Oncologic Emergencies

1
Oncologic Emergencies

• Heather Symons, MD

2
Oncologic Emergencies

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

3
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

4
(No Transcript)
5
Spinal Cord Compression

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

6
Spinal Cord Compression

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

7
Spinal Cord Compression

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

8
(No Transcript)
9
Spinal Cord Compression

• Treatment
• Dont delay
• Steroids
• XRT
• Chemotherapy, Surgery
• Outcome
• Depends on duration of symptoms
• ½ who are nonambulatory never recover!

10
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

11
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

12
Hyperleukocytosis

• Definition WBC gt 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

13
Symptoms of Hyperviscosity

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

14
Hyperleukocytosis

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

15
Case 3

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

16
(No Transcript)
17
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

18
(No Transcript)
19
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

20
SVC/SM Syndrome

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

21
SVC/SM Syndrome

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

22
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 Burkitts Lymphoma

23
(No Transcript)
24
(No Transcript)
25
Case 4

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

26
Tumor Lysis Syndrome

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

27
Tumor Lysis Syndrome

• Hyperuricemia arises from degradation of purines
  from tumor nuclei
• Symptoms
• 10-15 mg/dl lethargy, nausea, vomiting, urate
  crystals in urine, renal colic, hematuria
• gt20 mg/dl potential renal failure, mental
  status changes

28
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

29
Oxidation of nucleotide precursors into uric acid
Urate
pH5.6
pH7.3
Nucleotide Precursors
X
xanthine oxidase
xanthine oxidase
X
Xanthine
Uric Acid
Hypoxanthine
Urate Oxidase
X site of action of allopurinol
Allantoin
site of action of rasburicase
30
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.)

31
Tumor Lysis Syndrome

• 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 gt 60 mg/dl

32
Tumor Lysis Syndrome

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

33
Tumor Lysis Syndrome

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

34
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)

35
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

36
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

37
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

38
What is APML?

• APMLAcute Promyelocytic Leukemia
• Characteristic t(1517) resulting in PML-RARa
  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

39
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
40
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-a and IL-1b
• Plasma elastase levels increase

41
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
42
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
43
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

44
Typhlitis
45
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

46
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

47
(No Transcript)
48
Treatment of Typhlitis

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

49
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

50
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

51
Fever and Neutropenia

• Neutropenia defined as ANC lt 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

52
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

53
Fever and Neutropenia

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

54
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

55
Fever and Neutropenia

• Treatment
• Dont Delay!
• Broad spectrum antibiotics
• Anti-pyretics
• Systemic support if necessary
• Anaerobic coverage symptom dependent

56
Fever and Neutropenia

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

57
EMPIRIC THERAPY FOR FEVER NEUTROPENIA WITHOUT
SOURCE FEVER (gt38.5, or gt38.0 twice in 24hrs)
AND NEUTROPENIA (ANC lt500 or falling)
Sources include Peri-anal disease CXR
infiltrate CVL infection Typhlitis Cellulitis Othe
rs
Clinically unstable? 1
Yes Pip/Tazo 2 Amikacin Vanc3 Consider I.D.
Consult
No
Is the patient high risk?
Yes Pip/Tazo 2 /- Vanc (48hr r/o)3
No Pip/Tazo 2
Labs Blood Cx from all central line lumens CBC
with Diff CMP UA and UCx TS /- CXR Consider
Respiratory wash
Clinical decline ? 1
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 gt200 and rising
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. 3Coverage for
a-strep. Also consider additional anaerobic
coverage (metronidazole) for patients with risk
factors for anaerobic infections.
58
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)