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 (Colon cancer – 60/100,000/year) 14th most common cancer in Australia Highest in terms of average year lost (12 years per patient) 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

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) 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.

Glial cells Classification Characteristics Astrocytes Star-shaped cells Astrocytomas Oligodendrocytes Possess few dendrites Oligodendrogliomas Ependymal cells Line the ventricles Ependymomas 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 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 Reference: 1. Chamberlain MC, et al. Practical guidelines for the treatment of malignant gliomas. West J Med. 1998;168:114-120. 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 Type Median Survival, years Low-grade oligodendroglioma 4-10 Low-grade astrocytoma 5 Anaplastic oligodendroglioma 3-4 Anaplastic astrocytoma 3 Glioblastoma multiforme <1 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 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 MRI – image modality of choice Biopsy is crucial in determining treatment options and prognosis

Features of Glioblastoma Multiforme Rapid progression Enhancing tumor Surrounding edema Contains tumour ~ 5% multifocal 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.

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) 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. 12

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

Phase III Study: New GBM Radiation ± Temozolomide Concomitant TMZ + RT* Adjuvant TMZ R 6 10 14 18 22 26 30 Wks Phase III study is the gold standard method of proving if an experimental treatment is better when compared to standard treatment. 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. 15

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 100 Median Survival 90 80 RT + temozolomide: 14.6 months 70 RT alone: 12.1 months 60 Problem with clinical trials is that the participants do not reflect patients in the real world. Eg. >70, poor PS 50 Probability of OS (%) 40 30 20 10 6 12 18 24 30 36 42 Months Stupp R, et al. N Engl J Med. 2005;352:987-996. 16

Temozolomide - indications Recurrence of anaplastic astrocytoma and glioblastoma multiforme

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 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. Gliadel is a trademark of Guilford Pharmaceuticals.

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 Unfortunately most high grade glioma will eventually become resistant to treatment and progress. This is where the real challenge lies at present.

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 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.

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 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.

Avastin (Bevacizumab) – mechanism of action 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.

Bevacizumab: Anti-VEGF Antibody Radiological response. No data to support overall survival benefit. Not PBS indicated. Recurrent GBM at baseline After 4 cycles bev/irinotecan Vredenburgh JJ, et al. J Clin Oncol. 2007;25:4722-4729. National Comprehensive Cancer Network guideline: CNS cancers (V.1.2008) 26

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 Anticonvulsants weight gain, elevated BSL, proximal myopathy, emotional lability, reversal of sleep/wake cycle Anticonvulsants Antiemetics / aperients / antibiotics Anticoagulants Medications for other medical conditions ?compliance ~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%,

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 MGMT, methylguanine methyltransferase. 33