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Tumor Lysis Syndrome in Patients With Solid Tumors: A Systematic Review of Reported Cases

Tumor lysis syndrome (TLS) in patients with solid tumors is a rare and potentially fatal condition associated with anti-cancer treatment. Its outcome depends on awareness, identification of high-risk patients, and implementation of appropriate preventive measures. A systematic review was conducted according to PRISMA guidelines of case reports describing the occurrence of TLS in patients with solid tumors, primarily to identify potentially unrecognized or unusual clinical findings and outcomes. We searched the PubMed, EMBASE, and Cochrane databases and conference abstracts and performed manual searches for case reports and case series published in English and describing patients who developed TLS. A total of 124 studies (118 case reports and six case series) describing the findings for 132 patients were included. The most common cancers were hepatocellular carcinoma (17%, n = 22), lung cancer (13%, n = 17), and melanoma (10%, n = 13). The most common risk factor was metastatic disease (75%, n = 100). TLS was induced by chemotherapy in 48% (n = 64) of the patients. Clinical manifestations of TLS developed within three days of anti-cancer treatment in 37% of the patients (n = 49), while 52% (n = 68) received the full dose of anti-cancer treatment. Gastrointestinal symptoms occurred in 33% of the patients (n = 44), hyperuricemia in 95% (n = 125), and elevated creatinine level occurred in 85% of the patients (n = 112), While 58% (n = 77) of the patients received intravenous fluids, only 49% received allopurinol, and 24% (n = 32) received rasburicase. A total of 101 patients (77%) were treated in the ward, and 54% (n = 71) died. The mortality rate associated with TLS in patients with solid tumors remains high. Adequate management requires awareness, early recognition, and identification of patients at high risk. Interdisciplinary team management is essential to reduce mortality.


Introduction And Background
Tumor lysis syndrome (TLS) is an oncological emergency that occurs secondary to the breakdown of intracellular components such as potassium, phosphorus, and nucleic acids [1]. The release of these products into the bloodstream leads to hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia, inducing severe complications such as acute renal failure, cardiac arrhythmia, heart failure, seizure, and ultimately death if the patient is not managed appropriately [2,3]. Although the rapid destruction of malignant cells occurs after exposure to anti-cancer treatments such as chemotherapy, radiotherapy, monoclonal antibody treatment, radiofrequency ablation (RFA), corticosteroid treatment, hormonal therapy, and surgery, it can also occur in the absence of anti-cancer treatments, especially if the tumor is bulky or rapidly proliferating. These cases are categorized as spontaneous TLS [4][5][6].
TLS is commonly observed in hematological malignancies such as Burkitt or non-Burkitt lymphoma and acute leukemia. However, since solid tumors have a relatively prolonged doubling time and slower growth rate, and the effect of therapy takes longer time than hematological malignancies, TLS is rarely observed in solid tumors. However, some cases of TLS have been reported in patients with small-cell lung cancer, breast cancer, medulloblastoma, melanoma, and sarcoma. [7][8][9][10][11][12][13] The risk factors for TLS could be due to patientrelated factors such as dehydration, chronic renal failure, elevated pretreatment lactate dehydrogenase (LDH) or uric acid levels, and azotemia or tumor-related factors such as bulkiness, rapid growth, or a tendency to spread to other organs, specifically the bone marrow [14]. TLS is an oncological emergency that needs to be recognized urgently, and if treated early, complications can be prevented, thereby improving the outcomes [15]. The Cairo-Bishop laboratory and clinical criteria are used to diagnose TLS ( Table 1) [16]. The presence of two or more laboratory abnormalities starting either three days before or seven days after treatment of the tumor can be used to define laboratory TLS. However, clinical TLS is characterized by the appearance of two laboratory abnormalities and one or more clinical symptoms [17,18]. history, physical examination, and outcomes (alive or dead)), (iii) adequate description of anti-cancer drugs (identification of the drug class, dosage, drug reaction, and concomitant therapy) and time to develop adverse events; (iv) adequate description of the adverse event (TLS); and (v) discussion section supporting the relationship between the anti-cancer drug and the reported adverse events (TLS). Each aspect was classified as yes, partial, or no. Any disagreements were resolved by a third reviewer. The results of the assessment are presented in Appendix 2.

Data Synthesis and Analysis
All data were analyzed using IBM SPSS Statistics for Windows, Version 25.0 (Released 2017; IBM Corp., Armonk, New York, United States). Descriptive statistics (mean, percentage, and standard deviation) were used to report continuous variables, and frequencies and percentages were used to present categorical variables.

Study Characteristics
In total, 238 citations were retrieved. After the removal of duplicates, we identified 172 relevant citations and reviewed the full publications. We excluded 17 studies since they were not case reports. We included 124 studies reporting on 132 patients as provided in Figure 1. The characteristics of the included studies are given in Appendix 3. adequate descriptions of patients' demographic data (96.7%), current health status (95.1%), medical history (87.9%), physical examination findings (97.5%), and disposition (98%). The anti-cancer drugs were identified for all reported cases of drug-induced TLS, but the drug dosage was not provided in approximately onequarter of the cases. The duration of drug administration, route, and first dose were reported (70.9%). Furthermore, concomitant therapy had no potential influence (94.3%). A description of the adverse event and severity was reported (92.7%), and an appropriate discussion supporting a causal link between the drug and the adverse events was provided (92.7%).

Anti-cancer therapy N (%)
Chemotherapy  Due to the use of combination therapies such as chemo-targeted, immune-targeted, and chemo-radiation, some variables may not add up to 100%.

Clinical Manifestations of TLS in Patients with Solid Tumors
TLS occurred spontaneously in 24% (n = 32) of the cases and was treatment-induced in the remaining 76% (n = 100). The number of doses before TLS development was variable, with 17% of the cases showing TLS occurrence after the first dose (n = 23). Time to TLS development was within 3 days of anti-cancer treatment in 37% (n = 49) of the cases, while 52% (n = 68) of the patients received a full dose of anti-cancer treatment. The most commonly reported symptoms were gastrointestinal, genitourinary, and central nervous system symptoms in 33%, 33%, and 26%, respectively. The most reported laboratory abnormalities were hyperuricemia in 95% of the cases (n = 125), followed by elevated creatinine levels in 85% (n = 112) and hyperphosphatemia in 83% (n = 110) of the cases ( Table 4).

Discussion
Our results showed that males aged 58 years are at higher risk for TLS, which is similar to the findings reported by Mirrakhimov et al. [21]. However, we also observed that hepatocellular carcinoma and lung cancer were the most common cancers, in contrast to the findings reported by Mirrakhimov et al. [21]. This is because our review is more up-to-date and the incidence of TLS in solid tumors is increasing due to advancements in novel anti-cancer treatments [22]. Our review demonstrated that metastatic cancer was a major risk factor for TLS, which is similar to the findings reported by Jallad et al. [23] and Vodopivec et al. [24]. Lastly, chemotherapy was the most common anti-cancer treatment attributed to TLS (48%), as reported by Vodopivec et al. (58%) [24].
To the best of our knowledge, this is the first report to address the manifestations of TLS in solid tumors. TLS occurred spontaneously in 24% of the patients and was induced by the treatment in the remaining 76%. Time to TLS development was ≥3 days following anti-cancer treatment, and 52% of the patients received the full dose of anti-cancer treatment. Additionally, the most commonly reported symptoms were gastrointestinal and genitourinary symptoms in 33% of the patients. The most reported laboratory abnormalities were hyperuricemia (95%), followed by elevated creatinine level (85%), as reported by Vodopivec et al. [24].
In patients with solid tumors who had risk factors for TLS development, large amounts of fluids and allopurinol should be administered before the start of treatment [25]. Once the patient is diagnosed with TLS, treatment should be started using massive amounts of fluids and xanthine oxidase inhibitors such as rasburicase [26]. Our systematic review demonstrated that 58% of patients received intravenous fluids, 49% received allopurinol, and only 24% received rasburicase. These findings illustrate the need for continuous education programs and awareness campaigns to enhance the knowledge of physicians to identify patients at risk and start anti-TLS treatment early and effectively. Moreover, 77% of the patients were treated in the ward, not in the ICU setting. Surprisingly, we found that the mortality rate was 54%, and this is the first report describing the mortality rate associated with TLS in patients with solid tumors. Previous reports evaluating TLS in patients with hematological malignancies described mortality rates ranging from 20% to 30%, with the highest reported rate of 79% in AML patients [27][28][29][30].
Our systematic review has several strengths, including the fact that it is the largest and most comprehensive systematic review of case reports describing TLS in patients with solid tumors, manifestations of TLS following anti-cancer treatment, and the most common symptoms. However, our study also has several limitations: an important caveat for interpreting our study findings is the nature of case reports, since authors report unique cases and the findings may not account for unpublished reports of TLS. One inherent weakness of this study is the limited availability of data in case reports. Another important limitation is that the reporting of the drug dosage, number of doses, and schedule was incomplete in several case reports, and we were unable to determine whether the number of doses influenced the incidence of TLS.
We believe that the management of TLS should focus on risk assessment, prophylaxis, and treatment [31]. Aggressive hydration with oral and intravenous fluids should be initiated before the start of anti-cancer treatment, and oral hydration and adequate urine output should be maintained for several days after the completion of the treatment [32]. Urate-lowering agents, such as allopurinol or rasburicase, are recommended for prophylaxis and management of TLS [26]. Febuxostat is also a urate-lowering agent that can provide better control of hyperuricemia in TLS with a good safety profile if allopurinol is contraindicated or not available.
The findings show that TLS is a lethal condition, and early identification with prompt initiation of preventative measures is essential to save patient lives. Although the data indicated modest prognostic benefits, early initiation of anti-TLS measures will improve oncological outcomes. Care of patients with TLS requires an interdisciplinary approach including nephrologists, intensivists, oncologists, and internists in closed observation units, such as intermediate care or ICUs [33,34].

Conclusions
In this systematic review, we found that older men had a higher tendency to develop TLS. Hepatocellular carcinoma was the most common type of cancer leading to TLS development, followed by lung cancer and melanoma. Metastatic cancer was a contributing risk factor for TLS development. Chemotherapy was the most common class of anti-cancer treatment that induced TLS. Manifestations of TLS developed within ≥3 days following anti-cancer treatment, and half of the patients received the full dose of anti-cancer treatment. Gastrointestinal and genitourinary symptoms were the most commonly reported, and almost all patients showed high uric acid and elevated creatinine levels.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.