Transcript Medical Treatment for High Grade Gliomas

Medical Treatment for High
Grade Gliomas – An Overview
Dr Daphne Tsoi
MBBS MSc FRACP
Medical Oncologist
Royal Perth Hospital
SJOG Hospitals Subiaco, Murdoch
Incidence
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~ 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)
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
Classification
Characteristics
Astrocytes
Star-shaped cells
Astrocytomas
Oligodendrocytes
Possess few
dendrites
Oligodendrogliomas
Ependymal cells
Line the ventricles
Ependymomas
http://ovidsp.com/spb/ovidweb.cgi
Chamberlain MC et al. West J Med. 1998;168:114-120.
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
Chamberlain MC, et al. West J Med. 1998;168:114-120.
Median Survival:
Importance of Histologic Grading
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Pathologic diagnosis is crucial in determining
treatment and prognosis
Tumor Type
Low-grade oligodendroglioma
Low-grade astrocytoma
Anaplastic oligodendroglioma
Median
Survival, years
4-10
5
3-4
Anaplastic astrocytoma
3
Glioblastoma multiforme
<1
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
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Primary GBM
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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)
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Secondary GBM
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Develops from low-grade or
anaplastic astrocytoma
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~ 70% of lower grade
gliomas develop into
advanced disease within 510 years of diagnosis
Comprises < 5% of GBM cases
Occurs in younger patients
(median age: 45 years)
Presentation
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Headache
Seizure
Motor weakness/speech deficit
Altered personality
Loss of memory/cognition
Dizziness
Investigations
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MRI
Biopsy
Features of Glioblastoma Multiforme
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Rapid progression
Enhancing tumor
Surrounding edema
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Contains tumour
~ 5% multifocal
Treatment
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Surgery
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Radiotherapy
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Chemotherapy
Temozolomide
(Temodal)
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Methylating agent
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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)
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Temozolomide – Side Effects
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Tiredness / fatigue
Nausea
Constipation (from anti-emetics)
Low blood counts – red/white/platelets
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Particularly lymphocytes (risk of Pneumocystis
carinii pneumonia)
Rash
Standard Treatment for GBM
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Radiotherapy concurrently with
Temozolomide followed by 6 months of
Temozolomide
Phase III Study: New GBM
Radiation ± Temozolomide
Concomitant
TMZ + RT*
R
0
Adjuvant TMZ
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 ± Temozolomide
Phase III study (N = 573): 2-year OS rate improved from
10.4% with RT alone to 26.5% with temozolomide
Probability of OS (%)
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100
90
80
70
60
50
40
30
20
10
0
Median Survival
RT + temozolomide: 14.6 months
RT alone: 12.1 months
0
6
12
Stupp R, et al. N Engl J Med. 2005;352:987-996.
18
24
Months
30
36
42
Temozolomide - indications
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Recurrence of anaplastic astrocytoma and
glioblastoma multiforme
Surgical Implantation of
Chemotherapy Wafers: Gliadel®
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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
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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
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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 (10/9712/97, 65 Gy)
 Thereafter slight clinical improvement for more than 1
year
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Further Treatment for Progression
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Surgery
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Radiation (stereotactic radio-surgery)
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2nd line chemotherapy
nd
2
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line Chemotherapy
No consensus
Low dose temozolomide (+/- procarbazine)
Carboplatin
BCNU/CCNU
Bevacizumab (+/- Irinotecan)
Clinical trials if possible
Glioblastoma: A Highly Vascular Tumour
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The vascular network formed in GBM is
abnormal
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vessels are dilated, tortuous, disorganised, highly
leaky
Angiogenesis
Avastin (Bevacizumab) – mechanism of
action
Bevacizumab: Anti-VEGF Antibody
Recurrent GBM
at baseline
After 4 cycles
bev/irinotecan
1. Vredenburgh JJ, et al. J Clin Oncol. 2007;25:4722-4729.
2. National Comprehensive Cancer Network guideline: CNS cancers (V.1.2008)
Bevacizumab for recurrent glioblastoma
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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
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Erlotinib
Enzastaurin
Edotecarin
Cediranib
Approach to Patients
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Complex challenges specific to brain tumour
patients
Disease
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Physical impairment – weakness, poor mobility,
speech, vision
Cognitive impairment – memory, insight,
judgment, personality, disinhibition
Depression
Seizures
Approach to Patients
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Polypharmacy
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Steroids
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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 Patients
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Financial / income source
Family / dependents
Transfers to frequent clinic visits
Home modifications / hire equipments
Carers
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burn-out, financial source
Approach to Patients
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Multidisciplinary approach
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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
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Management of GBM remains challenging with median survival
at 9-15 months
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Survival improved by
 Resection
 Adjuvant radiotherapy plus concurrent chemotherapy
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Temozolomide is component of standard of care
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Promising investigational directions – the use of targeted therapy
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Individually tailored therapy based on genetic profile
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Clinical trials participation should be considered
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Multidisciplinary team approach is paramount