Brain Tumours: An overview on current clinical care and research Dr Brindha Shivalingam, Keynote

Hosted by Cure Brain Cancer Foundation

Brain Tumours An overview on current clinical care and research

Dr Brindha Shivalingam

Neurosurgeon

Royal Prince Alfred Hospital

Introduction

Brain cancer compared to other cancers

Cancer incidence

Breast

Brain

Prostate

Melanoma

Bowel

Other

Current Clinical care

Most patients present to hospital or their GP with new symptoms that concern them :

Headache (new onset or change in pattern)

Seizures (generalised or partial)

weakness of limbs

speech problems

visual problems

Confusion

Incidental finding

New onset of symptoms

• Referral to Neurosurgeon or present to ED

Stabilisation of symptoms

and investigations

• Potential diagnosis. Discussion of plan of management.

Surgery (biopsy or resection)

• Post operative care in hospital

Confirmation of diagnosis

• Referral to radiation oncology and medical oncology

Commence radio/chemo

• Ongoing followup

Benign tumours

Communication

Stabilisation of symptoms Dexamethasone.

Strong steroid that reduces swelling (oedema) in the brain.

Can dramatically reverse symptoms

Side effects :

Short term – appetite, restlessness, agitation, sleeplessness, delirium

Long term – weight gain, muscle atrophy, thin fragile skin, decreased immunity, osteoporosis, diabetes.

Stabilisation of symptoms

Anticonvulsants.

Many available.

Traditionally used drug is phenytoin.

Newer agents are better tolerated with fewer side effects.

Side effects : lethargy, dizziness, unsteadiness, headache, nausea, insomnia, rash, liver toxicity.

Is there a role for prophylactic anticonvulsants?

No.

Investigations

CT

MRI

PET fMRI/DTI

Surgery When ever possible, the general consensus now is to offer maximal surgery.

Benign tumours

complete curative resection is possible.

Location is always the issue.

Metastatic tumours

complete resection is generally possible.

Gliomas

Gross total resection/radical resection/subtotal resection/biopsy

Surgery

Many techniques are used to resect tumours

¤  craniotomy with frameless stereotactic navigation

¤  Endoscopic resections

¤  iMRI

¤  5- ALA

¤  awake surgery

Post operative care

¤  Hospital stay for an uncomplicated course is in the order of 2-7 days ¤  Mobility

¤  Attending to personal care

¤  Weaning off medication

¤  Pain management

¤  Discharge planning

Diagnosis

¤  The final diagnosis is made by the pathologist analysing the tumour tissue.

¤  Once a name is given to the tumour, we can then be more definitive about what the future holds.

Radiotherpy ¤  Given in fractions (small doses) to maximise brain recovery

between doses.

¤  Overall 6 weeks of treatment.

¤  Side effects (short term) ¤  Hair loss

¤  Fatigue

¤  Headache, nausea

¤  Side effects (long term) ¤  Short term memory loss, cognitive decline

¤  Unsteady gait

¤  Radiation necrosis

Chemotherapy

¤  Temozolomide – alkylating agent that impairs DNA repair enzymes.

¤  Oral agent

¤  Given daily for 6 weeks with radiation ¤  Adjuvant 6 cycles

¤  Well tolerated in general

¤  Can cause pseudoprogression which can be very confusing.

Benign Tumours

¤  If a complete resection has been achieved, then a cure has been achieved.

¤  Some benign tumours have a propensity to recur.

¤  Location is the key.

¤  Residual tumour : ¤  Watch and wait

¤  Radiotherapy/SRS

Benign Tumours

¤  Some small benign tumours can be treated purely with SRS

¤  Others can just be watched with regular MRIs

¤  Some benign tumours in difficult locations should be managed as a chronic disease.

Patient

Neurosurgeon and team

Radiation oncology

Medical oncology

Case managers/CNS/nurses

Rehabilitation

OT/Physio/speech

pathology Palliative care

Neurologist

Family/friends

Psychologist

GP

Go To Person????

Ideal set up

Centres that are optimally set up for management of these cancers, should have:

¤  Surgical expertise and specialisation

¤  Surgical technology

¤  Dedicated specialists in Radiation oncology, Medical oncology ,Neuroradiology and Neuropathology departments with regular MDT meetings

¤  Strong supportive staff for case management and coordination of care

¤  Access to trials – both local and international

¤  Onsite tissue banking facilities and research facilities

Current situation

At present in NSW there are ~ 20 hospitals where Neurosurgery is possible.

~520 new gliomas are diagnosed every year.

Therefore each hospital may see about 26 gliomas a year.

This causes incredible fragmentation and dilution.

Current situation

¤  Dilution and fragmentation is good for no body. ¤  Surgeons are unable to develop skills and knowledge

¤  Difficulty with setting up tissue banks and research labs

¤  Difficult to recruit patients into trials

¤  Funding bodies can’t identify where to infuse funds

¤  Difficulty attracting allied health professionals with a specialty interest

Current situation

Lack of cohesive care of the patient and their families

Patients and families feeling out of depth and unsupported.

This is most true for patients from rural areas and sadly other small states in Australia

Research

1898-1937. Died aged 39 of Glioblastoma multiforme

History

For many decades, there was very little research or development in the treatment of GBM.

First real change came with temozolomide in 1997.

Prof Malcolm Stevens (Birmingham UK):

I don’t think there was ever a ‘Eureka’ hats-in-the-air moment,” said Professor Stevens. “There was no particular moment in time when temozolomide was ‘discovered’”.

….. it was funding from Cancer Research UK that was vital

History

¤  After under going the usual trial process, the drug was authorised for use in recurrent GBM in 2001

¤  2005 – Stupp et al showed benefit of concurrent radiation and chemo. 2 yr survival rate of 26.5%

¤  All of the above was what was achieved in the pre genetic era

Basic tumour biology

Uncontrolled growth of cells

Due to genetic abberations

Cell cycle is very tightly regulated by numerous genes

Basic Tumour Biology

Genetic functions involved in tumour formation:

Stimulate cell division.

Suppress cell division

Promote cell death

cell migration or spread

What causes these mutations ????

inherited factors

environmental factors

The era or targeted therapies

¤  1956 – Watson and Crick described DNA

¤  Human genome project started in 1995 and was completed in 2003

¤  DNA sequencing technology has significantly improved and developed and become affordable.

Era of targeted therapies

¤  Most other previously deadly cancers are now treated with targeted therapies.

¤  Resulted from identifying crucial genetic mutations.

¤  Significant improvement in survival even with advanced cancer.

Targeted therapies

¤  Agents that target specific tumour cellular functions in order to kill the tumour cell.

¤  There are several of these on the market.

¤  They target various cellular functions and immune functions ¤  Small molecules

¤  Monoclonal antibodies

Brain Cancer and targeted therapy

¤  Bevacizumab (Avastin) – anti VEGF targeted drug ¤  Shown not to be of value when given upfront with standard

Stupp protocol

¤  CABARET study will reveal its effects at recurrence

¤  Current study by Celldex (US) ¤  ACT IV – rindopepimut . EGFR vIII positive.

¤  ReACT – recurrent GBM

Trial process

Ensures safety

¤  Phase I – <10 patients. Aim is to look for significant toxicity.

¤  Phase II – 30 patients. Ongoing assessment of toxicity but start to assess for benefit.

¤  Phase III – 300 patients. Randomised to assess for benefit when compared to current standard therapy.

Funding and research pitfalls

Every step of cancer research requires funding.

Current model is to apply for grants to various bodies.

This has problems :

competition

time consuming

project comes to a halt when the money is used up

lack of job security for researchers

Result : inefficient research with low productivity

Funding and research pitfalls

Rare Cancers and conditions are even harder to research due to

lack of funding

being less competitive with the grant process

difficulty enrolling patients into trials due fragmentation of care

The Future ¤  Specialist neuro oncology centres

¤  Cohesive care and support through these centres

¤  Establish functional tissue banks ¤  Neuropathological diagnosis

¤  Genetic profiling of all tumours

¤  Data collection

¤  Increased funding for research with funding channeled to research laboratories set up in these specialist centres.

¤  Funding for laboratories should ideally come form sources other than the grant system.