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See article on page442
In this issue Kouroumalis et al (see page 442) report extended survival in patients with hepatocellular carcinoma (HCC) treated with octreotide, a somatostatin analogue. Somatostatin is a cyclic peptide consisting of 14 amino acids which regulates growth hormone release. It is the product of a multigene family of peptides with two biological derivatives, namely somatostatin 14 and 28. Somatostatin regulates release of growth hormone, thyrotropin and acts as an autocrine and paracrine molecule to suppress neurotransmission, immunocyte activity, smooth muscle contractility, and uptake of nutrients. (reviewed by Lamberts et al 1). Somatostatin action is mediated through a specific receptor (SSR). Somatostatin suppresses pituitary and adrenal secretion of growth hormone or thyrotropin after surgery, and inhibits secretory activity of metastatic islet cell tumours such as vipoma, glucagonoma and metastatic carcinoid. It has also been reported to be beneficial in reducing splanchnic circulation and controlling bleeding from oesophageal varices, suppression of fluid secretion by pancreatic and enteric fistula as well as secretory diarrhoea.
Somatostatin receptors were identified recently in a variety of malignant tumours including lung and ovary carcinoma, adenocarcinoma of breast, kidney, colon, and even lymphomas.2-5 However, the heterogeneous expression of SSR on the various tumours makes assessment of the antitumour effect(s) of somatostatin difficult.6 Octreotide exerts a cell growth regulatory or suppressive effect in various tumours. This effect may operate through inhibition of growth hormone secretion, insulin and gastrointestinal hormones and/or direct effect(s) on production of insulin-like growth factor I or its binding proteins as well as direct inhibition of angiogenesis. On a molecular level, there is evidence that the antimitotic activity of somatostatin, mediated through its receptor on the tumour cells, is the result of receptor activation leading to stimulation of tyrosine phosphatase activity. This in turn leads to reversal of epidermal growth factor (EGF) induced phosphorylation of EGF receptor tyrosine kinase. These processes lead, most probably, to shrinkage of individual tumour cells.1 6 Thus, there is a rationale for testing the effect of somatostatin in patients with HCC.
In their article Kouroumalis et al had two goals: (1) semiquantitative determination of somatostatin receptors in liver tissue obtained from patients at various stages of hepatitis and HCC; and (2) assessment of treatment with octreotide (250 μg twice daily) on survival of patients with HCC with a heterogeneous functional reserve. As to their first goal, the investigators were able to identify somatostatin receptors in liver tissue homogenates obtained from 23 patients in various stages of liver disease, of whom only four had HCC. However, the sample size was small with notable variability of receptor concentration, which does not allow definitive conclusions to be drawn. A more refined method is required to produce membrane preparations from larger tissue specimens which are available at surgery or liver transplantation. Standard reference preparations derived from transformed cell lines7 8 could also be helpful for comparison. As to the second goal, the investigators showed that octreotide treatment had a beneficial effect in a group of 28 patients with HCC in whom median survival was 13 months compared to only four months in 30 control patients who received no treatment. All patients had unresectable HCC and the majority were at Child-Pugh class B-C and Okuda class II or III. Thus, the authors suggest that treatment with octreotide significantly improves survival of patients with HCC and state that the treatment is a valuable alternative for inoperable HCC.
Before embracing this warm recommendation it seems prudent to make a few comments. Physicians who treat patients with HCC are well aware of the many factors that determine the heterogeneous clinical presentation and prognosis of HCC, which include, among others, presence and size of uni- or multifocal tumours, background of cirrhosis, the functional reserve of the liver at time of treatment, the presence or absence of portal hypertension and portal vein thrombosis (reviewed by Bruix9). The pattern of clinical presentation will dictate the treatment strategy and the chance of survival. It is well agreed that surgical removal/debulking of unifocal HCC tumours with a diameter <5 cm is the initial treatment of choice provided the functional capacity of the liver and the patient’s condition permit surgery. However, in most patients and regardless of the aetiological agents involved, surgery is not possible and even in those who undergo successful tumour resection the underlying inflammatory processes will continue to operate as a risk factor for emergence of newly transformed HCC foci. Currently, surgical resection, transarterial chemoembolisation (TAE) and percutaneous ethanol injection (PEI) are the cornerstones of palliative treatment offered to patients with HCC worldwide,9 while systemic chemotherapy has been practically abandoned. Clinicians find it difficult to adopt a new form of therapy if data are not derived from adequately controlled studies. HCC has such a variable and heterogeneous course and clinical presentation, that design of well controlled trials for assessment of a new treatment modality is exceedingly difficult. Therefore, the attempt Kouroumalis et al to perform a controlled study at an early stage of assessment of their hypothesis is valuable even in face of some uncertainty as to the validity of matching between groups of patients in their study. It is useful to remind the reader that regardless of the initial treatment modality chosen by individual physicians to treat HCC, most patients will reach a stage where they will need further palliation. In recent years, several non-invasive treatments have been evaluated in these patients, including tamoxifen or retinoic acid derivatives.9 Unfortunately, the results of such studies are difficult to analyse as we currently lack the proper methods to make an accurate assessment, prior to initiation of treatment, about adequate recruitment guidelines. The attempt to determine the relative density of somatostatin receptors (SSR) in HCC from biopsy specimens may be of value, although the uniformity of expression of these receptors in HCC tumours remains to be established. Kouroumalis et al have not been able to correlate the density/concentration of SSR to the success rate of treatment with octreotide. Nevertheless, this study is a beginning. Future studies should tackle the issue of receptor density as measured in purified membrane preparations taken from a larger number of patients and controls. In addition screening for somatostatin receptors with111I-labelled pentertic acid-d-phe-octreotide9 may improve selection of candidates for treatment provided that the initial reported efficacy of octreotide in patients with HCC is confirmed.
So far, evaluation of the antitumour effect of somatostatin and its analogues has not been associated with significant adverse effects or even emergence of escape or breakthrough cell growth. Moreover, some patients report an improvement in their well being, an effect which is not necessarily the result of tumour suppression, but could be related to the physiological effects of somatostatin which include reduction of endogenous fluid secretion in the jejunum, stimulation of intestinal fluid and electrolyte absorption, and prolongation of gastrointestinal transit time.
Octreotide treatment is expensive. Based on the protocol suggested by Kouroumalis et al, the estimated annual cost of treatment with 500 μg/day could be in the range £6100–8000 (US$10 000–13 000). Thus, before adding another new and costly modality to the many (and often experimental) options currently available for treatment of HCC, further studies are required to confirm and extend the preliminary observation. It is tempting to speculate that somatostatin treatment could be used as adjuvant therapy for patients who have already taken advantage of other forms of treatment such as surgical resection, TAE or PEI.
In summary, the promising results of this early study on the effect of octreotide administration on survival of patients with HCC deserve to be explored further. Nevertheless, although the effects of somatostatin analogues on suppression of tumour growth have been documented in some tumours in vitro and in vivo it has yet to be established in patients with HCC that the effects reported by Kouroumalis et alare not indirect effects such as reduced gastrointestinal congestion and pain as well as suppression of growth factors and tumour angiogenesis.
See article on page442
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