A CACS Special Presentation

“Carcinoid Tumors - What's A Patient To Do? The latest data on diagnosis, follow-up, and therapy”

By Professor Kjell Öberg, M.D

Saturday November 1, 2003, 10:00 a.m. - - approximately Noon George Washington University

Ross Hall, Room 117 2300 Eye St NW

Washington, DC 20037-2336 Note: Dr. Öberg is professor (and now Dean), Medical Faculty, Uppsala University, Sweden. He is the head of the Endocrine Oncology Unit and specialist in Endocrinology and Internal Medicine. He’s the founder of the Endocrine Oncology Unit, with more than 20 years experience in the field of Neuroendocrine Tumors. Between 1986 and 1992, Dr. Öberg was Clinical Associate Director of the Ludwig Institute for Cancer Research and Coordinator of the European Neuroendocrine Tumour Network (ENET). He pioneered the treatment of carcinoid tumor patients with interferon and somatostatin analogues, and described for the first time (1988) the genetic deletion in MEN-1. Dr. Oberg received in 1991 the European Interferon Research Award. He has given more than 100 lectures at international meetings and published more than 300 papers within the research field.

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Good morning, everybody. I am really honored to be here. Usually to be invited to different

scientific seminars and other meetings is an honor. But to be invited to the patients, I think that

is an even greater honor. So thank you for inviting me.

What I will do this morning is to talk to you about some new features on how to diagnose and

how to treat these neuroendocrine tumors. And I am not only going to talk about carcinoid - -

Oberg-cacs--Page 1 of 38

because usually we include in neuroendocrine tumors the carcinoids and pancreatic tumors, lung

tumors, and so forth.1

[slide 2: Neuroendocrine-GEP tumors]

These are actual tumors, and of course it’s necessary to concentrate these patients to doctors that

are interested and also to different centers. We expect the neuroendocrine gastroenteropancreatic

(gastro-entero-pancreatic) tumors to be about 1% of all tumors that are diagnosed a year. This

high figure, 8.4 per 100,000, was done in Malmo, Sweden, where they autopsied all patients

dying during a couple of years. And then they found that the incidence is very high - - indicating

that a lot of patients are not dying from the carcinoid, but they are dying with the carcinoids.

And a number of these patients were also those with appendiceal carcinoids, which are rather

benign.

In the first SEER study (a U.S. National Cancer Institute series of surveillance studies), the

incidence was 1.2 per 100,000. We did a study in 1990 on endocrine pancreatic tumors (another

member of this group of neuroendocrine tumors), with an incidence of 0.3 per 100,000. And the

prevalence of MEN1 (multiple endocrine neoplasia type 1), which is an inherited form of

neuroendocrine tumors, is about 0.2 per 100,000.

[slide 3: Incidence of Carcinoid Tumors]

Next is a newer compilation of data done by Irv Modlin (from Yale) and published in the journal

Cancer (volume 97, page 934) in March 2003, and it was a fine detailed analysis, and the

incidence for white people is 2.58 per 100,000. That is the same as in Sweden when we look at

clinically significant carcinoids. But you can see that black people, particularly black males,

have a significantly higher rate (4.48 per 100,000).

If we look at the different types of carcinoid tumors, about 42% are found in the small intestine,

27% in the rectum, 25.3% are bronchopulmonary, and stomach tumors are 8.7%. The small

intestine is still the most common area for development of carcinoid tumors.

1 The powerpoint slides accompanying this talk are available as a pdf file called - - .

Oberg-cacs--Page 2 of 38

[slide 4: The Neuroendocrine Cell]

This is a complicated slide just showing you that these are the cells where the tumor starts to

develop. This is a normal neuroendocrine cell, and this cell has the capacity to produce a lot of

different hormones. They are taking up precursors, like tryptophan, coming into the cell, and

then they make a hormone called serotonin, and serotonin is then going out from the cell to the

bloodstream, but it can also be sent into the gut lumen, and we don’t know exactly what activity

it might have in the gut lumen.

In this process, of course there are a lot of enzymes which are involved in packaging hormones.

And I’m coming back to chromogranin A (CgA), which is an important marker. It’s a packaging

hormone within the cell.

We have another one called VMAT [vesicular monoamine transporter] (VMAT-1 and VMAT-

2). Actually, what we are doing today is trying to develop a vaccine against midgut carcinoid.

And this vaccine is seeing [targeting] VMAT-2, and we hope that this new vaccine will stimulate

the immune system to attack this target.

[slide 5: Carcinoid Tumors/Secretary Products]

The carcinoids, if they are located in the midgut, have a very uniform secretion pattern:

tachykinin, serotonin, chromogranin A are the most common secretory products. But if you go

to the foregut, which means the lungs, the thymus, and the stomach, and so forth, you can see

that they can produce almost every known peptide or amine, so these patients can develop

different clinical syndromes; they can develop Cushing’s syndrome, acromegaly, and they can

get the severe flushing due to secretion of histamine, and so on.

The hindgut, the rectal carcinoids, are more indolent. They produce hormones CgA, PP

[pancreatic polypeptide], and HCG-alpha [human chorionic gonadotropin-alpha], but these

hormones do not produce any clinical symptoms (carcinoid syndrome).

Oberg-cacs--Page 3 of 38

[slide 6: Carcinoid Syndrome]

If you look at the carcinoid syndrome, you know that it includes flushing, diarrhea, right heart

failure, and bronchoconstriction. About 40% to 45% of patients present with the carcinoid

syndrome. And we know that some of these agents are causing some of these symptoms. The

flushing is mainly related to tachykinins. These belong to the family of neurokinins, and they

give this reddish or blue-reddish color in the face. Diarrhea is related to serotonin and also to the

prostaglandins, which are sometimes secreted. The right heart failure that we’ve studied quite

extensively at our unit, and we know that TGFb (Transforming Growth Factor beta) is up-

regulated on the right side of the heart, and might be responsible for the fibrotic process seen on

that side. And then bronchoconstriction: in the only 10-15% of patients developing it,

tachykinins might be responsible.

[slide 7: Two Views of Same Man]

This is a patient with typical carcinoid flushing (see slide) - - this is before and during flushing.

You can see that he is more red in this area now. And this is often due to pentagastrin. You can

provoke this flushing by giving the patient pentagastrin.

This is a patient with constant flushing. The problem for this guy is that he was a salesman

traveling in Baltic countries selling table-tennis equipment, and when he wanted to do some

business, every time he started to flush, the other person on the other side of the table thought he

was doing wrong. That’s bad business [audience laughter]. But we solved that problem for that

guy by giving him Sandostatin - - I can promise you.

[slide 8: Red-Faced Male]

Now this is constant flushing, but if you ask this guy “Are you flushing?” he says “No - - I can’t

feel anything.” He is not feeling the flushing attacks.

[slide 9: Endocrine Pancreatic Tumors & Their Products]

I said that we have endocrine pancreatic tumors, other members of the neuroendocrine tumor

group, and these are patients with different clinical syndromes. I will not discuss these in detail,

Oberg-cacs--Page 4 of 38

but some of them are very spectacular. Those patients get multiple gastric ulcers, insulinoma,

low blood sugar. This one, the Verner-Morrison syndrome, gives severe diarrhea. Some of the

patients might have 15 liters of diarrhea [per day]. And of course they are the patients in

intensive care.

The glucagonoma patients present with a special necrolytic migratory erythema, and you have

also patients developing acromegaly and Cushing’s syndrome.

[slide 10: Back View of Gaunt Man]

This is a patient with a tiny, small glucagonoma - - only a 2-centimeter tumor in the pancreatic

tail - - producing glucagon. He is a 42-year-old farmer from the southern part of Sweden. And

what we see is the significant effects of glucagons, with this muscle wasting. It’s a catabolic

hormone. You get a skin rash down here, also loss of hair, and loss of muscle. This is a farmer,

42-years-old, and what we did was we resected this tumor - - it was a tiny, small tumor, 2

centimeters - - and he became quite healthy afterward. I’ve seen him for 10 years now, and he is

still working on his farm; he has recovered completely from the loss of muscle. So as you can

see, these tumors produce a lot of factors which are so active in the metabolism in the body.

[slide 11: Neuroendocrine GEP Tumors - - List of Topics]

So what I will talk to you a little bit about is a tumor biology program we have developed in our

unit; the importance of correct histopathology, biochemical diagnosis, and some neuroimaging

procedures.

[slide 12: Molecular Genetics in Neuroendocrine Tumors]

This is a slide showing a lot of genetic changes in the tumor. People are asking how these

tumors develop. We don’t know exactly how it happens. But we know that there is a range of

different changes in the genome, in the genetic material inside the cells.

One area is the so-called MEN1 area on chromosome 11, where you have, in at least 30% of the

patients, mutations of the gene. You have what we call loss of heterozygosity. A fragment of

the gene might be lost, or also one of the chromosomes, or a part of one of the chromosomes

Oberg-cacs--Page 5 of 38

might be lost. And as you can see, there is a lot of different changes within the cell. So there is

not just one genetic change in these tumors. I think that is very important to remember.

[slide 13: Growth Factors in Neuroendocrine Tumors]

These tumors secrete a lot of growth factors. These are factors that stimulate the cells to divide

and to continue to grow. Usually a regular cell is dividing 20 to 22 times, but then they start to

grow. But these cells can then continue forever to divide, stimulated not only by growth factors,

but also other factors.

[slide 14: The Emergent Integrated Circuit of the Cell]

And this is, I think, the most busy slide; someone called it a map of the Underground in London

[audience laughter]. But actually this is a cartoon of how a tumor cell is regulated by a lot of

different factors. So just to give you an idea, it’s not one factor that is stimulating; it’s a number

of factors, and the endpoint is that they are stimulating the genome to split off and to make new

tumor cells. So there are a lot of influences, and we call this thing the “signal transduction

pathway.”

We have sorted most of this out at the moment, so now it’s for the medical industry to start to

target different parts of this signal transduction pathway. What you will see in the future is that

you will see a lot of new treatments coming which are actually targeting different important

junctions in this signal transduction pathway.

[slide 15: Two Graphs of CgA and 5-HIAA for Two Patients]

I like to show this slide because carcinoids are not always the same. These are two patients

coming to our ward at the same time - - two males the same age - - and they have a similar extent

of disease, both [have] liver metastases, and you can see that they have also increased levels of

urinary 5-HIAA. The level is also the same in this guy, but the scale is different because he had

some high levels in the end.

And this guy was started on alpha-interferon and has now been treated for 15 years and is still

controlled and is working full-time, and is doing wonderfully.

Oberg-cacs--Page 6 of 38

That other guy started on the same type of treatment, but he didn’t do so well. He continued to

progress, so we had to do chemoembolization, and had to add somatostatin. We had to add

cytotoxic agents, but despite all these efforts, he died within 7 years.

[slide 16: Two ki-67 Stains, One Above the Other]

And what was the difference between these guys? I think this is one of the explanations: this is

the [top tissue] good guy doing well on alpha-interferon, and we can see some dark spots here.

This is the ki-67 stain, which stains dividing tumor cells, and the first guy has very low

proliferation; he has only a few dividing cells, and of course he is responding quite well to

biological treatment.

This [bottom tissue] was the bad guy who didn’t do well on the treatment, and you can see a lot

of dark spots indicating that he has a lot of dividing cells, a more aggressive tumor than the

[other] one. With this [top tumor], you can live for 25-30 years. With this [bottom tumor], you

have to have very significant treatment from the very beginning.

[slide 17: Neuroendocrine Tumors: Histopathology - - Tumor Biology]

So what we are doing at our center today is that we are doing tumor biology profiles on each

patient. We take a biopsy the first time they come to us, and we analyze for the general

neuroendocrine markers (chromogranin A, synaptophysin, neurospecific amylase). And of

course we also analyze for the specific markers (gastrin for gastrinomas, serotonin for

carcinoids), but we take these markers, proliferation marker ki-67, adhesion molecules (I will not

try to talk about that, but CD44 is an adhesion molecule), and then we have angiogenic factors,

VEGF [vascular endothelial growth factor], bFGF [basic fibroblast growth factor], TGF

[transforming growth factor]-alpha, and what we are rather proud about is that we can analyze all

the somatostatin receptors, the expression on the tumor cells, we have specific antibodies for

receptors type 1 to type 5.

[slide 18: Tumor (Red/Orange Staining)]

Oberg-cacs--Page 7 of 38

This is a carcinoid tumor (for those not seeing them or reading textbooks), and as you can see,

this is a very small tumor growing below the outer layer of the intestine. And sometimes you

can have up to 30 of these small tumors in the distal part of the island. It is staining with

chromogranin.

[slide 19: Two Columns of 12 Stained Tissue Samples]

This slide is staining with somatostatin receptors for a carcinoid tumor. This area is receptor

type 1 and type 2. As you can see, type 3 is also very specially expressed. Type 4 is heavily

expressed, but type 5 is not that much expressed in this tumor.

We can also stain for blood vessels which we have seen, and you will have expression of the

different somatostatin receptors also in the blood vessels, which makes it a good target for

antiangiogenic treatment.

[slide 20: Neuroendocrine Tumors - - Biochemistry]

What about the biochemistry - - what shall we do today in terms of the biochemical markers? I

hope that everyone has chromogranin A analyzed. I think that is the most important tumor

marker we have at the moment. We developed it 15 years ago, and I think now most centers

worldwide [have] actually accepted that as a good model.

Chromogranin B can also be analyzed. Pancreastatin is another general marker. HCG subunits

mostly indicate a more malignant behavior of the tumor. Pancreatic polypeptide is also

increased in some patients.

And then, of course, we have specific markers (5-HIAA) for the carcinoid syndrome itself. And

we have stimulatory tests which can also be performed in selected patients.

[slide 21: The Chromogranin Family]

The chromogranin family [of markers] consists actually of 5 members, but these are the most

common partners of the family - - chromogranin A and chromogranin B - - and are analyzed in

many centers today.

Oberg-cacs--Page 8 of 38

[slide 22: Chromogranin A-Related Peptides]

The molecule is like this: it’s glycoprotein, 439 amino acids, and the interesting thing with this

molecule is that they have splicing areas so small that their fragments can be spliced. Also as

you can see, we have the group of peptides called vasostatins; we have a group of peptides called

pancreastatins; and we have [a group of peptides in] the c-terminal called parastatins.

We can analyze all these different fragments, and we can get different patterns. And at the

moment we are putting together a paper indicating that these vasostatins are significant

prognostic markers in carcinoid tumors. Low levels of vasostatins are a good prognostic factor.

[slide 23: Chromogranins in Plasma - - Comparing Different Neuroendocrine Tumors]

We developed this assay a couple years ago as I mentioned. The CgA is very good to

discriminate between patients with tumors and normal individuals. The same for CgB.

Pancreastatin is a problem. As you can see, there is an overlap between healthy individuals and

patients with carcinoids and neuroendocrine pancreatic tumors. And the reason for that is that

some of these tumors can’t splice off pancreastatin from the mother molecule, and therefore

centers measuring pancreastatin might have a lower sensitivity in that assay.

[slide 24: Endocrine Pancreatic Tumors (EPT) - - Localization Procedures]

Localization is very important. So when you have done the biochemical workup, you have done

the histopathology workup and the tumor biology, you have to localize all the tumor mass you

have. And as you can see, ultrasonography, CT, and MRI are not good to diagnosis primary

tumors, [although] metastases are seen quite readily, particularly liver metastases [with these

methods].

Somatostatin receptor scintigraphy [known to many patients as octreoscans]- - I am coming back

to that - - is a very important imaging procedure for staging of the disease. Then we have

endoscopic ultrasonography, particularly useful for patients with endocrine pancreatic tumors.

Oberg-cacs--Page 9 of 38

[slide 25: Localization of Pancreatic Neuroendocrine Tumors - - Univ. of Michigan]

This is a study done at University of Michigan. They did endoscopic ultrasonography on

patients with endocrine pancreatic tumors, and the sensitivity and specificity were very high,

93% to 95%. So actually this is a good method to detect small endocrine pancreatic tumors.

[slide 26: Octreoscan - - (Showing Use of Indium-111)]

Octreoscan is, I think, one of the most important scanning procedures which has been developed

in the last 10 years. We are using the isotope indium-111 (In111). That is then coupled to the

octreotide molecule (as you’ll remember; commercial name Sandostatin), and giving this

radioactive substance, you can get a picture like this.

[slide 27: Carcinoid Tumor - - 2 Scans, Side-by-Side Figures]

We’ve got a lot of metastases in this patient with carcinoid, and you’ll see also lumped down

here the mesentery metastases.

[slide 28: Somatostatin Receptor Scintigraphy - - Foregut Carcinoid Tumor]

And this is another patient with a foregut carcinoid - - you’ll see the lung tumor up here - - and

you can see a lot of liver metastases.

This is very important as a diagnostic procedure, and I think everyone of you should have an

Octreoscan done at least once during the workup of your tumor.

[slide 29: Positron Emission Tomography (PET)]

This technique is available also in the U.S., but not with the tracers we have developed (very

short-lived tracers, carbon-11, oxygen-15, nitrogen-13, and gallium-68). [The U.S. uses]

fluorine-18, or FDG [fluorodeoxyglucose]. It is used for detection of other malignant tumors,

but it’s unfortunately not working in carcinoid tumors. So for detection of carcinoid tumors, you

must [use] 5-HTP labeled with carbon-11.

Oberg-cacs--Page 10 of 38

[slide 30: Flow Chart of Isotope Synthesis and PET Scan at Uppsala University]

This is the PET center we have at our university. We have a cyclotron, and we have a synthesis

area where a lot of robots are actually doing the work. We have an analysis area, and then we

have a lot of cameras.

[slide 31: Radionuclide/Decay Time]

We are using these short-lived isotopes, carbon-11, oxygen-15 particularly, and you can see the

half-life is very short, so you must have the cylotron in-house.

[slide 32: Tryptophan and Related Compounds]

When we developed this tracer, we were looking at precursors of serotonin synthesis, because we

were knowing that they could be taken up by tumor cells. So we started with tryptophan, one of

the precursors, but it didn’t work quite well. Then we went to the next step, 5-HTP [5-

hydroxytryptophan], and that was lucky for us. It turned out to be a very good tracer - - so we

labeled 5-HTP with carbon-11, and we’re using that as a tracer.

[slide 33: Other Scans]

And this shows a patient who came to us because all other methods to reveal the tumor had

failed. This is a 40-year-old lady with an ectopic Cushing’s syndrome, and she was really in bad

clinical condition. They couldn’t find the tumor by other means of investigations, so we made a

PET scan, and we could demonstrate the tumor in the lung. We could also demonstrate the

metastases in the mediastinum, and the patient was operated on in our center, and she is now

cured.

[slide 34: 5-HTP PET Showing Multiple Pancreatic Tumors in a Young Woman with

MEN1]

Multiple endocrine neoplasia type 1 is an inherited form of neuroendocrine tumors, and these

tumors are very small - - from 1 millimeter up to a couple of centimeters. And I think that this is

Oberg-cacs--Page 11 of 38

the first time you can demonstrate that you have multiple tumors within the pancreas. This is the

pancreas of this patient, and what you can see here are multiple small, small tumors all [through-

out] - - and then you have a big lump in the pancreatic head. And of course, this is important for

the surgeon to know before he goes in to operate on such a patient.

[slide 35: Method 2 (Comparing Types of Scans)]

So what we did now is that we compared the efficiency and sensitivity of the PET scanning with

other methods of investigation - - with somatostatin receptor scintigraphy, and also with

computerized tomography, and these are the patients we included in the study: 16 patients with

midgut carcinoids, 7 with lung carcinoids, 2 with thymic carcinoids, 4 with

gastrinomas/insulinomas of the pancreas (some nonfunctioning endocrine pancreatic tumors),

and 2 with foregut carcinoids (which were unspecified locations from the beginning), and 1 with

paraganglioma. You’ll see that there are a number of other neuroendocrine tumors also which

can be included. And we also have 2 endocrine pancreatic cancers.

[slide 36: Results 1]

PET could visualize in these 38 patients. In 95%, it could visualize the tumor, compared to 84%

for somatostatin receptor scintigraphy, and 79% for CT. So it is superior to all other diagnostic

procedures. And just to show you the efficacy, and efficiency and sensitivity of this method, this

is the PET scan from the patient, and this is the somatostatin receptor scintigraphy. [In the PET

scan,] you can clearly see the metastases, and also the metastases here in this patient. But [in

the] somatostatin receptor scintigraphy - of course you see some blurring here, which can be

interpreted as tumor - - but you can definitely not see anything in this area because you have this

uptake in the spleen.

So the resolution is significantly better for PET scanning than for somatostatin receptor

scintigraphy.

[slide 37: Results 2]

And this is another patient where we have these primary tumors in the pancreas, but we have also

metastases here. And when you go to the somatostatin receptor scintigraphy, of course you can

Oberg-cacs--Page 12 of 38

see the primary tumor down here. But you can’t see the metastases here (you can’t see the

uptake in this tumor) because you have a normal uptake in the colon.

[slide 38: Results 3]

And this is another patient presenting with liver metastases, and the primary tumor in the lung,

and this is the somatostatin scintigraphy, and you can see uptake here, and here, and here. This

is the normal uptake in the pituitary; this is the normal uptake in the thyroid; and perhaps this is

the uptake in the primary tumor - - but you are missing the liver metastases.

So I think there’s no doubt that PET scanning is the best procedure at the moment. The problem

is that there’s only one center which can provide this isotope. We are trying to see if gallium-68

could be as good as carbon 11-5-HTP. If so, every center can, with a PET camera, get gallium-

68 working, and then we can spread this method worldwide.

[slide 39: Neuroendocrine Tumors - - Diagnosis - - Conclusion]

So if I summarize the diagnosis, I conclude that chromogranin A is a very important general

tumor marker. I think everyone of you should have this test done. We have also this

histopathology investigation which should be performed on all tumor specimens: ki-67 staining.

It is very easy to do. You can do it on old [biopsy] material from the first operation; you don’t

have to take a new biopsy for that. Somatostatin receptor scintigraphy should be performed in

every patient. It’s important for staging and content of somatostatin receptors.

Endoscopic ultrasonography is just for endocrine pancreatic tumors. And we are able to analyze

somatostatin receptor subtype in the tumor, and this is important for the future when we get new

analogs.

[slide 40: Diagnostic Algorithm for NETs]

So if you have an algorithm, or however you want to diagnose a patient who has symptoms of a

neuroendocrine tumor, we do the biochemical workup. Then we proceed with the somatostatin

receptor scintigraphy. If that is positive, we go directly to CT/MRI, and ultrasonography with a

biopsy to get the correct histopathology.

Oberg-cacs--Page 13 of 38

If the somatostatin receptor scintigraphy is negative, we go for a PET scanning, and usually that

becomes positive in 95% of the patients, so we can go on in the diagnostic [process].

Treatment

[slide 41: Treatment Rationale]

So now I will discuss treatment. At least at our center, the majority of patients present with

metastatic disease, and there is the patient’s and doctor’s delay due to some vague carcinoid

symptoms. I can assure you that the median delay for a carcinoid patient to come to a doctor, or

to get the correct diagnosis is median 4.5 years. We did that analysis in over 380 patients with

classical midgut carcinoids.

[slide 42: Treatment Rationale Cont’d]

We have a wide spectrum of clinical course. Many of the tumors are indolent, demonstrating the

first guy with a low proliferating tumor, but there are also patients with a rapid progression, and

there’ll be death within 6 months. And you have sometimes life-threatening clinical symptoms

due to excessive hormone production, and you saw that guy with the glucagonoma, how

intensive the catabolic action was in his body.

The tumor releases substances which can be used for diagnosis, which is good, and also as

surrogate markers during treatment to follow. And there is a unique expression of peptide

receptors, not only somatostatin receptors, which we can use for the skin, and for the treatment in

the future. They can also express VIP [vasoactive intestinal peptide] receptors, substance P

receptors, neurokinin A receptors, and so forth.

There is a slow tumor progression which makes it possible to test different treatments - - and

good performance status despite extensive disease. I have patients with their abdomens full of

the [enlarged diseased] liver, and yet they have normal liver function tests, and they have a very

good performance status.

Oberg-cacs--Page 14 of 38

[slide 43: Therapeutic Objectives]

The objectives of when we want to treat these patients is, of course, amelioration of clinical

symptoms. We want to abrogate the tumor growth, improve and maintain quality of life - - I

think this is very important - - and prolong survival.

[slide 44: Therapeutic Options]

And these are the therapeutic options we are able to perform today. And so it is very important, I

think, [that] the medical oncologist should have a good collaboration with a surgeon trained in

this area because today this surgery is really more aggressive than it has been for the previous 10

or 15 years. We do more resections. We do more debulking procedures and bypassing

procedures, [and more] radiofrequency treatment, and laser, and in selected patients, also liver

transplantation.

And we have a regular conference with the surgeons every week seeing most of our patients. We

have a 15-bed ward for just patients with neuroendocrine tumors, and we see about 35 patients a

week.

We perform embolization and chemoembolization to reduce the tumor masses in the liver.

Irradiation can be performed externally, or irradiation particularly for bone and brain metastases.

But today, tumor-targeted treatment is mostly performed in terms of radiation treatment. I’m

coming back to that.

Medical treatment includes cytotoxic agents, alpha interferon, and somatostatin analogs.

[slide 45: Hepatic Artery Embolization]

Hepatic artery embolization is quite effective in reducing the symptoms and also the tumor

masses. And these are some studies I have listed here, but the chemoemboliztaion seems to be a

little bit more effective than plain embolization, in terms of response rate, and in terms of median

duration.

Oberg-cacs--Page 15 of 38

Unfortunately these are really toxic procedures, and some patients are actually dying during the

chemoembolizations, so we are really reluctant today to do chemoembolizations. We are doing

plain embolizations, and instead you are seeing other new treatment procedures.

(Question from the audience: “When you say ‘median duration’, is that duration of treatment?”)

(Answer: Yes. Median duration means from the start of treatment until failure.)

[slide 46: Cytotoxic Therapy in Carcinoids]

The cytotoxic treatment in carcinoid is very dismal. There has been over the years a lot of

substances tested, as you can see, and the objective response rates have been very low; usually

it’s down to less than 10%. I mean, these figures with 40% - - no one has been able to reproduce

that data, and we had a response rate of [only] 10% in a large study we did with streptozotocin

and 5-FU [5-fluorouracil].

So for classical midgut carcinoid, the cytotoxic treatment is not first-line treatment. That is an

important message.

[slide 47: Cytotoxic Therapy for Endocrine Pancreatic Tumors]

For endocrine pancreatic tumors, there is a clear difference. There you have a combination of

streptozotocin and doxorubicin and 5-FU. You have a response rate of about 60%, or almost

70%. And these responses might be long-lasting. So for endocrine pancreatic tumors, cytotoxic

treatment might be a first-line therapy.

[slide 48: Treatment of Undifferentiated Neuroendocrine Tumors]

Treatment of undifferentiated or low-differentiated neuroendocrine tumors, this is a really bad

time for a neuroendocrine tumor. It includes endocrine small-cell carcinoma and atypical

carcinoids, and a lot of these tumors with high proliferation capacity. And there we’ve been

using cisplatinum, etoposide, and we have also just published our own study presenting the same

results, complete and partial remission, in about 65%, and a rather long survival for this serious

type of neuroendocrine cancer.

Oberg-cacs--Page 16 of 38

[slide 49: Interferon on Cover of Time Magazine: The “It” Drug for Cancer]

So what about interferon? Actually in the early 1980s, many physicians believed that interferon

was the “it” drug for cancer; they believed that it could cure all patients with cancer, and of

course that gives drawbacks. So today there are just a number of tumors that are sensitive to

interferon, and these are including midgut carcinoids. for which it has been registered for use in

Europe and in Canada, but not in the U.S. today. And there are other non-Hodgkin’s

lymphomas, malignant melanomas, and some other diseases, such as chronic mylogenous

leukemia, and so forth.

[slide 50: Alpha-Interferons (brands available)]

Today we have no leukocyte interferons. We are working with recombinant interferons which

are synthetically produced, and these are the compounds which are available. For example,

[there is] Intron A. This is the regular short-acting form, 3 to 5 million units, 3 to 5 times per

week, subcutaneous. And you can use PegIntron A, which is 75 to 150 micrograms per week,

subcutaneous. This is the long-acting formulation. Or Roferon - - this is the regular Roferon,

and this is the long-acting Roferon.

And I think it is very important to make an individual treatment for the patient, and we have

tested out that the leukocyte count might be very good to get an idea about the efficacy of alpha-

interferon. So we want to have a dose, individually titrated, so the patient has a leukocyte count

of about 3.0 or below.

[slide 51: Graph of “B.K.’s” Carcinoid]

This is just a patient with carcinoid. She was treated [initially] with streptozotocin and 5-FU

which was the standard treatment in the early 1980s. She progressed in hormone levels and also

tumor size, and then we gave her alpha-interferon, and it took 8 years to come to normal levels.

But she still has tumor left, so the interferon is not actually curing the patient, it’s controlling the

disease, such as how the somatostatin analogues also are acting. It’s a cytostatic effect, not the

cytotoxic effect.

Oberg-cacs--Page 17 of 38

[slide 52: Therapy with A-Interferon (IFN-alpha) in Patients with Midgut Carcinoids]

This is a summary of different studies. Today more than 1,000 patients have been treated with

alpha-interferon, mostly in Europe and Canada, and the biochemical response rate is about 50%

to 60%. Subjective response is up to about 72%, and tumor volume responses only 10% to 15%.

The thing is that when you look into those patients with stable disease, you can find that most of

the tumor is no longer tumor cells, but fibrotic tissue, which can not be delineated by standard

CT or sonography. So there are changes happening within the tumor which cannot be detected

with standard procedures.

[slide 53: Human Somatostatin/Octreotide Acetate/Lanreotide]

Human somatostatin 14 was the compound I actually worked with in the mid-1970s. You can

infuse it into your patients and get a good effect on the flushing and diarrhea, but the patient

couldn’t get it at home because the half-life was only 2 hours. So it was really an advantage

when the first somatostatin analogue developed, an octreotide acetate developed by Novartis. At

that time, [the pharmaceutical company] Sandoz [later merged into Novartis] was really a step

forward and made a revolution for patients with the carcinoid syndrome. [Hence octreotide was

called Sandostatin.]

This is an octreopeptide, and [in] this part of the molecule you’re seeing the somatostatin

receptor, receptor type 2, and receptor type 5.

A couple years of later, Ipsen [pharmaceutical company] developed lanreotide {commercial

name Somatuline], which is also an octreopeptide with a similar binding profile to receptor 2 and

receptor type 5.

And these two substances are, at least in Europe, available. I know that lanreotide is coming also

to the U.S., and I think in a couple of years, you might have the long-acting formulation of both

lanreotide “ultra yield” and lanreotide prolonged release.

Today you have the long-acting formulation of octreotide, Sandostatin LAR.

Oberg-cacs--Page 18 of 38

[slide 54: Tumor Tissue with Octreotide]

This is just to show you a beautiful staining with antibody for somatostatin receptor type 2,

which can be performed on tumor tissue. This is a classical midgut carcinoid appearance on the

histopathology, and you can see the beautiful stain on the plasma membrane of the tumor (this

brownish color indicating that you have a significant content of somatostatin receptors in your

tumor), and that is a good background for treatment with octreotide.

[slide 55: Graph of Hormone Levels Before and After Sandostatin Therapy]

And when you give octreotide, you get the following: you get a drop in the circulating hormone

levels, neurotensin, VIP, PP (Pancreatic Polypeptide), and motilin. In this particular patient, all

went down to normal levels. So it’s quite effective in blocking the release of hormones and

peptides from the tumors.

[slide 56: Two Pairs of Legs With/Without Skin Rash]

This is a patient with a glucanoma. It’s not the same guy as I showed before. It’s another

patient, and you can see the skin rash (necrolytic migratory erythema), and this is after 10 days

of this octreotide treatment that significantly cleared the skin rash. Usually these patients

[are referred by] the dermatologist because they believe that they have an eczema. But then

when you take a biopsy, or if the physician is a trained dermatologist, he can always recognize

the glucagonoma with its necrolytic migratory erythema.

[slide 57: Neuroendocrine Tumors - - Somatostatin Analogue Therapy - - Summary of

Several Trials]

If you look at responses to somatostatin analogues, we are using standard doses up to 1,500

micrograms per day, which means 500 micrograms, 3 times per day. We have high-dose

treatment, more than 3,000 micrograms per day, and then we have ultra high-dose treatment

which we have performed with 160 milligrams per 4 weeks once a month. And then we have the

slow-release, 20 or 30 (up to 60) milligrams every 2 to 4 weeks.

Oberg-cacs--Page 19 of 38

If you look at symptomatic improvements, it is quite similar between slow-release and standard

dose. High dose is not giving more symptomatic improvement in these studies. Biochemical

responses are quite similar, but if you look at tumor responses (significant tumor shrinkage), it is

higher in the group of high dose, and if you go to ultra high dose, it’s even higher than 11%.

[slide 58: Quality of Life - - Lanreotide PR - - European Multicenter Trial]

Quality of life was a study we did (a European multicenter trial) with 55 patients with

neuroendocrine tumors, mostly carcinoid patients. And you can see a significant improvement in

a lot of different functions indicating that somatostatin analogues are significantly improving

quality of life in the patients with neuroendocrine tumors.

[slide 59: Endocrine Pancreatic Tumors - - Combination Therapy with Alpha-IFN and

SMS (Octreotide/Somatostatin)]

What we did a couple of years ago in our lab was that we examined the effect of alpha-interferon

plus somatostatin on tumor cells in culture, and later on, transplanted to nude mice. And what

we could see was that you have a synergistic effect of the alpha-interferon when you combined it

with the somatostatin analogue.

And this is a study in neuroendocrine pancreatic tumors, and what you can see is that you have a

significant [response]. These are patients who are resistant to either interferon alone or

somatostatin alone, so they are resistant to both of these as a single drug, but when you combine

[them], you can get significant responses, and you go to rather larger radiological responses in

25% of these patients, with the long duration of 23 months.

And we have also biochemical responses, and what is quite significant is a medium survival from

diagnosis of 70 months, which is very long for this group of endocrine pancreatic tumors.

Usually, these patients have a survival rate of about 18 to 24 months, and, as you can see with

this combination treatment, we can reach significantly long survival, with 9 of the 16 still alive.

[slide 60: Malignant Neuroendocrine GEP Tumors (Diagnosis to Treatment Chart)]

Oberg-cacs--Page 20 of 38

What we are doing today in our center is to try to get a good diagnosis very early on. [We look

at the] pathology [using] ki-67, molecular genetics, tumor biology, localization with somatostatin

receptor scintigraphy, and PET scanning, and of course [get a] good staging of the disease. Then

we discuss with our surgeons what they can do for reducing the extent of the disease; surgery or

different types of surgery, embolization, radiofrequency laser treatment, and if it’s a low-

proliferating tumor, they receive after or during the surgery, biological treatments, somatostatin

analogues plus alpha-interferon, or somatostatin alone, or interferon alone - - and then in high

proliferating tumor [cases] (ki-67 more than 10%), they receive cytotoxic treatment from the

very beginning.

In progression, this group of patients can receive cytotoxic treatment, but this group gets no

value from biotherapy, so they must go to tumor-targeted treatment [such as] yttrium-90 (DOTA-

octreotide), Lu-177 (DOTA-octreotate), or experimental protocols such as Gleevec, angiogenesis

inhibitors, and a new somatostatin analog called SOM230.

[slide 61: Treatment of NETs - - Future Aspects]

What can we do for the future? I didn’t show you but these patients express tyrosine kinase

receptors. This is very important, because many of you know of imatinib (Gleevec). Gleevec is

binding to c-kit and PDF-alpha and beta receptor. But also the EDF [epidermal growth factor]

receptor is expressed on carcinoid tumor cells, so they can, for example, also consider Iressa as a

treatment. SOM230 is a new somatostatin analog which is seeing [targeting] receptor types 1, 2

and 3, but not 4, but 5. So 4 out of the 5 somatostatin receptors are binding SOM230

somatostatin analog, which we expect to have quite significant effect in carcinoid patients. And

the trial will start in January in both Europe and the U.S.

Rapamycin is quite an interesting product. It was initially developed for preventing rejection

after transplantation, and then they noticed that it had an anti-tumor effect. So what we have

done now in the lab is that we have looked at tumor cells from the patients and also the [human

endocrine pancreatic] cell line called Bon1. And notice that rapamycin has a significant anti-

tumor effect, and we plan to start phase 1 and phase 2 trials with this compound early next year.

Oberg-cacs--Page 21 of 38

[Dr. corrects the slide] This should be Lutetium, not Latetium, but Lutetium-177 octreotate. And

this is a new tumor-targeting treatment. Octreotate is a compound very similar to octreotide, and

it goes into the tumor cells and causes a very strong irradiation of the tumor cells. And the

preliminary results from Rotterdam during the first Phase 1 trials are indicating response rates of

about 50%.

For antiangiogenesis, we have a new compound ZD6126, which is quite interesting. It has an

effect directly on the blood vessels leading to the tumor, and we have a vaccination program (as I

indicated previously in my talk), that is a gene therapy program where we tried to target the

tumor angiogenesis, not the tumor cell by itself.

[slide 62: Glory Lily Tiger Claw (Gloriosa superba)]

This is a very beautiful flower (Gloriosa superba or glory lily tiger claw), and from this flower

AstroZeneca [pharmaceutical company] is now developing this compound ZD6126, which is a

very important antiangiogenic agent.

[slide 63: Host Phenomena: Angiogenesis, Invasion, and Metastasis]

A tumor can’t live without blood vessels. It needs nutrition, it can’t [grow] larger than a couple

of millimeters without blood supply. So what we have is a significant blood supply to the tumor,

and we have also newly formed blood vessels, so-called “sprouting” to new metastases. So this

new compound ZD6126 is actually targeting already formed blood vessels. So what is

happening is the blood vessels die, and the endothelial cells disrupt, and the blood supply is

“clotting” the blood vessel, and the blood supply goes down, and it causes a significant reduction

in the tumor mass.

[slide 64: Patient 25a/Treatment with ZD1626 Causes Blood Flow Decrease in Liver

Metastasis (Colorectal Primary)]

And this it just to show you one of the early studies. This is done in a colorectal patient.

This is a new type of magnetic resonance imaging (MRI) where we can study the blood flow.

And the red one is the very high blood flow in this metastasis in the liver And you can see

already after 6 hours of giving this compound, there’s a significant reduction, and after 24 hours

Oberg-cacs--Page 22 of 38

it is completely absent; all the blood supply goes away, and of course, the tumor cells are dying.

The problem is that you have a rim of tumor cells under the membrane to normal liver tissue, so

after 3 weeks, it started to develop a new blood supply, and you can see it’s coming back.

So what we are planning to do in our first studies after these very rapid killing of the blood cells,

[is] we are also combining this compound with alpha-interferon to prevent regrowth of the tumor

vessels afterwards. We strongly believe that this is a really important treatment for many

patients in the future.

And so I thank you for your attention. APPLAUSE. 62 min 35 sec

Oberg-cacs--Page 23 of 38

QUESTION AND ANSWER PERIOD

Q1. I wonder if you would talk about treatments for other kinds of carcinoid metastases besides

liver metastases, such as bone (which my husband has).

A. Actually all the standard treatments have been tested. We usually go for one of the

radioactive treatments, such as yttrium-90 or indium-111 octreotide, or now the lutetium-177

octreotate. Together with that we also give tiludronic acid [one of the bisphosphonates], which

is used for the development of the bone.

Q2. Any data on how effective this has been?

A. For both lutetium-177 and for yttrium-90, we have data. The response rates are still only in

the range of 45% to 50%. But what it does is not only reduce the tumor size, it’s also preventing

further growth of the tumor. So, besides the 45% to 50% response rate, you have another 30%

[with] stabilization of the disease. I think that’s quite effective. Another protocol of course

might be the new Gleevec study or Iressa study. The Iressa is just ongoing down in Houston at

MD Anderson [Cancer Center].

Q3. (Female voice with related question but unknown question)

A. But not the bone? Okay. And of course then we have these new antiangiogenic treatments

rather than use somatostatin analog SOM230 with a very strong effect on Insulin Growth Factor-

1 (IDF-1). So there are a lot of new compounds, and I think in the future we might make a very

individualized treatment for each patient based on the tumor biology program, so every patient

gets a different kind of treatment, and often a combination of different drugs from the very

beginning. Okay?

Q4. With an unknown primary and carcinoid syndrome, would the PET scan be more effective

than the octreotide scan?

A. Definitely it is more effective. We get a lot of patients with unknown primaries sent to us for

detection, and as you saw, 95% of the tumors could be detected. The only patients we fail are

those with low differentiated neuroendocrine cancer, because [this type of] neuroendocrine

cancer cells are not taking up 5-HTP, and the reason is that they don’t have the enzymes

Oberg-cacs--Page 24 of 38

necessary for that. So only the very low differentiated cancers are missed by PET scan.

Otherwise, we can see patients down to 2 millimeters [in tumor size].

Q5. How important do you feel that the 24-hour scan is for the Octreotide scan?

A. A usually standard procedure is either a 24-hour or 48-hour scan. But I was quite struck

when I visited Cedar Sinai in Los Angeles when I was on the west coast, and they were doing

scanning after 1 week. And they could have a good resolution after 1 week. So they were

claiming that they had better scanning with this long 1-week scan.

Q6. It’s interesting to hear you say that because you don’t know which one to insist on.

A. Oh yes. But the standard is either 24 hours or 48 hours, not longer.

Q7. Is a biopsy necessary to confirm carcinoid syndrome?

A. Actually, you should always have a piece of tumor. So if you have been operated on for the

primary tumor, or for a metastasis, of course that’s enough and you don’t have to take another

biopsy because you can do most of the tumor biology workup on the old tumor tissue. But if you

don’t have any tissue available from your tumor, you should definitely have a biopsy taken, and

then of course do the ki-67 [stain] and all the other tumor biology procedures.

Q8. How do you treat people with unknown primaries, since here in this country, a lot of doctors

refuse to treat with Sandostatin if they can’t find the tissue?

A. Actually if a patient presents with an unknown primary but has the carcinoid syndrome with

diarrhea and flushing, we put them always on Sandostatin, and in the meantime, we do all the

necessary workup; we do the PET scanning and all that stuff to find the primary tumor and to get

the correct diagnosis. In our material of more than 1,000 patients with carcinoid, I think we have

only 4 or 5 patients with still unknown primaries. We detect them everywhere.

Q9. Doctor, are you finding that the body becomes resistant to Sandostatin after 2 or 3 years?

A. Yes, that’s quite often. Unfortunately, it happens. And sometimes it starts after only 9

months of treatment with the long-acting formulation. And usually it starts already after 15

months with the long-acting formulation. And the good thing with the alpha-interferon

Oberg-cacs--Page 25 of 38

combination with Sandostatin is that you prevent this resistance, this tachyphylaxis, so it comes

later on, and you can also take a Sandostatin rest and continue with alpha-interferon, and then

after 3 to 6 months you can [re-introduce] the Sandostatin again and continue with the

combination. Another good thing with the combination is that you tolerate the side effects of

interferon better when using it in combination with the Sandostatin. And you have a synergistic

effect on the tumor in terms of anti-proliferation.

Q10. So are you recommending the alpha-interferon from the outset, or only after it appears that

you have become Sandostatin resistant?

A. Actually in practice if you have a typical carcinoid, you have no symptoms, but you have

been diagnosed for some reason, perhaps you have an obstruction of the intestine, and you go for

an operation, and you have some lymph nodes left after the primary operation; I recommend that

you start with alpha-interferon if you have no symptoms. If you are still in progression in terms

of an increasing chromogranin or if you have any increase in size on CT scan, we add

somatostatin analogue. On the contrary, if you have a tumor which already from the very

beginning presents with clinical syndrome, you’ll start with somatostatin analogue, and you can

add alpha-interferon afterwards.

Q11. What is better: treatment with alpha-interferon alone or Sandostatin alone?

A. Often it’s a matter of cost-effectiveness because both these are rather expensive drugs. In

many patients you can manage quite well on alpha-interferon alone, or on somatostatin

[analogue] alone. But I strongly recommend for long-term management - - and most of you need

long-term management - - I think that a combination of alpha-interferon plus somatostatin

analogue is superior to single treatment.

Q12. How often does the resistance to the somatostatin occur?

A. Actually, I think it’s occurring in 65% to 70% of the patients if you wait long enough. Some

of them start after 9 months, and some of them after 15 months, and some of them after 25

months.

Q13. Does it matter whether it’s subcutaneous [Sandostatin injections] or the LAR?

Oberg-cacs--Page 26 of 38

A. We have a feeling that LAR is giving more resistance than the subcutaneous, and what we

are doing in some patients is that we are taking out the LAR, giving the patients sub-Q for 3 to 6

months, and then we can go back to the LAR again after the 3 to 6 months.

Q14. What are signs of resistance?

A. It is increasing clinical symptoms, increasing hormone levels, and sometimes also increasing

size on CT.

Q15. If a patient was interested in coming to see you to have the PET scan [what would they

do?]

A. Usually they send me an e-mail. (audience laughter) And then we can work everything out.

Usually I ask for their medical reports so I can see what has been done before, and then we make

a program. Not only for PET scanning, but we can also make the tumor biology workup if you

bring your tumor tissue or slides. We can also take necessary biochemical markers.

Q16. For people going to Sweden from America, how much does it cost them or their

insurance?

A. Actually, the PET scanning costs about $3,000 U.S. dollars. That’s for the carbon-labeled 5-

HTP PET. So altogether, the program will cost about not more than $4,000 U.S. dollars,

including the tumor biology workup and seeing the doctor and taking the blood tests.

Q17. How important is it to find the primary tumor, to find where it’s located? And also how

important is it to do differential studies?

A. Do you mean proliferation studies? (“Yes.”) Actually of course if you don’t know the

location of the primary tumor, you can take a biopsy from the liver metastases, and you can do

all the tumor biology on that. The good thing in knowing about the primary tumor is that you

might be able to resect the primary tumor, and if you have a midgut carcinoid, we know with

time that you can get problems from the primary tumor because you get kinking of the intestine

due to fibrosis around the primary tumor. So with time, you get obstruction of the intestine and

other problems, and so we are better off if we take away the primary tumor as early as possible.

Oberg-cacs--Page 27 of 38

It’s not necessary to take [the tumor] away the first day you get the diagnosis, but you should

definitely have a correct histopathology.

Q18. If you have a diagnosis from the liver biopsy of carcinoid but aren’t able to find the

primary source [what should you do]?

A. Of course you can continue to have the treatment you have at the moment - - whether it’s

Sandostatin or a Sandostatin/alpha-interferon combination, but I think with time, at least at our

center, we really want to know where the primary tumor is to be able to pick it out. But I think

there are different opinions from different doctors. I think there are doctors saying, “Okay, what

matters is this is a small 1-centimeter tumor. Let’s keep it there. It’s not doing any harm.” But

you know that it’s doing harm in the long run, because in 10 or 15 years you have a severe

fibrosis in the abdomen, which is not a good thing to have because in the future, the fibrotic

process might even kill the patient because it reduces the blood flow to the intestine, and you can

get necrosis on the intestine also.

Q19. We cannot find my primary tumor. What should I do?

A. Actually what I would do in your situation - - I assume you would not go to Sweden for a

PET scan - - so what I would do is I would continue the treatment you’re on now, and I would

repeat some of the investigations with time, so that perhaps after 9 to 12 months on treatment,

you might be able to see the primary tumor on a regular somatostatin scintigraphy or Octreoscan,

or also on CT scan, or on MRI. If you do the new MRI with this new technique which they can

perform, it’s very high sensitivity. So you should continue to look for it, and not just say, “It’s

an unknown primary and I won’t bother about it,” but at least once a year, you should have a

workup to try to find it.

Q20. I have liver tumors that are growing but are untreated right now, so I’m trying to decide

whether to go on Sandostatin and interferon - - or go to Rotterdam and try that program. Do you

have a feeling about what’s the smart thing to do?

A. You can do both. The thing is that if you take interferon in combination with Sandostatin,

you up-regulate the number of somatostatin receptors, and this is a good thing. Then come to

Oberg-cacs--Page 28 of 38

Rotterdam to get the Lu-177, and then you have a very high number of somatostatin receptors

type-2, and you can take up this radioactive compound much easier.

Q21. What is the relationship of carcinoid and body pain “all over the body”?

A. Ah, that’s an interesting question. Actually I have gotten this question by e-mail from

several patients over the years, and I must say that this is a phenomenon I can’t explain well.

One thing I’ve noticed in my own patients - - I think I have 4 or 5 patients with total body pain

(as you were explaining) - - and they have very high levels of substance P and urokinin A. And

these are substances which are involved in the feeling of pain in some way. So that is the only

thing I can say at the moment. I don’t know why it happens. Or perhaps they are secreting some

new substance that we don’t know of that’s causing this problem.

Q22. Is there any way to treat it though?

A. Actually, usually we recommend painkillers and not any strong type of treatment.

Q23. If you do not have any symptoms, how long should you be taking the alpha-interferon?

A. We recommend at least 18 months or 24 months of treatment, and you should [have] a new

somatostatin scintigraphy [performed] after you decide to finish the alpha-interferon.

Q24. Once you finish it, should you have an MRI to see what’s going on, or just go on to the

Sandostatin?

A. No, actually I’d do it to see that the tumor is not existing any longer, and also it’s a good sign

to know if you want to make another CT scan, or whatever, later on to see if there is a regrowth.

Sometimes, there can be regrowth after 2 or 3 years, you can have regrowth of the tumor.

Q25. When you talk about Sandostatin, can the Sandostatin resistance be reversed?

A. Actually what is happening in the patient during long-term treatment with LAR (long-acting

formulation) is that the symptoms are increasing with time, and the hormone levels are going up,

indicating that you are developing a resistance. And what we’re doing at this time is that we take

out the LAR, and we put you on repeated doses of regular Sandostatin. And we know that

hormone receptors are quite tricky figures. If you have a long stimulation of a receptor, during

Oberg-cacs--Page 29 of 38

long term, you have a constant level of a hormone or a peptide, we get the down-regulation of

the receptor.

That is what is happening in the other receptors in the body for somatostatin; otherwise

you would have so many side effects, you would be almost dead. So what is happening in the

normal cell is that they are down-regulating the somatostatin receptor. And that is happening

also in the tumor cells with time, and what we are doing then when we are giving divided doses

is that we can recover the receptor between the divided doses because you have some hours

when you don’t have any concentration, or any high concentration of Sandostatin in your body.

So then after 3 to 6 months, you might go back to the long-acting formulation again because you

have recovered so many somatostatin type-2 and type-5 receptors.

The problem is that after another 6 to 9 months, you again have this resistance. And

therefore if you give alpha-interferon together with somatostatin analogue, you push that

resistance into the future. And you can also take off the Sandostatin for a while, and keep just

the alpha interferon, and keeping down the tumor proliferation, keeping down the hormone

production, keeping down the clinical symptoms.

Q26. If a patient has had a bowel resection and was treated on Sandostatin, and now he’s

symptom free, and all hormone levels have been normal for a while, what scans or tests should

he have before he stops treatment?

A. Actually, before you stop the treatment, you should have definitely a new Octreoscan

performed.

Q27. And if that’s all normal?

A. If it’s normal, I would take out the somatostatin analogue and see what happens with the

hormone levels because then you can very easily start it again, and you get the effect

immediately. So what I would do is take it out, look at chromogranin A levels, urinary 5-HIAA

levels, and perform another Octreoscan within 3 to 6 months.

Q28. My father has been on Sandostatin and interferon for several years but still has diarrhea

and some other symptoms. He’s had a bowel resection.

Oberg-cacs--Page 30 of 38

A. That indicates that you have a combination of not only the carcinoid syndrome, but you have

also perhaps a short-bowel syndrome, which indicates that you are losing a lot of nutrients with

the stools. Have you tried Loperamide? Loperamide is rather good for the diarrhea. You can

take up to 9 pills a day, 3 pills with every meal.

Q29. Since he’s had the diarrhea for several years now, is that resistance?

A. No it’s not “resistance” if the symptoms have been the same over that period of time. But if

the symptoms have increased during the last 3 to 6 months, of course that might be a resistance.

If it’s resistance, you can do two things: (1). You can increase the dose of somatostatin. I don’t

know exactly what dose he’s on now, but if it’s LAR, you can go to 60. (2). [Questioner

interrupted the Doctor at this point, and he did not provide the second thing one could do for

“resistance”- induced diarrhea.]

Q30. Which is best: long-acting or regular interferon?

A. I think it is better to take the long-acting formulation. It’s easier to tolerate. It has fewer side

effects because you don’t have these fluctuations in the interferon levels. So 75-100 micrograms

of pegulated interferon might be an advantage for him, and also perhaps give a better control of

his symptoms.

Q31. Can you tell me if interferon is something new for the treatment of carcinoid? I was

diagnosed 4 years ago. I’ve had lots of surgeries, and I had chemoembolization, and no one

mentioned anything about interferon.

A. Actually I think the U.S. is a little bit behind. (audience laughter) I didn’t want to say it

before, but the reason is that we started to use alpha-interferon in Europe in 1980 or 1981, and it

is registered in all European countries for midgut carcinoid tumors. So there’s a lot of

experience in Europe. What happened in the U.S. was that one of my close friends, Charles

Moertel at the Mayo Clinic, saw my data from the first study, and he said, “Okay, I’m an

oncologist. I will go to super-high doses of alpha-interferon to see if I can get more significant

tumor shrinkage.” And what happened was that after he gave the patients 48 million units every

day of alpha-interferon instead of giving 5 to 6 million units, which I was doing, and of course he

got a lot of side effects. After 8 weeks of treatment, he had to take the patients off.

Oberg-cacs--Page 31 of 38

Q32. What kind of side effects?

A. There was chronic fatigue, fever, chills, and there were also effects on the liver function and

also autoimmune reaction and so on. And what happened then is he wrote an editorial in the

Journal of Clinical Oncology that said although alpha-interferon is a very effective compound,

and that we had received 20% tumor reduction in 8 weeks of treatment, it’s too toxic; it can’t be

used for humans. So I think that blocked most of the use in the U.S. of alpha-interferon for many

years. But now I must say that for the last 5 or 6 years, it has started to increase in use in the

U.S., and definitely most doctors in Canada are using it.

Q33. How near may a cure be for carcinoid, such as the use of the ZD6126, and what effect

might that have on other cancer tumors?

A. I think it will be investigated in a lot of different cancers. I know that they have programs for

breast cancer, colorectal cancer, not only neuroendocrine tumors (NETs). The good thing with

NETs is that we have very good markers. We can follow the hormone, we can follow with PET

scanning, we are measuring oxygen-15 in the blood supply directly in the tumor. So we can do a

very careful study, which our center really wants to have now. So this is a phase 1/phase 2 study

that we really want to see. I don’t know if this holds true for the future, but it’s always like this

when you’re working with new compounds. But since we are starting to know how cancer cells

are behaving, we have so many interesting things in the pipeline that I think within 5 to 10 years

we will have really good treatments for carcinoid tumors and other neuroendocrine tumors.

Q34. Do the United States’ insurance companies cooperate with the workup and pay it?

A. Yes, many of the patients got refunded, and particularly if they are doing this carbon-5-HTP

panel because they know it cannot be done in the U.S.

Q35. We have at least one person in the room allergic to Sandostatin. Do you offer anything for

those kinds of people?

A. As soon as you get lanreotide, ultimately this problem is solved, because I have so many

patients that I have changed. And it’s not that you are allergic to the Sandostatin itself, but the

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solvent (the carrier) of the compound. So if you change from one drug to another, you get rid of

this problem.

Q36. Would that likely develop resistance as well?

A. No. There is an Italian study - - which I don’t believe in - - showing that if you change from

octreotide to lanreotide, you’ll get a better response than from the tachyphylaxis that occurs with

octreotide. We have looked at that in our own series, but we can’t find that. So I think that if

you develop tachyphylaxis, it’s due to something happening in the receptor type 2 and type 5.

And since lanreotide has the same receptors as octreotide, you have the same problem. But the

new compound SOM230 may really be interesting because you can prevent tachyphylaxis

because it’s in receptors 1, 2, 3 and 5, not only 2 and 5.

Q37. Does age play a factor as far as the aggressiveness of the proliferation of carcinoid tumors?

A. Sometimes you are seeing that. Of course these are mostly patients with bronchial

carcinoids, foregut carcinoids - - they are generally more aggressive; they have a higher

proliferation capacity. But if you have a young person with midgut carcinoid, they usually have

the same pattern with a low proliferation, less than 2% or 3%. So in these patients it’s not more

aggressive. And I think that most young patients have the bronchial carcinoids.

Q38. How do you diagnosis resistance? Do you just get more symptoms, or is there some actual

way to measure it?

A. Yes, the symptoms go up. That is the first sign. The other one is that the hormone levels

start to rise. So if you follow chromogranin A, for example, and you take it every 3 months, you

can quite easily see that something is going on. And I think that usually the CgA goes up earlier

than when you see increased symptoms. So this is a more sensitive marker. You can’t do an

Octreoscan and then say you have resistance because if you do the Octreoscan, it will still be

positive. So it’s not a defect in the receptor itself - - it’s seeing the somatostatin - - but

something is happening with the signal transduction from the receptor into the cell nucleus, and

we don’t know exactly what’s going on.

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Q39. Do you have any preference for the long-acting Sandostatin (LAR) as opposed to the

daily?

A. Actually, at the moment we are switching most of our patients to the long-acting formulation.

But I think it will take another 2 or 3 years until we have a good idea about if it’s as effective as

the sub-q, the short-acting. But most patients tolerate it well, and so far we have not seen any

escape.

Q40. Why does it cost so much?

A. (laughs) I think you should ask the industry, and not me.

Q41. Would increasing the LAR twice a month to 40 make any difference in resistance?

A. Yes, we do that on some patients. So when we start to see resistance, what we’re doing is

that we shorten the interval between the injections, so if you are on 30 milligrams, we go down

[from every 4 weeks] to every 2 or 3 weeks. If that is not necessary, we go up to 60 milligrams

every 4 weeks. Or if that is not necessary, we try to go to every 3 weeks.

Q42. What about making it 40 every 2 weeks.

A. Yes, 40 every 2 weeks is also a model you can use if you can control it. The problem you’ll

run into in the future is that the resistance goes on.

Q43. On the resistance issue, is it advantageous to try to lower the dose to the lowest effective

dose in order to maximize the time that you can prevent resistance?

A. No, I don’t think it matters if you take 10 milligrams or 20 milligrams of Sandostatin LAR.

I think instead you should consider to go back to sub-q shorter-acting.

Q44. Is there a baseline that you should start at?

A. Usually most patients are taking 20 or 30 milligrams and go up to 60 milligrams. Some

patients are taking 90 milligrams, but the volume is so big - - so I think it’s hard to take.

But I must say that you had a substance called OncoLar…It was high-dose Sandostatin palmate;

another salt, not acetate. And we could load 160 milligrams in one milliliter. And that was quite

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effective. Unfortunately, Novartis is not pursuing this compound any longer because it failed in

breast cancer and prostate cancer studies.

Q45. Without the carcinoid syndrome, is it necessary to take Sandostatin without having any

hormone analysis?

A. You are bringing up a very good question, and I think that you can divide the doctors into

two categories. One which is believing that you should continue to take it, and the other one

which does not believe that you should continue to take it. I am in the first category because I

know that somatostatin has an anti-proliferative effect, and it has an immuno-regulatory effect.

Anyhow, even if you are not presenting with the carcinoid syndrome, you have an anti-tumor

effect on the tumor which is good. I have several patients actually responding dramatically to

just a single somatostatin analogue treatment, with a significant reduction of the tumor, and these

patients had no previous symptoms. So there is an anti-tumor effect; there is a stabilization of

the disease over years; not only shrinkage, but stabilization of the disease.

Q46. What are your thoughts on using the pump?

A. Oh yes. We were using the pump over the years when we had the regular somatostatin. It

was the way to get rid of the short half-life - - the 1 to 2 minutes - - of the regular somatostatin.

But nowadays, when we have this long-acting formulation, I don’t think it’s an advantage to

have the pump. So therefore, I think you should take the long-acting formulation instead of the

pump. There is a compound coming out on the market called Vapreotide or octostatin. It’s a

Canadian company which is trying to get it marketed. They have a 3-month formulation. So this

might be quite interesting to look into instead of having pumps and so forth.

Q47. What about using a combination of the long-acting and short-acting Sandostatin?.

A. Yes. We do that quite often, and that is to prevent breakthrough. Perhaps you want to go to

a party, and you don’t want to decrease the interval for LAR. Then you can take short-acting at

the end of the period just before the long-acting; or if you want to have it when you go to a party,

or where you’re going to travel or something like that. And also when you start long-acting, you

must have regular octreotide/Sandostatin for at least 10 days in order to get a significant level of

Sandostatin in the blood.

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Q48. If your hormone levels are going down, must you continue on the Sandostatin?

A. Actually, you must also have a CT scan or MRI to see if you still have tumor. If so, you

must continue on Sandostatin. But if you are not seeing anything, if you have normal CgA, and

you have a normal somatostatin scintigraphy, you have normal CT, you have normal MRI, you

have normal ultra-sonography, then I would stop the Sandostatin.

Q49. This is a three-part question please. On the long-duration shots, do you have any reports

of blood pressure going up, being less able to read fine print, and also itching effect?

A. After LAR only? (“Yes.”). Yes, I have noticed that a very few patients have had problems

with their blood pressure. Some of them have very low blood pressure, but some of them have

high readings. And there’s also some effects of the rhythm of the heart. We don’t know exactly

why that happens. You have somatostatin receptors in the blood (as I’ve shown you), and you

also have somatostatin receptors in the heart. So it might be a direct effect of the compound.

But usually you get tachyphylaxis in these receptors so you can tolerate the compound, so you

can continue with trying. So in most patients I have seen, if you lower the dose (that’s going

back to sub-q for awhile), you can then re-start on a 10 milligram, 20 milligram, 30 milligram,

and see if you can manage. Or you can switch to another compound - - lanreotide - - and see if

it’s better.

Q50. And what about not being able to read smaller print?

A. Well, that has something to do with the eye, and I don’t know. Is your blood sugar okay?

Because sometimes you can get slight diabetes during somatostatin analogue treatment, and that

gives you sometimes effects on your vision.

Q51. I have no signs of glucose problems or anything like that.

A. Okay… (the Doctor’s answer is interrupted again by the same person)

Q52. What about itching?

A. Itching might be related to the compound, so if you switch to another somatostatin analogue,

the itching might disappear. The itching can also be a part of the carcinoid syndrome. If you

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have very dry skin, pellagra-like skin lesions, you can try to use a multivitamin tablet to see if

you can get rid of the itching.

Q53. I wonder if you would talk about the micro-tumors some people have. You could have

carcinoid, but the scans are not going to show micro-tumors.

A. Actually, if you are not using the special PET scan that I told you about (audience laughter),

[then you won’t see them]. Usually, you can expect to have micro-metastases. I think if you

have metastases anyhow, you have circulating tumor cells in the blood. But if you have

normalized everything during treatment, I think you should have a period of rest to see if

anything is coming up. And I think if you have a good CgA assay, you will be very well off to

see if you have a recurrence of the disease. And if you have a recurrence of the disease, in this

situation I usually give the patient a combination of alpha-interferon plus somatostatin analogue

directly afterward.

Q54. What part does heredity or genetics play in developing carcinoid tumors?

A. That’s a good question. Actually, there are “families” with midgut carcinoids. And out of

1,000 patients now, we have 4 families in our register with a mother-son or father-daughter with

midgut carcinoids. But usually most hereditary forms of carcinoid are the foregut ones. And

those members belong to the MEN1 families (multiple endocrine neoplasia type 1). And they

might have pituitary tumors, they might have hyperparathyroid tumors, they might have thymic

carcinoids, they might have bronchial carcinoid, endocrine pancreatic tumors, and also

adrenocorticoid tumors. And these are hereditary. And that is a 50% penetrance.

Q55. My father has carcinoid and my brother has it. Are there lifestyles like smoking or

drinking, or anything like that, that would increase your chance of ?

A. First let me ask this: Is it midgut carcinoid - - classical carcinoid - - or is it bronchial

carcinoid? Well, an interesting study made in Sweden and published last year is that if you have

high education and if you’re living in large cities, you have an increased risk. (audience

laughter). And so it’s a higher risk for a physician that for other people. Of course, I didn’t want

to say that, but it might be some compounding factors, of course, that people with high education

go more often to the doctor and get a correct diagnosis. But we don’t know of any lifestyle

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factors otherwise. Smoking has no effect, alcohol has no effects so far as we know. We don’t

know anything about other habits; it’s not related to any particular work that you do, or things

like that.

Q56. Dr. [Stephen] Marx at NIH studied families, and found some genetic links with

carcinoid…

A. I must make a comment about that. This is for the MEN1. But for making an LOH [loss of

heterozygosity] analysis of the chromosomes as I indicated in one of my first slides, we must

have at least 9 families because they are so small. But you can of course analyze one

chromosome, chromosome 18Q. That can be done and perhaps Dr. Marx can analyze that for

you. And if you have a deletion on 18Q, you have a higher risk to develop carcinoid. But I

don’t think you should worry for your children; that’s my ethics. And definitely not until they

are 20, 25 years of age, because these tumors develop later in life. Then when they are 20, 25,

they can decide by their 30s if they want to have any genetic testing done, or if they want to have

CgA taken, or something else.

(We do have a representative from Novartis here, Nancy Cass. Nancy, stand up. You may

want to ask Nancy questions later on, but right now, do not ask her about the cost. She can’t

do anything about it.)

We want to thank Dr. Oberg for coming, and we want to thank his wife for letting him come.

(extended audience applause)