Rasburicase in treating tumor lysis syndrome: An umbrella review

Tumor lysis syndrome (TLS) remains a debilitating cause of hospitalization and death in patients with cancer and is a significant challenge for healthcare providers despite advancements in its management. This umbrella review analyzed the results of meta-analyses on the use of rasburicase in the treatment of patients with cancer. A literature search was performed of five databases (PubMed, Google Scholar, Cochrane Library, Scopus, Global Index Medicus, and ScienceDirect) for articles with full texts available online. A measurement tool to assess systematic reviews 2 (AMSTAR 2) was used to assess the quality of the included studies, and Review Manager software was used to conduct all statistical analyses. The systematic search identified eight relevant meta-analyses, with primary analyses including outcome data that analyzed mortality, renal failure, and comparisons with allopurinol. The pooled data showed that rasburicase effectively reduced TLS development and serum uric acid levels in children and adults with malignancies. Most outcomes did not differ significantly compared with those of allopurinol. Future trials should focus on the cost-effectiveness of rasburicase compared to that of allopurinol while including high-, intermediate-, and low-risk patients. Rasburicase is safe and effective for managing patients with TLS. However, recent large-scale meta-analyses have reported conflicting results. Most meta-analyses were graded as low to critically low as per AMSTAR 2. The analysis revealed that the benefit of rasburicase did not differ significantly from that of allopurinol, which has higher cost-effectiveness and fewer side effects.


Introduction
Tumor lysis syndrome (TLS) is the most common hematologic cancer emergency and is equally prevalent in children and adults. 1,2TLS was initially identified in patients with acute leukemia and non-Hodgkin's lymphoma; however, since then, it has become more prevalent and is associated with several other types of cancer. 3,4TLS occurs when tumor cells burst, leading to the release of large amounts of phosphate, potassium, and uric acid into the circulation. 5everal factors can trigger TLS, including acute lymphoblastic leukemia and high-grade lymphomas.TLS can occur in patients receiving cytotoxic therapy during the course of the disease. 6Other factors include a high proliferative rate and sensitivity to cytotoxic therapy, which make the tumor more likely to burst, leading to TLS. 6 Signs of at-risk patients are bulky malignancies; increased serum phosphorus, uric acid, and potassium levels; proliferating tumors; and large tumor surface area after therapy. 7,8dditionally, the latest treatment options for chronic lymphocytic leukemia, such as oral kinase inhibitors and venetoclax, B-cell lymphoma-2 protein inhibitors, ibrutinib, and idelalisib, can also lead to TLS because of the extreme sensitivity of such treatment and enhanced tumor growth. 9he diagnosis of TLS requires two laboratory tests and one clinical criterion.Laboratory TLS (LTLS) is often characterized by one of three conditions.In the first condition, uric acid levels are normal, and potassium and phosphate levels are 25% above the baseline level.The second condition is characterized by normal uric acid levels and potassium and phosphate levels that exceed the upper limit of the normal levels.In the third condition, uric acid levels are increased by 25% from baseline or exceed the upper normal limit, along with increased phosphate or potassium levels.Combined with these laboratory findings, several clinical criteria are often present due to the deposition of toxic metabolites in the blood and the underlying electrolyte imbalance.One of the clinical criteria is an increased creatinine level !1.5 times the upper normal limit, usually manifesting as anuria or oliguria.Cardiac arrhythmia or sudden death resulting from hyperkalemia is also common. 10,11][13][14][15][16][17][18][19][20][21] The prophylactic management of TLS in high-risk patients includes treatments to reduce uric acid production (using allopurinol), uric acid removal through enzymatic action (using rasburicase), and vigorous hydration. 11Additionally, external administration of phosphorus and potassium is avoided.Close monitoring is required during prophylactic management to detect and treat any metabolic abnormalities before they start causing symptoms.
The current treatment options for TLS and uric acid management are allopurinol and rasburicase.Allopurinol inhibits the enzymatic activity of xanthine oxidase, thereby preventing uric acid formation and reducing urinary and serum uric acid levels. 22Rasburicase, obtained from modified Aspergillus flavus and is usually expressed in Saccharomyces cerevisiae, 23 is a urate oxidase that converts uric acid to a non-pathological and 10 times more soluble allantoin, thus reducing serum uric acid levels. 22The conversion of uric acid to allantoin via the enzymatic action of rasburicase leads to the production of carbon dioxide and hydrogen peroxide. 24llopurinol decreases uric acid production during TLS but has no significant effect on the current uric acid levels.In contrast, rasburicase not only reduces the current uric acid levels but also decreases the risk of tumor lysis. 22Therefore, rasburicase is used for the initial management of TLS and uric acid levels in high-risk patients (children and adults) with solid tumors, leukemia, and lymphoma. 23he overall half-life of rasburicase is 18 h, depending on the dosing regimen.For instance, the half-life of a 0.15 mg/kg dose regimen is 16 h, while that of a 0.2 mg/kg dose regimen is 21 h.Observation after 1 d of treatment indicated no rasburicase deposition. 23,25Rasburicase is degraded in the body through peptide hydrolysis; thus, its clearance from the body is independent of hepatic and renal functions (usually impaired during TLS). 26he recommended dose of rasburicase is 0.15 mg/kg/day or 0.2 mg/ kg/day for children and 0.2 mg/kg/day for adults.The course should be 5 days, and medication beyond 5 days is usually not recommended.The first dose of rasburicase should be administered 4-24 h before initiating chemotherapy/radiotherapy, and it is administered intravenously for 30 min. 23In contrast to weight-based rasburicase dosage, a single-dose regimen is recommended.The literature has established that a single dose of 7.5 mg/day is the most efficacious in minimizing the risk of laboratory and clinical TLS. 274][15][16][17][18][19][20][21] However, the area lacks a review that evaluates information and the quality of overarching evidence provided by the systematic reviews on this topic.Hence, this umbrella review aimed to synthesize the results of systematic reviews exploring the efficacy of rasburicase in TLS development.The primary outcomes analyzed were TLS development and uric acid levels, while the secondary outcomes were adverse events, AKI, creatinine levels, mortality, and economic outcomes.

Search strategy
Electronic databases (PubMed, Google Scholar, Cochrane Library, Scopus, Global Index Medicus, and ScienceDirect) were searched from their earliest dates until February 2023.Database-specific subject headings were also used, which were mapped onto the search terms (listed below).These online literature searches were supplemented by checking for any additional potentially eligible papers cited by the included articles and the reference lists of the relevant reviews.The keywords and combinations used in the search were as follows: PubMed: ("tumour lysis syndrome"[All Fields] OR "tumor lysis syndrome"[MeSH Terms] OR ("tumor"[All Fields] AND "lysis"[All Fields] AND "syndrome"[All Fields]) OR "tumor lysis syndrome"[All Fields]) AND ("rasburicase"[Supplementary Concept] OR "rasburicase"[All Fields] OR ("urate oxidase"[MeSH Terms] OR ("urate"[All Fields] AND "oxidase"[All Fields]) OR "urate oxidase"[All Fields])) AND ("systematic review"[Publication Type] OR "systematic reviews as topic"[MeSH Terms] OR "systematic review"[All Fields] OR ("review"[Publication Type] OR "review literature as topic"[MeSH Terms] OR "review"[All Fields]) OR ("meta analysis"[Publication Type] OR "meta analysis as topic"[MeSH Terms] OR "meta analysis"[All Fields])).
The advanced search function was used in Google Scholar as follows: Search for articles containing all the words: Rasburicase Tumor Lysis Syndrome Return the articles authored by [left].Published in Journal: [Left blank].Where my words occur: in the title of the article.
Data were screened in two steps.First, two independent reviewers (K.M. and A.G.) screened titles and abstracts based on the inclusion and exclusion criteria.Articles were retained in cases of uncertainty.Second, the full-text articles were screened.The titles/abstracts and full texts were parallelly screened at both stages.Discrepancies were resolved through discussions and intervention by a third person (H.S.).

Inclusion and exclusion criteria
Both published and gray literature were included.Studies were included if they met the population, intervention, comparator, or outcome (PICO) criteria as follows: (1) population: adults and children with malignancies; (2) intervention: rasburicase; (3) comparator: allopurinol or any other control group; and (4) outcomes: TLS development and serum uric acid level (secondary outcomes: AKI, mortality, adverse events, renal replacement therapy [RRT], and economic outcomes).Studies were excluded if they were individual studies, case reports, conference proceedings, editorials, letters, commentaries, non-English articles, or if the full text was unavailable.

Risk of bias
A risk of bias assessment of the included reviews was conducted using a measurement tool to assess systematic reviews 2 (AMSTAR 2). 28,29MSTAR 2 is a critical appraisal tool for systematic reviews and meta-analyses that includes randomized controlled trials (RCTs), non-randomized studies, or both to assess healthcare interventions.The tool consists of 16 review questions, review methodology (inclusion/exclusion criteria, search strategy, and article screening), risk of bias assessment, quantitative synthesis in the review, and ethical concerns.The questions were answered as yes, no, or partial."Yes" responses were scored as 1, and the responses were categorized based on the method described by the Canadian Agency for Drugs and Technologies in Health (CADTH). 28AMSTAR 2 uses a critical appraisal approach with four overall confidence categories: high, moderate, low, and critically low. 29

Data extraction
Quantitative information was extracted independently by at least two reviewers (D.G. and V.V.) using a data extraction spreadsheet.Data related to the database and period of search for the review, sample characteristics of the included studies, study characteristics, interventions, outcomes, and results were extracted.Any disagreements were resolved after discussion among team members.The authors were contacted to provide additional information when data were missing or unclear.The primary outcomes were TLS development and serum uric acid levels.

Data analysis
The inverse variance method was used to pool the data.A metaanalysis was performed using Review Manager v5.4 (RevMan) software.Effect sizes are expressed as the log of the odds ratio (OR) with a 95% confidence interval (CI).This method assigned more weight to studies with smaller standard errors (or greater precision) and less weight to those with larger standard errors (or less precision).In the context of our review, studies with larger sample sizes and lower variability in their outcomes were considered more precise; hence, they contributed more to the pooled estimates.By taking the logarithm of the OR, the data were transformed to a scale more amenable to statistical analysis.This calculation rendered the data more symmetrically distributed and suitable for meta-analyses.We then back-transformed the pooled estimate to obtain the overall OR by calculating the exponential (anti-log) of the pooled log OR.In this inverse variance methodology, the overall estimate was influenced more by studies with smaller variances (greater precision) than by those with larger variances (lower precision).

Results
The process of searching databases and screening results is illustrated in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) flowchart.Nine studies were included in the umbrella review [Figure 1].Table 1 depicts the study characteristics of the included metaanalyses.

Risk of bias assessment
The risk of bias of the included studies was assessed using the AMSTAR 2 tool, followed by qualitative and quantitative syntheses.
Except for four studies, most of the reviews defined their review questions according to the PICO format, defined the method before conducting the review, explained the study design for the review, selected studies, extracted data based on the agreement of two reviewers, and conducted risk of bias assessments. 33,34,36,37The search strategy was not reported appropriately in one review. 37Only one review provided a list of excluded studies, the impact of RoB on quantitative and qualitative synthesis, and publication bias. 38None of the included reviews reported the funding sources for the included studies.Three reviews discussed study heterogeneity, 31,33,38, and the source of conflict was declared in five of the included reviews. 32,33,35,37,39 To evaluate the quality of the evidence, the AMSTAR 2 scores were evaluated as confidence categories, including high, moderate, low, and critically low [Table 3].
The search strategy for including reviews was conducted from inception to December 2021.The databases were PubMed, EMBASE, MEDLINE, Web of Science, ClinicalTrails.gov,Scopus, Google Scholar, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and the Cochrane Central Register of Controlled Trials (CENTRAL).Five of the nine included reviews assessed the risk of bias of the included studies.Of these five reviews, four used the Cochrane Collaboration's Risk of Bias Assessment tool, while one used the Newcastle-Ottawa scale (NOS).
The total sample size of the included reviews was 3331 for both the intervention and control groups.Four reviews did not mention the total sample size of the included studies. 33,36,37,39The sample size for one of the studies (n ¼ 807) by Bose et al. 36 was calculated manually from the included studies, resulting in a combined sample size of the umbrella review of 4138.Only two reviews mentioned the population (children or adults), 33,39 while another review mentioned neither population nor sample size, as no meta-analysis was conducted. 39Three reviews included both children and adults as samples, 32,33,39 whereas the other reviews were conducted on adult patients.
Regarding the intervention, four of the nine included reviews explored the efficacy of a single dose of rasburicase for TLS outcomes, 33,36,37,39 while two reviews compared the efficacy of a single dose vs. a weight-based dose of rasburicase in terms of TLS outcomes. 32,34The single doses of rasburicase were 1.5, 3, 4.5, 6, and 7.5 mg per day, while the weight-based doses were 0.05 and 0.15 mg/kg.Three reviews compared the efficacy of rasburicase with allopurinol 31,34,38 in reducing TLS outcomes, and one review explored the efficacy of urate oxidase, including rasburicase, with intravenous hydration using crystalloid solutions and sodium bicarbonate on TLS outcomes. 35his review examined a wide variety of TLS outcomes.The outcomes included TLS development (26 studies), white blood cell counts (one study), lactate dehydrogenase level (two studies), disease prognosis (16 studies), adverse events (39 studies), AKI (25 studies), mortality (four studies), mortality due to TLS (four studies), serum uric acid level (91 studies), creatinine levels (14 studies), the incidence of RRT (24 studies), admission or length of stay in the intensive care unit (ICU) (two studies), tolerability (two studies), and dose reduction (12 studies).

TLS development
The results of RCTs on the development of TLS are contradictory.Two reviews reported that rasburicase, as compared to allopurinol, has a significant effect on the development of TLS among patients (risk ratio [RR] ¼ 0.74, 95% CI ¼ 0.17-3.22; 35OR ¼ 4.06, 95% CI ¼ 3.11-5.28), 39hile two reviews reported no difference in the incidence of TLS (RR ¼ 0.74, 95% CI ¼ 0.17-3.20; 31RR ¼ 0.77, 95% CI ¼ 0.44-1.33). 38he meta-analysis exploring the difference in the efficacy between rasburicase and allopurinol excluded a study by Feng et al. 34 because of the low certainty of the evidence.The results of the meta-analysis of the meta-analyses indicated no significant difference in efficacy between rasburicase and allopurinol in TLS development (RR ¼ 0.98, 95% CI ¼ 0.74-1.31,p > 0.05) [Figure 2].
According to observational studies, 7.40% (95% CI ¼ 1.70-16.70%) of patients experienced TLS even after rasburicase administration; 31 however, a 7.5 mg/day dose of rasburicase was the most effective in reducing the incidence of TLS among patients (98.6%, 95% CI ¼ 0.90-1.01). 32However, other studies reported no difference in the efficacy of single and daily doses of rasburicase against TLS development; 34 nevertheless, the quality of evidence was low.The combined effect size (RR) for the observational study was 0.07 (95% CI ¼ 0.02-0.25). 31The meta-analysis of the meta-analyses also  established the efficacy of rasburicase against TLS development; however, the effect was not significant (RR ¼ 0.76, 95% CI ¼ 0.20-2.87,p > 0.05) [Figure 3].The efficacy of single-dose rasburicase over that of allopurinol in reducing the risk for laboratory and clinical TLS was established in retrospective and prospective studies (OR ¼ 3.83, 95% CI ¼ 2.17-6.76), 33,34,36but the quality of evidence was not robust.The response rate for rasburicase reported in retrospective and prospective studies (effect ratio [ER]) was 0.87 (95% CI ¼ 0.82-0.93). 32

Uric acid levels
RCTs and clinical controlled trials indicated that rasburicase had a significant main effect on reducing and maintaining serum uric acid levels compared to the effects of allopurinol (mean difference [MD] ¼ À569 mg/dL, 95% CI ¼ [À796.38,À341.62]mg/dL 35 32 The combined estimated effects of the observational studies were RR ¼ 0.93 (95% CI ¼ 0.92-0.95) 31 and ER ¼ 7.0 (95% CI ¼ 5.84-8.17). 32Meta-analyses also reported that while rasburicase reduced serum uric acid levels compared to those of the control group, the change was not significant (RR ¼ 2.55, 95% CI ¼ 0.35-18.41,p ¼ 0.35) [Figure 4].The results of prospective and retrospective studies indicated that rasburicase significantly controlled serum uric acid levels compared to that observed with allopurinol; 33,36 the quality of the evidence was significantly low.Moreover, a daily dose of rasburicase resulted in a greater reduction of uric acid levels than that with a single dose of rasburicase. 36

Economic outcomes
The results of the included reviews established the cost-effectiveness of rasburicase, as it reduced the administration frequency and duration of ICU stay. 33Moreover, they established that single-dose rasburicase is the most cost-effective drug for treating TLS. 33,34However, whether rasburicase is economically superior to allopurinol remains unknown.

Discussion
This umbrella review synthesized the literature on the efficacy of rasburicase against TLS development and in reducing uric acid levels.The results indicated that although rasburicase reduced the risk of TLS development, rasburicase did not differ significantly from the control (including allopurinol) in reducing the risk of TLS development.The included reviews also reported that rasburicase significantly reduced serum uric acid levels; however, the reduction in serum uric acid did not differ significantly between rasburicase and allopurinol.Similarly, rasburicase did not reduce the mortality rate, adverse events, or RRT incidence.
Rasburicase reduces serum uric acid levels but does not significantly affect TLS development. 40Limited literature is available on the efficacy of rasburicase in preventing TLS among low-risk patients; however, the absence of an advantage of rasburicase in reducing renal failure among high-risk patients raises skepticism about its potential efficacy among low-risk patients.Some of the results align with previous literature by showing the 7.5 mg/day dose to be the most efficacious in reducing TLS outcomes, 27 but others contradict the literature by indicating that rasburicase does not reduce the number of inpatient days. 41iforatos et al. 42 analyzed a previously conducted head-to-head RCT to identify the differences in serum uric acid reduction by rasburicase, rasburicase plus allopurinol, and allopurinol alone.The results indicated significant reductions in serum uric acid levels in all three arms but no change in other outcomes, including TLS development, increased creatinine levels, AKI, and renal failure.A similar finding was reported by Martens et al. 43 in their retrospective analysis, which showed no difference in TLS development, AKI, RRT, or creatinine levels between patients receiving rasburicase and allopurinol.Although rasburicase has been associated with greater serum uric acid reduction than was allopurinol, according to meaningful RCTs 38 described earlier, this efficacy of rasburicase does not translate into clinically meaningful risk reduction.The literature further suggests that rasburicase does not prevent renal injury or mortalities. 44asburicase is an expensive medicine, costing $37,500.Most studies on the efficacy of rasburicase usually include high-risk patients in their sample, resulting in an overestimation of the cost-effectiveness of rasburicase among patients who are at low to intermediate risk of developing TLS. 45,46Its highly established efficacy makes physicians more prone to inappropriately prescribe rasburicase to patients at low to intermediate risks of developing TLS.The inappropriate use of rasburicase ranges from 32% to 70% and includes prescriptions in cases of   hyperuricemia without evidence of high-risk TLS, no trials of allopurinol, and no renal failure. 45,46Additionally, several side effects are associated with using rasburicase, with 1% of patients experiencing rasburicase-induced anaphylaxis and 20-50% experiencing viral syndrome-like and gastrointestinal symptoms. 47The side effects of rasburicase also include pruritus, nausea, gout, maculopapular rash, and renal failure, which occur in 1-10% of patients.
Our review highlights the need for future research focusing on the cost-effectiveness of rasburicase compared with that of allopurinol, which is less expensive and has fewer side effects.This information can help inform clinical decision-making by considering the relative costs and benefits of each medication and can potentially lead to more efficient and cost-effective use of healthcare resources.Our recommendation is to stratify patients based on risk in future large-scale trials, which can also help ensure that the findings are generalizable to a broader population of patients with malignancies.
This review may be subject to publication bias, which may skew the results.The meta-analyses included in this umbrella review may have used different study designs, populations, and outcome measures, which may have limited the ability to draw meaningful conclusions across studies.Moreover, the included meta-analyses may have used different methods of data extraction, analysis, and synthesis, which may have affected the quality and validity of the results.Additionally, the quality and reporting of individual studies included in the meta-analyses may have been inconsistent, which could have affected the accuracy of the findings.Some of the included meta-analyses had limited sample sizes, which may have affected the statistical power and precision of the results.The review was limited to studies published in English, and relevant studies from non-English language sources were excluded.Finally, the included meta-analyses may have been subject to funding bias, where the funding source could influence the study design, conduct, or reporting.

Conclusion
The analysis of the evidence and associated literature demonstrated that rasburicase is effective in reducing TLS development and serum uric acid levels in children and adults with malignancies; however, its effect does not differ significantly from that of allopurinol, which has greater cost-effectiveness and fewer side effects.Future trials should focus more on the cost-effectiveness of rasburicase compared to that of allopurinol and include high-, intermediate-, and low-risk patients.

Figure 1 .
Figure 1.PRISMA flow chart of the study. 30PRISMA: Preferred reporting items for systematic reviews and meta-analyses; TLS: Tumor lysis syndrome.

Figure 2 .
Figure 2. Efficacy of rasburicase vs. allopurinol to prevent the development of TLS.CI: Confidence interval; df: Degrees of freedom; IV: Inverse variance; SE: Standard error; TLS: Tumor lysis syndrome.
Table 2 illustrates the quality appraisal using AMSTAR 2.

Table 1
Study characteristics of the included systematic reviews.

Table 2
AMSTAR 2 quality appraisal for all studies.Not applicable; PICO: Population, intervention, comparator, outcome; RoB: Risk of bias.