Welcome to the session, Personalized Treatment in Acromegaly. My name is Irina Benkes, and I will be serving as your moderator today. You'll be hearing a lecture from Dr. Maria Flesseriu on this very fundamental subject. Maria Flesseriu is a professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health and Science University in Portland, Oregon, United States, and she's also immediate past president of the Pituitary Society. She has a longstanding clinical and research interest in the pathophysiology and treatment of pituitary and adrenal disorders, and has been a global principal investigator in many pituitary clinical trials. She is a frequent plenary guest speaker at national and international meetings and has authored over 200 manuscripts in prestigious journals, including guidelines, consensus papers, and book chapters. Her major focus on research now is individualized treatment of Koshering syndrome and acromegaly with a goal of improving patients' outcomes. She has been involved in leadership positions of educational programs sponsored by the Endocrine Society, the Pituitary Society, and patient advocacy groups to teach physicians and patients about pituitary tumors and neuroendocrine disorders. She has also served on multiple scientific advisory boards for biotechnology and pharmaceutical companies and participated in the study design and has been a global principal investigator in several acromegaly studies. Please help me welcome Professor Flacirio. Thank you. Hello, and welcome to the neuroendocrinology plenary at the ACE annual meeting. Thank you for the invitation, and it's my pleasure to talk to you about acromegaly management, exploring the therapeutic landscape. I'm Maria Flacirio, Professor of Medicine and Neurological Surgery and Director of the Pituitary Center at Oregon Health and Science University in Portland, Oregon. These are my disclosures potentially related to this topic, scientific consultant from Pfizer Recordatic Krinetics Chiasma and Ibsen and grand recipient to the university from Chiasma Krinetics and Lyonis. So let's start with a case. When we're talking about acromegaly, that's overall a rare disease, a 47-year-old male presented to the ER with cough, dyspnea, and syncope in the middle of the COVID pandemic, and he was found to be COVID-19 positive, as you see with multifocal pneumonia on imaging. His past medical history was significant for untreated prediabetes and sleep apnea. He was not using a CPAP, and the hospital has noticed that the patient has a suspicious feature for gross hormonal excess, and as you can see here, the patient signed consent and wanted his case to be presented. He clearly has significant facial features with frontal bossing. He also has increased nose, increased lips, his hands were very, very large, and also he has acanthosis nigricans, skin tags, so this shows that he has acromegaly for many, many years, and the hospitalist noticed because he was one of our residents in the past and saw a lot of cases. The laboratory findings confirmed he has acromegaly. His IGF-1 was very high, as you can see, for his age, and the gross hormone was significantly, significantly higher. You know, we don't recommend gross hormone in general because it has a pulsatile secretion, so it could be a little bit high, especially in younger patients, however, a gross hormone of almost 30, it's clearly consistent with the diagnosis of acromegaly. His prolactin was minimally elevated, and the other pituitary function besides the hypogonadism that I'm not showing it here was normal. His A1c was consistent with prediabetes, remarkable for such a gross hormone, high, and also overall, as you could see on the images, clear long-standing disease, so we're lucky that the patient was in the hospital and we could do all this lab work while we were in the full COVID pandemic, and we also got an MRI. So, as you can see, he has a small pituitary tumor, this is a sagittal view, and you can see this gray area, but overall that possibly was a hemorrhage, but look at the enlarged pituitary overall. So he has, this is the coronal view, he has this tumor for a while, and now what are we going to do? So this was a patient presented in a hospital, usually we see these patients in clinic, and we're trying to think, based on the circumstances, how we can achieve the fastest, but also the best outcomes for the patient, and yes, the therapeutic goals are age-normalized serum IGF-1 and random serum GH less than 1, and you see where he started, and we do this in the same time, we're trying to decrease the tumor mass and prevent regrowth while preserving the normal pituitary function, and you've seen in this patient, he had normal adrenal function and normal thyroid to reduce the mortality risk, manage the comorbidities in the same time, and then furthermore, especially for the last several years, we have many studies and I'm going to show you some of them that we can improve the quality of life of patients and how can we do this the best. Overall, how good are we all over the world, and you see here studies from many, many countries from national registry data to epidemiological studies or meta-analysis, how good are we in achieving biochemical control in all our patients? So for whatever reasons, as you can see here, from 24 to 28 to the largest one that was 65, at least for the last decades, we were not able to control every patient, and you've seen how important it is to actually control it, so we clearly have to do better in this respect, and why is it important? There are many, many studies, this is a little bit older, but it's the best designed study at looking in long-term mortality in patients that had the IGF-1 elevated, so there were several studies that looked at what happened with the patients if they still had the IGF-1 elevated, so not controlled, and this is based on IGF-1, not both, and then if they had several other studies, if they had the IGF-1 normalized, so if you're looking at this, the difference in standard mortality ratio was clearly significant, so you have higher mortality if you are not controlled, so we have to improve our therapeutic approaches and use more aggressive or even combination therapy, and you'll hear a little bit later, just to get to normal. So one is mortality, but also we have to think about all the comorbidities that the patients with acromegaly have, and as you know from hypertension and heart disease, sleep apnea as our patient, insulin-resistant diabetes, arthritis, all of these have been known for a while. However, over the last several years, we noticed that patients with acromegaly have more vertebral fractures, and this is the idea that we thought that the gross hormone is good for bone, but too much gross hormone is clearly not good for bone, and keep in mind that the DEXA is not reliable because you can have normal DEXA in patients with acromegaly and still have vertebral fracture. Furthermore, there are now more recent studies in association with the neuropsychological dysfunction that we knew for a while persists in patients with acromegaly, even after they are controlled with a spectroscopy done, that actually you can see in some cases increased cortical thickness. So we have to think about complications in addition to numbers, as I mentioned earlier. What other type of dysfunction we see in patients, and we still don't know exactly how to fix it. So this is a combination of studies, some from Boston and some from Spain, that looked at, you see on the left, patients with active acromegaly, and on the right, patients after the therapy, and there are several therapies for acromegaly, and as you can see, the patients after treatment, they will have decreased muscle mass, as you can see here, comparison, and unfortunately, they will have increased thiaedipal tissue. So overall, in addition to that, if you check for muscle performance, sometimes it's not recovering even after long term, after GH and IGF-1 normalization, and furthermore, we all hear from our patients that are gaining weight after we have them controlled. So we have to always think, yes, numbers are important. What else can we do for our patients? Talking about other comorbidities, hypertension, this is the most recent study in ACRO study, larger observational study over the world, that these were more than 1,000 patients with both hypertension and mortality, and if we look at other causes of mortality in addition to the hypertension in patients with acromegaly, look at these curves. This is for anterior pituitary dysfunction. Patients with pituitary dysfunction are in red, patients without pituitary dysfunction are in blue, and you can see that the curves are separating, and it was statistical significance for higher mortality, but furthermore, look on the right. These are patients with cardiovascular disease. So we don't even need statistical significance. Almost looking at these curves, the study entry, this independently predicted mortality in patients with acromegaly and hypertension. So these, again, are patients that we have to pay even more attention to try to control them as quick as possible. Furthermore, yes, complications are important, numbers are important, but if we're looking at a patient in general, the patients have a lot of symptoms that we have to address. They have impaired physical functioning, as I showed you earlier, that all of them can actually concur in the patients having a poor body image, negative illness perception, depression, and cognitive dysfunction. And in addition to that, the burden of chronic medication that we're adding, the radiation therapy, sometimes it's inducing hypopituitarism, including GH deficiency, that we know it has even more effects on lowering the quality of life. So this is something that we have to think in advance for when we choose a treatment overall. And then more recently, and this is a meta-analysis earlier this year, when the patients are asked directly, so through patient-assessed acromegaly symptoms questionnaire, are they improving overall? As you can see, there are two types of studies overall. The treatment naives clearly, they didn't feel good. But if they were treated before the study with a goal of improvement, all of these were negative. With a goal of no deterioration in patient symptoms overall, we could see some improvement, though we touch the vertical line. So overall, if we're really asking the patients how good we're doing, yes, we improve their mortality clearly, we improve their numbers, but not always we address their symptoms overall. And why it's important to address the symptoms? This is a study that looked at patients with high symptoms group and also a low symptom group. So if they're doing well versus not doing well. And if we compare the lower symptom group with a high symptom, the depression, the cardiovascular disease, and including the costs were significantly different. So we have to look at this in correlation overall and look clearly through screening for all the comorbidities once they have one. So briefly, I try to focus on why it's important to look at the patients in general and all their comorbidities. Now let's switch to treatment. Surgery in acromegaly is the treatment of choice for intracellular noninvasive tumors and it controls in 75 to 95% of patients. However, as you can see here on the right, most frequently the tumors are much larger because the patients are not diagnosed for many, many years, even 11 years. So even in the best centers with tumors that are invading the cavernous sinus, the remission rate, I rarely call it cure directly, is very low. The surgeon experience is crucial though because control rates are even poorer with less skilled surgeons that do less than 50 pituitary surgeries per year. I'm not going to talk particularly, but I would be happy to discuss further the role of surgical debulking. So we know that the patient is not going to be in remission. However, with less volume of the tumor, it's a higher likelihood of control overall. So surgery in acromegaly is important and we're still using it for a large majority of cases in the US as first line. In other countries, primary medical therapies use more. Can we predict, as I said earlier, who's going to be in remission or not? And we have newer data that the early biochemical remission could be predicted, but how large is a tumor? And this makes sense. And also, very interestingly, and we should change our approach, how we'll check gross hormone in everybody post-op, because it seems that the random gross hormone, both the diagnosis as you can see here, but also in the day one or two post-op, will actually predict who's going to be in long-term remission. A systematic review in almost 1,000 patients indicated a higher impact also at cavernous sinus invasion. And as you can see here in this example, clearly, if you have significant cavernous sinus invasion, the likelihood of remission is very low. And it's important to know, not just for scientific discussion, but also to tell the patients from the beginning so they can prepare for the idea that they will need adjuvant treatment, either medication or radiation, or sometimes BOST. So our patient that I presented earlier was, if you can say lucky to have COVID, was diagnosed late, but still with a smaller tumor. So with surgery, could be in remission. Let's talk about another patient, the one that I showed you the MRI earlier, that the patient had clearly extension in the cavernous sinus. So you can see this is a lot of post-op changes, but you know that there will be tumor. Furthermore, the pathology gives us the type of tumor. And I'm going to show you how important it is. This is not done everywhere yet. However, the type of sparsely granulated versus densely granulated is very important in predicting the response to medical treatment. So for patients with large invasive tumors, we strongly recommend that everybody will have pathology. If it cannot be done in the hospital that they have, it can be sent out to have several details on the type of tumor, as you can see here. In our patient, as you can imagine, with invasion of the cavernous sinus, the patient was not in remission. So we started somatostatin receptor ligand, either laryngotide or octreotide as first line. In this case, we chose, and as you all know, the insurance sometimes decides for us, the laryngotide at the regular dose of 90. And you can see IGF-1 is in orange and IGF-1 is in dark blue. And they are going down, however, clearly not normal. And I have to say now that when we are talking about a sparsely granulated tumor, I think in my mind from the beginning that they might not be controlled quickly enough and or never, and we have to think what to do in general. So recently, we updated the Pituitary Society acromegaly management guidelines with a large international group, and we talked of all the therapies and focused more on medical therapies, how to decide to use when and overall what are we looking at. So for a medical therapy, in my mind, efficacy is very important as well as safety. So these are the first thing I'm thinking of. Yes, frequency of administration and the route of administration and patient preference are also very important. For large tumor, I'm thinking of something that works at the tumor level. So the tumor volume plays a role in some patients, especially if they didn't have surgery, but even after. And of course, if it's availability and cost in the same time. So what do we have available right now approved in the U.S.? So we have several somatostatin receptor ligands, octreotide LAR, lanreotide autogel, oral octreotide capsules, and pasireotide LAR, and I'm going to talk a little bit about each of them. And all of them are working at the pituitary level, and they will decrease the GH, subsequently the IGF-1 secretion, and act at the tumor level. Now, these were the treatments that were first available for many, many years right now. So we thought that all the patients will respond, or at least many more, because the initial studies were patients were pre-selected who's going to go in the study. However, in a meta-analysis now several years ago, you can look that the IGF-1 normalized rate overall, looking at all the studies, is somewhere around 50%, and the same with the GH response rate, with huge, huge variation. And also, I wanted to point out that was not looked at directly in that meta-analysis, it's very important when you take the IGF-1 in corresponding with injections for the monthly injections. What was very interesting was that the clinical design characteristics, including switching, that we thought they will be really significant for this type of study and retrospective design, did not make a huge difference, but the study duration and the year of publication with prior SRLUs did. Now, in the U.S., the preoperative medical treatment is not used a lot. We have used it more in the COVID times when we couldn't access surgery immediately. However, if we're thinking about using medication to improve surgical outcomes, the initial studies showed several of them were negative, several of them were positive, but depends on when do you look, because as you know, the long-acting are staying in the system for a while, and you can measure, if you measure three months, it doesn't mean the patient is in more biochemical control, it could be still the effect of the somatostatin receptor ligand, and overall, no improvement at long term. So if we're using preoperative medical treatment with the idea that the patient should feel better by the time of surgery, this might make sense, so the data doesn't show that will pan out. If we can do surgery for a while, then definitely the patient doesn't need treatment. However, with the role of improving surgical outcomes, this has not been proven consistently. So what else are we looking? And I briefly mentioned the sparsely granulated in our patient, but overall, there are many, many factors. Some are just in research studies and some have been proven in clinical and in large clinical trials, that if you have a young patient with a sparsely granulated tumor, and now we're also looking at how it looks on the MRI, especially on T2, if we can do receptors and our center is doing also the receptors type two, the ratio between two and five, and then a lot of other factors that some of them are still in research and some of them are with controversial results. However, the most important thing that I want you to remember is those response, that up titration plays a significant role and I'm going to show you some data on that. So talking about response by granulation pattern and receptors type two, this is a study that we did in our group now many, many years ago, and you can see the sparsely granulated tumor, I'm going to focus on that, they had response significantly lower than the densely and furthermore, if the patient's pathology did not have staining for type two, then was zero. If they had it, it's not 100%. However, the likelihood of responding is much higher. How about T2 hypo-intense tumors? This was a large study done in a multicenter in Liege, and if you're looking, this is a patient that had, as you can see, very, very high IGF-1 at the beginning, and then very quickly, the tumor shrank in addition to decrease in IGF-1, and this was a pure hypo-intense adenoma. Not all of them look so clear, some of them have parts of hypo-intense and hyper-intense, but in patients that don't have surgery, so we don't have the pathology yet, this is a predictor in trying to think if the patient will control. It doesn't change what I'm starting the patient on, but it changes how quickly I move from a therapy to the other. So what we did for the patient, we increased the dose, and as you can see, both the GH and IGF-1 went down, but not to normal. So uptitration can play a role, so if this patient would have started a little bit lower after the initial dose, maybe it would have been normalized, and this has been proven in several studies that if you have modest IGF-1 elevation will generally benefit from those increase in good tolerability, and you can see here, this was a study with changes in GH and IGF-1 from baseline to week 24, and there were several study that done both poropterotide and areotide, and when I'm saying uptitration, you can go uptitration, as you can see here, or high dose, that's in blue, or high frequency. I usually do high dose rather than high frequency to avoid more injections and more trip to our injection unit. So in this patient, the injections, the monthly injection after surgery, this is the MRI, and this is three months after, three months after lerotide high dose, so that's six months from before, we were observing some tumor shrinkage. So this is the idea that why we're using somatosensory receptor ligands as first line if we're trying to expect decrease in tumor volume overall. So based on that, in Europe, they are using sometimes primary medical therapy with somatosensory receptor ligands and looking at tumor shrinkage. So this is the largest study available that we have with a main goal for tumor shrinkage. These patients were started directly on a maximum approved dose of somatosensory receptor ligands, and if you look, this is the mean in red, mean tumor volume, and this is an example of a patient, and again, some respond very nicely, as you can see, look at this tumor here, and it's a week 12 already, it's decreasing in almost half, and then significantly decreased, continue up to week 48. Not everybody is the same, and I'm going to show you here that if we're looking overall, this is week 48 value for changing tumor volume, and significant in studies, it's somewhere between 20 and 25%. In clinic, that depends where the tumor is, and you all know when you've seen these patients that what's significant in a study doesn't mean it's significant for individual patient overall. However, look, a lot of patients had tumor shrinkage, and in some of them, however, the tumor grew. So can we predict who's going to shrink more? Now, if we're looking here at normalization of IGF-1, I want you to look at red, these are overall baseline, week 12, 24, and 48, and then last visit, if they withdrew earlier, was about 50% at week 48. So some patients can be controlled even without surgery if they have the right treatment, and they respond, but not everybody, and we cannot count on that, and we have minimal predictive factors as I showed you earlier. Now, in addition to control biochemically, I told you that we have to think more about are the patients happy with the treatment that we're giving them? So now several years ago, and we published it last year, created a questionnaire to try and find out how the patients are doing, from symptoms interference, how many symptoms they had since the last injection, from treatment convenience, the treatment convenience part was particularly for the monthly injection, and the same with injection site interference. Since your last injection, did you have treatment-related injection site reactions that included leisure activities and work disturbances? So that's very important. We did not ask them specifically in clinic before if it changes their life overall. Of course, we're interested in GI interference, both for injections, and we ask this for all the other treatments. Treatment satisfaction in general, and also the emotional reaction overall of patients from the treatment they are receiving. So we apply this questionnaire to a large group of patients, as you can see here on the left, that were in a study that were thinking of a different therapy. So potentially it's a bias that the patients were not very happy with the treatment, and that's why they were interested in screening, but clearly not all of them. Look at their IGF-1 and GH. These were patients very well controlled. And then if we're looking at both their acromegaly index of severity with formal surveys and the treatment satisfaction questionnaire, the results were very surprising because I thought that once they are biochemical controlled, most of the patients are doing great. So two-thirds of them had acromegaly symptoms, and 82% had all the time. Three-fourths had GI side effects after the injection. And what was interesting was that the higher severity scored in symptoms also correlated with worse ACRO-TSQ that I showed you earlier from symptom interference, GI interference, treatment satisfaction, and emotional reaction. Furthermore, a study also done last year looking at all these type of questions, but asked not just about to the patients, but also to their respective providers and endocrinologists that are seeing the patients. So as you can see in dark gray are the results from healthcare professional, and again, from symptom interference to GI interference, treatment satisfaction, and in light gray were patients. It was significant difference for a lot of these factors. And it's possible that it was a recall, providers relied on chart notes and recollection from prior visits, and we all know how good are sometimes their notes. However, this is not reassuring that it's such a difference in how we think our patients are doing and how actually they are doing when they tell us. So regular communication is clearly needed, and we should probably incorporate patient outcome in the management decision, including in clinical work, not just in studies. However, this will lengthen our clinic visit and we have to restructure completely our clinics. So how about the oral octreotide? As you know, it has been FDA approved based on the large study that looked at oral octreotide compared with placebo. However, now we have data. This has not been published yet, but presented at the end earlier this year, comparing the oral octreotide with the monthly injection. So the primary endpoint of this study was a non-inferiority, and this was met through the study. I want you to look at the data. This is for oral octreotide and in green, the injectable SRLs. So clearly, this was non-inferiority, and if you look at the details in this particular study, we didn't use a normal IDF1, so that's why you're going to see less than 1.3 because we used time-weighted averages of several IDF1, especially to counteract what we talked, but this was for both groups, what we talked earlier about, the fact that when you check the IDF1 in function with the injection might make a significant difference. When the patients were on oral octreotide, the number and severity of ACRO symptoms decreased from 4.5 to 3.5 at the end of run-in, and also the proportion of patients reporting symptoms at run-in end, the fatigue and swelling validates previous studies. When we asked the patients directly, three of five treatment satisfaction domains that I mentioned earlier were improved. How about differences in adverse effects? Between the oral octreotide capsules and injectable SRLs, the treatment-related adverse events were very similar, as you can see, and some of the selected days between oral octreotide and injectable SRLs for nausea was a little bit higher in oral octreotide. For the injection site nodules, of course, it was more in the injectable and relatively similar for everything else. Furthermore, for the patients that were mildly uncontrolled with this oral octreotide in the study, we had a combination treatment sub-study, adenocarburgaline, less than 3.5 milligrams per week, and very interestingly, there were patients, and as you can see here, all patients maintain or reduce overall number of acromegaly symptoms, 71% improved or maintained the score for symptoms, no more AEs, but five out of nine with IGF-1 more than 1.3 responded, so became less than 1.3. We had the same numbers, so basically there were responders at week 36, so this is very exciting for patients that potentially even patients with mild elevations in IGF-1 after oral octreotide could be potentially just on an oral treatment overall. How should oral octreotide be integrated in treatment? We covered briefly in the Pituitary Society Acromegaly Management Guidelines because this is the new drug approved, and patients who have demonstrated complete or partial biochemical response on injectable octreotide and laryotide, and we still don't have data, but if the patients have known octreotide resistance, probably they would then be good candidates. The dose should be 40 milligram a day, though sometimes we're starting with 60, and we did this in the extension study, and I'm also doing it in clinic, and more importantly, when we should start, we should start at a time when it's the next scheduled injection, and then every two, four weeks, very quickly up the iteration and not how we are used to with injectable to wait at least three months. How about pasireotide LAR? It's a multi-receptor targeted SRL and binds with high affinity to several receptors, including five, reduces GH and IGF-1, and improves clinical signs of acromegaly associated with significant tumor volume reduction, and as you can see here, in about another 20% of patients, both GH and IGF-1 normalization, hyperglycemia-related adverse events were high in most of the studies. When we looked at all the studies combined, the patients that had less frequent hyperglycemia were patients with younger age, normal glucose tolerance, no history of hypertension or dyslipidemia at baseline, and in one of the studies that we did initially, look at patients that started at normal and lower baseline FPG. This is they were continuing the treatment in gray with octreotide or lanreotide and then different doses of pasireotide. So clearly, if you start lower, the likelihood of developing hyperglycemia is lower overall in addition to several other comorbidities. How about gross hormone receptor antagonist? The only approved gross hormone receptor antagonist is pegvisomab that blocks the peripheral synthesis of IGF-1, reduces IGF-1 in most patients, and you remember that the initial study was 97%, and then in real life, it's a little bit lower, around 63% in patients treated for five years, and tumor growth is reported about three to 5%, very rare, and most likely due to natural history, and elevated liver enzymes, about 9% of patients, and we'll have soon the final data for the actual study. Same as with the initial treatment, do we know who's going to respond? And that's even a more complicated picture and more research is needed. However, we know that this is also dose dependent. Patients that had low IGF-1 at baseline with a higher dose will respond. Most patients will respond overall, as you've seen, if you increase the dose initially. The absence of diabetes seems to be a very good predictor of response. Older patients, male sex, but again, this goes with what type of tumor they had to begin with. So if we're looking at the dose relationship that I was talking to you earlier, this is the ACRO study, and all these patients were treated, as you can see, higher number of patients at the beginning, and then of course it got lower. But the point is that the dose of, this is the mean dose for patients that were normalized versus non-normalized, was not significantly differently. So clearly for a drug that we know, if you increase the dose, you can control the patients, we should do better in up titrating the dose appropriately. And if we're looking overall of the effects of pegbisomethane glucose homeostasis, this is the main data from the ACRO study. And then of course, after that, there were some smaller studies and then the methanalysis, but I wanted to show you the main data. In green are patients with no diabetes, in blue patients with diabetes, and this is the glucose, and it's a mirror for A1C also. So overall, though you don't see significant, you see some improvement over time, and at least it's not deteriorating. And for some patients that have diabetes, this is very important, especially in comparison with other therapy. So what did we do with this patient? Not control on maximum dose of somatostatin receptor ligand, so we added pegbisomethane every other day, and then finally we can't take GH anymore, but the IGF-1 finally normalized, the sweating reduced, headaches and joint pain resolved, and the patient had normal glucose and normal A1C. So we have data right now, though it's not FDA approved per se, that combining SRLs and pegbisoment longer term, this was a study up to nine years, can control the patients, as you can see here, almost everybody, with a relatively lower dose of pegbisoment per week, so this was about 80 milligram overall, given either every day, bi-weekly, or even once a week. So when we looked for the recent guidelines of which one would be the best cost-effective treatment, the main study that looked at this was from Dr. Melman's group, and they found that the low dose of LAR or Lerotide plus weekly pegbisoment, and usually I use bi-weekly, but now I'm convinced to change to weekly, is both cost-effective and efficacious options for patients requiring combination therapy. Furthermore, based on a few studies, and I'm not going to show you that separately, but I would be happy to answer questions, the combination of Lerotide plus pegbisoment can yield biochemical control in more than 70% of patients. And keep in mind, these are patients that have very severe disease, they have no control on anything else before that. And so 70% overall, it's a good number, and we all have these patients that we just keep adding medication, then nothing works. However, the selection should be carefully considered because these patients will still have hyperglycemia. Initially, we thought that combination will actually decrease the rates of hyperglycemia, but that did not happen. So the right patient should be on a combination that's both costly and also could have potentially side effects. There are several new drugs currently in development, and I'm not going to spend too much time on it, I just wanted to bring them up to you, and I would be happy to answer questions. The one that's further developed, it's an orally available SST2 selective non-peptide somatostatin-biased agonist with a high oral bioavailability and pharmacokinetic profile. So once a day, and there were two phase two studies, one presented data at ENDO earlier this year, and the patient switched the treatment from either octreotide and lanreotide, and there was no loss of IGF-1 control at week 13, so seemed similar with the injection effect overall, but this was a phase two, clearly more studies are needed. An octreotide subcutaneous depot, it's also in phase two, almost phase three. A novel somatostatin receptor ligand with preferential binding to more receptors, including four that potentially, at least in vitro, has better effects on glucose metabolism, and then there are several studies, phase two in progress, for a new antisense drug, a Lica generation. How about radiation? So some patients will need multiple therapies. As I showed you before, there could be control on treatment, or the tumor is growing, or they can continue the treatment. For most patients, I consider radiation as a third line, however, also could be used immediately after surgery if the tumor is growing back in addition to the adjuvant medical therapy. It provides tumor control in 85 to 95% long-term. However, the normalization of hormonal hypersecretion for GH comes at the cost of hypopituitarism, which represents the most commonly reported complication of radiation, and it's more than 50% of patients overall. So in conclusion, the therapy for acromegaly in an ideal world should be efficacious, safe and well-tolerated, high adherence to treatment, cost-effective and improving patient satisfaction. And I've shown you many data showing that asking the patients how satisfied they are through patient reported outcome does not show what we thought before. And then I think based on several biomarkers that I've shown you earlier, that we should move from these are the therapies, first line, second line combinations that we should use for every patient to really changing to a personalized treatment. So if we look here, patients with persistent disease after surgery, we should be able to stratify them by comorbidities. If they have hypertension, as I said earlier, or if they have diabetes or what other comorbidities they have, if they still have a large tumors, plus the biomarkers that predict the biochemical response. So if we know it's a sparsely granulated tumor, we're not going to wait a year for the treatment to kick in if we see no response. When we know in advance that the likelihood of responding, it's pretty low, and then separate the patients so we know the response is going to be the one that we're expecting, as I have to say, they're doing much better than us in oncology right now. So in summary, uncontrolled acromegaly is associated with excess morbidity and mortality, as well as impaired quality of life. Surgery is first line therapy in majority of cases in US. However, more than 50% will require adjuvant therapy because of the late diagnosis, and I didn't have time to spend more on that, how we have to improve even before talking about therapy. Octreotide and laryotide are the most frequently used first line medical treatment now, indicated when surgery has failed or is not an option. Pegvisomine can be first line in selected patients, and it's FDA approved for that. Carburgaline might be used in very mild cases. I haven't shown you the data on that, and it's not FDA approved for this. Oral octreotide, recently FDA approved, improves symptoms control and patient satisfactions. Bacerotide, Pegvisomine, and or combination medical therapy are alternative therapeutic options for patients who do not achieve biochemical control. And therapeutic approaches should be tailored to the individual clinical situation in order to achieve optimal outcomes for patients. Thank you so much. It was an immense pleasure to talk to you about acromegaly and looking forward to answering your questions. Have a good day. Thank you, Dr. Flaciru, for this presentation on very informative topic. We will now go ahead and open the floor up for questions and answers. Please type your question into the chat and we will do our best to try to address each question. And we have quite a few, Dr. Flaciru. So clearly it's a very good subject to talk about because people always have a lot of questions. And I'll try to combine several questions in one starting with the new diagnosis of acromegaly. There are several questions from our audience members who ask, how do you consider medical therapy to shrink the tumor before the surgery? What agents you use? What are those patients to consider that rather than just go ahead strictly with a surgery? Thank you, Irina, for your introduction and thank you for the question. I wanted to take a few seconds to thank ACE for inviting me to present a plenary in neuroendocrinology. I am the represented for the Pituitary Award at this meeting plenary-wise and I'm very happy that acromegaly was chosen. Going back to the question, it's very interesting how do we approach and I hope I made it clear overall that this is a long process and should be a multidisciplinary discussion between patients and physicians and also between physicians of multiple specialties. The data on medical therapy and shrinkage for somatostatin receptor ligands, especially for primary medical therapy, we have some predictors but not all the tumors will respond. So I don't know who asked the question, which countries are from. In U.S., we rarely use medical therapy because we have access, with exception of the COVID times, we have access to pituitary surgeons specialized in centers like yours, Irina, or mine and many others in U.S., but they can get surgery within a few weeks. So the likelihood of knowing which will respond, and keep in mind, we don't have pathology, as I said earlier, to know at least partially granulated, we have some indications on MRI and we have some indication, depending on how large is the tumor, if they will respond or not, but we don't know if the tumor will shrink. So if we have access to a good surgeon, then surgical debulking, and I didn't have time to show you the data, will actually improve the biochemical outcomes much faster. Hopefully, we'll have better drugs at some point that we can, would be like a bergaline that we don't even need surgery. I hope there are not a lot of surgeons in the audience to hear me saying that, but that's my hope. But I don't think that with the role of shrinkage, we should use medical therapy. I have patients that didn't want surgery, I have used it, they did great, and I told them from the beginning, I can probably control you, but let's see, if they didn't want surgery and the tumor was shrinking, that's good, but sometimes when you think we'll shrink, it's not, and the opposite is also true. Okay, thank you. I'll try to combine a few other questions. And the number one voted question here is about combination therapy. So I'm guessing it's really about patients who did have surgery, and let's say have procedural disease and not properly treated with one agent. So it's time for the second agent. So the first question is, how do you decide when to proceed with combination therapy instead of actually just changing from one agent A to agent B? And the second related question is, when is the best time to check IGF-1 to make this decision? That's a very important question, and I think for aggressive tumors, it's probably one of the most important questions. So in my mind, most of the time, I'm starting with somatostatin receptor ligands as first therapy, extremely rare, if it's a very small tumor residual and the patient has contraindications or diabetes, or I would start with Pegvisomant. Keep in mind for the audience, in U.S. Pegvisomant is used as first line and approved in other countries, it's not. Now, the decision to switch or to combine depends on several factors, and I go back to the individualized therapy. So for example, if a patient has large residual, as you mentioned earlier, and it's in the cavernous sinus, so we know another surgery somewhere else is not going to work, and the patient, let's say, had radiation, but then we know it's going to take at least five years or more for the radiation to kick in, then that patient has to be on somatostatin receptor ligand. So if it's not controlled, that patient, I will just add Pegvisomant. And there are new studies coming from Dr. Melmed that actually probably we could do away with once a week Pegvisomant, and it's actually cost-effective, as I mentioned earlier. I usually used twice a week just to decrease the volume of injections to avoid lipodystrophy, but now that I found out it's cost-effective once a week, I might switch to that. Now, if the patient has adverse events to a therapy, then definitely you have to try to switch. Sometimes I just decrease the dose, for example, if they have adverse events, and then add Pegvisomant, for example, on this combination. Rarely, rarely I use combinations between somatostatin receptor ligand and cabergoline. There, I definitely use combination because the likelihood of cabergoline working by itself, so a switch there is not going to work. If you are not controlling somatostatin receptor ligand and you are barely a little bit high, then adding cabergoline, assuming they don't have adverse events or they don't have risks, as you've beautifully shown that impulse control disorder is much higher than we thought, then cabergoline would be an option. Now, the third issue that's probably the less frequent, but these are the tumors that we all ask around what to do next, are the most aggressive tumors that are on somatostatin receptor ligands. They didn't respond to normal combinations. So, for example, if you have a tumor that's not on somatostatin receptor ligand, then you have to switch to bacillotide with Pegvisomant. So, that's a combination that, one, is expensive. It's still not reducing significantly the risk of hyperglycemia, but it's inducing control in over 70% of patients with very aggressive tumors and hard to control. So, I have some patients on it. So, again, there, I'm not even thinking about switching. There, it's what else can we add to prevent pregnancy? But before we get there, just a related question about combination of cabergoline and octreotide LAR, if it's a cost-secreting tumor, prolactin and growth hormone together. Now, that's very interesting. And we have seen all these tumors that in the meta-analysis agree with my experience. The staining for prolactin, and that's a mixed tumor, and even if they had surgery, is not going to tell us if they will respond to cabergoline or not in a mixed tumor. That being said, if the prolactin is very high, of course I will start cabergoline first and see how the patient is doing, and then add octreotide. But I don't think we have predictive factors. So, it's a trial and error. And usually I use both medications. Sorry, I didn't answer the other questions, when to take the IGF-1. That's it, yes. If the patient is on pegvisomab, when to take the IGF-1 would probably be better related to the injectable, somatosarcoma receptor ligands, or if the patient is on oral, it doesn't really matter when it's checked. For injectable, I usually like to, especially now that we have a lot of other therapies, I like to check the one week after, and then also immediately before the patient is due for the next injection, especially if they have symptoms when the injection is due. I'm using the IGF-1 to see one if they need those up titration, or if they would need to be switched to a different therapy, like oral octreotide, for example, especially for combinations. Okay, we're getting to pregnancy now. So, there are two questions on pregnancy. Let me just give us an area that one of our audience members would like us to address. And it's a patient who was acromegaly, who have had a surgery to remove that pituitary mass. But six months later became pregnant, and actually throughout the pregnancy, IGF-1 is increasing, but maybe early in the pregnancy, IGF-1 is higher. What do we do? Wait until this patient delivers, start treatment, anything else? Of course, we can't address individual patients. However, in a scenario similar like this, we never tell the patients that you have to interrupt the pregnancy because of acromegaly. And now we have ways of managing it. In general, if you look at the chances, most of the patients, once they get pregnant, because of the resistance of placenta, they will have normalized IGF-1, looks like this particular patient, or a scenario like this, when the other way. So there are no approved medications for pregnancy. Keep in mind, not even cabergoline for prolactinoma, it's actually approved. However, there are now several studies and multicenter studies, and we all have experience with using several drugs that looking at the outcomes, theoretically, they don't have higher risks compared with other natural pregnancies. So this would be a patient that I would start, especially if it's some residual tumor, I would start immediately a somatostatin receptor ligand. We'll look at the tumor. If the tumor is growing, again, it's very rare to have significant shrinkage. They can have surgery in a pituitary tumor center of excellence in second trimester. I had patients on combinations during pregnancy on both somatostatin receptor ligands and PEG-Visomed. It's a retrospective study looking at over 17 cases with PEG-Visomed. Though it's counterintuitive, you block the GH, what's going to happen with a baby? There were no issues. And several of them were followed longer term. Those cases were all outside US. And of course, it's cabergoline, our friend, that we're always using it, though I'm not sure it's working, but it makes us feel better, definitely. Okay. We have another interesting question here. So the scenario here that the patient has been treated on one or more agents for residual acromegaly, so history of surgery as well. And we're actually seeing shrinkage on the follow-up imaging, shrinkage of the tumor. The question is, what is the best strategy to deescalate the therapy? Either stop one of the medication or decrease a dose. Do we do it gradually? Do we do it abruptly and see what's happening? What is your strategy? What would you recommend in this favorable scenario? So this is a rare scenario, but it's a case that I like it, and I can't wait for the patient to show up or on video in clinic to tell them, your tumor is shrinkage, you're doing great, your IGF-1 is going down, and we can change some of the therapies. Depends on how aggressive the tumor was to begin with. In aggressive tumors, that's a sparsely granulated, even if it shrank, I'm happy that they responded. My tendency would be not to actually stop the treatment for a while for somatostatin receptor ligands and continue the combination, but just going down on the doses. Keep in mind that rebound after stopping the somatostatin receptor ligands was seen in a lot of cases that we didn't expect when there were the initial studies with PEG-B cement, that was the whole idea that actually some tumors grew with PEG-B cement because later on we see they didn't, was because they stopped the somatostatin receptor ligands. There are very, very few data, and I have worked with a Brazilian study looking at patients that actually stopped somatostatin receptor ligand and treatment completely. They are very, very rare and very interesting. A lot of them, they had low IGF-1, the treatment was stopped, they were able to stay without treatment. So how long the effects stay in the system varies from patient to patient, but they usually decrease the doses. However, if the patient had radiation in the past, were sometimes able to stop the treatment, but without radiation, stopping long-term, it's very hard, but first decrease doses of both, then try and stop the PEG-B cement if it was not a sparsely granulated tumor and leave a little bit of somatostatin receptor ligand there either injectable or oral. Okay. Another question is on immediate management after surgery. So the scenario is a macrodenoma with some cavernous sinus invasion. Surgery was done, but we know that some of the disease is left in the cavernous disease. What is the best strategy here? Start the medication right away, let's say somatostatin therapy, or do we wait and how much do we wait before we actually assess the need for this additional medication? That's a very good question. And usually I wait about three months. I do a GH value, day one or two seems to be a good predictor factors. If the GH is five, then we know it's not going to get controlled. That being said, maybe some delayed remission, maybe some hemorrhage in the tumor. That's probably the only time in this or Cushing's when I want some hemorrhage in the residual tumor. But in general, I'm preparing for treatment. In US, you all know, you have to prepare with insurance and all that. So I want to have the treatments prepared that if at three months, the AGF-1 is still significantly high, I will start therapy. I wouldn't wait more. Now, if the AGF-1 is almost normal, then of course I'm going to wait another three months. But if you look at the studies with the curves, usually by three months, you know who's going to be controlled. Very few patients will normalize by six months if they're almost there, not if they're double. And then there are very, very few that they can trickle down. And yes, one or two can be even at a year, but usually you should see this on a curve. So in summary, keep in mind, patients with acromegaly have delayed diagnosis up to 11 years. I know that another three months wouldn't change too much, but if it's a tumor in the cavernous sinus, the patient has symptoms, I'm not going to wait more than three months. Okay. And we hopefully have time just for one last question. And it's now that we have the oral medication available and with all the other options that we have available, how much do you consider quality of life on different medication, the oral route versus injectable when you decide on the therapy? Maybe based on the experience you've had also with your patients. That's probably the most complicated questions and you left it for the end and you tell me I have a minute. I think we change over time and we have more studies and asking the patients and especially for quality of life or injections versus oral, this is not up to me to decide which one would be better. So I'm keeping my recommendations to tell the patients efficacy, safety, and then the patients should tell me which route of administration they prefer and how they feel. So my job is to convince them that they need treatment even if they feel good. So yes, biochemical control, it's important for survival. So I do that. And sometimes I have to scare them because especially for headaches, they feel so good after surgery that if they start at five times up per limit of normal and they go to two, suddenly this is it and they don't want treatment. So there I push. However, what type of treatment? I give them the numbers of efficacy and safety. And then the patient tells me, and the more we look into quality of life, and as you know, for Cushing's is the same thing, we note, and especially for the patient reported outcome, we see that they are not doing as well as we thought when we looked just at numbers. So I ask the patient, what do you prefer? Keep in mind in some of these studies, the patients were interested in changing the treatment. So of course this was biased towards they wanted to get rid of injections. Injections could be a problem, not for everybody, but for some are. So I ask them what they want. I tell them what are the numbers. For a sparsely granulated tumor, I'm finding directly going to peglycemic to control quickly, for example. For others, injectable. And now I found lately that it's easier to convince them because you tell them potentially you can have several months of injections and then go to oral if you need to. And then at any point they can switch in between. So I let them decide and see how they do. All about sure decision-making. Well, unfortunately, this is all the time we had. It was a very popular session. We actually have not addressed at least half of all the questions. I'll be happy to see and answer them online. So I just would like to thank everyone for participating. I would like to, again, thank Professor Fisuru. That was just absolutely wonderful. Thank you. Thank you so much. And thank you everybody for watching P2E Theory. Thank you.

acromegaly

personalized treatment

growth hormone

biochemical control

surgery

medical therapy

somatostatin receptor ligands

combination therapy

tumor characteristics

quality of life