Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours☆
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.
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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).