Therapeutic Goals of Acromegaly

CARLOS R. HAMILTON, JR., MD, FACE: Hello, and welcome to the AACE Clinical Conversations. I'm Dr. Carlos Hamilton. Today we'll be discussing the therapy of acromegaly. Joining me today is Dr. David Cook, Professor of Medicine at Oregon Health and Sciences University, and Dr. Lawrence Katznelson, Associate Professor of Medicine at Stanford University School of Medicine. Thank you very much for being with us today.

The therapy of acromegaly involves the controlling of the tumor mass, the normalizing of the biochemical markers of acromegaly, preserving pituitary function when possible, relieving signs and symptoms, and eliminating excess mortality associated with active disease. Now, since acromegaly is caused by a pituitary adenoma in most cases, surgery has been historically considered to be the initial treatment of choice. Dr. Katznelson, is that still the case in your experience?

LAWRENCE KATZNELSON, MD: Yes, that is correct. Surgery is the primary therapy of choice because it can lead to a rapid lowering, if not normalization, of growth hormone levels. It can debulk the tumor, and patients who have large tumors that are compressing local structures, including the optic chiasm, and have associated visual field compromise, we need surgery to decompress the tumor and allow for normal vision.

There are situations where we consider primary medical therapy, and this is largely in patients who have a tumor that has grown beyond the confines of the sella turcica, and therefore there is a relatively low likelihood of cure by surgery.

And there is consideration of using radiation treatment, which, many years ago, was a primary therapy, but now we've pretty much relegated radiation therapy to an adjuvant role following incomplete surgery or medical therapy.

CARLOS R. HAMILTON, JR., MD, FACE: Now, Dr. Cook, we understand that there are limitations to surgery. What are some of the limitations, or what are some of the circumstances in which surgery is not curative in this condition?

DAVID M. COOK, MD: Well, basically, there's two sides to that coin. One, of course, is the skill of the surgeon, and that's not said lightly. The neurosurgical societies have suggested that dedicated pituitary surgeons perform this operation. And what is that? It's usually determined by 25 pituitary surgeries or more per year. It's a pretty arbitrary figure, but that's a figure thrown out by neurosurgical societies. So a dedicated surgeon, a skilled surgeon is one side of the coin.

The other side of the coin, as Dr. Katznelson pointed out, was the extent of the tumor. With good MRI techniques, we can see the extent of the tumor these days, and if there is extension of the tumor lateral to the internal carotid on either side or arachnoid invasion, we know those tumors will not be cured by surgery. So the two sides of the coin would be the skill of the surgeon and the extent of the tumor.

CARLOS R. HAMILTON, JR., MD, FACE: Now, Dr. Katznelson, the usual procedure is a transsphenoidal hypophysectomy. Is that the case? And are there circumstances where a transfrontal hypophysectomy is indicated still?

LAWRENCE KATZNELSON, MD: Yes. The transsphenoidal surgery is the primary surgery that is used. In experienced hands, as Dr. Cook described, it is a highly efficacious and very safe surgery with a very, very low mortality rate and very low morbidity rate in terms of hypopituitarism and other local consequences.

In rare situations, we need to perform a craniotomy, usually a transfrontal craniotomy, and these are for patients who have tumors that usually have extended superiorly beyond the confines of the sella and are causing loss of vision, compression of the hypothalamus and other local brain structures. And a transsphenoidal surgery will not be able to reduce that tumor, if not remove it.

CARLOS R. HAMILTON, JR., MD, FACE: Of course, as a medical endocrinologist, a lot of the patients that we see, at least long term, are those that have not had complete success from the surgical procedure, and they obviously are back for management of recurrent disease or persistent disease. What are some of the criteria for successful surgical treatment, or successful treatment of any sort, in patients with acromegaly?

LAWRENCE KATZNELSON, MD: The criteria for therapy are basically those that address the goals that you brought up at the beginning of this conversation. For example, we look for mass effects. Has the tumor been debulked? Is the tumor pressing on local structures? Because, if so, then we have not been effective in our therapy. Does the patient have tumor that is pressing upon -- very important -- the cranial nerves, resulting in loss of vision, for example?

Other criteria are biochemical, meaning, have we controlled the growth hormone and IGF-1 values? The control strategies there include normalizing growth hormone, such as with a glucose tolerance test, or in some centers using a measurement of a growth hormone level drawn multiple times in the morning and parts of the day. An average level of less than 2 (ng/mL) may be considered control. We also use IGF-1 normalization.

We use biochemical criteria, as well, to assess therapeutic management. So we look for evidence of tumor compression, we look for evidence of biochemical control, and how the patient feels. Have we been able to help this patient? Have we reduced the pains or other consequences that we've heard earlier regarding acromegaly?

CARLOS R. HAMILTON, JR., MD, FACE: So from a biochemical perspective, normalization of both the IGF-1 and normalization of the growth hormone level would be something that the endocrinologist would want to follow. Is that basically correct?

LAWRENCE KATZNELSON, MD: That is correct.

CARLOS R. HAMILTON, JR., MD, FACE: Now, there are obviously other types of treatment if surgery is not completely successful, such as radiotherapy. Dr. Cook, do you have any experience with radiotherapy as an adjunct to --

DAVID M. COOK, MD: We do. We sort of put that down in the treatment algorithm after failed medical therapy or failed surgery. But tumors that continue to grow despite surgery and/or medical therapy are relegated to radiotherapy.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Katznelson, there are other types of radiation other than conventional radiation that have been talked about, including proton beam therapy, gamma knife treatment. Are these appropriate for patients with acromegaly?

LAWRENCE KATZNELSON, MD: Yes, these other modalities of radiotherapy fall under the heading of radiosurgery. Stereotactic radiosurgery is a technique which delivers a high dose of radiation to a structure over one to several days. So it's a very high dose given over a very short time period.

There are some data, which have suggested that this may lead to an increase in efficacy compared to conventional radiotherapy, although this is controversial. There are other data that suggest that time to biochemical control may be faster with patients who receive the radiosurgery. But that is not so clear, as well.

There are several modalities of radiosurgery available, and that includes gamma knife, CyberKnife? and proton beam, which is a type of particular radiotherapy. These all to date appear to have a similar type of efficacy and side effect profiles.

CARLOS R. HAMILTON, JR., MD, FACE: Are there preferences for these as opposed to the transsphenoidal surgery, or how does one select that, or is it the experience of the surgeon or the radiotherapist?

LAWRENCE KATZNELSON, MD: As Dr. Cook described, we have a treatment algorithm, and we usually relegate radiotherapy to those patients who have failed surgery, have growing tumors, and/or are unresponsive or not tolerating medical therapy. So we use it as a secondary, if not tertiary, role in patients who have acromegaly. And we can consider radiosurgery, which is a very focal type of radiation treatment, for those patients who have, I should say, smaller tumors, or at least tumors that are not very close to important structures such as the optic chiasm, because if the tumor's touching the optic chiasm, then the radiation doses given could result in consequences to the vision.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Cook, for those patients that don't respond as well as we would hope to either surgery or some other type of radiation therapy, there are obviously some medical treatments that are now available for the management of these patients. Tell us a little bit about what some of those agents are.

DAVID M. COOK, MD: Yes. We have good choices now for medical therapy. Of course, historically, the first were dopamine agonists, predominantly bromocriptine, and, more recently, cabergoline. Cabergoline has been the treatment of choice as far as dopamine agonists, but it is used when the tumor is combined secretion of not only growth hormone, but prolactin. So combined secretors, we can use that single agent. Otherwise, dopamine agonists are usually added as a second drug to the backbone of therapy, somatostatin analogs.

CARLOS R. HAMILTON, JR., MD, FACE: So in a pure growth hormone-secreting adenoma, the dopamine agonists are generally not very effective. Is that what you're saying?

DAVID M. COOK, MD: That is correct.

CARLOS R. HAMILTON, JR., MD, FACE: But if it's combined growth hormone and prolactin, they may be more effective, and that would be a situation where you would possibly want to try that as the initial medical treatment?

DAVID M. COOK, MD: Correct. If they're a co-secretor, not just a stalk effect -- so we can have a little bit of prolactin elevation with stalk effect, or isolation of the pituitary from the hypothalamus that we see with prolactin concentrations usually up to 100 (ng/ml), but not exceeding (100 ng/ml), we can use dopamine agonists. But they're usually added to another drug that is incompletely working.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Katznelson, many of us have had some experience with the somatostatin analog treatment of patients with acromegaly. Tell us a little bit about your experience and use of those drugs.

LAWRENCE KATZNELSON, MD: There are two that are currently available to us in the United States. That includes octreotide-LAR and lanreotide Autogel?. These are two very similar formulations in that they both hit similar somatostatin receptor subtypes. They have similar efficacy in terms of control of growth hormone and IGF-1. There are some differences in that they are administered differently. Octreotide-LAR is administered as an intramuscular injection at a monthly interval. Lanreotide Autogel? is administered as a deep subcutaneous injection, also at a monthly interval. The tolerability is very similar between these medications.

CARLOS R. HAMILTON, JR., MD, FACE: Are these drugs used as primary therapy, and are they effective in that way, or are they primarily as adjunctive therapy to surgery?

LAWRENCE KATZNELSON, MD: Yes. The somatostatin analogs have largely been developed as adjunctive therapy, as you said, for patients who had surgery but had residual disease and residual growth hormone hypersecretion. In that capacity, the somatostatin analogs overall have approximately 60% control rates, keeping growth hormone levels at our controlled level and normalizing IGF-1.

Approximately 40% of patients have shrinkage of tumors, but it is usually modest. You asked the question about whether we can use somatostatin analogs as a primary, de novo therapy. And there is a growing literature and experience in using this. In situations where the patient is not a good surgical candidate or it is felt that the surgery would not be curative because the tumor has extended beyond the sella into the outlying areas, called the cavernous sinuses, where we know the surgeon cannot safely remove the tumor, and the tumor is not causing compression of the eye nerves leading to visual field compromise, we can consider primary medical therapy. And the results are very similar to those we have with secondary therapy in that we are able to control the tumors in terms of growth hormone hypersecretion in approximately two-thirds of patients, and we could lead to tumor shrinkage, as well.

CARLOS R. HAMILTON, JR., MD, FACE: Are there problems with the long-term use of it, and do you have to continually increase the dose, or do they fail to respond to it after a period of time?

LAWRENCE KATZNELSON, MD: There are many patients who have received somatostatin analogs for long-term. There are several issues we need to consider. One is cost. These are not cheap medications, and that has to be considered when we're discussing administering a medication for the next 30 to 50 years.

There are other issues in terms of side effects profiles, which include gallstones. Gallstones occur in about 30 to 40% of patients. They're usually asymptomatic. In days of past, when we would start somatostatin analogs and follow patients, we would perform frequent gallbladder ultrasounds. We tend not to do that nowadays. We tend to wait for symptoms to occur.

In terms of tolerance or medical response, it is unusual that the growth hormone levels or the IGF-1 levels rise in patients who are receiving somatostatin analogs. We do need to follow the IGF-1 levels, and there are also very small rates of tumor increases, usually in patients who are not responding to somatostatin analogs.

CARLOS R. HAMILTON, JR., MD, FACE: Now, Dr. Cook, the other class of drugs that seem to be helpful in this are the growth hormone receptor antagonists. Tell us a little bit about your experience with those drugs.

DAVID M. COOK, MD: Yes. Pegvisomant is really a growth hormone molecule that's modified and pegylated -- polyethylene glycol added to it -- to occupy the growth hormone receptor, but not active it. So it sort of blocks it so that the -- there is no activation of the growth hormone receptor activity. So this has been a new development, but this therapy is -- has been relegated to those that fail somatostatin analog therapy or are intolerant to somatostatin analog therapy.

But it has also achieved a bit of a new role, to be added to somatostatin therapy when you have a partial response to somatostatin analogs and a smaller two or three times a week dose of pegvisomant. It is given -- injected by the patient subcutaneously. If given alone, it's a daily dose.

CARLOS R. HAMILTON, JR., MD, FACE: How effective is this treatment?

DAVID M. COOK, MD: It's virtually effective in almost all patients, so it's a very sort of generic response. You're just blocking very effectively the growth hormone receptor. As opposed to what Dr. Katznelson nicely explained, it does nothing to the tumor. So the tumor, if you're using pegvisomant, the growth hormone receptor antagonist, as sole therapy, you have to keep a closer eye on the pituitary tumor that's remaining. So it is in the package inserts that serial MRIs every six months need to be obtained.

CARLOS R. HAMILTON, JR., MD, FACE: The every six months seems to be an appropriate interval for that.

DAVID M. COOK, MD: Yes.

CARLOS R. HAMILTON, JR., MD, FACE: Very interesting. And the combination of this with other drugs, has that been -- You alluded to that.

DAVID M. COOK, MD: Combination with somatostatin analog therapy is sort of a new kid on the block, and it's been able to use this pegvisomant, the growth hormone receptor antagonist, at lower doses.

CARLOS R. HAMILTON, JR., MD, FACE: And do you have any statistics as to what percentage of patients with active acromegaly that have not had complete remission with surgery can be controlled adequately with this treatment?

DAVID M. COOK, MD: It's virtually 98%.

CARLOS R. HAMILTON, JR., MD, FACE: Really?

DAVID M. COOK, MD: So almost all will respond. The Achilles' heel here is that you're not doing anything to the tumor. So the backbone of therapy would be, really, first choice, somatostatin analogs. If intolerant -- about 10% of the patients will be intolerant to somatostatin analogs -- or completely unresponsive, then the second choice would be pegvisomant.

LAWRENCE KATZNELSON, MD: We've come a long way in the last 15 to 20 years in that we are able to, as Dr. Cook said, virtually control everybody with medical therapy. There are pros and cons of these different classes of medications. Costs is another one regarding pegvisomant. This is by no means an inexpensive drug, but it is a terrific drug and able to control patients.

In terms of new drugs that are coming down the pipeline, there are several very interesting ones. These are largely in terms of the somatostatin analog category, methods of giving longer-acting somatostatin analogs, so different types of depot preparations. As of right now, the somatostatin analogs are administered in a monthly-type dosing, and down the line this will be extended for a longer period of time.

CARLOS R. HAMILTON, JR., MD, FACE: So there are lots of really good treatments for acromegaly that should basically make it possible to control this in almost all patients that are affected by this condition, and there may be even some better things on the horizon. That's been very helpful. I really appreciate your input into this clinical conversation, and thank you for watching.