Medical treatment for high grade gliomas an overview
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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 l.jpg

Medical Treatment for High Grade Gliomas – An Overview

Dr Daphne Tsoi

MBBS MSc FRACP

Medical Oncologist

Royal Perth Hospital

SJOG Hospitals Subiaco, Murdoch


Incidence l.jpg
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 l.jpg

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 l.jpg
Glial cells UK, 2001, by cancer type

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

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


Glioma grading l.jpg
Glioma: Grading UK, 2001, by cancer type

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


Median survival importance of histologic grading l.jpg
Median Survival: UK, 2001, by cancer type 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.


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Primary vs Secondary GBM UK, 2001, by cancer type

  • 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)


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Presentation UK, 2001, by cancer type

  • Headache

  • Seizure

  • Motor weakness/speech deficit

  • Altered personality

  • Loss of memory/cognition

  • Dizziness


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MRI UK, 2001, by cancer type

Biopsy

Investigations


Features of glioblastoma multiforme l.jpg
Features of Glioblastoma Multiforme UK, 2001, by cancer type

  • Rapid progression

  • Enhancing tumor

  • Surrounding edema

    • Contains tumour

  • ~ 5% multifocal


Treatment l.jpg
Treatment UK, 2001, by cancer type

  • Surgery

  • Radiotherapy

  • Chemotherapy


Temozolomide temodal l.jpg
Temozolomide UK, 2001, by cancer type (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)


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Temozolomide – Side Effects UK, 2001, by cancer type

  • Tiredness / fatigue

  • Nausea

  • Constipation (from anti-emetics)

  • Low blood counts – red/white/platelets

    • Particularly lymphocytes (risk of Pneumocystis carinii pneumonia)

  • Rash


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Standard Treatment for GBM UK, 2001, by cancer type

  • Radiotherapy concurrently with Temozolomide followed by 6 months of Temozolomide


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Phase III Study: New GBM UK, 2001, by cancer type 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.


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Phase III Study: New GBM UK, 2001, by cancer type 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.


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Temozolomide - indications UK, 2001, by cancer type

  • Recurrence of anaplastic astrocytoma and glioblastoma multiforme


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Surgical Implantation of Chemotherapy Wafers: Gliadel UK, 2001, by cancer type ®

  • 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.


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Progressive Disease UK, 2001, by cancer type

  • 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 UK, 2001, by cancer type

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


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Further Treatment for Progression UK, 2001, by cancer type

  • Surgery

  • Radiation (stereotactic radio-surgery)

  • 2nd line chemotherapy


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2 UK, 2001, by cancer type nd line Chemotherapy

  • No consensus

  • Low dose temozolomide (+/- procarbazine)

  • Carboplatin

  • BCNU/CCNU

  • Bevacizumab (+/- Irinotecan)

  • Clinical trials if possible


Glioblastoma a highly vascular tumour l.jpg
Glioblastoma: A Highly Vascular Tumour UK, 2001, by cancer type

  • The vascular network formed in GBM is abnormal

    • vessels are dilated, tortuous, disorganised, highly leaky


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Angiogenesis UK, 2001, by cancer type



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Bevacizumab: Anti-VEGF Antibody UK, 2001, by cancer type

  • 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)


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Bevacizumab for recurrent glioblastoma UK, 2001, by cancer type

  • 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


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New drugs that failed to impress UK, 2001, by cancer type

  • Erlotinib

  • Enzastaurin

  • Edotecarin

  • Cediranib


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Approach to Patients UK, 2001, by cancer type

  • Complex challenges specific to brain tumour patients

  • Disease

    • Physical impairment – weakness, poor mobility, speech, vision

    • Cognitive impairment – memory, insight, judgment, personality, disinhibition

    • Depression

    • Seizures


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Approach to Patients UK, 2001, by cancer type

  • 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 l.jpg
Approach to Patients UK, 2001, by cancer type

  • Financial / income source

  • Family / dependents

  • Transfers to frequent clinic visits

  • Home modifications / hire equipments

  • Carers

    • burn-out, financial source


Approach to patients32 l.jpg
Approach to Patients UK, 2001, by cancer type

  • 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 l.jpg
Conclusions UK, 2001, by cancer type

  • 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