What is carcinoid syndrome?
Carcinoid syndrome is not a disease, but rather a group of signs and symptoms produced upon metastases of neuroendocrine tumors that are most noted for their lack of symptoms, stated Thomas M. O'Dorisio, M.D., professor of internal medicine and endocrinology, department of endocrinology and metabolism, University of Iowa, Ames, Iowa.

Carcinoid tumors arise from cells in the endocrine system and are able to release a host of hormones, neuropeptides, and neurotransmitters including serotonin, histamine, tachykinins, prostaglandins, and kallikrein. These tumors may remain asymptomatic and "silent" for a long period of time, often being uncovered during surgery or during examination for some other medical condition. Once metastases occurs, however, the clinical signs and symptoms of metastatic spread-known as carcinoid syndrome-can result in significant morbidity and mortality. The difficulty is that generally, symptoms related to this condition are so vague that it is commonly misdiagnosed as some other more frequently seen disorder with similar symptomatology such as gastrointestinal disorders, irritable bowel syndrome, small cell lung cancer, heart disease, or asthma.

Medical management of carcinoid syndrome
Over the years, somatostatin analogues have been proven to be effective agents for the medical management of the flushing and diarrhea associated with carcinoid syndrome, according to Eugene A. Woltering, M.D., James D. Rivas, professor of surgery and neuroscience, chief of the section of surgical endocrinology, and director of surgical research for the Louisiana State University Health Sciences Center, New Orleans, Louisiana.

Somatostatin receptors are expressed on 90% to 100% of carcinoid tumors, and receptor activation leads to decreased synthesis and secretion of many bioactive substances. Native somatostatin is one of the main peptides in the body which can bind to specific somatostatin receptors, inhibiting secretion of secretagogues ranging from insulin to gastrin, 5-HIAA excretion, and motilin, the latter of which cause the flushing and diarrhea common to carcinoid syndrome.

Octreotide acetate was the original somatostatin analogue approved by the FDA for the relief of signs and symptoms of carcinoid syndrome. This preparation is 100 times more potent than native somatostatin, with the additional benefit of a half-life of 1.7 hours compared to the half-life of one to three minutes with naturally occurring somatostatin. Furthermore, the drug has been shown to be capable of blocking growth factor release, angiogenesis, peptide release, and tumor growth. In addition, in a comparison of octreotide versus cytotoxic drugs, octreotide was shown to be extremely safe. It can be given in very high doses without any serious adverse effects. Interestingly, octreotide dosing is not dependent on the size of the dose. Once the most effective dose is reached, more drug is not better.

A newly developed octreotide formulation
Recently, a long-acting octreotide formulation, octreotide acetate for injectable suspension (Sandostatin LAR® Depot, Novartis), has been approved for use, Dr. O'Dorisio noted. The new preparation is composed of microspheres of a biodegradable glucose copolymer linked to octreotide. Availability of this long-acting preparation administered as an intragluteal injection once every 28 days provides consistent steady-state plasma levels of octreotide as compared to the dosing schedule of three daily subcutaneous injections required with the immediate-release formulation.

The future of diagnosis and therapy: Radiolabelled somatostatin analogues
The newest approaches for the medical management of carcinoid tumors and carcinoid syndrome revolve around the development of radiolabelled somatostatin analogues, Dr. Woltering stated. These can be used in low doses for diagnosis and at high doses as peptide receptor targeted radiotherapy.

The first of these formulations ¹¹¹Indium-DTPA-ocreotide (OctreoScan®, Mallinckrodt Medical) now is licensed as a diagnostic, establishing the presence of somatostatin receptors or cells with appropriate imaging technology. With some experimental changes and at higher doses of 600 milliCuries or more, ¹¹¹Indium-DTPA-octreotide (SomatoTher™, LSU Medical Center Foundation) is being used therapeutically. When radiation is given in combination with octreotide, the radiation slows down blood vessel growth in the tumor while the somatostatin analogue slows down cell growth.

In a Phase II study, 85 patients, most of whom presented with neurocrine tumors, received a total of 140 treatments, 44 of whom were given one dose at 493 milliCu, 28 of whom received two doses for a total of 983 milliCu, and 10 of whom were given four doses for a total of 1,483 milliCu. The survival rates were 18.2 months in the one-dose group, 22.1 months in the two-dose group, and 19.7 months in the four-dose group. Overall, to date, over 300 patients worldwide have been treated with high-dose ¹¹¹In-DTPA-octreotide, either in clinical studies or on a compassionate basis.

A second radiolabelled somatostatin analogue also is under study-⁹⁰Yttrium-DOTA-octreotide (OctreoTher™, Novartis). Unlike ¹¹¹Indium-DPTA-octreotide, which is a γ- emitter, ⁹⁰Yttrium-DOTA-octreotide is a ß-emitter and can not be seen with a γ camera. Uptake in normal cells can be seen with PET scans and is even more evident in the organs of carcinoid patients. Phase II studies have recently been completed in a three-center trial carried out at the University of South Florida, Erasmus University in Rotterdam, The Netherlands, and Catholic University, Leuven, Belgium. Preliminary analyses demonstrated a 10% partial response rate, 50% of patients having stable disease, and 28% going on to disease progression. The preparation is now under consideration at the FDA.

A novel cytotoxic agent
While most cytotoxic chemotherapeutic agents are not of much value in treating carcinoid tumors, since these are so slow growing and cytotoxic drugs are most effective against actively growing cells, a new tubulin inhibitor, epothilone B (Novartis), with actions comparable to those seen with taxane, appears to provide significant efficacy. This novel drug blocks the polymerization of tubule vessels and is a potent antiangiogenesis agent. Given in clinically relevant doses to patients with carcinoid liver metastases, there is absolutely no capillary growth seen on the angiogeneic index scale.

It should be noted that there is a great difference between a chemotherapeutic drug that kills tumor tissue and an agent that kills blood vessels. Chemotherapy works fast, destroying the rapidly growing cells almost immediately. The antiangiogenic agent, on the other hand, takes time to get going. Initially, there is a transient growth spurt up, and then the drug's effect takes over and there is a great decrease in angiogenesis. The key here is that the tumor does not have to shrink. It is sufficient to stop growth and get stabilization.