Chemotherapy and trials for brain tumours

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

2. Distribution of primary CNS Tumors by Histology All others13.9% Glioblastoma20.3% Lymphoma3.1% Nerve sheath8.0% Astrocytomas9.8% Craniopharyngioma0.7% Pituitary6.3% Ependymomas2.3% Oligodendrogliomas3.7% Embryonal, including medulloblastoma1.7% Meningioma30.1% CBTRUS Report, 2004-2005.

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] 1. Wen PY, et al. N Engl J Med. 2008;359:492-507.2. DeAngelis LM. N Engl J Med. 2001;344:114-123.

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

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 • Aim • 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 0 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.

12. Significant improvement in survival Stupp et al. Lancet Oncology 2009

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

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

15. Pneumocystis Jerovecii (Carinii) Pneumonia Mahindra AK, et al. J Neurooncol. 2003;63:263-270.

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

17. Treatment options at recurrence • Surgery • Re-resection • BCNU (Carmustine) wafer • Repeat radiation • Chemotherapy • Temozolomide rechallenge • Nitrosoureas (CCNU, BCNU) • Bevacizumab • Clinical trial

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 Friedman HS, et al. JCO 2009

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. AvaGlio[1] Phase III Trials of Bevacizumab in newly diagnosed GBM 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) Bevacizumab10 mg/kg q2w + standard RT (60 Gy D1-5) x 6 wks + TMZ 75 mg/m2 PO/day for 6 wks then 150-200 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 150-200 mg/m2 Days 1-5 of each 6 x 4-wk cycle until progression 4 wks after chemoRT: Adjuvant TMZ 200 mg/m2 D1-5 Q28D for up to 12 courses + placebo 1. ClinicalTrials.gov. NCT00943826. 2. ClinicalTrials.gov. NCT00884741.

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 ClinicalTrials.gov.

26. Genetic Targets in Glioblastoma EGFR, mutated/amplified in 45% HER2mutated in 8% PDGFRα,amplified in 13% MET,amplified in 4% SRC SRC SRC SRC PI3K,mutated in 15% RAS,mutated in 2% PTEN, mutated/deleted in 36% NF1, mutated/ deleted in 18% AKT,amplified in 2% Proliferation,survival,translation FOXO,mutated in 1% Wick W, et al Neuro-Oncol. 2011

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 • http://www.anzctr.org.au/ • COGNO (Co-operative trials group for neuro-oncology) • http://www.cogno.org.au/

29. Conclusion • Current standard of care • 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