Update on the Treatment of Glioblastoma

Transcription

1 Update on the Treatment of Glioblastoma Kara Laing MD, FRCPC Chair and Associate Professor, Discipline of Oncology, Memorial University of Newfoundland Medical Oncologist, Cancer Care Program, Eastern Health October 24, 2014

2 Disclosures In the past three years, I have received speaker s honorarium and travel grants from Roche

3 Learning Objectives Review standard of care for treatment of glioblastoma: upfront and recurrent Outline how to monitor for and manage the toxicities of systemic therapy Highlight important role of GPO in the care of these complex patients

4 Brain Tumors About 2% of all malignancies Account for 85% of primary CNS tumors In Canada in new cases (1700 males and 1200 females) 1950 deaths (1150 males and 800 females) Approximately 45 cases per year in NL Gliomas are most common in adults Cause significant morbidity and mortality

5 Canadian Cancer Statistics 2014

6 Tier 3 (<50%) Tier 2 (50-80%) Tier 1 (>80%) Five-year relative survival ratio (RSR) for most common cancers, by sex, Canada, RSR (%) Thyroid Testis Prostate Melanoma Breast Hodgkin lymphoma Body of Uterus Bladder Cervix Kidney Larynx Oral Colorectal Non-Hodgki lymphoma Leukemia Ovary Multiple myeloma Stomach Brain Liver Lung Esophagus Pancreas Males Females Data source: Canadian Cancer Statistics 2013

7 Gliomas WHO Presence or absence of nuclear atypia Mitotic activity Microvascular proliferation Presence or absence of necrosis

8 Astrocytic Tumors WHO Grade WHO Designation Histology Criteria Median Survival I Pilocytic astrocytoma Absence of all criterion Most cured II 15-20% Diffuse astrocytoma One criterion, nuclear atypia 5 to 15 years III 30-35% Anaplastic astrocytoma 2 criteria, nuclear atypia and mitotic activity 3 to 5 years IV 40-50% Glioblastoma 3 criteria, endothelial proliferation and/or necrosis 12 to 18 months

9 Glioblastoma Most common primary brain tumor in adults High grade, WHO grade IV astrocytoma Poor prognosis Supportive care 2 to 3 months Radiation 6 to 9 months RT and chemotherapy 15 months Majority of patients recur within 2 years

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11 Case Presentation 61 yo lady presents with new onset seizure Word finding difficulty Otherwise well No focal deficits on examination MRI vague enhancement in left temporal lobe Repeated in one month showed enhancing mass Surgery: gross total resection Pathology: glioblastoma

12 MRI: T1 Post / T2

13 Case Presentation ECOG PS 1 No further seizures Medications Dexamethasone 4 mg po bid Carbamazepine 200 mg po tid Ranitidine 150 mg po bid Lorazepam 1 mg po q 8hr PRN Allergies Trimethoprim sulfamethoxazole

14 Case Presentation What is best treatment option? What is her prognosis? Should steroids by tapered? Does she need antiepileptic therapy?

15 Management Multidisciplinary team involved Surgery Radiation Systemic therapy Supportive care

16 Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma EORTC and NCIC CE.3 Roger Stupp, M.D., Warren P. Mason, M.D., Martin J. van den Bent, M.D., Michael Weller, M.D., Barbara Fisher, M.D., Martin J.B. Taphoorn, M.D., Karl Belanger, M.D., Alba A. Brandes, M.D., Christine Marosi, M.D., Ulrich Bogdahn, M.D., Jürgen Curschmann, M.D., Robert C. Janzer, M.D., Samuel K. Ludwin, M.D.,Thierry Gorlia, M.Sc., Anouk Allgeier, Ph.D., Denis Lacombe, M.D., J. Gregory Cairncross, M.D., Elizabeth Eisenhauer, M.D.,and René O. Mirimanoff, M.D., On behalf of the EORTC Brain Tumor and Radiotherapy Groups and NCIC Clinical Trials Group R Stupp, et al. NEJM 352: (2005)

17 Patient Eligibility Age years WHO PS 0-2 Newly diagnosed, histologically proven GBM 6 weeks since biopsy or resection No prior chemotherapy or RT Stable or decreasing doses corticosteroids for 14 days Adequate hematological, hepatic and renal function Written informed consent R Stupp, et al. NEJM 352: (2005)

18 Treatment Schema Concomitant TMZ/RT* Adjuvant TMZ R Weeks RT Alone Temozolomide 75 mg/m 2 po qd for 6 weeks, then mg/m 2 po qd d1 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.

19 During RT +/- TMZ: Hematologic Toxicity Grade 1/2 RT alone (n=286) % Grade 1/2 RT + TMZ (n=287) % Grade 3/4 RT alone (n=286) % Grade 3/4 RT alone (n=287) % Anemia <1 Leukopenia Neutropenia Febrile neutropenia 0 4 Thrombocytopenia R Stupp, et al. NEJM 352: (2005)

20 During RT +/- TMZ: Non-hematologic Toxicity Fatigue/Consti tutional Rash/Dermat ologic Nausea/Vomit ing Grade 1/2 RT alone (n=286) % Grade 1/2 RT + TMZ (n=287) % Grade 3/4 RT alone (n=286) % Grade 3/4 RT alone (n=287) % Infection Visual R Stupp, et al. NEJM 352: (2005)

21 Adjuvant Temozolomide Started 4 weeks post radiation +/- TMZ 78% patients (n=223) started monthly TMZ Median number cycles=3 (range 0 to 7) 47% completed all 6 cycles Only 8% stopped due to toxicity Dose escalation to 200 mg/m 2 at cycle 2 67% had increased dose 9% did not due to hematologic toxicity

22 Adjuvant Temozolomide: Hematologic Toxicity Grade 1/2 (n=223) % Grade 3/4 (n=223) % Anemia 45 <1 Leukopenia 41 5 Neutropenia 23 4 Febrile neutropenia 1 Thrombocytopenia R Stupp, et al. NEJM 352: (2005)

23 Adjuvant Temozolomide: Non-hematologic Toxicity Grade 1/2 (n=223) % Grade 3/4 (n=223) % Fatigue/Constitutional Rash/Dermatologic 23 2 Nausea/Vomiting 50 2 Infection 7 5 Visual 20 <1 R Stupp, et al. NEJM 352: (2005)

24 Overall Survival % months O N Number of patients at risk : RT TMZ/RT Median OS, mo: yr survival: 10% 26% HR [95% C.I.]: 0.63 [ ] p < RT TMZ/RT RT TMZ/RT

25 EORTC NCIC CE3 Randomized Study in GBM Subset Analysis: Overall Survival ITT population 286/287 Age < 50 yr 81/90 50 yr 205/197 Biopsy only 46/47 Resected 240/240 WHO PS = 0 112/116 PS = 1 140/135 PS = 2 34/36 Mini-mental status / /128 Baseline steroids 215/193 No baseline steroids 70/94 Males 175/185 Females 110/102 Stupp R, et al. ASCO Hazard ratio (95% CI)

26 EORTC/NCIC CTG 2007 Results: Overall Survival Treatment RT n = RT+TMZ n = year OS (%) year OS (%) year OS (%) year OS (%) Hazard ratio [ ] P < Years O N Number of patients at risk: Treatment RT RT+TMZ

27 EORTC RPA System Class III Age < 50, WHO PS 0 1 IV V Age < 50, WHO PS 2 or Age 50, MMSE 27 and resection Age 50, MMSE < 27, and biopsy only

28 Overall Survival RPA III Overall survival: Treatment in RPA class Treatment RT n = O N Number of patients at risk: Treatment RT RT+TMZ RT+TMZ n = year OS (%) year OS (%) year OS (%) year OS (%) Hazard ratio [ ] P = Years

29 Overall Survival RPA IV Treatment RT n = RT+TMZ n = year OS (%) year OS (%) year OS (%) Hazard ratio 0.62 [ ] P = Years O N Number of patients at risk: Treatment RT RT+TMZ

30 Overall Survival RPA V Overall survival : Treatment in RPA class Treatment RT n = 286 RT+TMZ n = year OS (%) year OS (%) year OS (%) Hazard ratio 0.69 [ ] P = O N Number of patients at risk: Treatment RT RT+TMZ Years

31 MGMT O6-methylyguanine DNA methyltransferase Enzyme involved in DNA repair Expression is regulated by methylation of promoter region Methylation silences the gene Continuous TMZ depletes MGMT Tumor more sensitive to damaging effects of alkylating chemotherapy and radiation

32 Overall Survival Methylated MGMT Promoter Overall survival : Treatment and Methylated MGMT Treatment RT 100 meth RT+TMZ meth 2-year OS (%) year OS (%) year OS (%) Hazard ratio 0.51 [ ] P = 0.04 Years O N Number of patients at risk: Treatment RT RT+TMZ

33 Overall Survival Unmethylated MGMT Promoter Overall Survival: Treatment and Unmethylated MGMT Treatment RT unmeth RT+TMZu nmeth year OS (%) year OS (%) year OS (%) Hazard ratio 0.66 [ ] P = Years O N Number of patients at risk: Treatment RT RT+TMZ

34 Conclusions Clinically meaningful and statistically significant survival advantage Temozolomide safe and well tolerated Greatest benefit in those with better prognosis and MGMT methylation New standard of care for first-line therapy of GBM Translational research aiming to identify predictive markers and new targets is ongoing

35 Temozolomide (Temodal )

36 Temozolomide Oral alkylating chemotherapy Spontaneous conversion to MTIC Active in glioma and melanoma Excellent toxicity profile

37 Pharmacokinetics 100% bioavailability Peak plasma concentrations in 1 hour Rapid, complete absorption: T max = h Crosses blood-brain barrier: 30% CSF to plasma ratio Rapid elimination: mean t 1/2 = 1.8 h No accumulation after repeat dosing Temozolomide (package leaflet); 2000 Aganwala SS et al. Ann Oncol 1998; 9 (suppl 4):659

38 Myelosuppression Nausea and vomiting Anorexia Fatigue Constipation Headache Alopecia Rash Toxicities

39 Temozolomide for Glioma Single agent activity in recurrent disease Synergy with radiation in vitro Crosses the blood brain barrier Daily dosing depletes cells of the DNA repair enzyme MGMT

40 Temozolomide for Glioma Complete absorption after oral administration Rapid renal elimination No cumulative toxicity Well tolerated Approved in 1998 for recurrent anaplastic astrocytoma and glioblastoma Generic forms now available

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42 Patient Selection Performance status is most important If PS 0-2 offer concurrent treatment If PS 3 consider radiation alone If PS 4 consider best supportive care Elderly patients Limited data Awaiting results of NCIC CE.6 trial Consider short course of radiation Chemo alone may be an option for select patients

43 Concomitant Temozolomide Chemo started early in course of disease Allows chemo to be given for longer duration Synergy with radiation Increase dose intensity of chemo Depletion of MGMT and prevent DNA repair

44 Concomitant Temozolomide Start at 75 mg/m 2 po daily Start of first day of radiation, approximately one hour prior to radiation dose Given every day for 42 days (maximum 49 days) Anti-nausea medication Prochlorperazine 10 mg or metoclopramide 10 mg Assess patients weekly CBC, LFTs, glucose, serum creatinine Toxicity assessment Compliance

45 Concomitant Temozolomide Toxicity Management Discontinuation Neutropenia Hold drug if ANC < 1.5 and then restart once counts recover Thrombocytopenia Hold drug if platelets < 100 and then restart once counts recover Lymphopenia Pneumocystis prophylaxis If ANC < 0.5 Second occurrence If platelets < 10 Second occurrence Nausea and vomiting Add 5-HT3 antagonist Do not repeat dose Deterioration in performance status Grade 3 or 4 nonhematologic toxicity Start/increase steroids PS 3 or 4 Stop temozolomide Yes

46 Concomitant Temozolomide Weekly prescriptions Consider blister pack Involve family member/caregiver Dose banding Supplied as 250 mg, 140mg, 100 mg, 20 mg and 5 mg tablets

47 Adjuvant Temozolomide Starts four weeks after completion of temozolomide and radiation 150 mg/m 2 po daily x 5 days of a 28 day cycle If problems with counts during concurrent treatment start at 100 mg/m 2 and dose escalate with caution to 150 mg/m 2 CBC day 22 and 29 Monitor LFTs, glucose, serum creatinine, electrolytes prior to each cycle

48 Adjuvant Temozolomide Dose escalate to 200 mg/m 2 if ANC 1.5 and platelets 100 and nadir ANC 1.0 and platelets 50 If ANC < 1.5 or platelets < 100 then hold for a week and dose reduce by 50 mg/m 2 /day Dose levels 100, 150 and 200 mg/m 2 Discontinue for any grade 3 or 4 nonhematologic toxicity

49 Thrombocytopenia Most common hematologic side effect Occurs in 10 to 20% of patients Hold temozolomide if platelets < 100 If nadir < 50, then dose reduce subsequent cycles by 50 mg/m 2 /day If platelets < 50, do CBC every 2 to 3 days If platelets < 20 hold RT and transfuse If prolonged recovery, stop chemotherapy

50 Neutropenia Hold temozolomide if ANC < 1.5 If ANC falls below 0.5 during concurrent treatment with radiation then stop drug If nadir ANC < 0.5 during adjuvant treatment then dose reduce subsequent cycle If prolonged recovery, then discontinue Growth factors not used

51 Hepatotoxicity Rare but fatal severe cases reported January 1994 to March cases, 19 fatal Reported within 6 wk of initiation to 16 wk post Baseline LFTs (bilirubin, AST, ALT) Repeat midway through concurrent treatment Repeat prior to each monthly dose Discontinue if grade 3 or 4 toxicity

52 Rash Higher risk if on corticosteroids and antiepileptic medications Consider other drugs especially phenytoin If mild, rechallenge If severe or worsens, stop the drug May need corticosteroids to treat Stevens-Johnson syndrome and toxic epidermal necrolysis reported

53 Less Common Side Effects Secondary malignancies Myelodysplasia, t-aml, aplastic anemia Pneumonitis/fibrosis Arterial or venous thromboembolism Hypersensitivity reactions Hepatotoxicity

54 Duration of Treatment Initial trial gave 6 cycles of adjuvant TMZ May continue for up to 12 cycles but no clinical trial data to support this Depends on individual patient tolerance and response to treatment Need to consider amount of residual tumor No role for treating until progression

55 Temozolomide Monitoring in NL Combined Modality Clinic Seen by GPO or Nurse Practitioner Pharmacy input as needed Pharmacist Toxicity Assessment Assess all patients receiving oral systemic therapy

56 Combined Modality Clinic Weekly follow up clinic for concurrent chemotherapy/radiation patients Monitor hematologic toxicity Monitor other toxicities Prescription given weekly to increase safety GPO or Nurse Practitioner Pharmacy is available as needed Consult with medical oncologist as needed

57 Pharmacist Toxicity Assessment Seen at baseline in the clinic Medication reconciliation Drug interaction Drug coverage and need for special access Contact local pharmacy Telephone follow-up at day 5 Toxicity assessment including grading Intervention as needed Seen in clinic as needed for subsequent cycles Contact info given to patient to call as needed

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59 Seizure Management Initial manifestation in 50% of glioblastoma Causes significant morbidity Focal seizures which can generalize Need to treat with antiepileptic drugs Monitor levels and compliance No role for seizure prophylaxis Given postoperatively and if no history of seizure can be discontinued after few weeks

60 Antiepileptic Drugs Increased compliance, tolerance and cost effectiveness with monotherapy Use lowest, effective dose If seizures not controlled check levels and increase dose before adding another drug Non-enzyme inducing drugs are preferred Be cautious about MRI changes seen postseizure including edema and enhancement

61 Antiepileptic Drugs Drug Dose Interactions Monitoring Phenytoin (Dilantin) Carbamazepine (Tegretol) Valproate (Valproic acid) Levetiracetam (Keppra) mg/d Multiple interactions Potent and broad spectrum enzyme inducer mg/d Potent and broad spectrum enzyme inducer mg/d Moderate enzyme inhibitor May have anti-tumor effect Increases hematologic toxicity mg/d No enzyme induction/ inhibition Measure levels prior to dose Yes Measure levels prior to dose Not required

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63 Corticosteroids Use at minimal amount needed for symptoms Taper quickly unless patient on long-term Dosing bid with breakfast and lunch/supper Some patients require small daily dose 1-2mg Supplied as 0.5 mg, 2 mg and 4 mg tabs Prednisone : dexamethasone 7:1 ratio

64 Side Effects Myopathy Behavioral changes Visual blurring Tremor Insomnia Reduced taste/olfaction Cerebral atrophy Psychosis Osteoporosis Infections Weight gain Lymphocytopenia Peripheral edema Hyperglycemia Worsening DM control Wen PY, et al. J Neurooncol. 2006;80:

65 Pneumocystis Prophylaxis Pneumocystis jirovecii pneumonia Incidence 1%, mortality > 50% if untreated Increase risk of infection due to lymphopenia Corticosteroids, TMZ, radiation Indicated during concurrent chemoradiation Continue until lymphocytes recover > 1.0 Consider during temozolomide chemotherapy if patient on long-tem steroids

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67 Disease- Related Considerations Pseudoprogression 1 of 3 Pseudo-progression diagnosed retrospectively when the postradiotherapy MRI shows increased tumour enhancement that stabilizes or improves with the same or no further therapy. Can occur in 20-30% of cases post-chemoradiation Can be accompanied by progressive clinical signs and symptoms Patients with imaging evidence suggesting progression 12 weeks post- RT/TMZ should be continued on planned adjuvant chemotherapy unless evidence of clinical deterioration or until evidence of further disease progression with imaging Easaw JC, et al. for the Canadian Glioblastoma Recommendations Committee. Curr Oncol. 2011;18(3):e126-36; Sanghera P, et al. Can J Neurol Sci. 2010;37:36 42; Wen PY, et al. J Clin Oncol. 2010;28:

68 Criteria for Determining First Progression Depending on Time From Initial Chemoradiotherapy 2 of 3 First Progression Progressive disease <12 weeks after completion of RT/TMZ Progressive disease 12 weeks after RT/TMZ completion Definition New enhancement outside radiation field (beyond the highdose region or 80% isodose line) or if unequivocal evidence of viable tumor on histopathologic sampling Given the difficulty of differentiating true progression from pseudoprogression, clinical decline alone, in the absence of radiographic or histologic confirmation of progression, is not sufficient New contrast-enhancing lesion outside radiation field on decreasing, stable, or increasing doses of corticosteroids Increase by 25% in sum of products of perpendicular diameters between scans on stable or increasing doses of corticosteroids Clinical deterioration not attributable to concurrent medication or comorbid conditions For patients receiving antiangiogenic therapy, significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of corticosteroids Wen PY, et al. J Clin Oncol. 2010;28:

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70 Recurrent Glioblastoma Progression/recurrence > 90% Usually within 4 cm of original tumor Treatment is palliative Responses not durable Surgery plays limited role Re-irradiation Systemic therapy

71 Standard of Care for Recurrent GBM No established standard of care Therapy should be individualized based on: patient age performance status possibility of further resection type of, and response to, initial therapy time since diagnosis tumour specific factors (location, nature, resectability) Repeat surgery, re-irradiation, and second-line mono- or combination therapy are all directed primarily at reducing tumor burden and extension Also important is improving neurologic symptoms, reducing need for steroids, preventing VTE Easaw JC, et al. for the Canadian Glioblastoma Recommendations Committee. Curr Oncol. 2011;18(3):e126-36;

72 Patient 1 63 yo female diagnosed with left temporal lobe GBM Gross total resection Sept 2012 Temozolomide and radiation x 6 weeks Monthly temozolomide x 12 cycles completed Nov 2013 Now MRI shows progressive disease adjacent to resection cavity with minimal surrounding edema Clinically well, ECOG PS 1 What next?

73 Options Rechallenge with TMZ: monthly vs. daily Bevacizumab Bevacizumab + chemotherapy Single agent chemotherapy: Etoposide, CCNU Re-resection Radiation Clinical trial Other

74 Rescue Trial Continuous low dose TMZ 50 mg/m2 Depletion of MGMT Anti-angiogenic properties Well tolerated Mild nausea Neutropenia and lymphopenia

75 Survival (%) TMZ: Continuous Dose-Intense Therapy Nonrandomized, Multicentre, Phase II Study N = 91 GBM patients with progression after standard TMZ Continuous dose-intense TMZ 50 mg/m 2 /d for up to 1 year or until progression 6-month PFS: 23.9% 1-year survival Early/B1: 27.3% Extended/B2: 14.8% Rechallenge/B3: 28.6% Median OS: 9.3 months Six-month PFS and 1-year survival in patients with GBM by subgroup* 6-month PFS 1-year survival 27.3% 27.3% 7.4% 14.8% 35.7% 28.6% Early Extended Rechallenge Groups *patients with GBM were prospectively divided into 3 groups (early [B1],extended [B2], and rechallenge [B3]) according to the timing of progression during adjuvant therapy Perry JR, et al. J Clin Oncol. 2010;28: [RESCUE]

76 TMZ in Recurrent GBM Phase II Study Comparison Trial TMZ 5/28 1 (n=112) Randomized, multi-centre (one arm) Continuous TMZ 2 (N=91) Non-randomized, multi-centre Progression after RT ± chemotherapy After std TMZ Median PFS 3.1 months 3.0 months Survival 6 month: 60% 12 months: 23.6% 6 mo PFS 21% 23.9% 1. Yung WKA, et al. Br J Cancer. 2000;83: Perry JR, et al. J Clin Oncol. 2010;28: [RESCUE]

77 Bevacizumab Anti-VEGF antibody Activity against many cancers Colorectal, lung, ovary, brain Combination with chemotherapy Synergistic Normalize vasculature, improve hypoxia Toxicities Hypertension, proteinuria, bleeding, arterial and venous thrombus

78 Bevacizumab in GBM: Randomized, Open-Label Phase II Trial N = 85* patients experiencing first or second relapse after failing with TMZ BEV 10 mg/kg Primary endpoints: 6-mo PFS and ORR Secondary endpoints: OS, toxicity Bevacizumab First Relapse Bevacizumab Second Relapse ORR, % 31.9% 12.5% 6-mo PFS, % 46.4% 27.8% OS, mos DoR, mos 5.6 A trend for patients taking corticosteroids at baseline took stable or decreasing doses over time *BEV arm of BRAIN study ORR: overall response rate; OS: overall survival; DoR: duration of response; PFS:progression-free survival Friedman HS, et al. J Clin Oncol. 2009;27: [BRAIN]

79 Bevacizumab in GBM: Randomized, Open-Label Phase II Trial N = 167 experiencing first or second relapse after failing with TMZ BEV 10 mg/kg vs. BEV 10 mg/kg + irinotecan Primary endpoints: 6-mo PFS and ORR Secondary endpoints: OS, toxicity BEV First Relapse BEV Second Relapse BEV+I First Relapse BEV+I Second Relapse ORR, % 31.9% 12.5% 39.4% 31.3% 6-mo PFS, % 46.4% 27.8% 49% 57.1% OS, mos DoR, mos A trend for patients taking corticosteroids at baseline took stable or decreasing doses over time ORR: overall response rate; OS: overall survival; DoR: duration of response; PFS: progression-free survival Friedman HS, et al. J Clin Oncol. 2009;27: [BRAIN]

80 Bevacizumab in recurrent GBM: McGill Experience Survival Probability Survival Probability N = 27 patients with recurrent glioma BEV 5-10 mg/kg every 2 weeks ± chemotherapy Primary endpoint PFS Clinical benefit rate 59% 6 month PFS rate 43% Median OS 8.9 months Clinically significant reduction in cerebral edema in 12 patients (44%); decrease in steroid dose in 17 patients (63%) Product-Limit Survival Estimate With Number of Subjects at Risk Censored Product-Limit Survival Estimate With Number of Subjects at Risk Censored Median PFS: 4.3 months, 95% CI: 3.0 to 10.9 months Time to progression or death (days) Kaplan-Meier plot for progression free survival Median OS: 8.9 months, 95% CI: 5.8, not estimable Time to death (days) Kaplan-Meier plot for overall survival after relapse Sahebjam S, et al. Can J Neurol Sci. 2013;40:

81 Toxicity Monitoring Monitor and treat hypertension Monitor for proteinuria Urinalysis and 24 hr urine Thromboembolic disease Bleeding GI and CNS Wound dehiscence GI perforation

82 CCNU Oral alkylating chemotherapy Dose 90 to 130 mg/m 2 po every 6 weeks Cause cumulative myelosuppression Difficult to deliver Dose reduction when given with bevacizumab

83 Lomustine in recurrent GBM Open Label Studies One arm of phase III openlabel studies Lomustine 1 (n=84) Lomustine 2 (n=64) Patients with recurrent GBM after previous radiation ± chemotherapy Lomustine mg/m 2 6-week cycle PFS 1.6 months 2.7 months OS 7.1 months 9.8 months 6 mo PFS 19% 25% 1. Wick W, et al. J Clin Oncol. 2010; 28(7): Batchelor TT, et al. J Clin Oncol. 2013;31:

84 BEV + Lomustine in recurrent GBM: Three-arm RCT Phase II Study Three-arm Dutch multicenter randomized phase II study: i. BEV 10 mg/kg iv every 2 weeks ii. iii. BEV 10 mg/kg iv every 2 weeks and lomustine 110 mg/m 2 every 6 weeks Lomustine 110 mg/m 2 every 6 weeks Primary endpoint was 9 months overall survival Treatment* n % 9 mo OS [95% CI] Median PFS (mo) % 6 mo PFS [95% CI] BEV 50 38% [25, 51] 3 16% [7, 27] Lomustine 46 43% [29, 57] 2 13% [5, 24] BEV/lomustine 90 mg/m % [43, 72] 4 41% [26, 55] BEV/lomustine 110 mg/m % [39, 98] 11 50% [15, 77] n: number of patients, PFS: progression free survival, CI: confidence interval, mo: months. *Median number of cycles 2 Taal W, et al. J Clin Oncol (suppl; abstr 2001), updated at SNO 2013.[BELOB]

85 Conclusion Advances in treatment and understanding of biology Concurrent chemoradiation followed by monthly Temozolomide is now standard Emerging role of bevacizumab and other targeted therapies Treatment of recurrent disease is challenging Multidisciplinary team needed for these complex patients GPO role is very important

86 Thank you Questions?

87 References Stupp R, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Eng J Med 2005;352: Stupp R, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised. phase III study Lancet Oncol 2009;10: Wen PY, et al. Medical management of patients with brain tumors. J Neuroncol 2006;80: Easaw JC et al. Canadian recommendations for the treatment of recurrent or progressive glioblastoma multiforme. Current Oncology 2011;18(3):e UpToDate