as possible; there is also virtue in examining as full a sample of the tumour as possible. A small biopsy may not be representative of the whole, heterogeneous mass.

PATHOLOGY

Analysis can differ markedly in interpretation of material from a tumour. Experts disagree in 20-30% of cases. In the United States, in a study several years ago, material was sent to the highly respected tumour centres at the Mayo Clinic, M.D. Anderson at the University of Texas, Sloan Kettering and UCLA. There was 70% agreement between them in their interpretations.

As more precise genetic information and techniques for genetic analysis become available, more accurate interpretation will be possible.

There is a need in particular to distinguish oligodendroglioma, anaplastic oligodendroglioma, and mixed anaplastic oligodendroglioma from anaplastic gliomas (anaplastic astrocytomas - AA; gliomas). Oligodendroglioma are rare, and were only identified ten years ago. They are very responsive to chemotherapy, and trials in the US are assessing the value of chemotherapy while delaying radiotherapy for this type of tumour.

Cairncross at the London (Ontario) Medical Centre in Canada has identified specific genetic distinctions which are indicative of differential response to chemotherapy, some, including in GBM. However, the ability to test for such distinctions is not generally available at the present time.

Distinguishing the grade of the tumour (from grade 2 to grade 4, in ascending order of aggressiveness and degree of mutation) is important to treatment decisions. Patients with low grade tumours may not be offered any further treatment (after craniotomy for biopsy and or debulking), just kept under observation. European studies suggest that the survival of patients with grade 2 tumours may be the same with or without radiotherapy.

RADIOTHERAPY

Patients with high grade gliomas will be offered radiotherapy. There are some new devices for stereotactic radiotherapy (gamma knife, cyber knife, etc.). These bring very high doses of radiation to bear on specific targets. The value is problematic, as the tumour margin will be irregular and the margin between normal brain tissue and tumour ill-defined, as therefore is the prospect of damage to normal tissue. Also, very high doses of radiation will produce large amounts of dissolving tumour and a consequent inflammation and oedema problem - causing difficulties for the patient.

Conventional radiotherapy is shown to increase survival time in patients with grade 3 and grade 4 tumours, and should also improve quality of life during remaining months. It is to be avoided, or delayed, in children, however, as it will cause hearing and learning difficulties. However, 10% of patients will show an early or delayed reaction to radiotherapy. Some may present with clinical deterioration during radiotherapy. Such patients need support with increased steroids, and may need imaging to exclude hydrocephalus (fluid accumulation, requiring intervention). Patients usually recover from such effects in four to ten months.

Delayed radiation necrosis may become evident four to 24 months after radiotherapy (DXRT). It is difficult on MRI scans to distinguish between such radiation product and recurrent tumour. A PET scan may help - however, there are few PET resources available. (A CT scan is a sophisticated x-ray, useful in tumour cases mainly for checking for oedema; an MRI (magnetic resonance imaging) distinguishes fat and water; a PET (positron emitting tomograph) or similar scan can identify metabolism in the brain. Live tumour will show metabolic activity; dead material will not.)

• • • •

CHEMOTHERAPY

The blood-brain barrier means that not many drugs will penetrate to the brain.

It has also recently been realised that as anti-convulsant drugs (Dilantin, Neurontin, etc.) cause an increase in liver metabolism, running up to ten times faster, chemotherapy drugs administered to brain tumour patients taking anti-convulsants are rapidly metabolised before having effect. One recent study suggests that where a particular drug may be effective in dose X every three weeks in breast cancer, an effective dose of the same drug in brain tumour may be 2 times X, administered weekly. It is clear that the efficacy of chemotherapy in brain tumour has not been properly tested. Johns Hopkins University Hospital in Baltimore has begun retesting chemotherapies previously rejected for brain tumour, at potentially more effective dosages. There is, however, a lack of interest on the part of drug companies in retesting against this anti-convulsant therapy background. Drugs worthy of review include CPT11, Taxol and Procarbazine.

Timing: there is probably some advantage (15%?) in survival prospects if chemotherapy is used immediately after radiotherapy. SNOG practice is to institute chemotherapy six weeks after radiotherapy to treat residual tumour - except in the case of oligodendromas, where chemotherapy may be appropriate pre or post operative.

PROGNOSIS

Grade III - 24 to 60 months
Grade IV - 2 to 10 months

However...
Accurate pathology is essential in deciding among treatment options. We now see some people surviving two to five years with Grade IV. Factors improving survival prospects include:
• debulking surgery helps;
• radiotherapy helps;
• value of immediate chemotherapy is controversial;
• there is a 20-40% response to chemotherapy on relapse

Things that make a difference:
• diagnosis/distinction between necrosis and tumour regrowth;
• watch for hydrocephalus, possible need for a shunt to drain fluid;
• careful monitoring to ensure patient is maintained on the minimum necessary dose of steroid for oedema control, to avoid steroid myopathy and diabetes;
• if on steroids, it is important to keep up exercise to avoid myopathy;
• the steroid dose and the anti-convulsant dose must be correlated. Elevation of steroids speeds up the metabolism (that is, eliminates, removes from the system, lowers the blood levels) of anti-convulsants, reducing protection against seizure. Conversely, lowering steroids slows such metabolism, elevating levels of anti-convulsants, which can reach toxic levels;
• thus, carefully monitor anti-convulsant levels, especially when steroid dosages are altered;
• watch for deep vein thrombosis (DVT), which may appear even if a patient is receiving therapeutic doses of Warfarin. 50% of patients end up with clots, and may need to be maintained on low molecular weight heparin. The risks associated with flying are much higher for brain tumour patients than for the general population;
• watch for hypothalamic dysfunction, and possibility of hypothyroidism - arising especially from the impact of corticosteroid treatment.

It is essential that medical carers, including hospital emergency staff, recognise that because of preexisting brain damage, a tumour patient suffering seizure will take much longer to recover than a person who has a seizure without having had such damage. I have had (Dr Wheeler said) battles with hospitals, where staff in emergency departments have not understood the importance and value of prompt intravenous anti-convulsant treatment, believing instead that the patient should just be moved to palliative care. Patients in that situation, properly cared for, regularly walk out of the hospital in a day or so. All this underscores the importance of proper monitoring of serum levels of anticonvulsant.

In all this remember that 10% of patients deteriorate on DXRT, and 10% similarly deteriorate in chemotherapy, especially in week 1. Probably it is the killing of cancer cells - the effectiveness of treatment - which causes swelling and symptoms.

• • • •

NEW DEVELOPMENTS

Note that because of the brain's isolation from the rest of the body, there is unique advantage in treating brain cancer that it is a matter of treating a cavity, whereas for example, breast cancer may travel all over the place.

There is a lot of work going on to try to squirt treatment materials into the cavity in the brain. For example, gene therapy, genetically modified viruses, immune system modulators. Catheters may be installed to make insertion of material easier. The objective being to maximise local effect and avoid wider systemic harm.

However, we don't know how brain tumours spread.

Two gene therapy trials so far completed have been complete failures; there are some ongoing gene therapy trials.

In the area of chemotherapy, gliadel wafers are in use in the US, but not in Australia. These are polymer wafers soaked in BCNU (an established chemotherapy drug - BCNU is normally used intravenously; the same substance orally is CCNU); inserting the chemical into the brain cavity during a craniotomy provides a local level of the cytotoxin 500 times that available via blood circulation. And this is with standard 3.5% soak of the polymer. Johns Hopkins is experimenting with a saturation of 28%, the limit of the polymer, which it is hoped may improve their therapeutic value.

Gliadel wafers may be recommended for all patients in Australia, but as yet they are not accepted treatments. The cost for eight wafers is $10,000 and the problem with individual import of the wafers is that they must be kept at -20 degrees Celsius and must be carried with great care, often enough shattering while being conveyed to the brain cavity by the surgeon. A quote for courier delivery to Australia of one treatment was $1,000.

Temozolomide: This is a BCNU derivative, which is taken five days a month orally, and is generally well tolerated. It can, like other chemotherapy, cause nausea, but some patients don't need anti-nausea drugs, which cause severe constipation. There is a need to monitor blood levels, weekly to start, then fortnightly, for drops in white blood cell and platelet counts. Of one hundred patients, only two crashed, 98 of 100 experiencing minor lowering of blood counts. (See also response to question below)

Anti-angiogenics: There are thirty new anti-angiogenic drugs being tested or used. Angiogenesis is the making of new blood vessels. Cancer cells develop their own very distinctive blood vessels. Cancer cannot grow beyond pinhead size without angiogenesis. These anti-angiogenic drugs oppose that process.

Brain tumours are among the most angiogenic - as they rapidly grow, the centre of a tumour mass, where blood supply is lost, may just become dead muck.

Thalidomide was introduced into the United States in 1996, and final results of clinical trials were presented in 2000. However, the precise therapeutic dose is not known. In the United States the standard dose is 1200mg nightly. In Australia, at RNSH, the maximum dose in trials was 500mg. Overall, whichever dosage, thalidomide seems to help one third of patients. It does cause sedation, which diminishes, and constipation, and there is long term peripheral nerve damage, affecting hands and feet. It can also cause dizziness. Some patients were helped for three months, or 6 or 12 months, or 3.5 years, Thalidomide stopping tumour growth, in the RNSH trial.

• • • •

FUTURE DIRECTIONS

Of greatest interest are the local therapies, and combination of chemotherapy with anti-angiogenics. There is a need for further laboratory study of what thalidomide actually does.

Clinical trials (in the news controversially on the day of this presentation) involve rigorous testing of drugs, and the full process takes from 5 to 10 years. Many things promising in the laboratory have failed in trials, e.g. gene therapy. There has been an explosion in the number of drugs being proposed as chemotherapies, though it is difficult to find drug company support for trials for brain tumours, the market being small. We (not sure whether this 'we' is RNSH or broader, or drugs for BT or cancer generally) get clinical trial proposals ten to fifteen times a year, and probably say yes to half of them. Any proposal for a clinical trial must go before the ethics committee. There is considerable attention to the research evidence of potential benefit for patients.

• • • •

ANSWERS TO QUESTIONS

Can I travel by aircraft? If the brain tumour is under control, and if the patient is not taking large doses of steroid for oedema, then yes, but with added steroid protection against oedema - "I usually recommend that a dose of 8mg dexamethasone several hours before the flight." Otherwise, the answer is no. Long trips, e.g. to Perth, represent a greater problem than short trips. The critical point is that pressurisation of the aircraft does not maintain the same air pressure as on the ground, but is proportional to the actual altitude of the aircraft. Well people suffer, for example with swollen feet. With an oedema problem in the brain the problem is much more serious.

How long to I take temozolomide? No one knows how long you can or should take temozolomide. "I had two patients who ceased taking it after six months with clear scans. Both relapsed, one very swiftly. I am never going to stop it on anyone again."

Why try a higher dose of BCNU on the gliadel wafers? Because the purpose of the chemotherapy is to kill tumour cells and the increased dose may be more effective.

How much time do the wafers give? A couple of months - noting again the problems of storage and delivery to Australia, and cost, as above.

Do you have results for combined temozolomide-thalidomide treatment? We do not have the funding for a formal study. The previous clinical trial had no support from the drug company, as thalidomide is out of patent and there aren't prospective profits. The previous trial cost $100,000 and that money is not available again. However, the clear anecdotal evidence is that people are doing much much better on combined thalidomide-temozolomide than was to be expected were they taking either drug alone. It may be that the manufacturer of temozolomide will support a combined trial.

If there is an absence of nausea symptoms, can you go without Zofran? It is possible to get away with using Maxolon or Stemetil, There is a very powerful psychological factor in the nausea associated with chemotherapy. Thalidomide alone is not a sufficient anti-nausea treatment.

What studies have been made of 'alternative' treatment approaches, such as meditation? There have been no formal trials. It seems clear, however, that stress is relevant, and during periods of stress people produce elevated levels of antiangiogenic factors, which drop when stress falls away. There is no scale for measuring stress.

If it feels right, and is comfortable, good. But is it not good to have pressure on patients from people who claim they have a cure and that patients 'must' do something. It is bad when a patient comes to the doctor and is stressed by not being able to follow a relaxation or meditation routine. Urine tests at one time in the oncology outpatients clinic indicated that half the patients were taking large supplements of vitamin C. A study of the effect on vitamin C on bowel cancer, with controls not taking the supplement showed no benefit, but it's hard to know.

At the end of the day, if a patient is doing well, the treatment doesn't matter. But some herbal treatments are antidotes to chemotherapy, or retain chemotherapy, which makes it hard to know, if a patient is not doing well, whether it is a failure to respond to chemotherapy or something else at work. I have worked in a lab with a Beijing professor, doing tests on whether substances stimulate the immune system. Some of the Chinese substances were fantastic.

• • 0 • •