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Journal of Clinical Oncology, Vol 26, No 14 (May 10), 2008: pp. 2406-2408 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.7603
Cetuximab-Related Tumor Lysis Syndrome in Metastatic Colon CarcinomaDepartment of Internal Medicine, Division of Hematology and Oncology, Michigan State University, East Lansing, MI This is a 64-year-old white male who was initially evaluated in December 2006 for right upper quadrant pain. Ultrasound and computed tomography scan of the abdomen revealed multiple hepatic nodules, the largest being 5.5 cm in the left lobe of the liver (Figs 1A and 1B). Liver biopsy on December 26, 2007, revealed multiple foci of adenocarcinoma consistent with metastasis (Figs 2A and 2B). Subsequent colonoscopy showed a mass in the mid-transverse colon, and the biopsy confirmed a moderately differentiated adenocarcinoma of the colon. He had no other medical problems. In the next 4 weeks, the patient developed obstructive jaundice. Symptoms included nausea, reduced oral intake, and clay-colored stools with narrow caliber. Repeat computed tomography scans of the chest abdomen and pelvis without contrast revealed conglomerate adenopathy in the mediastinum with bilateral pleural effusions. The CBC showed elevated leukocytes of 18,000/µL (up from 11,000 4 weeks previously) with 80% neutrophils, hemoglobin of 12.4 g/dL, and platelet count of 318,000/µL. Transaminases were elevated (ALT, 150 U/L; AST, 279 U/L). Alkaline phosphatase was also elevated to 1,000 U/L with direct bilirubinemia of 14 mg/dL (total bilirubin was 17 mg/dL). He underwent gastroduodenoscopy and endoscopic retrograde colangiopancreatography with a biliary stent placement. There was no obvious biliary ductal dilation noted during this procedure. Chemotherapy was not considered, due to extensive liver metastasis causing hyperbilirubinemia and transaminitis. Single agent cetuximab was planned with the intention of adding standard chemotherapy when the patient's liver function improved. He received single agent cetuximab at 400 mg/m2. He tolerated the infusion well without any major complications. After 18 hours, his renal function started to deteriorate. In that time period, his blood urea nitrogen went up from 24 to 36 mg/dL, creatinine has increased from 0.9 to 1.8 mg/dL, and potassium went up from 4.2 to 7.4 meq/L. Phosphorous increased from 2.1 to 5.7 to 10 mg/dL. His calcium went down from 7.9 to 6.2 mg/dL, and during that time his albumin was 2.2 g/dL. His uric acid was elevated to 12 mg/dL, creatine phosphokinase to 4,200 U/L, and lactate dehydrogenase to 59,000 U/L. His bilirubin was slightly elevated. He also developed hypotension and respiratory failure requiring intubation. His biochemical profile was consistent with acute tumor lysis syndrome (TLS). Approximately 6 hours later, he had further deterioration of his renal function with blood urea nitrogen of 44 mg/dL, creatinine of 3.1 mg/dL, and phosphorous of 10 mg/dL. His lactate level was elevated to 15 mmol/L. Transaminases were elevated significantly (ALT, 3,600 U/L; AST, 17,000 U/L). Hemodialysis was recommended. The patient's family decided against it. He did receive a dose of rasburicase and his uric acid came down to 8.3 mg/dL about 20 hours later. The patient eventually died due to complications of TLS.
TLS is an oncologic emergency characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and uremia that are results of the rapid destruction of malignant cells and the abrupt release of nucleic acids, intracellular ions, proteins, and their metabolites into the extracellular space. High uric acid and calcium phosphate crystals can deposit in the renal tubules and may lead to acute renal failure. TLS has been reported mostly with hematological malignancies. Solid malignancies that can cause TLS include small-cell lung carcinoma and breast carcinoma. TLS can occur following initiation of chemotherapy or spontaneously in the absence of treatment.1 Laboratory TLS is much more common in the early acute phase (40% to 60%) than clinical TLS (3% to 6%).1 On the other hand, TLS is an extremely rare complication in patients treated with biologic therapies. Several cases of imatinib mesylate–associated TLS were reported in the literature.2-4 TLS was also reported with rituximab5 in lymphomas, with sunitinib6 in gastrointestinal stromal tumor, and with bortezomib7 in multiple myeloma. In the past decade, several targeted biologic therapeutic agents revolutionized the field of cancer therapeutics. Cetuximab is widely used in the treatment of metastatic colorectal carcinoma and squamous cell carcinoma of the head and neck. In the phase II European randomized BOND (EMR-007) trial, single-agent cetuximab and cetuximab in combination with irinotecan were examined in patients with irinotecan-resistant tumors.8 The overall response (OR) rate for the combination of cetuximab and irinotecan was 22.9% compared with 10.8% for cetuximab monotherapy. Based on these observations, cetuximab was approved by the US Food and Drug Administration in February 2004, both in combination with irinotecan and as a single agent for the treatment of patients with epidermal growth factor receptor–expressing metastatic colorectal carcinoma who are intolerant to irinotecan-based chemotherapy. Another nonrandomized, single arm study confirmed the antitumor activity of cetuximab as a single agent.9 Detailed subgroup analysis revealed that cetuximab was equally active in all patient subgroups regardless of numbers of prior therapy or the sequence of prior agents including irinotecan and oxaliplatin.10 The safety and efficacy of combined biologics (ie, cetuximab and bevacizumab), with or without irinotecan, were evaluated in the randomized BOND-2 study.11 Patients receiving cetuximab, bevacizumab, and irinotecan experienced a 38% OR rate, and patients on cetuximab and bevacizumab experienced a 23% OR rate. Cetuximab was also studied in combination with fluorouracil/leucovorin/oxaliplatin12 and fluorouracil/leucovorin/irinotecan13 with significant efficacy and safety in metastatic colon cancer patients. In the previously mentioned clinical trials involving cetuximab, dermatological adverse effects in the form of acne or allergic skin reactions were more prevalent. Other adverse effects include asthenia, atrial fibrillation, diarrhea, nausea, vomiting, headache, and hypokalemia. There was also a positive correlation between the severity of the skin rash and survival. Adverse events like TLS were never reported to be associated with cetuximab. Our patient developed TLS within 24 hours after the first dose of the cetuximab. To our knowledge, this is the first case of TLS associated with cetuximab treatment in the literature. In the light of our observation, we conclude that TLS should be taken into account as a rare complication of cetuximab, and renal function should be monitored in patients receiving cetuximab treatment. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Cairo MS, Bishop M: Tumour lysis syndrome: New therapeutic strategies and classification. Br J Haematol 127:3-11, 2004[CrossRef][Medline] 2. Vora A, Bhutani M, Sharma A, et al: Severe tumor lysis syndrome during treatment with STI 571 in a patient with chronic myelogenous leukemia accelerated phase. Ann Oncol 13:1833-1834, 2002 3. Pou M, Saval N, Vera M, et al: Acute renal failure secondary to imatinib mesylate treatment in chronic myeloid leukemia. Leuk Lymphoma 44:1239-1241, 2003[CrossRef][Medline] 4. Ali R, Ozkalemkas F, Ozkan A, et al: Tumour lysis syndrome with acute renal failure during imatinib therapy. Leuk Res 31:573-574, 2007[CrossRef][Medline] 5. Abou Mourad Y, Taher A, Shamseddine A: Acute tumor lysis syndrome in large B-cell non-Hodgkin lymphoma induced by steroids and anti-CD 20. Hematol J 4:222-224, 2003[CrossRef][Medline] 6. Saylor PJ, Reid TR: Tumor lysis syndrome after treatment of a gastrointestinal stromal tumor with the oral tyrosine kinase inhibitor sunitinib. J Clin Oncol 25:3544-3546, 2007 7. Sezer O, Vesole DH, Singhal S, et al: Bortezomib-induced tumor lysis syndrome in multiple myeloma. Clin Lymphoma Myeloma 7:233-235, 2006[Medline] 8. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 9. Lenz HJ, Gold PJ, Mirtsching B, et al: Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin. J Clin Oncol 23:248s, 2004 (suppl; abstr 3510)[CrossRef] 10. Lenz HJ, Mirtsching B, Cohn AL, et al: Consistent response to treatment with cetuximab monotherapy in patients with metastatic colorectal cancer. J Clin Oncol 24:255s, 2005 (suppl; abstr 3536) 11. Saltz LB, Meropol NJ, Loehrer PJ, Sr, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201-1208, 2004 12. Diaz Rubio E, Tabernero J, van Cutsem E, et al: Cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer. An international phase II study. J Clin Oncol 23:254s, 2005 (suppl; abstr 3535)[CrossRef] 13. Rougier P, Raoul JL, Van Laethem JL, et al: Cetuximab + FOLFIRI as first-line treatment for metastatic colorectal CA. J Clin Oncol 22:248s, 2004 (suppl; abstr 3513)[CrossRef]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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