Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours

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Abstract

A few studies have suggested an antitumour activity of somatostatin analogues in neuroendocrine tumours (NET). The aim of this study was to evaluate the antitumour efficacy of somatostatin analogues in patients with documented progressive tumours. 35 consecutive patients with documented tumour progression were treated with somatostatin analogues. Patients were classified into two groups. In Group 1, tumours were progressing rapidly (an increase of 50% or more in the lesion surface area in 3 months) and in Group 2, tumours were progressing more slowly (an increase of less than 50% in the lesion surface area in 3 months but greater than 25% in 6 months). Treatment consisted of subcutaneous (s.c.) octreotide, 100 μg thrice daily for 17 patients, intramuscular lanreotide, 30 mg/every 14 days for 11 patients and for 7 patients both somatostatin analogues were used successively during the follow-up. Primary tumour sites were the small intestine (n=12), pancreas (n=13), lungs (n=5), and other sites (n=5). 18 patients had the carcinoid syndrome with flushing and/or diarrhoea. The median duration of treatment was 7 months. Treatment was discontinued in 3 patients due to side-effects. One patient (3%) achieved a partial response and the disease was stabilised in 20 patients (57%) for a median duration of 11 months (6–48 months). Stabilisation of patients in Group 1 was significantly less frequent at 6 months than that of patients in Group 2 (4/12 and 13/17 respectively, P<0.02). Somatostatin analogue treatment resulted in one partial response (3%) and 20 cases of stabilisation (57%) in 35 patients with progressive NET. A slow tumour growth rate before treatment is predictive of a good response to somatostatin analogues which could be considered an option for first-line treatment.

Introduction

Malignant neuro-endocrine tumours (NET) are rare, accounting for approximately 1% of all human tumours. Gastroenteropancreatic (GEP) NET are derived from endodermal cells with a secretory capacity that are found in practically all the organs in the human body. The main primary carcinoid tumours arise in the digestive tract (small bowel 29%, appendicular 19% and rectum 13%) and in the respiratory tract 25% [1]. GEP NET are classified into three different groups according to their embryological origin as lesions of the foregut- (upper digestive tract, duodenum, proximal jejunum, pancreas and lung), midgut- (distal jejunum, ileum and proximal colon) and hindgut- (distal colon and rectum) derived tumours [2].

Despite common morphological and immunohistochemical features, the prognosis and treatment strategy differ considerably according to the primary site, histological differentiation (poor- or well-differentiated) and stage 3, 4, 5.

GEP NET subtypes, poorly-differentiated NET and well-differentiated pancreatic NET, are known to be chemosensitive 6, 7, 8. However, in other well-differentiated GEP NET, the results of systemic chemotherapy are disappointing, yielding only a 30% response rate of short duration [6]. Multiple therapeutic approaches have been developed for patients with inoperable disease. They include hormonotherapy, immunotherapy, or locoregional therapy mainly targeting the liver 9, 10, 11. However, given the heterogeneous growth pattern of these tumours, and the absence of well-established prognostic factors, the natural growth pattern of these tumours was proposed as a target for the selection of patients and the evaluation of therapeutic approaches [12]. GEP NET are characterised by the expression of somatostatin receptors [13] and by hormonal secretion which has been demonstrated to be life-threatening [14]. Somatostatin analogues have proved effective in controlling hormonal secretions in GEP NET 9, 15. With respect to anti-tumour activity, three phase II studies have pointed out frequent stabilisation with somatostatin analogue therapy in progressive GEP NET 16, 17, 18. No factors predictive of antitumour activity were identified in these studies. In order to further define the profile of patients with NET likely to benefit from somatostatin analogue therapy, we studied 35 patients with NET, who were subclassified according to their slope of tumour growth.

Section snippets

Patients

From September 1992 to February 1997, 79 patients with metastatic NET were treated with somatostatin analogues at the Institut Gustave-Roussy, Villejuif, France.

The histological diagnoses of NET were reviewed in our institution. Among these 79 patients, 28 had stable disease before treatment, 16 were on another anticancer treatment or had missing data and were not included in the study. 35 patients were classified as having progressive NET according to World Health Organization (WHO) criteria

Results

35 patients had documented disease progression and were analysed. Patient and tumour characteristics are detailed in Table 1, Table 2. The median time from the diagnosis to entry in the study was 37 months, (range 3–155 months). The performance status (PS) was 0 or 1 in 94% of cases. 77% of patients had undergone surgical debulking of tumour and 74% had received chemotherapy. Most of the primary tumours were located in the small intestine and pancreas (71%). Thirty tumours (86%) were well

Discussion

In our study, somatostatin analogues arrested the growth of progressive NET in 21/35 (60%) cases for a median duration of 11 months. Moreover, two patient subgroups were distinguished based on to their tumour growth rate before somatostatin analogue treatment. Disease stabilisation was achieved in 76% of patients classified in the ‘slowly progressing’ group with a low pretreatment tumour growth rate. In contrast, stabilisation was achieved in only 33% of patients classified in the ‘rapidly

Acknowledgments

We are indebted to Lorna Saint Ange for editing.

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    This work was presented at the American Gastroenterological Association Meeting (New Orleans, May, 1998).

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