Current Treatment for Glioblastoma multiformecme.baptisthealth.net/miamineuro/documents/presentations/birkhimer glioblastoma thurs...LP had a sub-total resection of his 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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� 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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� 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


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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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� 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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� 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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� 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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� 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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� 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


Local

Resectable+/- wafer

Palliative

Systemic chemo OR

Radiation

Unresectable Alternating electric field therapy

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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


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


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


Picturegoes here,From just below the gray bar to bottom (over the footer).

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� 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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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


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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


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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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Documents

Current Treatment for Glioblastoma multiformecme.baptisthealth.net/miamineuro/documents/presentations/birkhimer glioblastoma thurs...LP had a sub-total resection of his glioblastoma