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Medical Treatment for High Grade Gliomas – An Overview. Dr Daphne Tsoi MBBS MSc FRACP Medical Oncologist Royal Perth Hospital SJOG Hospitals Subiaco, Murdoch. Incidence. ~ 1400 cases of primary brain tumour diagnosed in Australia each year Primary CNS cancers – 7/100,000/year

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medical treatment for high grade gliomas an overview

Medical Treatment for High Grade Gliomas – An Overview

Dr Daphne Tsoi

MBBS MSc FRACP

Medical Oncologist

Royal Perth Hospital

SJOG Hospitals Subiaco, Murdoch

incidence
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)
slide3

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)

glial cells
Glial cells

http://ovidsp.com/spb/ovidweb.cgi

Chamberlain MC et al. West J Med. 1998;168:114-120.

glioma grading
Glioma: Grading

Chamberlain MC, et al. West J Med. 1998;168:114-120.

median survival importance of histologic grading
Median Survival: Importance of Histologic Grading
  • Pathologic diagnosis is crucial in determining treatment and prognosis

1Bruce J. Available at: http://www.emedicine.com.

2Hariharan S. Available at: http://www.emedicine.com.

3DeAngelis LM. N Engl J Med. 2001;344:114-123.

primary vs secondary gbm
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)
presentation
Presentation
  • Headache
  • Seizure
  • Motor weakness/speech deficit
  • Altered personality
  • Loss of memory/cognition
  • Dizziness
features of glioblastoma multiforme
Features of Glioblastoma Multiforme
  • Rapid progression
  • Enhancing tumor
  • Surrounding edema
    • Contains tumour
  • ~ 5% multifocal
treatment
Treatment
  • Surgery
  • Radiotherapy
  • Chemotherapy
temozolomide temodal
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)

temozolomide side effects
Temozolomide – Side Effects
  • Tiredness / fatigue
  • Nausea
  • Constipation (from anti-emetics)
  • Low blood counts – red/white/platelets
    • Particularly lymphocytes (risk of Pneumocystis carinii pneumonia)
  • Rash
standard treatment for gbm
Standard Treatment for GBM
  • Radiotherapy concurrently with Temozolomide followed by 6 months of Temozolomide
phase iii study new gbm radiation temozolomide
Phase III Study: New GBM Radiation ± Temozolomide

Concomitant TMZ + RT*

Adjuvant TMZ

R

0

6

10

14

18

22

26

30

Wks

RT Alone

TMZ 75 mg/m2 PO QD for 6 weeks, then 150-200 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;352:987-996.

phase iii study new gbm radiation temozolomide16
Phase III Study: New GBM Radiation ± Temozolomide

100

Median Survival

90

RT + temozolomide: 14.6 months

80

RT alone: 12.1 months

70

60

50

Probability of OS (%)

40

30

20

10

0

0

6

12

18

24

30

36

42

Months

  • Phase III study (N = 573): 2-year OS rate improved from 10.4% with RT alone to 26.5% with temozolomide

Stupp R, et al. N Engl J Med. 2005;352:987-996.

temozolomide indications
Temozolomide - indications
  • Recurrence of anaplastic astrocytoma and glioblastoma multiforme
surgical implantation of chemotherapy wafers gliadel
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

Gliadelis a trademark of Guilford Pharmaceuticals.

progressive disease
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
pseudoprogression the index case
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

further treatment for progression
Further Treatment for Progression
  • Surgery
  • Radiation (stereotactic radio-surgery)
  • 2nd line chemotherapy
2 nd line chemotherapy
2nd line Chemotherapy
  • No consensus
  • Low dose temozolomide (+/- procarbazine)
  • Carboplatin
  • BCNU/CCNU
  • Bevacizumab (+/- Irinotecan)
  • Clinical trials if possible
glioblastoma a highly vascular tumour
Glioblastoma: A Highly Vascular Tumour
  • The vascular network formed in GBM is abnormal
    • vessels are dilated, tortuous, disorganised, highly leaky
bevacizumab anti vegf antibody
Bevacizumab: Anti-VEGF Antibody
  • After 4 cycles bev/irinotecan
  • Recurrent GBM at baseline
  • Vredenburgh JJ, et al. J Clin Oncol. 2007;25:4722-4729.
  • National Comprehensive Cancer Network guideline: CNS cancers (V.1.2008)
bevacizumab for recurrent glioblastoma
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
new drugs that failed to impress
New drugs that failed to impress
  • Erlotinib
  • Enzastaurin
  • Edotecarin
  • Cediranib
approach to patients
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
approach to patients30
Approach to Patients
  • Polypharmacy
    • Steroids
      • weight gain, elevated BSL, proximal myopathy, emotional lability, reversal of sleep/wake cycle
    • Anticonvulsants
    • Antiemetics / aperients / antibiotics
    • Anticoagulants
    • Medications for other medical conditions
    • ?compliance
approach to patients31
Approach to Patients
  • Financial / income source
  • Family / dependents
  • Transfers to frequent clinic visits
  • Home modifications / hire equipments
  • Carers
    • burn-out, financial source
approach to patients32
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
conclusions
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
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