Medical Treatment for High Grade Gliomas – An Overview

Dr Daphne TsoiMBBS MSc FRACP

Medical OncologistRoyal Perth HospitalSJOG Hospitals Subiaco, Murdoch

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)

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

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

Classification Characteristics

Astrocytes Star-shaped cells

Astrocytomas

Oligodendrocytes Possess few dendrites

Oligodendrogliomas

Ependymal cells Line the ventricles

Ependymomas

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

Pathologic diagnosis is crucial in determining treatment and prognosis

Tumor TypeMedian

Survival, years

Low-grade oligodendroglioma 4-10

Low-grade astrocytoma 5

Anaplastic oligodendroglioma 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

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

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

Investigations

MRI Biopsy

Features of Glioblastoma Multiforme Rapid progression Enhancing tumor Surrounding edema

Contains tumour

~ 5% multifocal

Treatment

Surgery

Radiotherapy

Chemotherapy

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

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

Radiotherapy concurrently with Temozolomide followed by 6 months of Temozolomide

Focal RT daily—30 x 200 cGy;total dose: 60 Gy

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

Concomitant TMZ + RT*

Adjuvant TMZ

Wks6 10 14 18 22 26 30

RT Alone

R0

*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.

Phase III Study: New GBM Radiation ± Temozolomide

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

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

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00 6 12 18 24 30 36 42

Pro

bab

ility

of

OS

(%

)

Months

Median SurvivalRT + temozolomide: 14.6 monthsRT alone: 12.1 months

Temozolomide - indications

Recurrence of anaplastic astrocytoma and glioblastoma multiforme

Surgical Implantation of Chemotherapy Wafers: Gliadel®

Gliadel is a trademark of Guilford Pharmaceuticals.

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

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

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 Surgery

Radiation (stereotactic radio-surgery)

2nd 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 The vascular network formed in GBM is

abnormal

vessels are dilated, tortuous, disorganised, highly leaky

Angiogenesis

Avastin (Bevacizumab) – mechanism of action

Bevacizumab: Anti-VEGF Antibody

1. Vredenburgh JJ, et al. J Clin Oncol. 2007;25:4722-4729.2. National Comprehensive Cancer Network guideline: CNS cancers (V.1.2008)

Recurrent GBM at baseline

After 4 cycles bev/irinotecan

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 Erlotinib Enzastaurin Edotecarin Cediranib

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 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 Patients

Financial / income source Family / dependents Transfers to frequent clinic visits Home modifications / hire equipments Carers

burn-out, financial source

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

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