Tumor Lysis Syndrome: Narrative Review of Risk Stratification and Management

The quick death of cancer cells causes tumor lysis syndrome (TLS), a life-threatening oncologic emergency that results in the release of intracellular components like potassium. nucleic acids and phosphate into the systemic circulation. Hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia are all produced by this cascade, and if they are not identified and treated right away, they can lead to arrhythmias, seizures, acute kidney injury, and even death. This review synthesizes data from PubMed, Embase, Web of Science, and the Cochrane Library, concentrating on clinical studies, randomized trials, retrospective analyses, and meta-analyses that were published between 2000 and 2025. According to research, the risk of TLS depends on the kind of tumor, the patient's profile, and the course of therapy. Rasburicase has consistently demonstrated superiority over allopurinol among pharmacological treatments for quickly lowering uric acid in adults and children, particularly in those at high risk. Febuxostat has proven non-inferior to allopurinol, making it a viable option when allopurinol is contraindicated. Cost-effective approaches, such as singledose rasburicase protocols, have become popular in resource-constrained environments. Rasburicase is the preferred treatment for high-risk instances, while allopurinol and febuxostat are still suitable for patients with low-to intermediate risk. Ultimately, accurate risk stratification, early intervention, And increasing the availability of successful treatments is still essential for lowering the incidence and death associated with TLS.

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Tumor Lysis Syndrome: Narrative Review of Risk
Stratification and Management

Venkatesh
1
, Shivani Venkatesh
2
, Oshina Ugrani Manoj Kumar
2
, Meghana Narayana
2
,
Abhilash Gollarahalli Hanumanthappa
3
, Sheba Baby John*
2
, Maniraj
3
,
Charan Chabbanahalli Somashekhar
2
, Hanumanthachar Joshi
4

1
Department of Pharmaceutics, Sarada Vilas College of Pharmacy, Mysuru.
2
Department of Pharmacy Practice, Sarada Vilas College of Pharmacy, Mysuru.
3
Bharath hospital and institute of oncology, Mysuru.
4
Department of Pharmacognosy, Sarada Vilas College of Pharmacy, Mysuru.
[email protected], [email protected], [email protected]

Abstract:
The quick death of cancer cells causes tumor lysis syndrome (TLS), a life-threatening oncologic emergency
that results in the release of intracellular components like potassium. nucleic acids and phosphate into the
systemic circulation. Hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia are all produced
by this cascade, and if they are not identified and treated right away, they can lead to arrhythmias, seizures,
acute kidney injury, and even death. This review synthesizes data from PubMed, Embase, Web of Science,
and the Cochrane Library, concentrating on clinical studies, randomized trials, retrospective analyses, and
meta-analyses that were published between 2000 and 2025. According to research, the risk of TLS depends
on the kind of tumor, the patient's profile, and the course of therapy. Rasburicase has consistently
demonstrated superiority over allopurinol among pharmacological treatments for quickly lowering uric acid
in adults and children, particularly in those at high risk. Febuxostat has proven non-inferior to allopurinol,
making it a viable option when allopurinol is contraindicated. Cost-effective approaches, such as single-
dose rasburicase protocols, have become popular in resource-constrained environments. Rasburicase is the
preferred treatment for high-risk instances, while allopurinol and febuxostat are still suitable for patients
with low-to intermediate risk. Ultimately, accurate risk stratification, early intervention, And increasing the
availability of successful treatments is still essential for lowering the incidence and death associated with
TLS.

Keywords: Tumor Lysis Syndrome, Risk Stratification, Rasburicase, Allopurinol, Febuxostat, Prophylaxis,
Acute Kidney Injury


1. Introduction
Tumor lysis syndrome (TLS) is a fatal oncological
emergency caused by the fast destruction of
cancer cells either naturally or more usually after
the Initiation of cytotoxic therapy. The great
release of intracellular contents like as potassium,
phosphate, and nucleic acids overpowers normal
homeostatic processes and sets off a cascade
including hyperkalemia, hyperphosphatemia,
secondary hypocalcemia, and hyperuricemiaThese
metabolic anomalies can cause acute kidney
injury, cardiac arrhythmias, seizures, and sudden
death unrecognized or improperly treated (2)
Though TLS was first reported in highly
proliferative hematologic malignancies, notably
Burkitt lymphoma and acute lymphoblastic
leukemia (ALL), its scope has grown to
encompass solid tumors, especially those with
high tumor load and chemosensitivity like small-
cell lung cancer and hepatocellular carcinoma (3).
The growing frequency of TLS in solid tumors is
explained by the more intense chemotherapy
regimens and focused medicines, which could
cause rapid tumor cytoreduction.
The Cairo–Bishop criteria (2004) divided TLS
diagnosis: laboratory TLS, characterized by
biochemical evidence of uric acid, potassium,

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phosphate, and calcium abnormalities; and
clinical TLS, which combines lab TLS with
symptoms including renal failure, convulsions, or
cardiac arrhythmias (3). Enabling more consistent
recognition and reporting of TLS, this
categorization has come to be used in clinical
studies as well as in clinical practice.
TLS still has a lot of morbidity and mortality even
with improvements in supportive care. Its clinical
effects go beyond the initial emergency since it
might postpone or change anti-cancer treatment,
therefore jeopardizing long-term results (1). Early
identification, precise risk Effective TLS
management depends on stratification and suitable
prophylaxis; these two pillars of this approach
remain fundamental. Over the last two decades,
especially rasburicase, new pharmacological
compounds have been created with shown
superiority over allopurinol in high-risk patients
and febuxostat. In moderate-risk situations, one
possible substitute for allopurinol has surfaced.
This study seeks to present a comprehensive
synthesis of first clinical findings published
between 2000 and 2025 with a focus on risk.
Models for stratification, preventative measures,
and the relative efficacy of pharmacological
therapies in TLS include data from adult and
pediatric populations, hematological and solid
tumors, by highlighting current best practices, this
review aims to identify research topics for the
future.

2. Methodology
2.1 Study Design
The study was conducted as a sequential narrative
review focused only on original clinical research.
The review aimed to analyse evidence regarding
the risk stratification, prevention and treatment of
tumour lysis syndrome (TLS) from the original
clinical trial data, notably urate-lowering therapies
rasburicase, allopurinol and febuxostat.

2.2 Literature-search strategy
The literature was searched for publications in
PubMed/MEDLINE entries, Embase, Web of
Science, and the Cochrane Library published
between January 2000 and May 2025. The search
terms included Medical Subject Heads (MeSH)
and free-text terms: “tumour lysis
syndrome”,”TLS”,”risk
stratification”,”management”,”prevention”,”rasbu
ricase”,”allopurinol” and “febuxostat.” By using
Boolean operators (AND, OR), and filters,
combinations limited to human studies, English
language, and the defined date searches were
used.

2.3 Inclusion Criteria
Studies were acceptable as long as they met the
following criteria:
1. Original clinical research studies reporting on
forward or backward cohorts, random controls, or
meta-analyses based on actual data sets.
2. Diagnosed with tumour lysis syndrome or
could be diagnosed with tumour lysis syndrome,
adults or children with established metastatic or
haematological malignancies.
3. Included outcomes related to renal outcomes
(dialysis, acute kidney injury), survival, clinical
incidence of TLS, biological results (calcium,
potassium, phosphate, uric acid), or health
careoutput

2.4 Exclusion Criteria
The following studies were left out:
1. Articles like case reports, case series, editorials,
and expert opinions that don't contain primary
data.
2. Work published in languages other than
English.
3. Pre-2000 studies are still relevant to oncology
today.
4. Preclinical or animal studies.

2.5 Study Selection and Data Extraction
Numerous citations were found in the first search,
these were filtered by abstract and title. Full texts
of studies that might be eligible were retrieved
after duplicates were eliminated. The most
thorough or recent study was included to resolve
overlapping datasets after articles were carefully
examined for eligibility.
A structured form was used to extract the data,
documenting:
• Patient characteristics and type of malignancy
• Study design and publication year
• Primary and secondary results (biochemical
correction, incidence of TLS, renal outcomes,
hospitalization, cost, and mortality)

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• Intervention (dosage and regimen of rasburicase,
allopurinol, or febuxostat) and Comparator

2.6 Data Synthesis
Considering the narrative character of this review,
results were thematically grouped and
summarized qualitatively rather than being
statistically combined:
1. TLS classification and pathophysiology
2. Methods of risk stratification
3. Preventative strategies and medical prophylaxis
4. Relative effectiveness of febuxostat,
allopurinol, and rasburicase
Fresh information and clinical problems
This systematic technique ensured the review
properly reflected the clinical efficacy of current
oncology practice as well as the realistic elements
including dose schedules of TLS management and
cost-effectiveness.

3. Results
3.1 Pathophysiology and Classification
The quick release of intracellular metabolites
from cancer cells causes TLS to arise.
Metabolized into uric acid, which is poorly
soluble and prone to crystalizing within renal
tubules, nucleic acids released into the
bloodstream cause acute kidney damage? At the
same time, phosphate release causes
hyperphosphatemia and subsequent calcium–
phosphate precipitation, which shows as
hypocalcemia, while potassium efflux from tumor
cells results in hyperkalemia, which can cause
fatal arrhythmias. The biochemical profile of TLS
(2) is produced by all of these derangements.
The Cairo–Bishop classification separates TLS
into laboratory TLS, defined by ≥25% change or
threshold abnormality in two or more biochemical
indicators, and clinical TLS, Complications
including renal failure, seizures, or cardiac
dysrhythmias accompany some lab changes (3).
For both clinical trials and bedside diagnosis, this
definition still serves as the base.

3.2 Risk Stratification
Proper risk stratification is essential for directing
proactive measures. Defining risk are three main
categories: tumor-specific, patient-specific, and
therapy-related components. Among high-risk
hematological malignancies are Burkitt
lymphoma, high leukocyte-count acute
lymphoblastic leukemia, and other fast-spreading
malignancies with great chemosensitivity. The
probability of TLS raises even more when patient
features include as dehydration, elevated lactate
dehydrogenase (LDH), and baseline renal
insufficiency. Treatment factors include the use of
corticosteroids, high-intensity chemotherapy, or
novel targeted therapies also influence risk.
These criteria help patients to be grouped into
low, moderate, or high risk categories. Low-risk
patients usually need observation and hydration;
intermediate-risk patients need hydration plus uric
acid–lowering treatment such allopurinol or
febuxostat; and high-risk patients call for
hydration plus rasburicase (2).(Table.1).
Table.1. Risk Stratification and Management of TLS
Risk
Category
Defining Features Prophylaxis /
Management
Preferred Drug
Low Risk Indolent tumors, low tumor
burden, normal renal function
Observation + IV
hydration
None /
Allopurinol (if
mild risk)
Intermediate
Risk
Moderate tumor burden, some
risk factors (↑LDH, borderline
renal function)
IV hydration + uric
acid–lowering agent
Allopurinol or
Febuxostat
High Risk Burkitt lymphoma, ALL with
high WBC, bulky chemosensitive
tumors, renal impairment
Aggressive IV
hydration + uric acid–
lowering agent
Rasburicase

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3.3 Pharmacological Management
Table.2. Comparative Pharmacological Profile of TLS Drugs


Drug Mechanism Onset of
Action
Strengths Limitations Best Use
Case
Allopurinol Xanthine
oxidase
inhibitor →
prevents new
uric acid
formation
Slow (24–
72 hrs)
Widely
available,
cheap
Cannot reduce
existing uric
acid, risk of
xanthine
accumulation
Low–
Intermediate
risk TLS
Rasburicase Recombinant
urate oxidase
→ converts
uric acid →
allantoin
Rapid (≤4
hrs)
Fast,
effective,
prevents
AKI,
reduces
hospital
stay
Expensive,
contraindicated
in G6PD
deficiency
High-risk
TLS (adult
& pediatric)
Febuxostat Non-purine
xanthine
oxidase
inhibitor
Intermediate
(12–24 hrs)
Non-
inferior to
allopurinol,
safe in
allopurinol
allergy
Limited data in
high-risk TLS,
costlier than
allopurinol
Alternative
in
Intermediate
risk or
Allopurinol
intolerance

3.3.1 Allopurinol
By preventing the formation of new uric acid,
xanthine oxidase inhibitor allopurinol inhibits
purine metabolism. It has long been the standard
agent for TLS prophylaxis in low- to
intermediate-risk patients. But its inability to
lower current uric acid and its possibility for
xanthine buildup restrict its utility in high-risk
situations (4).

3.3.2 Rasburicase
Directly metabolizing uric acid into allantoin,
which is five to ten times more soluble and easily
excreted, is rasburicase, a recombinant urate
oxidase enzyme. Its advantage over allopurinol
has been proven by several experiments. Cortes et
al. (2010) found in a major multicenter phase III
randomized trial that rasburicase provided uric
acid regulation in 87% of adult patients when
compared with at 66%, with allopurinol, with a
significantly faster onset of action (4 hours vs 27
hours)(1). Likewise, a demonstration of pediatric
RCT showed that rasburicase decreased uric acid
area under the curve more than twice as compared
to allopurinol, therefore lowering the risk of renal
problems (4).
Apart from efficiency, rasburicase showed
financial benefits. Compared to those receiving
allopurinol (5), patients treated with rasburicase
showed shorter ICU stays and lower total
hospitalization costs according Cairo et al. (2012).
Significantly, studies have proved that single
fixed-dose regimes save money as well as work
effectively. With repeat dosing necessary just in a
small proportion of cases (6), Vadhan-Raj et al.
(2009) verified that a single dose in the majority
of adults normalized uric acid levels. (Table.2).

3.3.3 Febuxostat
Alternative to allopurinol, Febuxostat, a non-
purine selective xanthine oxidase inhibitor, has
developed. FEBuxostat showed non-inferiority to

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allopurinol in stopping TLS among patients with
hematologic malignancies (7) in a phase III study
by Kuwabara et al. (2016). Retrospective
Including Ichida et al. (2014), studies further
verified similar decreases in uric acid levels with
no notable variance in TLS incidence (8). A meta-
analysis by 6 studies with 658 patients were
combined by Yan et al. (2019) to highlight the
non-inferiority of febuxostat to allopurinol,
making it a possible prophylactic choice
especially in patients intolerant of allopurinol (9).
(Fig.1).

Fig.1 Comparative effectiveness of TLS pharmacological agents

4. Discussion
4.1 Importance of Risk Stratification
Finding patients at highest risk is the basis of TLS
management. Because of their quick spread and
high chemosensitivity (2), patient-related factors
including preexisting renal impairment, high
lactate dehydrogenase (LDH), and dehydration
further elevate vulnerability (3). Treatment-related
issues include the use furthermore elevating the
risk profile are corticosteroids or intense multi-
agent chemotherapy. Consequently, directing
strong treatments like rasburicase toward high-
risk patients helps to guide prophylactic strategies
by stratifying into low, intermediate, and high-risk
groups. Reserving allopurinol or observation for
lower-risk groups helps doctors to avoid excessive
treatment while avoiding mortality in at-risk
patients.

4.2 Role of Supportive Care Measures
Still fundamentals of TLS prevention across all
risk groups are hydration and thorough
monitoring. Proper intravenous fluid management
improves renal perfusion and helps uric acid and
electrolytes to be excreted. Early detection of
electrolyte abnormalities is made possible by
regular laboratory monitoring, especially in high-
risk individuals, therefore preventing organ failure
(2). Though once advised, urine alkalinization's
advantages are debatable owing to the possible
risk of calcium–phosphate precipitation in renal
tubules. Most environments now favor hydration
without alkalinization.

4.3 Efficacy of Rasburicase
For high-risk individuals, rasburicase always
shows to be the most potent urate-lowering
medication. In a phase III randomized trial, Cortes
et al. (2010) showed that, as opposed with 66%
for allopurinol, rasburicase normalized uric acid
in 87% of adults having a median time to control
of just 4 hours (1). Pui et al. (2001) found a 2.6-
fold decrease in uric acid exposure in pediatric
populations with rasburicase compared to
allopurinol, hence lowering the frequency of
Beyond effectiveness, rasburicase also enhances

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healthcare outcomes; a retrospective study by
Cairo et al. (2012) showed shorter ICU stays and
lower hospital Costs in patients on rasburicase
versus those on allopurinol (5). Significantly more
cost-effective than conventional multi-day dosing,
single-dose rasburicase regimens are also
effective in most people, according to studies such
Vadhan-Raj et al. (2009) (6).

4.4 Limitations of Allopurinol
Although inexpensive and readily available,
allopurinol has a mechanism of action that limits
its utility. While it prevents the formation of new
uric acid by blocking the enzyme xanthine
oxidase, it does not lower any currently existing
uric acid levels. This delay in action is clinically
relevant, particularly in patients with substantial
elevations in uric acid levels, as they may, from
time to time, require urgent treatment to prevent
kidney damage (2). In addition, there is concern
that allopurinol may increase xanthine levels,
which itself may crystallize within renal tubules.
So while allopurinol is still appropriate for low-
and medium-risk patients, its potential usage to
treat high-risk situations cannot be compared to
rasburicase.

4.5 The Rising Role of Febuxostat
Febuxostat, especially beneficial in patients who
are allergic to or intolerant of allopurinol, is
gaining traction as an alternative xanthine oxidase
inhibitor. In a phase III randomized trial,
Kuwabara et al. (2016) demonstrated that
febuxostat was non-inferior to allopurinol with
respect to TLS prevention for patients with
hematological malignancies (7). Similarly, a
retrospective analysis by Ichida et al. (2014)
supported a similar reduction in uric acid levels
when comparing febuxostat and allopurinol with
no significant differences in TLS rate (8). A meta-
analysis of six studies by Yan et al. (2019) has
further corroborated that febuxostat is non-inferior
to allopurinol with a comparable safety profile
(9).Although febuxostat is improbable to replace
rasburicase in high-risk circumstances, it does
provide a useful choice for those with
intermediate-risk or if allopurinol is
contraindicated.


4.6 Clinical Issues and future directions
Despite new advances, many issues remain. It is
still often overlooked that reasons for delayed
detection and treatment of TLS in solid tumors
come from the unreasonable burden of the disease
state TLS also brings. Below are some of the
elements that lead to inadequate treatment too
many patients. Furthermore, even in patients with
high-risk factors, the expense of Rasburicase
limits treatment and it also excludes so many low-
and middle-income countries from access to it. In
addition to this problem, there are not yet
adequate prognostications to predict TLS to be
achieved a priori; the current stratifications are
based on clinical and laboratory parameters and
are not meeting the needs of recognizing TLS in
early stages Overly reliance on accepted
laboratory values contributes to missing subtle
early clues.
Future work should focus on accurate predictive
algorithms inclusive of molecular markers,
operationalizing affordable rasburicase dosing
protocols such as utilizing the fixed low-dose
regimen, and broader comparative Febuxostat
reviews at various demographic levels. Electronic
Monitoring combined with electronic health
records and decision-support systems could
enhance early detection/delivery of rapid
treatment to TLS.

5. Conclusion
Currently, TLS remains a serious issue in modern
oncology. Future action to lessen the associated
morbidity and mortality of TLS still depends too
much on the timely detection of TLS, proper risk
stratification, and acting in an appropriate
prophylactic manner. While febuxostat and
allopurinol are appropriate treatments in lower-
risk settings, rasburicase is the only drug that can
also effectively lower urate levels in patients at
highest risk for TLS. Future studies should work
to enhance the ability to accurately predict TLS,
validate biomarkers, and enhance access to
affordable rasburicase dosing guidelines
particularly in countries with shared low
socioeconomic healthcare.

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6. References
[1] J. Cortes, et al., “Control of plasma uric acid
in adults at risk for tumor lysis syndrome: efficacy
and safety of rasburicase alone and rasburicase
followed by allopurinol compared with
allopurinol alone—a multicenter phase III study,”
J. Clin. Oncol., vol. 28, no. 27, pp. 4207–4213,
2010.
[2] S. C. Howard, D. P. Jones, and C. H. Pui,
“The tumor lysis syndrome,” N. Engl. J. Med.,
vol. 364, no. 19, pp. 1844–1854, 2011.
[3] M. S. Cairo and M. Bishop, “Tumour lysis
syndrome: new therapeutic strategies and
classification,” Br. J. Haematol., vol. 127, no. 1,
pp. 3–11, 2004.
[4] C. H. Pui, et al., “Rasburicase versus
allopurinol in children with hyperuricemia and
malignancy: results of a randomized, controlled
trial,” Blood, vol. 97, no. 10, pp. 2998–3003,
2001.
[5] M. S. Cairo, et al., “Costs and outcomes
associated with rasburicase versus allopurinol in
patients with tumor lysis syndrome,” Blood, vol.
120, no. 21, p. 3175, 2012.
[6] S. Vadhan-Raj, et al., “Randomized clinical
trial of rasburicase: single dose versus daily
administration in adults at risk for tumor lysis
syndrome,” Blood, vol. 114, no. 22, p. 105, 2009.
[7] M. Kuwabara, et al., “Efficacy and safety of
febuxostat compared with allopurinol for the
prevention of tumor lysis syndrome in patients
with hematologic malignancies: a phase III,
randomized, multicenter trial,” Int. J. Hematol.,
vol. 103, no. 2, pp. 262–270, 2016.
[8] K. Ichida, et al., “Hypouricemic effect and
safety of febuxostat for prevention of tumor lysis
syndrome: a retrospective cohort study,” Int. J.
Hematol., vol. 100, no. 6, pp. 593–600, 2014.
[9] X. Yan, et al., “Febuxostat administration for
the prevention of tumor lysis syndrome: a meta-
analysis,” Hematol. Oncol., vol. 37, no. 2, pp.
132–140, 2019.