1 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Current Treatment for Glioblastoma multiforme Danette Birkhimer, MS, RN, CNS, AOCNS Apply current standards of practice in the treatment of a patient with newly diagnosed Glioblastoma Discuss current standards of practice for management of recurrent Glioblastoma Identify common complications for a patient with a Glioblastoma 2 Objectives 23,130 will be diagnosed with a malignant tumor of the brain or spinal cord An estimated 14,080 will die from those tumors (American Society, 2013) Glioblastoma multiforme (GBM) is the most common and aggressive Median survival is ~ 15 months Most recur within 9 months (Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987-996 3 Glioblastoma Multiforme
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Current Treatment for Glioblastoma multiforme
Danette Birkhimer, MS, RN, CNS, AOCNS
� Apply current standards of practice in the treatment of a patient with newly diagnosed Glioblastoma
� Discuss current standards of practice for management of recurrent Glioblastoma
� Identify common complications for a patient with a Glioblastoma
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Objectives
� 23,130 will be diagnosed with a malignant tumor of the brain or spinal cord
� An estimated 14,080 will die from those tumors� (American Society, 2013)
� Glioblastoma multiforme (GBM) is the most common and aggressive
� Median survival is ~ 15 months
� Most recur within 9 months� (Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for
glioblastoma. N Engl J Med 2005;352(10):987-996
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Glioblastoma Multiforme
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Case Study: Newly diagnosed glioblastoma
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� LP, 58 year old white male presents to his PCP with the following complaints:
� 1 month history of headaches
� Decreased sensitivity to smell and taste
� Progressive left sided weakness
� Diminished motor dexterity in left hand
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Case Study
� ROS: positive for decreased smell and taste and change
in balance; additionally family noted slower speech and
dragging left foot
� PE: positive for slow speech, left facial droop, pronator
drift of left arm, unable to touch nose with eyes closed with
left hand
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Case Study
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Case Study
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Case Study
Imaging-glioma
Resection not feasible
Stereotactic biopsy OR
Open biopsy
Subtotal resection
Maximal resection
Resection
+ carmustinewafer
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NCCN Guidelines 2.2014
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Glioblastoma
KPS > 60
< 70: RT + TMZ
>70: RT + TMZ RT
TMZ
KPS < 60
RT / chemotherapy / Palliative care
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NCCN Guidelines 2.2014
� Follow up� MRI 2-6 weeks after Radiation� Then every 2-4 months for 2-3 years� Less frequently after 3 years
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NCCN Guidelines 2.2014
� Goals
� Diagnosis
� Maximal tumor resection
� Alleviation of symptom
Ivan, Tate & Clarke (2012). Malignant gliomas in adulthood. In RJ Packer & D Schiff (Eds.), Neuro-Oncology (63-75). Hoboken, NJ: Wiley-Blackwell
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Treatment: Surgery
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� Types:
� Stereotactic biopsy
� Open biopsy
� Debulking
� Total resection
� Chemotherapy wafer implants
NCCN guidelines Version 2.2014
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Treatment: Surgery
� McGirt, et al� Does extent of surgery prolong survival?� 451 patients undergoing primary resection
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Treatment: Surgery
02468
101214
Gross-total
resection
Near-total
resection
Subtotal resection
McGirt, Chaichana, Gathinji, et al. Independent association of extent of resection with survival in patients with malignant brain astrocytoma. J Neurosurg 2009; 110(1):156-162.
� Goal:� Destroy tumor cells without injuring normal cells
� Typical dose = 60 Gy, given in 1.8-2.0 Gy, 5 days/week for 6 weeks
Ivan, Tate & Clarke (2012). Malignant gliomas in adulthood. In RJ Packer & D Schiff (Eds.), Neuro-Oncology (63-75). Hoboken, NJ: Wiley-Blackwell
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Treatment: Radiation Therapy
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Treatment: Radiation Therapy
� Side Effects:
Acute Early delayed Late
Scalp erythema Somnolence Radiation necrosis
Cerebral edema Neuro deficits Dementia
Seizures Fatigue Cognitive function
Headache leukoencephalopathy
N & V New neoplasm
Neuro deficits Fatigue
Fatigue
McQuestion & Daniels. (2011). Treatment modalities: Radiation. In DH Allen & LL Rice (Eds.). Central Nervous System Cancers. 91-104. Pittsburgh, PA: Oncology Nursing Society.
� Implanted wafer� Carmustine biodegradable wafer
� Placed at time of initial or recurrent surgery
� Released immediately and lasts for several weeks
Anton K, Baehring JM, Mayer T. Glioblastoma multiforme overview of current treatment and future perspectives. Hematol Oncol Clin N Am 2012;26:825-853
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Treatment: Chemotherapy
� Westphal, et al.� 240 patients randomized to either carmustine wafer or
placebo� Groups similar for age, sex, KPS and tumor histology� Median survival= 13.9 months vs 11.6 months� Adverse effects comparable except:
� CSF leak: 5% carmustine vs 0.8% placebo;
� Intracranial hypertension: 9.1% carmustine vs 1.7% placebo
Westphal, M, Hilt, DC, Bortey, E, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 2003;5(2):79-88.
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Treatment: Chemotherapy
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� Temozolomide (TMZ)� Standard of care � Alkylating agent� Crosses the blood brain barrier
Rosso L, Bock CS, Gallo JM, et al. A new model for prediction of drug distribution in tumor and normal tissues: pharmacokinetics of temozolomide in glioma patients. Cancer Res 2009;69(1):120-127.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987-996
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Treatment: Chemotherapy
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� Yung and colleagues:� Phase II trial for recurrent GBM� Randomized 225 patients� Improved survival with TMZ vs procarbazine
Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 2000;83(5):588-593
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Treatment: Chemotherapy
� Stupp and colleagues� Phase III study for newly diagnosed GBM� 573 patients from 85 centers� Randomized to either RT alone or RT plus TMZ� Median survival: 14.6 months RT + TMZ vs 12.1 months in
the RT group� 2 year survival: 26.5% for the RT + TMZ group vs 10.4%
RT group� 5 year survival: 9.8% vs 1.9%
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Eng J Med 2005;352(10):987-996.
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Treatment: Chemoradiation
Case Study: Recurrence
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� LP had a sub-total resection of his glioblastoma.
He completed fractionated EBRT with concurrent and adjuvant TMZ.
� His initial MRI 4 weeks after RT is clear of tumor.
He continues taking the temozolomide.
� MRI at 12 months shows a recurrence.
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Case Study
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Diff
use Palliative
Systemic Chemo /
Surgery
Alternating electric field therapy
NCCN Guidelines 2.2014
Local
Resectable+/- wafer
Palliative
Systemic chemo OR
Radiation
Unresectable Alternating electric field therapy
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NCCN Guidelines 2.2014
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� Virtually all relapse
� No standard of care for relapse
� Pseudoprogression
Anton K, Baehring J, Mayer T. Glioblastoma Multiforme overview of current treatment and future perspectives. HematolOncol Clin N Am 2012;26:825-853.
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Recurrent Disease
� Re-resection� Studies have shown re-resection to increase survival
time� Patient bias- high functional status, tumor location,
minimal medical contraindications
Anton K, Baehring J, Mayer T. Glioblastoma Multiforme overview of current treatment and future perspectives. HematolOncol Clin N Am 2012;26:825-853.
Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet1995;345(8956):1008-1012.
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Recurrent Disease
� Chemotherapy-impregnated wafers: � double-blind, randomized study� 6 month survival 64% with wafer vs 44% with
placebo
Anton K, Baehring J, Mayer T. Glioblastoma Multiforme overview of current treatment and future perspectives. HematolOncol Clin N Am 2012;26:825-853.
Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet1995;345(8956):1008-1012.
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Recurrent Disease
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� Bevacizumab� Monoclonal antibody for VEGF-A (vascular endothelial
growth factor A)� Inhibits proliferation of endothelial cells and angiogenesis� Side effects:
� Intracranial hemorrhage
� Thrombotic events- DVT, PE and ischemic stroke
� Hypertension
� Impaired wound healing
Anton K, Baehring J, Mayer T. Glioblastoma Multiforme overview of current treatment and future perspectives. Hematol Oncol Clin N Am 2012;26:825-853.
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Recurrent Disease
� Bevacizumab� May used alone or in combination with chemotherapy
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Recurrent Disease
6 month progression free survival
Overall survival
Bevacizumab(n=85)
42.6% 9.2
bevacizumab + irinotecan (n=82)
50.3% 8.7
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2009;27(28):4733-4740
� Temozolomide rechallenge� Perry et al conducted a phase II study to assess the
efficacy and safety of continuous dose-intense TMZ � 91 patients who progressed after standard treatment� Divided into groups according to when they progressed
� Early: progression before completion of 6th cycle
� Extended: progression after 6th cycle but before end of adjuvant
� Rechallenge: progression after adjuvant and treatment free > 2 months
� Received TMZ 50mg/m2 per day up to a year or until progression
Perry JR, Belanger K, Mason WP, et al. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma:RESCUE study. J Clin Oncol 2010;28(12):2051-2057
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Recurrent Disease
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Recurrent Disease
Perry JR, Belanger K, Mason WP, et al. Phase II trial of continuous dose-intense temozolomidein recurrent malignant glioma:RESCUE study. J Clin Oncol 2010;28(12):2051-2057
Results of RESCUE study
� Re-irradiation� Local recurrence: single fraction or fractionated
stereotactic radiation
� Focused delivery reduce the dose to surrounding tissue, decrease risk of radiation toxicity (Combs SE, Thilmann C, Edler L, et al. Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long term results in 172 patients treated in a single institution. J Clin Oncol 2005;23:8863-8869)
� Combining low dose TMZ with re-irradiation showed both tolerability and efficacy (Combs SE, Wagner J, Bischof M, et al. Radiochemotherapy in patients with primary glioblastoma comparing two temozolomide dose regimens. Int J Radiat Oncol Biol Phys 2008;71:999-1005.
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Recurrent Disease
� Approved by FDA in 2011
� Delivers alternating low-intensity and intermediate frequency electrical fields to a tumor
� The electrical fields cause apoptosis
Treatment: Alternating Electric Field Therapy
Picturegoes here,From just below the gray bar to bottom (over the footer).
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Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A vs physician’s choice chemotherapy in recurrent glioblastoma: a randomized phase III trial of a novel treatment option. Eur J Cancer2012;(48);2192-2202
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� Clinical trial by Stupp et al.
� 237 patients randomized either to best standard chemotherapy or to electric field therapy
� Median survival: 6.6 vs 6.0 months
Treatment: Alternating Electric Field Therapy
Picturegoes here,From just below the gray bar to bottom (over the footer).
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Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A vs physician’s choice chemotherapy in recurrent glioblastoma: a randomized phase III trial of a novel treatment option. Eur J Cancer2012;(48);2192-2202
� Best result if worn for at least 18hrs/day
� Decreased adverse effects� Most common- scalp
irritation
� QOL favored electric field therapy
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Treatment: Alternating Electric Field Therapy
Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A vs physician’s choice chemotherapy in recurrent glioblastoma: a randomized phase III trial of a novel treatment option. Eur J Cancer2012;(48);2192-2202
Case Study: Complications of Glioblastoma
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� LP opted for a re-resection, continued with temozolomide and started alternating electric field therapy. He started back to work part time as a college professor and was doing some traveling with family.
� His symptoms have mostly subsided, being replaced with fatigue.
� Experienced his first seizure and presented to the local ED.
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Case Study
� If witnessed: keep patient safe, assess movement, time
� Anti-epileptic drugs (AEDs)� Seizure prophylaxis is not recommended; may consider
perioperatively� First generation drugs: phenytoin, phenobarbital should be
avoided due to effects on metabolism� Newer agents: levetiracetam, topiramate, valproic acid
NCCN Guidelines v.2.2014
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Complications: Seizures
� Hypercoagulability� Risk for DVT/ PE� Risk for hemorrhage into tumor� Anticoagulation: low molecular weight heparin
Ivan, Tate & Clarke (2012). Malignant gliomas in adulthood. In RJ Packer & D Schiff (Eds.), Neuro-Oncology (63-75). Hoboken, NJ: Wiley-Blackwell
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Complications: Thrombosis
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� Signs & symptoms depend on location of tumor� Manage the symptoms� Treat the underlying cause vs palliative care
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Complications: Progression
� Dexamethasone� Tumor-associated edema� 24 hours before RT when extensive mass effect present� Lowest dose possible for shortest time possible� Monitor blood glucose� H2 blockers or proton pump inhibitors for GI prophylaxis
Ivan, Tate & Clarke (2012). Malignant gliomas in adulthood. In RJ Packer & D Schiff (Eds.), Neuro-Oncology (63-75). Hoboken, NJ: Wiley-Blackwell
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Supportive Care: Corticosteroids
� Newly diagnosed GBM� Maximal resection with/out carmustine wafer� Radiation with concurrent and adjuvant temozolomide
� Recurrent GBM� Re-resection with/out carmustine wafer� Bevacizumab� Rechallenge with temozolomide� Re-irradiation� Alternating electric field therapy
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Conclusion
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Thank YouTo learn more about Ohio State’s cancer program, please visit cancer.osu.edu or