1. Chemotherapy and trials for brain tumours
Kate Cuff
Medical Oncologist
Princess Alexandra Hospital

2. Distribution of primary CNS Tumors by Histology
All others 13.9%
Glioblastoma 20.3%
Lymphoma 3.1%
Nerve sheath 8.0%
Astrocytomas 9.8%
Craniopharyngioma 0.7%
CBTRUS, Central Brain Tumor Registry of the United States; CNS, central nervous system.
Pituitary 6.3%
Ependymomas 2.3%
Oligodendrogliomas 3.7%
Embryonal, including medulloblastoma 1.7%
Meningioma 30.1%
CBTRUS Report, 2

3. Prognostic Classification
WHO classification system
Released in 1993; updated in 2007
Tumors classified by cell origin and level of aggression (grades 1-4)[1,2]
Grade
Histology
Median Survival, Yrs[2] 1
Pilocytic astrocytoma
>10 2
Well-differentiated astrocytoma
>5 3
Anaplastic astrocytoma 4
Glioblastoma multiforme
WHO, World Health Organization.
1. Wen PY, et al. N Engl J Med. 2008;359: DeAngelis LM. N Engl J Med. 2001;344: 3

4. Malignant Gliomas Annual incidence 7 cases / 100,000 people
Glioblastoma
Most commonly seen 6th-8th decade of life
Incidence 1.6 fold higher in males than females
No modifiable risk factors

5. Challenges to treatment
Biologically aggressive
Drug delivery
Blood brain barrier
Toxicity to normal brain
Infiltration of malignant cells into brain parenchyma

6. Timing of chemotherapy
Adjuvant
After surgery or radiation
Defined number of cycles
Aim
prolong time to recurrence
Recurrence
Number of cycles limited by side effects
improve symptoms, quality of life and slow progression

7. A bit of history..
Surgery and radiation mainstays of treatment (and still are)
Chemotherapy options
PCV standard of care for many years
Procarbazine
Carmustine (BCNU)
Vincristine
Significant side effects
Single agent nitrosurea (lomustine/carmustine) equivalent

8. Mechanism of action of chemotherapy agents

9. Side effects of alkylating agents
Cell counts
Low neutrophils
Increased risk of infections
Low platelets
Increased risk of bleeding
Nausea and vomiting
Second cancers
Leukaemia
Solid cancers

10. NEJM 2005

11. Stupp Treatment Schema
Concomitant
Adjuvant TMZ
TMZ/RT* R 6 10 14 18 22 26 30
Weeks
RT Alone
Temozolomide 75 mg/m2 po qd for 6 weeks,
then 150–200 mg/m2 po qd d1–5 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. 11

12. Significant improvement in survivalRT
RT + TMZ
Median, mos
12.1
14.6
2 yr, %
10.9
27.2
3 yr, %
4.4
16.0
4 yr, %
3.0
12.1%
5 yr, %
1.9
9.8
Stupp et al. Lancet Oncology 2009

13. Adverse events during treatment
May be related to
Steroids
Chemotherapy
Radiation
Brain tumour

14. Steroid related adverse events
Common
Muscle weakness
Behavioural changes
Visual blurring
Tremor
Insomnia
Reflux
High blood sugar
Uncommon
Hallucinations
Psychosis
Peptic ulcer
Diabetes
Dependence

15. Pneumocystis Jerovecii (Carinii) Pneumonia
Mahindra AK, et al. J Neurooncol. 2003;63: 15

16. Venous Thromboembolic Disease
Common
Highest incidence among cancers, comparable to pancreatic and gynecologic malignancies
Majority occur in postoperative period
> 40% occur outside postoperative period
21% rate at 12 mos; 32% at 24 mos
Gerber DE, et al. J Clin Oncol. 2005 16

17. Treatment options at recurrence
Surgery
Re-resection
BCNU (Carmustine) wafer
Repeat radiation
Chemotherapy
Temozolomide rechallenge
Nitrosoureas (CCNU, BCNU)
Bevacizumab
Clinical trial
BCNU, bis-chloroethylnitrosourea (carmustine); CCNU, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; OS, overall survival; PFS 6, 6-month progression-free survival. 17

18. Bevacizumab (Avastin)
VEGF inhibitor
Targets angiogenesis

19. Bevacizumab (Avastin)
To date mainly investigated in Phase II trials
Usually in combination with irinotecan chemotherapy
TGA approved for use in relapsed glioma
Not approved on PBS
Requires co-payment (~$20,000)
No trials have demonstrated a survival benefit

20. Bevacizumab ± Irinotecan in Recurrent GBM
Phase II study in 167 patients
Bevacizumab
(n = 85)
Bevacizumab +
Irinotecan
(n = 82)
Response %
28.2
37.8
6-mo PFS %
42.6
50.3
Survival (months)
9.2
8.7
GBM, glioblastoma multiforme; PFS, progression-free survival.
Friedman HS, et al. JCO 2009 20

21. Bevacizumab adverse events
Side effects include
Hypertension (9%)
Delayed wound healing (2%)
Bowel perforation (2%)
Intracranial haemorrhage (2%)
Venous and arterial clots (4%)

22. Ongoing clinical trials

23. Phase III Trials of Bevacizumab in newly diagnosed GBM
AvaGlio[1]
RTOG 0825[2]
Newly Diagnosed GBM
≥ 18 years; KPS 70% to 100%
Standard RT + concurrent TMZ (Planned N = 942)
Newly diagnosed GBM (planned N = 920)
Bevacizumab 10 mg/kg q2w + standard RT (60 Gy D1-5) x 6 wks + TMZ 75 mg/m2 PO/day for 6 wks then mg/m2 Days 1-5 of each 6 x 4-wk cycle until progression
Wk 4 of chemoRT: Bevacizumab q2w, continuing until completion of adjuvant TMZ
4 wks after chemoRT: Adjuvant TMZ 200 mg/m2 Days 1-5 Q28D for up to 12 courses + placebo
Placebo q2w + standard RT (60 Gy D1-5) x 6 wks + TMZ 75 mg/m2 PO/day for 6 wks then mg/m2 Days 1-5 of each 6 x 4-wk cycle until progression
GBM, glioblastoma; Gy, gray; KPS, Karnofsky performance status; PO, orally; RT, radiotherapy; RTOG, Radiation Therapy Oncology Group;TMZ, temozolomide.
4 wks after chemoRT:
Adjuvant TMZ 200 mg/m2 D1-5 Q28D for up to 12 courses + placebo
1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT 23

24. Randomised Phase II study of carboplatin and bevacizumab in recurrent Glioblastoma (Cabaret)
Recurrent glioblastoma post radiation and temozolomide
Bevacizumab ± carboplatin
Closed to accrual
Results awaited

25. Angiogenesis-Targeting Agents for Glioblastoma
Disease Setting
Study Phase
Integrins
Cilengitide
nGBM
rGBM
Phase III
Phase I/II
Angiopoietin/Tie 2
CVX-060
VEGF
VEGF-trap (aflibercept)
VEGFR TKIs (cabozantinib, cediranib, axitinib, pazopanib)
Bevacizumab + strategies
rGBM, nGBM
nGBM, rGBM
Phase II
Phase I
Phase I, II, III
Endothelial cell proliferation
Metronomic temozolomide
Phase II, III
nGBM, newly diagnosed glioblastoma multiforme; rGBM, recurrent glioblastoma multiforme; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.
ClinicalTrials.gov. 25

26. Genetic Targets in Glioblastoma
EGFR, mutated/ amplified in 45%
HER2 mutated in 8%
PDGFRα, amplified in 13%
MET, amplified in 4%
SRC
SRC
SRC
SRC
RAS, mutated in 2%
PI3K, mutated in 15%
PTEN, mutated/ deleted in 36%
EGFR, epidermal growth factor receptor; PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidylinositol-3-kinase.
NF1, mutated/ deleted in 18%
AKT, amplified in 2%
Proliferation, survival, translation
FOXO, mutated in 1%
Wick W, et al Neuro-Oncol. 2011 26

27. Current trials available in Brisbane
Elderly Glioblastoma
Temozolomide and short course radiation vs short course radiation alone in pts > 65yrs
Catnon
Addition of temozolomide to radiation in Grade III gliomas without 1p/19q deletion
EGFR vaccine
Stupp protocol ± vaccine in EGFR mutation positive pts

28. Where to find trials? Talk to your clinician
Australian and New Zealand clinical trials registry
COGNO (Co-operative trials group for neuro-oncology)

29. Conclusion Current standard of care Recurrence
TMZ + RT followed by 6 months of TMZ
Recurrence
Treatment options unsatisfactory
TMZ / nitrosurea / bevacizumab
Involvement in clinical trials encouraged
Multiple new therapies under development