Oncologic Emergencies

Nick Fustino, MD Blank Children’s Hospital

Pediatric Hematology-Oncology

Pediatric Nursing Conference November 7, 2014

Objectives • Discuss pathophysiology and diagnosis of common

pediatric oncologic emergencies – Tumor Lysis Syndrome – Hyperleukocytosis / Leukostasis – Disseminated Intravascular Coagulation (DIC) – Respiratory Emergencies (SVC / SMS) – Spinal Cord Compression – Fever & Neutropenia – Neutropenic Colitis

• Learn to anticipate, prevent, recognize and treat emergencies

• All of these scenarios have occurred at Blank Children’s within the past year

Pediatric Malignancies

Adapted from: American Cancer Society Cancer Facts & Figures, 2007. Atlanta, American Cancer Society, 2007.

Leukemia, 30%

CNS, 22.3% Other, 17.1%

Neuroblastoma, 7.3%

Wilms, 5.6%

NHL, 4.5% HL, 3.5%

Rhabdo, 3.1% Rb, 2.8% Osteo, 2.4% Ewing’s, 1.4%

Etiology of Oncologic Emergencies

• Initial presentation of primary disease

• Complication/ progression of known disease

• Complication of therapy

Why are Oncologic Emergencies Important?

• Need to be addressed before therapy can begin or continue

• Avoid end-organ injury • Avoid compromising long-term QOL

• In complex emergent situations, teamwork

and bedside nursing acumen are critical

Appearance? Urine output? Pain? A-B-C’s? Wt change? Fevers? Sweats? Pallor? Headache? Neuro change? Gait?

Biopsy?

Really a mass? CBC? How big? For how long? Growing? How fast?

Chemo? Labs?

Resect?

Open Protocol?

Bed on 4?

CT / MRI?

Metastatic?

Consent?

Prognosis? HVA / VMA?

Differential Diagnosis CanCer or not CanCer? Constipation HsM infeCtion all Brain tuMor WilMs lyMpHoMa neuroBlastoMa

Immediate Concerns A-B-C’s

Tumor Lysis Renal Failure

Intracranial Pressure Obstruction

Is the patient safe? Where is he/she?

With whom? What is available? What’s been done?

ER charge nurse in Ft. Dodge has 6yM with large abd mass. Requests direct admit to floor.

Oncologic Differential Diagnosis

• Neuroblastoma • Wilm’s Tumor • Rhabdomyosarcoma • Lymphoma • Other rare abdominal tumors (clear cell

sarcoma, MPNST, rhabdoid, etc.)

Rapidly expanding abdominal mass

Uric Acid: 11 Creatinine: 1.2

Tumor Lysis Syndrome (TLS)

• Definition: – Metabolic derangements from rapid,

spontaneous, or treatment-related death of tumor cells

– Laboratory or clinical – 3 days prior and up to 7 days after starting tx – Peak risk ~ 24-48 h after start of tx

Howard et al., NEJM, 2011

TLS - Pathophysiology

Howard et al., NEJM, 2011

TLS - Complications

• ↑K Cell Lysis

• ↑Uric Acid

DNA Breakdown

• ↑PO4 DNA

Breakdown

• ↓Ca Ca

complexing with PO4

Cytokine release

Renal failure

Fatal dysrhythmias

Renal failure

Tetany, dysrhythmia, renal failure

Multi-organ failure

Howard et al., NEJM, 2011

TLS - Complications

• Lymphoblasts have 4x the PO4 than lymphocytes

• If Ca x P > 60, CaPO4 crystals can precipitate in renal tubules

Howard et al., NEJM, 2011

TLS - Risk Factors and Epidemiology • High tumor burden

– High-grade lymphomas (ie. Burkitt’s), acute leukemias (T-cell)

• High turnover – Elevated uric acid/LDH pre-

therapy • Organ infiltration: liver,

spleen • Sensitivity to therapy • Intensity of therapy • Pre-existing renal

impairment

Howard et al., NEJM, 2011 Radiopaedia.com

TLS - Evaluation and Diagnosis

• ANTICIPATION, Laboratory assessment • Close attention to symptoms of electrolyte

abnormalities – Abdominal pain – Back pain – Vomiting – Cramps – Diarrhea – Dehydration – Muscle spasms – Tetany, seizures

TLS Management

• Goal: preserve renal function, prevent life-threatening dysrhythmia, avoid hemodialysis

• Hyperhydration: bolus, IVF at 1.5-4X MIVF – Improve renal perfusion, uric acid excretion – Minimizes acidosis – MAINTAIN GOOD URINE OUTPUT

• Goal 2 mL/kg/hr • May need diuretics (loop)

Howard et al., NEJM, 2011

TLS Management - Hyperuricemia • Hydration • Alkalinization

– Unclear efficacy – Not routinely done anymore – Decreases Ca, P solubility

• Allopurinol – Slower – Risk of xanthine nephropathy

• Rasburicase (0.2 mg/kg) – Fast – Contraindicated in G6PD deficiency – Rash, hemolysis, anaphylaxis,

methemoglobinemia – Stop Bicarb

Howard et al., NEJM, 2011

TLS Management - Hyperkalemia

Can be fatal Monitoring • Frequent laboratory

assessment • Accurate laboratory

assessment – Repeat if abnormal – False elevation in venous

sample during hyperkeukocytosis; use iSTAT

• EKG/Cardiac Monitor • 7.5 mEq/L may → sinus arrest • 10-12 mEq/L may → cardiac

standstill or V Fib

K+=

Merckmanuals.com

TLS Management - Hyperkalemia

• Limit K and Phos input (DON’T PUT IN IVF) Treatment Dose Notes

Albuterol 0.5 mg neb

Kayexalate 1g/kg po q6h w/ 50-150 mL sorbitol, slow onset

CaCl2 10-20 mg/kg IV Stabilizes myocardium, Rapid onset, lasts 30 min

Ca Gluconate 100-200 mg/kg IV Stabilizes myocardium

NaHCO3 1-2 mg/kg IV Onset 30 min, last several hours

Glucose + Insulin 0.5g/kg/h + 0.1 unit/kg/h Shifts K+ intracellular, onset 30 min

Hemodialysis

TLS Management - Hypocalcemia

• Only treat if symptomatic – Fatigue, cramping, tetany, laryngospasm, weakness,

paresthesias, AMS, Seizure, EKG changes (long QTc)

• Control Phos Level – PO4 binders

• CaCl2 – 10 mg/kg IV

• Ca Gluconate – 100 mg/kg IV

Hall and Todd, Postgrad Med J, 2006

Bedside TLS Monitoring

• Clinical assessment – Hourly intake / output & vital signs

• Laboratory – Na, K, Glu, iCa q4-6 h – BUN, Cr, uric acid, P q4-6 h – CBC / Diff / Plt q6-8 h – Coags, LFTs, Albumin q24 h – Imaging as indicated

• Continue for 2-4 days of initial therapy; gradually reduce

3yM with big spleen, WBC 390, T97, BP 102/78, HR 115, RR 44. Nml Hgb & plt. Looks good. By car ok? (4hrs)

OSH: 3yM with big spleen, WBC 315K, T97, BP 102/78, HR 115, RR 48. Hgb/plt WNL. To Floor?

Hyperleukocytosis and Leukostasis

• WBC > 100K • Leukostasis

– Blasts lack deformability – Increased viscosity, WBC

aggregates, thrombi – Blasts are sticky,

Myeloblasts > Lymphoblasts – Can be fatal (greatest risk at

WBC > 300K) • CNS hemorrhage, thrombosis • Pulmonary Leukostasis

babraham.ac.uk

CNS and Pulmonary Leukostasis

Leukostasis – Signs and Symptoms

Systemic Tumor Lysis, DIC

CNS AMS, HA, blurred vision, papilledema, dizziness, gait instability, stroke, Sz

CV MI Pulmonary Dyspnea, tachypnea, cyanosis, acidosis, hypoxia Renal RVT, ARF GI Abd pain, bowel infarction Other Priapism, dactylitis

Leukostasis - Management • A – B – C • IV access • Prevent TLS Hydrate / reduce uric acid • Platelets: keep >20 (prevent hemorrhage) • Hemoglobin: AVOID pRBC transfusion (prevent

hyperviscosity)

• If WBC rises rapidly / does not drop quickly, consider cytoreduction – Steroids – Hydoxyurea – Leukopheresis – Exchange transfusion

15yF with headache, emesis, LOC at school. WBC 105. ICU doc wants VasCath for leukopheresis.

APML

Image uaz.edu.mx

APML PT: 70 INR: 7.8 PTT: >200 Fibrinogen: <60 D-Dimer: > 20

12 105 29

81% Blasts

DIC

• Microthrombi and bleeding – Platelet and clotting

factor consumption – Microangiopathy – Hyperfibrinolysis

• Etiologies – Gram negative sepsis – Leukemia (AML M3,M5;

ALL with high WBC) – Metastatic solid tumors

Semin Thromb Hemost. 2007 33(4):408-15

www.medscape.com

Sepsis/ Malignancy

Systemic activation of coagulation

Widespread intravascular

fibrin deposition

Consumption of plts, clotting factors

Severe Bleeding

Thrombosis, organ failure

Hemorrhage is a common cause of early death in pediatric AML

Semin Thromb Hemost. 2007 33(4):408-15

Hemorrhage: Dominant clinical APML manifestation

• Distinct form of DIC – Severe hyperfibrinolysis, disseminated

microthrombi • Fatality due to hemorrhage

– At presentation or shortly after start of Tx – Almost always intracranial or pulmonary – Historical incidence: 20-30% – Current incidence: ~10% with fatal coagulopathy – Coagulopathy can last months (hyper/hypo)

Tallman et al. Semin Thromb Hemost. 2007 33(4):330-8

Wang. Blood 2008 111(5) 2505-15

Zuckerman et al., Blood, 2012 Tallman et al. Semin Thromb Hemost. 2007

Wang et al., Blood. 2008

DIC - Management • Anticipation, frequent lab/clinical monitoring • Replace consumed factors

– Platelets: Transfuse to keep > 50K initially – Fibrinogen: FFP or Cryo to keep > 150 mg/dL – Can consider ATIII, APC in severe cases – No routine use of heparin or antifibrinolytics

• Treat underlying cause – AML: Start chemo – APML: start ATRA as soon as suspected – Sepsis: antibiotics

• No leukopheresis – Need for anticoagulation – Large-caliber vascular access – Hypocalcemia, hypothermia, anemia, thrombocytopenia – Equipment/expertise availability

Zuckerman et al., Blood, 2012

12yM w/pallor, bruising, WBC 190. Hgb 10, plt 42. BM Bx & aspirate on floor w/ sedation?

18yF w/big neck LN. Mild cough, HA. Very Anxious. Resident to order Ativan for CT scan.

Chee et al., Nature Clinical Practice Cardiovascular Medicine, 2007

Mediastinal Mass – Malignant Differential Diagnosis

• Lymphoma (NHL, Hodgkin’s) • T-Cell Leukemia • Germ cell tumor • Rhabdomyosarcoma, neuroblastoma, thyroid

tumors, parathyroid tumors • Thymoma

Pathophysiology – SVCS/SMS

• Superior Vena Cava Sx – Compression, obstruction

of SVC – Thin wall, low intraluminal

pressure – Impaired venous return

• Superior Mediastinal Sx – Airways more compliant

and compressible in children

Wilson et al. NEJM 2007: 356 (18): 1862

Pathophysiology - SVCS

Clinical Picture – SVCS/SMS

Airway Compromise

• Cough (54%) • Dyspnea (54%) • Hoarseness (17%) • Stridor (4%) • Tachypnea • Orthopnea • Wheezing • Anxiety

CNS

• Syncope (10%) • Headache (9%) • Confusion (4%) • Lethargy (2%) • Blurry vision (2%) • Papilledema • Ear fullness

Venous Obstruction

• Facial swelling, edema (82%)

• Engorged chest wall vessels (53%)

• Arm edema (42%) • Cyanosis of face,

neck, & upper extremities

• Petechiae of head, neck, arms, & trunk

• Pleural effusion • Pulsus paradoxsus

Seth & Bhat, Ind J Pediatr, 2011 Wilson et al., NEJM, 2007

Clinical Picture – SVCS / SMS

• Rare entity in pediatrics • Malignancy #1 primary cause

– Other paraneoplastic etiologies: thrombosis, infection

• St. Jude’s Experience (n= ~3700) – Non-hodgkin’s Lymphoma: 70% with mediastinal

mass – Hodgkin’s: 30% – Respiratory compromise in up to 75%

Seth & Bhat, Ind J Pediatr, 2011

Diagnosis and Management – SVCS/SMS

• Diagnosis – History, Physical, CBC, CXR, CT, Echo • Management

– IV access (lower limbs if possible), hydration – Keep pt calm, minimal handling, no sedation – Upright, left lateral position with face mask O2 – CT scan ASAP – Tissue diagnosis ASAP

• Least invasive means possible with minimum of sedation • Pleurocentesis/Pericardiocentesis (also therapeutic) • Lymph node biopsy • Peripheral blood/tumor markers

– Monitor and treat TLS – ECMO on standby if available – Start treatment (chemo or radiation) – Intubate only for life threatening obstruction

Seth & Bhat, Ind J Pediatr, 2011

Intubation?

ET tube stops here

Airway obstruction occurs distally

12yM w/leg pain/tingle, incontinence. Won’t walk. Mass on CXR. Neuro consult tomorrow?

Spinal Cord Compression

Ewing Sarcoma Pediatricneurosciences.com

SCC - Oncologic Differential Diagnosis

• Neuroblastoma • Metastatic Brain Tumor • Primary Spinal Tumor • Ewing Sarcoma • Osteosarcoma • Rhadbomyosarcoma • Lymphoma/Leukemia

(chloromas) • Soft tissue sarcoma

Oncolink.org

SCC - Signs and Symptoms

• Acute cord compression – 3-5% of children at diagnosis – Spinal or para-spinal in origin

• Local or radicular pain > 80% – May be present for weeks

• Weakness / Sensory loss / Paresis – Motor weakness often present at diagnosis – Incontinence (cauda lesions) – Paraplegia / Quadriplegia can progress rapidly &

can be irreversible

Management - SCC

• Any compromise of the spinal cord, conus medullaris, or cauda equina requires emergent attention

• Imaging – X-ray can miss up to 50% of cases – Back pain alone: MRI within 24h – Emergent MRI if non-ambulatory or significant deficits

• Emergent Surgery, Radiation, Chemotherapy • Dexamethasone in some situations • Prognosis: better if tx within 10 days of onset, regain of

function better in children

4yF. ALL d32 induction. Call to clinic T102 at 4pm. Looks OK per mom. ONC clinic in a.m. ok?

Pt coming to the Blank 3. 13yF day 24 ALL induction. Fever, HR 140. CR ~ 3 sec. Looks “gray.”

Fever and Neutropenia • This is a medical

emergency • Every oncology patient on

therapy needs immediate evaluation for new fever

• Fever (definition variable) – T>38.3° C x1 or – T>38.0°C x2 in a 24 hour

period • Absolute neutrophil count

(ANC) – < 500 or – < 1000 with expected decline – WBC count x (% segs + bands)

Pseudomonas aeruginosa

Meckler, Lindemulder. Emerg Med Clin N Am, 2009.

Why are cancer pts at risk for life-threatening infection?

• Chemotherapy – Decreased number and

function of immune cells

• Radiation • Surgeries • Breakdown of

mucocutaneous barriers • Foreign bodies (CVL,

grafts, etc.)

Meckler, Lindemulder. Emerg Med Clin N Am, 2009.

Fever and Neutropenia

• Infectious risk correlates with – Duration of neutropenia – Rate of decline – Degree of neutropenia (ANC < 100 vs. ANC < 500)

• Nadir of neutropenia occurs ~7-14 days post-chemo, but can occur at any point on treatment

Meckler, Lindemulder. Emerg Med Clin N Am, 2009.

F & N – Common Pathogens GP

Bacteria

Staph spp

Strep spp

Enterococcus spp

Corynebacterium spp

Bacillus spp

Clostridium spp

GN Bacteria

E. Coli

Pseudomonas aeruginosa

Klebsiella spp.

Enterobacter

Anaerobes

Viral

HSV, VZV

RSV, Influenza, Parainfluenza

Adenovirus

Rotavirus, enterovirus

CMV, EBV, HHV6

BK, JC

Fungal

Candida spp

Aspergillus spp

Zygomycetes

Fusarium

Scedosporium

Cryptococcus

Other

Pneumocystis jiroveci

Protozoa

Meckler, Lindemulder. Emerg Med Clin N Am, 2009.

F & N – General Management Principles

• Rapid triage and evaluation • CBC with differential and LARGE VOLUME blood culture

– From central line, ALL LUMENS – Ideally least 5 mL (min 2 mL) – Peripheral blood culture controversial

• Other studies only as clinically indicated (CXR, UA, etc.) • Immediate broad spectrum antibiotics • No rectal manipulation

– Theoretical risk of bacterial translocation • Frequent reassessment

– Hypotension, hypothermia, vomiting, shaking chills • Culture q24h if while febrile, or in situations of clinical decline

Meckler, Lindemulder. Emerg Med Clin N Am, 2009.

F & N – Antibiotic Coverage • Microbial diagnosis made: Only 10-30%

– Usually bacterial (85-90% of the time), Pathogen dynamics vary by geography

• Individual antibiotic choices vary by institution, principles are similar • Broad spectrum Abx with anti-pseudomonal coverage

– Cefipime, Piperacillin-Tazobactam, Ceftazidime, Meropenem – Give this anti-gram-negative Abx FIRST – Double cover for gram-negatives if toxic or awaiting speciation (Gentamicin, Amikacin)

• Add gram-positive coverage (Vancomycin, Clindamycin) in certain situations

– If toxic, or suspicion of gram positive infection (skin/soft tissue infections) – AML s/p HD-Ara C (Viridans Strep)

• WATCH OUT FOR BACTERIOLYSIS AFTER ANTIBIOTICS – Be prepared for decompensation, observation period before transfers – Anticipate need for blood products, more liberal transfusion criteria

• Rotate antibiotics through all lumens Meckler, Lindemulder. Emerg Med Clin N Am, 2009.

F & N - Prognosis • Must continue to treat even if other source of fever proposed (Ara-C, viral) • Gram negative sepsis mortality

– Historically 80% – Now 1-3%

• Increased risk of first line failure – Pneumonitis – Severe Mucositis – Signs of shock, hypotension – Dehydration – Relapsed disease, bone marrow transplant

• Second line: rarely indicated emergently – F/N x 5 days: chest, abdomen, sinus investigation + ambisome – Antivirals – G-CSF/GM-CSF (non-emergent, not shown to reduce mortality)

4yM on Blank 4 w abd pain. s/p chemo for Burkitt’s 10d ago. No BM x 4d. Increase Miralax?

10 days following chemotherapy for Burkitt lymphoma. Now fever, neutropenia, obstipation, abdominal pain: TYPHLITIS

Abdominal Pain

Neutropenic Colitis

• Necrotizing colitis of the cecum in neutropenic patients

• Pathogenesis – Bacterial / fungal invasion of cecal mucosa

• Pseudomonas, Klebsiella, Enterobacter most frequent • Other gram negative rods • Gram positive: Clostridium • Fungal: Candida & Aspergillus

– Can progress into full thickness infarction and perforation

Destruction of normal mucosa (chemo, xrt, cancerous infiltrates)

Intramural hemorrhage (↓plts)

Shift in normal flora (Abx, hospitalization)

www.meddean.luc.edu radiology.rsna.org

Neutropenic Colitis

• Thickened cecum • Peri-intestinal soft-tissue stranding • Free Fluid • Pneumatosis Intestinalis

Van de Wetering, Supp Care Can, 2003

Neutropenic Colitis - Evaluation • Clinical

– ~1 week of neutropenia prior – Diffuse abdominal pain, possibly RLQ – Triad: fever, abdominal pain, diarrhea

• Laboratory – CBC, lytes, LFTs, Amylase/Lipase – Blood culture

• Imaging – Abdominal x-ray (flat and decubitus) – CT scan – Pneumatosis or non-specific bowel wall thickening

• False negatives: CT 15%, US 23%, AXR 48%

Van de Wetering, Supp Care Can, 2003

Neutropenic Colitis - Management • High mortality rate • Medical

– Pain control – Bowel rest / NG suctioning – Broad spectrum antibiotics

• eg. Piperacillin-Tazobactam, Metronidazole, Vancomycin – Blood Products, fluid replacement

• Surgical – Intervention rarely indicated – Persistent bleeding – Perforation – Clinical deterioration, septic picture requiring pressors – Development of another intrabdominal process that normally requires

surgery

Van de Wetering, Supp Care Can, 2003

Summary

• Oncologic emergencies are common in the pediatric population

• The majority of these can be anticipated with awareness of the clinical situation

• Teamwork and communication among health care professionals is essential to good outcomes

References • Special thanks to Paul Harker-Murray, MD, PhD of

UTSouthestern/Children’s Medical Center of Dallas

• Selected publications: – Howard et al. The Tumor Lysis Syndrome. NEJM,

2011;364:1844-54. – Nazemi, Malempati. Emergency Department Presentation

of Childhood Cancer. Emerg Med Clin N Am 27 (2009) 477–495.

– Meckler, Lindemulder. Fever and Neutropenia in Pediatric Patients with Cancer. Emerg Med Clin N Am 27 (2009) 525–544.

References

Wendy Woods-Swafford, MD, MPH • Leukemia • Paliative Care

Carla Schwalm, MD • Late Effects and Survivorship • Nutritional Anemias

Christopher Rokes, MD • Solid Tumors • Neuro-oncology

Nick Fustino, MD • Sickle Cell Disease • Embryonal Solid Tumors

Blank Children’s Hospital

Pediatric Hematology-Oncology 1215 Pleasant St., Suite 306

Des Moines, IA 50309 Phone: 515-241-8912

Fax: 515-241-8988

fustinnj@ihs.org