The major symptoms of neuroendocrine tumors are flushing and diarrhea. The precise pharmacology and pathophysiology of these symptoms remain obscure. Whereas most cases are associated with excessive serotonin production, there is no invariable relationship between episodes of flushing and blood serotonin levels. Some patients have low blood serotonin levels and intense flushing or diarrhea, whereas others have inordinately high levels without symptoms. Although many peptides and biogenic amines have been suspected, none have been reliably implicated as causative. While there are several potential candidates we will focus our attention upon the role of the potent vasoactive peptides, Substance P (SP) and Neurokinin A (NKA), known products of neuroendocrine tumors, in the symptom complex. Basal and pentagastrin (PG)-stimulated measurements will be made. PG is the most reliable means of provoking flushing in a controlled manner. The somatostatin analogue (Sandostatin, SMS) has been shown to ameliorate flushing and is capable of inhibiting secretion of a variety of gut neuropeptides. To determine if NKA and SP are involved in flushing, PG stimulation will be done with and without the administration of SMS and the effects upon flushing and hormonal responses recorded. When the blood levels of SP and NKA in spontaneous flushing as well as those induced by PG have been established, we will infuse SP and NKA to duplicate these levels and determine the ability to reproduce the symptoms. Patients will then receive a 6 month course of treatment with SMS and be reevaluated. In patients who initially respond but develop tachyphylaxis, we will reevaluate responses to PG and PG given with SMS. If after 6 months of treatment there is evidence of tumor growth confirmed by CT scanning and/or biochemical failure, patients will be entered into protocols for treatment with chemotherapy. These studies are designed to improve our understanding of the pathogenesis of the symptom complex of neuroendocrine tumors. If it transpires that these vasoactive compounds are implicated in the symptom complex, then therapeutic modalities directed towards molecular modification of the neurokinins may prove rewarding.
