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Acute Tumor Lysis Syndrome After Thalidomide Therapy in Advanced Hepatocellular Carcinoma
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     We read with great interest the article by Dr. Zhu and colleagues on the phase II study using the combination of epirubicin (Ellence®; Pfizer Pharmaceuticals, New York) and thalidomide (Thalomid®; Celgene Corporation, Warren, NJ in patients with advanced hepatocellular carcinoma (HCC) [1]. The authors describe how the combination therapy had limited activity in HCC, but that the main toxicities of thalidomide, including constipation, fatigue, and sensory neuropathy, were well tolerated.

    Recently, tumorlysis syndrome (TLS) has been reported in patients with multiple myeloma treated with thalidomide [2], but this complication has not been reported in HCC. We report, herein, a rare case of TLS after thalidomide therapy in an HCC patient to alert the clinician to this potentially life-threatening complication.

    A 62-year-old man presented to the emergency department with the acute onset of shortness of breath. He had a history of HCC diagnosed 6 months earlier, when an 8-cm hepatic tumor was found on screening sonography along with an elevated serum alpha-fetoprotein level of 7,426 ng/ml. The tumor was spanning the left and right hepatic lobes, making it unresectable on presentation. He underwent transarterial chemoembolization several times from August to November 2002, with partial response, and had had stable disease for 4.5 months. In April 2003, tumor recurrence was noted and compassionate thalidomide therapy was suggested. He had started to receive low-dose (200 mg every 24 hours) thalidomide monotherapy 2 weeks previously, and the dose was increased to 300 mg every 24 hours 5 days before this admission. On examination, jaundice and a distended abdomen with right upper quadrant tenderness were noted. Laboratory exams showed elevated serum creatinine (3.6 mg/dl) and lactate dehydrogenase (1,453 u/dl) levels, hyperkalemia (6.2 mg/dl), hyperphosphotemia (6.8 mg/dl), hyperuricemia (11.4 mg/dl), and metabolic acidosis. Three weeks earlier, he had had normal renal function, with a serum creatinine level of 1.0 mg/dl (Table 1). Sonographic examination revealed a reduced tumor of 6 cm in diameter, compared with 9 cm 2 weeks earlier. Under the suspicion of TLS, thalidomide treatment was stopped. Symptomatic treatment with diuretics, allopurinol, and alkalinization and antihyperkalemia measures, such as insulin plus glucose infusion, were started. Because of rapid deterioration of renal function, hemodialysis was suggested. However, the family refused hemodialysis and transferred him to a hospice for palliative care. Two days later, he died of refractive hyperkalemia and ventricular arrhythmia. Blood and ascites culture did not yield any growth.

    Until now, few renal complications associated with thalidomide therapy have been reported [3–5]. Renal excretion is not the major route of elimination of thalidomide, with an excretion rate of only 0.7% [6]. Hyperkalemia has been reported in patients with multiple myeloma and pre-existing renal insufficiency, but not in those with normal renal function [3]. Elevated serum creatinine levels and hypocalcemia have been noted in some patients coadministered thalidomide and zoledronic acid (Zometa®; Novartis Pharmaceuticals Corporation, East Hanover, NJ), but this was not confirmed by a later study [4]. Recently, TLS was reported in two patients with multiple myeloma treated with thalidomide [5]. TLS usually occurs in patients with hematological malignancies or bulky, rapidly growing solid malignancies treated with cytotoxic agents. In our case, the patient had normal baseline renal function and did not receive any medications other than thalidomide. He developed acute renal failure with hyperphosphatemia and hyperuricemia and showed some evidence of tumor response to thalidomide on sonography, supporting the diagnosis of TLS. Because such patients usually present with a fulminant manifestation, close monitoring and prevention of TLS are warranted at the beginning of the therapy.

    DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

    The authors indicate no potential conflicts of interest.

    REFERENCES

    Zhu AX, Fuchs CS, Clark JW et al. A Phase II Study of Epirubicin and Thalidomide in Unresectable or Metastatic Hepatocellular Carcinoma. The Oncologist 2005;10:392–398.

    Cany L, Fitoussi O, Boiron JM et al. Tumor lysis syndrome at the beginning of thalidomide therapy for multiple myeloma. J Clin Oncol 2002;20:2212.

    Peuckmann V, Fisch M, Bruera E. Potential novel uses of thalidomide: focus on palliative care. Drugs 2000;60:273–292.

    Harris E, Behrens J, Samson D et al. Use of thalidomide in patients with myeloma and renal failure may be associated with unexplained hyperkalaemia. Br J Haematol 2003;122:160–161.

    Spencer A, Robert A, Bailey M et al. No evidence for an adverse interaction between zoledronic acid and thalidomide: preliminary safety analysis from the Australasian Leukemia and Lymphoma Group MM6 Myeloma Trial. Blood 2003;102:383.

    Hsu C, Chen CN, Chen LT et al. Low-dose thalidomide treatment for advanced hepatocellular carcinoma. Oncology 2003;65:242–249.(Chien-Chang Lee, Yuan-Hue)