# Presentation: 049881

## Oncologic Emergencies

- Heather Symons, MD

## Oncologic Emergencies

- Presenting Emergencies
- Spinal Cord Compression
- Hyperleukocytosis
- SVC Syndrome
- APML
- Therapy-associated Emergencies
- Tumor Lysis Syndrome
- Typhlitis
- Fever and Neutropenia

## Case 1

**2 yo previously well girl**
**Two week history of difficulty walking**
**No acute infectious symptoms**
**Admitted to neurology service for eval.**
**Initial workup including EMG, muscle bx**
**Eventual MRI of spine**

## Slide 4

## Spinal Cord Compression

- Presentation:
- Back pain (50%) – local or radicular
- Motor deficits (70%)
- Sensory deficits (30%)
-  Bowel/bladder dysfunction
- Hydrocephalus – high cervical tumors

## Spinal Cord Compression

- Oncologic Differential
- Sarcomas (50%)
- Neuroblastoma
- Lymphoma
- Leukemia
- Chemotherapy-induced transverse myelitis

## Spinal Cord Compression

- High Index of Suspicion
- Plain films abnormal 2/3 of cases
- MRI
- CT

## Slide 8

**Notes:**
most often epidural compression from extension of paravertebral tumor through the intervertebral foramina or extension of tumor in the vertebral column.

## Spinal Cord Compression

- Treatment
- Don’t delay
- Steroids
- XRT
- Chemotherapy, Surgery
- Outcome
- Depends on duration of symptoms
- 1⁄2 who are nonambulatory never recover!

**Notes:**
With normal neuro exam, may start dexamethasone 0.25 to 0.5 mg/kg/day PO divided q 6 hrs and perform MRI of spine within 24 hours. With abnormal neuro exam,start  dexamethasone 1 -2 mg.kg.day IV and obtain emergent MRI of spine. **Note:steroids may prevent diagnosis of lymphoma- plan diagnostic procedure as soon as possible.
If cause of tunor is known: emergent radiotherapy or chemotherapy for sensitive tumors, otherwise plan emergent neurosurgical consultation.
If cause of tumor is unknown: immediate surgery to decompress the spine.

## Case 2

- 14 year old boy, previously well
- Enlarged, nontender lymph node
- Outside biopsy consistent with lymphoma
- CBC at time of biopsy with WBC 17,000
- Referred to JHH for evaluation

## Case 2

- Admission Examination
- Massive hepatosplenomegaly
- Generalized lymphadenopathy
- Admission Labs
- WBC 440,000
- BUN/Cr 50/3.2, Uric Acid 20.9, Ca 14.2

## Hyperleukocytosis

- Definition:  WBC > 100,000
- Seen in 10-15% of patients with ALL or AML
- Hyperviscosity more common in AML patients
- Metabolic disturbances more common in ALL patients

**Notes:**
The risk of hyperviscosity is greater with AML than with ALL (myeloid cells are 	“stickier” than lymphoid cells), but the risk of tumor lysis syndrome is greater with ALL 	than with AML.  These are TENDENCIES, though.  One can see symptomatic 	hyperviscosity with ALL, and AML patients have tumor lysis syndrome.

## Symptoms of Hyperviscosity

- Pulmonary
- Dyspnea, hypoxemia, right ventricular failure
- CNS
- Blurred vision, confusion, headache, coma
- Other
- CNS or pulmonary hemorrhage
- Priapism
- Renal insufficiency

**Notes:**
Increased pulm markings diffusely on CXR
Any of the above findings in the context of a white blood cell count >100,000 must be treated as evidence of hyperviscosity caused by hyperleukocytosis, but DO NOT FORGET a differential diagnosis.  Patients can present with pneumonia, congestive heart failure, renal infiltration with leukemia or lymphoma cells, infection, intoxication, or other etiologies for each of the signs listed above, and these alternatives need to be considered

## Hyperleukocytosis

- Treatment:
- Hydration, alkalinization, allopurinol or Rasburicase
- Transfuse for thrombocytopenia
- Avoid PRBC transfusions.  Do partial exchange if necessary
- Leukapheresis – transient effect
- Chemotherapy when stable

**Notes:**
The choice between exchange transfusion and leukapheresis depends in part on patient size and in part on physician preference. 
Contact surgery IMMEDIATELY upon learning of a patient with an elevated 	white blood cell count and any of the above signs of hyperviscosity
Encourage the surgeon to place the largest caliber central line possible, to 	facilitate leukapheresis 
Very small children and infants may not tolerate the fluid shifts associated with leukapheresis and will require exchange transfusion instead
No study has demonstrated a benefit, in terms of long term outcome, for leukapheresis or exchange transfusion
The decreased white blood cell count in the peripheral blood is temporary, and reverses within hours
Dropping the peripheral white blood cell count does NOT alter the risk of tumor lysis syndrome. Therefore, the role of leukapheresis and exchange transfusion is in the management of symptomatic hyperviscosity.  In the absence of symptoms, these interventions are not necessary.
The vast majority of the tumor cells are present in the bone marrow, even in patients with peripheral white blood cell counts exceeding 500,000

## Case 3

- 11 year old girl, previously well
- 2 week history of increasing dyspnea
- CXR in pediatrician’s office shows mediastinal mass
- Referred to JHH for evaluation with increasing respiratory compromise

## Slide 16

## SVC/SM Syndrome

- Pathology:
- Compression of SVC
- Tracheal compression by mass in superior mediastinum
- 15% of anterior mediastinal tumors, esp NHL
- Pleural/pericardial effusions
- Thromboembolism
- Increased ICP
- Decreased CO
- Respiratory Failure

## Slide 18

## SVC/SM Syndrome

- Symptoms
- Cough, hoarseness, dyspnea, orthopnea, chest pain
- Headache, visual changes, nausea, lethargy
- Signs
- Swelling face/neck, plethora, cyanosis of face/neck, suffusion of conjunctiva, distended neck and chest wall veins, diaphoresis, wheezing, stridor

## Diagnosis:
	 -  CXR, CT/MRI to evaluate airway
Tissue diagnosis by least invasive means possible
CBC, thoracentesis, BMA/Bx, lymph node bx
AFP,-hCG
Delay diagnosis if necessary to save the patient

- 	 -  CXR, CT/MRI to evaluate airway
- Tissue diagnosis by least invasive means possible
- CBC, thoracentesis, BMA/Bx, lymph node bx
- AFP,-hCG
- Delay diagnosis if necessary to save the patient

- SVC/SM Syndrome

## Treatment:
Avoid anesthesia/heavy sedation
XRT
Steroids
Chemotherapy
Cardio-respiratory support as indicated

- Avoid anesthesia/heavy sedation
- XRT
- Steroids
- Chemotherapy
- Cardio-respiratory support as indicated

- SVC/SM Syndrome

## Case 4

- 14 year old boy, previously well
- Increasing abdominal pain
- Abdominal mass on exam
- CT scan reveals thickened peritoneum and ascites
- Diagnostic paracentesis reveals Burkitt’s Lymphoma

## Slide 23

## Slide 24

## Case 4

- Admission Labs:
- Uric Acid 17.2
- Potassium 6.0
- Creatinine 0.9
- LDH 1582
- WBC 11,800

## Tumor Lysis Syndrome

- Chemotherapy-induced cell lysis
- Sometimes seen spontaneously, prior to institution of therapy, especially with Burkitt’s Lymphoma
- Metabolic triad of:
- Hyperuricemia
- Hyperkalemia
- Hyperphosphatemia (associated with hypocalcemia)
- Associated with large tumor burden, rapid doubling time, sensitivity to chemotherapy

## Hyperuricemia arises from degradation of purines from tumor nuclei
Symptoms:
10-15 mg/dl:  lethargy, nausea, vomiting, urate crystals in urine, renal colic, hematuria
>20 mg/dl:  potential renal failure, mental status changes

- Symptoms:
- 10-15 mg/dl:  lethargy, nausea, vomiting, urate crystals in urine, renal colic, hematuria
- >20 mg/dl:  potential renal failure, mental status changes

- Tumor Lysis Syndrome

## Treatment of Hyperuricemia
Decrease production – allopurinol, Rasburicase
Promote solubility – alkalinization (goal urine pH 7.0-7.5)
Reduce concentration – volume expansion with IVF

- Decrease production – allopurinol, Rasburicase
- Promote solubility – alkalinization (goal urine pH 7.0-7.5)
- Reduce concentration – volume expansion with IVF

- Tumor Lysis Syndrome

## Oxidation of nucleotide precursors into uric acid

**Nucleotide**
**Precursors**

**Hypoxanthine**

**Xanthine**

**Uric Acid**

**Allantoin**

**xanthine**
**oxidase**

**Urate**

**Urate**
**Oxidase**

**xanthine**
**oxidase**

**pH~7.3**

**pH~5.6**

**X**

**X**

**X = site of action of allopurinol**

**= site of action of rasburicase**

**Notes:**
Allopurinol blocks the production of uric acid by inhibiting xanthine oxidase
Rasburicase is recombinant urate oxidase and catalyzes the conversion of uric acid to allantoin.  This drug works almost instantaneously to reduce uric acid levels to almost undetectable.

## Tumor Lysis Syndrome

- Hyperkalemia arises from release of intracellular K from dying tumor cells
- Worsened by renal failure, acidosis, increased intake (ie. From PRBC transfusions and K-containing meds)
- Remain aware of pseudohyperkalemia (RBC lysis from venipuncture, for example)
- Standard treatments (insulin/glucose, bicarb, kayexalate, etc.)

## Hyperphosphatemia/hypocalcemia
Lymphoblasts have 4x more PO4 as normal lymphocytes
Glomerular filtration sole means of eliminating PO4
Worry  about calcium phosphate crystal  formation and precipitation when
   Ca x PO4 > 60 mg/dl

- Lymphoblasts have 4x more PO4 as normal lymphocytes
- Glomerular filtration sole means of eliminating PO4
- Worry  about calcium phosphate crystal  formation and precipitation when
-    Ca x PO4 > 60 mg/dl

- Tumor Lysis Syndrome

## Treatment of Hyperphosphatemia/Hypocalcemia
Hydration
Diuretics
D/C alkalinization (crystals less soluble at pH > 6)
Correct hypocalcemia, if possible, with calcium gluconate
Treat hypomagnesemia 
Avoid alkalosis (lowers iCa++)

- Hydration
- Diuretics
- D/C alkalinization (crystals less soluble at pH > 6)
- Correct hypocalcemia, if possible, with calcium gluconate
- Treat hypomagnesemia
- Avoid alkalosis (lowers iCa++)

- Tumor Lysis Syndrome

## Tumor Lysis Syndrome

- Management
- Frequent electrolyte monitoring (often q 2 hrs)
- Consider dialysis for
- Potassium > 7
- Uric Acid > 10
- PO4 > 10
- Hypertension
- Volume overload
- Other symptomatic electrolyte abnormalities

## Standard Initial Approach to Acute Tumor Lysis

- 	IVF D5 1/2NS +40 meq/L NaHCO3 at 2x   	maintenance
- 	Adjust fluids to maintain urine pH 7.0-7.5
- 	Frequent monitoring of electrolytes (as 	frequent as every 2 hours)
- 	Allopurinol or rasburicase (there are specific 	eligibility criteria for rasburicase)
- 	Dialyze for the usual indications
- 	Monitor for other metabolic complications 	(hyponatremia, hypomagnesemia)

## Case 5 

- 15 year old girl with 3 day history of oral bleeding following extraction of impacted wisdom teeth on 12/23/04
- Seen at community hospital on 12/26/04, and CBC demonstrated white blood cell count of 22,000 with 83% blasts

## Case 5

- Patient transferred to JHH PICU late at night 12/26/04
- Oncology consult 0030 12/27/04
- Peripheral blood smear found to be morphologically consistent with APML at 0130 12/27/04
- Diagnosis confirmed by flow cytometry at 1100 12/27/04

## Case 5

- Family told of confirmed diagnosis 1200 12/27/04 and presented with options of standard care vs. enrollment in J0442 (institutional protocol for APML)
- Family provided informed consent for J0442 1500 12/27/04
- Patient had progressive renal failure and pulmonary failure and taken to OR for intubation and placement of dialysis catheters at 1730 12/27/04
- Decadron therapy begun upon return to PICU
- Patient expired of uncontrollable pulmonary hemorrhage at 0045 12/28

## What is APML?

- APML=Acute Promyelocytic Leukemia
- Characteristic t(15;17) resulting in PML-RAR fusion protein
- Fusion protein is a retinoic acid-sensitive transcription factor
- Pharmacologic doses of all-trans retinoic acid downregulate activity of transcription factor
- Recognition that ATRA is effective in the treatment of APML changed OS from 10% to 70% in adults

## The Importance of Managing Bleeding in APML Patients

- 3% of APML patients die of hemorrhage before institution of specific therapy
- Half of the hemorrhagic deaths seen in treated APML patients occur within the first week of induction
- If CR rate is 90%, and if 5% of patients die of hemorrhagic complications, then half of the patients who do not achieve remission do not because they die of bleeding

- Tallman et al., 2007

## Pathogenesis of the Bleeding Diathesis

- Most common abnormalities are hypofibrinogenemia, elevated FDPs and D-dimer, and prolongation of PT and TT
- APML cells express Tissue Factor and Cancer Procoagulant
- They also express high levels of u-PA and t-PA, enzymes such as elastase and chymotrypsin, and annexin II-associated fibrinolytic activity
- Bleeding exacerbated by cytolytic chemotherapy
- Depressed PAI-1 levels
- Increase levels of TNF- and IL-1
- Plasma elastase levels increase

## Recommended Management of the Bleeding Diathesis 

- Liberal use of FFP and Cryoprecipitate to maintain fibrinogen above 150 mg/dl
- Liberal use of platelet transfusions to maintain platelet count above 50,000/ml
- “The benefit of heparin, tranexamic acid or other anticoagulant/fibrinolytic therapy remains undetermined and should be a matter for clinical trial investigation”

- Sanz et al., Blood in press

## Falanga and Rickles, Pathogenesis and

- management of the bleeding diathesis in
- acute promyelocytic leukaemia.  Best Prac
- and Res Clin Haematol, 16(3): 463-482, 2003

## Case 6

- 12 year old girl with newly diagnosed ALL
- Day 11 of induction therapy
- Meds include vincristine, decadron, daunorubicin, asparaginase, zantac
- Increasing abdominal pain, RLQ

## Typhlitis

## Typhlitis

- Inflammatory cellulitis of the intestines, especially in the cecum
- Think “NEC” in cancer patients
- Historically seen in patients with ALL early in therapy, but can be seen in other settings
- Pancytopenia

## Typhlitis

- Presentation
- Abdominal pain
- N/V, diarrhea
- Septic Shock
- Presentation can be subtle due to neutropenia and steroid therapy
- Diagnosis
- Serial examinations
- Serial films
- Bowel wall thickening
- Mucosal edema
- Pneumatosis intestinalis
- Free Air

## Slide 47

## Treatment of Typhlitis

- NPO
- Surgical consultation
- Antibiotics, including anaerobic coverage (triples)
- Surgical excision of infarcted or perforated bowel

## Case 7

- 18 year old boy with metastatic osteosarcoma
- 11 days s/p chemotherapy with ifosfamide and doxorubicin
- Presents to clinic with fever to 38.9oC
- Chills
- BP 95/60

## Case 7

- Central line accessed
- Cultures drawn
- Line flushed
- Rigors and worsening hypotension (74/40)
- Volume resuscitation with crystalloid and blood
- Amikacin pushed
- Less responsive, BP 50/P, poor perfusion

## Fever and Neutropenia

- Neutropenia defined as ANC < 500
- Falling counts just as ominous
- Fever defined as 38.5oC or 38.0oC twice in 24 hours
- ALL ILL-APPEARING CHILDREN GET EVALUATED
- Signs of infection are altered by neutropenia

## Fever and Neutropenia

- History:
- Date and type of last chemotherapy (usual nadir 7-14 days)
- Previous documented infections
- Presence of central line
- Infectious exposures
- History of splenectomy/functional asplenia

## Fever and Neutropenia

- Symptoms:
- Cough/dyspnea/chest pain
- Retrosternal pain
- Sore throat/dysphagia
- Abdominal pain
- Pain with defecation
- Vomiting and diarrhea

## Fever and Neutropenia

- Good physical examination
- 	 - carefully note vital signs
- Include peri-rectal area
- Central line site
- Sites of previous studies
- Diagnostic Studies
- Blood cultures from all lumens (peripheral not necessary)
- Urine culture (no cath)
- Specific sites

## Fever and Neutropenia

- Treatment:
- Don’t Delay!
- Broad spectrum antibiotics
- Anti-pyretics
- Systemic support if necessary
- Anaerobic coverage symptom dependent

## Fever and Neutropenia

- Duration of Therapy
- Afebrile
- Well-appearing
- No source?  ANC > 200 and rising
- Source?  Standard duration for that source AND ANC > 500 and rising

## EMPIRIC THERAPY FOR FEVER &  NEUTROPENIA WITHOUT SOURCE

**FEVER ** (>38.5, or >38.0 twice in 24hrs) **AND** **NEUTROPENIA** (ANC <500 or falling)

-          Clinically unstable? **1**

- _No_

- _Yes_
- Pip/Tazo **2**
- Amikacin
- Vanc3
- Consider I.D. Consult

_**Labs**_
- Blood Cx  from all central line lumens
- CBC with Diff
- CMP
- UA and UCx
- T&S
- +/- CXR
- Consider Respiratory wash

- Is the patient high risk?

- _Yes_
- Pip/Tazo **2**
- +/- Vanc (48hr r/o)3

- _No_
- Pip/Tazo **2**

- Persistent fever 3-7 days or new fever after deffervescence?

- _Yes_
- Reassess risk
- Consider adding amino-glycoside
- Add antifungal

- _No_
- D/C Pip/Tazo if ANC >200 and rising

_**Sources include**_
- Peri-anal disease
- CXR infiltrate
- CVL infection
- Typhlitis
- Cellulitis
- Others

-          Clinical decline ? **1**

**1**** **Refer to Nuts and Bolts for details
**2**** **Consider alternative monotherapy (cefepime, ceftazidime, carbapenems) if surveillance cultures document history of resistant organisms, with addition of anaerobic coverage (metronidazole) if indicated by presence of mucositis .  For PCN allergy – consider aztreonam/vancomycin.
**3**Coverage for -strep.  Also consider additional anaerobic coverage (metronidazole) for patients with risk factors for anaerobic infections.

## High Risk Features

- Specific Clinical Situations
- Myeloablative BMT preparative regimens
- Treatment with High Dose Cytoxan
- AML induction, consolidation, intensification
- ALL relapse induction
- Intensified therapy for metastatic/recurrent solid tumors
- Acute GVHD
- Chronic GVHD
- Steroid-refractory GVHD
- Host Features
- Characteristics of an individual patient that might make the patient “high risk” despite not fitting one of the specified situations outlined above.
- Compromised mucosal or skin integrity
- Compromised or absent lymphocyte function
- Prolonged neutropenia
- Colonization with resistant organisms
- Compromised organ function (consider effects on drug metabolism)