Brain Tumours: An overview on current clinical care and research. By Dr Brindha Shivalingam, Neurosurgeon, Royal Prince Alfred Hospital

1. Brain Tumours: An overview on current clinical care and research
Dr Brindha Shivalingam, Keynote
Hosted by Cure Brain Cancer Foundation

2. Brain Tumours
An overview on current clinical
care and research
Dr Brindha Shivalingam
Neurosurgeon
Royal Prince Alfred Hospital

3. Introduction

4. Brain cancer compared to other cancers
Cancer incidence
Breast
Brain
Prostate
Melanoma
Bowel
Other

5. 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

6. 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

7. 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.

8. 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.

9. Investigations
CT
MRI
PET
fMRI/DTI

10. 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

12. Surgery
Many techniques are used to resect tumours
¤ craniotomy with frameless stereotactic navigation
¤ Endoscopic resections
¤ iMRI
¤ 5- ALA
¤ awake surgery

13. 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

14. 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.

15. 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

16. 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.

17. 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

18. 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.

19. 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????

20. 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

21. 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.

22. 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

23. 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

24. Research
1898-1937.
Died aged 39 of
Glioblastoma
multiforme

25. 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

26. 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

27. Basic tumour biology
Uncontrolled growth of cells
Due to genetic abberations
Cell cycle is very
tightly regulated
by numerous
genes

28. 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

29. 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.

30. 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.

31. 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

32. 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

33. 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.

34. 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

35. 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

36. 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.