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Kouroumalis et al. Hepatoma Res 2018;4:34 I http://dx.doi.org/10.20517/2394-5079.2018.33 Page 11 of 18

The results of the combination of octreotide plus sorafenib were reported in a prospective non controlled
phase II study of advanced viral associated HCC (mostly HCV), Child-Pugh A or B; 10% of patients achieved
partial response and 66% had stable disease with a median survival of 12 months. The combination was well
tolerated .
[126]
Further work from the same group has shown that responders had a significant decrease of reactive oxygen
species in the peripheral blood mononuclear cells and this reduction was enhanced when octreotide was
added to sorafenib. A 50% pERK activity reduction was observed in responders compared to an 80% increase
in non responders. Sorafenib induced a 40% increase in serum NO and this was further increased after
octreotide . Whether SSAs offer any advantage as an addition to sorafenib remains to be established.
[127]
Unfavorable data
A retrospective observational non controlled study found no evidence of survival benefit in 63 patients
(40% alcoholics) . The first negative randomized controlled study was reported by Yuen et al. . It has
[128]
[129]
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]

A non-randomized subsequent study found limited beneficial response after octreotide administration.
However, 4 patients (6%) did not receive any octreotide because their disease progressed so rapidly they were
unable to start treatment. These patients were included in the survival analysis; 5% received 1 dose, 19% 2
doses, 16% 3 doses and 16% 4 doses. Additionally, from the 30 patients surveyed, 6 were not enrolled due to
intolerance to the test dose. The selection of patients also raises some questions. A significant number (50%)
had vascular thrombosis (extent is not specified) and 13% had metastatic disease. It should be noted that
among the 14 patients who received treatment of more than 3 months, 50% were judged to be stable, which
is in accordance to virtually all previous results [131,132] .

Another open-label study of 63 patients (22% alcoholics) reported little anti-cancer activity and a median
survival of 8 months. However, the reason for stopping treatment was disease progression or toxicity and
therefore assessment of survival was not really feasible .
[133]

A randomized controlled study compared the effect of tamoxifen (control group) with tamoxifen plus
octreotide in 109 patients (52.4% alcoholics) and reported no survival benefit. Again the median survival
of the treatment group was only 3 months and 44% of patients received only 1-3 injections. Moreover the
median survival in Child-Pugh A patients was only 6 months .
[134]
The HECTOR study, a randomized double-blind placebo-controlled multicenter trial of 120 patients, showed
no survival benefit for octreotide compared to placebo, with a median survival of 4.7 and 5.3 months
respectively. Quality of life was also unaffected. However 52% of the treatment group had alcoholic cirrhosis
and at 6 months the survival rate was only 40% .
[135]

Similarly negative were the results from another multicenter randomized placebo controlled study. But again
50% of the randomized patients had alcoholic cirrhosis . A recent everolimus plus pasireotide open-label
[136]
study of 26 patients (BCLC stage C 88%, and > 60% alcoholics) also gave negative results with a median
survival of 6.7 months. However the reason for treatment discontinuation was disease progression and not
death. Treatment was administered for only a median of two 28-day cycles. Yet, 10/22 evaluable patients had
stable disease as best response .
[137]