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 [4-6].
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. [7-13] The risk factors for TLS could be due to patient-related 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].
Table 1
Cairo-Bishop criteria for tumor lysis syndrome
| Laboratory criteria | (≥2 of the following): Uric acid ≥ 476 μmol/mL (8 mg/dL) or 25% increase from baseline; Phosphorus ≥ 1.45 mmol/L (4.5 mg/dL) or 25% increase from baseline; Potassium ≥ 6.0 mmol/L (6 mEq/L) or 25% increase from baseline; Calcium ≤ 1·75 mmol/L or 25% decrease from baseline |
| Clinical criteria | Any of following with laboratory criteria: Creatinine ≥ 1.5 upper limit of normal. Cardiac arrhythmia or sudden death. Seizures. |
TLS is a potentially fatal condition in patients with solid tumors and is associated with worse outcomes if it occurs spontaneously [16], It has a poor prognosis, especially if it is not diagnosed early; therefore, awareness, recognition, prevention, and early intervention are warranted to prevent the fatal consequences of TLS.
In this paper, we present a systematic review of the reported cases of TLS in patients with solid tumors that developed spontaneously or as adverse effects of anti-cancer treatments such as chemotherapy, immunotherapy, targeted therapy, and hormonal therapy. By describing the occurrence of TLS in patients with solid tumors, we primarily aim to identify potentially unrecognized or unusual clinical findings and outcomes. Also, determine the most common clinical manifestations, time to TLS, number of doses administered before TLS, treatment dosage used, presenting symptoms, and laboratory abnormalities. We also reported the management and clinical outcomes to identify patterns that could facilitate early diagnosis and management of this potentially fatal condition.
Review
Materials and methods
Search Method
Digital databases were used including PubMed, EMBASE, and Cochrane from 1983 to July 1, 2020, for case reports and case series of TLS in patients with solid tumors. In addition, abstracts and presentations from relevant conference proceedings, including the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) have been used.
Study Selection and Eligibility criteria
Two independent reviewers (ZA and HT) initially screened the abstracts and titles. Then, two other reviewers (AA and RA) assessed the full texts of the retrieved articles and resolved disagreements in conjunction with a third reviewer (HT). The eligibility criteria were as follows: case reports published in English, describing adults with solid tumors, and reporting spontaneous TLS or TLS that developed after anti-cancer treatments such as chemotherapy, targeted therapy, hormonal therapy, immunotherapy, or radiotherapy. We excluded studies involving hematological tumors, pediatric patients, and non-case reports/series. Keywords for the literature search included published case reports, case series, TLS, solid tumors, and anti-cancer treatment. The search strategy is provided in Appendix 1.
Data Extraction
This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [19]. A protocol was created in advance, and data extraction for reported cases of spontaneous TLS or TLS that developed as an adverse effect of anti-cancer treatment was performed independently by two reviewers (ZA and AA), with disagreements resolved by a third reviewer (RA).
We extracted data on patient characteristics (first author, year of publication, age, sex, type of cancer), risk factors (metastasis, elevated pre-treatment LDH level, bulky tumor, and pre-existing renal compromise), and comorbidities. The anti-cancer treatments administered in the cases included chemotherapy, immunotherapy, targeted therapy, hormonal therapy, and radiotherapy. The most common clinical parameters were time to TLS (1-2 days, ≥3 days, spontaneous), number of doses administered before TLS (1 dose, 2-3 doses, >3 doses, spontaneous), dosage of treatment used (full or reduced dose), presenting symptoms, and laboratory abnormalities (uric acid, phosphorus, potassium, calcium, creatinine, urea, and LDH levels). Lastly, we collected information regarding management and clinical outcomes, use of anti-TLS measures, location of treatment received (ward or ICU), and outcome (dead or alive).
Quality Assessment
We assessed the quality of each study by using the criteria recommended by the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance [20]. Two independent reviewers (HT and RA) assessed the quality of the included studies across the following domains: (i) relevance of the title for TLS, (ii) adequate description of clinical characteristics (demographics, medical 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.
Results
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.
Figure 1
PRISMA flowchart of our study selection
PRISMA: preferred reporting items for systematic reviews and meta-analysis; TLS: tumor lysis syndrome
Quality Appraisal
The quality of the included studies was moderate to high since all included studies had relevant titles, 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 one-quarter 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%).
Patient Characteristics
The median age was 58 years (Interquartile range (IQR) 19-94 years) and the proportion of males was 62% (n = 83). The most common tumors were hepatocellular carcinomas (17%, n = 22), lung cancer (13%, n = 17), melanoma (10%, n = 13), breast cancer (10%, n = 13), prostate cancer (8%, n = 10), and colon cancer (8%, n = 11). The risk factors were metastatic disease in 75% of the patients (n = 100), elevated pre-treatment LDH level in 26% (n = 35), and bulky tumors in 25% (n = 33). The main comorbidities were hypertension, hepatitis B, and diabetes mellitus in 11%, 8%, and 6% of patients, respectively (Table 2).
Table 2
Characteristics of patients in the reported cases
HCC: hepatocellular carcinoma; LDH: lactate dehydrogenase; HTN: hypertension; DM: diabetes mellitus; COPD: chronic obstructive pulmonary disease; CKD: chronic kidney disease
A Other tumors included choriocarcinoma, osteosarcoma, oligodendroglioma, neuroendocrine tumors, Merkel cell carcinoma, vulvar tumor, gastrointestinal stromal tumors, pheochromocytoma, thymoma, and retroperitoneal soft tissue sarcoma.
B Other comorbidities included congestive heart failure, cirrhosis, and arthritis
| Patient characteristics | N (%) |
| Median age | 58, (range 19-94) years |
| Sex | |
| Male | 83 (62%) |
| Female | 49 (37%) |
| Cancers | |
| HCC | 22 (17%) |
| Lung cancer | 17 (13%) |
| Melanoma | 13 (10%) |
| Breast cancer | 13 (10%) |
| Colon cancer | 11 (8%) |
| Prostatic cancer | 10 (8%) |
| Renal cell carcinoma | 6 (5%) |
| Gastric cancer | 6 (5%) |
| Ovarian cancer | 5 (4%) |
| Uterine cancer | 5 (4%) |
| Germ cell tumors | 3 (2%) |
| Othera | 21 (16%) |
| Risk factors | |
| Metastasis | 100 (75%) |
| Elevated pre-treatment LDH | 35 (26%) |
| Bulky tumor | 33 (25%) |
| Large tumor burden | 14 (11%) |
| Pre-existing renal compromise | 2 (2%) |
| NA | 21 (16%) |
| Main Comorbidities | |
| HTN | 14 (11%) |
| Hepatitis B | 10 (8%) |
| DM | 8 (6%) |
| Dyslipidemia | 4 (3%) |
| COPD | 3 (2%) |
| CKD | 3 (2%) |
| Coronary artery disease | 3 (2%) |
| Otherb | 6 (5%) |
| NA | 94 (71%) |
Anti-Cancer Treatment Characteristics
The most common anticancer treatments that induced TLS were chemotherapy (48%; n = 64), targeted therapy (8%; n = 11), and radiotherapy (7%; n = 9). Details of the classes and names are displayed in Table 3.
Table 3
Characteristics of the anti-cancer treatments
Her2: human epidermal growth factor receptor 2; eGFR: epidermal growth factor receptor; VEGF: vascular endothelial growth factor; CTLA4: cytotoxic T-lymphocyte-associated protein 4; ER: estrogen receptor; PR: progesterone receptor.
Due to the use of combination therapies such as chemo-targeted, immune-targeted, and chemo-radiation, some variables may not add up to 100%.
A Others included corticosteroid, eribulin, immunomodulatory therapy (thalidomide), bone-modifying agent (zoledronic acid), and surgery.
| Anti-cancer therapy | N (%) |
| Chemotherapy o Alkylating agents (cisplatin, cyclophosphamide, carboplatin, dacarbazine, oxaliplatin, ifosfamide) o Plant alkaloids (paclitaxel, vincristine, docetaxel, vinblastine, hydroxcamptothecin) o Antimetabolites (fluorouracil, gemcitabine, capecitabine, methotrexate) o Anthracyclines (doxorubicin, epirubicin, adriamycin, mitoxantrone) o Topoisomerase inhibitors (etoposide, irinotecan) o Antibiotics (bleomycin, actinomycin, mitomycin) | 64 (48%) |
| Targeted therapy o Kinase inhibitor (pazopanib, sorafenib, sunitinib, imatinib) o Anti-Her2 (trastuzumab, pertuzumab) o Anti-EGFR (cetuximab) o Anti-VEGF (bevacizumab) | 11 (8%) |
| o Radiotherapy o Radiofrequency ablation | 9 (7%) |
| Immunotherapy o Interleukin-2 o Anti CTLA4 (Ipilimumab) o Autologous lymphocyte therapy | 4 (3%) |
| Hormonal therapy o Anti ER/PR receptors (letrozole) o Anti-androgens (bicalutamide) o Antiestrogen (tamoxifen) o Combined androgen blockade (goserelin acetate) | 3 (2%) |
| OthersA | 7 (5%) |
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).
Table 4
Clinical manifestations of TLS in patients with solid tumors
TLS: tumor lysis syndrome; GI: gastrointestinal; CNS: central nervous system; GU: genitourinary; NA: not available
| TLS manifestation | N (%) |
| Spontaneous | 32 (24%) |
| Treatment-induced | 100 (76%) |
| Number of doses before TLS | |
| 1 | 23 (17%) |
| 2-3 or more | 5 (4%) |
| NA | 72 (55%) |
| Time to TLS development | |
| Spontaneous | 32 (24%) |
| 1-2 days | 37 (28%) |
| ≥3 days | 49 (37%) |
| NA | 13 (10%) |
| Dose of anti-cancer treatment | |
| Spontaneous | 32 (24%) |
| Full-dose | 68 (52%) |
| Dose reduction | 3 (2%) |
| NA | 29 (22%) |
| Presenting symptoms | |
| GI symptoms | 44 (33%) |
| GU symptoms | 44 (33%) |
| CNS symptoms | 34 (26%) |
| Respiratory symptoms | 25 (19%) |
| Constitutional symptoms | 15 (11%) |
| Others | 13 (10%) |
| Cardiovascular Symptoms | 11 (8%) |
| NA | 20 (15%) |
| Presenting laboratory findings | |
| Elevated uric acid | 125 (95%) |
| Elevated creatinine | 112 (85%) |
| Elevated phosphate | 110 (83%) |
| Elevated LDH | 95 (72%) |
| Elevated potassium | 95 (72%) |
| Low calcium | 79 (60%) |
| Elevated urea | 68 (52%) |
Management and Clinical Outcomes
Treatment of TLS was mainly based on hydration (58%; n = 77), allopurinol administration (49%; n = 65), and dialysis (30%; n = 40). However, rasburicase use was reported in 24% of patients (n = 32). The majority (77%, n = 101) of the patients were treated in the ward, while 16% (n = 21) were treated in the ICU. More than half (54%, n = 71) of the patients who developed TLS died, and 45% (n = 59) survived (Table 5).
Table 5
Management and clinical outcomes in reported cases
IVF: intravenous fluid; NA: not available; ICU: intensive care unit; ED: emergency department
| Management | N (%) |
| IVF | 77 (58%) |
| Allopurinol | 65 (49%) |
| Dialysis | 40 (30%) |
| Diuretics | 34 (26%) |
| Rasburicase | 32 (24%) |
| Mechanical ventilation | 10 (8%) |
| Urate oxidase | 2 (2%) |
| NA | 16 (12%) |
| Location | |
| Ward | 101 (77%) |
| ICU | 21 (16%) |
| ED | 10 (8%) |
| Outcomes | |
| Dead | 71 (54%) |
| Alive | 59 (45%) |
| NA | 2 (2%) |
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 [27-30].
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.
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