Oncologic EmergenciesOncologic Emergencies

Greg V. Manson Greg V. Manson Sept 5, 2008 and Sept 18, 2008Sept 5, 2008 and Sept 18, 2008

Oncologic EmergenciesOncologic Emergencies

4 Major types4 Major types– Metabolic emergenciesMetabolic emergencies (hypercalcemia, (hypercalcemia,

hyponatremia, hypoglycemia, adrenal failure, lactic acidosis)hyponatremia, hypoglycemia, adrenal failure, lactic acidosis)

– Hematologic emergenciesHematologic emergencies (hyperleukocytosis, DIC, thrombosis )(hyperleukocytosis, DIC, thrombosis )

– Infectious / Inflammatory emergenciesInfectious / Inflammatory emergencies (typhlitis, pancreatitis, chemo infiltration, hemorrhagic cystitis )(typhlitis, pancreatitis, chemo infiltration, hemorrhagic cystitis )

– Mechanical emergenciesMechanical emergencies (cerebral (cerebral herniation/status epilepticus, cardiac tamponade, SVC herniation/status epilepticus, cardiac tamponade, SVC syndrome?)syndrome?)

911

VS

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Case 1:Case 1:

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

Case #1Case #1

potassium 5.3 mEq/L potassium 5.3 mEq/L

calcium 8.1 mg/dL calcium 8.1 mg/dL

phosphate 5.5 mg/dL phosphate 5.5 mg/dL

lactate dehydrogenase (LDH) 28,900 U/Llactate dehydrogenase (LDH) 28,900 U/L

and uric acid 14.3 mg/dL and uric acid 14.3 mg/dL

creatinine was normal, at 1.1 mg/dL creatinine was normal, at 1.1 mg/dL

TUMORLYSIS

SYNDROME

Tumor Lysis SyndromeTumor Lysis Syndrome

TLS:TLS: Metabolic derangements caused by the Metabolic derangements caused by the massive and abrupt release of cellular massive and abrupt release of cellular components into the blood after the rapid lysis of components into the blood after the rapid lysis of malignant cells. (malignant cells. (↑phos , ↑K , ↑uric acid , ↓Ca) ↑phos , ↑K , ↑uric acid , ↓Ca)

Uric acid crystalsUric acid crystals and/or and/or CaPOCaPO44 in renal in renal tubules = impaired renal function, ARF, even tubules = impaired renal function, ARF, even deathdeath↑↑phosphos leads to leads to ↓Ca↓Ca : tetany, seizures, : tetany, seizures, arrhythmiaarrhythmia↑↑KK = life-threatening arrhythmia = life-threatening arrhythmia

……Tumor Lysis Syndrome: WHO GETS IT?Tumor Lysis Syndrome: WHO GETS IT?

High tumor cell proliferation rate, large tumor High tumor cell proliferation rate, large tumor burden, tumor chemosensitivityburden, tumor chemosensitivityALL, AML, NHL, Burkitt’s Lymphoma ALL, AML, NHL, Burkitt’s Lymphoma (heme (heme

malignancies) malignancies) Small cell >>> Hodgkin’s disease, Small cell >>> Hodgkin’s disease, Multiple Myeloma, Solid Tumors Multiple Myeloma, Solid Tumors ( breast, GI, prostate etc.) ( breast, GI, prostate etc.)

Signs and Symptoms are non-specific: Can Signs and Symptoms are non-specific: Can occur before chemo, but usually within 12 to occur before chemo, but usually within 12 to 72hrs after starting chemo 72hrs after starting chemo

NauseaNauseaVomitingVomitingDiarrheaDiarrheaAnorexiaAnorexiaSyncopeSyncope

LethargyLethargyEdemaEdemaFluid overloadFluid overloadCrampsCrampsSudden deathSudden death

……Tumor Lysis Syndrome: WHO GETS IT?Tumor Lysis Syndrome: WHO GETS IT?

Usually develops after chemotherapy Usually develops after chemotherapy (paclitaxel, (paclitaxel, fludarabine, etoposide, thalidomide, bortezomib, and hydroxyurea )fludarabine, etoposide, thalidomide, bortezomib, and hydroxyurea )

Can occur after radiation therapy, Can occur after radiation therapy, corticosteroids, chemoembolization, intrathecal corticosteroids, chemoembolization, intrathecal chemotherapy, rarely from spontaneous chemotherapy, rarely from spontaneous necrosisnecrosis

LDH is considered by some a measure of tumor LDH is considered by some a measure of tumor load and a marker of TLS riskload and a marker of TLS risk

……Tumor Lysis SyndromeTumor Lysis Syndrome Prevention & Prevention & ManagementManagement

““The best management is preventionThe best management is prevention.”.”

FLUIDS and HYDRATION:FLUIDS and HYDRATION:– Aggressive hydration and diuresisAggressive hydration and diuresis– Improve intravascular volume, renal blood Improve intravascular volume, renal blood

flow, GFR (decrease [solute] in distal flow, GFR (decrease [solute] in distal nephron/renal microcirculation)nephron/renal microcirculation)

– +/- diuretics (contraindicated in hypovolemia +/- diuretics (contraindicated in hypovolemia and obstructed uropathy)and obstructed uropathy)

……Tumor Lysis SyndromeTumor Lysis Syndrome Prevention & Prevention & ManagementManagement

ALKALINIZATION OF URINE:ALKALINIZATION OF URINE:

-Uric acid > 10x’s more soluble -Uric acid > 10x’s more soluble in pH of 7.0 compared to pH of 5.0in pH of 7.0 compared to pH of 5.0

-Xanthine/hypoxanthine is also -Xanthine/hypoxanthine is also significantly more soluble in basic urine significantly more soluble in basic urine

- Historically used, but not based - Historically used, but not based on evidence based practice. NOT on evidence based practice. NOT RECOMMENDEDRECOMMENDED

-Complications of alkalinization -Complications of alkalinization outweighs benefits (calcium phosphate outweighs benefits (calcium phosphate precipitation, metabolic alkalosis)precipitation, metabolic alkalosis)

……Tumor Lysis SyndromeTumor Lysis Syndrome Prevention & Prevention & ManagementManagement

ALLOPURINOL:ALLOPURINOL:-Competitive inhibitor of xanthine oxidase -Competitive inhibitor of xanthine oxidase which decreases conversion of purine which decreases conversion of purine metabolites to uric acid. Used metabolites to uric acid. Used prophylactically for TLSprophylactically for TLS

-Prophylactic option for patients with a -Prophylactic option for patients with a medium risk of TLSmedium risk of TLS-Limitations: -Limitations: ----1)ineffective in reducing uric acid levels ----1)ineffective in reducing uric acid levels before chemoTxbefore chemoTx----2) Xanthine and hypoxanthine ----2) Xanthine and hypoxanthine precipitateprecipitateobstructive uropathyobstructive uropathy----3)reduces clearance of some chemoTx ----3)reduces clearance of some chemoTx (azothiopurine & 6-mercaptopurine)(azothiopurine & 6-mercaptopurine)

……Tumor Lysis SyndromeTumor Lysis Syndrome Prevention & Prevention & ManagementManagement

RASBURICASERASBURICASE (recombinant urate oxidase) :(recombinant urate oxidase) :

-promotes catabolism of uric acid:-promotes catabolism of uric acid:

Uric acid Uric acid allantoin (10x more soluble than uric acid) allantoin (10x more soluble than uric acid)

-100 adult pt (w/ aggressive NHL) got 3 to 7 days of -100 adult pt (w/ aggressive NHL) got 3 to 7 days of rasburicase beginning day 1 of chemo: rasburicase beginning day 1 of chemo:

1)Uric acid levels decreased w/i 4 hrs of rasburicase1)Uric acid levels decreased w/i 4 hrs of rasburicase

2)Normalized uric acid levels maintained throughout chemo2)Normalized uric acid levels maintained throughout chemo

3)No increase in creatinine observed3)No increase in creatinine observed

4)No patient required dialysis4)No patient required dialysis

-One European and one US study showed that rasburicase -One European and one US study showed that rasburicase prophylaxis resulted in net savings in health care costs ($9,978 prophylaxis resulted in net savings in health care costs ($9,978 for 7 day stay VS. $51,990 for 21 day stay w/ HD)for 7 day stay VS. $51,990 for 21 day stay w/ HD)

Case #2:Case #2:

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

Case #2:Case #2:

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

NEUTROPENICFEVER

Neutropenic FeverNeutropenic FeverNeutropenia:Neutropenia:– ANC < 500 or <1000 w/ a predicted nadir of <500 cells ANC < 500 or <1000 w/ a predicted nadir of <500 cells

– ANC = (WBC) x (% of neutrophils + % of bands)ANC = (WBC) x (% of neutrophils + % of bands)– Nadir usually occurs 5 to 10 days after last chemo Nadir usually occurs 5 to 10 days after last chemo

dose and usually recovers w/i 5 days of nadirdose and usually recovers w/i 5 days of nadir (certain (certain leukemia/lymphoma regimens cause longer lasting and more leukemia/lymphoma regimens cause longer lasting and more profound neutropenia)profound neutropenia)

Fever:Fever:- Single temp of 38.3- Single temp of 38.3ooC (101.3C (101.3ooF)F)

- Sustained Temp of 38.0- Sustained Temp of 38.0ooC (100.4C (100.4ooF) for more than 1 F) for more than 1 hourhour

Neutropenic FeverNeutropenic Fever

Before era of empiric antibiotics, infections Before era of empiric antibiotics, infections accounted for 75% deaths related to accounted for 75% deaths related to chemotherapychemotherapyFever is commonly the only symptom. Fever is commonly the only symptom. Common infections present atypically Common infections present atypically (asymptomatic UTIs, PNA w/o infiltrates, meningitis w/o (asymptomatic UTIs, PNA w/o infiltrates, meningitis w/o nuchal rigidity, bacteremia w/ only fatigue)nuchal rigidity, bacteremia w/ only fatigue)

Avoid digital rectal exams/manipulationsAvoid digital rectal exams/manipulationsCareful oral exam and exam of catheter Careful oral exam and exam of catheter sites if anysites if anyPan Cx Pan Cx

Neutropenic FeverNeutropenic Fever

BACTERIA:BACTERIA:– Until 1980s, GNR (Until 1980s, GNR (P.aeruginosaP.aeruginosa) were the most ) were the most

commonly identified pathogenscommonly identified pathogens– 1995-2000, Gram + organisms = 62-76% of all 1995-2000, Gram + organisms = 62-76% of all

bloodstream infectionsbloodstream infections– Trend toward Gram + due to introduction of long-term Trend toward Gram + due to introduction of long-term

indwelling lines (Hickmans,Mediports)indwelling lines (Hickmans,Mediports)FUNGAL:FUNGAL: - Risk increases w/ duration and severity of neutropenia, - Risk increases w/ duration and severity of neutropenia, prolonged antibiotic use, and number of chemotherapy prolonged antibiotic use, and number of chemotherapy cyclescycles--CandidaCandida (lines), (lines), aspergillusaspergillus (immunocompromised, (immunocompromised, skin,sinus, PNA) >>>skin,sinus, PNA) >>>histo, blasto, coccidiohisto, blasto, coccidio, , TB(prolonged steroids, other high risk patients)TB(prolonged steroids, other high risk patients)

……(Neutropenic Fever)(Neutropenic Fever) TREATMENT TREATMENTNumerous regimens studied: monotherapy Numerous regimens studied: monotherapy demonstrated equivalent to two drug demonstrated equivalent to two drug regimensregimens (i.e.: piperacillin/tazobactam , cefepime, (i.e.: piperacillin/tazobactam , cefepime, meropenem)meropenem)

In critically ill, add on aminoglycosideIn critically ill, add on aminoglycoside (better G - (better G - coverage)coverage)

Addition of Gram (+) as initial empiric coverage Addition of Gram (+) as initial empiric coverage in patients w/o port/catheter/line or mucositis has in patients w/o port/catheter/line or mucositis has nono proven clinical benefit ( proven clinical benefit (↑VRE↑VRE) )

Vancomycin or Linezolid :Vancomycin or Linezolid :-Skin or catheter infection-Skin or catheter infection-Hx of MRSA colonization-Hx of MRSA colonization-recent quinolone proph-recent quinolone proph

-Clinical deterioration-Clinical deterioration-Hypotension-Hypotension-Mucositis-Mucositis

……(Neutropenic Fever)(Neutropenic Fever) TREATMENT TREATMENTFungal coverage Fungal coverage ((candidacandida or or aspergillusaspergillus sspssp. ):. ):

– Routinely added after 5-7 days of persistent Routinely added after 5-7 days of persistent neutropenic fever w/o clear sourceneutropenic fever w/o clear source

– Post mortem of fatalities after prolonged Post mortem of fatalities after prolonged febrile neutropenia (1966-1975) = 69% w/ febrile neutropenia (1966-1975) = 69% w/ evidence of systemic fungal diseaseevidence of systemic fungal disease

– Tx with Tx with liposomal amphotericin Bliposomal amphotericin B (most (most

common),common), voriconazolevoriconazole(? failed noninferiority trial?),(? failed noninferiority trial?), caspofungincaspofungin (passed noninferiority trial, less nephrotoxic (passed noninferiority trial, less nephrotoxic aspergillus failure?)aspergillus failure?)

– No fluconazole = No fluconazole = ↓↓ efficacy efficacy

……(Neutropenic Fever)(Neutropenic Fever) TREATMENT TREATMENTColony Stimulating Factors (CSF):Colony Stimulating Factors (CSF):– NOT routinely used for neutropenic fever NOT routinely used for neutropenic fever

unless the patient had previous bout of unless the patient had previous bout of neutropenic fever with prior chemo cycle. neutropenic fever with prior chemo cycle.

– Not shown to decrease mortalityNot shown to decrease mortality– Beneficial effects are quite modestBeneficial effects are quite modest– Used in neutropenic septic shock/severe Used in neutropenic septic shock/severe

sepsis (hypotension, organ dysfunction, PNA)sepsis (hypotension, organ dysfunction, PNA)– Used in patients whose bone marrow Used in patients whose bone marrow

recovery is expected to be especially recovery is expected to be especially prolonged. prolonged.

Case #3:Case #3:

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

Case #3:Case #3:

In ED: vitals and labs were within normal In ED: vitals and labs were within normal limitslimits

MRI of spine showed metastatic disease MRI of spine showed metastatic disease diffusely noted w/ thecal sac impingement diffusely noted w/ thecal sac impingement at level of L2-L3at level of L2-L3

PSA sent from ED = 68PSA sent from ED = 68

SPINALCORD

COMPRESSION

Spinal Cord CompressionSpinal Cord CompressionNeoplastic epidural spinal cord compression

Neoplastic invasion of space between vertebrae and spinal cord (epidural invasion)

Defined as ANY thecal sac indentation radiographically (spinal cord or cauda equina)

LOCATION:LOCATION:

Thoracic spine: 60%Thoracic spine: 60%

Lumbosacral spine: 30%Lumbosacral spine: 30%

Cervical spine: 10%Cervical spine: 10%

Spinal Cord CompressionSpinal Cord CompressionCord compression is a common Cord compression is a common complication in oncology patients complication in oncology patients (5-10% of all (5-10% of all

cancer patients: prostate, lung, breast)cancer patients: prostate, lung, breast) which is a which is a cause of pain and irreversible loss of cause of pain and irreversible loss of neurologic function. neurologic function. NOT immediately life threatening unless it NOT immediately life threatening unless it involves C3 or aboveinvolves C3 or aboveBack pain is the precursor to spinal cord Back pain is the precursor to spinal cord injury in almost all (96%)patients w/ spinal injury in almost all (96%)patients w/ spinal mets. mets. Pain similar to disc disease: except ↑ pain supine, ↓upright

Spinal Cord CompressionSpinal Cord CompressionBesides back pain:– Radicular pain– Motor weakness– Gait disturbance– Bowel bladder dysfunction

Spinal Cord CompressionSpinal Cord CompressionDiagnosis– Back pain + known malignancy = SCC until

proven otherwise– Plain films NOT enough– Exam has poor accuracy with localizing level– MRI without contrast is the best test for SCC

when suspected– Can resort to CT (myelography) if pt cannot

tolerate MRI, is not candidate for MRI, or not available.

Spinal Cord CompressionSpinal Cord CompressionTREATMENT– Steroids– Radiation Therapy– Surgery

……Spinal Cord Compression:Spinal Cord Compression:TreatmentTreatment

Corticosteroids– Provides pain relief and anti-inflammation– Dexamethasone: 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:Spinal Cord Compression:TreatmentTreatmentRadiation Therapy– This 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 treatment

– For extensive disease; limited survival = meaningful palliation (short courses)

– Chemotherapy can be used but most tumor types not particularly chemosensitive (unless NHL, Hodgkin’s, germ cell, breast).

……Spinal Cord Compression:Spinal Cord Compression:TreatmentTreatment

Surgery---evolving science– THEN: Previous studies: Laminectomy w/ or w/o RT vs

RT alone = NO difference in outcome

– Decompressive 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:Spinal Cord Compression:TreatmentTreatment

Other Management issues– Quickly involve Rad/onc and NeuroSx / Ortho– Analgesia: opioids, steroids– Bed rest: controversial- but generally

unnecessary– Anticoagulation: DVT prophylaxis– Bowel regimen: autonomic dysfunction,

opioids, limited mobility all contribute to constipation

– Spinal bracing: only in patients with refractory pain

……Spinal Cord Compression:Spinal Cord Compression:PrognosisPrognosis

Best predictor is pre-treatment functional/neurologic status – Rapid onset and quick progression = poor Px– 75% of patients treated correctly while still

ambulatory, will remain ambulatory– Only 10% of patients presenting with

paraplegia will regain ambulatory status

References:References:

Guidelines for the Management of Pediatric and Adult Tumor LYsis Syndrome: An Guidelines for the Management of Pediatric and Adult Tumor LYsis Syndrome: An Evidence Based Review.Evidence Based Review. Bernard et al. Journal of Clinical Oncology. Vol 26. June 1 Bernard et al. Journal of Clinical Oncology. Vol 26. June 1 20082008

Harrison’s Principles of Internal Medicine. Kasper, Dennis MD, et al. 16Harrison’s Principles of Internal Medicine. Kasper, Dennis MD, et al. 16 thth ed. 577- ed. 577-582. 2006. 582. 2006.

Oncologic Emergencies: Diagnosis and TreatmentOncologic Emergencies: Diagnosis and Treatment. Halfdanarsan et al. Mayo Clinic . Halfdanarsan et al. Mayo Clinic Procedings. June 2006: 81(6). 835-848Procedings. June 2006: 81(6). 835-848

Fever in the neutropenic adult patient with cancerFever in the neutropenic adult patient with cancer. Robbins,Gregory. Up to Date . Robbins,Gregory. Up to Date Online. May 31, 2008Online. May 31, 2008

Oncologic Emergencies for the InternistOncologic Emergencies for the Internist. Krimsky, William, et al. Cleveland Clinic . Krimsky, William, et al. Cleveland Clinic Journal of Medicine. Vol 69. 3. March 2002Journal of Medicine. Vol 69. 3. March 2002

Treatment and Prognosis of Epidural Spinal Cord Compression, Including Cauda Treatment and Prognosis of Epidural Spinal Cord Compression, Including Cauda Equina SyndromeEquina Syndrome. Schiff, David et al. Up to Date Online. May 31, 2008. . Schiff, David et al. Up to Date Online. May 31, 2008.

Tumor Lysis Syndrome. eMedicine. Tumor Lysis Syndrome. eMedicine. Koyamangalath Krishnan

Learning ObjectivesLearning Objectives

Identification of 3 major oncologic Identification of 3 major oncologic emergenciesemergencies

Management of tumor lysis syndromeManagement of tumor lysis syndrome

Management of neutropenic feverManagement of neutropenic fever

Management of spinal cord compressionManagement of spinal cord compression