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Journal of Clinical Oncology, Vol 25, No 16 (June 1), 2007: pp. e15-e16 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.5760
Complete, Long-Standing Regression of Hepatocellular Carcinoma After Somatostatin Analogue TreatmentDepartments of Medicine, Pathology, and Radiology, Institut Gustave Roussy, Villejuif, France To the Editor: Hepatocellular carcinoma (HCC) harbors a poor prognosis, as it is in most cases unresectable, poorly chemosensitive, and superimposed on advanced liver cirrhosis. Somatostatin and its long-acting derivatives (eg, octreotide) have been shown to exert an antimitotic effect against endocrine tumors, as well as against various nonendocrine tumors such as breast, kidney, colorectal, and ovarian cancers.1 The effect of somatostatin receptor activation, and of their inhibition as a result of therapeutic intervention, in HCC, are poorly known. We report a case of HCC which completely and durably responded to octreotide. A 54-year-old-man underwent a right hepatectomy for HCC developed on well-compensated, hepatitis C virus-related liver cirrhosis. Histologic examination showed a well-differentiated HCC. Serum alpha-fetoprotein (AFP) level decreased from 8,900 ng/mL preoperatively to 4 ng/mL postoperatively (normal, < 10 ng/mL). Three months later, the patient was diagnosed with a multifocal intrahepatic recurrence without distant metastasis, and was given systemic chemotherapy with doxorubicine and etoposide. Abdominal computed tomography (CT) scan 2 months later showed tumor progression (Fig 1), and serum AFP level rose up to 40,327 ng/mL. A compassionate trial of octreotide (250 µg twice daily subcutaneously) was therefore proposed to the patient, who gave informed consent for it. Four months later, serum AFP level fell to 1 ng/mL, and CT scan showed an objective tumor response. Lanreotide (30 mg every other week, intramuscularly) was then substituted for octreotide. This long-acting somatostatin analog was well-tolerated, except for transient local pain at the site of injection. Nine months later, the AFP level was still normal and lung and abdominal CT scan disclosed a complete response. Lanreotide treatment was continued for 39 months, then stopped (with the patient's consent). The patient received follow-up at our outpatient clinic, with physical examination, serum AFP, and lung and abdominal CT scan every 4 months. At the last visit, 55 months after initiation of the somastotatin analog treatment, the patient remained disease free (Fig 2).
No standard systemic therapy is available for locally advanced or metastatic HCC. Chemotherapy is associated with low response rates and/or toxicity, and drugs with immunomodulatory or antiangiogenic properties are under investigation. Trials assessing the efficacy of somatostatin analogs in HCC are conflicting. In some studies, somatostatin analogs were found (or suggested) to improve significantly overall survival of patients with unresectable HCC,2-4 including one randomized controlled trial,2 while these results were not confirmed by other studies, including two randomized controlled trials.5,6 Thus, although occasional patients appear to have stable disease on long-acting octreotide therapy, overall the beneficial response in terms of time to tumor progression and survival is limited.7 Somatostatin analog treatment has been associated with partial regression of HCC in rare instances.8 To our knowledge, this case is the first one showing a complete remission of histologically proven, unresectable, multifocal HCC with somatostatin analogs. Complete tumor response was confirmed by concomitant serum AFP normalization and serial CT scan examinations over a 55-month period. Somatostatin and its analogs act through five G protein receptors (SSTR1-5). Overexpression of SSTRs has been described in 40% to 100% of patients with HCC, depending on the SSTR subtype studied, the method, and the study.9,10 Activation of these receptors cause apoptosis, growth arrest, inhibition of migration, inhibition of release of growth factors or cytokines, and inhibition of neoangiogenesis, which all may contribute to the antitumoral effect of somatostatin analogs.10-12 However, there is considerable variation in expression of SSTRs in human HCC, and the mechanisms by which somatostatin analogs may exert an antitumoral effect in HCC remains unclear. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: N/A Consultant or Advisory Role: Michel Ducreux, Ipsen-Biotech Stock Ownership: N/A Honoraria: Michel Ducreux, Ipsen-Biotech Research Funding: N/A Expert Testimony: N/A Other Remuneration: N/A
REFERENCES
1. Lamberts SWJ, Van Der Lely AJ, de Herder WW, et al: Octreotide. N Engl J Med 334:246-254, 1996 2. Kouroumalis E, Skordilis P, Thermos K, et al: Treatment of hepatocellular carcinoma with octreotide: A randomised controlled study. Gut 42:442-447, 1998 3. Dimitrilopoulos D, Xinopoulos D, Tsamakidis K, et al: The role of sandostatin LAR in treating patients with advanced hepatocellular cancer. Hepatogastroenterology 49:1245-1250, 2002[Medline] 4. Samonakis DN, Moschandreas J, Arnaouitis T, et al: Treatment of hepatocellular carcinoma with long acting somatostatin analogues. Oncol Rep 9:903-907, 2002[Medline] 5. Yuen MF, Poon RT, Lai CL, et al: A randomised pooled-placebo controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology 36:687-691, 2002[CrossRef][Medline] 6. Allgaier HP, Becker G, Olschewski M, et al: Octreotide treatment in patients with advanced hepatocellular carcinoma: First results of the randomised placebo-controlled double blind Hector trial. Hepatology 38:760A, 2003 (suppl 1) 7. Slijkhuis WA, Stadheim L, Hassoun ZM, et al: Octreotide therapy for advanced hepatocellular carcinoma. J Clin Gastroenterol 39:333-338, 2005[CrossRef][Medline] 8. Rabe C, Pilz T, Allgaier HP, et al: Clinical outcome of a cohort of 63 patients with hepatocellular carcinoma treated with octreotide. Z Gastroenterol 40:395-400, 2002[CrossRef][Medline] 9. Reynaert H, Rombouts K, Vandermonde A, et al: Expression of somatostatin receptors in normal and cirrhotic human liver and in hepatocellular carcinoma. Gut 53:1180-1189, 2004 10. Reubi JC, Zimmermann A, Jonas S, et al: Regulatory peptide receptors in human hepatocellular carcinomas. Gut 45:766-774, 1999 11. Pollack MN, Schally AV: Mechanisms of antineoplastic action of somatostatin analogs. Proc Soc Exp Biol Med 217:143-152, 1998[CrossRef][Medline] 12. Ferjoux G, Bousquet C, Cordelier P, et al: Signal transduction of somatostatin receptors negatively controlling cell proliferation. J Physiol Paris 94:205-210, 2000[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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