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 New Orleans.  I'm sure that you're enjoying the humid


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


Orleans when they had fish from all over, different types of fish.


      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


serial killer." 


      “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


facial features.  


      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. 


      In Europe and the U.S. we've got octreotide and the Indium 111 scanning


drug called pentetreotide.  In Europe there is a product called Lanreotide that


has a slow release formulation that releases over over two weeks or so and that


drug is being developed for the U.S. market.  It's probably several years before


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




      The 111Indium product is one that our colleagues in Rotterdam were the


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


the Octreoscan.


      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


in Cincinnati that made the original microencapsulated product.  And this plant


was then eventually shut down because of manufacturing logistics.  Novartis had


a job to build a new plant in Austria.

      The first patient in the United States was injected in 1995 and the drug


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 4 to 6, 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




      There is a center in the U.K. that reported on eight of their carcinoid


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


go back.


      Well, this sort of made us say: well, here in the United States, what do


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 four to six.  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


alkaline phosphatase.


      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


before chemotherapy.


      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


to occur.


      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


polyglycolic acid. 


      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


a day. 


      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


two years.




      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


laparotomy involved.




      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


vary widely. 




      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


America going to get a shot at it?




      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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