The format is wrong on the
papers from New Orleans, shall redo ASAP. Susan, May 10, 2005
DR. LOWELL ANTHONY, Associate Professor of Medicine:What’s New in Somatostatin Analog Therapy
I've been instructed I have 40 minutes. So I want to first of all teach
you-all a little bit about
atmosphere that we have. But some recent visitor -- anybody recognize this
gentleman? (Audience response.) This is Ivan IV. He's just been here. Just to
give you a little bit of history. He was a czar; he was the very first czar.
Other recent visitors and there may be some left here, these are the zoo
people; they are in town. This is the announcement of the zoo people coming to
town, but their conference ended yesterday. I have a hint that some of them may
be staying over to enjoy the “Big Easy” over the weekend. So they're on a quest
to find unusual things.
And this is one thing that they're going to possibly find. It's a purple
striped fish. This fish actually lives at LSU. It is called “Mike the LSU
Flying Tiger Fish”. It was part of the year 2000 art exposition here in New
And he's been adopted and he's called “Mike the Tiger” fish. So the zoo
people were out there looking for something they can't find elsewhere. But more
than likely they're going to be looking for this creature. But if you run
across somebody and they kind of wonder, where are the purple polka-dotted
striped zebras, you'll know exactly what they're all about. Because they'll
probably go back to their zoos and explain this unusual creature.
And here's a cartoon in Dr. Woltering's office that says: "According to
your occupational preference test, you like to remove vital organs from helpless
people." And the response is: "That narrows the career choices to doctor or
“Do you get along with other people?”
“Other people are insignificant insects."
And if you know a little bit about Dr. Woltering, if he says something to
you of that nature, you oughtn't to get too offended because he's well known to
tell you what he thinks. Something he has been known to say would be: “You're
ugly and your mother dresses you funny. Why don't you leave?”
Well, today is an opportunity to review with you some issues as they
relate to octreotide therapies. Specifically, that's the analog that when I
say I'm going to capture, most of my comments are going to be related to that
particular product. So it's really about three things I want to tell you. And
one of them is octreotide can be used at doses to control symptoms, and those
doses may be larger than what the package label says. So we know the product is
safe. When we were testing it from 1500 milligrams a day and took it up to 2
milligrams every 8 hours or 6 milligrams a day. And there was another peptide
(lanreotide) that's not on the market here that we took it up to 18 milligrams.
So one of the things that we've learned over the last decade is that the
somatostatin analogs are safe products. We really can't find a dose that would
be dose limiting. It's probably one of the safest drugs we use in medicine.
Another aspect of the product is one where we learn about how the drug may
work in our various models, laboratory models, et cetera and the human model
that's available. We're convinced that the analog not only makes people live
better but it makes people live longer. And hopefully SOM 230, when it comes
along, will be not only for symptom control but a treatment that stops the
disease process itself.
So the current rationale for the use of the analogs would be that they are
the best method at present of controlling and thus decreasing the hormones
that are causing the symptoms, and thus attacking the underlying physiology
The key thing here is that these peptides have growth stimulatory effects.
And if we can lower the amount of these affecting hormones, then that would make
us more able to control these tumors. And of course it's easy for us when the
syndrome is present, then we know the disease is somewhere in the body. So
that's something that usually, the majority of the time, we can find this out.
The occurrence of the syndrome represents a small percent of patients with
carcinoid. The incidence of carcinoid tumor is three to five per 100,000. This
is larger than we were saying a few years back when we were saying three per
million. So I think we're probably getting a better handle on the incidence of
this disease as we focus more on it and look at more recent data and how people
present based on where the tumors arise and how big they are.
These tumors are derived from the neural crest. They derive mostly from
the gut, pancreas, or bronchus. The classification merely helps us to simply
predict what to expect and to talk to people in a more rational manner. This is
where people who have tumors that arise in the foregut area which would be the
lung, the stomach, the pancreas, the duodenum. Carcinoid symptoms may be
present and not even have the disease spread to the liver.
Other hormones may also be secreted and are listed here. So these are
very specialized types of classifications which help us understand more, to
communicate better, and to know what to expect.
So the midgut would be what we see most of. People with the syndrome
usually have metastases and people with carcinoid of the hindgut with metastases
very rarely have the syndrome. The hindgut tumors in the left side of the colon
and the rectal area. You really don't see the syndrome with these patients and
for the most part it's a tougher disease to handle.
The syndrome consists of flushing, diarrhea, and may also induce valvular
heart disease. The kinds of things in patients that we can see on physical exam
might be lower extremity edema, cardiac murmur, enlarged liver and reddened
Now the hormones that can be elevated are shown here. What we're
attempting to do which is decrease all these markers with somatostatin analogs.
But in addition, there are a number of substances, some of which are considered
“growth factors” that we also want to suppress. So with somatostatin analog
therapy we can potentially suppress the whole group, amines, peptides, etc.
So at the initial evaluation, we can make a diagnosis (for the most part).
And that's done usually with the hormone marker scans and any biopsies. So
drawing on the blood level of serotonin marker which might help with a diagnosis
of the disease.
The decision-making is entirely into basically three categories: what's
happening with the symptoms, what's happening with the laboratory test, and
what's happening radiographically. Once the diagnosis is made, treatment is
initiated. And this is where your physician is critical in this part of the
management with the weighing of risk/benefits.
If we're looking at side effects of treatment, we've got to balance that
with the disease itself in causing side effects. A rule of thumb here is to not
make the treatment worse than the disease.
My experience has been with monitoring. And this is where it gets a
little tricky. How do you go about adjusting therapy?
You can't cookbook this. You can't really look at a cookbook of medicine
and say: Gee, for this patient I'm going to do this, and I'm also going to tell
them make sure that you don't do that. It pays to know all the past treatments
in order to know what the future treatment ought to be.
So it's hard to do this on the Internet or through e-mail. I know my good
friend Dr. Woltering is probably more aggressive in making these calls without
having the patient in front of him. And I found it to be difficult to do that
without seeing the patient myself and evaluating the overall complications and
the side effects in person because frequently when I see somebody, I probably
would have done something differently if I had not seen that person, something
new that I encounter that changes something.
The somatostatin analogs came to us as a result of the radioimmunoassay
technology of the ‘60s. With octreotide’s use in the early '80s and our good
friend Larry Kvols was probably right there on the forefront of being a first
And at about that time Dr. Jerry Gardner was working on it at NIH in GI
and started the first patient with a VIPoma on the analog and found it to be
very helpful. And then Larry and other interested individuals did their own
IND. This was not a corporate-sponsored protocol. And Dr. Kvols did the
greatest number of patients in the same manner. His report included 25
patients. Then he came back after that and did another 25 or 30 patients as
So we can look and see where the mid-'80s were clearly a time of
transition, and we sort of call it pre-somatostatin era and post-somatostatin
Shortly after finding that octreotide was a targeted agent, the
radiolabeled drugs were shown to be helpful in therapy and with some patients it
really made a difference.
drug called pentetreotide. In
has a slow release formulation that releases over over two weeks or so and that
drug is being developed for the
the studies will be completed and filed with the FDA for approval.
From an investigational standpoint this list has changed just in the last
few months. SOM 230 is a product that we'll talk a little bit more about later,
but it's one that's in clinical trial that's going on right now. We're looking
for people whose symptoms are not as well-controlled on the LAR product as we
want them to be. So this is a somatostatin analog that's seeks four subtypes of
the five somatostatin receptor subtypes.
Dr. Andrew Schally has developed vapreotide or octastatin. In the last
few months the licensing company decided to shelve that product for use in
carcinoid. The market is just not big enough to to have three drugs available.
And then Novartis has submitted an NDA( New Drug Application) for Y-90
labeled octreotide in March of last year and we'll see how that product comes
product is one that our colleagues in
first to show that if you gave higher doses to Octreoscan positive patients you
could impact symptoms. We went on to give it to 35 patients over about a year's
time to show that you can control symptoms in about 2/3 of the patients with
this. We really aren't in a position where we can predictably shrink tumors,
but we can certainly help people after all other modalities have failed. So
this is something that is not first line, and there needs to be good uptake on
Now a property of octreotide is it slows gut motility. It decreases the
secretions so that if we're looking at a condition in which there is watery
stool, octreotide would be a potential benefit. Obviously, it depends on what's
causing the watery stool. If it's tumor related, it's going to be driven by
these excess hormones. Loose stools could be caused by short gut; it could be
caused by other exologies such as bile, acids, overgrowth of bacteria, lactose
insufficiency and so on.
A number of things need to be considered. But with octreotide, we're
going to slow up gut motility, and we're going to decrease secretions, and we'll
alter the gut blood flow. This allows the gut time to rest and time to heal in
the event of a toxic injury. So the “on label”, that is, what the FDA has
approved, indication for octreotide would be carcinoid neoplasm with syndrome
present, VIPoma and acromegaly.
So the next advance in this area would be where the microencapsulation of
octreotide was achieved. This was a long tedious process that went from a plant
was then eventually shut down because of manufacturing logistics. Novartis had
a job to build a new plant in
patient in the
became commercially available in 1998. So it's been eight-year span from
concept to product on the market.
What happens when you take a subcutaneous injection of octreotide is that
the blood levels shoot up and then over the course of about six hours it comes
straight down. And then you take another injection; the blood levels go back up
and then they come down.
For the LAR product, you're looking at 10 milligrams, 20 milligrams, and
30 milligrams. And this is in terms of days after injection, so it takes about
a 2-week period to get to those levels. And then the levels stay constant and
then you'll notice that it decays over several weeks. Another injection wil
keep the levels up and therapeutic.
Now because of the complexity or the uniqueness of octreotide's
development it wasn't until the LAR registration trial was done that we really
had a uniform multicenter study. And for this registration trial, we put
patients who were on octreotide and asked them to report any flushing -- in
terms of number of flushings on a day to day basis.
You can tell from this slide that for the most part, people don't flush a
whole lot, maybe -- You can see right over here maybe 1 flush a day. And when
you stop octreotide, this became the new base line. The carcinoid patients will
go to from 4 to 6 flushes a day. And then they went back on the subcu and you
can see that it really controls their symptoms.
Likewise, on the frequency of stools around 2 being the screening days.
Without the octreotide, it jumps up to , initially 5 to 6, and then comes
back down to being controlled adequately.
Recently there's been a new packaging of LAR. The dilutent is in a
syringe rather than an ampule. There is a little bit more volume in this
syringe. This drug is meant to be administered intramuscular.
So anytime we talk about the good things a drug does, we might also talk
about the bad things.
With octreotide, we've got a double edge sword. We're looking at a drug
that's indicated for diarrhea and then one of the side effects is diarrhea. So
it's not surprising when you see all the trials that have been done with subcu
octreotide the largest side effect is diarrhea.
And this is where it gets very confusing to the practitioner. What do we
do? It's hard to say: well, I'll take you off octreotide.
Warnings I give to the patient when they start octreotide. Your stool is
going to change. You're going to notice that when you have fat in your diet or
such, you'll notice your body's going to excrete more fats than before
octreotide. And this is to be expected. You can eat fats. You just have to
pay penalty for that dietary indiscretion.
The diarrhea is such that it rarely is dose-limiting. We deal with it
sometimes with cholestyramine that binds bile acids. And we deal with it by
sometimes giving pancreatic enzymes.
Abdominal cramping may occur in the first week or so after starting
octreotide but usually resolves and is not a problem. Flatulence can be a side
effect. Some people have severe constipation on octreotide. I've had a VIP
patient that wouldn't take his octreotide because he said it was constipating.
And he waited for his VIP to cause diarrhea. But the biliary side effects are
what the FDA is really focused on (gall stones, sludge).
The LAR formulation of octreotide is not perfect. There's probably no
drug out there that's perfect, but one of the way's of measuring its weakness is
to see how many times you have to take rescue. And that was done during the
registration trial. During the first three months of this protocol, there was
more rescue taken by the 10 milligram patients than there were the 20 or 30
milligram patients. This is where we say the 20 or 30 milligram doses becomes
the initial dose recommendation.
Now this first opportunity of understanding how octreotide LAR could be
used will be a situation where this gentleman, who's 63, develops flushing and
malaise, and is diagnosed with a heart murmur, has a palpable liver edge that
extends below the rib cage. His 5-HIAA is elevated.
The standard of care here would be to suppress those offending hormones
with octreotide acetate. There's not much else to do. You could give diuretics
to control the heart failure problem, but there's no other reason to start doing
any kind of surgery or a radiofrequency ablation or chemoembolization. To start
octreotide makes future management much easier.
Well, what typically happens is that over time there's slow progression.
A year later these flushing episodes were just a little bit more common.
And the radiologist can't measure any one particular tumor but states that
it looks like a slight progression. So that word commonly gets put in CT scan
reports. These are several choices as indicated on the slide.
You can take one attitude which is, “Gee, you know, I'm not going to get
any better just by sitting around and watching this slowly progress. So if I'm
going to better control my disease, I'd better take some chances. And therefore
I'll consider some procedure that might have some risk to it.”
Or you could say, “Well, I'm exhausted conventional therapy and we haven't
used a form of Interferon such as pegylated Interferon. We don't know exactly
how to predict who it helps, so we'll just have to try it.”
Or we could say, “We wanted to use the LAR formulation in a higher dose
and go from there.” It makes sense to maximally use one drug rather than
continue to put the added risk of doing things that potentially have more side
So this would be where the symptoms are still controlled by the drug. You
get the feeling that it's going to be another six months to a year longer before
you have to do something. So this would be where I personally tell them to
increase the dose simply to cut down on the rescue. Because from the cost
standpoint it's probably a break-even deal.
Now, is there anything in the literature? We really want to look and see
what other people have observed. And there's not much in the literature right
now on dosing above what we did with the registration trial: 10, 20, 30
center in the
patients from subcu to the LAR. When they did that conversion, they had six
patients that took 20mg every month. They had 10 milligrams in one patient and
one patient at 60mg and one patient at 20 milligrams every two weeks.
And then after they made this conversion, they did the titration of the
product. And what they found was that six of the eight patients, their symptoms
improved or were maintained by that amount. Two of the eight patients had
symptom stabilization; one still had some diarrhea and one still had some
But they titrated the LAR dose in four patients to 20 milligrams every 30
days, 20 milligrams every month, and 120 every month. The 120 every month, I
think is the highest dose that I've seen anywhere in the literature to date. So
that particular patient got 30 milligrams every week.
And this was the first experiences of high doses and they concluded that
you can -- that the high dose was acceptable in all patients. No one wanted to
sort of made us say: well, here in the
we do in terms of dosing? We decided to review a physician’s practice and a
carcinoid support group on Yahoo and just ask, “What do physicians -- or what do
patients/physicians commonly do?”
93 people in the support group responded. There were individual subject
identifiers here. And then in one physician office practice, ICD-9 code for
carcinoid syndrome--251.2 was reviewed and over 300 cases were identified. And
of that, about 50 or so patients were looked at at random, 50 charts were
Of the 93 patients responding to the survey, thirteen patients were taking
40 milligrams on a monthly basis. One patient at 50; thirteen at 60; and one
patient at 80. From looking at 50 charts at random, 36 of them were actually
receiving LAR and of those 36 patients, the most common dosage was 30 milligrams
every four weeks, 20 milligrams every . And then one patient each
had doses that exceeded the package label of 30 milligrams every two, 30
milligrams every three and 20 milligrams every three weeks.
So people will commonly say: well, how do we get from 20 to one of these
bigger doses? We go from 30 to 60; we do 40 to 60. And there's really no rule
or guidelines here. I personally like multiples of 10; if I start somebody off
at 20 or 30 and go to 40, 50, 60. I personally stop at 60 milligrams every
three or four weeks.
So what we could conclude based on these studies is that we can continue
to push higher. About 17% of the time in a single physicians' practice and
about 30 percent based on patients in the survey.
Well, this next case is one where we are looking at how these drugs might
effectively control carcinoid and not just the symptoms. So this is a
gentleman, again 63. A routine exam, he's found to have an enlarged liver
that's firm. The unusual thing here is there are no symptoms. And here we have
disease that's localized to the liver that we could see on the CT scans. The
biopsy of this case showed carcinoid. The laboratory revealed an elevated
So the management of the neoplasm without the syndrome: after six months,
we repeated the CT of this gentlemen and we have evidence of progressive disease
and his chromogranin-A was increasing.
So what do we do? Just say continue like you're doing. When we know the
disease is progressing, am I just going to let him get worse? That's very
unfulfilling to go to somebody's office and tell him that their disease is
getting worse but that's okay. 'Cause you just need to go home and let it
get even more worse.
So, what do we do? If we add Interferon, it will probably produce
more side effects.
So the LAR product then would become an option. But what do we do when we
get really enthusiastic? Well, we say maybe you ought to do the LAR with the
Interferon or we just say, well, chemo. Invariably, a lot of practitioners do
just that. The lack of symptoms rules out toxic drugs, myelosupressive, hair
loss, nausea and vomiting and those kind of things.
Well, is there any evidence out there to support this approach? This
would be where the symptoms (when present) are controlled, we know the hormonal
levels are lowered and we know the scans, stabilize or progress more slowly.
We know that of the five different somatostatin receptor subtypes, Subtype
Receptor 2 is involved with slowing cell division. There are some data to
suggest that octreotide activates the pathway leading to normal natural cell
death or apoptosis. And then there is good evidence in multiple labs of
inhibiting angiogenesis as well.
We all know that these tumors are highly vascular. You can see this
blush, this vascular blush, around this tumor. If we could have an impact on
the angiogenic effects, it would make sense to take this approach.
Well, where else do we look? We looked at laboratory evidence where there
are clearly cells or in vitro models that might predict what we're up against.
But what happens, you know, in the clinic? From a survival standpoint, we
looked at what happened in a single series, Dr. Mortel’s series, and where we
had somatostatin analogs. The five-year survival would be increased threefold
in the time period following the availability of octreotide.
So can we really look at this retrospectively and historically and say
it's an effective somatostatin model? And the answer to that is we really can't
because a lot of other things have changed from the 1960s and 1980s -- to the
diuretics got better or at least had less potential side effects, procedures got
better, scannings got better. So there's a lot of other things going on here
and we can't really do the clinical trial now randomizing people between
octreotide and no octreotide.
So we have to sort of look at other things-such as ther model of
gastrinoma. Gastrinoma is a neuroendocrine tumor that arises in the pancreas
and make gastrin.
Dr. Robert Jensen at the NIH tested antitumor activity of octreotide ie
has an antineoplastic activity in a, neuroendocrine model, a gastrinoma. He had
the luxury of being able to take his patients and just give them H-2 antagonists
like Zantac, Tagamet, or Pepcid, or PPIs, proton pump inhibitors, like Prilosec
and others and just control symptoms.
So in gastrinoma what he does is to control symptoms totally different
from what we're dealing with in carcinoid. We can't use those drugs to control
carcinoid symptoms. So Dr. Jensen had the opportunity of waiting for his
patients to actually show progression before he started somatostatin analog
therapy. And that's what this whole study is about. He took 15 patients and at
the time the gastrin levels were going up and their disease was progressing on
CT Scans or MRIs or Octreoscans, he then would start octreotide. And he started
it at really low doses.
And again, I think what saved him was the LAR formulation. He started
this study in 1996 and the LAR Became available in 1998.
The phenomenal thing here is that over 52% of the patients had some kind
of tumor response. And in the majority, the final response was stable disease.
He did have one patient that had an increase in tumor size. And he had one
patient that had a marked decrease in tumor size.
But the real magic here is that two years later, Jensen's patients were
still taking the drug. This was where he concluded that octreotide was an
effective antitumor treatment. But we can't promote this drug for
carcinoid as an antitumor treatment just because it works in gastrinoma.
Dr. Jensen is saying that once there is progression on the PPIs or its
antagonists, it makes sense to try octreotide. And it should be considered
So where are we? We've got many unresolved issues. We don't know the
right octreotide dose to use as an antineoplastic. Could be that Dr. Jensen
could do a better job if he used even higher doses of octreotide.
Right now the standard of care would not include Interferon with our
therapy. That is just being a little bit too overly aggressive to start
somebody off on combination therapy unless there is some part of a clinical
I suggest using the drug as a single agent then add another drug at the
time of progression. If we extrapolate from gastrinomas to carcinoids -- and
that's a limitation. Can we or can we not? This is a tough situation. The two
are not necessarily the same. They have some things in common.
So from a perspective of if the drug is safe we know the side effects, we
deal with them. If the disease itself is not causing a lot symptoms, it makes
more sense to use a form of treatment that has few side effects and risks. We
know that octreotide can be given safely at higher doses. We know that people
live longer when taking octreotide. And we know that we can control tumor
growth in gastrinomas that progress on another therapy.
So where are we headed? And this is really a story that needs to evolve.
This story is not coming to any definitive conclusion today. We haven't cured
it. But we can see that with octreotide binding to mainlevel subtype two or
five subtypes, maybe if we had one that bonded more to the other subtype
receptors, we might do a better job at controlling the symptoms and/or the
Conjugating? Conjugating it with some other toxic agents such as
radioisotopes you heard of this morning or to chemotherapy drugs. These are
products that may be brought to testing.
Now, in one trial at M.D. Anderson, Dr. James Yao is working on using
Gleevec in combination with octreotide, and there's been some benefit in
controlling symptoms. It seems like octreotide needs to be present for benefit
We're looking at anti-VEGF, anti-VEGF monoclonal antibodies. This is
something you may have heard a lot about in the press in February 2004 when two
products for colon cancer were approved. Whenever a drug is approved in one
condition, we are all interested to know whether it can be used in other
Again, it was piloted at M.D. Anderson. Carcinoid patients with
progressive disease will have an opportunity to remain on octreotide and then
see whether that anti-VEGF (Avastin) offers any additional benefit.
Small molecules are shown here. This is PTK 787. This agent is being
looked at in colon cancer and other diseases as well. We'll have to wait and
see if that pans out for carcinoid patients. In about a year we'll have some
idea on that.
About 40 percent of the carcinoid tumors express what's called the
epidermal growth factor (EGF). This growth factor stimulates cells to divide
and exists in the epidemial cells that are on your skin and the tissue
throughout the body. A side effect to inhibiting EGF is dermatitis.
We'll have to wait for a report on the patients tested with EGF receptor
Newer agents? The epothilones have not been shown to be active in
carcinoid. They failed to fulfill expectations and is probably not going to be
approved for carcinoid. But some people have certainly benefitted. Hopefully,
the epothilones can get on the market for other things such as colon cancer or
breast cancer so you can use it off label in carcinoid.
Dr. Anthony, didn't Dr. James Yao have a problem at M.D. Anderson with the
fact that he had a lack of positive results?
Well, it depends on how you define results. He looked at controlling
syndrome symptoms. He showed some benefit. It was enough activity to warrant a
subsequent trial. Dr. Yao's study would be classified as a pilot trial. Pilot
trials sometimes are able to tell us where we end up with an active product.
So I think we have to have hats off to Dr. Yao for having the interest and
the energy to conduct such a trial, and this is a compound (Avastin) that will
be further studied. I would encourage you to contact Dr. Yao if you want more
information about that clinical protocol to see exactly when it will be
available. I suspect it will be sometime next year.
As a rule, does insurance cover higher doses of Sandostatin?
Beyond 30 milligrams?
Give the definition for dose titrations and SOM 230. What kind of dose
do we use for that?
Titrating octreotide is better for flushing symptoms rather than for
diarrheal symptoms. It's hard to titrate for diarrhea.
For the subcutaneous form of octreotide, it's generally – I use a
tritation in 50 microgram amounts, 150 or 200 a day to 250 or 300 a day.
Sometimes for diarrhea you have to back down the dose in some people. With
titrations, it's specifically to control symptoms. You sort of have to
decide what those symptoms are. And that's kind of the way I got started in
this business because people would tell me they feel better at higher doses.
Initially I didn’t know what to make of this. After three people told me that,
that is when I went to Sandoz (now Novartis) and studied higher doses.
Is it advisable and/or necessary to do some kind of trial of aqueous
octreotide before starting LAR?
In general, yes. I think it's a good thing to start somebody on a two-
week period of the aqueous subcutaneous to let them understand more about what
the drug does.
How can you treat painful lumps when you get 20 or 30 milligrams? And if
somebody has a reaction to the 30 milligram and they don't at 20, are they
compromising their cancer growth at the lower dose?
Well, the incidence of local reactions because we went through some of
the side effects with the LAR registration trials. No one quit the trial
because of local reactions.
It's a relatively small amount of actual people who have persistent lumps.
We commonly see with erythema at the injection site. It's uncommon and I'd say
it's under 2 percent of pateints in whom I'm really seeing persistent lumps.
And what's interesting is that if you ask the people who make suture
material out of the polyglycolic acid which is what the LAR is made out of, the
people who make the sutures will tell you there is no immune response to
People who spit sutures will tell you that that's a crock of bull, that,
you know -- and people who have injection sites with the polymer with 20 or 30
and get a hard, red, hot nodule every time they get an injection will tell you
that some people do have severe immunologic response to polyglycolic acid
Does Sandostatin lose its effect on control of carcinoid symptoms after a
period of time?
And is there really tachyphylaxis and does drug holiday help? Or do you
need more drug when you “lose control” of your syndrome????
The answer is yes to all of them. Now, this is a lot of where you have to
work to sort these problems out. What we called tachyphylaxis early on in our
experience, people would come back to me and say just the opposite of what they
really felt. So it was not the original fault that after two or three months
that the drug will no longer work like calcitonin--- which doesn't work after
So we were stuck with trying to figure out what it all means. The concept
here is you want to maximize receptors and keep them saturated. And how best to
go about doing that is on an individual basis. We can't say what optimal dose
is. We have to really do it on an individual basis.
Where's the sludge go in the gallbladder if you don't have a gallbladder?
What generally happens if you have no strictures or such, it will
just drain into your intestines via the common bile duct.
Does low dose oxycontin interfere with octreotide or vice versa?
Case No. 2 - disease confined to liver only when asymptomatic - why aren't
chemoembolizations and radioisotopes therapy then initiated instead of higher
doses of octreotide?
This will be sort of what, I think, we basically had. Somebody with
progressive disease if there are more symptoms or if we can clearly say we're
losing the battle, then we need to pull the plug and try everything. So I think
it's a timing issue. If we can debulk 90 percent of the disease and someone is
going to live maybe another 10 or 20 years or longer, it probably would make
sense to maybe try to embolize the disease.
So I think you have to factor in how long a person's had it; how well they
are coping with the symptoms; where the disease itself is localized; how
difficult a procedure it would be. But generally those procedures are not
curative. They're only buying time. We usually like to think at least one or
Patient on LAR 30 has her gallbladder removed and has fat malabsorbtion.
Should we use pancreatic replacement enzymes for the entire time or should it be
used intermittently for therapy?
This is the where we want the gallbladder taken out if there's a
Anytime you open the abdomen, tell your surgeon, “Take out my
gallbladder”. Don't let him think about it. You tell him.
As a result, I would say in my 20 years of dealing with carcinoid
patients, I can probably think of 2 patients that had relatively urgent
emergency surgery for gallstones. I think we do a better job with prophylactic
removal. Enzyme replacement may or may not reduce stool frequency of number.
If it does work, chronic therapy (taken with meals) would be required.
Okay. SOM and LAR 30, last week of their 28-day cycle and it's “return of
symptom time”. Do they go up on their dose or do they back off and do it every
21 days or do they go to, like, 60 milligrams at one dose?
Okay. These are symptoms of the disease coming back--- not the side
effects of the drug.
For dose titration, I personally prefer to keep the drug on a four-week
basis, and I don't have anything to say about that. The problem is that I
believe it's really a personal issue. Do you do two injections at the same time
on a monthly basis? Or do you do one injection every two or three weeks?
Does it matter do you think that the initial wash off that normally occurs
with the 30 milligrams dose and now you get 30 milligrams in each hip, do you
get double the usual wash off at one time?
You know, this really hasn't been studied to give us harder evidence to
guide. I individualize my patients. I usually stop at 60 milligrams.
Do you believe there's benefit to adding Interferon to Sandostatin; i.e,
is combination Interferon/Sandostatin therapy better than either one or alone?
At the time of progression on octreotide, then I think it warrants about a
three-month trial of adding Interferon. I think with the pegylated form, this
would be where the drug can be given weekly and not daily.
But if someone had only four lesions in their liver and they were 6 to 4
centimeters in diameter and growing, I may take consider other options depending
upon their general health. I generally offer a trial of Interferon before
recommending cytotoxic chemotherapeutic agents.
A question I'll sort of answer. Is there a reason for measuring serotonin
levels to follow patients with carcinoid?
You take a normal person's tube of blood; you bounce it on the counter a
few times. It sits in the sunshine and normally your platelets will release
serotonin. So if you're talking about just a blood level of serotonin, blood
levels of serotonin - (if the specimen is not absolutely properly handled) – can
If you have tumor progression, no symptoms, and a maximum dose of
subcutaneuous Sandostatin -- there is no maximum dose of subcutaneous
Sandostatin -- what is the next course of treatment?
Well, technically the maximum dose subcutaneous Sandostatin would be 2
cc's and that's just -- it's literally based on volume. So there is other
suggestion considering how large a volume you'd want to inject with a
similar injection. That was arbitrarily chosen to be the top dose.
If you look at how somatostatin receptors saturate, by the time
you get to 2 milligrams of octreotide per day(about 10-12,000pg/ml octreotide
blood levels), you should have saturated 100 percent of your somatostatin
receptors subtype 2. And that's where that number 2 cc's a day or 2,000
micrograms a day came, based on the blood level of 12,000picograms per
milliliter of blood.
SOM 230, how close is it to being clinically available? Is it available
in a trial or is it commercially available? When are the first patients in
It started in April or May this year, and about 30 patients have been
enrolled in the trial so far. It's probably getting close to completion. So
this trial is pretty much on the downhill slope. So completion, it will take
some time to look at it and see whether the next level trial is indicated or
what the strategy will be there. Larry has probably done more patients on this
trial than anyone else.
Well, I had about 4 or 5 people on it; it certainly controlled the
carcinoid syndrome. In terms of looking at tumor shrinkage, it's certainly too
early to tell. If the drug makes it, we're probably going to be at least
another two years for commercial availability.
If you have atypical carcinoid, the bad guys, the fast growers, would it
be reasonable to go on octreotide as a sole therapy or would you recommend that
they go on to chemotherapy ASAP?
Octreotide is for treating carcinoid syndrome as a general statement. In
atypical carcinoid--- chemotherapy drugs are the standard of care. I would not
advocate octreotide as first line in this instance.
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