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Re: Complete regression of advanced hepatocellular carcinoma under therapy with long-acting octreotide

Dear Editor

Various therapeutic approaches for unresectable hepatocellular carcinoma (HCC) have been suggested during recent years. However, major advances concerning tumor regression or patient survival were not achieved. Few trials assessed the effect of the somatostatin analogue octreotide in advanced HCC with divergent results.[1,2] The latter might be due to the expression of somatostatin receptor type 2 (SSTR2) in some but not all patients with HCC.[3,4] Herein, we describe a patient with advanced HCC who was treated with long-acting octreotide, which resulted in complete and prolonged regression of the tumor.

The patient was diagnosed with HCC after a suspect nodule was detected in the abdominal ultrasound. Laboratory testing revealed a highly increased a -fetoprotein (AFP) and positive HCV antibodies. Computed tomography (CT) of the liver displayed multiple tumors (maximum diameter 5 cm) in segment seven and two smaller nodules in segments six and one. Histology of an ultrasound-guided biopsy revealed hepatocellular carcinoma. Due to the advanced stage of the tumor a surgical resection was not feasible. As the patient refused local ablative therapies a therapy with octreotide was initiated (initially 250 µg twice daily, followed by long-acting octreotide, Sandostatin LAR®, 10 mg monthly). Four months later a 50-70% reduction in the size of the multifocal tumors was demonstrated by CT. Furthermore, a complete regression of the formerly described tumors was noted ten months after initiation of octreotide therapy. This was paralleled by a normalization of the formerly elevated AFP values (33,1 ng/ml vs. 7615,3 ng/ml). Octreotide receptor scintigraphy performed after 12 months and 19 months of therapy did not reveal any suspicious enhancement. However, after 13 and 19 month a gradual increase of the AFP levels from 37 to 223 ng/ml and a new suspicious liver nodule by CT scans were observed. The patient has so far not experienced any tumor-associated symptoms or any drug-related side effects and up to now has been in excellent condition during the 22 months of treatment.

The survival-improving treatment effects of octreotide described by Kouroumalis et al. [1] were not confirmed in a subsequent randomized placebo-controlled trial.[2] Of the octreotide receptors expressed in the liver, octreotide has the highest affinity to SSTR2 compared with the four other isoforms of the somatostatin-receptors.[3] SSTR2 is expressed in HCC [3,4] and has been shown to play a major role in mediating cell cycle arrest.[5] Although we were not able to proof SSTR expression in our patient due to tissue preparation in another hospital, a high SSTR2 expression in our patient might be the reason for the unusual beneficial clinical course. The recent increase in AFP levels could reflect the ability of the tumor cells to escape somatostatin receptor treatment, possibly by down regulation or mutation of the respective receptor.

To the best of our knowledge, the complete and prolonged regression of advanced HCC with normalized AFP levels during octreotide treatment has not been described before. Based on our observation and the divergent results of recent studies, forthcoming trials evaluating the effect of octreotide in advanced HCC might additionally stratify patients according to the respective somatostatin receptor expression profile of the tumor cells.

References

(1) Kouroumalis E, Skordilis P, Thermos K, et al. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut 1998;42:442-447.

(2) Yuen MF, Poon RT, Lai CL, et al A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology 2002;36:687-691

(3) Reubi JC, Waser B, Schaer JC, Laissue JA. Somatostatin receptor sst1- sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med 2001;28:836-846

(4) Reubi JC, Zimmermann A, Jonas S, et al. Regulatory peptide receptors in human hepatocellular carcinomas. Gut 1999;45:766-774

(5) Benali N, Cordelier P, Calise D, et al. Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238. Proc Natl Acad Sci USA 2000;97:9180-9185