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Program Written Summary
Audio-Digest Oncology
Volume 04, Issue 17
September 7, 2013

Symptoms Associated with CNS Malignancies – David M. Peereboom, MD
Leptomeningeal Metastases – Dr. Peereboom
Antidepressants and Cancer – Walter F. Baile, MD,=

Sponsored By Cleveland Clinic Center For Continuing Education And Taussig Cancer Institute
Digital Media $24.99
Audio CD $27.99

The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.

Oncology Program Info  Accreditation InfoCultural & Linguistic Competency Resources

Highlights from Future Directions:
Palliative Medicine and Supportive Oncology 2013 — Part 2

Sponsored by Cleveland Clinic Center for Continuing Education and Taussig Cancer Institute

Educational Objectives

The goal of this program is to improve palliative or supportive care of patients with cancer. After hearing and assimilating this program, the clinician will be better able to:

1. Anticipate symptoms associated with certain types, locations, and treatments of central nervous system (CNS) malignancies.

2. Prescribe appropriate therapies for symptoms of CNS malignancies.

3. Manage treatment of patients with metastases to the leptomeninges.

4. Differentiate clinical depression from other disorders with similar presentation in cancer patients.

5. Choose antidepressant drugs that treat concomitant conditions as well as depression.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose. In their lectures, Drs. Peereboom and Baile present information that is related to the off-label or investigational use of a therapy, product, or device.

Symptoms Associated with CNS Malignancies

David M. Peereboom, MD, Associate Professor of Medicine, Cleveland Clinic Lerner College of Medicine, and Director of Clinical Research, Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH

Duration of symptoms (prognosis): glioblastoma15 mo; anaplastic glioma — 3 to 5 yr; low-grade gliomas — 6 to 20 yr; central nervous system (CNS) metastases — short life expectancy; primary CNS lymphoma5 yr

Origins of symptoms: growth of tumor; exposure of pituitary to radiation therapy (RT); toxicity associated with therapy (surgery, cranial RT, steroids, antiepileptic drugs [AEDs], chemotherapy [CXT]); depression

Impaired communication: aphasia or dysarthria (due to tumor in language areas); change in personality; seizures; irritability (toxic effects of, eg, steroids, levetiracetam); RT-induced fatigue; frontal lobe dysfunction; two-thirds of patients with CNS tumors have impaired communication; implications — difficulty reporting symptoms; poor self-advocacy; depression; caregiver stress; communication diverted to caregiver; delayed discussion of end-of-life issues

Fatigue: most common symptom affecting quality of life (QOL) (occurs in 40%-70% of patients with primary tumor and >80% of patients receiving RT); Struik study — 40% of patients with low-grade gliomas report fatigue >8 yr after completion of treatment; causes — cranial RT; disturbance of hypothalamic-pituitary-adrenal axis; sleep disturbance; AEDs, especially first-generation; treatment — manage reversible causes; dose steroids no later than early afternoon; transition patients off sedating AEDs; consider use of stimulants (eg, methylphenidate); cognitive rehabilitation; armodafinil — stimulant drug approved for excessive daytime sleepiness due to variety of disorders; study in progress in patients with malignant glioma

Seizures: experienced by 20% to 40% of patients with brain tumor; frequency inversely related to growth rate of tumor (most common presentation of low-grade glioma [often with no other symptoms]); less frequent with malignant glioblastoma; patients with low-grade disease often not treated with aggressive surgical therapy if controlled by standard doses of AED (unclear whether resection of seizure focus would have prevented years of AED use); seizures distressing to patients and families; patients may develop stepwise neurologic decline; seizures may cause more seizures; may result in decline in independence (eg, prohibition of driving)

Prophylactic AEDs: American Academy of Neurology meta-analysis — strategy shown to be ineffective for preventing seizures in this population; therefore, no AEDs recommended unless seizure has occurred; one study showed 70% of neurosurgeons continue to use prophylactic AEDs; recommendation — taper and discontinue perioperative AEDs after 1 wk; if patient taking AED >1 wk postoperatively, obtain reliable history to prevent unnecessary long-term therapy; management — aggressive resection of low-grade gliomas; use AEDs (if needed) that do not react with cytochrome P450 (CYP450) enzymes; become familiar with state driving laws addressing seizures; treat tumor with CTX; seizure surgery (if refractory)

Vasogenic edema: common in gliomas, metastases, and nonmalignant disease; major immediate and reversible cause of neurologic decline; radiation necrosis — significant cause of edema; common after stereotactic radiosurgery (SRS) for malignant and nonmalignant disease; may occur months to years after SRS; management — steroids; corticorelin (corticotropin-releasing factor analogue); surgical resection or debulking (decreases mass effect); bevacizumab — markedly reduces edema; improves QOL; safe for CNS tumors (if patient has no history of bleeding); approved for recurrent glioblastoma (studies of use with RT and SRS in progress)

Cognitive problems: multiple causes; associated with focal lesions in temporal lobes and posterior cortex; also occur due to changes in white matter (mostly occlusion of small vessels) caused by RT; treatmentsstimulants; cholinesterase inhibitors; N-methyl-D-aspartate (NMDA) receptor antagonists; donepezil study — shown to improve cognition, mood, and QOL in patients with low-grade gliomas; Gehring study — methylphenidate and modafinil equally improved neurocognitive function

Deep venous thrombosis: common in patients with CNS tumors (especially if paretic); consider routine duplex scanning; anticoagulation safe in patients with no history of bleeding; if possible, avoid inferior vena cava filters

Leptomeningeal Metastases

Dr. Peereboom

Leptomeninges: includes arachnoid and pia mater (ie, subarachnoid space)

Cerebral spinal fluid (CSF): produced in choroid plexus; route of flow — lateral ventricles to cerebral aqueduct, to third and fourth ventricles, then to surrounding area of spinal cord (small amount through central canal); returns cephalad, and flows anteriorly and posteriorly over convexities; absorbed into arachnoid granulations

Choroid plexus: produces 800 mL/day of CSF; actual space 140 mL; turnover of CSF occurs 5 times/day; tumor can invade CSF via multiple paths

Epidemiology: leptomeningeal metastases diagnosed in 5% of patients with metastatic disease (20% asymptomatic); common origins — breast (especially lobular) and lung cancer; lymphoma and hematologic malignancies may affect CSF without other evidence of systemic disease

Risk categories: high — low Karnofsky performance status; multiple fixed neurologic deficits; extensive systemic cancer; encephalopathy or bulky CNS disease; low (consider for active therapy) — better performance status; few or no fixed deficits; have viable treatment options for other areas of cancer; prognosis — survival 1 mo if untreated; 2 mo if no response to treatment; longer (4–10 mo) for various tumor histologies; patients with non-AIDS-related lymphoma have best prognosis

Symptoms: cerebral hemispheres — headache; altered mental status; cranial nerves — coated by malignant cells in CSF; III, IV, VI, and VII most commonly affected; spinal roots — radicular pain; numbness over dermatomes; weakness and paresthesias down legs; pain in back and neck; consider leptomeningeal disease in patients with pain or deficits in disparate areas

Diagnosis: obtain images of symptomatic areas (if possible, avoid lumbar puncture [LP]); magnetic resonance imaging (MRI) reveals rough, thick coating of leptomeninges; symptoms and MRI findings in patients with known cancer obviate need for LP; LP — obtain high volume of CSF (fill tube); obtain during working hours to avoid degradation of tumor cells before analysis; order flow cytometry if lymphoma suspected; high white blood cell count, high protein level, and low glucose level typical; meningeal biopsy — occasionally required

Evaluation: assess risk category; discuss goals of treatment; assess sites of disease; CSF flow study mandatory if intrathecal (IT) CTX planned

Management: high risk — RT to symptomatic sites; consult with palliative medicine; goals of therapy — improve or stabilize neurologic deficits; prolong survival; treat entire neuraxis; optimize therapy schedule (to facilitate response); maintain QOL; other approaches — craniospinal RT (rarely used); IT CTX; systemic CTX (eg, high-dose methotrexate, capecitabine); general medical management (steroids, anticonvulsants, analgesics, and antiemetics); leukoencephalopathy — damage to white matter; may occur with RT or methotrexate (but risk increased if given in proximity)

Management of symptoms: increased intracranial pressure — dexamethasone; ventricular-peritoneal shunt (for refractory headaches and hydrocephalus); focal deficits — RT (for palliation of pain, treatment of bulky disease, and removal of obstruction to flow before IT CTX); if possible, avoid craniospinal RT (causes myelosuppression; irradiates esophagus and intestines); consider systemic CTX (eg, high-dose methotrexate) if flow of CSF obstructed

Intrathecal CTX: candidates — tumor chemosensitive (eg, breast cancer [BC], lymphoma); performance status good; systemic disease controlled or controllable; no bulk disease (IT CTX penetrates only 1-3 mm); method — CTX injected into Ommaya reservoir; response — assessed via QOL, neurologic evaluation, and cytology; follow-up bulky disease with MRI

IT CTX agents: standard methotrexate or cytarabine (both given twice per week); liposomal cytarabine (given once every 2 wk); thiotepa; mafosfamide (analogue of cyclophosphamide); rituximab; trastuzumab; common side effects — nausea and vomiting; headache; aseptic meningitis or arachnoiditis; (infection of wounds and bacterial meningitis uncommon); route of administrationintraventricular (via reservoir) results in better delivery of drug throughout entire CSF space; more convenient than repeated LP; Glantz study — progression-free survival (PFS) better with intraventricular vs lumbar methotrexate; liposomal cytarabine — drug placed in sphere of small lipid chambers for sustained release; half-life 80 hr; however, causes higher incidence of arachnoiditis than with standard cytarabine or methotrexate; studies — patients with solid tumors had increased time to neurologic progression when treated with liposomal cytarabine (and trend toward improved survival), compared to methotrexate group; no difference in PFS; trend toward longer time to neurologic progression and better response rates seen in patients with lymphomatous meningitis; measures of QOL also showed improvement; systemic agents — capecitabine (for BC); high-dose gefitinib or erlotinib (for lung cancer); high-dose methotrexate; newer therapies — use established agents, but delivery into CSF novel; rituximab (for lymphoma); trastuzumab (for HER2-positive BC)

Answer to question: CSF flow studies — Ommaya reservoir likely best method of delivery for patient able to tolerate IT CTX; tube placed in lateral ventricle; blockage in flow of CSF causes build-up of medication; blockage also prevents CTX delivered via lumbar route from reaching ventricles; CSF flow studies usually performed by nuclear medicine team; place reservoir after blockage cleared

Antidepressants and Cancer

Walter F. Baile, MD, Professor of Psychiatry and Behavioral Science, University of Texas MD Anderson Cancer Center, Houston

General principles: antidepressants treat multiple conditions (eg, obsessive-compulsive disorder, anxiety, pain, hot flashes, insomnia); all equal in efficacy for depression (except trazodone slightly weaker); Cochrane review — antidepressants better than placebo; most antidepressants well tolerated in most patients; even those with advanced disease likely to benefit if correct symptoms targeted

Drug interactions; antidepressants can affect CYP450 system, so may reduce or increase efficacy of other drugs; high dosage most common reason drugs not tolerated; start with low dose and gradually increase; patient education about what to do, what to look for, and duration of treatment essential for compliance

Diagnosis: Diagnosis and Statistical Manual of Mental Disorders — categorizes depression as major depression, adjustment disorder (ie, assumes depression caused by patient’s life experiences; difficult to confirm), or bipolar disease; International Classification of Diseases — categorizes clinical depression as mild, moderate, or severe; patients with moderately severe to severe symptoms more likely to respond to antidepressants

Other possible conditions: demoralization — may improve with psychotherapy; however, tearfulness or feeling upset (eg, after hearing bad news) occurs frequently in oncology; often responds to social support; grief reaction — usually of limited duration; consider antidepressant if prolonged; hypoactive delirium — patients become confused and unresponsiveness; evaluate mental status before starting antidepressants; organic affective disorders — hypothyroidism or drugs causing changes in mood

Core symptoms: loss of interest in social and other activities; hopelessness about future; mood worse in morning and improves somewhat during day; increased irritability; sleep disturbance, with early morning awakening; anhedonia; clinical depression never “normal”

Treatment algorithm: ensure patient has depressive disorder (history of depressive illness common); distinguish from sadness, frustration, nervousness, anger, and sense of defeat (consider supportive counseling and possibly anxiolytics); rule out organic factors (eg, interferon, hypothyroidism); patients with untreated pain or on steroid taper susceptible to changes in mood; consider trial of antidepressants if other possibilities ruled out

Types of antidepressants: categorized by effects on neurotransmitter system; psychostimulants (eg, methylphenidate) often used in terminally ill patients; selective serotonin reuptake inhibitors (SSRIs) — benefits include good safety profile, being well tolerated, and anxiolytic properties; may block hot flashes; fluoxetine has weekly formulation and long half-life (taper not required if discontinued); risks include adverse effects (eg, gastrointestinal distress, sexual dysfunction [30% of patients], potential for significant drug interactions due to inhibition of CYP450 system); serotonin-norepinephrine reuptake inhibitors (SNRIs) — venlafaxine and desvenlafaxine useful in treatment of hot flashes and neuropathic pain; duloxetine also used for neuropathic pain; however, venlafaxine can cause nausea and hypertension; desvenlafaxine may cause nausea; duloxetine may inhibit CYP450 enzymes; atypical antidepressants — eg, mirtazapine (stimulates appetite [so may cause weight gain] and has sedating and antiemetic effects); bupropion has activating effect; earlier formulations of bupropion exacerbated seizures in vulnerable patients (not seen with newer long-acting formulation)

Approach to prescribing: become familiar with 1 or 2 antidepressants and prescribe those regularly; do not use — if patient not clinically depressed or has high potential for drug interactions or side effects (eg, avoid venlafaxine if patient has nausea); match antidepressant choice to patient’s concomitant symptoms (eg, mirtazapine for patient with insomnia); avoid simultaneous use of 2 antidepressants (can create risk for serotonin syndrome); ask patients about previous or family members’ use of antidepressants

Other information: antidepressants often work in days (rather than weeks); look for contraindications to use; advise patients of duration of treatment; continue for 6 mo before tapering dose; use lower dose if patient elderly or has renal or hepatic dysfunction; if drug ineffective, change to another in same class, then to different class; advise patients to continue medication even if feeling better


Drs. Peereboom and Baile were recorded at Future Directions: Palliative Medicine and Supportive Oncology 2013, the 16th International Symposium, held February 21-23, 2013, in Key Largo FL, and sponsored by the Cleveland Clinic Center for Continuing Education and Taussig Cancer Institute. Information about upcoming conferences from Cleveland Clinic can be found at The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Suggested Reading

Centeno C et al: Multicentre, double-blind, randomised placebo-controlled clinical trial on the efficacy of methylphenidate on depressive symptoms in advanced cancer patients. BMJ Support Palliat Care 2:328, 2012; Chamberlain MC: Leptomeningeal metastases: a review of evaluation and treatment. J Neurooncol 37:271, 1996; Faithfull S et al: Palliative care of patients with a primary malignant brain tumour: case review of service use and support provided. Palliat Med 19:545, 2005; Gehring K. et al: A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor. J Neurooncol 107(1), 165-174, 2012; Glantz MJ et al: Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 54:1886, 2000; Glantz MJ et al: Route or intracerebrospinal fluid chemotherapy administration and efficacy of therapy in neoplastic meningitis. Cancer 116:1947, 2010; Hart SL et al: Meta-analysis of efficacy if interventions for elevated depressive symptoms in adults diagnosed with cancer. J Natl Cancer Inst 104:990, 2012; Sandler A et al: An evidence-based review of the incidence of CNS bleeding with anti-VEGF therapy in non-small cell lung cancer patients with brain metastases. Lung Cancer 78:1, 2012; Sadrael MH et al: Treatment of cerebral radiation necrosis with bevacizumab: the Cleveland Clinic experience. Am J Clin Oncol, Jun 24, [Epub ahead of print] 2013; Shaw EG et al: Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. J Clin Oncol 24:1415, 2006; Siomin V et al: Results of a survey of neurosurgical practice patterns regarding the prophylactic use of anti-epilepsy drugs in patients with brain tumors. J neurooncol 74:211, 2005; Struik K et al: Fatigue in low-grade glioma. J Neurooncol 92:73, 2009.

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