Current Treatment for Glioblastoma...
Transcript of Current Treatment for Glioblastoma...
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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
� Reduce or stabilize size of tumor after surgery
� Fractionated EBRT (external beam radiation therapy)
� Standard adjuvant therapy
� 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.
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Treatment: Chemotherapy
� Temozolomide� Peak level at 1.2 hours� Half-life 1.9 hours� Dosing
� Concurrent with RT: 75mg/m2 per day for 42 days� Adjuvant: given for 5 days of each 28 day cycle
� Dose of first cycle = 150mg/m2 for 5 days� Cycles 2-6: 200mg/m2 for 5 days
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Treatment: Chemotherapy
� Temozolomide� Side Effects:
� Dose limiting: myelosuppression- neutropenia, thrombocytopenia
� Thromboembolism
� Fatigue
� Pneumonia
� Nausea/vomiting
� Rash
� Constipation
� Arthralgias
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
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