Oncological Emergencies

Oncological emergencies are defined as any acute life-threatening events in those with cancers that arise either spontaneously or due to the effect of the therapy for the illness.

• Infectious
• Haematological
• Metabolic
• Mechanical
• Miscellaneous

RISK FACTORS:

• NEUTROPENIA (ANC or APC < 500/μl): A condition with an absolute neutrophil count (ANC) or absolute polymorphonuclear cell count (APC) less than 500 per microliter.
• IMMUNE SUPPRESSION: Weakened immune response due to various causes.
• FOREIGN BODIES: Presence of foreign objects within the body.

The usual signs of infection may be subtle or absent in patients unable to mount an effective inflammatory response due to neutropenia, lymphopenia, or corticosteroid therapy.

Febrile Neutropenia

Should be considered an emergency:

• Early studies have shown high mortality when delaying the initiation of appropriate antibiotics.
• Before the era of empiric antibiotics, infection accounted for up to 75% of deaths associated with chemotherapy.

Definitions:

• Fever: Defined as a single temperature measurement exceeding 38.3°C (101.3°F) or 38.0°C (100.4°F) sustained for more than one hour.
• Neutropenia: Typically characterized by an ANC less than 500.
• Absolute Neutrophil Count (ANC): Calculated as the total white blood cell count multiplied by the sum of the percentage of neutrophils and the percentage of band cells.
• Seeding of the bloodstream: Most commonly occurs from endogenous flora in the gastrointestinal tract.

Commonly Cultured Bacterial Pathogens:

• Gram-negative: Including organisms like Pseudomonas, E. Coli, and Klebsiella.
• Gram-positive: Encompassing Coagulase-negative staph, Staphylococcus aureus, Streptococcus, and more.

Commonly Cultured Fungal Pathogens:

• Candida species, Aspergillus: These infections typically arise later as secondary infections in patients with prolonged neutropenia and antibiotic use.

Viral Pathogens:

• HSV (Herpes Simplex Virus), VZV (Varicella-Zoster Virus): Viruses that can cause severe infections.

Treatment of Febrile Neutropenia

Empiric Antibiotics:

• Appropriate coverage of known or suspected infection based on history, examination findings, and radiographic studies.

Monotherapy:

• Commonly used antibiotics include ceftazidime, imipenem, meropenem, or cefepime.

Double Coverage:

• Combination therapy with a beta-lactam antibiotic and an aminoglycoside.

Awareness of Institutional Resistance Patterns:

• Consideration of local resistance patterns when choosing empiric antibiotics.

Addition of Empiric Vancomycin:

• Consider adding empiric vancomycin in cases of skin or catheter site infection, hypotension, history of MRSA colonization, mucositis, or quinolone prophylaxis.

Empiric Anti-fungal Coverage:

• If fever persists despite broad-spectrum antibiotics and prolonged neutropenia, consider empiric antifungal coverage with options like liposomal amphotericin B, caspofungin, or voriconazole.

Colony Stimulating Factors:

• These should not be used routinely but may be appropriate for critically ill patients.

Guidelines for Managing Neutropenic Patients

1. Instruct the patient to seek medical help if a fever develops when the neutrophil count is low or declining.
2. Evaluate the patient at least daily.
3. Initiate prompt therapy with broad-spectrum antibiotics when a patient with neutropenia (neutrophil count, <500/mm3) becomes febrile (single elevation in oral temperature to >38.5°C, or three elevations to >38°C during a 24-hour period).
4. If the patient has an indwelling intravenous catheter, obtain cultures from each catheter port and lumen as well as from a peripheral vein. Rotate antibiotic therapy through each lumen of multiple-lumen catheters.
5. Monitor the patient closely for secondary infections requiring additions or modifications to the initial antibiotic regimen.
6. Continue empirical antibiotic therapy if the patient has prolonged (>1 week) neutropenia, particularly if there is persistent fever.
7. Add empirical antifungal therapy if a patient with neutropenia remains febrile after a week of broad-spectrum antibiotic therapy or has recurrent fever.
8. Discontinue antibiotic therapy when the neutrophil count rises above 500/mm3 in a patient at high risk or is increasing in a patient at low risk.
9. Although 10 to 14 days of treatment is adequate in most patients with neutropenia, prolonged therapy is necessary for a patient with a residual focus of infection or invasive mycoses (e.g., hepatosplenic candidiasis).
10. All those caring for a febrile patient with neutropenia should wash their hands carefully before any contact with the patient.

• Hyperleucocytosis: Very high white blood cell count
• Bone Marrow Suspension: Disruption of bone marrow function
• DIC (Disseminated Intravascular Coagulation): Abnormal blood clotting throughout the body

Hyperleukocytosis

• Criteria: TWBC (Total White Blood Cell Count) > 100,000/mm³
• Leukemic Blasts (AML - Acute Myeloid Leukemia): These cells are nondeformable
• Hyperviscosity: Hyperviscosity of blood occurs at lower counts (approximately 70,000+)
• Clinical Symptoms: Leukostasis in microvasculature can lead to clinical symptoms including:
• Pulmonary: Hypoxemia (low oxygen levels in the blood)
• CNS (Central Nervous System): Headaches, vision changes/loss, and focal deficits
• Note: Symptomatic hyperleukocytosis in AML is associated with high initial mortality

Treatment of Hyperleukocytosis

• Leukophoresis: A procedure that can be used as an adjunct to chemotherapy
• Role: Temporizing measure to quickly reduce white blood cell count
• Immediate Cytoreductive Therapy: Initiate cytoreductive therapy as soon as possible
• Rationale: Leukemic blasts rapidly accumulate, potentially leading to another oncologic emergency

HYPERVISCOSITY: Treatment

• Oxygen: Administration of oxygen to alleviate hypoxemia (low oxygen levels) associated with hyperviscosity
• Hydration: Intravenous fluid therapy to maintain proper hydration levels
• Transfusions: Blood component transfusions may be necessary:
• Platelets: Maintain platelet count above 20,000/μL to prevent bleeding complications
• Red Blood Cell (PRBC) Transfusions: Generally, avoid unless symptomatic since they can increase viscosity further
• Lower White Blood Cell (WBC) Count: Strategies to reduce white blood cell count:
• Leukapheresis (Exchange TFX): A procedure to exchange white blood cells to lower their count
• Chemotherapy: Medications to target and reduce the abnormal white blood cell population
• Irradiation: Radiation therapy may be considered in certain cases

• Tumour Lysis Syndrome (TLS): A potentially life-threatening condition that can occur after cancer treatment
• Causes: Rapid breakdown of cancer cells, releasing their contents into the bloodstream
• Manifestations: Elevated levels of uric acid, potassium, phosphate, and decreased calcium
• Symptoms: Can include kidney dysfunction, heart arrhythmias, and seizures
• Treatment: Aggressive hydration, allopurinol, and rasburicase to prevent or manage TLS
• Hypercalcemia: Elevated calcium levels in the blood
• Causes: Often due to malignancies like multiple myeloma or hyperparathyroidism
• Symptoms: Fatigue, confusion, kidney stones, and cardiac arrhythmias
• Treatment: Address the underlying cause, intravenous fluids, and medications like bisphosphonates
• Hyponatremia: Low sodium levels in the blood
• Causes: Often seen in conditions like SIADH (Syndrome of Inappropriate Antidiuretic Hormone) or certain medications
• Symptoms: Headaches, confusion, seizures, and in severe cases, coma
• Treatment: Address the underlying cause, fluid restriction, and sometimes hypertonic saline
• Hypoglycemia: Low blood sugar levels
• Causes: Can result from insulin or oral diabetes medications, fasting, or alcohol consumption
• Symptoms: Shaking, sweating, confusion, and in severe cases, loss of consciousness
• Treatment: Rapid consumption of glucose, such as sugary foods or glucose gel, or administration of glucagon

Tumor Lysis Syndrome

• Definition: Tumor lysis syndrome (TLS) occurs when cancer cells release their contents into the bloodstream, either spontaneously or following antineoplastic therapy, leading to an influx of electrolytes and nucleic acids into the circulation.
• Cause: Rapid cell death in the face of a high tumor burden results in the release of large amounts of intracellular metabolites, including uric acid and potassium.
• Commonly Associated with: TLS is most commonly associated with poorly differentiated lymphomas and leukemias, including:
• Burkitt’s lymphoma
• ALL (Acute Lymphoblastic Leukemia): More commonly than AML (Acute Myeloid Leukemia)
• Complications: Uric acid can deposit in the kidneys, leading to Acute Renal Failure (ARF).
• Treatment for ARF: Dialysis can support the patient in cases of severe renal dysfunction.
• Medication: Rasburicase or Elitek (urate oxidase) can be used as treatment.
• Mechanism of Action: It oxidizes uric acid to allantoin, which is water-soluble and can be excreted more easily.

Pathogenesis of Hyperuricemia in TLS

• Purine Catabolism: Hyperuricemia in Tumor Lysis Syndrome (TLS) is intricately tied to purine metabolism and uric acid formation.
• Breakdown of Purines: The breakdown of purines (adenosine and guanosine) within tumor cells is central to the pathogenesis.
• Xanthine Oxidase Activity: As tumor cells lyse, xanthine oxidase, an enzyme responsible for converting hypoxanthine and xanthine to uric acid, is activated.
• Conversion of Purines to Uric Acid: The purine breakdown yields hypoxanthine and xanthine, which are rapidly converted to uric acid within the tumor lysis milieu.
• Impaired Renal Clearance: The sheer volume of uric acid generated during TLS can overwhelm the kidneys' ability to excrete it efficiently. This is particularly problematic if the patient already has compromised kidney function.
• Hyperuricemia: The combination of increased uric acid production and impaired renal clearance results in hyperuricemia, with uric acid levels rising to critical levels within hours or days.
• Uric Acid Crystallization: Hyperuricemia in TLS can lead to the formation of urate crystals, which may deposit in the kidneys, joints, and other tissues, potentially causing kidney stones, gout attacks, and tissue damage.

1. Hypoxanthine (Enzyme: Xanthine oxidase) → Xanthine
2. Xanthine (Enzyme: Xanthine oxidase) → Uric Acid
3. Uric Acid (Enzyme: uric acid oxidase) → Allantoin

×

Laboratory definition of TLS using the Cairo-Bishop Classification

Laboratory	Tumor Lysis Syndrome
Uric acid	>8 mg/dL (≥ 476 μmol/L) or 25% increase from baseline
Potassium	6 mEq/L (≥6 mmol/L) or 25% increase from baseline
Phosphorus	6.5 mg/dL (2.1 mmol/L) or 25% increase from baseline
Calcium	7 mg/dL (< 1.75 mmol/L) or 25% decrease from baseline

Prevention of Tumor Lysis Syndrome

• Vigorous Hydration: Adequate hydration is crucial to prevent TLS by helping dilute and flush out uric acid and other metabolic byproducts.
• Allopurinol: Allopurinol is used to inhibit xanthine oxidase, thus decreasing uric acid production. It can be given preventively, starting up to 48 hours before treatment.
• Dosing: Recommended doses are typically 100 mg/m² every 8 hours (maximum daily dose: 800 mg).
• Limited Effect on Pre-existing Uric Acid: Allopurinol does not alter uric acid that has already formed.
• Not Recommended for High Pre-Treatment Uricemia: It's not recommended as prophylaxis for patients with pre-treatment uric acid levels of 7.5 mg/dL or greater.
• Rasburicase: Rasburicase is a urate oxidase that converts uric acid to allantoin, a water-soluble compound.
• Dosing: Dosages typically range from 0.15 to 0.2 mg/kg/day for up to 5 or 7 days.
• Role of Urine Alkalinization (Debatable): While alkalinizing urine increases the solubility of uric acid and decreases the tendency for precipitation, its use is debated.
• Potential Drawbacks: Alkalinizing agents could promote calcium phosphate deposition, and animal studies have shown that increased tubular flow rate may be the most important protective measure.
• Vigorous Hydration with Saline: Vigorous hydration with saline is likely as effective in preventing TLS.

Treatment of Metabolic Derangements in TLS

Problem	Intervention	Dosages	Comments
Renal Insufficiency and Hypovolemia	Intravenous Fluids	Normal Saline, 3 L/m² daily	Use with caution if decreased systolic function
	Dialysis		For fluid-unresponsive oliguric renal failure or patients with CHF
Hyperuricemia	Allopurinol	100mg/m² per dose orally every 8h (maximum daily dose: 800mg)	Drug-drug interactions with 6-MP and azathioprine; only effective for prophylaxis
	Rasburicase	0.15-0.2 mg/kg/d iv	Contraindicated in pregnancy and G6PD deficiency; costly
Hyperphosphatemia	Minimize Phosphate Intake	Minimal consumption of dairy and bread products
	Phosphate Binders (Aluminum Hydroxide or Aluminum Carbonate)	30 mL orally every 6h
	Dialysis		If no response to oral therapy
Hyperkalemia	Insulin (Regular)	10 U iv
	Dextrose	50 mL of 50% dextrose iv push, then infuse 50 – 75mL of 10% dextrose over 1h
	Albuterol	20 mg nebulized
	Dialysis		If no response to other therapy
	Calcium Gluconate	1000 mg iv	If hyperkalemic EKG changes are noted
Hypocalcemia	Calcium Gluconate	1000 mg iv (no faster than 200 mg/min)	Use with caution in severe hyperphosphatemia

Hypercalcemia

• Causes: Hypercalcemia can result from bone metastasis and other factors.
• Manifestations: Hypercalcemia is associated with the classic "bones, stones, groans, and moans" symptoms:
• Bones: Nausea, constipation, polyuria
• Stones: Weakness, bradyarrhythmias, renal insufficiency, coma
• Life-Threatening Levels: Levels > 12mg/dL are considered life-threatening and can lead to irreversible renal failure.
• Treatment
• Acute: Immediate interventions include:
• Increased Excretion: Hydration with Normal Saline (NS) and furosemide (not thiazide diuretics)
• Increased Mobilization: Prednisone (acts slowly), calcitonin, and bisphosphonates
• Long Term: Address the underlying primary disease to manage hypercalcemia in the long term.

Treatment of Hypercalcemia

Medication	Usual Dose	Points to Remember
Normal Saline	Rapid infusion 300 – 500 cc/n until euvolemic	Use caution in patients with heart failure
Furosemide	20 – 40 mg iv every 12-24h	Only after adequate hydration
Pamidronate	60 – 90 mg iv	Adjust infusion time to creatinine clearance
Zoledronic acid	4 mg iv	Consider alternative treatment in patients with renal failure
Calcitonin	4 – 8 IU/kg sq. or iv every 12h	Tachyphylaxis occurs quickly
Steroids	Hydrocortisone, 100mg iv every 6h or prednisone, 60mg orally daily	Role usually limited to lymphomas; anticipate hyperglycemia
Mithramycin and Gallium		Of historical interest only
Denosumab	Under investigation	Currently approved only for the prevention of skeletal-related events from bone metastases

• Associated with a Mass Effect: Mechanical complications are often associated with a mass effect that causes obstruction or compression of vital organs.
• Common Sites Include: Mechanical complications can occur in various locations, including:
• SPINAL CORD
• SUPERIOR VENA CAVA/TRACHEA
• GENITOURINARY
• GASTROINTESTINAL
• CNS (Central Nervous System)

Spinal Cord Compression

Spinal Cord Compression Statistics

Tumor Type	Number of Cases	Percentage (%)
EWING SARCOMA	30/168	17.9%
NEUROBLASTOMA	32/402	7.9%
OSTEOSARCOMA	16/243	6.5%
RHABDOMYOSARCOMA	14/287	4.9%
SOFT TISSUE SARCOMA	4/102	3.9%
GERM CELL TUMOR	5/130	3.8%
HODGKIN DISEASE	8/404	2.0%
HEPATOMA	1/69	1.4%
WILMS TUMOR	2/290	0.7%
OTHER	0/164	-
TOTAL	113/2259	5.0%

Source: Klein, JNs 74:70, 1991

Spinal Cord Compression Treatment

Asymptomatic:

• Dexamethasone: Dexamethasone is typically used for asymptomatic cases.
• Chemotherapy (especially for Leukemia, Lymphoma, and Neuroblastoma): Consider chemotherapy as a treatment option for specific types of cancers.
• Irradiation: Radiation therapy may be indicated for certain cases.
• Surgery: Surgical intervention may be necessary in some instances.

Symptomatic (24-hour Rule):

• Dexamethasone: Administer dexamethasone for symptomatic cases.
• Surgery (especially if no disseminated tumor): Surgical intervention is recommended within the 24-hour rule, particularly when there is no disseminated tumor.
• Irradiation: Radiation therapy may be necessary to address symptoms.

Superior Vena Cava Syndrome

• Cause: Superior Vena Cava (SVC) Syndrome is typically caused by the invasion or external compression of the SVC.
• Common Causes: Malignant tumors are responsible for approximately 80% of cases, while infections and thrombosis account for most of the rest.
• Symptoms: Symptoms of SVC Syndrome include:
• Dyspnea: Difficulty breathing.
• Facial Swelling, Arm Edema, Cyanosis: Swelling of the face, edema in the arms, and bluish discoloration of the skin.
• Signs: Clinical signs of SVC Syndrome may include:
• Venous Distension on Neck and Chest Wall: Visible distension of the veins in the neck and chest wall.
• Facial Edema: Swelling of the face.

Superior Vena Cava Syndrome Statistics

Disease	No. of Cases	Mediastinal Mass	SVCS Episodes
ALL (Acute Lymphoblastic Leukemia)	1,464	130	6
AML (Acute Myeloid Leukemia)	392	9	0
HODGKIN	333	102	2
NHL (Non-Hodgkin Lymphoma)	330	230	8
NBLASTOMA (Neuroblastoma)	332	69	3
GERM CELL	114	10	2
SARCOMAS	696	26	3

Source: Ingram, MPO 18:476, 1990

Superior Vena Cava Syndrome Symptoms and Findings at Diagnosis

Symptoms/Findings	Number of Cases (Percentage)
Cough/Dyspnea	11 (68%)
Dysphagia/Orthopnea	10 (63%)
Wheezing	5 (31%)
Hoarseness	3 (19%)
Facial Edema	2 (12%)
Chest Pain	1 (6%)
Pleural Effusion	8 (50%)
Pericardial Effusion	3 (19%)

Source: Ingram, MPO 18:476, 1990

Superior Vena Cava Syndrome Evaluation

• Pulse Oximetry: Utilize pulse oximetry to assess oxygen saturation levels.
• Chest X-Ray: Evaluate the trachea, which is a three-dimensional structure, with both PA (Posteroanterior) and lateral views. The latter often requires a high KV (kilovoltage) film.
• Echocardiogram: Consider an echocardiogram if there are any questions regarding size or motion.
• Pulmonary Function: If anesthesia is being considered, perform pulmonary function tests in both upright and recumbent positions.

Superior Vena Cava Syndrome

• CT Preferred Diagnostic Tool: CT (Computed Tomography) is the preferred diagnostic tool for Superior Vena Cava Syndrome.
• Importance of Biopsy:
• Short Delay Not Compromise Outcome in Most Cases: A short delay in performing a biopsy does not compromise the outcome in most cases.
• Histology Helps Determine Treatment and Prognosis: Histological analysis helps determine the appropriate treatment and prognosis.
• Treatment Responsive Tumors: Some tumors, such as SCLC (Small Cell Lung Cancer), germ cell tumors, and NHL (Non-Hodgkin Lymphoma), may respond to specific treatments.

Superior Vena Cava Syndrome Treatment

• Consults: Consider consulting with the following specialists:
• ENT (Ear, Nose, and Throat) / Anesthesia
• Surgery
• Treatment:
• Oxygen (O2), IV Access, Intravenous Fluids (IVF): Provide oxygen therapy, establish intravenous access, and administer intravenous fluids as needed.
• Surgery: Surgical intervention may be required as part of the treatment plan.
• Irradiation: Radiation therapy may be recommended.
• Chemotherapy: Consider chemotherapy, which may include:
• Corticosteroids: Corticosteroids are often part of the chemotherapy regimen.
• Other Chemotherapeutic Agents: Depending on the specific case, other chemotherapy drugs may be used.