Oncology Relate Emeregency

What is Tumor Lysis Syndrome (TLS)?

What is Tumor Lysis Syndrome (TLS)?

• Metabolic syndrome caused by rapid destruction of malignant cells.

• Usually treatment related, but can occur spontaneously.

Tumor Lysis Syndrome is characterized by:

• Hyperuricemia

• Hyperkalemia

• Hyperphosphatemia

• Hypocalcemia

• Possible clinical problems: renal failure, cardiac arrhythmias, seizure

Describe the pathophysiology of TLS:

What lab values do you look at in a patient to see if they have TLS?

• Two or more of the following within 3-7 days after chemotherapy:

  • Increase Uric Acid: > 8 mg/dL or 25% increase from baseline.

  • Increase potassium: > 7 mEq/L or 25% increase from baseline.

  • Increase phosphorus: > 4.5 mg/dL or 25 increases from baseline.

  • Decrease calcium: < 7 mg/dL or 25% decrease from baseline.

What are some risk factors of TLS?

• Tumor type:

  • Burkitt’s lymphoma

  • Diffuse Large-B cell lymphoma.

• Tumor Burden:

  • Bulky disease (>10 cm)

  • Elevated lactate dehydrogenase (> 2x ULN)

  • Elevated WBC count(>25,000 microliters)

• Renal function:

  • Pre-existing renal impairment

  • Decreased urine output.

• Baseline uric acid:

  • Uric acid level > 7.5 mg/dL

• Treatment:

  • Intensity of cancer therapy ( disease/tumor-specific)

Risk Factors for Certain types of Cancer of getting TLS:

How do you manage hyperkalemia?

• Stabilize myocardium if EKG changes:

  • Calcium gluconate 1-2 g, slow IV infusion.

• Reduce serum potassium:

  • IV insulin 10 IU + dextrose ( 25-50 g)

  • Cation exchangers ( e.g. sodium polystyrene sulfate 15-30 g PO)

  • Nebulized albuterol 10-20 mg.

  • IV sodium bicarbonate 150 mEq

• Dialysis:

  • If refractory to other interventions.

How do you manage hyperphosphatemia?

• Minimize phosphate intake:

  • Avoid IV phosphate administration.

  • Avoid food sources ( e.g. bread and dairy).

• Initiate phosphate binders:

  • Calcium acetate 1334 mg po with meals.

  • Aluminum hydroxide300 mg Po with meals.

  • Non-calcium/aluminum-containing ( e.g. sevelamer800 mg po with meals).

• Dialysis:

  • If refractory to other interventions

How do you manage hypocalemia?

• No treatment if asymptomatic.

• Calcium treatment if symptomatic:

  • Calcium gluconate 1 g IV , no faster than 200 mg/min.

    • Ideally correct hyperphosphatemia first ( risk of calcium-phosphate precipitation).

What is the pharmacotherapy plan for patients with Low Risk for TLS?

• May defer prophylaxis if negligible risk.

  • IV hydration, Allopurinol, Monitor Labs.

What is the pharmacotherapy plan for patients with intermediate risk for TLS?

• IV Hydration, Allopurinol, Monitor Labs.

• Rasburicase if hyperuricemia develops.

What is the pharmacotherapy plan for patients with high risk for TLS?

• IV Hydration , Allopurinol + Rasburicase, Monitor Labs.

When do you start treatment/management for TLS?

• Start it 24 hours before chemotherapy if possible.

How much IV hydration fluid do you give patients for treatment/management for TLS?

• IV fluids 2 to 3 L/m²/day to achieve high urine output.

What medications are given patients for treatment/management for TLS if the patient has hyperuricemia?

• Allopurinol: 100-300 mg.

• Rasburicase: considered for high TLS Risk

What labs are monitored during the treatment/management of patients with TLS?

• CBC, CMP, uric acid, phosphorus monitored twice daily (note: more or less frequently based on TLS risk and clinical judgment)

•  Lactate dehydrogenase (LDH) reflects tumor burden/breakdown.

Allopurinol:

Indication	Prevention of hyperuricemia
Mechanism of Action	Xanthine oxidase inhibitor Inhibit the production of uric acid; does not break down acid crystals already formed.
Dosing	100mg/m^2 po 8 hours ( max 800 mg/day) 200 to 400 mg/m^2/day iv in 1-3 divided doses ( max 600 mg/day) >50% dose reduction in renal impairment Start 24-48 hours before the start of chemotherapy, continue 3-7 days afterward or until normalization of any evidence of TLS.
Adverse Effects	Rash nauseam Diarrhea
Warnings	HLA-B*5801 allele= increased risk for severe cutaneous adverse reactions.
Cost	$
Other Considerations	Tablet size: 100 mg and 300 mg Drug interactions: 6-mecaptopurine and Azathioprine

Rasburicase:

Indication	Prevention(high risk) treatment of hyperuricemia
Mechanism of Action	Recombinant urate oxidase enzyme Converts uric acid to allantion.
Dosing	0.5-0 2 mg/kg IV over 30 min once daily for 1-7 days. Single-dose strategies (non-inferior and cost-saving):       • Weight based: 0.15 mg/kg IV x1 dose     • Flat dose: 3 to 7.5 mg IV x1 dose      • Additional dose may be required
Adverse Effects	Peripheral edema, headache, rash, nausea
Warnings	Contraindicated in G6P deficiency ( risk for hemolysis)
Cost	$$$
Other Considerations	Blood samples should be placed on ice

What is the clinical presentation of hypercalcemia?

• Musculoskeletal: bone pain

• Renal: nephrogenic diabetes insipidus, acute kidney injury, nephrolithiasis

• Gastrointestinal: anorexia, constipation, nausea, vomiting

• Neuropsychiatric: lethargy, coma

What is the pathophysiology of hypercalcemia?

• Humoral hypercalcemia of malignancy (secretion of parathyroid hormonerelated peptide [PTHrP]) – 80%

• Local osteolytic hypercalcemia – 20%

• 1,25-Dihydroxyvitamin D-secreting lymphomas - <1% • Ectopic hyperparathyroidism - ><1%

What corrected calcium level is considered mild hypercalcemia?

• 10.5-11.9 mg/dL

What corrected calcium level is considered moderate hypercalcemia?

• 12-14 mg/dL

What corrected calcium level is considered severe hypercalcemia?

• >14 mg/dL

What patient characteristics is considered low risk ( outpatient management) for hypercalcemia?

• Serum calcium < 12 mg/dL

•  Minimal nausea/vomiting

• Able to ingest fluids easily.

• Mild fatigue, otherwise, neurologically stable.

•  Normal renal function.

•  Stable cardiac rhythm.

•  Mild, if any, constipation

What patient characteristics is considered high risk ( inpatient management) for hypercalcemia?

• Serum calcium > 12 mg/dL

• Severe nausea/vomiting

•  Clinically dehydrated.

• Altered mental state.

•  Renal insufficiency.

• Cardiac arrhythmia.

  • Severe constipation or ileus

How many mLs of Normal Saline do you give a patient for treating their hypercalcemia?

200-500 mL/hr.

Zoledronic Acid for Hypercalcemia:

Mechanism of Action	Inhibit bone resorption by disrupting osteoclasts activity
Indication	First line therapy for most patients
Dose	Zoledronic acid 4 mg IV over 15 minutes. Contraindicated if serum creatinine > 4.5 mg/dL
Onset of action	Within 2-4 days
Adverse effects	Flu like symptoms, bone aches, nephrotic syndrome, acute
Other considerations	Do not repeat dose earlier than 1 week after initial dose

Calcitonin:

Mechanism of action	Inhibits osteoclast activity. Increases renal calcium excretion
Indication	Severe or symptomatic hypercalcemia
Dose	4-8 international units/kg SQ or IM every 12 hours Maximum 8 international units/kg every 6 hours
Onset of action	Within 4 hours
Adverse effects	Anaphylaxis, flushing, nausea
Other considerations	Duration limited to 48 hours due to rapid tachyphylaxis. Intranasal form is ineffective.

Denosumab for Hypercalcemia treatment:

Mechanism of action	RANKL monoclonal antibody; inhibits osteoclasts.
Indication	Hypercalcemia refractory to bisphosphonates
Dose	120 mg SQ every 4 weeks. Additional 120 mg on every 8 and 15 of first month. No renal or hepatic adjustment
Onset of action	Within 2-4 days
Adverse effects	Bone pain, nausea, diarrhea, shortness of breath, osteonecrosis of jaw, infection risk
Other considerations	Monitor for hypercalcemia in setting of severe renal impairment.

What is corrected calcium formula?

• Corrected Calcium = calcium ( mg/dL) + 0.8(4-albumin level)

What is chemotherapy extravastion?

§  Unintended chemotherapy leakage into extravascular space.

What are the causative agents of chemotherapy extravasation?

Causative Agent Categories
Vesicants	Irritants
Potential to cause tissue necrosis	Potential to cause inflammation at administration site but rarely cause necrosis.

What is the clinical presentation of chemotherapy extravasation?

Vesicants	Irritants
Initial symptoms: pain, bleeding, induration, discoloration Ulceration Necrosis of skin/tissues	Phlebitis Hyperpigmentation Sclerosis Erythema, swelling, tenderness

What medications are vesicants and irritants?

Vesicants	Irritants
DNA-binding:  Anthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin) Mitomycin C, dactinomycin Trabectedin Mechlorethamine	Taxanes (docetaxel, paclitaxel)  Platinums (carboplatin, cisplatin, oxaliplatin)  Epipodophyllotoxins (etoposide, teniposide) Topoisomerase I inhibitors (irinotecan, topotecan)  Alkylating agents (carmustine, thiotepa, dacarbazine, melphalan, cyclophosphamide, ifosfamide) Antimetabolites (cytarabine, fludarabine, 5-fluorouracil, gemcitabine, methotrexate)
Non-DNA binding: Vinca alkaloids (vincristine, vinblastine, vinorelbine)

What is the management of chemotherapy extravasation?

What is the treatment of chemotherapy extravasation?

Drug	Nonpharmacologic treatment	Pharmacologic treatment/antidote
Anthracyclines	Cold compress	Dexrazoxane Topical DMSO
Vinca alkaloids	Warm compress	Hyaluronidase SQ
Taxanes	Warm compress	Hyaluronidase SQ

Dexaroxane used for treatment of Chemotherapy Extravasation:

Used for anthracycline extravasation

DMSO ( Dimethyl Sulfoxide) for chemotherapy extravasation

Hyaluronidase for chemotherapy extravasation:

Used for vinca alkaloid and taxane