Lowell Anthony MD: One of the very first things that any clinician will do in assessment of these patients is to determine resectability, because this is really the only time we can talk about cure. Unfortunately, that happens very infrequently. That's simply because we can't diagnose these tumors early enough to effect a cure.

Second is to intervene invasively at the time of some progressive symptoms, if things are not being controlled with medical therapy, and to integrate therapy. Really, it's not either-or. It's to see how best we can avoid a potential complication or take care of a complication, with our surgical colleagues and integrate that with medical therapy.

Holly Atkinson MD: Which presentations are the ones most amenable to surgical resection?

Holly Atkinson MD

Lowell Anthony MD: Patients who present with a specific complaint, like bowel obstruction or bleeding, will have to go to surgery regardless of where their disease metastatic sites might be. Here we're looking at surgery to control the primary complications of tumor growth, but we can also look at surgery to debulk other areas, particularly in the liver, where radiofrequency ablation can be used along with resection to decrease the tumor burden. We have found that the more aggressive we are with these patients, not only medically but surgically, the more years, if not decades, we can add to people's lives.

Holly Atkinson MD: Let's talk about cytoreductive surgery.

Lowell Anthony MD

These tumors are generally very slow-growing, so palliation can be very, very long-lasting. Therefore one will be more aggressive in pursuing cytoreduction in this type of tumor than one would be in the ordinary cancer, where the disease would be more rapid and it wouldn't be useful to palliate in this fashion.

Richard Warner MD

Thomas O'Dorisio MD: If I can follow up Lowell's point, the rationale relates to the blood supply, the circulation and the venous return for, especially, the ilial carcinoids, which are quite common and present with the obstruction initially. The superior mesenteric vein and the splenic vein come together to form the portal vein and become the one organ that seems to catch these neuroendocrine tumors. It's almost like a sponge for them, and it's really based on anatomy.

The same goes for the pancreatic or duodenal return into the splenic circulation for the portal vein. So there's another rationale for trying to remove the primary tumor when you can. I think this argues for an aggressive first-time surgery for the patients.

Regarding the cytoreductive, we have done that to show proof of concept of it, and it's as Richard says. When you take a somatostatin congener like octreotide acetate, and you put radio-iodine-125 with a very low, soft keV of 30 on it, and use a gamma-detecting counter, you can detect lesions as small as 3 mm. When you can do that type of fastidious surgery, it does just what Richard said. It takes out the factories. It takes out the hormone producers.

The best example is the fastidious dissection done for medullary thyroid cancer. The ears, nose and throat specialist will resect painfully and fastidiously all the lymph nodes, and the more nodes that he can take out, the longer the remission rate. It's dramatic.

Richard Warner MD: I would add one other comment. Whenever the surgeon is in the abdomen for one of these tumors, if it does not complicate the procedure, he should also take out the gall bladder whether there's disease or not, because of the high incidence of gallstone formation in patients who are treated with a long-time somatostatin analog therapy. They don't all become symptomatic, but enough do to make this a useful prophylactic undertaking.

Holly Atkinson MD: Interesting observation. Tom, help us think about medical therapy now. What are the broad approaches we can use for medical therapy?

Thomas O'Dorisio MD: As Krenning pointed out in the Annals of Nuclear Medicine with his large European experience, when you have a neuroendocrine tumor that is replete with somatostatin receptor subtype 2, that's predicated on the octreotide acetate, if you will, you should use as somatostatin congeners as first-line therapy. It's been shown, or at least alluded to, by Arnold in Europe -and I would stand to be corrected here-that octreotide acetate is therapeutic. Whether patients are symptomatic or they're functioning or nonfunctioning, if they have receptors you know that by the attachment of the somatostatin congener to that receptor on that tumor, the effect is antiproliferative and it's going to slow down the progression of that tumor.

Arnold has shown very clearly that you can get stabilization in 55 to 60% using octreotide acetate alone. Durability is a different issue. But clearly, for me, that would be a first-line therapy, along with the rationale of the OctreoScan, which says, "This tumor is positive with receptors."

Richard Warner MD: I think that I agree with that, but I don't believe that one should rely on octreotide as the sole inhibiting modality for tumor growth. As you heard, it works in better than half the cases, but it's very slow and gradual, and it's better when it's combined with a second inhibiting treatment of some sort.

Holly Atkinson MD: Such as?

Richard Warner MD: Such as alpha interferon, which acts synergistically, at least for midgut carcinoids and also for foregut carcinoids, and for other neuroendocrine tumors, although the latter effect has been less well established. In certain instances, another inhibiting treatment would be chemotherapy of one sort or another. But that is not usually the first line of approach.

Holly Atkinson MD: Let's concentrate on chemotherapy for a moment. Lowell, there are single agents, there's combination agents.

Lowell Anthony MD: Well, chemotherapy for the neuroendocrine tumor has to be thought of in terms of the cell of origin. For tumors that may be arising from the small bowel, particularly the distal portion of the small bowel, the fluoropyrimidines, or 5-FUs, are the most active agents singly, not in combination. Again, these are not to be used in the first several lines of treatment., but ssually after failing somatostatin analog therapy plus/minus interferon and maybe some investigational protocol.

For tumors that arise from the pancreas-and these would be the islet cells-quite a bit of work has been done looking at combination of drugs like streptozotocin, Adriamycin or Adriamycin-5-FU, and these combinations can effect some partial responses. The Eastern Cooperative Oncology Group has done the most in terms of numbers of cases. Unfortunately, these responses are not durable. They don't last for a long period of time.

We're left right now with developing new drugs, potentially cytotoxic drugs, and we've got one drug in the epothilone-B classification, a taxane-like drug that might be the first cytotoxic drug approved for neuroendocrine cancer.

Holly Atkinson MD: Lowell, tell us about the use of interferon-alpha.

Lowell Anthony MD: Interferon grew up in Sweden, in the Scandinavian countries, so most of the work that's been done in mechanisms of interferon has been done in Dr Kjel Oberg's lab. He has shown that there are specific nuclear enzymes that control DNA synthesis that are inhibited so that cell division is arrested. But interferon throws a lot of things at us. It has capabilities of activating the immune system. So it's rather than just a direct cytotoxic effect by the agent, it's more through other mediators. Potentially, inhibition of angiogenesis is another one that may keep these tumors from growing.

When I start somebody on interferon, usually they're already on somatostatin analogs and their disease may be progressing. I'll see good control of symptoms if flushing is a dominant symptom. And then usually the next scan will show stable disease. Dr Oberg has reported on a small percent of the patient set that may actually have a partial response or a true tumor reduction, but that's not to be expected with biotherapy.

Holly Atkinson MD: What do you find is the limitation to interferon-alpha?

Richard Warner MD: There are a lot of side effects. On the average, the dosage varies considerably, but in treating carcinoid or other neuroendocrine tumors, the customary dosage is about the same as used for treatment of chronic hepatitis C, mainly a low dosage. This is not the same level as used for various other hematologic malignancies.

The side effects are less with a low dosage. In fact, they correlate with the dosage. In general, Dr Oberg proposes that we regulate the dosage by the white count, and whatever dose is required to maintain the white count at a slightly reduced level of, say, 3,500 would be an adequate dose. That usually means that about half the patients will experience some muscle aches or pains, some fatigue. A few will have some nausea. A few may have cramps or diarrhea. Many will have transient fever, at least during the first six weeks or so of treatment. Some will have mood changes with depression.

Now, also, with the passage of time, antibody formation occurs, and there may be thyroid disease. Hypothyroidism is something that occurs in a significant number of patients. Consequently, thyroid function tests must also be followed periodically. In addition, depression occurs sometimes, and anybody with a past history of significant major depression really shouldn't, in my opinion, be treated with interferon, although there are some who favor using some of the newer psychotropic drugs to control that and just go ahead with the interferon. I've not felt encouraged in its use. It is useful, though, when you can do it, because it augments the effects of the Sandostatin.

Thomas O'Dorisio MD: I didn't know that about the interferon-but clearly Sandostatin in high doses can also be associated with secondary hypothyroidism, so that the combination, which has been reported to be effective, would alert the physician to watch for, you know, the ultimate result of hypothyroidism.

Holly Atkinson MD: Tom, you've raised the issue of somatostatin early on. Take a moment, and review for us what it is, what the analogs are, and what you see as the benefit to the analogs today.

Thomas O'Dorisio MD: The FDA (U.S.. Food and Drug Administration) has insisted that the pharmaceutical be called a congener, not an analog, because the amino acid residues that are put in there are not the naturally occurring L-form. They're D-forms, and that stabilizes it.
This is an eight amino acid, identical look-alike of the native somatostatin, which was initially isolated from the pituitary gland by Guillemin and reported about 1973. This was ultimately synthesized in 1980. It came out of the work of Janos Pless and his group at Sandoz, now Novartis, in Basel, Switzerland, and got into the United States and Europe for clinical development almost simultaneously.

They didn't know at the time that somatostatin has five receptor subtypes. In fact, I think this is the peptide that exists naturally in us that has the most receptor subtypes of all the peptides-gastrin, insulin, etc. So octreotide is an absolute mimic of the native somatostatin 1 to 14, but with the highest affinity for the receptor subtype 2. It happens that the neuroendocrine tumors predilect for a high affinity number of somatostatin receptor subtype 2, and that's how the development started. Ultimately, other non-neuroendocrine tumors, such as meningiomas, have receptor subtype 2. The small-cell cancer that was alluded to is really a muted cell. It's not a neuroendocrine cell per se. It transforms. And it has a high number.

Lymphocytes, when they're irritated or inflamed-lymphoma, histoplasmosis-will also upregulate receptor subtype 2, and so it's a very critical receptor. And that's why other agents are being developed, other receptors or subtypes of somatostatin. Somatostatin is the circulating pituitary gland for the neuroendocrine system, just like the pituitary controls, the endocrine organs, somatostatin circulates like a hormone to regulate the gastrin cell, the insulin cell, all of the normally secreting neuroendocrine cells.

Holly Atkinson MD: Dick, what are the key effects of the analog on the neuroendocrine tumors?

Richard Warner MD: Well, it inhibits or prevents the production, elaboration and the secretion of these products, and also blocks the target cell. It also inhibits many of the growth factors that you heard about, the trophic factors that seemed to stimulate the growth of the tumors, and also has an effect on inhibiting new blood vessel formation, upon which tumor growth is so dependent. So it works in many different ways.

Holly Atkinson MD: Lowell, how about adverse side effects? How well do patients tolerate it?

Lowell Anthony MD: Somatostatin congeners are well-tolerated. The initial common side effects might be some abdominal cramping. We have to take into consideration the inhibition of the ectocrine function of the pancreas, where the lipase enzymes may not be secreted to the same degree. So we kind of come to expect some steatorrhea. We warn the patient about that. It's more cosmetic, really, than anything really medically indicative of problems.

Generally, in starting someone on a somatostatin congener, I usually talk to the patient, very similar to the way a physician might talk to them about starting insulin. I'll be telling that patient that their blood sugar, if they've had some tendency to diabetes, is more likely over time to drift upward a little bit, where their glucophage or their oral hypoglycemic agent may have to be adjusted. In some instances, we have to start insulin. But that's not common.

Now, on the other hand, I also warn them and teach them what a hypoglycemic reaction is, and that's something that can happen with these hormones. Common symptoms, abdominal cramping seems to resolve over the first week or so. Rarely, abdominal cramping may be severe enough that the drug cannot be used.

Thomas O'Dorisio MD: The differential inhibition of the hormones with octreotide, as with native somatostatin, is that it has a tenfold greater inhibition of glucagon, which then leaves the insulin unopposed and can result in hypoglycemia. But I really agree with Lowell. I think we tend to see more of a drifting up. I haven't really been able to understand why that works-namely, that you see a hyperglycemia more than you see hypoglycemia, even though the mechanism is to suppress glucagon and leave insulin unopposed.

Lowell Anthony MD: In the early evaluation of the somatostatin analogs, it was thought that steatorrhea was going to be the dose-limiting effect. Even though that's predictable and certainly occurs, it really does not dose-limit in terms of using the drug.

We may be really looking more at a cost issue, in terms of how much we use. We want to emphasize that we need to control symptoms. Titrating the drug to diarrhea is a little bit more complicated than titrating it to flushing, because the drug can cause diarrhea at the same time that it's preventing diarrhea.

Richard Warner MD: I think that there's another point that requires emphasizing. The tumor-inhibiting or cytostatic effect generally requires a larger dose than the dose necessary to control endocrine symptoms, so it's not always necessary to give the minimum dose that will control symptoms. A larger, more generous dose is useful, because it will have a better cytostatic effect.

Holly Atkinson MD: That's an excellent point. Dick, what about the formulation itself, the longer-acting forms? Is there a difference that you see in its effect on the tumor?

Richard Warner MD: Yes, in general, because with the longer-acting intramuscular preparations, the therapeutic blood levels are maintained as a plateau without the up-and-down fluctuations several times a day that accompany the subcutaneous, immediate-release preparations. Therefore there's a more steady and continuing effect, both antihormonal and also cytostatic. I don't know of any study that has been done to compare or contrast the two preparations-in a quantitative way-but the impression has been that this steady therapeutic level with less fluctuation is generally better.

There are some patients in whom it's not so easy to obtain a good, steady therapeutic level, for a variety of reasons, but at least it should be tried.

Holly Atkinson MD: Lowell, what about second-generation, radiolabeled forms coming on line now?

Lowell Anthony MD: This is a concept that came out of Steve Lamberts's and Eric Krenning's work in 1987, when they were able to get a European grant to simply do what had been done in tissue. This was where Jean-Claude Robert was able to look at immunohistochemistry, and using autoradiography, visualize the somatostatin-staining cells. So what Steve Lamberts and Eric Krenning did was say, "We can visualize it in the tissue. We should visualize it in vivo." And with that successful development of the indium-111 with pentetreotide, in 1992 and during that era, the concept was, "Let's give higher doses of this drug and use treatment." This is where the messenger can deliver the fatal blow.
Building on some of that early experience from Brussels has increased our experience with the indium-pent peptide, because it's on the market now, and we can simply chelate a larger amount of radioactivity to the peptide and use that for treatment. The alternative is to use a different isotope, specifically yttrium-90, for this is a stronger beta emitter than the I-131 that we're accustomed to using for thyroid cancer.

These drugs have clearly given us new options. If a patient fails octreotide or interferon or surgery or any combination of those, we have something else to offer. We're not at the point of wanting to move these drugs up closer to the front line, but we've got them back there and we're still learning about them. It may be that we might be bringing them up earlier for insulinomas than for carcinoids, and this is what will be determined over the next few years as we learn more.

Holly Atkinson MD: I'd like to close this segment by having each of you give me your final thoughts-pearls, if you will-to leave with the clinician on management of these tumors. Dick?

Richard Warner MD: As far as I'm concerned, the proper approach to the long-term management of these patients is the sequential use of multiple modalities in their treatment. It's not a one-modality treatment and that's it. It's a question of choosing the right time. There will be surgery first. There will be biotherapy. There may be cytoreduction, whether it be by surgery, radiofrequency ablation or hepatic artery chemo-embolus injection. Then there will be chemotherapy following that, and then there will be also nutritional support and various drugs to help the side effects, such as pancreatic extract substitutes and so forth. And all of these, timed appropriately over a long time, will prolong the patient's survival very significantly and also make a good quality of life.

Holly Atkinson MD: Tom?

Thomas O'Dorisio MD: Even though I just learned from Dr Robert Zollinger this identifier of the gastrinoma, he always used to say, "The way you treat these tumors is by surgery, surgery, surgery." After the modalities have been tried-hepatic arterial chemoembolization, the newer drug, phase II taxane derivative-I find myself and our clinic coming back again to take out functional tumor. These are not unsophisticated tumors. These tumors make something, and by taking them out you're moving that clock backward again, as Richard says. I also believe, just like with the treatment of I-131 or the treatment of thyroid cancer over the years, that it's been surgery, and then it's been radioablation. Ideally, if we can get patients that are diagnosed early enough with minimum metastasis, we will be able to do the surgery and then do the novel radio-metal ablations that Lowell alluded to.

Holly Atkinson MD: Lowell?

Lowell Anthony MD: Holly, I think the parting line here is not to make the treatment worse than the disease. This is the balance to strike in our assessment of these patients. We want to be aggressive, but at the same time we don't want to get our goals too far out there beyond what we'd really want for our patients. We want our patients to be cured. We unfortunately can't achieve those goals, so we really have to think about control, and we don't want those methods of control to be unacceptable, so in our minds we have to be thinking, what would the disease be doing for these patients, and then what are our treatments doing, and then balancing those two things.

Holly Atkinson MD: That's a great final point.

Moderated panel discussion: management of neuroendocrine tumors

Thomas O'Dorisio MD