Successful treatment of tumor lysis syndrome associated with hepatic artery infusion chemotherapy in a patient with hepatocellular carcinoma: a case report

Abstract

Background

Tumor lysis syndrome is a life-threatening complication in the treatment of cancer. However, it rarely occurs in solid tumors, especially in hepatocellular carcinoma.

Case presentation

We present a 52-year-old male Asian patient with advanced hepatocellular carcinoma treated with hepatic artery infusion chemotherapy that resulted in tumor lysis syndrome. The patient developed symptoms of oliguria, seizure, hyperkalemia, hyperuricemia, hypocalcemia, hyperphosphatemia, and increased creatinine. He recovered from it after adequate hydration, correction of metabolic abnormalities, and renal replacement therapy.

Conclusions

This case highlights the importance of maintaining a high index of suspicion of TLS even in solid tumors such as hepatocellular carcinoma, especially with a large tumor burden. It also underscores the need for early intervention in suspected TLS for a successful outcome.

Background

Hepatocellular carcinoma (HCC) is a global health challenge with an estimated incidence of > 1 million cases by 2025 [1]. Many patients are diagnosed with advanced HCC and their prognosis is poor, especially those with extrahepatic metastasis whose median survival time is only 11.2 months [2]. Hepatic artery infusion chemotherapy (HAIC) has been found to be an effective treatment for advanced HCC, especially for those with portal vein tumor thrombus (PVTT). HAIC achieved better survival outcomes than sorafenib in advanced HCC, even in patients with a high intrahepatic disease burden [3]. In the current Pan-Asian adapted European Society for Medical Oncology Guidelines, HAIC is recommended as the first-line option for advanced, non-metastatic HCC with macrovascular invasion [4].

Tumor lysis syndrome (TLS) is a life-threatening catastrophe caused by massive tumor cell lysis with the release of large amounts of intracellular substances, such as potassium, phosphate, uric acid, etc. [5]. TLS most commonly occurred in hematologic malignancies such as non-Hodgkin’s lymphoma (NHL) but rarely occurs in patients with HCC [5]. The incidence of TLS in acute lymphocytic leukemia was 5.2–23%; however, TLS was very rare in the treatment of HCC [6]. Only several cases of transcatheter arterial chemoembolization (TACE) or tyrosine kinase inhibitors -associated TLS have been reported in the literature to date. As far as we know, no HAIC-associated TLS has been previously reported. Here, we present a case of TLS after HAIC therapy in advanced HCC.

Case presentation

A 52-year-old male Asian patient was admitted to our hospital to perform the third-cycle of HAIC treatment. He had a history of trauma with left kidney contusion, splenectomy, and left femoral neck fixation, and was diagnosed with HCC 2 months before admission. The abdominal magnetic resonance imaging (MRI) showed hepatic malignant tumors (MT) with intrahepatic metastasis and portal vein invasion (Fig. 1). The chest computed tomography (CT) showed multiple metastases in the lung. The alpha-fetoprotein (AFP) was > 60,500 ng/mL at the time of diagnosis. He has no family history of liver cancer or other illnesses. Before this admission, he received HAIC therapy twice (every 3 weeks) and fluorouracil and oxaliplatin-based chemotherapy was used as the infusion chemotherapy regimen. At the same time, the patient received lenvatinib 8 mg orally daily and sintilimab 200 mg intravenously every 3 weeks as combination therapy. The patient developed symptoms of high fever and abdominal pain during the previous two cycles of HAIC treatments, and the symptoms improved after symptomatic treatment. The follow-up abdominal MRI before admission indicated that the intrahepatic tumors improved compared with before, and the AFP level was > 60,500 ng/mL. He was categorized as Child Class A (Child–Pugh score = 5), so the third cycle of HAIC treatment was performed. During the surgery, intraoperative hepatic arteriography showed multiple tumor stains in the liver. Then a 4FRH catheter was super-selected to the right hepatic artery for chemotherapy perfusion. The chemotherapy regimen for hepatic artery infusion was oxaliplatin 150 mg d1, leucovorin 0.7 g day 1 (d1), fluorouracil 0.7 g d1, and fluorouracil 4.2 g continuous infusion venous‌ (civ) 44h d1. One day after HAIC, the patient felt severe pain in the abdomen and the symptom did not relieve after symptomatic treatment. So he performed abdomen CT which showed large necrotic lesions in the liver. As a result, the chemotherapy was not complete and the catheter was pulled out in advance. Two days after HAIC, the patient developed oliguria with elevations of laboratory investigations of aminotransferase, bilirubin, uric acid, creatinine, inflammatory markers, potassium level, and D-dimer. The physical examination revealed right upper abdominal pain and cold clammy limbs. At that time, his vital signs were within the normal range, with a blood pressure of 106/62 mmHg, a heart rate of 92 beats per minute (bpm), and a fingertip oxygen saturation of 98%. He was treated with measures including antibiotic therapy, supportive liver and kidney protection therapy, anticoagulation, and maintaining fluid balance and electrolyte acid–base balance. His treatment regimen included an antibiotic (meropenem), antioxidant (glutathione), aggressive hydration, urine alkalinization, diuresis, and anticoagulation (heparin). That night, the patient had a sudden seizure, characterized by limb convulsions accompanied by loss of consciousness. The seizure lasted about 20 minutes. After that, he recovered consciousness, but still exhibited symptoms of bradypsychia. The patient was subsequently admitted to the intensive care unit. The follow-up laboratory investigations showed improved liver function, but renal function continued to deteriorate, with hyperuricemia, hyperphosphatemia, and hypocalcemia (Table 1). TLS with acute kidney injury (AKI) was subsequently diagnosed, and it was classified to grade 4 according to the Cairo–Bishop classification proposed in 2004. With antibiotics, adequate hydration, diuresis, bedside hemodialysis (twice, 7 days and 9 days after HAIC, respectively), and correcting the electrolyte disorder (hyperkalemia, hyperphosphatemia, and hypocalcemia), the patient’s symptoms improved dramatically. Finally, he was discharged 17 days after HAIC without any other complications. At the time of discharge, the AFP level was 14,365 ng/mL. One month after discharge, the patient returned to hospital for a re-examination. The patient was in good condition with both the liver and kidney function returned to normal, but the abdominal MRI indicated tumor progression. A second-line treatment was advised, but due to economic reasons and concerns about intervention therapy, the patient refused. Then he continued the first-line systemic therapy of lenvatinib and sintilimab. He is currently undergoing regular follow-up.

Fig. 1.

Abdominal magnetic resonance imaging with enhancement performed about 3 days prior to this admission revealed multiple viable HCCs in both lobes of the liver and some lesions with necrosis

Table 1.

Laboratory data before and after HAIC

Laboratory investigation	Reference range	Baseline	After HAIC
			2d	5d	7d	9d	11d	14d	16d	37d
TBIL	3.4–10.4 μmol/L	10.5	21.1	28.4	24.4	25.5	25.6	22.5	20.2	38.7
ALT	9–50 U/L	38	332	71	22	7	5	6	6	20
AST	15–40 U/L	84	1392	179	43	24	20	29	29	87
Cr	44–115 μmol/L	89	347	576	766	605	455	310	211	91
UA	208–428 μmol/L	358	584	872	921	609	424	401	336	280
K	3.5–5.3 mmol/L	4.6	6.1	3.6	3.4	3.4	3.8	3.6	3.6	3.7
P	0.9–1.34 mmol/L	1.47	3.05	1.97	1.67	0.87	0.56	0.32	0.34	1.39
Ca	2.15–2.55 mmol/L	2.38	1.61	2.01	2.10	2.20	2.24	2.26	2.27	2.36

HAIC hepatic artery infusion chemotherapy, TBIL total bilirubin, ALT alanine aminotransferase, AST aspartate aminotransferase, Cr creatinine, UA uric acid, K potassium, P phosphorus, Ca calcium

Discussion

TLS is a constellation of metabolic abnormalities due to a burst release of intracellular metabolites when massive lysis of tumor cells occurs, causing a significant amount of damage to the systemic circulation of the human body [5]. It is accompanied by significant metabolic derangements, including hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia [7]. The metabolic abnormalities can lead to cardiac arrhythmias, seizures, and subsequently death [5]. TLS is a life-threatening oncologic emergency that could rapidly cause acute  AKI resulting from uric acid and calcium phosphate deposition in the kidneys. The overall in-hospital mortality of TLS was 21% and the most common complication was AKI with a rate of 58% [8]. Risk factors involved in TLS include huge tumors, highly proliferating tumors, and tumors that are highly sensitive to cytotoxic therapy [7].

TLS rarely occurs in patients that have solid tumors, especially HCC [9]. However, the mortality rate is much higher compared with that occurring in hematologic malignancies [10]. To our knowledge, only individual cases reported on TLS in patients with HCC [11, 12]. Recently, a systematic review summarized published case reports of TLS in patients with HCC and found that the two most common attributed factors of TLS were TACE and sorafenib [10]. Combination therapy of nivolumab and sorafenib-induced TLS [13] or lenvatinib-induced TLS [14] have also been reported. However, HAIC-induced TLS has been rarely reported.

The mechanism of TLS following TACE in patients with HCC is mainly due to cell necrosis caused by vascular embolism. TLS after sorafenib or lenvatinib may happen as a result of interruption of the replication and angiogenesis of tumor cells without direct cytotoxic effects [10]. Although the exact mechanism of TLS following HAIC is unknown, we suggest that high sensitivity to cytotoxic therapy may be a predisposing factor for TLS in HCC following HAIC. HAIC is a therapy that directly delivers chemotherapeutic agents into tumor-associated arterial branches at increased local drug concentrations [3]. Because of a greater first pass in the liver, HAIC provides stronger antitumor efficacy than systemic therapy [15]. In some cases, when the tumors are highly sensitive to chemotherapeutic agents, a large amount of cell necrosis occurs and TLS happens. In the present case, the patient was highly sensitive to chemotherapeutic agents, for that the abdominal CT performed after HAIC showed large necrotic lesions in the liver and the AFP level decreased dramatically from more than 60,500 ng/mL at admission to 14,365 ng/mL at discharge. What is more, the atrophy of one kidney caused by renal contusion is partly responsible.

TLS is classified as either laboratory or clinical. The laboratory criteria and clinical criteria for TLS are shown in Table 2 [16]. It is vital to differentiate TLS from other diseases that may cause similar symptoms, such as sepsis, obstructive renal disease, medication toxicities, use of contrast dye for imaging, and rhabdomyolysis. Although these diseases may exhibit similar symptoms, accurate differential diagnosis can be made through detailed medical examination and medical history inquiry. According to the Cairo-Bishop classification proposed in 2004 [16], the present case can be classified as clinical and laboratory TLS. The diagnosis of TLS was delayed in this case and it was misdiagnosed as an infectious shock because of abdominal pain, elevated inflammatory markers, and oliguria. Fortunately, TLS was diagnosed on the second day after HAIC and he recovered after supportive treatment. TLS in HCC usually presents with different symptoms, such as dyspnea, abdominal pain, symptoms related to electrolyte imbalance (for example, tetany, seizure, and arrhythmia), and oliguria [10, 17, 18]. Because of the diverse symptoms at onset, many patients are easily misdiagnosed. But with the change in laboratory indicators and the outcome of clinical presentations of AKI, the diagnosis of TLS is easily defined.

Table 2.

Laboratory and clinical diagnosis of TLS

Laboratory TLS	Clinical TLS
At least two of the following criteria within 3 days prior to and up to 7 days posttreatment initiation: • Uric acid ≥ 8 mg/dL or 25% increase • Potassium ≥ 6 mmol/L or 25% increase • Phosphorus ≥ 6.5 mg/dL (children), ≥ 4.5 mg/dL (adults), or 25% increase • Corrected calcium ≤ 7 mg/dL or 25% decrease	Laboratory-defined TLS accompanied by at least one of the following: • Elevated creatinine level (≥ 1.5 ULN) • Cardiac arrhythmia or sudden death • Seizure

TLS tumor lysis syndrome, ULN upper limit of normal

Management of TLS involves hydration to maintain a high urine flow, correction of metabolic abnormalities, and treatment of renal failure [5]. Aggressive fluid administration is recommended because it can reduce serum concentrations of uric acid, phosphate, and potassium. Given their role in increasing potassium secretion, loop diuretics are recommended to maintain a high urine flow. The use of urine alkalinization is not recommended for the prevention and management of TLS, because it can increase the risk of calcium phosphate deposition in the kidneys and affect kidney function [19]. Correction of metabolic abnormalities should be addressed in a timely manner, or this condition will be fatal. Hyperkalemia and hypocalcemia are the most life-threatening consequences of TLS. Measures should be considered to control hyperkalemia such as glucose and insulin administration, use of loop diuretic, and calcium gluconate supplementation. Renal replacement therapy should be considered in refractory hyperkalemia. Hyperphosphatemia could aggravate hypocalcemia by increasing calcium phosphate precipitation. Control of hyperphosphatemia through intravenous hydration helps to correct hypocalcemia. Patients with oliguria or anuria, volume overload, refractory hyperkalemia, symptomatic hypocalcemia due to hyperphosphatemia, and a calcium phosphate product greater than 70 mg²/dL will require renal replacement therapy [8, 19]. Moreover, continuous renal replacement therapy may be a better option for those with continuous lysis of tumor cells [5]. As we discussed above, due to the interference of the patient’s abdominal pain and elevated inflammatory markers, TLS was not diagnosed initially until the patient showed elevated blood creatinine levels, hyperkalemia, hyperphosphatemia, and hypocalcemia. Fortunately, owing to timely symptomatic treatments including hydration, correction of metabolic abnormalities, and treatment of acute renal failure, the patient ultimately recovered.

Conclusion

TLS rarely occurs in HCC, especially after HAIC therapy. Evaluations and measures prior to HAIC therapy should be taken to prevent TLS. When TLS develops, early recognition and treatment are critical to reducing the mortality rates of TLS.

Abbreviations

AFP

Alpha-fetoprotein

CT

Computed tomography

HCC

Hepatocellular carcinoma

HAIC

Hepatic artery infusion chemotherapy

PVTT

Portal vein tumor thrombus

TLS

Tumor lysis syndrome

NHL

Non-Hodgkin’s lymphoma

MRI

Magnetic resonance imaging

MT

Malignant tumors

AKI

Acute kidney injury

TACE

Transcatheter arterial chemoembolization

AFP

Alpha-fetoprotein

Author contributions

ML acquired the data and wrote the manuscript. BWY conceived the study. YTZ contributed to the revisions. All authors have read and approved the final manuscript.

Funding

Not applicable.

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.