Octreotide treatment of hepatocellular carcinoma

Abstract

We read with interest the report by Yuen et al. on treatment of hepatocellular carcinoma (HCC) with octreotide published in HEPA-TOLOGY. 1 Their conclusions are different from our study, 2 recently confirmed with long-acting somatostatin analogues. 3 We found a clear survival benefit for treated patients. In the study of Yuen et al., the control group had a poor survival of 1.9 months. This is surprising, since 82% of their patients were Okuda stage I and II, which, according to the original Okuda study should have a better survival. In our study of untreated patients, Okuda I patients survived for a median of 16 months and Okuda II for 7 months. 4 Similar findings are reported for inoperable patients in a Spanish study. 5 However a report from Thailand 6 also shows a poor median survival of 8.7 weeks. Therefore, either the natural course is different in the East, or only terminal patients are included. In any case, such patients are moribund and no treatment can be effective. This is exemplified by the fact that 21 out of 35 treated patients in the study of Yuen et al. received either none or only one injection of long-acting octreotide. Any effect of octreotide should require some time before becoming evident. If our Kaplan Meier survival curves are compared with these of Yuen et al., they are identical for the first 6 months. Any treatment benefit becomes significant for those surviving for at least 6 months. We emphasized that these patients are most likely to benefit from such a treatment. Moreover, trials on HCC have the unique characteristic of usually dealing with two potentially fatal diseases (one being the underlying cirrhosis), which influence each other. Many patients die of complicated cirrhosis rather than from HCC itself. This is true in the case of alcoholic cirrhosis, but according to our experience (manuscript in preparation) the natural course of HBV-related cirrhosis is worse than that of HCV cirrhosis. Therefore, we agree with Yuen et al. that their group consists mainly of HBV-related HCC, whereas in ours, HCV is the predominant etiologic factor, and this might affect the outcome. The antiproliferative effect of octreotide is probably regulated by the expression of somatostatin receptors. Not all HCC express somatostatin receptors. In a recent study only 40% of HCC expressed receptors by autoradiography, 7 while an immunohistochemical study showed expression of somatostatin receptors in cirrhotic nodules and HCC, but not in chronic hepatitis. 8 Since approximately 40% of our patients respond favorably to octreotide, 2,3 we believe that somatostatin receptors will be important for the response to octreotide. In conclusion, the selection of patients is critical in any study of HCC treatment. Patients with such a short expected survival like those reported by Yuen et al. should not be suitable for the detection of any benefit by octreotide treatment. Probably, patients at stage D of Barcelona classification 9 or patients with CLIPP score more than 4 or 5 10 should be excluded.

The effect of co-administration of Lawsonia inermis extract and octreotide on experimental hepatocellular carcinoma

“…So, our study will certainly help newly discovered subjects with moderate or higher expected survival. This was confirmed by Kouroumalis et al [44].…”

Cortistatin production by HepG2 human hepatocellular carcinoma cell line and distribution of somatostatin receptors

“…The somatostatin analogue octreotide has been used for the treatment of HCC with variable results [18][19][20][21], probably due to differences between studies in the selection of patients and disease etiology [31]. It appears that the presence of ssts may be important for tumor response to octreotide treatment [20].…”

Somatostatin in hepatocellular carcinoma: experimental and therapeutic implications

“…Selection of patients is critical in any study of HCC treatment [18,130,132] . It seems that SST is suitable for patients with viral cirrhosis ideally after identification of the expression on the tumor of SSTR2 and 5, either with scintigraphy or even better by immunofluorescence after a liver biopsy.…”

“…The first negative randomized controlled study was reported by Yuen et al [129] . It has been heavily criticized by us and many others, because the selected patients had a very short survival of 1.9 months in the control group (n = 35) vs. 2 months in the octreotide group (n = 35) indicating that most patients belonged to BCLC stage D. In fact 21/35 patients received either none or just one long-acting octreotide injection [130] .…”