TUMOUR LYSIS
SYNDROME
DR. AMA ADOMA YEBOAH
OBJECTIVES
To understand what tumour lysis is
and why it occurs
To know the risk factors of tumour lysis syndrome
To know the signs and symptoms of tumour lysis syndrome
To know how to prevent and treat tumour lysis syndrome
OUTLINE
Introduction
Pathogenesis
Signs and symptoms
Risk factors and Risk stratification
Classification
Investigations
OUTLINE
Management
Conclusion
References
CASE PRESENTATION
A 5 year old previously well boy presents to PEU with a
3 week history of easy fatigue and dizziness and a 2
week history of bone pain in both lower limbs. Mother also
noticed his palms and soles are whiter than previously.
His vitals are normal apart from a heart rate of 130 bpm
On physical examination, he is very pale, with petechiae seen on his
upper limbs and abdomen. He has hepatosplenomegaly.
Weight-15 kg, height- 100 cm
CASE PRESENTATION
FBC done: Urea, creatinine, calcium
WBC-120 x 10^9 magnesium and phosphate are
Hb-4.8 g/dl normal
Plt-23
Uric acid- 8.2 mg/dl (2.5-5.5) Blood film comment from
LDH- 600 IU/L (155-280) periphery:
lymphoblasts of 30%
CASE PRESENTATION
What is the most likely diagnosis?
What are the risk factors for TLS?
Does the patient qualify for laboratory or clinical TLS?
How will you manage him in relation to TLS?
INTRODUCTION
Tumour lysis syndrome(TLS) is a common life-threatening
metabolic and oncological emergency encountered in paediatrics.
It is caused by massive lysis of tumour cells either
spontaneously, during or after initiation of cytotoxic
therapy and release of their intracellular components; potassium,
phosphates and nucleic acid into the systemic circulation.
INTRODUCTION
It is characterized by the following metabolic abnormalties:
Hyperkalemia
Hyperphosphatemia
Secondary hypocalcemia
Hyperuricemia
INTRODUCTION
These abnormalities cause a myriad of signs, symptoms
and complications.
TLS can occur spontaneously at presentation and up
to 7 days following treatment initiation.
TLS is most often seen in acute leukemias and lymphomas
(especially B cell Non-Hodgkins Lymphoma) and less
commonly in solid tumours.
PATHOGENE
SIS
Howard et al NEJM, 2011
SIGNS AND SYMPTOMS
Hyperkalemia: Cardiac arrhythmias
Nausea ECG changes
Vomiting
Diarrhoea
Slow, weak or irregular pulse
Muscle weakness
SIGNS AND SYMPTOMS
Hyperuricemia: Metallic taste in the mouth
Nausea Oliguria or anuria
Vomiting Crystals forming in urine
Diarrhoea Azotemia
Peripheral oedema Hypertension
Flank pain
SIGNS AND SYMPTOMS
Hypocalcemia: Seizures
Muscles cramps Laryngeal stridor
Very late signs: ECG abnormalities (shortened
Facial twitch (Chvostek sign) QT, bradycardia , widened T
waves)
Carpopedal spasm (Trouseau
Confusion
sign)
Delirium
Paresthesias
Wheezing
Tetany
IMAGE
DEPICTING
CHVOSTEK
AND
C
TROUSSEAU’S
SIGNS FOR
HYPOCALCEM
IA
SIGNS AND SYMPTOMS
Hyperphosphatemia:
No obvious signs.
Often associated with hypocalcemia so signs and
symptoms of hypocalcemia and azotemia.
RISK FACTORS
Intrinsic tumor-related factors include :
High tumor cell proliferation rate
Chemosensitivity of the malignancy
Large tumor burden (as manifested by bulky disease
>10 cm in diameter) and/or a white blood cell count(WBC) >50,000
per microl, a pretreatment serum lactate dehydrogenase (LDH)
more than 2x the upper limit of normal(ULN)
RISK FACTORS
• Intrinsic tumor-related factors continued:
Organ infiltration
Bone marrow involvement
RISK FACTORS
Patient-related risk factors of TLS:
Pretreatment hyperuricemia (serum uric acid >7.5 mg/dL [446
micromol/L])
Pretreatment hyperphosphatemia (serum phosphate >4.5 mg/dL [1.44
micromol/L])
A preexisting nephropathy or exposure to nephrotoxins
RISK FACTORS
• Patient-related risk factors of TLS:
Oliguria and/or acidic urine
Dehydration, volume depletion, or inadequate hydration
during treatment
RISK STRATIFICATION
Risk for TLS is divided into Low Risk (<1%), Intermediate Risk (1-5%)
and High Risk (>5%)
LABORATORY
TUMOUR
LYSIS
SYNDROME
CLASSIFICATION OF TLS
Clinical TLS: Defined as laboratory TLS plus ≥ 1 of the following:
Acute kidney injury
• ↑in serum creatinine by 26.5μmol/L from baseline
• serum creatinine ≥ 1.5x ULN of the age appropriate
normal range if baseline was unknown
• Presence of oliguria- urine output < 0.5mls/Kg/hr for 6 hours
CLASSIFICATION OF TLS
Cardiac arrythmias/sudden death/ neuromuscular irritability
Seizures
INVESTIGATIONS
Full blood count Ct scan/MRI
Blood film comment Bone marrow aspirate
Urea, creatinine Biopsy
Uric acid Urinalysis, urine microscopy
Serum electrolytes: calcium, phosphate, Renal ultrasound
potassium
ECG
LDH
MANAGEMENT
Assess the patients risk for TLS
The main prophylactic strategies are
Intravenous (IV) hydration -Hyperhydration
The use of hypouricemic agents, such as allopurinol and rasburicase.
Close monitoring
Urine alkalinization*
Same strategies are used for used for treatment including
management of electrolyte abnormalities and AKI.
PREVENTION
Prophylaxis recommendations
LOW RISK INTERMEDIATE HIGH RISK
RISK
Monitoring Monitoring Monitoring
Hydration Hydration Hydration
±Allopurinol Allopurinol Rasburicase*
Copyrights apply
MANAGEMENT
Immediately review drug charts to eliminate nephrotoxic
drugs if possible
Ideally manage in ICU/HDU with continuous ECG monitoring
Urethral catheterization (for strict input and output documentation)
Consider central venous access
MANAGEMENT
Blood gases – serum pH and electrolytes- frequency
depends on severity of clinical symptoms and checks to
assess effectiveness of interventions
Involve nephrologist early
MANAGEMENT–IV
HYDRATION
Intravenous hydration: Hyperhydration
2 to 3 L/m2 per day of IV fluid (or 200 mL/kg per day
in children weighing ≤10 kg
0.45% Saline in 5% Dextrose or 5% Dextrose in 0.9% Saline
Potassium and calcium should be withheld from the hydration fluids
MANAGEMENT–IV
HYDRATION
Strict input and urine output:
Urine output: 80 to 100 mL/m2 per hour (2 mL/kg per hour,
4 to 6 mL/kg per hour if ≤10 kg)
Diuretics may be used if necessary. (Loop diuretics preferrable)
No guidelines for optimal duration of hydration
MANAGEMENT–IV
HYDRATION
This should be dependent on :
The tumour burden
Type of chemotherapy used
Drug sensitivity of the tumour
Patient’s ability to drink and renal function
MANAGEMENT–IV
HYDRATION
IV hydration should be continued at least until:
Tumour burden is largely resolved
There is no evidence of significant tumour lysis (as indicated
by serum uric acid and phosphorus level)
Patient can drink adequately with good urine output
MANAGEMENT-
HYPOURICEMIC AGENTS
Hypouricemic agents: Allopurinol (xanthine oxidase inhibitor)
It effectively decreases the formation of new uric acid
Administered orally(IV option available for
patients who cannot drink)
Preferred for patients with low and intermediate
risk for TLS
MANAGEMENT-
HYPOURICEMIC AGENTS
Allopurinol
Dose: 50 to 100 mg/m2 every 8 hours (maximum 300 mg/m2 per
day)or 10 mg/kg per day in divided doses every 8 hours
Some limitations to its use include:
Associated with a number of hypersensitivity reactions
including vasculitis and Stevens-Johnson syndrome
MANAGEMENT-
HYPOURICEMIC AGENTS
Allopurinol
Increase serum level of purine precursors
Deposition in renal tubules and causing AKI
MANAGEMENT-
HYPOURICEMIC AGENTS
Hypourecemic agents: Rasburicase (recombinant urate oxidase)
Preferred for patients at high risk for TLS
Evidence from various studies show that it is very
effective in preventing and treating hyperuricemia and TLS
Dose: 0.2mg/kg/day as a 30min IV infusion
MANAGEMENT-
HYPOURICEMIC AGENTS
Rasburicase
The average duration of therapy is 2 days
but can vary from 1 to 7 days
Duration is guided by clinical response.
Addition of allopurinol is unnecessary.
Contraindicated in G6PD deficiency
MANAGEMENT-
HYPOURICEMIC AGENTS
Rasburicase
Other restrictions/contraindications:
• Can cause methaemoglobinemia
• Can cause anaphylaxis
Spuriously low uric acid levels(if uric acid sample
taken is left at room temperature)
MANAGEMENT-
HYPOURICEMIC AGENTS
New hypouricemic agent: Febuxostat
It may be used in patients with hyperuricemia who
cannot tolerate allopurinol in a setting in which rasburicase
is either not available or contraindicated
A selective inhibitor of xanthine oxidase
MANAGEMENT-URINE
ALKALINIZATION
Urine alkalinisation
The role of urinary alkalinization with either acetazolamide
and/or sodium bicarbonate is unclear and controversial.
In the past, alkalinization to a urine pH of 6.5 to 7
or even higher was recommended to increase uric acid
solubility, thereby diminishing the likelihood of uric acid
precipitation in the tubules
MANAGEMENT-URINE
ALKALINIZATION
Urine alkalinisation
Currently, this is not in favour because:
It has the potential disadvantage of promoting
calcium phosphate deposition in various organs and
can lead to renal failure
There are no data demonstrating the efficacy of this approach.
MANAGEMENT-URINE
ALKALINIZATION
Urine alkalinisation
In addition, the only available experimental study suggested
that hydration with saline alone is as effective as alkalinization
in minimizing uric acid precipitation
MANAGEMENT-
ELECTROLYTE
ABNORMALITIES
Hyperkalemia
Continuous ECG monitoring
Stop feeds rich in potassium
No fluids containing potassium
ECG-peaked T waves, loss of P wave or widened
QRS complex, treat with:
• Calcium gluconate 10% solution 50mg/kg or 0.5mls/kg (max
20mls=2grams) ideally through a central line to stabilise myocardium
MANAGEMENT-
ELECTROLYTE
ABNORMALITIES
Hyperkalemia
• Soluble insulin 0.1units/kg (max 10units) in dextrose
solution at 0.5grams/kg over 30minutes
• Nebulised salbutamol 2.5mg (<25kg), 5mg (25-50kg),
10mg (>50kg) in 2ml normal saline
• Need to check potassium levels after these initial
interventions while planning for hemodialysis (above are temporary)
MANAGEMENT-
ELECTROLYTE
ABNORMALITIES
Hyperkalemia
• Kayexalate 1g/kg/dose PO 4x daily (1g/kg lowers
potassium by 1mmol if patient is passing
stool appropriately)- this removes potassium slowly
MANAGEMENT-
ELECTROLYTE
ABNORMALITIES
Hypocalcemia
Symptomatic hypocalcemia should be treated with calcium
at the lowest doses required to relieve symptoms.
Frequent monitoring of serum phosphate and calcium
(every 4–6 hours)
MANAGEMENT-
ELECTROLYTE
ABNORMALITIES
Hyperphosphatemia
Eliminate exogenous phosphate intake
Hyperhydration
Phosphate binder therapy: Aluminum hydroxide
25mg/kg/dose 4x daily
Renal replacement therapy
MANAGEMENT- RENAL
REPLACEMENT THERAPY
Indications for renal replacement therapy in patients with TLS include:
Severe oliguria or anuria
Intractable fluid overload
Persistent hyperkalemia
Hyperphosphatemia-induced symptomatic hypocalcemia
A calcium-phosphate product ≥70 mg2/dL2
CONCLUSION/TAKE HOME
MESSAGE
TLS is a life-threatening oncological and metabolic
emergency characterized by a classic tetrad of hyperuricemia,
hyperkalemia, hyperphosphatemia, and hypocalcemia
There is a need to have a high index of suspicion for TLS,
closely monitor and manage aggressively to reduce morbidity
and mortality of children with cancer.
We need to assess cancer patients risk for TLS and prevent it
There is a need for a multidisciplinary approach(paediatric oncologist,
nephrologist, intensivist)
CASE PRESENTATION
A 5 year old previously well boy presents to PEU with a
3 week history of easy fatigue and dizziness and a 2
week history of bone pain in both lower limbs. Mother also
noticed his palms and soles are whiter than previously.
His vitals are normal apart from a heart rate of 130 bpm
On physical examination, he is very pale, with petechiae seen on his
upper limbs and abdomen. He has hepatosplenomegaly.
Weight-15 kg, height- 100 cm
CASE PRESENTATION
FBC done: Urea, creatinine, calcium
WBC-120 x 10^9 magnesium and phosphate are
Hb-4.8 g/dl normal
Plt-23
Uric acid- 8.2 mg/dl (2.5-5.5) Blood film comment from
LDH- 600 IU/L (155-280) periphery:
lymphoblasts of 30%
CASE PRESENTATION
What is the most likely diagnosis?
What are the risk factors for TLS?
Does the patient qualify for laboratory or clinical TLS?
How will you manage him in relation to TLS?
MCQS
1. In which of the following conditions is rasbirucase contraindicated?
a. Sickle cell anaemia
b. G6PD
c. Hepatitis B
d. Haemophilia
MCQS
2. How does rasburicase help in the treatment/prevention of TLS?
a. Recombinant Urate oxidase
b. Phosphate binder
c. Xanthine oxidase inhibitor
d. Prevents hyperkalemia
MCQS
3. Which of the following electrolytes is not involved in the
pathophysiology of TLS?
a. Calcium
b. Potassium
c. Sodium
d. Phosphate
MCQS
4. Which of the following is not a risk factor for tumour lysis syndrome?
a. Dehydration
b. Nephrotoxic drugs
c. High tumor cell proliferation rate
d. Pretreatment hypouricemia
MCQS
5. Which of the following is not part of clinical TLS?
a. AKI
b. Jaundice
c. Seizures
d. Cardiac arrythmias
MCQS
6. Which of the following cancers is least likely to be associated with
TLS?
a. Burkitts’s lymphoma
b. ALL
c. Large B cell lymphoma
d. Osteosarcoma
MCQS
7. The following electrolyte abnormality is not part of the
pathogenesis of TLS?
a. Hypocalcemia
b. Hypophosphatemia
c. Hyperkalemia
d. Hyperuricemia
MCQS
8. Which of the following electrolyte abnormalities cause arrythmias in
TLS?
a. Hypokalemia and hypocalcemia
b. Hyperkalemia and hypocalcemia
c. Hypocalcemia and hypophosphatemia
d. Hypercalcemia and hyperkalemia
TRUE OR FALSE QUESTIONS
1. Hypocalcemia should always be treated in TLS: T/F
2. When using Rasburicase all blood samples sent for uric acid testing
must be placed on ice before sending to the laboratory: T/F
3. Allopurinol prevents the formation of new uric acid whereas
rasburicase breaks down uric acid: T/F
REFERENCES
Tumour
lysis syndrome, Medscape: https://emedicine.medscape.com/article/282171-
overview#a4
https://starship.org.nz/guidelines/tumour-lysis-syndrome/
https://www.uptodate.com/contents/tumor-lysis-syndrome-pathogenesis-clinic
al-manifestations-definition-etiology-and-risk-factors?search=tumor%20lysis%
20syndrome&source=search_result&selectedTitle=2~150&usage_type=defaul
t&display_rank=2
https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.13403
https://www.uptodate.com/contents/tumor-lysis-syndrome-prevention-and-tre
atment?search=tumor%20lysis%20syndrome&topicRef=1154&source=see_lin
k#H21712107
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426989/
ACKNOWLEDGEMENT
Dr Yaa Gyamfua Oppong-Mensah
Dr Barbara Sekyere
Dr Vivian Paintsil
THANK YOU
