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Page 12 of 18 Kouroumalis et al. Hepatoma Res 2018;4:34 I http://dx.doi.org/10.20517/2394-5079.2018.33

A seemingly not favorable open label trial of twenty patients (all HBV or HCV) treated with pasireotide was
recently reported. 90% had prior therapy, 75% had BCLC stage C, and 55% had metastatic disease. Despite
this, a stable disease in 9 patients was demonstrated (45%), and the median survival was 9 months .
[138]

The situation is possibly clarified from a Chinese meta-analysis of approximately 800 patients from 9 trials.
The 6- and 12-month survival rates in the octreotide group were significantly higher than those of the control
group (6-month: RR 1.41, 95% CI: 1.12-1.77, P = 0.003; 12-month: RR 2.66, 95% CI: 1.30-5.44, P = 0.008) but
this was not the case when only western studies were analyzed . This meta-analysis vividly describes that
[139]
there is a discrepancy in results between China (and in that regard Greece) and Western countries. This is
also evident from the analysis presented in this review.

One possible explanation for the negative results is the tachyphylaxis through which SSTRs are internalized
upon prolonged exposure of tumors to somatostatin analogues. However there is evidence that resensitization
may occur . In addition the expression profile of receptors is variable among tumors. Also production of
[35]
[95]
endogenous cortistatin may further affect the expression and internalization of the receptors .
Serum levels of octreotide may also be a critical parameter in HCC response. As mentioned before
-8
octreotide decreased proliferation only at concentrations of 10 mol/L, while lower concentrations increased
proliferation, making drug serum levels an important parameter at least in clinical trials . However, these
[53]
possible resistance mechanisms cannot explain the differences between the East (and Greece) and the West.
A critical evaluation of the reported studies offers potential explanations for the discrepancies. First, as we
pointed out, the survival benefit is evident only in patients that live long enough to have a treatment period
of more than 6 months. Somatostatin is not a magic bullet and the potential molecular pathways of its action
require some time to produce measurable results. The second explanation is very important. Practically all
negative western studies recruited a large number of alcoholic cirrhosis (between 25% and 60%) reflecting the
etiological background of their population. In contrast, Chinese studies have almost exclusively recruited viral
cirrhosis in accordance with cirrhosis etiology in their population. The same was true in the original Greek
studies. It was our impression that our few alcoholics did not respond equally well to somatostatin particular
those that do not abstain from alcohol. This critical point is not mentioned in any of the negative papers. As
mentioned before, a very recent report from Germany found very low rates of weak expression of SSTRs in
liver tissue from alcohol related HCC patients . Only two of their patients had virus-related HCC.
[17]

CONCLUSION
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. Eligible patients are those classified
as BCLC stage B or C which is the same indication with TACE and possibly sorafenib. Patients with
[140]
alcoholic cirrhosis-related HCC may be treated as those in BCLC stage B, but the response will be limited.
In that respect it is tempting to use SST as an adjunct to TACE.

Finally, it would be interesting in future to see if there are additional differences between viral and alcoholic
related HCC like differential expression of receptors or production of trophic factors. In a recent study an
increase of serum IGF2 level was reported to be associated with the occurrence of HCC metastasis after
TACE and octreotide, as metastatic foci were found in 97% when IGF2 was increasing in contrast to only
13.6% of patients with an IGF2 decrease . In the context of the previous discussion, it should be noted that
[141]
the expression of IGF2 in HCC was strongly associated with HBV infection .
[142]