Oncologic EmergenciesGreg V. Manson Sept 5, 2008 and Sept 18, 2008

Oncologic Emergencies4 Major typesMetabolic emergencies (hypercalcemia, hyponatremia, hypoglycemia, adrenal failure, lactic acidosis)Hematologic emergencies (hyperleukocytosis, DIC, thrombosis )Infectious / Inflammatory emergencies (typhlitis, pancreatitis, chemo infiltration, hemorrhagic cystitis )Mechanical emergencies (cerebral herniation/status epilepticus, cardiac tamponade, SVC syndrome?)

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Case 1:77 y/o AAM w/ PMHx of CAD s/p CABG, DM, gout, bipolar I disorder, 5 year history of CLL comes to UCC fast track w/ severe fatigue, nausea, mild abdominal discomfort. Pt admitted to VA on ward 3B. He was seen by heme/onc and started on oral hydroxyurea after diagnosis of acute blastic transformation. Youre signed-out to follow up on PM renal function panel.

Case #1potassium 5.3 mEq/L calcium 8.1 mg/dL phosphate 5.5 mg/dL lactate dehydrogenase (LDH) 28,900 U/Land uric acid 14.3 mg/dL creatinine was normal, at 1.1 mg/dL

TUMORLYSISSYNDROME

Tumor Lysis SyndromeTLS: Metabolic derangements caused by the massive and abrupt release of cellular components into the blood after the rapid lysis of malignant cells. (phos , K , uric acid , Ca) Uric acid crystals and/or CaPO4 in renal tubules = impaired renal function, ARF, even deathphos leads to Ca : tetany, seizures, arrhythmiaK = life-threatening arrhythmia

Tumor Lysis Syndrome: WHO GETS IT?High tumor cell proliferation rate, large tumor burden, tumor chemosensitivityALL, AML, NHL, Burkitts Lymphoma (heme malignancies) Small cell >>> Hodgkins disease, Multiple Myeloma, Solid Tumors ( breast, GI, prostate etc.) Signs and Symptoms are non-specific: Can occur before chemo, but usually within 12 to 72hrs after starting chemo NauseaVomitingDiarrheaAnorexiaSyncopeLethargyEdemaFluid overloadCrampsSudden death

Tumor Lysis Syndrome: WHO GETS IT?Usually develops after chemotherapy (paclitaxel, fludarabine, etoposide, thalidomide, bortezomib, and hydroxyurea )Can occur after radiation therapy, corticosteroids, chemoembolization, intrathecal chemotherapy, rarely from spontaneous necrosisLDH is considered by some a measure of tumor load and a marker of TLS risk

Tumor Lysis Syndrome Prevention & ManagementThe best management is prevention.FLUIDS and HYDRATION:Aggressive hydration and diuresisImprove intravascular volume, renal blood flow, GFR (decrease [solute] in distal nephron/renal microcirculation)+/- diuretics (contraindicated in hypovolemia and obstructed uropathy)

Tumor Lysis Syndrome Prevention & ManagementALKALINIZATION OF URINE:-Uric acid > 10xs more soluble in pH of 7.0 compared to pH of 5.0-Xanthine/hypoxanthine is also significantly more soluble in basic urine - Historically used, but not based on evidence based practice. NOT RECOMMENDED-Complications of alkalinization outweighs benefits (calcium phosphate precipitation, metabolic alkalosis)

Tumor Lysis Syndrome Prevention & ManagementALLOPURINOL:-Competitive inhibitor of xanthine oxidase which decreases conversion of purine metabolites to uric acid. Used prophylactically for TLS-Prophylactic option for patients with a medium risk of TLS-Limitations: ----1)ineffective in reducing uric acid levels before chemoTx----2) Xanthine and hypoxanthine precipitateobstructive uropathy----3)reduces clearance of some chemoTx (azothiopurine & 6-mercaptopurine)

Tumor Lysis Syndrome Prevention & ManagementRASBURICASE (recombinant urate oxidase) :-promotes catabolism of uric acid:Uric acid allantoin (10x more soluble than uric acid)-100 adult pt (w/ aggressive NHL) got 3 to 7 days of rasburicase beginning day 1 of chemo: 1)Uric acid levels decreased w/i 4 hrs of rasburicase2)Normalized uric acid levels maintained throughout chemo3)No increase in creatinine observed4)No patient required dialysis-One European and one US study showed that rasburicase prophylaxis resulted in net savings in health care costs ($9,978 for 7 day stay VS. $51,990 for 21 day stay w/ HD)

Case #2:55 y/o w/ Hx of AML s/p stem cell transplant several months prior. Comes to ICC for scheduled and routine RBC transfusion. He is also receiving outpatient chemo therapy via PICC. Pt complains of fatigue and constipation. ICC nurses note temp of 36.1 C, BP= 82/58, + orthostasis. He is given 1L IVF and has routine labs drawn as he is transferred to Tower 6. He is admitted under the diagnosis of hypotension.

Case #2:Upon admission to floor he denies any other complaints, and is compliant w/ meds. Additionally he has been taking tylenol for 1 day hx of headache and 2 weeks of bisacodyl suppositoriesHis admission vitals : 99.5, 109/76, 88, 20, 97% on room air but is actively rigoring when you arriveWBC = 0.2 , ANC=0.06

NEUTROPENICFEVER

Neutropenic FeverNeutropenia:ANC < 500 or

Neutropenic FeverBefore era of empiric antibiotics, infections accounted for 75% deaths related to chemotherapyFever is commonly the only symptom. Common infections present atypically (asymptomatic UTIs, PNA w/o infiltrates, meningitis w/o nuchal rigidity, bacteremia w/ only fatigue)Avoid digital rectal exams/manipulationsCareful oral exam and exam of catheter sites if anyPan Cx

Neutropenic FeverBACTERIA:Until 1980s, GNR (P.aeruginosa) were the most commonly identified pathogens1995-2000, Gram + organisms = 62-76% of all bloodstream infectionsTrend toward Gram + due to introduction of long-term indwelling lines (Hickmans,Mediports)FUNGAL: - Risk increases w/ duration and severity of neutropenia, prolonged antibiotic use, and number of chemotherapy cycles-Candida (lines), aspergillus (immunocompromised, skin,sinus, PNA) >>>histo, blasto, coccidio, TB(prolonged steroids, other high risk patients)

(Neutropenic Fever) TREATMENTNumerous regimens studied: monotherapy demonstrated equivalent to two drug regimens (i.e.: piperacillin/tazobactam , cefepime, meropenem)In critically ill, add on aminoglycoside (better G - coverage)Addition of Gram (+) as initial empiric coverage in patients w/o port/catheter/line or mucositis has no proven clinical benefit (VRE) Vancomycin or Linezolid :

-Skin or catheter infection-Hx of MRSA colonization-recent quinolone proph-Clinical deterioration-Hypotension-Mucositis

(Neutropenic Fever) TREATMENTFungal coverage (candida or aspergillus ssp. ):Routinely added after 5-7 days of persistent neutropenic fever w/o clear sourcePost mortem of fatalities after prolonged febrile neutropenia (1966-1975) = 69% w/ evidence of systemic fungal diseaseTx with liposomal amphotericin B (most common), voriconazole(? failed noninferiority trial?), caspofungin (passed noninferiority trial, less nephrotoxic aspergillus failure?)No fluconazole = efficacy

(Neutropenic Fever) TREATMENTColony Stimulating Factors (CSF):NOT routinely used for neutropenic fever unless the patient had previous bout of neutropenic fever with prior chemo cycle. Not shown to decrease mortalityBeneficial effects are quite modestUsed in neutropenic septic shock/severe sepsis (hypotension, organ dysfunction, PNA)Used in patients whose bone marrow recovery is expected to be especially prolonged.

Case #3:64 y/o WM w/o significant past medical history comes to ED w/ complaints of progressive LBP. He notes pain initially started approx 6-8 weeks ago w/o inciting event. He is normally very active and enjoys jogging/biking ; currently still working as bartender. He went to Chagrin Highlands Urgent Care two weeks ago and got routine lumbosacral films which were essentially normal. He was discharged home w/ course of high dose NSAIDS. He comes to UH ED w/ complaints of persistent and progressive band like lower back pain. He notes new unsteadiness when he walks for the last two days, which prompted him to come to medical attention.

Case #3:In ED: vitals and labs were within normal limitsMRI of spine showed metastatic disease diffusely noted w/ thecal sac impingement at level of L2-L3PSA sent from ED = 68

SPINAL CORDCOMPRESSION

Spinal Cord CompressionNeoplastic epidural spinal cord compressionNeoplastic invasion of space between vertebrae and spinal cord (epidural invasion)Defined as ANY thecal sac indentation radiographically (spinal cord or cauda equina)

LOCATION:Thoracic spine: 60%Lumbosacral spine: 30%Cervical spine: 10%

Spinal Cord CompressionCord compression is a common complication in oncology patients (5-10% of all cancer patients: prostate, lung, breast) which is a cause of pain and irreversible loss of neurologic function. NOT immediately life threatening unless it involves C3 or aboveBack pain is the precursor to spinal cord injury in almost all (96%)patients w/ spinal mets. Pain similar to disc disease: except pain supine, upright

Spinal Cord CompressionBesides back pain:Radicular painMotor weaknessGait disturbanceBowel bladder dysfunction

Spinal Cord CompressionDiagnosisBack pain + known malignancy = SCC until proven otherwisePlain films NOT enoughExam has poor accuracy with localizing levelMRI without contrast is the best test for SCC when suspectedCan resort to CT (myelography) if pt cannot tolerate MRI, is not candidate for MRI, or not available.

Spinal Cord CompressionTREATMENTSteroidsRadiation TherapySurgery

Spinal Cord Compression:TreatmentCorticosteroidsProvides pain relief and anti-inflammationDexamethasone: Loading dose of 10mg to 16mg; followed by 4mg q 4hrs. Higher doses (100mg) may be associated w/ slightly better outcome in exchange for higher incidence of adverse effects. Reserved for paraplegia/paraparesis generally. (low vs high dose studies = equivocal)Taper once definitive treatment is underway

Spinal Cord Compression:TreatmentRadiation TherapyThis alone can be used for patients who are ambulatory and for pretreatment before paresis occurs. Doses is variable and determined by the quantity of previous XRT, type of tumor, and the field of treatmentFor extensive disease; limited survival = meaningful palliation (short courses)Chemotherapy can be used but most tumor types not particularly chemosensitive (unless NHL, Hodgkins, germ cell, breast).

Spinal Cord Compression:TreatmentSurgery---evolving scienceTHEN: Previous studies: Laminectomy w/ or w/o RT vs RT alone = NO difference in outcomeDecompressive resection reserved for unstable spine, life threatening compression, unknown etiology, tumors that are not reliably radiosensitive or chemosensitive.NOW: Newer studies show surgical intervention + XRT show BETTER functional status than XRT alone (anterior approach, improvements in instrumentation)

Spinal Cord Compression:TreatmentOther Management issuesQuickly involve Rad/onc and NeuroSx / OrthoAnalgesia: opioids, steroidsBed rest: controversial- but generally unnecessaryAnticoagulation: DVT prophylaxisBowel regimen: autonomic dysfunction, opioids, limited mobility all contribute to constipationSpinal bracing: only in patients with refractory pain

Spinal Cord Compression:PrognosisBest predictor is pre-treatment functional/neurologic status Rapid onset and quick progression = poor Px75% of patients treated correctly while still ambulatory, will remain ambulatoryOnly 10% of patients presenting with paraplegia will regain ambulatory status

References:Guidelines for the Management of Pediatric and Adult Tumor LYsis Syndrome: An Evidence Based Review. Bernard et al. Journal of Clinical Oncology. Vol 26. June 1 2008Harrisons Principles of Internal Medicine. Kasper, Dennis MD, et al. 16th ed. 577-582. 2006. Oncologic Emergencies: Diagnosis and Treatment. Halfdanarsan et al. Mayo Clinic Procedings. June 2006: 81(6). 835-848Fever in the neutropenic adult patient with cancer. Robbins,Gregory. Up to Date Online. May 31, 2008Oncologic Emergencies for the Internist. Krimsky, William, et al. Cleveland Clinic Journal of Medicine. Vol 69. 3. March 2002Treatment and Prognosis of Epidural Spinal Cord Compression, Including Cauda Equina Syndrome. Schiff, David et al. Up to Date Online. May 31, 2008. Tumor Lysis Syndrome. eMedicine. Koyamangalath Krishnan

Learning ObjectivesIdentification of 3 major oncologic emergenciesManagement of tumor lysis syndromeManagement of neutropenic feverManagement of spinal cord compression