An Unusual Presentation of Tumor Lysis Syndrome in a Patient with Advanced Gastric Adenocarcinoma: Case Report and Literature Review

Tumor lysis syndrome (TLS) is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia in patients with a malignancy. When these laboratory abnormalities develop rapidly, clinical complications such as cardiac arrhythmias, acute renal failure, seizures, or death may occur. TLS is caused by rapid release of intracellular contents by dying tumor cells, a condition that is expected to be common in hematologic malignancies. However, TLS rarely occurs with solid tumors, and here we present the second chemotherapy-induced TLS in a patient with advanced gastric adenocarcinoma to be reported in the literature. We also provide information regarding the total cases of TLS in solid tumors reported from 1977 to present day. Our methodology involved identifying key articles from existing reviews of the literature and then using search terms from these citations in MEDLINE to find additional publications. We relied on a literature review published in 2003 by Baeksgaard et al., where they gathered all total 45 cases reported from 1977 to 2003. Then, we looked for new reported cases from 2004 to present day. All reports (case reports, brief reports, letters to editor, correspondence, reviews, journals, and short communications) identified through these searches were reviewed and included.


Introduction
Tumor lysis syndrome is a life-threatening oncologic emergency that occurs when a large amount of malignant tumor cells breakdown rapidly and release their intracellular contents into the systemic circulation causing electrolyte and metabolic disturbances, such as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Renal insufficiency, cardiac arrhythmias, seizures, and death due to multiorgan failure may be the final consequences of these biochemical derangements [1][2][3][4][5][6][7][8].
To the best of our knowledge, the present study case is the second report describing TLS following chemotherapy for advanced gastric adenocarcinoma [37]. Also, a review of the literature regarding TLS in solid tumors is presented and recommendations for management are discussed.

Case Report
The patient is a 57-year-old Hispanic man with a history of stage III moderately differentiated gastric adenocarcinoma intestinal type, diagnosed in late 2006      Five months later, recurrence of the primary tumor was found in the liver; therefore, the patient was started on a different regimen (paclitaxel 120 mg/m 2 , floxuridine 150 mg/kg, leucovorin 500 mg/m 2 , and cisplatin 100 mg/ m 2 ), and liver segmentectomy was performed.
Unfortunately, patient failed regular controls, and by 2011 a CT of the chest and abdomen revealed extensive metastatic liver nodules which ranged from 3.5 cm to subcentimeter in size, and metastasis to the sternum were also found. Consequently, he was again included in the initial experimental chemotherapy regimen as a first line therapy for his metastatic disease (oxaliplatin, docetaxel, floxuridine, and leucovorin).
Seven days after receiving the first chemotherapy cycle, he developed nausea, vomiting, oliguria, generalized weakness, and was referred to the emergency department by his oncologist due to abnormal laboratory data ( Table 2).
On arrival the patient was alert and appeared in poor general condition, pale, volume depleted with low blood pressure (102/63 mmHg), tachycardia (102/min), respiratory rate of 20/min, and body temperature of 36.6 • C. A firm, nontender, 2 cm below the costal margin of the right midclavicular line hepatomegaly was appreciated. There was no peripheral lymphadenopathy, and laboratory findings are shown on Table 2.
Urinalysis determined urine pH of 5.0 (4.5-7.5). The chest radiograph appeared to be normal. An EKG demonstrated atrial fibrillation with rapid ventricular response, left anterior fascicular block, and peaked T waves ( Figure 3). A renal ultrasound examination revealed an increased bilateral cortical echogenicity but no evidence of hydronephrosis. A diagnosis of chemotherapy-induced TLS with acute renal failure was made. The patient was given vigorous volume expansion, intravenous sodium bicarbonate, calcium gluconate, insulin given together with 50% dextrose, and allopurinol. His laboratory data did not improve and hemodialysis was started. The patient underwent a total of 6 hemodialysis over a course of two weeks and was discharged 18 days after with normal serum electrolyte and metabolic parameters. However, his renal function continued to be impaired with a serum creatinine of 3.86 mg/dL, blood urea nitrogen of 23 mg/dL, and eGFR of 16.
Irrespective of the cancer type, there is a 20-50% increase in mortality for undiagnosed or late-diagnosed TLS cases in solid tumors [8]. This high mortality rate may be due to the fact that in solid tumors, contrary to what is observed in hematological malignancies, TLS is usually evident after a few days within treatment when the patient may have already left the hospital [3,8]. Another cause is that in hematological malignancies, prophylactic measures are more often implemented, and awareness of the syndrome is higher. The fatality rate of the 100 cases presenting TLS in solid tumors was found to be 41%.
The fact that urine is acidic facilitates uric acid to precipitate, thus excessive overproduction and over excretion could accumulate uric acid in the form of crystal precipitation in the renal tubules, leading to obstructive uropathy with acute kidney injury [1,2,4,5,8,65]. Uric acid or calcium phosphate accumulation does not always imply urinary tract symptoms; however, flank pain due to renal pelvic or ureteral stone formation may occur [1,4]. The urinalysis quite often discloses a number of uric acid crystals, amorphous urates, calcium phosphate crystals, and/or hematuria [1,4].
The treatment principles for TLS are prevention, early diagnosis, and proper management of disorders [3]. In 2008, an international expert panel published evidencebased guidelines, for the prevention and treatment of TLS depending on the malignancy risk category. According to this evidence-based guidelines unless tumor and/or hostrelated risk factors are associated, solid tumors are considered low risk (<1%) for developing TLS. Thus, adequate recommendations for the prevention and management of TLS in solid tumors are accurate hydration prior to therapy and a "watch and wait" approach with close monitoring on looking for the first biologic derangements characterizing TLS (hyperuricemia, hyperphosphatemia, hypocalcemia, increased creatinine level) without any form of prophylactic hypouricemic therapy or phosphate binders [1-3, 6, 37].
Once TLS is established, the standard therapy strategy for treating TLS is based on volume expansion, decreasing the metabolic abnormalities, and in most cases providing supportive treatment of renal failure [1,5,8].
Maintaining urine pH above 7 with the aid of acetazolamide and/or sodium bicarbonate for the prevention and/or treatment of TLS may reduce the precipitation of uric acid crystals but at the same time may decrease the solubility of calcium phosphate or xanthine, and in the setting of acute renal failure, metabolic alkalosis may be an unintended consequence [1,3,4,6,7]. Consequently, the use of sodium bicarbonate should be restricted to those patients with severe metabolic acidosis [1].
Hyperkalemia may be an acute life-threatening emergency in patients with TLS. In case of hyperkalemia, cardiac membrane stabilization with 10% calcium gluconate may not be effective in the setting of severe hyperphosphatemia, and given an increased risk of calcium phosphate tissue precipitation, calcium administration is only appropriate for symptomatic hypocalcemia (arrhythmia, hypotension, tetany, or muscle cramps) [1,7]. Consequently, measures to reduce serum potassium or enhance potassium excretion should have priority. These include primarily insulin and beta-2 agonists to shift potassium into cells and volume expansion and loop diuretics to enhance potassium elimination. Sodium bicarbonate may be used as a slow continuous infusion in the face of severe acidosis. Exchange resins may be administered but should not be relied upon in the setting of acute hyperkalemia due to their unpredictable efficacy. For patients with renal failure, dialysis should be initiated as soon as possible [1][2][3][4][5][6][7]. For hyperphosphatemia, phosphate binders and/or hypertonic dextrose with insulin may be used [1][2][3][4][5][6][7].
Allopurinol is a competitive inhibitor of xanthine oxidase (Figure 4), and it has been successfully prescribed for the treatment of hyperuricemia. Allopurinol is metabolized to oxypurinol, which in turn inhibits xanthine oxidase; therefore, it blocks the metabolic process of xanthine and hypoxanthine to uric acid, leading to an increase in the  levels of these two metabolites [1,[3][4][5][6]. As a result, patients with massive TLS who have been prescribed allopurinol may develop xanthine precipitation leading to acute renal failure [1,2,4,5,7,65]. This can be avoided by replacing allopurinol with urate oxidase, which catabolizes uric acid to the more soluble compound allantoin [1][2][3][4][5][6] (Figure 4). Urate oxidase is an enzyme that can be found in many mammals except humans [1,3,4,6]. The two available commercial forms of urate oxidase are a nonrecombinant form (uricozyme) and a recombinant form (rasburicase), which is the preferred one. Rasburicase has been shown to be more effective than allopurinol, since it has higher uricolytic effect [1, 3-7], it does not increase xanthine levels [1,2,4,5,7], and it reduces high uric acid levels prior treatment initiation [1][2][3][4][5][6][7]. In some patients, despite prophylactic and therapeutic measures, acute renal failure ensues, and its management includes careful monitoring of fluid intake and output, electrolyte balance, hypertension control [4], and renal dialysis [94]. Indications for renal replacement therapy include volume overload with pulmonary edema or hypertension that is refractory to therapy, low urine output (oliguria), persistent or symptomatic hyperkalemia, hyperphosphatemia, hypocalcemia, and/or hyperuricemia despite conservative measures, metabolic acidosis with pH less than 7.2 or bicarbonate less than 10 mEq/l, rapidly rising blood urea nitrogen greater than 150 mg/dL, and neurologic symptoms secondary to uremia or electrolyte imbalance [4,95]. From the above-mentioned criteria, oliguria and other biochemical disturbances related to TLS have become more frequent indications for dialysis than hyperuricemia since the introduction of rasburicase [2,94]. Both hemodialysis and hemofiltration are affective, while peritoneal dialysis is not [94,96]. Dialysis should be continued until proper renal function is reestablished.

Discussion
Our patient with metastatic gastric adenocarcinoma developed metabolic (hyperkalemia, hyperuricemia, hyperphosphatemia, and hypocalcemia) and clinical (cardiac arrhythmia and acute renal failure) derangements 7 days after instituting chemotherapy, meeting CTLS diagnostic criteria. According to previous reports, there are 2 patients with advanced gastric adenocarcinomas who developed TLS documented in the literature (34,35), although only one occurred after chemotherapy [37] (Table 5). Therefore, our case would be the second gastric adenocarcinoma chemotherapy-induced TLS but the first to be reported after the use of the experimental chemotherapeutic regimen consisting on oxaliplatin, leucovorin, floxuridine, and docetaxel.
Chemotherapy-related nephrotoxicity was less likely due to the fact that the anticancer agents the patient was receiving are not considered to be nephrotoxic, except for oxaliplatin and docetaxel which have less than a 1% probability of causing renal failure, and it usually occurs with high doses and after repeated exposures.
Large tumor burden, multiple metastases to liver and bone, the use of combination chemotherapy drugs, pretreatment elevated LDH, and dehydration were the risk factors that placed the patient in a high-risk group for developing TLS [1][2][3][4][5][6][7][8], although his renal function and uric acid levels were normal before getting anticancer treatment.
The purpose for giving sodium bicarbonate to the patient was to correct the metabolic acidosis, rather than alkalinizing urine. Despite intensive medical treatment, the patient developed refractory electrolyte imbalances, metabolic acidosis, uremia, and oliguria. Thus, hemodialysis was performed with an improvement of the mentioned abnormalities, and the TLS was resolved. However, his renal function never returned to baseline, which has been linked to increased morbidity and mortality.
Even though solid tumors with high sensitivty to therapy are considered to be at high risk for developing TLS, we noticed that the syndrome was also present in tumor types considered as relatively insensitive to therapy such as melanoma, sarcoma, hepatocellular carcinoma, vulvar carcinoma, non-small cell lung cancer, and gastric cancer. According to our observations, the predominant risk factors to induce TLS in solid tumors are large tumor burden and liver metastases, rather than tumor sensitivity to therapy agents.
Liver metastases in solid tumors were found in most TLS cases, regardless whether patients had liver function abnormalities or not [3]. Apparently, liver involvement creates a risk for the development of TLS in solid malignancies, possible causes being high purine pools, increased tumor burden, and/or impaired uric acid metabolism [3].

Conclusion
Even though TLS in solid tumors is a rare condition, physicians should be aware of it, especially in therapy-sensitive large burden tumors with metastatic disease, increased pretreatment LDH, renal impairment, hyperuricemia, and hyperphosphatemia, all of which are here documented to be mayor risk factors for the development of TLS.
If there is a possibility to develop TLS, the metabolic abnormalities should always be corrected before starting an anticancer regimen, since prevention is the best way to reduce its high morbidity and mortality.
In conclusion, TLS in solid tumors requires special attention for its prevention, early diagnosis, and management due to its poor clinical course. Physicians should be alert since improvement in the anticancer treatment may increase the incidence of TLS in solid tumors.