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New Treatments for Carcinoid and Islet Cell Tumors

Carcinoid tumors are not terribly common tumors; the incidence is only 1 to 2:100,000 per year. We classify them according to whether they are foregut, hindgut and midgut. This is not an impractical issue because it implies how you should look for them and how you should diagnose them. Rectal carcinoid tumors rarely cause carcinoid syndrome. They donít have a lot of somatostatin receptors, so doing OctreoScanís and 5HAs donít make a lot of sense to stage someone with a rectal carcinoid.

If you look at the distribution of these tumors, the majority of the ones that did result in carcinoid tumor come from the ileum; the prevalence is much higher in the appendix and in the rectum, or the incidence is higher in the appendix and the rectum. Appendiceal carcinoid occurs in about 1:250 appendectomies. Itís typically found incidentally or serendipitously so people donít usually present with symptoms related to the carcinoid, per se.

Rectal carcinoids are less frequent, but they typically occur on routine endoscopies. Rectal carcinoids are usually less than 1 cm. The reason is that gut carcinoids are submucosal; therefore, they donít bleed or typically obstruct because of the tumor. They are under the mucosa. Typically local excision alone for tumors less than 1-2 cm, either excited, fulgurated or otherwise locally dealt with, is curative.

Carcinoid tumors of the small bowel metastasize and cause carcinoid syndrome. The primary location is almost always in the distal ileum and an important point is that about one-quarter of these patients will have multiple, multicentric tumors. if the surgeon is running the bowel.

Carcinoid syndrome is simply the syndrome of hypersecretion of bio-active amines and peptides from some but not all carcinoid tumors. Usually this occurs with hepatic metastases. Because you can have ovarian metastases and subdiaphragmatic metastases that bypass the liver and go directly to the superior vena cava without passing through the liver and being inactivated.

Islet cell tumors are either gastrinomas or insulinomas. Those are by far and away the two most common, and the way to differentiate them - aside from what they produce - is that insulinomas are almost always benign, gastrinomas are almost always malignant in their behavior; meaning that they metastasize. There have been other clinical pathologic classifications of these tumors. The important factor here is the heterogeneity of them. They can be extraordinarily well-differentiated, either functioning or nonfunctioning. The classic here is insulinoma.

A relatively uncommon neuroendocrine tumor of the pancreas is the VIPoma. It secretes VIP, vasoactive intestinal polypeptide, and this results in what is known as the WDHA syndrome; with watery diarrhea, dehydration, hypochlorhydria and then less frequently some of these symptoms. These are the patients who develop gallons of secretory diarrhea. The most likely second symptom in these patients is diarrhea, and this is due to gastric hypersecretion typically. So this syndrome should be looked for in patients who are not being well managed with

As with carcinoid tumors, islet cells have a long natural history and both of these tumors have variable disease courses with different therapies that seem applicable at different points in their natural history. Including periods of expectant therapy where one simply observes, in the most benign tumors. Sort of like treating the very indolent lymphomas where one can watch and

What about chemotherapy for carcinoid? The combination that was best shown to be effective in a small number of patients at the Mayo Clinic was 5FU and streptozocin. That was compared with another combination that they developed; 5FU and Adriamycin. In 1981 ECOG did a randomized trial, which is the largest trial done in this disease, to find out what the role of

If one looks at islet cell tumors, the message here is that a lot of drugs have been used. Some you have probably never heard of, like the famed maytansine. But the bottom line is that, at least at the Mayo Clinic in the early phase II studies, the responsiveness of islet cell tumors seems considerably higher than for true carcinoids. This was actually borne out in another ECOG study comparing 5FU/strep, Adria/strep and a nitrosourea call chlorazotasine that only Jim Ahlgren and I, as Georgetown graduates, would remember. Because our boss was one of the people who originally designed this drug and then brought it to clinical trials. This study was

Treating carcinoid syndrome with drugs other than chemotherapy. Somatostatin, a naturally occurring peptide, is an inhibitory hormone and it act on a number of different sites in the body. It primarily acts on endocrine and exocrine secretion and GI motility. But we also know it works on GI hemodynamics since it is mostly used, the largest volume of use, is probably not for this disease but for people with bleeding varices. This is the human somatostatin molecule and 

Thirty years ago native somatostatin was used to inhibit tumor secretion and the first tumor that was treated was at the NIH with very small quantities of human somatostatin to decrease secretory diarrhea in a patient with a VIPoma. But itís used for all of these particular scenarios and the one we are going go talk bout today is primarily for gut neuroendocrine tumors. The problem with native somatostatin is that it has a very short half-life, of less that

Subcutaneous octreotide is used to determine the tolerability and response before giving LAR Sandostatin. The common practice is to give two weeks of subcu Sandostatin and then to give the LAR injection. Continue the subcu for another two weeks until the LAR gets released and then to stop the subcutaneous variety. You can use this as salvage, much as we use MSIR and.

Now there is this other peculiar aspect of Sandostatin, which is, in the laboratory at least, there appears to be an anti-proliferative activity which might be mediated through Sandostatin receptors. It may be an autocrine growth factor inhibitor. This has been tested in metastatic pancreatic carcinoma and it was unsurprisingly a negative trial. Itís also being tested in early