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Journal of Clinical Oncology, Vol 23, No 21 (July 20), 2005: pp. 4805-4806 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.4332
Antitumoral Effect of Celecoxib in Hepatocellular CarcinomaGastroenterology Unit and Department of Radiology, Institut Gustave Roussy, Villejuif, France To the Editor: Effective therapeutic options for unresectable hepatocellular carcinoma (HCC) are still lacking. Cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, is overexpressed in many types of malignant tumors, including HCC.1 Here we report a case of HCC, which dramatically responded to celecoxib, a selective COX-2 inhibitor. A 76-year-old man underwent a left liver resection for well-differentiated HCC, developed on underlying hemochromatosis and liver cirrhosis. Serum alphafoetoprotein level decreased from 251 ng/mL preoperatively to 5 ng/mL postoperatively (upper limit of normal values, 10 ng/mL). Twenty months later, percutaneous radiofrequency ablation was performed for intrahepatic tumor recurrence. One year later, multifocal intrahepatic recurrence, mediastinal and celiac lymph node metastases, and radiofrequency needle-track peritoneal seeding with visible prehepatic bulging developed (Fig 1A). Two lines of systemic chemotherapy (gemcitabine plus oxaliplatin; capecitabine) and octreotide proved unsuccessful. Celecoxib (200 mg, bid) was then introduced. Three months later, clinical examination noted a dramatic regression of the prehepatic tumoral bulging, and alphafoetoprotein level fell from 9,700 to 150 ng/mL. Computed tomography scan showed a 75% to 100% response of intrahepatic and lymph node metastases, with residual lesions disclosing a hypodense, almost avascular pattern, suggesting tumoral necrosis (Fig 1B). However, this contrasted with the onset of right pleural effusion and Pancoast-Tobias syndrome, which led to a diagnosis of poorly differentiated large-cell lung carcinoma. The patient died of respiratory insufficiency 3 months later. Alphafoetoprotein level was of 300 ng/mL at this time. Necropsy was not performed.
COX-2 overexpression may promote tumorigenesis through vascular endothelial growth factor (VEGF) –mediated neoangiogenesis, Bcl-2-mediated inhibition of apoptosis, and inhibition of tumor cell migration.1 COX-2 inhibitors have been shown experimentally to induce tumor regression through proapoptotic and antiangiogenic effects on malignant tumors and to inhibit their invasion to surrounding tissues.1,2 In addition, COX-2–independent antitumoral effects of COX-2 inhibitors, particularly through peroxisome proliferator-activated receptor  -mediated growth inhibition, have been recently described.3 COX-2 has been shown to be expressed as higher levels in HCC, especially in well-differentiated tumors, than in normal or cirrhotic liver.4 Advanced HCC produces VEGF and, therefore, can be described as hypervascular.1 Recent data suggest a role for COX-2 in early stages of hepatocarcinogenesis, and for COX-2 inhibitors in chemoprevention for patients with liver cirrhosis.4 Of note, the onset of poorly differentiated large-cell lung carcinoma in this patient suggests that COX-2–mediated oncogenesis is cell- or tissue-specific. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. Koga H: Hepatocellular carcinoma: Is there a potential for chemoprevention using cyclooxygenase-2 inhibitors? Cancer 98:661-667, 2003[CrossRef][Medline]
2. Bae SH, Jung ES, Park YM, et al: Expression of cyclooxygenase-2 (COX-2) in hepatocellular carcinoma and growth inhibition of hepatoma cell lines by a COX-2 inhibitor, NS-398. Clin Cancer Res 7:1410-1418, 2001
3. Lehmann JM, Lenhard JM, Oliver BB, et al: Peroxisome proliferator-activated receptors 4. Koga H, Sakisaka S, Ohishi M, et al: Expression of cyclooxygenase-2 in human hepatocellular carcinoma: Relevance to tumor dedifferentiation. Hepatology 29:688-696, 1999[CrossRef][Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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) after percutaneous radiofrequency ablation. (B) Three months after starting celecoxib treatment, dramatic tumoral regression (arrow), contrasting with the onset of right pleural effusion (*), which led to diagnose poorly differentiated large-cell lung carcinoma.
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