Panel discussion II

Abstract

SMS 201495 EFFECTS ON TUMOR FUNCTION AND TUMOR GROWTH Dr. Larry K. Kvols: I would like to address two questions to the panel. First, does the somatostatin analogue SMS 209-995 inhibit peptide synthesis or merely inhibit peptide release? In isolated D cells from canine gastric mucosa, somatostatin’s auto-regulatory effect inhibits both release and synthesis. In normal cells, at least, somatostatin can inhibit peptide synthesis. Second, should you expect to see tumor regression with SMS 201-995 therapy as well as decreased secretion or synthesis of peptides by the tumor? Some peptides from these tumors may be growth factors. For example, bombesin in oat-cell carcinomas of the lung has been shown to be a tumor growth factor for the identical tumor that is secreting it. Possibly by inhibiting the secretion or synthesis of the tumor-produced peptide, some important trophic factors produced by the tumors could be eliminated, resulting in some degree of tumor growth diminution. We are carefully studying SMS 201-995 as we would any drug for true antitumor effect. In these studies, we found that rapid symptomatic control is achieved with SMS 201-995 in many of the syndromes. Dr. Robert Jensen: We studied SMS 201-995 therapy in six patients with gastrinoma who had not shown a response to many forms of chemotherapy and had confirmed tumor growth on imaging techniques. No tumor shrinkage was noted in any of the patients; in one patient, tumor growth may have been slowed. However, at this time, SMS 201-995 does not appear to reduce tumor size or slow tumor growth in patients with gastrinomas. Dr. E. Christopher Elllson: ‘Dr. Arthur Vinik has demonstrated angiographically a diminution of tumor blood flowless of a blush and less accentuation-following administration of SMS 201-995. Has anyone studied the development of tumor necrosis through computerized axial tomographic (CAT) scan assessment of tumor density rather than just actual tumor bulk? Do the tumor characteristics change when the tumor is necrotic? Dr. Werner J. Creutzfeldt: I would like to point out that spontaneous necrosis occurs in endocrine tumors (especially in liver metastases) even in untreated patients, although not frequently. So a 5 or 10 percent rate in treated tumors could really be spontaneous necrosis, and not an effect of the drug, especially in liver metastases. I believe that a conclusion that SMS 201-995 is a cytostatic drug would be very premature based on the few tumor regressions reported thus far. Now that these endocrine tumors are being so carefully studied and these patients are being monitored with CAT scans and other advanced imaging methods, spontaneous regressions with necrosis independent of treatment will be detected in a certain percentage of patients. Dr. Kvols: I do not think anyone is stating affirmatively that the analogue SMS 201-995 has a cytotoxic potential. In our experience, disease stability was achieved in 19 of 25 carcinoid patients treated with SMS 201-995; the median follow-up is 12 months. In one of these patients, liver scans indicated tumor shrinkage. Spontaneous regression has been very rare in our large population of carcinoid patients. This is unlike the experience with melanoma and renal cell carcinoma where spontaneous remission does compound studies of the effectiveness of therapeutic regimens. Dr. Stephen R. Bloom: How much evidence do we have that the analogue SMS actually inhibits the growth of normal endocrine cells? For example, have developing G cells or beta cells been studied with SMS 201-995 to see if their growth is inhibited? Experimental animal studies have shown that regular administration of SMS results in a fewer number of acinar cells and a thinning of the mucosa of the gastrointestinal tract. Dr. Keith D. Buchanan: Based on Dr. Johnson’s data in animals with experimental tumors, the size of the tumors did not change following SMS therapy. Dr. Bloom: In our laboratory, when we administered SMS 201-995 to animals after gut resection, the remaining gut did not show mucosal hyperplasia as it normally does. But this is not really the situation in pancreatic acinar cell tumors. We did a small trial in patients with pancreatic acinar cell tumors and found that survival seemed to be shorter in patients treated with SMS 201-995.