Copyright © 2010, Research To Practice, All rights reserved.
Part V: Central Nervous System CancersMonday, October 18, 20107:30 PM - 8:30 PM ET
Monday Night with Research To Practice: An 8-Part Live CME Webcast Series
Tracy Batchelor, MD, MPHExecutive DirectorStephen E and Catherine Pappas Center for Neuro-OncologyAssociate Professor of Neurology, Harvard Medical SchoolAssociate Neurologist, Massachusetts General HospitalBoston, Massachusetts
James J Vredenburgh, MDProfessor of MedicinePreston Robert Tisch Brain Tumor CenterDuke University Medical CenterDurham, North Carolina
Neil Love, MDModeratorResearch To PracticeMiami, Florida
Disclosures for Moderator Neil Love, MD
Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Abraxis BioScience, Allos Therapeutics, Amgen Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, Lilly USA LLC, Millennium Pharmaceuticals Inc, Myriad Genetics, Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi-Aventis and Spectrum Pharmaceuticals Inc.
Disclosures for Tracy Batchelor, MD, MPH
Consulting AgreementsRoche Laboratories Inc, Schering-Plough Corporation
Research SupportAstraZeneca Pharmaceuticals LP, Millennium Pharmaceuticals Inc.
Disclosures for James J Vredenburgh, MD
N/A = Not Applicable
Advisory Committee and Consulting Agreements
Genentech BioOncology
Paid Research N/A
Speakers Bureau N/A
Case History: Dr Batchelor
• A 37 year old man presents with a generalized seizure
• Left fronto-parietal mass deemed unresectable
• Biopsy: Anaplastic astrocytoma
WHO Grading of Astrocytic Tumors of the CNS
Grade I• Subependymal giant cell astrocytoma• Pilocytic astrocytoma
Grade II
• Pilomyxoid astrocytoma• Diffuse astrocytoma• Pleomorphic xanthoastrocytoma
Grade III • Anaplastic astrocytoma
Grade IV
• Glioblastoma• Giant cell glioblastoma• Gliosarcoma
Louis DN et al. Acta Neuropathol 2007;114(2):97-109.
1) What treatment would you recommend for this patient?
98%
2%
0%
0%
0% 20% 40% 60% 80% 100%
Radiation therapy
Temozolomide
Radiation therapy plus temozolomide
Other
Case History: Dr Batchelor (continued)
• Received radiation therapy/temozolomide on RTOG 98-13
• Follow-up MRI 9 months after diagnosis revealed increased size of the mass
• Biopsy: GBM
2) What treatment would you recommend for this patient?
2%
5%
2%
5%
65%
21%
0%
0%
0% 10% 20% 30% 40% 50% 60% 70%
Bevacizumab
Chemo/bevacizumab
Temozolomide
Nitrosourea
Combination PCV
Cyclophosphamide
Platinum-based regimen
Other
Case History: Dr Batchelor (continued)
• Phase II study with cilengitide monotherapy, with radiographic partial response
• After > 1 year on cilengitide, nodular enhancement outside the radiation field
• Cediranib x 4 months with initial tumor reduction followed by progression of FLAIR signal abnormality
Copyright © 2010, Research To Practice, All rights reserved.
Phase I/IIa Study of Cilengitide and Temozolomide With Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma
Stupp R et al.J Clin Oncol 2010;28(16):2712-8.
Hypothesized Mechanisms of Action of Cilengitide
With permission from Stupp R et al. Presentation. ASCO 2010;Abstract TPS152.
Survival Outcomes of Cilengitide Combined with Temozolomide and Radiation Therapy
Stupp R et al. J Clin Oncol 2010;28(16):2712-8.
Overall(n = 52)
MethylatedMGMT Promoter
(n = 23)
UnmethylatedMGMT Promoter
(n = 22)
Median progression-free survival (PFS)
8.0 mo 13.4 mo 3.4 mo
PFS rate at 24 mo 15% 28% 5%
Median overall survival (OS) 16.1 mo 23.2 mo 13.1 mo
OS rate at 24 mo 35% 46% 20%
Copyright © 2010, Research To Practice, All rights reserved.
Phase II Study of Cediranib, an Oral Pan-vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma
Batchelor TT et al.J Clin Oncol 2010;28(17):2817-23.
Efficacy of Cediranib for Recurrent GBM
Volumetric criteria
Partial response by MRI 3-D measurement (n = 30) 56.7%
Minor response (n = 30) 20.0%
Macdonald criteria
Partial response (n = 30) 26.6%
Alive and progression-free at 6 months (n = 31) 25.8%
Progression-free survival 117 days
Overall survival 227 days
Batchelor TT et al. J Clin Oncol 2010;28(17):2817-23.
Case History: Dr Batchelor (continued)
• Received bevacizumab/irinotecan (9 months) and bevacizumab/carboplatin (2 months) with stability of FLAIR until significant clinical decline
• Death 3 years after initial diagnosis
• Autopsy: extensive tumor infiltration throughout the left hemisphere, basal ganglia, splenium of the corpus callosum and right parietal and occipital lobes
Copyright © 2010, Research To Practice, All rights reserved.
Updated Safety and Survival of Patients with Relapsed Glioblastoma Treated with Bevacizumab in the BRAIN StudyCloughesy T et al.Proc ASCO 2010;Abstract 2008.
BRAIN Study: Updated Survival Data Comparing Bevacizumab versus Bevacizumab plus Irinotecan in Recurrent GBM
Bevacizumab(n = 85)
Bevacizumab + Irinotecan (n = 82)
12-months survival 38% 38%
18-months survival 24% 18%
24-months survival 16% 17%
30-months survival 11% 16%
Cloughesy T et al. Proc ASCO 2010;Abstract 2008.
BRAIN Study: Updated Safety Data Comparing Bevacizumab versus Bevacizumab plus Irinotecan in Recurrent GBM
Grade > 3 BevacizumabBevacizumab +
Irinotecan
Hypertension 10.7% 3.8%
Cerebral Hemorrhage 0% 1.3%
Venous Thromboembolism 3.6% 10.1%
Arterial Thromboembolism 3.6% 2.5%
GI Perforation 0% 2.5%
Cloughesy T et al. Proc ASCO 2010;Abstract 2008.
Copyright © 2010, Research To Practice, All rights reserved.
Long-Term Survival from the Initial Trial of Bevacizumab and Irinotecan
Desjardins A et al.Proc ASCO 2010;Abstract 2045.
Efficacy and Safety of Bevacizumab plus Irinotecan in Recurrent GBM (N = 35)
Partial Response
Median Overall Survival
6-Month Survival
4-Year Survival
57% 9.7 months 46% 8.6%
Desjardins A et al. Proc ASCO 2010;Abstract 2045.
Adverse events
Thromboembolic events 11%
Grade 2 fatigue 11%
>Grade 3 GI toxicity 11%
Grade 2 proteinuria 6%
CNS hemorrhage 3%
In the past year, how many new patients with GBM have you managed?
Patterns of Care Survey of US-Based Medical Oncologists (n = 100)
Patients
Median = 4 patients
12%
47%
26%
15%
>5
3-5
1-2
0
In the past year, how many patients with recurrent GBM have you treated with bevacizumab?
Patterns of Care Survey of US-Based Medical Oncologists (n = 85)
Median = 1 patient
18%
22%
35%
25%
>2
2
1
0
Patients
Have you observed a clinically meaningful antitumor response to bevacizumab?
Patterns of Care Survey of US-Based Medical Oncologists (n = 85)
62%Yes
What type of antitumor response to bevacizumab have observed in a patient with GBM?
Patterns of Care Survey of US-Based Medical Oncologists (n = 53)
22%
12%
13%
25%
37%
Other improvements
Partial response
Near complete response
Stable disease
Tumor shrinkage
— Erik Rupard, MDFort Gordon, GA
I have a patient in his early 60s with an unresectable, infratentorial Grade II astrocytoma with cerebellar involvement.
Generally, we treat patients who have low grade disease with radiation therapy alone.
Is there a role for adding in temozolomide for a patient like this man?
— Frank Rodriguez, MDFort Myers, FL
I am treating a 27-year-old woman with a resected anaplastic astrocytoma. She is receiving radiation therapy/temozolomide and tolerating therapy well.
Would the thought leaders consider adding bevacizumab to temozolomide in an off-protocol setting, given her age, after she finishes chemo/radiation?
Case History: Dr Vredenburgh
• A 46 year old man with GBM
• Radiation therapy/temozolomide followed by temozolomide x 8 before progression
• Tumor EGFRv3-positive, PTEN-normal
3) What treatment would you generally recommend?
6%
2%
12%
69%
11%
0%
0%
0%
0% 10% 20% 30% 40% 50% 60% 70% 80%
Bevacizumab
Chemo/bevacizumab
Temozolomide
Nitrosourea
Combination PCV
Cyclophosphamide
Platinum-based regimen
Other
Case History: Dr Vredenburgh (continued)
• Received bevacizumab/erlotinib x 8 months, with response and clinical improvement
• Developed 1+, 2+, 3+ proteinuria
Case History: Dr Vredenburgh (continued)
• Patient continues receiving bevacizumab 5 mg/kg plus erlotinib for 19 months
MRI at Diagnosis
MRI at Progression
MRI Post-bevacizumab/erlotinib
Copyright © 2010, Research To Practice, All rights reserved.
Clinical Features, Mechanisms, and Management of Pseudoprogression in Malignant Gliomas
Brandsma D et al.
Lancet Oncol 2008;9(5):453-61.
Brandsma D et al. Lancet Oncol 2008;9(5):453-61.
Clinical Features of Pseudoprogression
• Discordance between the radiologic findings and the clinical status — most patients are asymptomatic
• Lesions decrease in size or stabilize without additional treatments
• Can occur in up to 20% of patients who have been treated with temozolomide plus radiation therapy
• Can explain ~ 50% of all cases of MRI-progression
• Adjuvant temozolomide should be continued
Copyright © 2010, Research To Practice, All rights reserved.
Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group
Wen PY et al.
J Clin Oncol 2010;28(11):1963-72.
Response Criterion
Complete Response Complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically
Partial Response ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no new lesions; stable or reduced corticosteroid dose; and stable or improved clinically
Stable Disease Does not qualify for complete response, partial response, or progression; and stable clinically
Progression ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration
Wen PY et al. J Clin Oncol 2010;28(11):1963-72.
Current McDonald Criterion
Wen PY et al. J Clin Oncol 2010;28(11):1963-72.
Select RANO Criterion
• Progression within 12 weeks after completion of chemoradiotherapy can only be defined using diagnostic imaging if there is a new enhancement outside of the radiation field or if there is viable tumor on histology.
In the past year, how many patients with GBM in your practice experienced “pseudoprogression”?
Patterns of Care Survey of US-Based Medical Oncologists (n = 85)
7%
24%
25%
15%
>2
2
1
0
Not familiar with pseudoprogression
Patients
29%
Copyright © 2010, Research To Practice, All rights reserved.
Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma
Stupp R et al.N Engl J Med 2005;352(10):987-96.
Copyright © 2010, Research To Practice, All rights reserved.
Effects of Radiotherapy with Concomitant and Adjuvant Temozolomide versus Radiotherapy Alone on Survival in Glioblastoma in a Randomised Phase III Study: 5-year Analysis of the EORTC-NCIC Trial
Stupp R et al.Lancet Oncol 2009;10(5):459-66.
Survival Benefit of Adjuvant Temozolomidein GBM
Radiation Alone
Radiation-Temozolomide1
Hazard Ratio p-value
Overall Survival (Median)
12.1 months 14.6 months 0.63 < 0.001
2-Year Survival 10.4% 26.5%Not
ReportedNot reported
PFS (Median) 5.0 months 6.9 months 0.54 < 0.001
Temozolomide was administered at 75mg/m2 PO QD for up to seven weeks with RTPost-RT, temozolomide was administered at 150 mg/m2, days 1-5 cycle 1, and then temozolomide 150-200mg/m2 q 28 days in cycles 2-6
Stupp R et al. N Engl J Med 2005;352(10):987-96.
Phase III Trial of Radiation Therapy with or without Temozolomide for Newly Diagnosed GBM: Five-Year Survival Analysis
Stupp R et al. Lancet Oncol 2009;10(5):459-66.
Hazard ratio
Median survival
Two years
Five years
Overall XRT XRT + T
1.00.6
12.1 mo14.6 mo
10.9%27.2%
1.9%9.8%
MGMT unmethylated XRT XRT + T
1.00.6
11.8 mo12.6 mo
1.8%14.8%
0%8.3%
MGMT methylated* XRT XRT + T
0.50.3
15.3 mo23.4 mo
23.9%48.9%
5.2%13.8%
* Hazard ratio relative to MGMT unmethylated XRT
Copyright © 2010, Research To Practice, All rights reserved.
Bevacizumab (BEV) in Combination With Temozolomide (TMZ) and Radiation Therapy (XRT) Followed by BEV, TMZ, and Irinotecan for Newly Diagnosed Glioblastoma Multiforme (GBM)
Vredenburgh JJ et al.Proc ASCO 2010;Abstract 2023.
Survival Outcomes of Bevacizumab, Temozolomide and Radiation Therapy
Vredenburgh JJ et al. Proc ASCO 2010;Abstract 2023.
Efficacy data (n = 75) Outcome
Median progression-free survival (PFS) 14.2 months
Two-year PFS 13.3%
Median overall survival (OS) 21.2 months
Two-year OS 45%
Copyright © 2010, Research To Practice, All rights reserved.
Phase II trial of Bevacizumab in Combination with Temozolomide and Regional Radiation Therapy for Up-front Treatment of Patients with Newly Diagnosed Glioblastoma Multiforme
Lai A et al.Proc ASCO 2009;Abstract 2000.
Bevacizumab in Combination with Radiation and Temozolomide in Up-front Management of GBM
Bevacizumab-Radiation-
Temozolomide (n = 70)
Radiation-Temozolomide
(Matched Control-Group) p-value
Progression-Free Survival
13.0 months 8.1 months 0.0395
Overall Survival 25.0 months 21.1 months 0.4
Lai A et al. Proc ASCO 2009;Abstract 2000.
RTOG-0825: Phase III Trial Evaluating the Role of Bevacizumab in the Up-Front Management of GBM
Target Accrual: 720
Radiation therapyTemozolomide
Placebo
Radiation therapyTemozolomideBevacizumab
Newly diagnosed GBMPartial or complete surgical resection within 3-5 weeks
R
www.clinicaltrials.gov, October 2010.
In the past year, how many patients with GBM have you treated with bevacizumab + temozolomide + radiation after primary surgery?
Patterns of Care Survey of US-Based Medical Oncologists (n = 85)
Patients
Median = 1 patient
4%
15%
20%
60%
>3
2-3
1
0
— Richard Polkinghorn, MDBrunswick, ME
Recently, I treated two men in their 40s who had GBMs with nearly complete resections and radiation therapy/temozolomide.
I sent them to Duke and both were put on bevacizumab and continued temozolomide. That’s in variance with many of our consultants in Boston, who do not tend to use bevacizumab as initial adjuvant therapy.
Any thoughts?
— Neal Fishbach, MDFairfield, CT
I was intrigued by reports at ASCO this year, which raised the issue of whether radiation therapy was indicated in elderly patients with GBM. What do the investigators think about that data?
Treating patients with temozolomide alone would probably result in a big improvement in quality-of-life for some patients.
Case History: Dr Batchelor
• A 68-year-old man presents with a generalized seizure
• MRI: Right parietal mass
• Subtotal-resection of a pathologically-confirmed GBM
MRI at Diagnosis
4) Which additional diagnostic tests would you obtain on this patient?
MGMT methylation status of the tumor
Chromosome 1p and 19q testing
Spinal MRI to screen for extent of tumor
dissemination
None 28%
10%
23%
39%
0% 10% 20% 30% 40% 50%
Case History: Dr Batchelor (continued)
• Patient receives radiation and temozolomide• Evidence of tumor progression at 26-months after
initial diagnosis
MRI at Progression
5) How would you manage the patient now?
Hospice care
Dose-dense temozolomide
Bevacizumab monotherapy
Bevacizumab + irinotecan
Second course of radiation 1%
57%
35%
4%
3%
0% 10% 20% 30% 40% 50% 60%
Case History: Dr Batchelor (continued)
• Patient started on bevacizumab therapy with objective improvement
• Remains on bevacizumab therapy for 24 months with sustained disease control and mild fatigue
MRI Post-bevacizumab
6) Would you continue bevacizumab?
1%
99%
0% 20% 40% 60% 80% 100%
Yes
No
Copyright © 2010, Research To Practice, All rights reserved.
NOA-08 Randomized Phase III Trial of 1-week-on/1-week-off Temozolomide Versus Involved-Field Radiotherapy in Elderly (Older Than Age 65) Patients With Newly Diagnosed Anaplastic Astrocytoma or Glioblastoma (Methusalem)Wick W et al. Proc ASCO 2010;Abstract LBA 2001.
NOA-08 Phase III Trial Design
Temozolomide 100 mg/m2 daily x 7 q14d
Radiotherapy daily 30 x 1.8-2 Gy
• Anaplastic astrocytoma or• Glioblastoma• Age > 65
R
PD PD
Radiotherapy daily 30 x 1.8-2 Gy
Temozolomide 100 mg/m2 daily x 7 q14d
Wick W et al. Proc ASCO 2010;Abstract LBA 2001.
Survival Outcomes for Temozolomide versus Radiotherapy
ITT Population (N = 373)
Radiotherapy(n = 179)
Temozolomide (n = 194)
Median overall survival 293 days 245 day
12-month overall survival 38.3% 30.8%
Hazard ratio (95% CI) 1.24 (0.94-1.63)
The rate of adverse and serious adverse events was higher in the temozolomide arm
Wick W et al. Proc ASCO 2010;Abstract LBA 2001.
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Glioblastoma (GBM) in Elderly Patients: A Randomized Phase III Trial Comparing Survival in Patients Treated with 6-week Radiotherapy (RT) Versus Hypofractionated RT Over 2 Weeks versus Temozolomide Single-Agent Chemotherapy (TMZ)Malmstrom A et al.
Proc ASCO 2010;Abstract LBA 2002.
Nordic Clinical Brain Tumor Study Group Phase III Trial Design
Radiotherapy 60 Gy (2 Gy x 30)
Radiotherapy 34 Gy(3.4 Gy x 10)
• Glioblastoma
• Age ≥ 60
Temozolomide x 6(200 mg/m2 d 1-5 q 28 d)
R
Malmstrom A et al. Proc ASCO 2010;Abstract LBA 2002.
Survival Outcomes with Radiation Therapy versus Temozolomide (TMZ)
TMZ(n = 119)
RT 60 Gy(n = 100)
RT 34 Gy(n = 123)
Median overall survival (ITT)1 8.3 months 6.0 months 7.5 months
60-70 years old 7.9 months 7.6 months 8.8 months
>70 years old2 8.0 months 5.2 months 7.1 months
1 ITT60 Gy vs TMZ, p = 0.0260 Gy vs 34 Gy, p = 0.3234 Gy vs TMZ, p = 0.18
2 >70 years old60 Gy vs TMZ, p < 0.00160 Gy vs 34 Gy, p = 0.0234 Gy vs TMZ, p = 0.17
Malmstrom A et al. Proc ASCO 2010;Abstract LBA 2002.
Is there data to support retreatment with bevacizumab in patients with progressive primary CNS tumors?
I’m interested in your comment regarding telling patients on bevacizumab to get out and exercise. I may have missed something, but is that to counter-act the fatigue that occurs with the drug?Sarasota, FL