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Brain Tumor

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Abnormal mass in the brain parenchyma due to cancer

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Primary Brain Tumors

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Originate in the intracranial sphere, based on the organic tissues that make up the brain.

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Secondary Brain Tumors

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Metastatic tumors that invaded the intracranial sphere from cancers primarily located elsewhere

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Primary Brain Tumors

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- Present most often in early adult or middle life - Adults - usually supratentorial - Children - usually infratentorial

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Metastatic Brain Tumors

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- Most often from cancer of the lung, breast, kidney, GI tract, and melanomas - Usually are supratentorial, occur at the gray-white junction

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Headache & Brain Tumors

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- Presenting symptom in 35% of patients - Develops in up to 40% to 70% of patients during the course of their disease. - Majority are intermittent and nonspecific. - Usually dull and nonthrobbing. - Can occur on the same side as the tumor.

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Headache symptoms associated with tumor

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Headache upon waking, improves during the day Exacerbated by postural changes, coughing, exercise Is of new onset

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Seizures

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- Presenting symptom in 1/3 of patients with brain tumors. - Present in some form in 40-60% during course of illness - Location of the tumor can often predict what type of seizures are present and frequency of seizures.

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Tumors near the cortex...

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More associated with seizures, particularly tumors of the temporal lobe

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Tumors near the subcortical areas...

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Much less epileptogenic - includes thalamus and posterior fossa

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Increased intracranial pressure symptoms

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- Papilledema: more common in children, in slowly growing tumors, and posterior fossa tumors. Less common now due to better imaging & earlier dx - Vomiting - 6th nerve palsies

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Frontal lobes

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Includes the Motor Cortex

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Frontal lobe functions

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Movement of face and limbs Executive functioning Memory Production of speech - left side-in right handers Emotional control Personality

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Frontal lobe tumor symptoms

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- Impaired mental flexibility and spontaneity - Lack of attention - Risky behaviors - Impaired socialization - Lack of interest-Abulia, Apathy - Broca's Aphasia: difficulty producing speech - Impaired Motor Strength - Think "Frontal Lobotomy"

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Temporal lobes

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- Comprehension of speech - Hearing - Memory

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Temporal lobe tumor symptoms

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- Memory dysfunction: particularly short term memory - left side=visual memory; right side=object memory - Seizures - Wernicke's aphasia: ability to comprehend speech - Lack ability to recognize faces - right side - Alteration in sexual behavior

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Parietal lobes

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Includes the Sensory Cortex

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Parietal lobe functions

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- Movement of face and limbs - Right and left recognition - Motor planning/coordination - Calculation - Spatial recognition

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Parietal lobe tumor symptoms

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- Impaired Sensation - Neglect -on right side mainly: does not recognize left side of world or body. - Apraxia: inability to do motor tasks like dressing and brushing hair. - Left/right confusion - left side - Difficulties with calculia - left side

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Occipital lobes

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Visual Processing

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Occipital lobe tumor symptoms

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- If one side is damaged, one gets a visual field cut. - If both sides are damaged, one gets cortical blindness - cannot see but the eye is normal. - Patient often deny that they are blind - Anton's syndrome

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Brainstem

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Conduit for all Sensory and Motor Function, Eye Movements, Cardiopulmonary Function, Autonomic Function

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Cerebellum

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Balance, Movement, Planning and Control, Eye Movements

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Brainstem tumor symptoms

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Motor and Sensory Dysfunction, Eye Movement Abnormalities, Dysphagia, Dysarthria, Cardiopulmonary Dysfunction

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Cerebellum tumor symptoms

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Ataxia, Nystagmus, Nausea/Vomiting, Hydrocephalus

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Diagnosis of Brain Tumors

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Imaging is critically important

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Brain tumor imaging: CT with contrast

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- Will detect up to 90% of brain tumors - Used in the acute setting - May miss small tumors, brainstem tumors, or nonenhancing tumors

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Brain tumor imaging: MRI with gadolinium

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- Preferred modality for evaluation - Can seen nonenhancing and enhancing tumors equally well

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Brain tumor imaging: PET

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Metabolic assessment of tumor grade, differentiating between tumor & radiation necrosis.

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Glioblastoma on MRI

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Ring-enhancing mass with central necrosis

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Meningioma on MRI

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Homogenously enhancing mass with dural attachment

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Malignant glioma

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- Group of tumors including glioblastoma multiforme, anaplastic astrocytoma, and anaplastic oligodendroglioma - Glioblastoma multiforme has the worst prognosis - Surgical resection, radiation therapy, and chemotherapy are combined to improve symptoms and quality of life

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Low-grade glioma

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- Include astrocytoma, oligodendroglioma, and ependymoma - More common in young patients - Outcome is more favorable than in the malignant gliomas

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Meningioma

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- Arise from the meningeal lining surrounding the brain or spinal cord and generally grow slowly - Most are histologically benign - Treatment = complete resection - Risk of recurrence proportional to the extent of resection

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Malignant Meningioma

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- Radiation therapy should be recommended regardless of the extent of resection - No definitive role for chemotherapy

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CNS Lymphoma

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- No evidence of lymphoma outside the CNS - Most often arise deep within the brain and are therefore less likely to manifest with seizures than are other primary or metastatic CNS neoplasms - Headache, personality changes, & focal symptoms corresponding to the location of the tumor

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CNS Lymphoma Treatment

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- First requires correct diagnosis, can be confused with metastatic disease from a solid tumor - Diagnosis = surgical biopsy, but not resection - Corticosteroids improve symptoms, don't use before biopsy - Responds to radiation & chemo

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Diagnosis of Brain Tumors

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Pathology is the gold standard for diagnosis - helps predict prognosis and treatment.

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Diagnosis of Brain Tumors: Biopsy vs. Surgical Resection

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Based on classification and grade

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Diagnosis of Brain Tumors: Cerebrospinal fluid

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- Used to assess dissemination of brain tumors - Useful in staging - Can look at biologic markers in germ cell tumor patients such as a-fetoprotein, b-HCG, placental alkaline phosphatase - Serious risk for patients with increased ICP

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Primary intracranial tumors: Classified by:

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1. Predominant histologic appearance 2. Location

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Primary intracranial tumors: WHO Classification

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Based on cellular origin and histologic appearance.

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Primary intracranial tumors: Tumor Grade

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- Classifies cancer cells on how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. - Very important in neuroepithelial tumors and meningeal tumors.

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Primary intracranial tumors: Staging

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- The extent or severity of the cancer, based on location of the primary tumor, tumor size, number of tumors, and spread of the tumor - Usually reserved for primitive neuroectodermal tumors, as they can spread along the neuroaxis and in the CSF

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Primary intracranial tumors: risk factors

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Exposure to high-dose ionizing radiation is the only proven risk factor for the development of brain tumors

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Primary intracranial tumors: radiation as a risk factor

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- Linear dose-response association for all primary malignant tumors. -Increased risk of brain tumors in children after radiation for ALL

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Primary intracranial tumors - cellular phones as a risk factor

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- Brain absorbs the most radiofrequency fields during cell phone use - Studies do not support an association between cell phone use and the risk of glioma in adults.

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Primary intracranial tumors - CT scans as a risk factor

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- Risk is extremely small, but the cumulative effects are being evaluated - Lowest dose of radiation for which there is good evidence of increased cancer risks is 10-50 mSv

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Primary intracranial tumors - familial risk factors

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<5% of glioma cases are familial. - Can occur in families, the pattern suggests environmental causes - High frequency in siblings with brain tumors - Genetic risk factors: rare genetic conditions

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Primary intracranial tumors - allergic risk factors

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- Allergic conditions, including asthma, hay fever, eczema, and food allergies, reduce glioma risk. - Findings on this association are inconsistent

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Prognostic Factors in Primary Gliomas

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1. Extent of tumor resection 2. Age at diagnosis 3. Karnofsky performance status (KPS)

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Primary Glioma long-term survival

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Long-term survivors: >5 years from diagnosis, are younger, have a better KPS at baseline, and are more likely to have a gross total resection at initial diagnosis

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Glial Tumors Subtypes

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Astrocytic Oligodendroglial Mixed gliomas

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Pilocytic Astrocytoma - Grade I

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- Onset: childhood - Presentation: cerebellar disease, optic nerve glioma - occur in NF1 - MRI: Cystic mass with an intramural nodule. - Good prognosis, if complete resection.

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Diffuse Low-Grade Astrocytoma - Grade II

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- Onset: young adulthood - 3rd-4th decade - MRI: increased T2/FLAIR signal with no enhancement on T1 - Prognosis is good at diagnosis, but concerns for transformation to high grade glioma

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Anaplastic Astrocytoma, Oligoastrocytoma, Oligodendroglioma - WHO grade III

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- Onset: adulthood - 5th-6th decade - MRI: T1 hypointense, T2 increased signal, edema, patchy enhancement, irregular borders. There can be mass effect. - Prognosis: 5-year survival 15-20% - can vary, primary concern is transformation to GBM

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Glioblastoma - WHO grade IV

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- Onset: adulthood - 6th-7th decade - MRI: T1 hypointense, T2 increased signal, edema, T1+C-ring-like enhancement, irregular borders. Mass effect. "Butterfly pattern" - Prognosis: 5-year survival <5%

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Treatment Goals: Local vs. Systemic Control

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- Local Control: Surgery, Radiation, Stereotactic Radiosurgery - Systemic Control: Chemotherapy, Biological Therapy, Immunotherapy.

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Surgery Indications for Glioma

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- Reducing tumor burden - Alleviating mass effect - Confirmation of histological diagnosis - Diversionary shunting procedures in selected cases - Introduction of local antineoplastic agents: BCNU wafers, MR1-1

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Radiotherapy: Indications in Glioma

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- Is an appropriate form of treatment for virtually all patients with AA and GBM. - Performed over the course of 6 to 7 weeks, with the patient receiving treatment five days per week.

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Standard of care for newly diagnosed AA & GBM

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Surgical ressection 4 weeks later, being XRT+T MZ 6 weeks later, end XRT+T MZ 2-4 weeks later, MRI Then TMZ: dose-dense x 12 months

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Standard of care for newly diagnosed AA & GBM: Monitoring

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- MRI every 2 months for assessment; if progressive, we change therapy based on time of recurrence - Monitoring with CBC w/ differential on day 21- nadir, and day 28 - start of cycle, and CMP q monthly - LFTs are important

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Recurrent AA and GBM Treatment

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- Even with optimal treatment, nearly all malignant gliomas recur - Standard chemotherapy and targeted biological agents are used in this arena.

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Glioblastoma (GBM) Over-expresses Vascular Endothelial Growth Factor (VEGF)

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- GBM are highly vascularized tumors. - GBM over-express VEGF in high levels. - VEGF is the primary growth factor responsible for tumor angiogenesis. - Targeting this process with anti-angiogenic agents could lead to tumor cell death.

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Mechanism of Action of the Humanized Monoclonal Antibody to VEGF: Bevacizumab

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- Thought that anti-VEGF therapy exerts a 'dynamic' anti-angiogenic effect on tumor vasculature throughout the course of its use - Two early effects include regression of existing tumour microvasculature and normalization of remaining tumour vasculature - Also inhibits new tumour vasculature

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Bevacizumab

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- A monoclonal antibody to VEGF - Cannot have invasive procedures, including dental cleaning, for 4 to 6 weeks after discontinuation of agents because of the wound healing difficulties. - Follow CBC w/ differential, U/A, and CMP q2wk

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Bevacizumab Toxicities

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Hypertension, fatigue, wound healing difficulties particularly will steroids, deep venous thrombosis, pulmonary embolism, stroke, heart attack, joint pain, posterior reversible leukoencephalopathy, proteinuria, TTP, gastrointestinal perforation

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Other tumors

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Meningioma Primary CNS Lymphoma Brain Metastases

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Meningioma incidence/risk factors

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- Most are benign - Risk factors include exposure to ionizing radiation.

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Meningioma presentation

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- Onset: Most common in the 6th-7th decades, with a slight preference in females - Associated with neurofibromatosis type 2, Cowden syndrome, and Gorlin syndrome.

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Meningioma treatment

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- MRI: dural-based tumors cause enhancement of peripheral rim of dura surrounding the meningioma producing a dural tail - RX: surgery and radiotherapy

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Primary CNS Lymphoma

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- Usually B cell lymphomas, very rare

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Primary CNS Lymphoma Presentation

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- Onset: Most common in the immunosuppressed - HIV. EBV appears to play a role - Presentation: Depends on location. Initially may respond dramatically to steroids and/or radiation but eventually recurs

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Primary CNS Lymphoma Treatment

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- MRI: homogenous gad-enhancement located in the deep brain rather than the gray-white interface - RX: high dose methotrexate, rituximab, radiation

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Brain metastases

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Metastatic brain tumors are the most common neurologic complication of systemic cancer

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Brain metastases: Most common sites of primary involvement

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1. Lung: 40 to 60% - predominate in men 2. Breast: 10% - predominate in women 3. Melanoma: highest tendency to produce multiple lesions 4. Colon 5. Kidney: more likely to be solitary lesions

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Brain metastases Diagnosis

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Staging: CT chest, abdomen, pelvis; PET scan whole-body; tumor markers; colonoscopy; mammogram

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Neurological Complications and Emergencies in Brain Tumor Patients

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- Susceptible to a unique set of complications that require emergent evaluation and treatment - Prompt intervention can be life-saving, needs multidisciplinary team

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Cerebral Edema in Brain Tumor Patients

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- Results from the disruption of blood-brain barrier allowing protein-rich fluid to accumulate in the extracellular space. - Vasogenic edema affects the white matter more than gray matter, possibly because of lower resistance to flow

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Cerebral Edema Complications

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- Edema may disrupt synaptic transmission and lead to neuronal excitation. - Leads to headaches, seizures, altered mental status, and other focal neurological deficits. - If severe, vasogenic edema is life-threatening - can lead to herniation.

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How Cerebral Edema Disrupts the Blood-Brain Barrier

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1. Angiogenic factors such as VEGF and basic fibroblast growth factor (bFGF) lead to development of abnormal blood vessels characterized by the absence of tight endothelial cell junctions 2. Other factors such as aquaporins, matrix metalloproteinases, and angiopoietins.

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Bevacizumab and cerebral edema

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Supports blood-brain barrier disruption to control edema in brain tumor patients.

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Treatment of cerebral edema

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- Gold standard: CORTICOSTEROIDS - Most patients just need corticosteroids, sometimes other agents such as mannitol, hypertonics, and hyperventilation have to be used. - Dexamethasone commonly used, reduces the potential for fluid retention

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Dexamethasone Mechanism in brain tumor patients

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Not fully understood, but it is thought to upregulate angiopoietin 1, a strong blood-brain barrier stabilizing factor, whereas it downregulates VEGF

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Dexamethasone dosing in brain tumor patients

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General rule: try to use the lowest possible dose to avoid side effects - q12h rather than q6h

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Complications of Dexamethasone

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- Long term use = steroid dependence and tapering can lead to adrenal insufficiency. - Steroid withdrawal syndrome = arthralgias, myalgias, joint pain, headache, depression, lethargy, and postural dizziness.

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GI Complications of Dexamethasone

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1. Increased risk of gastritis or peptic ulcer disease when administered with NSAIDS 2. GI perforation when administered with Bevacizumab 3. GI bleeding when administered with anticoagulants Note: While on steroids, patients should be on GI prophylaxis with PPI or H2 blocker.

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Complications of Dexamethasone: Opportunistic Infections

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1. PJP: Pneumocystis jiroveci pneumonia, can consider prophylaxis 2. Candidiasis: usually easy to treat with nystatin or diflucan.

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Common Neurological Complications of Dexamethasone

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Myopathy Behavioral changes Visual blurring Tremor Insomnia Reduced taste and olfaction Cerebral atrophy

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Uncommon Neurological Complications of Dexamethasone, Continued

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Psychosis Hallucinations Hiccups Dementia Seizures Dependence Epidural lipomatosis

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Complications of Dexamethasone: Steroid myopathy

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- Contributes significantly to morbidity - Subacute onset, involves weaknesses in the proximal musculature, in particular the quadriceps. - Steroids should be discontinued, or lowest amount possible

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Thromboembolic Complications in Brain Tumor Patients

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- Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. - Patients receiving anti-angiogenic agents are at a higher risk, but anticoagulation is complicated because of the risk of hemorrhage

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VTE Risk Factors

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GBM pathology, > 60 years of age, patients with hemiplegia, large tumor size, patients on chemotherapy, and patients on hormonal therapy

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Diagnosis of VTE

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- Swollen extremities: duplex ultrasound. Think of DVT in brain tumor patients with fever of unknown origin. - Dyspnea/tachycardia/severe fatigue: think of PE, CT angiogram is the gold standard

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Treatment of VTE in Brain Tumor Patients

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- Anticoagulation: generally use enoxaparin - Avoid oral agents such as warfarin due to drug-drug interactions, can't be reversed. - Get head CT without contrast first to evaluate for blood products - IVC filter can be considered for selected patients, but there is always a risk of spontaneous PE

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Treatment of VTE in Brain Tumor Patients: Bleeding risk

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- A serious complication for patients on anticoagulation, especially with anti-angiogenic treatment. - Any change in neuro symptoms or new onset of headaches should prompt imaging and neurological examination - Reversal of enoxaparin includes stopping anticoagulation and use of protamine

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Neurocognitive Symptoms: Fatigue

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- Most frequently reported symptom, most difficult to treat - Usually multifactorial in etiology and can include radiation therapy, anemia, AEDs, chemotherapy, depression, steroids, inactivity, and hormonal changes.

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Neurocognitive Symptoms: Fatigue Workup

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- CBC with differential, TSH, testosterone, cortisol level, psychosocial evaluation, medication evaluation. - Consider lowering AEDs - Physical therapy/exercise - Psychosocial intervention - Stimulants: methylphenidate, modafinil

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Neurocognitive Symptoms: Fatigue & survival

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- Fatigue is strong independent predictor of survival

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Neurocognitive Symptoms: Cognitive Deficits

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- Very common, include poor short-term memory, distractibility, personality change, emotional liability, loss of executive function, and decreased psychomotor speed - Can be related to tumor and exacerbated by chemotherapy and radiation. - AEDS and corticosteroids can also be involved

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Neurocognitive Symptoms: Cognitive Deficits Treatment

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- Methylphenidate and modafinil to improve attention, memantine and donepizil to improve memory, antipsychotics for impulse control and psychosis. - VP shunt if hydrocephalus

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Neurocognitive Symptoms: Long-term Cognitive Deficits

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- Survivors have measureable cognitive impairment in multiple domains - In particular, complex attention, executive functioning, and cognitive flexibility

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Neurocognitive Symptoms: Depression

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- Very common, may be related to frontal lobe tumor location, meds & psychosocial impact of diagnosis - Sertaline & Citalopram are commonly used. Buproprion is avoided due to lowered seizure threshold.

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Neurocognitive Symptoms: Insomnia

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- Very common, may be related to dexamethasone and AED usage - Treatment includes sleep hygiene, eval for comorbidities, depression, other mood disturbances, sleep apnea, and pharmacologic sleep aids

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Immunologic Therapies for Newly Diagnosed and Recurrent GBM

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- Dendritic Cell Vaccines - Celldex Vaccine - peptide vaccine targeted to EGFR vIII - Recombinant Poliovirus study-targeted virus to GBM

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Genetically Engineered Poliovirus for Recurrent GBM

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- PVS-RIPO is a genetically engineered poliovirus that is being investigated as a new anti-cancer agent - PVS-RIPO is infused directly into a patients' tumor to ensure maximal amount of virus is delivered directly to the tumor. Once inside the tumor, PVS-RIPO infects and kills tumor cells and leads to immunologic response to the tumor

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Rindopepimut: EGRFvIII Targeted Vaccine

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- An injectable peptide vaccine for potential treatment of GBM - Specifically targets a novel junctional epitope of the EGFR deletion, a constitutively active receptor that is expressed in majority of GBM - EGFRvIII expression is correlated with worse prognosis, not expressed in normal brain tissue

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Tumor treating fields

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- A new modality in antimitotic therapy involving alternating electric fields delivered to the brain tissue through transducer arrays placed on the scalp - Target dividing cancer cell leading to apoptosis

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Radiotherapy & neurological effects

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- Radiation causes breakage of DNA, leading to loss of function and eventual cell death - Most prominent in S phase of mitosis, therefore targets rapidly growing cancer cells - Normal tissue can also be affected

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Epidemiology of Radiation Neural Damage

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- Neural damage dependent of the dose, duration, and location of the treatment - Children under 3 more prone to long-lasting neuro effects

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Pathogenesis of Radiation Neural Damage

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- Hippocampal neurons are most sensitive to radiation damage - Causes massive microglial inflammatory response and decreased differentiation of neural stem cells into neurons (in rodents) - Neurogenesis and performance in behavioral tasks that test hippocampal learning function decrease after radiation in animal studies.

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Pathogenesis of Radiation Neural Damage

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- Primary response to radiation due to inflammation with endothelial cell activation and disruption of the blood-brain barrier. - Leads to perivascular and interstitial edema and focal or multifocal necrosis - In later phases, may result in permanent demyelination

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Spinal Cord Tumors

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spinal cord tumors are described as extradural (outside of the dural sac) or intradural. Most extradural tumors result from extension of vertebral metastasis from other sites, typically lung, breast, and prostate cancers. Intradural tumors are further described as either extramedullary (arising outside the spinal cord) or intramedullary (arising within the spinal cord). Examples of intradural extramedullary tumors are schwannomas and meningiomas. Ependymomas and astrocytomas are the most common intramedullary tumors. The most common location for spinal tumors is the thoracic region. Patients with extradural or intradural extramedullary spinal cord tumors develop symptoms as a result of compression of normal structures by the tumor or impairment of the vascular supply, rather than by tumor invasion of the spinal cord parenchyma. Back pain and distal paresthesias in the legs are among the earliest symptoms, followed by loss of sensation and weakness below the level of the tumor and loss of bowel and bladder control.

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Spinal Cord Tumor Diagnosis

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MRI is the most useful test to evaluate the patient with suspected spinal cord tumor. Unless there is a contraindication to MRI, it has replaced myelography in most cases. In patients with progressing deficits, urgent evaluation and treatment are indicated. High doses of intravenous corticosteroids are indicated to reduce spinal cord edema. Surgical resection of extradural tumor followed by local radiation therapy or radiation therapy alone are the treatments of choice, depending on a variety of clinical factors. Surgery for biopsy is indicated if there is no known cancer.

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Spinal Cord Tumor Treatment

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Treatment of intradural intramedullary or extramedullary primary spinal tumors is with surgical resection, when possible. In many patients, however, resection carries an unacceptable risk of neurologic damage, and biopsy alone is performed to establish the diagnosis. Most patients require spinal radiation for definitive treatment.

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