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Kouroumalis et al. Hepatoma Res 2018;4:34 I http://dx.doi.org/10.20517/2394-5079.2018.33 Page 9 of 18

glucose. More importantly, octreotide significantly reduced liver steatosis in obese rats. If confirmed,
these results may justify the use of octreotide as a preventive measure of HCC in non alcoholic fatty
liver disease [107] .

These experimental preclinical data indicating anti-proliferative and anti-metastatic effects of SSAs in HCC,
supported the initiation of clinical studies in patients with HCC.

CLINICAL DATA
Favorable data
For the first time octreotide was used for HCC treatment by our group in a randomized controlled trial of
58 mostly Okuda II and III patients. Subcutaneous octreotide almost doubled survival while treated patients
clearly had a lower hazard of death (0.383), in the multivariate analysis.

We confirmed these results later in a non randomized trial with long-acting analogues where the relative risk
of death of the untreated patients was 2.7 (95% CI: 1.4-5.3) compared to the treated patients. Approximately
40% of tumors either regressed (10%) or remained stable (30%), a figure similar to the overall reported
expression of somatostatin receptors as mentioned before. Moreover patients retained their appetite, a
satisfactory body weight and sense of well being even if tumors were radiologically progressing. The etiology
of HCC in our group was related to viral hepatitis in over 90% of cases [108,109] . We have pointed out that
somatostatin is not a rescue drug and the survival benefit is significant in the Kaplan-Meier survival curves
only after 6 months of treatment. Moreover we observed that HCCs whose etiology was alcoholic cirrhosis
were less responsive, particularly in patients who continued drinking .
[18]
In an uncontrolled study of 21 patients, lanreotide caused a 43% response, similar to ours (one tumour
regressed and 8 were stable, despite the fact that no patient had SSTRs on octreotide scintigraphy). Five
patients (24%) had a decrease in serum-AFP levels by at least 30% . A similar uncontrolled study of
[15]
mostly viral HCC cases reported that octreotide improved survival time in non-cirrhotic patients. It
should be noted however that 40% of the cirrhotics were Child Pugh C stage and that most of them died
before 6 months .
[110]
Another Greek group also reported that octreotide doubled survival in a randomized trial of patients with
HBV or HCV related HCC who had detectable SSTRs on 111Indium octreotide scintigraphy. By contrast
SSTRs negative patients had no survival benefit. Again the Kaplan-Meier curve showed that the benefit was
significant after approximately 6 months of treatment .
[111]

In a controlled trial from China, a combination of tamoxifen and octreotide was compared to conventional
chemotherapy. In the octreotide arm, a complete response or partial response was found in 43% of patients
and survival was also doubled compared to chemotherapy .
[112]

A controlled study from Pakistan in reported tumor regression in 45.4% of patients with HCV related HCC,
while alpha fetoprotein reduction was noticed in 50%. Significant survival benefit and improvement of
quality of life were also found . A seemingly negative small observational study on patients with advanced
[113]
HCC has been reported from the USA. The median survival was only 4.5 months. However, 6/22 patients
(27%) survived for more than 10 months and most interestingly these were patients of Asian descent with a
history of HBV infection .
[114]
In a retrospective controlled study of 95 patients on octreotide (57% viral etiology and 43% alcoholics),
survival rates of patients with Barcelona classification stage B were significantly higher (22.4 months),