Medical Treatment for High Grade Gliomas – An Overview

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  • Brain cancers .are among the most devastating to patients and their carers because they affect the organ that defines the self.
    Australia-wide, the crude incidence of primary brain and other CNS cancers increased 0.3% per year from 1982 to 2004, similar to increases in some other countries. These increases have been attributed to the introduction CT/MRI.
    Risk: 1 in 100,000
  • Although these cancers are not common, the average person years of life lost due to primary brain cancers is estimated at 12 years per patient in Australia in 2001.
    This is much higher than the average for all cancers (three years) because these cancers tend to occur in younger people.
  • There is a wide variety of CNS tumours, with the World Health Organisation listing more than 120 types.
    glia (Greek for "glue"), are non-neuronal cells that provide support and nutrition
    Oligodendrocytes – main function is insulation of axons
    Astrocytes – provide nutritional support to neurons, biochemical support to endothelial cells that form BBB; repair of brain cells following injury
  • <number>
    Reference:
    1. Chamberlain MC, et al. Practical guidelines for the treatment of malignant gliomas. West J Med. 1998;168:114-120.
  • <number>
    The behavior of brain tumors is highly variable depending on cell type, with cell type and grade the most important determinants.
    Median survival – time at which 50% patients with this condition who are still alive
  • MRI – image modality of choice
    Biopsy is crucial in determining treatment options and prognosis
  • <number>
    Rapid growth is a key feature of glioblastoma multiforme, as seen in the progression of this lesion over a 68-day period. Median survival is poor, typically on the order of 9 to 14 months.
    On MRI, a glioblastoma typically appears as an irregular lesion with ring-like contrast enhancement surrounded by vasogenic edema. Tumor cells extend microscopically out from the apparent area of disease.
  • BBB is a defence mechanism of the brain to ward off anything foreign that is potentially harmful to the brain. A lot of drugs particularly chemotherapy can’t cross the BBB, therefore are inactive against brain disease. Tem is different, hence active in GBM.
  • Phase III study is the gold standard method of proving if an experimental treatment is better when compared to standard treatment.
  • Problem with clinical trials is that the participants do not reflect patients in the real world. Eg. >70, poor PS
  • <number>
    Aim is to kill off leftover cancer cells that often can’t be seen with the naked eyes.
    Gliadel is indicated in the treatment of newly diagnosed high-grade malignant glioma as an adjunct to surgery and radiation, and in recurrent GBM as an adjunct to surgery.
  • Unfortunately most high grade glioma will eventually become resistant to treatment and progress. This is where the real challenge lies at present.
  • There is no way of differentiating pseudoprogression from true disease progression by looking at the scans. The only definitive way is to obtain tissue sample from surgery which is not possible or advisable at times.
    Sometimes the presence of pseudoprogression is associated with better outcome. Patients tend to live longer. The changes on scans may represent more response to treatment.
    However, these observations are seen after the fact. Patients are often understandably distressed when faced with scans looking worse. My practice is to ignore the scans that are done closely following radiotherapy and push on with planned treatment schedule. I would monitor closely for any new symptoms and repeat scans more often in this setting.
  • Blood vessels grow toward a tumor (left). This contrasts with the normal gridlike pattern of blood vessels that appears at lower right. Dr. Judah Folkman of Children's pioneered the idea that cutting off a tumor's blood supply (anti-angiogenesis) will stop its growth. Today, angiogenesis is one of the most studied areas in science.
  • Tumors release the VEGF protein causing nearby blood vessels to sprout new vessels — a process called angiogenesis. These blood vessels feed the growth of the tumor. They also provide a "highway" for tumor cells to spread to other parts of the body
    Avastin is a therapeutic antibody that specifically binds to the VEGF protein theoretically interfering blood supply of tumour, hence stopping the growth of cancer cells.
    It is standard treatment for metastatic bowel cancer. Also has activity in cancers of the breast, lung, ovary.
    Limited studies have also shown activity in brain tumours.
  • Radiological response. No data to support overall survival benefit. Not PBS indicated.
  • ~30-60% patients with primary brain tumours have some seizures (simple/complex; focal / generalised)
    gabapentin, lamotrigine, and levetiracetam
    In the general population, the annual incidence of DVT is about 1 per 1000, with a case fatality rate
    range of 1 to 5%. The incidence of VTE complicating gliomas has been estimated at 20-30%,
  • MGMT, methylguanine methyltransferase.
  • Medical Treatment for High Grade Gliomas – An Overview

    1. 1. Medical Treatment for High Grade Gliomas – An Overview Dr Daphne Tsoi MBBS MSc FRACP Medical Oncologist Royal Perth Hospital SJOG Hospitals Subiaco, Murdoch
    2. 2. 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)
    3. 3. 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)
    4. 4. 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.
    5. 5. 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.
    6. 6. Median Survival: Importance of Histologic Grading  Pathologic diagnosis is crucial in determining treatment and prognosis Tumor Type Median 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.
    7. 7. 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)
    8. 8. Presentation  Headache  Seizure  Motor weakness/speech deficit  Altered personality  Loss of memory/cognition  Dizziness
    9. 9. Investigations  MRI  Biopsy
    10. 10. Features of Glioblastoma Multiforme  Rapid progression  Enhancing tumor  Surrounding edema  Contains tumour  ~ 5% multifocal
    11. 11. Treatment  Surgery  Radiotherapy  Chemotherapy
    12. 12. 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)
    13. 13. Temozolomide – Side Effects  Tiredness / fatigue  Nausea  Constipation (from anti-emetics)  Low blood counts – red/white/platelets  Particularly lymphocytes (risk of Pneumocystis carinii pneumonia)  Rash
    14. 14. Standard Treatment for GBM  Radiotherapy concurrently with Temozolomide followed by 6 months of Temozolomide
    15. 15. 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 R 0 *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.
    16. 16. 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. 100 90 80 70 60 50 40 30 20 10 0 0 6 12 18 24 30 36 42 ProbabilityofOS(%) Months Median Survival RT + temozolomide: 14.6 months RT alone: 12.1 months
    17. 17. Temozolomide - indications  Recurrence of anaplastic astrocytoma and glioblastoma multiforme
    18. 18. 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
    19. 19. 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
    20. 20. 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
    21. 21. Further Treatment for Progression  Surgery  Radiation (stereotactic radio-surgery)  2nd line chemotherapy
    22. 22. 2nd line Chemotherapy  No consensus  Low dose temozolomide (+/- procarbazine)  Carboplatin  BCNU/CCNU  Bevacizumab (+/- Irinotecan)  Clinical trials if possible
    23. 23. Glioblastoma: A Highly Vascular Tumour  The vascular network formed in GBM is abnormal  vessels are dilated, tortuous, disorganised, highly leaky
    24. 24. Angiogenesis
    25. 25. Avastin (Bevacizumab) – mechanism of action
    26. 26. 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
    27. 27. 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
    28. 28. New drugs that failed to impress  Erlotinib  Enzastaurin  Edotecarin  Cediranib
    29. 29. 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
    30. 30. 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
    31. 31. Approach to Patients  Financial / income source  Family / dependents  Transfers to frequent clinic visits  Home modifications / hire equipments  Carers  burn-out, financial source
    32. 32. 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
    33. 33. 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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