1. Medical Treatment for High Grade Gliomas – An Overview
Dr Daphne Tsoi
MBBS MSc FRACP
Medical Oncologist
Royal Perth Hospital
SJOG Hospitals Subiaco, Murdoch

2. Incidence
~ 1400 cases of primary brain tumour diagnosed in Australia each year
Primary CNS cancers – 7/100,000/year
(Colon cancer – 60/100,000/year)
14th most common cancer in Australia
Highest in terms of average year lost (12 years per patient)
Brain cancers .are among the most devastating to patients and their carers because they affect the organ that defines the self.
Australia-wide, the crude incidence of primary brain and other CNS cancers increased 0.3% per year from 1982 to 2004, similar to increases in some other countries. These increases have been attributed to the introduction CT/MRI.
Risk: 1 in 100,000

3. Average years of life lost for patients in Australia and the UK, 2001, by cancer type Sources: Burnet et al , Australian Institute of Health and Welfare (AIHW)
Although these cancers are not common, the average person years of life lost due to primary brain cancers is estimated at 12 years per patient in Australia in 2001.
This is much higher than the average for all cancers (three years) because these cancers tend to occur in younger people.

4. Glial cells
Classification
Characteristics
Astrocytes
Star-shaped cells
Astrocytomas
Oligodendrocytes
Possess few dendrites
Oligodendrogliomas
Ependymal cells
Line the ventricles
Ependymomas
There is a wide variety of CNS tumours, with the World Health Organisation listing more than 120 types.
glia (Greek for "glue"), are non-neuronal cells that provide support and nutrition
Oligodendrocytes – main function is insulation of axons
Astrocytes – provide nutritional support to neurons, biochemical support to endothelial cells that form BBB; repair of brain cells following injury
Chamberlain MC et al. West J Med. 1998;168:

5. Glioma: Grading Grade Tumor Type Glioma % I/II
Well-differentiated (low-grade) astrocytoma
15 to 20
III
Anaplastic astrocytoma
30 to 35 IV
Glioblastoma multiforme
40 to 50
Reference:
1. Chamberlain MC, et al. Practical guidelines for the treatment of malignant gliomas. West J Med. 1998;168:
Chamberlain MC, et al. West J Med. 1998;168:

6. Median Survival: Importance of Histologic Grading
Pathologic diagnosis is crucial in determining treatment and prognosis
Tumor Type
Median Survival, years
Low-grade oligodendroglioma
4-10
Low-grade astrocytoma 5
Anaplastic oligodendroglioma
3-4
Anaplastic astrocytoma 3
Glioblastoma multiforme
<1
The behavior of brain tumors is highly variable depending on cell type, with cell type and grade the most important determinants.
Median survival – time at which 50% patients with this condition who are still alive
1Bruce J. Available at:
2Hariharan S. Available at:
3DeAngelis LM. N Engl J Med. 2001;344:

7. Primary vs Secondary GBM
Primary GBM
Develops de novo from glial cells
Accounts for > 90% of biopsied or resected cases
Clinical history of 6 months
Occurs in older patients (median age: 60 years)
Secondary GBM
Develops from low-grade or anaplastic astrocytoma
~ 70% of lower grade gliomas develop into advanced disease within 5-10 years of diagnosis
Comprises < 5% of GBM cases
Occurs in younger patients (median age: 45 years)

8. Presentation Headache Seizure Motor weakness/speech deficit
Altered personality
Loss of memory/cognition
Dizziness

9. Investigations MRI Biopsy MRI – image modality of choice
Biopsy is crucial in determining treatment options and prognosis

10. Features of Glioblastoma Multiforme
Rapid progression
Enhancing tumor
Surrounding edema
Contains tumour
~ 5% multifocal
Rapid growth is a key feature of glioblastoma multiforme, as seen in the progression of this lesion over a 68-day period. Median survival is poor, typically on the order of 9 to 14 months.
On MRI, a glioblastoma typically appears as an irregular lesion with ring-like contrast enhancement surrounded by vasogenic edema. Tumor cells extend microscopically out from the apparent area of disease.

11. Treatment
Surgery
Radiotherapy
Chemotherapy

12. Temozolomide (Temodal)
Methylating agent
Principal mechanism is causing damage to DNA of tumour cell, leading to cell death
Taken orally, rapidly absorbed
Penetrates the blood-brain barrier
Dose according to ‘body surface area’ (height/weight)
BBB is a defence mechanism of the brain to ward off anything foreign that is potentially harmful to the brain. A lot of drugs particularly chemotherapy can’t cross the BBB, therefore are inactive against brain disease. Tem is different, hence active in GBM. 12

13. Temozolomide – Side Effects
Tiredness / fatigue
Nausea
Constipation (from anti-emetics)
Low blood counts – red/white/platelets
Particularly lymphocytes (risk of Pneumocystis carinii pneumonia)
Rash

14. Standard Treatment for GBM
Radiotherapy concurrently with Temozolomide followed by 6 months of Temozolomide

15. Phase III Study: New GBM Radiation ± Temozolomide
Concomitant TMZ + RT*
Adjuvant TMZ R 6 10 14 18 22 26 30
Wks
Phase III study is the gold standard method of proving if an experimental treatment is better when compared to standard treatment.
RT Alone
TMZ 75 mg/m2 PO QD for 6 weeks, then mg/m2 PO QD on Days 1-5 every 28 days for 6 cycles
Focal RT daily—30 x 200 cGy; total dose: 60 Gy
*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.
Stupp R, et al. N Engl J Med. 2005;352: 15

16. Phase III Study: New GBM Radiation ± Temozolomide
Phase III study (N = 573): 2-year OS rate improved from 10.4% with RT alone to 26.5% with temozolomide
100
Median Survival 90 80
RT + temozolomide: 14.6 months 70
RT alone: 12.1 months 60
Problem with clinical trials is that the participants do not reflect patients in the real world. Eg. >70, poor PS 50
Probability of OS (%) 40 30 20 10 6 12 18 24 30 36 42
Months
Stupp R, et al. N Engl J Med. 2005;352: 16

17. Temozolomide - indications
Recurrence of anaplastic astrocytoma and glioblastoma multiforme

18. Surgical Implantation of Chemotherapy Wafers: Gliadel®
BCNU-infused wafers
implanted to tumour bed at time of surgery
chemotherapy released to surrounding brain tissue over a period of 2 to 3 weeks
Clinical trials showed survival benefit
PBS difficulties
Aim is to kill off leftover cancer cells that often can’t be seen with the naked eyes.
Gliadel is indicated in the treatment of newly diagnosed high-grade malignant glioma as an adjunct to surgery and radiation, and in recurrent GBM as an adjunct to surgery.
Gliadel is a trademark of Guilford Pharmaceuticals.

19. Progressive Disease Challenges of diagnosing progressive disease
Pseudo-progression
increase in enhancement without tumor progression
Especially after chemo-radiation
First post-RT MR scan should not be used for treatment decisions
‘Treat the patient not the scan’
Techniques to help distinguish - MRS (spectroscopy), PET scans, SPECT scans
Unfortunately most high grade glioma will eventually become resistant to treatment and progress. This is where the real challenge lies at present.

20. Pseudoprogression: The Index Case
Male, gross total resection for anaplastic ependymoma in August ’97, no neurological deficits, pre-RT MRI:
Deterioration during/after radiation therapy (10/97-12/97, 65 Gy)
Thereafter slight clinical improvement for more than 1 year
There is no way of differentiating pseudoprogression from true disease progression by looking at the scans. The only definitive way is to obtain tissue sample from surgery which is not possible or advisable at times.
Sometimes the presence of pseudoprogression is associated with better outcome. Patients tend to live longer. The changes on scans may represent more response to treatment.
However, these observations are seen after the fact. Patients are often understandably distressed when faced with scans looking worse. My practice is to ignore the scans that are done closely following radiotherapy and push on with planned treatment schedule. I would monitor closely for any new symptoms and repeat scans more often in this setting.

21. Further Treatment for Progression
Surgery
Radiation (stereotactic radio-surgery)
2nd line chemotherapy

22. 2nd line Chemotherapy No consensus
Low dose temozolomide (+/- procarbazine)
Carboplatin
BCNU/CCNU
Bevacizumab (+/- Irinotecan)
Clinical trials if possible

23. Glioblastoma: A Highly Vascular Tumour
The vascular network formed in GBM is abnormal
vessels are dilated, tortuous, disorganised, highly leaky

24. Angiogenesis
Blood vessels grow toward a tumor (left). This contrasts with the normal gridlike pattern of blood vessels that appears at lower right. Dr. Judah Folkman of Children's pioneered the idea that cutting off a tumor's blood supply (anti-angiogenesis) will stop its growth. Today, angiogenesis is one of the most studied areas in science.

25. Avastin (Bevacizumab) – mechanism of action
Tumors release the VEGF protein causing nearby blood vessels to sprout new vessels — a process called angiogenesis. These blood vessels feed the growth of the tumor. They also provide a "highway" for tumor cells to spread to other parts of the body
Avastin is a therapeutic antibody that specifically binds to the VEGF protein theoretically interfering blood supply of tumour, hence stopping the growth of cancer cells.
It is standard treatment for metastatic bowel cancer. Also has activity in cancers of the breast, lung, ovary.
Limited studies have also shown activity in brain tumours.

26. Bevacizumab: Anti-VEGF Antibody
Radiological response. No data to support overall survival benefit. Not PBS indicated.
Recurrent GBM at baseline
After 4 cycles bev/irinotecan
Vredenburgh JJ, et al. J Clin Oncol. 2007;25:
National Comprehensive Cancer Network guideline: CNS cancers (V ) 26

27. Bevacizumab for recurrent glioblastoma
Unanswered questions
Phase II results only
?changes on MRI reflect tumour shrinkage, or reduced swelling from stopping leaking blood vessels
Concerns about rapid progression upon stopping treatment
Phase III trials underway

28. New drugs that failed to impress
Erlotinib
Enzastaurin
Edotecarin
Cediranib

29. Approach to Patients
Complex challenges specific to brain tumour patients
Disease
Physical impairment – weakness, poor mobility, speech, vision
Cognitive impairment – memory, insight, judgment, personality, disinhibition
Depression
Seizures

30. Approach to Patients Polypharmacy Steroids Anticonvulsants
weight gain, elevated BSL, proximal myopathy, emotional lability, reversal of sleep/wake cycle
Anticonvulsants
Antiemetics / aperients / antibiotics
Anticoagulants
Medications for other medical conditions
?compliance
~30-60% patients with primary brain tumours have some seizures (simple/complex; focal / generalised)
gabapentin, lamotrigine, and levetiracetam
In the general population, the annual incidence of DVT is about 1 per 1000, with a case fatality rate
range of 1 to 5%. The incidence of VTE complicating gliomas has been estimated at 20-30%,

31. Approach to Patients Financial / income source Family / dependents
Transfers to frequent clinic visits
Home modifications / hire equipments
Carers
burn-out, financial source

32. Approach to Patients Multidisciplinary approach Neurosurgeon
Radiation Oncologist
Medical Oncologist
Rehabilitation team
Clinical specialist nurse
Neurologist
Endocrinologist
OT/physio/dietitian/speech pathologist
Community/palliative care/hospice
Social worker
Inpatient team GP

33. Conclusions
Management of GBM remains challenging with median survival at 9-15 months
Survival improved by
Resection
Adjuvant radiotherapy plus concurrent chemotherapy
Temozolomide is component of standard of care
Promising investigational directions – the use of targeted therapy
Individually tailored therapy based on genetic profile
Clinical trials participation should be considered
Multidisciplinary team approach is paramount
MGMT, methylguanine methyltransferase. 33